SECTION 5

HORMONES AND RELATED DRUGS

Chapter 17a Introduction

Hormone (Greek hormaein—to stir up) is a sub- 1. Pituitary

stance of intense biological activity that is (a) Anterior Growth hormone (GH), Prolactin
produced by specific cells in the body and is (Prl),
transported through circulation to act on its target
Adrenocorticotropic hormone (ACTH, Corti-
cells.
cotropin),
Hormones regulate body functions to bring
Thyroid stimulating hormone (TSH, Thyro-
about a programmed pattern of life events and
tropin),
maintain homeostasis in the face of markedly Gonadotropins—Follicle stimulating hormone
variable external/internal environment. (FSH) and Luteinizing hormone (LH).
(b) Posterior—Oxytocin,
Body function Major regulator Antidiuretic hormone (ADH, Vasopressin).
hormone(s)
2. Thyroid Thyroxine (T4), Triiodothyronine
1. Availability of fuel : Insulin, Glucagon, (T3), Calcitonin.
Growth hormone
3. Parathyroid Parathormone (PTH).
2. Metabolic rate : Triiodothyronine, Thyroxine
4. Pancreas (Islets of Langerhans) Insulin,
3. Somatic growth : Growth hormone,
Insulin-like growth factors
Glucagon.
4. Sex and : Gonadotropins, Androgens, 5. Adrenals
reproduction Estrogens, Progestins (a) Cortex Glucocorticoids (hydrocortisone)
5. Circulating : Aldosterone, Mineralocorticoids (aldosterone)
volume Antidiuretic hormone Sex steroids (dehydroepiandro-
6. Adaptation to : Glucocorticoids, sterone)
stress Adrenaline (b) Medulla Adrenaline, Noradrenaline
7. Calcium balance : Parathormone, Calcitonin, 6. Gonads Androgens (testosterone)
Vitamin D
Estrogens (estradiol)
Progestins (progesterone)
Hormones are secreted by the endocrine or In addition, hypothalamus, which is a part of the
ductless glands. These are: CNS and not a gland, produces many releasing
 HORMONES AND RELATED DRUGS 235

Hypothalamic Chemical 1. At cell membrane receptors

hormone/factor nature a. Through alteration Adrenaline, Glucagon,
of intracellular TSH, FSH, LH,
1. Thyrotropin releasing Tripeptide
cAMP concentra- PTH, Calcitonin,
hormone (TRH)
tion  alteration of ACTH, some
2. Corticotropin releasing Peptide
hormone (CRH) (41 AAs) protein kinase A hypothalamic
3. Gonadotropin releasing Decapeptide regulation of cell releasing hormones,
hormone (GnRH, function: Ca2+ acting Vasopressin (V2)
LH-RH/FSH-RH), as third messenger
Gonadorelin in some situations.
4. Prolactin release inhibi- Dopamine b. Through IP3/DAG Vasopressin (V1),
tory hormone (PRIH)
generation: release Oxytocin
5. Growth hormone Peptide
of intracellular Ca2+
releasing hormone (40, 44 AAs)
(GHRH) and protein kinase C
6. Somatostatin (Growth Peptide (14 AA) activation.
hormone release c. Direct transmembrane Insulin,
inhibitory hormone) activation of tyrosine Growth hormone
protein kinase  Prolactin
phosphorylation
and inhibitory hormones which control the cascade  regulation
secretion of anterior pituitary hormones. Some of various enzymes.
important ones of these are given in the box. 2. At cytoplasmic receptors
Penetrating cell Steroidal hormones:
Placenta also secretes many hormones: membrane, hormone Glucocorticoids
Chorionic gonadotropin Prolactin combines with a Mineralocorticoid
Estrogens Progesterone
cytoplasmic receptor Androgens
Placental lactogen Chorionic
 exposes its DNA Estrogens
thyrotropin
binding domain  Progestins;
The natural hormones and in many cases migrates to nucleus Calcitriol

SECTION 5
their synthetic analogues which may be more and binds to specific
suitable therapeutically, are used as drugs for genes  DNA media-
substitution therapy as well as for pharma- ted mRNA synthesis
cotherapy. In addition, hormone antagonists and  synthesis of
synthesis/release inhibitors are of therapeutic functional proteins.
importance.
3. At nuclear receptor
The hormone pene- Thyroid hormones:
Sites and mechanisms of hormone action
trates the nucleus  Thyroxine,
The hormones act on their specific receptors combines with its Triiodothyronine
located on or within their target cells. Receptor receptor  alters
activation by the hormones is translated into DNA- RNA mediated
response in a variety of ways. protein synthesis.
Chapter 17b Anterior Pituitary Hormones

Anterior pituitary (adenohypophysis), the master GH acts on cell surface JAK-STAT binding protein kinase
endocrine gland, elaborates a number of important receptors (see p. 50) which are present on practically all
cells. Binding of one GH molecule to the extracellular domain
regulatory hormones. All of these are peptide in of a GH-receptor diamer results in the formation of a ternary
nature and act at extracellular receptors located complex which undergoes a conformational change and
on their target cells. Their secretion is controlled activates the intracellular domain to associate with cytoplasmic
by the hypothalamus through releasing and JAK-STAT tyrosine-protein kinase resulting in metabolic
effects as well as regulation of gene expression.
release-inhibitory hormones that are transported
via hypothalamohypophyseal portal system, and
is subjected to feedback inhibition by the
hormones of their target glands. Each anterior
pituitary hormone is produced by a separate group
of cells, which according to their staining
characteristic are either acidophilic or basophilic.
The acidophils are either somatotropes  GH;
or lactotropes  Prolactin.
The basophils are gonadotropes  FSH and
LH; thyrotropes  TSH; and corticotrope-lipo-
tropes  ACTH. The latter in addition to ACTH
also produce two melanocyte stimulating
hormones (MSHs) and two lipotropins, but these
are probably not important in man.

GROWTH HORMONE (GH)

It is a 191 amino acid, single chain peptide of
MW 22000.
Physiological functions GH promotes growth
of bones and all other organs by inducing hyper-
plasia. In general, there is a proportionate increase
in the size and mass of all parts, but in the absence
of gonadotropins, sexual maturation does not take
place. The growth of brain and eye is independent
of GH. It promotes retention of nitrogen, calcium
and other tissue constituents: more protoplasm is
formed. The positive nitrogen balance results from
increased uptake of amino acids by tissues and
their synthesis into proteins. GH promotes utili- Fig. 17.1: Action of growth hormone (GH) and
regulation of its secretion
zation of fat and spares carbohydrates: uptake of
GHRH—Growth hormone releasing hormone; IGF-1:
glucose by muscles is reduced while its output Insulin like growth factor-1; Stimulation (——); Inhibition
from liver is enhanced; fat is broken down. (- - - -)
 ANTERIOR PITUITARY HORMONES 237

The growth promoting, nitrogen retaining and Somatropin has been tried in children with constitutional
certain metabolic actions of GH are exerted short stature (only if epiphyses are open) with encouraging
results. Commercial interests are promoting it for accelerating
indirectly through the elaboration of peptides growth in children without GH deficiency, but medical, ethical,
called Somatomedins or Insulin-like growth factors cost-benefit and social objections have been raised.
(mainly IGF-1, also IGF-2) which are extracellular In adult GH deficient patients, rHGH 150–300 g/day
mediators of GH response (Fig. 17.1). Liver is s.c. adjusted later according to response increases lean body
mass, decreases body fat, improves energy and mentation
the major source of circulating IGF-1, while IGF-
and may reudce excess morbidity and mortality, but stature
1 produced by other target cells acts locally in is unaffected. Benefits of rHGH therapy in GH deficient
a paracrine manner. Like insulin, IGF-1 promotes adults are now well recognized. Unlimited availability of
lipogenesis and glucose uptake by muscles. The recombinant GH has provided opportunity for its trial in
IGF-1 receptor also is structurally and functionally catabolic states like severe burns, bedridden patients, chronic
renal failure, osteoporosis, etc. It is now approved for AIDS-
analogous to the insulin receptor (see p. 261). related wasting: higher dose (0.05–0.1 mg/kg/day) is needed.
GH acts directly as well to induce lipolysis However, it should not be given to postoperative, trauma,
in adipose tissue, gluconeogenesis and glyco- cancer and other critically ill patients. Somatropin is also
genolysis in liver and decreased glucose utilization being promoted for ageing, but benefits are uncertain. Its
abuse by athletes is banned, and it is one of the drugs included
by muscles. These effects are opposite to those in ‘dope testing’.
of IGF-1 and insulin. As such, GH accentuates Somatropin: NORDITROPIN 5, 10, 15 mg inj, HUMATROPE
the metabolic derangement in diabetes. 6 mg, 12 mg cartridges, 1.33 and 5.33 mg vials.

Regulation of secretion The hypothalamus produces Adverse effects Somatropin has low immunogenicity;
GH releasing (GHRH) as well as release inhibitory allergic reactions or resistance to treatment are not a problem.
(somatostatin) hormones. Both are peptides. Somatostatin Pain at injection site, lipodystrophy, glucose intolerance,
is also produced by D cells of islets of Langerhans in the hypothyroidism (due to unmasking of TSH deficiency), salt
pancreas and by few other tissues. Receptors for GHRH and water retention, hand stiffness, myalgia, headache are
and somatostatin are G protein coupled receptors (GPCRs) the possible adverse effects. Rise in intracranial tension occurs
which enhance or inhibit GH secretion by increasing or in few cases.
decreasing cAMP formation respectively in pituitary
somatotropes. Somatostatin has also been shown to inhibit
Ca2+ channels and open K+ channels. GH Inhibitors
Stimuli that cause GH release are—fasting, hypo- Somatostatin
glycaemia, exercise, stress and i.v. infusion of arginine. GH
This 14 amino acid peptide inhibits the secretion of GH,
secretion is inhibited by rise in plasma free fatty acid levels
prolactin, and TSH by pituitary; insulin and glucagon by

CHAPTER 17
and by high doses of glucocorticoids. Dopaminergic agents
cause a brief increase in GH release in normal subjects but pancreas, and of almost all gastrointestinal secretions including
paradoxically depress it in acromegalics. IGF-1 causes that of gastrin and HCl. The g.i. action produces steator-
feedback inhibition of GH secretion. Short-loop feedback rhoea, diarrhoea, hypochlorhydria, dyspepsia and nausea as
inhibition of secretion by GH itself has also been described. side effect. Somatostatin constricts splanchnic, hepatic and
renal blood vessels. The decreased g.i. mucosal blood flow
Pathological involvements Excess production of GH is
can be utilized for controlling bleeding esophageal varices
responsible for gigantism in childhood and acromegaly in
and bleeding peptic ulcer, but octreotide is preffered now
adults. Hyposecretion of GH in children results in pituitary
due to longer duration of action. Its antisecretory action is
dwarfism. Adult GH deficiency is rare, but when it occurs, it
beneficial in pancreatic, biliary or intestinal fistulae; can
results in low muscle and bone mass, lethargy, decreased work
capacity, hyperlipidaemia and increased cardiovascular risk. also be used to reduce complications after pancreatic surgery.
It also has adjuvant value in diabetic ketoacidosis (by
Preparations and use The primary indication for GH inhibiting glucagon and GH secretion).
is pituitary dwarfism—0.03–0.06 mg/kg daily in the evening Use of somatostatin in acromegaly is limited by its short
or on alternate days, upto the age of 20 years or more. Human duration of action (t½ 2–3 min), lack of specificity for
GH produced by recombinant DNA technique (rhGH)
inhibiting only GH secretion and GH rebound on
somatropin (191AA) is available for clinical use. Somatropin
discontinuation. Surgical removal of pituitary adenomas is
causes IGF-1 to appear in plasma after a delay of several
the preferred treatment modality, but somatostatin analogues
hours. IGF-1 then remains detectable for upto 48 hours. Early
are being increasingly used.
diagnosis and institution of GH therapy restores stature to
near normal. rhGH can also be used in Turner’s syndrome Dose: (for upper g.i.bleeding) 250 µg slow i.v. injection over
and in children with renal failure. 3 min followed by 3 mg i.v. infusion over 12 hours.
238 HORMONES AND RELATED DRUGS

STILMEN, SOMATOSAN, SOMASTAT 250 µg and 3 mg After parturition, prolactin induces milk secretion,
amps. since the inhibitory influence of high estrogen
Octreotide This synthetic octapeptide surrogate and progesterone levels is withdrawn.
of somatostatin is 40 times more potent in Prolactin suppresses hypothalamo-pituitary-
suppressing GH secretion and longer acting (t½ gonadal axis by inhibiting GnRH release. Continued
~90 min), but only a weak inhibitor of insulin high level of prolactin during breastfeeding is
secretion. It is preferred over somatostatin for responsible for lactational amenorrhoea, inhibition
acromegaly and secretory diarrhoeas associated of ovulation and infertility for several months
with carcinoid, AIDS, cancer chemotherapy or postpartum. Prolactin may affect immune response
diabetes. Control of diarrhoea is due to sup- through action on T-lymphocytes.
pression of hormones which enhance intestinal A specific prolactin receptor is expressed on the surface of
target cells, which is structurally and functionally analogous
mucosal secretion. to GH receptor: action is exerted by transmembrane activation
Dose: Initially 50–100 µg s.c. twice daily, increased upto 200 of JAK—cytoplasmic tyrosine protein kinases and STAT.
µg TDS; for acromegaly maintain with 10-30 mg i.m. of Placental lactogen and GH also bind to prolactin receptor
microsphere formulation every 4 weeks. and exert similar effects, but prolactin does not bind to GH
Adverse effects are abdominal pain, nausea, receptor.
steatorrhoea, diarrhoea, and gall stones (due to Regulation of secretion Prolactin is under predominant
biliary stasis). inhibitory control of hypothalamus through PRIH which is
Octreotide injected i.v. (100 µg followed by dopamine that acts on pituitary lactotrope D2 receptor.
Dopaminergic agonists (DA, bromocriptine, cabergoline)
25–50 µg/hr) reduces hepatic blood flow and helps
decrease plasma prolactin levels, while dopaminergic antago-
stop esophageal variceal bleeding. nists (chlorpromazine, haloperidol, metoclopramide) and DA
SANDOSTATIN, OCTRIDE 50 µg, 100 µg in 1 ml amps. depleter (reserpine) cause hyperprolactinemia.
SANDOSTATIN LAR (microsphere formulation) 20 mg/5 ml Though TRH, prolactin releasing peptide and VIP can
inj. stimulate prolactin secretion, no specific prolactin releasing
Lanreotide Another long-acting analogue of somatostatin, factor has been identified. Endogenous opioid peptides may
very similar in actions and specificity to octreotide, which on also be involved in regulating prolactin secretion, but no
i.m. injection acts for 10–15 days. It is indicated for feedback regulation by any peripheral hormone is known.
pharmacotherapy of acromegaly. Prolactin levels in blood are low in childhood, increase in
Pegvisomant This polyethylene glycol complexed mutant girls at puberty and are higher in adult females than in males.
GH binds to the GH receptor but does not trigger signal A progressive increase occurs during pregnancy, peaking at
transduction: acts as a GH antagonist. It is approved for term. Subsequently, high prolactin secretion is maintained
SECTION 5

treatment of acromegaly due to small pituitary adenomas. by suckling: it falls if breast feeding is discontinued. Stress,
exertion and hypoglycaemia also stimulate prolactin release.
PROLACTIN Physio-pathological involvement Hyperpro-
It is a 199 amino acid, single chain peptide of lactinaemia is responsible for the galactorrhoea–
MW 23000; quite similar chemically to GH. It amenorrhoea–infertility syndrome in women. In
was originally described as the hormone which males it causes loss of libido and depressed
causes secretion of milk from crop glands of fertility. The causes of hyperprolactinaemia are:
pigeon and later found to be of considerable (i) Disorders of hypothalamus removing the
importance in human beings as well. inhibitory control over pituitary.
(ii) Antidopaminergic and DA depleting drugs
Physiological function Prolactin is the
—these are a frequent cause now.
primary stimulus which in conjunction with
(iii) Prolactin secreting tumours—these may be
estrogens, progesterone and several other
microprolactinomas or macroprolactinomas.
hormones, causes growth and development of
(iv) Hypothyroidism with high TRH levels—also
breast during pregnancy. It promotes proliferation
increases prolactin secretion.
of ductal as well as acinar cells in the breast
and induces synthesis of milk proteins and lactose. Use There are no clinical indications for prolactin.
 ANTERIOR PITUITARY HORMONES 239

Prolactin inhibitors and serum prolactin levels fall to the normal range;
many women conceive. Bromocriptine should be
Bromocriptine
stopped when pregnancy occurs, though no
This synthetic ergot derivative 2-bromo-- teratogenic effect is reported. Most (60–75%)
ergocryptine is a potent dopamine agonist; most tumours show regression during therapy and
of its actions are based on this property. It has neurological symptoms (visual field defects, etc.)
greater action on D2 receptors, while at certain due to pressure on optic chiasma ease. However,
dopamine sites in the brain it acts as a partial response is maintained only till the drug is given—
agonist or antagonist of D1 receptor. It is also recurrences occur in many, but not all patients.
a weak  adrenergic blocker but not an oxytocic.
2. Acromegaly due to small pituitary tumours
Actions and inoperable cases. Relatively higher doses are
1. Decreases prolactin release from pituitary by required (5–20 mg/day) and it is less effective
activating dopaminergic receptors on lactotrope than octreotide/lanreotide. Oral administration and
cells: is a strong antigalactopoietic. lower cost are the advantages..
2. Increases GH release in normal individuals, 3. Parkinsonism Bromocriptine, if used alone,
but decreases the same from pituitary tumours is effective only at high doses (20–80 mg/day)
that cause acromegaly. which produce marked side effects. However,
3. Has levodopa like actions in CNS—anti- response is similar to that of levodopa. It is now
parkinsonian and behavioral effects. recommended in low dose only, as an adjunct
4. Produces nausea and vomiting by stimulating to levodopa in patients not adequately benefited
dopaminergic receptors in the CTZ. and in those showing marked ‘on-off’ effect.
5. Hypotension—due to central suppression of
postural reflexes and weak peripheral a 4. Diabetes mellitus (DM) A new use of bromocriptine
based on its dopamine D2 agonistic action in the
adrenergic blockade. hypothalamus has been found in type 2 DM, and it has
6. Decreases gastrointestinal motility. been approved by US-FDA as an adjunctive drug.
Pharmacokinetics Only 1/3 of an oral dose 5. Hepatic coma: Bromocriptine may cause arousal.
of bromocriptine is absorbed; bioavailability is 6. Bromocriptine suppresses lactation and breast engor-
further lowered by high first pass metabolism in gement in case of neonatal death, but is not recommended

CHAPTER 17
liver. Even then, it has higher oral: parenteral due to unfavourable risk: benefit ratio.
activity ratio than ergotamine. Metabolites are Side effects: Side effects are frequent and dose
excreted mainly in bile. Its plasma t½ is 3–6 hours. related.
PROCTINAL, PARLODEL, SICRIPTIN, BROMOGEN 1.25
mg, 2.5 mg tabs. Early: Nausea, vomiting, constipation, nasal block-
age. Postural hypotension may be marked at
Uses Bromocriptine should always be started
initiation of therapy—syncope may occur if
at a low dose, 1.25 mg BD and then gradually
starting dose is high. Hypotension is more likely
increased till response occurs otherwise side
in patients taking antihypertensives.
effects become limiting.
Late: Behavioral alterations, mental confusion,
1. Hyperprolactinemia due to microprolactino-
hallucinations, psychosis—are more prominent
mas causing galactorrhoea, amenorrhoea and
than with levodopa.
infertility in women; gynaecomastia, impotence
Abnormal movements, livedo reticularis.
and sterility in men. Bromocriptine and
cabergoline are the first line drug for most cases.
Cabergoline
Relatively lower doses (bromocriptine 2.5–10
mg/day or cabergoline 0.25–1.0 mg twice weekly) It is a newer D2 agonist; more potent; more D2
are effective. Response occurs in a few weeks selective and longer acting (t½ > 60 hours) than
240 HORMONES AND RELATED DRUGS

bromocriptine; needs to be given only twice pregnenolone—the first step in progesterone, testosterone and
weekly. Incidence of nausea and vomiting is also estrogen synthesis. In the testes FSH receptor is expressed
on seminiferous (Sertoli) cells while LH receptor is expressed
lower; some patients not tolerating or not respon- on interstitial (Leydig) cells. In the ovaries FSH receptors
ding to bromocriptine have been successfully are present only on granulosa cells, while LH receptors are
treated with cabergoline. It is preferred for widely distributed on interstitial cells, theca cells, preovulatory
treatment of hyperprolactinemia and acromegaly. granulosa cells and luteal cells.
Some patients who achieve total regression of Regulation of secretion A single releasing factor
prolactinoma and normalization of prolactin levels (decapeptide designated GnRH) is produced by the hypo-
can stop cabergoline without recurrence. thalamus which stimulates synthesis and release of both FSH
and LH from pituitary. It is, therefore, also referred to as
Dose: Start with 0.25 mg twice weekly; if needed increase
FSH/LH-RH or simply LHRH or gonadorelin. It has been
after every 4–8 weeks to max. of 1 mg twice weekly.
difficult to explain how hypothalamus achieves a divergent
CABERLIN 0.5 mg tab, CAMFORTE 0.5, 1 mg tabs. pattern of FSH and LH secretion in menstruating women
through a single releasing hormone. Since GnRH is secreted
GONADOTROPINS (Gns) in pulses and the frequency as well as amplitude of the
pulses differs during follicular (high frequency, low amplitude)
The anterior pituitary secretes two Gns viz. FSH and luteal (lower frequency, higher amplitude) phases, it is
and LH. Both are glycoproteins containing considered that frequency and amplitude of GnRH pulses
23–28% sugar and consist of two peptide chains. determines whether FSH or LH or both will be secreted,
as well as the amount of each. Further, the feedback regulation
The -chain (92AA) is common between FSH of FSH and LH may be different. In general, feedback
and LH, but their -chains are different: FSH inhibition of LH is more marked than that of FSH. In females
(111 AA), LH (121 AA). Paradoxically the MW estradiol and progesterone inhibit both FSH and LH secretion
of FSH (~33KD) is greater than that of LH (~30 mainly through hypothalamus, but also by direct action on
pituitary. However, the marked and sustained preovulatory
KD), because of the sugar moieties.
rise in estrogen level paradoxically stimulates LH and FSH
Physiological functions FSH and LH act secretion. In addition there are other regulatory substances,
e.g. Inhibin—a peptide from ovaries and testes, selectively
in concert to promote gametogenesis and secretion inhibits FSH release, but not LH release. Dopamine inhibits
of gonadal hormones. only LH release. Testosterone is weaker than estrogens in
inhibiting Gn secretion, but has effect on both FSH and
FSH In the female it induces follicular growth, LH. GnRH acts on gonadotropes through a G-protein coupled
development of ovum and secretion of estrogens. receptor which acts by increasing intracellular Ca2+ through
In the male it supports spermatogenesis and has PIP2 hydrolysis.
SECTION 5

a trophic influence on seminiferous tubules. The Gn secretion increases at puberty and is higher
in women than in men. In men, the levels of FSH and LH
Ovarian and testicular atrophy occurs in the remain practically constant (LH > FSH) while in menstrua-
absence of FSH. ting women they fluctuate cyclically. During the follicular
phase, moderate levels of FSH and low levels of LH prevail.
LH It induces preovulatory swelling of the ripe There is a midcycle surge of both, but more of LH, just
graafian follicle and triggers ovulation followed before ovulation, followed by progressive fall during the luteal
by luteinization of the ruptured follicle and sustains phase. Gn levels are high in menopausal women due to loss
corpus luteum till the next menstrual cycle. It of feedback inhibition by sex steroids and inhibin.
is also probably responsible for atresia of the Pathological involvement Disturbances of Gn secretion
remaining follicles. Progesterone secretion occurs from pituitary may be responsible for delayed puberty or
only under the influence of LH. In the male LH precocious puberty both in girls and boys.
Inadequate Gn secretion results in amenorrhoea and
stimulates testosterone secretion by the interstitial sterility in women; oligozoospermia, impotence and inferti-
cells and is designated interstitial cell stimulating lity in men. Excess production of Gn in adult women causes
hormone (ICSH). polycystic ovaries.
Distinct LH and FSH receptors are expressed on
Preparations
the target cells. Both are G protein coupled receptors which
on activation increase cAMP production. This in turn All earlier gonadotropin preparations were administered by
stimulates gametogenesis and conversion of cholesterol to i.m. route. The newer more purified preparations can be
 ANTERIOR PITUITARY HORMONES 241

given s.c. They are partly metabolized, but mainly excreted endogenous FSH/LH secretion either by
unchanged in urine: t½ 2–6 hours. continuous pretreatment with a superactive GnRH
1. Menotropins (FSH + LH): is a preparation obtained
from urine of menopausal women: agonist or by a GnRH antagonist.
PREGNORM, PERGONAL, GYNOGEN 75/150; 75 IU FSH
+ 75 IU LH activity per amp, also 150 IU FSH + 150 IU
2. Hypogonadotrophic hypogonadism in
LH per amp. males manifesting as delayed puberty or defective
2. Urofollitropin or Menotropin (pure FSH): METRODIN,
spermatogenesis  oligozoospermia, male
FOLGEST, FOLICULIN, PUREGON 75 IU and 150 IU per sterility. Generally, sexual maturation is induced
amp. This preparation has been preferred over the combined by androgens and therapy with HCG is started
FSH + LH preparation for induction of ovulation in women when fertility is desired. Start with 1000–4000
with polycystic ovarian disease: these patients have elevated
LH/FSH ratio; use of FSH alone is considered advantageous. IU of HCG i.m. 2–3 times a week (to stimulate
It is also claimed to improve chances of obtaining good testosterone secretion), add FSH 75 IU + LH
quality ova for in vitro fertilization. 75 IU after 3–4 months (to stimulate spermato-
3. Human chorionic gonadotropin (HCG): is derived from genesis) and reduce dose of HCG; continue
urine of pregnant women. treatment for 6–12 months for optimum
CORION, PROFASI, PUBERGEN 1000 IU, 2000 IU, 5000 IU,
10,000 IU, all as dry powder with separate solvent for injection. results, which nevertheless are not always
The foetal placenta secretes HCG which is absorbed in impressive.
maternal circulation and maintains corpus luteum of
pregnancy. It is a glycoprotein with 33% sugar and 237 3. Cryptorchidism Since undescended testes
amino acids in two chains, MW 38000. It is excreted in can cause infertility and predispose to testicular
urine by the mother from which it is commercially obtained. cancer, medical/surgical treatment is imperative.
HCG binds to LH receptor with equal avidity; action of
Descent of testes can be induced by androgens
HCG is indistinguishable from that of LH.
whose production is stimulated by LH. Treatment
Recombinant human FSH (rFSH: Follitropin  and follitropin with HCG can be tried at the earliest after the
) and recombinant human LH (rLH: Lutropin) as well as
recombinant HCG (rHCG: Choriogonadotropin ) have age of 1 year, preferably before 2 years if there
become available. These are more purified and have vertually is no anatomical obstruction; 1000–2000 IU is
replaced the urine derived preparations in the developed given i.m. 2–3 times a week till the testes descend.
countries. They are more expensive.
Recombinant human LH (rhLH) is marketed as
If 2–6 week treatment does not induce descent,
LUVERIS 75 IU inj.; indications and use is similar to HCG. surgery should be performed.

CHAPTER 17
Uses 4. To aid in vitro fertilization Menotropins
1. Amenorrhoea and infertility When it is due (FSH + LH or pure FSH) have been used to
to deficient production of Gns by pituitary. Gns induce simultaneous maturation of several ova
are generally tried when attempts to induce and to precisely time ovulation so as to facilitate
ovulation with clomiphene have failed or when their harvesting for in vitro fertilization.
nonovulation is due to polycystic ovaries. The Adverse effects and precautions
procedure is to give 1 injection of menotropins
(75 IU FSH + 75 IU LH or 75 IU pure FSH)) Ovarian hyperstimulation—polycystic ovary, pain
i.m. daily for 10 days followed the next day by in lower abdomen and even ovarian bleeding and
10,000 IU of HCG. Ovulation occurs within the shock can occur in females.
next 24–48 hours in upto 75% cases and the Precocious puberty is a risk when given to
woman may conceive. However, rates of abortion children.
and multiple pregnancy are high, but not of Allergic reactions have occurred and skin tests
teratogenesis. are advised. Hormone dependent malignancies
To improve predictability of time of (prostate, breast) must be excluded.
ovulation (controlled ovarian hyperstimulation) Other side effects are edema, headache, mood
most experts now concurrently suppress changes.
242 HORMONES AND RELATED DRUGS

GONADOTROPIN RELEASING HORMONE (GnRH): Uterine fibroids: Nafarelin 200 g BD intranasal

GONADORELIN for 3–6 months can reduce the size of leiomyoma
Synthetic GnRH injected i.v. (100 µg) induces prompt release and afford symptomatic relief.
of LH and FSH followed by elevation of gonadal steroid
levels. It has a short plasma t½ (4–8 min) due to rapid Endometriosis: 200 µg in alternate nostril BD
enzymatic degradation; has been used for testing pituitary- for upto 6 months. As effective as danazol, but
gonadal axis in male as well as female hypogonadism. second course cannot be given due to risk of
Since only pulsatile exposure to GnRH induces FSH/LH osteoporosis.
secretion, while continuous exposure desensitizes pituitary
gonadotropes resulting in loss of Gn release, therapy with Central precocious puberty: 800 µg BD by nasal
GnRH or its analogues is not useful in the treatment of spray; breast and genital development is arrested
hypogonadism. in girls and boys. The effect is reversible; pubertal
Superactive / long-acting GnRH agonists changes resume when therapy is discontinued.
Many analogues of GnRH, e.g. Goserelin, Leuprolide,
Nafarelin, Triptorelin, have been developed which are 15-150 Adverse effects: Hot flashes, loss of libido,
times more potent than natural GnRH and longer acting vaginal dryness, osteoporosis, emotional lability.
(t½ 2–6 hours) because of high affinity for GnRH receptor
Goserelin Another long-acting GnRH agonist
and resistance to enzymatic hydrolysis. Because physiological
release of GnRH is in pulses, whereas these agonists act available as a depot s.c./i.m. injection to be used
continuously; they only initially increase Gn secretion. After both for endogenous Gn suppression before
1–2 weeks they cause desensitization and down regulation ovulation induction, as well as for endometriosis,
of GnRH receptors  inhibition of FSH and LH secretion
 suppression of gonadal function. Spermatogenesis or
carcinoma prostate, etc. To achieve pituitary
ovulation cease and testosterone or estradiol levels fall to desensitization before ovulation induction with
castration levels. Recovery occurs within 2 months of stopping exogenous Gns: 3.6 mg of the depot injection
treatment. is given once in the anterior abdominal wall
The superactive GnRH agonists are used as nasal spray
or injected s.c. Long-acting preparations for once a month 1–3 weeks earlier.
s.c. injection have been produced (triptorelin, goserelin depot). For endometriosis and carcinoma prostate 3.6
The resulting reversible pharmacological oophorectomy/ mg is injected in the same way every 4 weeks
orchidectomy is being used in precocious puberty, prostatic or 10.8 mg is injected every 3 months. An
carcinoma, endometriosis, premenopausal breast cancer,
uterine leiomyoma, polycystic ovarian disease and to assist androgen antagonist (bicalutamide) is given
induced ovulation. They also have potential to be used as concurrently for 3–4 weeks when goserelin is used
contraceptive for both males and females. for carcinoma prostate.
SECTION 5

Nafarelin This long-acting GnRH agonist is ZOLADEX 3.6 mg prefilled syringe, ZOLDEX L-A 10.8
150 times more potent than native GnRH. It is mg vial depot injection.
used as intranasal spray from which bioavailability Triptorelin: This long acting GnRH agonist is
is only 4–5%. formulated as a regular release daily s.c. injection
NASAREL 2 mg/ml soln for nasal spray; 200 µg per actuation.
for short term indications, such as female
Down regulation of pituitary GnRH receptors
infertility, and as a depot i.m. monthly injection
occurs in10 days but peak inhibition of Gn release
for long-term Gn suppression in the treatment
occurs at one month. It is broken down in the
body to shorter peptide segments; plasma t½ is of carcinoma prostate, endometriosis, precocious
2–3 hours. Uses are: puberty and uterine leiomyoma. For prostate
Assisted reproduction: Endogenous LH surge cancer, it is combined with an androgen antagonist
needs to be suppressed when controlled ovarian flutamide or bicalutamide to prevent the initial
hyperstimulation is attempted by exogenous FSH flare up of the tumour that occurs due to increase
and LH injection, so that precisely timed mature in Gn secretion for the first 1–2 weeks.
oocytes can be harvested. This is achieved by Continuous treatment with any GnRH agonist
400 g BD intranasal nafarelin, reduced to is not advised beyond 6 months due to risk of
200 g BD when menstrual bleeding occurs. osteoporosis and other complications.
 ANTERIOR PITUITARY HORMONES 243

Fibroids, endometriosis, carcinoma prostate: 3.75–7.5 mg by the follicular cells and proteolysis of thyro-
i.m. every 4 weeks.
globulin to release more of T3 and T4. This
Precocious puberty: 50 g/kg i.m. of depot inj. every 4 weeks.
Assisted reproduction: 0.1 mg s.c. daily for 10 days from action starts within minutes of TSH
2nd day of cycle. administration.
DECAPEPTYL DAILY 0.1 mg inj., DECAPEPTYL DEPOT
3.75 mg inj. The TSH receptor present on thyroid cells is a GPCR which
utilizes the adenylyl cyclase-cAMP transducer mechanism
Leuprolide This long acting GnRH agonist is (by coupling to Gs protein) to produce its effects. In human
injected s.c./i.m. daily or as a depot injection once thyroid cells high concentration of TSH also induces
PIP2 hydrolysis by the linking of TSH receptor to Gq protein.
a month for palliation of carcinoma prostate The resulting increase in cytosolic Ca2+ and protein kinase C
alongwith an androgen antagonist, as well as for activation may also mediate TSH action, particularly
other conditions needing long term Gn suppression. generation of H2O2 needed for oxidation of iodide and
LUPRIDE 1 mg inj., 3.75 mg depot inj., PROGTASE 1 mg/ml iodination of tyrosil residues.
inj. Regulation of secretion Synthesis and release of TSH
GnRH antagonists Some more extensively substituted by pituitary is controlled by hypothalamus primarily through
GnRH analogues act as GnRH receptor antagonists. They TRH, while somatostatin inhibits TSH secretion. Dopamine
inhibit Gn secretion without causing initial stimulation. The also reduces TSH production induced by TRH. The TRH
early GnRH antagonists had the limitation of producing receptor on pituitary thyrotrope cells is a GPCR which is
reactions due to histamine release. Later agents like ganirelix linked to Gq protein and activates PLC–IP3/DAG–cytosolic
and cetrorelix have low histamine releasing potential and Ca2+ pathway to enhance TSH synthesis and release. The
are being clinically used as s.c. inj. in specialized centres negative feedback for inhibiting TSH secretion is provided
for inhibiting LH surges during controlled ovarian stimulation by the thyroid hormones which act primarily at the level
in women undergoing in vitro fertilization. Their advantages of the pituitary, but also in the hypothalamus. T3 has been
over long-acting GnRH agonists include: shown to reduce TRH receptors on the thyrotropes.
• They produce quick Gn suppression by competitive
antagonism, need to be started only from 6th day of Pathological involvement Only few cases of hypo-
ovarian hyperstimulation. or hyperthyroidism are due to inappropriate TSH secretion.
• They carry a lower risk of ovarian hyperstimulation In majority of cases of myxoedema TSH levels are markedly
syndrome. elevated because of deficient feedback inhibition. Graves’
• They achieve more complete suppression of endogenous disease is due to an immunoglobulin of the IgG class which
Gn secretion. attaches to the thyroid cells and stimulates them in the same
However, pregnancy rates are similar or may even be lower. way as TSH. Consequently, TSH levels are low. Contrary
to earlier belief, TSH is not responsible for exophthalmos
THYROID STIMULATING HORMONE seen in Graves’ disease because TSH levels are low.

CHAPTER 17
(TSH, THYROTROPIN) Use Thyrotropin has no therapeutic use. Thyroxine is the
drug of choice even when hypothyroidism is due to TSH
It is a 210 amino acid, two chain glycoprotein deficiency. The diagnostic application is to differentiate
(22% sugar), MW 30000. myxoedema due to pituitary dysfunction from primary thyroid
disease.
Physiological function TSH stimulates
thyroid to synthesize and secrete thyroxine (T4) ADRENOCORTICOTROPIC HORMONE
and triiodothyronine (T3). Its actions are: (ACTH, CORTICOTROPIN)
• Induces hyperplasia and hypertrophy of thyroid
It is a 39 amino acid single chain peptide, MW
follicles and increases blood supply to the
4500, derived from a larger peptide pro-opio
gland.
melanocortin (MW 30,000) which also gives rise
• Promotes trapping of iodide into thyroid by
to endorphins, two lipotropins and two MSHs.
increasing Na+: Iodide symporter (NIS).
• Promotes organification of trapped iodine and Physiological function ACTH promotes
its incorporation into T3 and T4 by increasing steroidogenesis in adrenal cortex by stimulating
peroxidase activity. cAMP formation in cortical cells (through specific
• Enhances endocytotic uptake of thyroid colloid cell surface GPCRs)  rapidly increases the
244 HORMONES AND RELATED DRUGS

availability of cholesterol for conversion to A variety of stressful stimuli, e.g. trauma, surgery, severe
pregnenolone which is the rate limiting step in pain, anxiety, fear, blood loss, exposure to cold, etc. generate
the production of gluco, mineralo and weakly neural impulses which converge on median eminence to cause
elaboration of CRH. The feedback inhibition appears to
androgenic steroids. Induction of steroidogenic be overpowered during stress—rise in ACTH secretion
enzymes occurs after a delay resulting in 2nd phase continues despite high plasma level of cortisol induced by it.
ACTH action. The stores of adrenal steroids are Arginine vasopressin (AVP) enhances the action of CRH on
very limited and rate of synthesis primarily corticotropes and augments ACTH release. AVP release and
governs the rate of release. ACTH also exerts augmentation of ACTH action appears to be important during
stress.
trophic influence on adrenal cortex (again through
cAMP): high doses cause hypertrophy and hyper- Pathological involvement Excess production of ACTH
plasia. Lack of ACTH results in adrenal atrophy. from basophil pituitary tumours is responsible for some cases
However, zona glomerulosa is little affected of Cushing’s syndrome. Hypocorticism occurs in pituitary
insufficiency due to low ACTH production. Iatrogenic
because angiotensin II also exerts trophic influence suppression of ACTH secretion and pituitary adrenal axis
on this layer and sustains aldosterone secretion. is the most common form of abnormality encountered
Regulation of secretion Hypothalamus regulates currently due to the use of pharmacological doses of
ACTH release from pituitary through corticotropin-releasing glucocorticoids in nonendocrine diseases.
hormone (CRH). The CRH receptor on corticotropes is also Use ACTH is used primarily for the diagnosis of disorders
a GPCR which increases ACTH synthesis as well as release
of pituitary adrenal axis. Injected i.v. 25 IU causes increase
by raising cytosolic cAMP. Secretion of ACTH has a circadian
in plasma cortisol if the adrenals are functional. Direct assay
rhythm. Peak plasma levels occur in the early morning,
decrease during day and are lowest at midnight. of plasma ACTH level is now preferred.
Corticosteroids exert inhibitory feedback influence on ACTH For therapeutic purposes, ACTH does not offer any
production by acting directly on the pituitary as well as advantage over corticosteroids and is more inconvenient,
indirectly through hypothalamus. expensive as well as less predictable.
SECTION 5
Chapter 18 Thyroid Hormones and
Thyroid Inhibitors

THYROID HORMONE transport process Na+:: iodide symporter (NIS)

to concentrate this anion; this trapping is stimu-
The thyroid gland secretes 3 hormones—thyro-
lated by TSH to exceed a gradient of more than
xine (T4), triiodothyronine (T3) and calcitonin.
100 fold by inducing and activating NIS. The
The former two are produced by thyroid follicles,
I2 content of thyroid gland somehow regulates
have similar biological activity and the term
the uptake mechanism: meagre store activating
‘thyroid hormone’ is restricted to these only.
and large store inhibiting it. The iodide concen-
Calcitonin produced by interfollicular ‘C’ cells
trating mechanism is not peculiar to thyroid. Skin,
is chemically and biologically entirely different.
salivary glands, gastric mucosa, intestine, mam-
It is considered along with parathormone, (Ch.
mary glands and placenta also possess it, but
24) with which it regulates calcium metabolism.
The physiological significance of thyroid gland was
uptake in these organs is not stimulated by TSH.
recognized only after Graves and Basedow (1835, 1840) 2. Oxidation and iodination Iodide trapped
associated the clinical features of the ‘Graves’ disease’ with
swelling of thyroid gland and Gull (1874) correlated myxo-
by follicular cells is carried across the apical mem-
edema with its atrophy. Kendall (1915) obtained crystalline brane by another transporter termed ‘pendrin’ and
thyroxine and postulated its chemical formula which was oxidized by the membrane bound thyroid
confirmed in 1926. Thyroxine was the first hormone to be peroxidase enzyme to iodinium (I+) ions or
synthesized in the laboratory. Since, T4 could not account hypoiodous acid (HOI) or enzyme-linked hypo-
for all the biological activity of thyroid extract, search was
made and more potent T3 was discovered in 1952. iodate (E-OI) with the help of H2O2. These forms
of iodine combine avidly with tyrosil residues
of thyroglobulin, apparently without any
CHEMISTRY AND SYNTHESIS
enzymatic intervention, to form monoiodotyrosine
Both T4 and T3 are iodine containing derivatives (MIT) and diiodotyrosine (DIT) while these
of thyronine which is a condensation product residues are still attached to the thyroglobulin
of two molecules of the amino acid tyrosine. chains.
Thyroxine; is 3, 5, 3´, 5´–tetraiodothyronine while
3. Coupling Pairs of iodinated tyrosil residues
T3 is 3, 5, 3´ triiodothyronine.
couple together (Fig. 18.2) to form T3 and T4.
The thyroid hormones are synthesized and
Normally much more T4 than T3 is formed,
stored in the thyroid follicles as part of thyroglo-
but during I2 deficiency relatively more MIT is
bulin molecule—which is a glycoprotein synthe-
available and a greater proportion of T3 is formed.
sized by thyroid cells, MW 660 KDa, contains
Thus, more active hormone is generated with
10% sugar. The synthesis, storage and release
lesser amount of I2.
of T4 and T3 is summarized in Fig. 18.1 and
Coupling is an oxidative reaction and is
involves the following processes.
catalysed by the same thyroid peroxidase.
1. Iodide uptake The total body content of Thyroglobulin is the most efficient protein,
I2, obtained from food and water, is 30–50 mg, compared to other similar proteins, in supporting
out of which about 1/5 is present in the thyroid. coupling by providing favourable spatial configu-
Concentration of iodide in blood is low ration to facilitate the reaction. Oxidation of iodide
(0.2–0.4 µg/dl) but thyroid cells have an active and coupling are both stimulated by TSH.
246 HORMONES AND RELATED DRUGS

Fig. 18.1: Synthesis, storage and secretion of thyroid hormone

TG—Thyroglobulin; MIT—Monoiodotyrosine; DIT—Diiodotyrosine; T3—Triiodothyronine; T4—Thyroxine
SECTION 5

(Tetraiodothyronine); HOI—Hypoiodous acid; EOI—Enzyme linked hypoiodate; NIS—Na+-iodide

symporter; Thyroid-stimulating hormone (TSH) activates steps 1, 2, 3, 4, and 5; Ionic inhibitors block
step 1; Excess iodide interferes with steps 1, 2, 3 and 5 with primary action on step 3 and 5; Propylthiouracil
inhibits steps 2 and 6; Carbimazole inhibits step 2 only

Fig. 18.2: Coupling of monoiodotyrosine (MIT) and diiodotyrosine (DIT)

to produce triiodothyronine (T3)
 THYROID HORMONES AND THYROID INHIBITORS 247

4. Storage and release Thyroglobulin of which 90–95% is T4 and the rest T3. Binding
containing iodinated tyrosil and thyronil residues occurs to 3 plasma proteins in the following
is transported to the interior of the follicles and decreasing order of affinity for T4:
remains stored as thyroid colloid till it is taken (i) Thyroxine binding globulin (TBG)
back into the cells by endocytosis and broken (ii) Thyroxine binding prealbumin (trans-
down by lysosomal proteases. The T4 and T3 so thyretin)
released is secreted into circulation while MIT (iii) Albumin
and DIT residues are deiodinated and the iodide The normal concentration of PBI is 4–10 µg/
released is reutilized. The uptake of colloid and dl; only 0.1–0.2 µg/dl of this is T3, rest is T4.
proteolysis are stimulated by TSH: the quiscent During pregnancy thyroxine binding globulin is
gland has follicles distended with colloid and cells increased—PBI levels are elevated, but there is
are flat or cubical, while the TSH stimulated gland no effect on thyroid status because the
has columnar cells and colloid virtually disappears. concentration of free hormone remains unaltered.
Normal human thyroid secretes 60–90 µg of T4 Only the free hormone is available for action
and 10–30 µg of T3 daily. as well as for metabolism and excretion. Meta-
5. Peripheral conversion of T4 to T3 Peripheral bolic inactivation of T4 and T3 occurs by deiodi-
tissues, especially liver and kidney, convert T4 nation and glucuronide/sulfate conjugation of the
to T3. About 1/3 of T4 secreted by thyroid under- hormones as well as that of their deiodinated
goes this change and most of the T3 in plasma products. Liver is the primary site (also salivary
is derived from liver. Target tissues take up T3 glands and kidneys). The conjugates are excreted
from circulation for their metabolic need, except in bile, of which a significant fraction is deconju-
brain and pituitary which take up T4 and convert gated in intestines and reabsorbed (enterohepatic
it to T3 within their own cells. Almost equal amounts circulation) to be finally excreted in urine.
of 3, 5, 3´ triiodothyronine (normal T3 : active) Plasma t½ of T4 is 6–7 days, while that of
and 3, 3´, 5´ triiodothyronine (reverse T3 or rT3: T3 is 1–2 days. The half-lives are shortened in
inactive) are produced in the periphery. The T4 hyperthyroidism and prolonged in hypothyroidism
to T3 conversion is carried out by the enzyme due respectively to faster and slower metabolism.
iodothyronine deiodinase which exists in 3 forms
(D1, D2, D3). These forms differ in their organ REGULATION OF SECRETION

CHAPTER 18
and cellular localization as well as product formed. The secretion of hormones from the thyroid is
Whereas type 2 deiodinase (D2) generates T3 and controlled by anterior pituitary by the elaboration
D3 generates rT3, the D1 form generates both of thyrotropin, while TSH secretion itself is
T3 and rT3. The antithyroid drug propylthiouracil regulated by TRH produced in hypothalamus (see
(but not carbimazole) inhibits Type1 deiodinase p. 243). Somatostatin elaborated by hypothalamus
and the antiarrhythmic amiodarone inhibits both inhibits not only GH and prolactin, but also TSH
D1 and D2 forms. Propranolol (high dose) and secretion from pituitary. The relation between
glucocorticoids also inhibit peripheral conversion thyroid, anterior pituitary and hypothalamus is
of T4 to T3 (except in brain and in pituitary). depicted in Fig. 18.3. The negative feedback by
the thyroid hormones is exercised directly on the
TRANSPORT, METABOLISM AND pituitary as well as through hypothalamus. The
EXCRETION action of TRH on pituitary and that of TSH on
Thyroid hormones are avidly bound to plasma thyroid cells is mediated by enhanced cAMP
proteins—only 0.03–0.08% of T4 and 0.2–0.5% synthesis. High concentration of TSH also acts
of T3 are in the free form. Almost all protein via IP3/DAG–increased intracellular Ca2+ pathway
bound iodine (PBI) in plasma is thyroid hormone, in the thyroid cells.
248 HORMONES AND RELATED DRUGS

Lipid T4 and T3 indirectly enhance lipolysis by

potentiating the action of catecholamines and other
lipolytic hormones, probably by suppressing a
phosphodiesterase → increased cAMP. As a result
plasma free fatty acid levels are elevated.
Lipogenesis is also stimulated. All phases of
cholesterol metabolism are accelerated, but its
conversion to bile acids dominates. Thus,
hyperthyroidism is characterized by hypocholes-
terolemia. LDL levels in blood are reduced.
Carbohydrate Carbohydrate metabolism is also
stimulated. Though utilization of sugar by tissues
is increased (mainly secondary to increased BMR),
Fig. 18.3: Regulation of thyroid function glycogenolysis and gluconeogenesis in liver as
TSH—Thyroid stimulating hormone; TRH—Thyrotropin
well as faster absorption of glucose from intestines
releasing hormone; T3—Triiodothyronine; T4—Thyroxine;
SST—Somatostatin more than compensate it → hyperglycaemia and
diabetic-like state with insulin resistance occur
in hyperthyroidism.
ACTIONS
Protein Synthesis of certain proteins is increa-
The actions of T4 and T3 are qualitatively similar sed, but the overall effect of T3 is catabolic—
and are nicely depicted in the features of hypo increased amounts of protein being used as energy
and hyperthyroidism. They affect the function of source. Prolonged action results in negative
practically every body cell. nitrogen balance and tissue wasting. Weight loss
1. Growth and development T4 and T3 are is a feature of hyperthyroidism. T3, T4 in low
essential for normal growth and development. The concentrations inhibit mucoprotein synthesis
most remarkable action is metamorphosis of which so characteristically accumulates in
tadpole to frog: the tail is used-up to build lungs, myxoedema.
limbs and other organs. The action cannot be 3. Calorigenesis T3 and T4 increase BMR
SECTION 5

broadly labelled as catabolic or anabolic. It is by stimulation of cellular metabolism and resetting

exerted through a critical control of protein of the energystat. This is important for maintaining
synthesis in the translation of the genetic code. body temperature. However, metabolic rate in
Congenital deficiency of T4 and T3 resulting in brain, gonads, uterus, spleen and lymph nodes
cretinism emphasizes their importance. The is not significantly affected. The mechanism of
milestones of development are delayed and calorigenesis was believed to be uncoupling of
practically every organ and tissue of the body oxidative phosphorylation: excess energy being
suffers. The greatest sufferer, however, is the ner- released as heat. However, this occurs only at
vous system. Retardation and nervous deficit is very high doses and is not involved in mediating
a consequence of paucity of axonal and dendritic the physiological actions of T3, T4. Dinitrophenol
ramification, synapse formation and impaired uncouples oxidative phosphorylation, but has no
myelination. In adult hypothyroidism also, intel- thyroid-like activity.
ligence is impaired and movements are slow.
4. CVS T3 and T4 cause a hyperdynamic state
2. Intermediary metabolism Thyroid of circulation which is partly secondary to
hormones have marked effect on lipid, carbo- increased peripheral demand and partly due to
hydrate and protein metabolism. direct cardiac actions. Heart rate, contractility and
 THYROID HORMONES AND THYROID INHIBITORS 249

output are increased resulting in a fast, bounding which belongs to the steroid and retinoid
pulse. T3 and T4 stimulate heart by direct action superfamily of intracellular receptors.
on contractile elements (increasing the myosin Two TR isoform families (TRα and TRβ) have been identified.
fraction having greater Ca2+ ATPase activity) and Both bind T3 and function in similar manner, but their tissue
distribution differs, which may account for quantitative
probably by up regulation of β adrenergic recep- differences in the sensitivity of different tissues to T3.
tors. Atrial fibrillation and other irregularities are In contrast to the steroid receptor, the TR
common in hyperthyroidism. Thyroid hormones resides in the nucleus even in the unliganded
can also precipitate CHF and angina. BP, specially inactive state. It is bound to the ‘thyroid hormone
systolic, is often raised. Myocardial O 2 response element’ (TRE) in the enhancer region
consumption can be markedly reduced by of the target genes along with corepressors (Fig.
induction of hypothyroidism. 18.4). This keeps gene transcription suppressed.
5. Nervous system T3, T4 have profound When T3 binds to the ligand-binding domain of
functional effect on CNS. Mental retardation is TR, it heterodimerizes with retinoid X receptor
the hallmark of cretinism; sluggishness and other (RXR) and undergoes a conformation change
behavioral features are seen in myxoedema. releasing the corepressor and binding the
Hyperthyroid individuals are anxious, nervous, coactivator. This induces gene transcription →
excitable, exhibit tremors and hyperreflexia. production of specific mRNA and a specific
pattern of protein synthesis → various metabolic
6. Skeletal muscle Muscles are flabby and
and anatomic effects. The expression of certain
weak in myxoedema, while thyrotoxicosis produ-
genes is repressed by T 3. In their case, the
ces increased muscle tone, tremor and weakness
due to myopathy. unliganded TR allows gene transcription, while
binding of T3 to TR halts the process.
7. GIT Propulsive activity of gut is increased Many of the effects, e.g. tachycardia, arrhy-
by T3/T4. Hypothyroid patients are often consti- thmias, raised BP, tremor, hyperglycaemia are
pated, while diarrhoea is common in hyperthy- mediated, at least partly, by sensitization of
roidism. adrenergic receptors to catecholamines. Induction
8. Kidney T3 and T4 do not cause diuresis of adenylyl cyclase, proliferation of β adreno-
in euthyroid individuals, but the rate of urine flow ceptors and a better coupling between these two

CHAPTER 18
is often increased when myxoedematous patients has been demonstrated.
are treated with it. Apart from the nuclear T3 receptor, other sites of thyroid
hormone action have been described. It acts on cell membrane
9. Haemopoiesis Hypothyroid patients suf- to enhance amino acid and glucose entry and on mitochondria
fer from some degree of anaemia which is res- to increase oxygen consumption. At these sites T4 appears
tored only by T4 treatment. Thus, T4 appears to to be equipotent to T3, while at the nuclear receptor T4 has
be facilitatory to erythropoiesis. much lower affinity, and even when bound to the TR, T4
does not promote gene transcription.
10. Reproduction Thyroid has an indirect
effect on reproduction. Fertility is impaired in Relation between T4 and T3
hypothyroidism and women suffer from oligo- • Thyroid secretes more T4 than T3, but in iodine
menorrhoea. Normal thyroid function is required deficient state this difference is reduced.
for maintenance of pregnancy and lactation. • T4 is the major circulating hormone because
it is 15 times more tightly bound to plasma
Mechanism of action proteins.
Both T3 and T4 penetrate cells by active transport • T3 is 5 times more potent than T4 and acts
and produce majority of their actions by combining faster. Peak effect of T3 comes in 1–2 days
with a nuclear thyroid hormone receptor (TR) while that of T4 takes 6–8 days.
250 HORMONES AND RELATED DRUGS

Fig. 18.4: Mechanism of action of thyroid hormone on nuclear thyroid hormone receptor (TR).
T3—Triiodothyronine; T4—Thyroxine; TRE—Thyroid hormone response element; RXR—Retinoid X
receptor; mRNA—Messenger ribonucleic acid; 5’DI—5’Deiodinase (See text for explanation)

• T3 is more avidly bound to the nuclear receptor Triiodothyronine (Liothyronine) is not freely available in India.
than T4 and the T4-receptor complex is unable It is occasionally used i.v. along with l-thyroxine in
myxoedema coma.
to activate/derepress gene transcription.
Clinically, l-thyroxine is preferred for all indi-
SECTION 5

• About 1/3 of T4 is converted to T3 in the thyroid

cations over liothyronine because of more
cells, liver and kidney by type 1 deiodinase
sustained and uniform action as well as lower
(D1) and released into circulation. In addition,
T3 is generated within the target cells (skeletal risk of cardiac arrhythmias.
muscle, heart, brain, pituitary) by another type
(D2) of deiodinase. Pharmacokinetics and interactions
Thus, it may be cocluded that T3 is the active Oral bioavailability of l-thyroxine is ~ 75%, but
hormone, while T4 is mainly a transport form;
severe hypothyroidism can reduce oral absorp-
functions as a prohormone of T3. However, it
tion. It should be administered in empty stomach
may directly produce some nongenomic actions.
to avoid interference by food. Sucralfate, iron,
Preparations calcium and proton pump inhibitors also reduce
l-thyroxine sod.: ELTROXIN 25 μg, 50 μg, 100 μg tabs, l-thyroxine absorption. CYP3A4 inducers like
ROXIN 100 µg tab, THYRONORM 12.5 μg, 25 μg, 50 rifampin, phenytoin and carbamazepine accelerate
μg, 62.5 μg, 75 μg, 88 μg, 100 μg, 112 μg, 125 μg, 137
μg, 150 μg tabs, THYROX 25 µg, 50 µg, 75 µg, 100 µg metabolism of T4; dose of l-thyroxine may need
tabs. An injectable preparation for i.v. use is available elsewhere. enhancement.
 THYROID HORMONES AND THYROID INHIBITORS 251

USES Though liothyronine (T3) acts faster, its use is

The most important use of thyroid hormone is attended by higher risk of cardiac arrhythmias,
for replacement therapy in deficiency states: angina, etc. Drug of choice is l-thyroxine (T4)
200–500 μg i.v. followed by 100 μg i.v. OD till
1. Cretinism It is due to failure of thyroid oral therapy can be instituted. Some authorities
development or a defect in hormone synthesis recommend adding low dose i.v. T 3 10 μg
(sporadic cretinism) or due to extreme iodine 8 hourly in younger patients with no arrhythmia
deficiency (endemic cretinism). It is usually or ischaemia. Alternatively oral T4 500 μg loading
detected during infancy or childhood; but dose followed by 100–300 μg daily may be used,
screening of neonates is the best preventive but in severe hypothyroidism, oral absorption is
strategy. Treatment with thyroxine (8–12 µg/kg) delayed and inconsistent.
daily should be started as early as possible, Other essential measures needed are—
because mental retardation that has already ensued warming the patient, i.v. corticosteroids to cover
is only partially reversible. Response is dramatic: attendant adrenal insufficiency, ventilatory and
physical growth and development are restored and cardiovascular support, correction of hypo-
further mental retardation is prevented. natraemia and hypoglycaemia.
2. Adult hypothyroidism (Myxoedema) 4. Nontoxic goiter It may be endemic or spo-
This is one of the commonest endocrine disorders radic. Endemic is due to iodine deficiency which
which develops as a consequence of autoimmune may be accentuated by factors present in water
thyroiditis or thyroidectomy; It may accompany (excess calcium), food or milk (goitrin, thiocya-
simple goiter if iodine deficiency is severe. nates). A defect in hormone synthesis may be
Antibodies against thyroid peroxidase or responsible for sporadic cases. In both types,
thyroglobulin are responsible for majority of cases deficient production of thyroid hormone leads to
of adult hypothyroidism. Important drugs that can excess TSH → thyroid enlarges, more efficient
cause hypothyroidism are 131I, iodides, lithium and trapping of iodide occurs and probably greater
amiodarone. Treatment with T4 is most gratifying. proportion of T3 is synthesized → enough hormone
It is often wise to start with a low dose—50 µg to meet peripheral demands is produced so that
of l-thyroxine daily and increase every 2–3 weeks the patient is clinically euthyroid. Thus, treatment
to an optimum of 100–200 µg/day (adjusted by with T4 is in fact replacement therapy in this

CHAPTER 18
clinical response and serum TSH levels). Further condition as well, despite no overt hypothyroi-
dose adjustments are made at 4–6 week intervals dism. Full maintenance doses must be given. Most
needed for reaching steady-state. Individualiza- cases of recent diffuse enlargement of thyroid
tion of proper dose is critical, aiming at regress. Long-standing goiter with degenerative
normalization of serum TSH levels. Increase in and fibrotic changes and nodular goiter regress
dose is mostly needed during pregnancy. little or not at all. Thyroxine therapy may be
Subclinical hypothyroidism characterized by withdrawn after a year or so in some cases if
euthyroid status and normal free serum thyroxine adequate iodine intake is ensured. Others need
(FT4) level (> 9 pmol/L) but raised TSH level life-long therapy.
(>10 mU/L) should be treated with T4. For TSH Endemic goiter and cretinism due to iodine deficiency in
level between 6–10 mU/L, replacement therapy pregnant mother is preventable by ensuring daily ingestion
of 150–200 µg of iodine. This is best achieved by iodizing
is optional. It is preferable if patient has other edible salt by adding iodate (preferred over iodide). In India
cardiovascular risk factors. iodization of table salt (100 µg iodine/g salt) is required
under the National Programme, but recently mandatory
3. Myxoedema coma It is an emergency;
iodization rule has been withdrawn.
characterized by progressive mental deterioration
due to acute hypothyroidism: carries significant 5. Thyroid nodule Certain benign functioning
mortality. Rapid thyroid replacement is crucial. nodules regress when TSH is suppressed by
252 HORMONES AND RELATED DRUGS

T4 therapy. Nonfunctional nodules and those non- 2. Inhibit iodide trapping (Ionic inhibitors)
responsive to TSH (that are associated with low Thiocyanates (–SCN), Perchlorates (–ClO4),
TSH levels) do not respond and should not be Nitrates (–NO3).
treated with levothyroxine. T4 therapy should be
3. Inhibit hormone release
stopped if the nodule does not decrease in size
Iodine, Iodides of Na and K, Organic iodide.
within 6 months, and when it stops regressing
after the initial response. 4. Destroy thyroid tissue
Radioactive iodine (131I, 125
I, 123
I).
6. Papillary carcinoma of thyroid This
type of cancer is often responsive to TSH. In Compounds in groups 1 and 2 may be collec-
nonresectable cases, full doses of T4 suppress tively called goitrogens because, if given in excess,
endogenous TSH production and may induce they cause enlargement of thyroid by feedback
temporary regression. release of TSH.
7. Empirical uses T4 has been sometimes used in the In addition, certain drugs used in high doses for prolonged
following conditions without any rationale; response is periods cause hypothyroidism/goiter as a side effect:
unpredictable. • Lithium: inhibits thyroid hormone release.
Refractory anaemias. • Amiodarone: inhibits peripheral conversion of T4 to T3;
Mental depression also interferes with thyroid hormone action.
Menstrual disorders, infertility not corrected by usual • Sulfonamides, paraaminosalicylic acid: inhibit thyro-
treatment. globulin iodination and coupling reaction.
Chronic/non-healing ulcers. • Phenobarbitone, phenytoin, carbamazepine, rifampin:
Obstinate constipation. induce metabolic degradation of T4/T3.
Thyroxine is not to be used for obesity and as a hypo- Goitrin—found in plants (cabbage, turnip, mustard, etc.),
cholesterolemic agent. is the cause of goiter in cattle who feed on these plants.
May contribute to endemic goiter in certain iodine deficient
THYROID INHIBITORS regions.

These are drugs used to lower the functional

capacity of the hyperactive thyroid gland. ANTITHYROID DRUGS (Thioamides)
By convention, only the hormone synthesis
Thyrotoxicosis is due to excessive secretion
inhibitors are called antithyroid drugs, though
of thyroid hormones. The two main causes are
this term has also been applied to all thyroid
Graves’ disease and toxic nodular goiter. Graves’
SECTION 5

inhibitors.
disease is an autoimmune disorder: IgG class of Thiourea derivatives were found to produce goiter
antibodies to the TSH receptor are detected in and hypothyroidism in rats in the 1940s. Open chain
blood. They bind to and stimulate thyroid cells, compounds were found to be toxic. Subsequently, methyl
and produce other TSH like effects. Due to feed- and propyl thiouracil and thioimidazole derivatives
methimazole and carbimazole were found to be safe and
back inhibition, TSH levels are low. The accom- effective.
panying exophthalmos is due to autoimmune Antithyroid drugs bind to the thyroid
inflammation of periorbital tissues. peroxidase and prevent oxidation of iodide/
Toxic nodular goiter, which produces thyroid iodotyrosyl residues, thereby;
hormone independent of TSH, mostly supervenes (i) Inhibit iodination of tyrosine residues in
on old nontoxic goiters. It is more common in thyroglobulin
the elderly; ocular changes are generally absent. (ii) Inhibit coupling of iodotyrosine residues to
form T3 and T4.
CLASSIFICATION Action (ii) has been observed at lower
1. Inhibit hormone synthesis (Antithyroid concentration of antithyroid drugs than action (i).
drugs) Thyroid colloid is depleted over time and blood
Propylthiouracil, Methimazole, Carbimazole. levels of T3/T4 are progressively lowered.
 THYROID HORMONES AND THYROID INHIBITORS 253

TABLE 18.1 Differences between propylthiouracil and carbimazole

Propylthiouracil Carbimazole
1. Dose to dose less potent About 5 × more potent
2. Highly plasma protein bound Less bound
3. Less transferred across placenta and in milk Larger amounts cross to foetus and in milk
4. Plasma t½ 1–2 hours 6–10 hours
5. Single dose acts for 4–8 hours 12–24 hours
6. No active metabolite Produces active metabolite—methimazole
7. Multiple (2–3) daily doses needed Mostly single daily dose
8. Inhibits peripheral conversion of T 4 to T3 Does not inhibit T 4 to T3 conversion

Thioamides do not interfere with trapping of ment of thyroid, and is due to excess TSH
iodide and do not modify the action of T3 and production. Goiter does not develop with
T4 on peripheral tissues or on pituitary. Goiter appropriate doses which restore T4 concentration
is not the result of potentiation of TSH action to normal so that feedback TSH inhibition is
on thyroid, but is due to increased TSH release maintained.
as a consequence of reduction in feedback Important side effects are: g.i. intolerance, skin
inhibition. No goiter occurs if antithyroid drugs rashes and joint pain.
are given to hypophysectomised animals or if T4 Loss or graying of hair, loss of taste, fever and
is given along with them. Antithyroid drugs do liver damage are infrequent.
not affect release of T3 and T4—their effects are A rare but serious adverse effect is agranulocytosis
not apparent till thyroid is depleted of its hormone (1 in 500 to 1000 cases); It is mostly reversible.
content. There is partial cross reactivity between propyl-
Propylthiouracil also inhibits peripheral thiouracil and carbimazole.
conversion of T4 to T3 by D1 type of 5’DI, but
Preparations and dose
not by D2 type. This may partly contribute to
its antithyroid effects. Methimazole and Propylthiouracil: 50–150 mg TDS followed by 25–50 mg

CHAPTER 18
BD–TDS for maintenance. PTU 50 mg tab.
carbimazole do not have this action (Table 18.1) Methimazole: 5–10 mg TDS initially, maintenance dose
and may even antagonize that of propylthiouracil. 5–15 mg daily in 1–2 divided doses.
Carbimazole: 5–15 mg TDS initially, maintenance dose
Pharmacokinetics All antithyroid drugs are 2.5–10 mg daily in 1–2 divided doses, NEO MERCAZOLE,
quickly absorbed orally, widely distributed in the THYROZOLE, ANTITHYROX 5 mg tab.
body, enter milk and cross placenta; are meta- Carbimazole is more commonly used in India.
bolized in liver and excreted in urine primarily Propylthiouracil (600–900 mg/day) may be prefer-
as metabolites. All are concentrated in thyroid: red in thyroid storm for its inhibitory action on
intrathyroid t½ is longer: effect of a single dose peripheral conversion of T4 to more active T3.
lasts longer than would be expected from the It is also used in patients developing adverse
plasma t½. Carbimazole acts largely by getting effects with carbimazole.
converted to methimazole in the body and is longer
Use Antithyroid drugs control thyrotoxicosis in
acting than propythiouracil.
both Graves’ disease and toxic nodular goiter.
Adverse effects Hypothyroidism and goiter Clinical improvement starts after 1–2 weeks or
can occur due to overtreatment, but is reversible more (depending on hormone content of thyroid
on stopping the drug. It is indicated by enlarge- gland). Iodide loaded patients (who have received
254 HORMONES AND RELATED DRUGS

iodide containing contrast media/cough mixtures, Thyroidectomy and 131I are contraindicated during
amiodarone) are less responsive. Maintenance pregnancy. With antithyroid drugs risk of foetal
doses are titrated on the basis of clinical status hypothyroidism and goiter is there. However, low
of the patient. The following strategies are doses of propylthiouracil are preferred: its greater
adopted. protein binding allows less transfer to the foetus.
(i) As definitive therapy (a) Remission may For the same reason it is to be preferred in the
occur in upto half of the patients of Graves’ disease nursing mother. However, methimazole has also
after 1–2 years of treatment: the drug can then be now been found to be safe during pregnancy.
withdrawn. If symptoms recur—treatment is Propylthiouracil is used in thyroid storm as
reinstituted. This is preferred in young patients with well (see p. 256).
a short history of Graves’ disease and a small goiter.
(b) Remissions are rare in toxic nodular goiter: IONIC INHIBITORS
surgery (or 131I) is preferred. However, in frail Certain monovalent anions inhibit iodide trapping by NIS
elderly patient with multinodular goiter who may into the thyroid probably because of similar hydrated ionic
be less responsive to 131I, permanent maintenance size—T4/T3 cannot be synthesized. Perchlorate is 10 times
more potent than thiocyanate in blocking NIS, while nitrate
therapy with antithyroid drugs can be employed. is very weak.
They are toxic and not clinically used now.
(ii) Preoperatively Surgery in thyrotoxic patients Thiocyanates: can cause liver, kidney, bone marrow and brain
is risky. Young patients with florid hyperthyroidism toxicity.
and substantial goiter are rendered euthyroid with Perchlorates: produce rashes, fever, aplastic anaemia,
carbimazole before performing subtotal thyroidec- agranulocytosis.
tomy.
IODINE AND IODIDES
(iii) Along with 131I Initial control with antithy-
Though iodine is a constituent of thyroid
roid drug—1 to 2 weeks gap—radioiodine dosing—
hormones, it is the fastest acting thyroid inhibitor.
resume antithyroid drug after 5–7 days and gra-
In Grave’s disease the gland, if enlarged, shrinks,
dually withdraw over 3 months as the response
becomes firm and less vascular. The thyroid status
to 131I develops. This approach is preferred in
starts returning to normal at a rate commensurate
older patients who are to be treated with 131I,
with complete stoppage of hormone release from
but require prompt control of severe hyperthyroi-
the gland. The thyroid gland involutes and colloid
SECTION 5

dism. This will also prevent initial hyperthyroidism

is restored. The response to iodine and iodides
following 131I due to release of stored T4. is identical, because elemental iodine is reduced
Advantages of antithyroid drugs over surgery/131I to iodide in the intestines. With daily adminis-
are: tration, peak effects are seen in 10–15 days, after
(a) No surgical risk, scar or chances of injury to which ‘thyroid escape’ occurs and thyrotoxicosis
parathyroid glands or recurrent laryngeal may return with greater vengeance. Worsening
nerve. of hyperthyroidism especially occurs in
(b) Hypothyroidism, if induced, is reversible. multinodular goiter.
(c) Can be used even in children and young All facets of thyroid function seem to be affec-
adults. ted, but the most important action is inhibition
Disadvantages are: of hormone release—‘thyroid constipation’. Endo-
(a) Prolonged (often life-long) treatment is cytosis of colloid and proteolysis of thyroglobulin
needed because relapse rate is high. comes to a halt. The mechanism of action is not
(b) Not practicable in uncooperative/unintelli- clear. Excess iodide inhibits its own transport into
gent patient. thyroid cells by interfering with expression of
(c) Drug toxicity. NIS on the cell membrane. In addition, it
 THYROID HORMONES AND THYROID INHIBITORS 255

attenuates TSH and cAMP induced thyroid 2. Chronic overdose (iodism) Inflammation
stimulation. Excess iodide rapidly and briefly of mucous membranes, salivation, rhinorrhoea,
interferes with iodination of tyrosil and thyronil sneezing, lacrimation, swelling of eyelids, burn-
residues of thyroglobulin (probably by altering ing sensation in mouth, headache, rashes, g.i.
redox potential of thyroid cells) resulting in symptoms, etc. The symptoms regress on stop-
reduced T3/T4 synthesis (Wolff-Chaikoff effect). ping iodide ingestion.
However, within a few days, the gland ‘escapes’ Long-term use of high doses can cause hypo-
from this effect and hormone synthesis resumes. thyroidism and goiter.
Preparations and dose Lugol’s solution (5% iodine
Iodide may cause flaring of acne in adoles-
in 10% Pot. iodide solution): LUGOL’S SOLUTION, cents. Given to pregnant or nursing mothers, it
COLLOID IODINE 10%: 5–10 drops/day. COLLOSOL may be responsible for foetal/infantile goiter and
8 mg iodine/5 ml liq. hypothyroidism. Thyrotoxicosis may be aggra-
Iodide (Sod./Pot.) 100–300 mg/day (therapeutic), 5–10 mg/
day (prophylactic) for endemic goiter.
vated in multinodular goiter.

Uses RADIOACTIVE IODINE

1. Preoperative preparation for thyroidectomy The stable isotope of iodine is 127I. Its radioactive
in Graves’ disease: Iodine is generally given for isotope of medicinal importance is:
10 days just preceding surgery. The aim is to
131
I: physical half-life 8 days.
make the gland firm, less vascular and easier to The chemical behaviour of 131I is similar to the
operate on. Though iodide itself will lower the stable isotope.
thyroid status, it cannot be relied upon to attain
131
I emits X-rays as well as β particles. The former
are useful in tracer studies, because they traverse
euthyroidism which is done by use of carbimazole
the tissues and can be monitored by a counter,
before starting iodide. Propranolol may be given
while the latter are utilized for their destructive
additionally for rapid control of symptoms.
effect on thyroid cells. 131I is concentrated by
2. Thyroid storm Lugol’s iodine (6–10 drops) thyroid, incorporated in colloid—emits radiation
or iodine containing radiocontrast media (iopanoic from within the follicles. The β particles penetrate
acid/ipodate) orally are used to stop any further only 0.5–2 mm of tissue. The thyroid follicular
release of T3/T4 from the thyroid and to decrease cells are affected from within, undergo pyknosis

CHAPTER 18
T4 to T3 conversion. and necrosis followed by fibrosis when a
sufficiently large dose has been administered,
3. Prophylaxis of endemic goiter It is
without damage to neighbouring tissues. With
generally used as “iodized salt”(see p. 251).
carefully selected doses, it is possible to achieve
4. Antiseptic As tincture iodine, povidone partial ablation of thyroid.
iodine, etc. see Ch. 65. Radioactive iodine is administered as sodium
salt of 131I dissolved in water and taken orally.
Adverse effects Diagnostic 25–100 µ curie is given; counting
1. Acute reaction It occurs only in individuals or scanning is done at intervals. No damage to
sensitive to iodine, and can be triggered even thyroid cells occurs at this dose.
by a minute quantity. Manifestations are swelling Therapeutic The most common indication is
of lips, eyelids, angioedema of larynx (may be hyperthyroidism due to Graves’ disease or toxic
dangerous), fever, joint pain, petechial haemor- nodular goiter. The average therapeutic dose is
rhages, thrombocytopenia, lymphadenopathy. 3–6 m curie—calculated on the basis of previous
Further exposure to iodine should be stopped tracer studies and thyroid size. Higher doses are
immediately. generally required for toxic multinodular goiter
256 HORMONES AND RELATED DRUGS

than for Graves’ disease. The response is slow— higher doses are required and prior stimulation
starts after 2 weeks and gradually increases, with TSH is recommended.
reaching peak at 3 months or so. Thyroid status
is evaluated after 3 months, and a repeat dose, β ADRENERGIC BLOCKERS
if needed, is given. About 20–40% patients require Propranolol (and other nonselective β blockers)
one or more repeat doses. have emerged as an important form of therapy
to rapidly alleviate manifestations of thyrotoxi-
Advantages cosis that are due to sympathetic overactivity, viz.
1. Treatment with 131I is simple, conveniently palpitation, tremor, nervousness, severe myopathy,
given on outpatient basis and inexpensive. sweating. They have little effect on thyroid
2. No surgical risk, scar or injury to parathyroid function and the hypermetabolic state. They are
glands/recurrent laryngeal nerves. used in hyperthyroidism in the following
3. Once hyperthyroidism is controlled, cure is situations.
permanent. (i) While awaiting response to propylthiouracil/
carbimazole or 131I.
Disadvantages (ii) Along with iodide for preoperative prepara-
tion before subtotal thyroidectomy.
1. Hypothyroidism: About 5–10% patients of
(iii) Thyroid storm (thyrotoxic crisis): This is
Graves’ disease treated with 131I become hypo-
an emergency due to decompensated hyper-
thyroid every year (upto 50% or more patients
thyroidism. Vigorous treatment with the following
may ultimately require supplemental thyroxine
is indicated:
treatment). This probably reflects the natural
• Nonselective β blockers (e.g. propranolol) are
history of Graves’ disease, because only few
the most valuable measure. They afford
patients of toxic nodular goiter treated with
dramatic symptomatic relief. In addition, they
131
I develop hypothyroidism. Moreover,
reduce peripheral conversion of T4 to T3 .
eventual hypothyroidism is a complication of
Propranolol 1–2 mg slow i.v. may be followed
subtotal thyroidectomy/prolonged carbimazole
by 40–80 mg oral every 6 hours .
therapy as well.
• Propylthiouracil 200–300 mg oral 6 hourly:
2. Long latent period of response.
reduces hormone synthesis as well as peripheral
3. Contraindicated during pregnancy—foetal
SECTION 5

T4 to T3 conversion.
thyroid will also be destroyed resulting in
• Iopanoic acid (0.5–1 g OD oral) or ipodate
cretinism, other abnormalities if given during
are iodine containing radiocontrast media. They
first trimester.
are potent inhibitors of thyroid hormone release
4. Not suitable for young patients: they are
from thyroid, as well as of peripheral T4 to
more likely to develop hypothyroidism later
T3 conversion.
and would then require life-long T4 treatment.
• Corticosteroids (hydrocortisone 100 mg i.v. 8
Genetic damage/cancer is also feared, though
hourly followed by oral prednisolone): help
there is no evidence for it.
to tide over crisis, cover any adrenal insuffi-
131
I is the treatment of choice after 25 years of
ciency and inhibit conversion of T4 to T3 in
age and if CHF, angina or any other contra-
periphery.
indication to surgery is present.
• Diltiazem 60–120 mg BD oral may be added
Metastatic carcinoma of thyroid (especially if tachycardia is not controlled by propranolol
papillary or those cases of follicular carcinoma alone, or when it is contraindicated.
which concentrate iodine), 131I may be used as • Rehydration, anxiolytics, external cooling and
palliative therapy after thyroidectomy. Much appropriate antibiotics are the other measures.
 THYROID HORMONES AND THYROID INHIBITORS 257

) PROBLEM DIRECTED STUDY

18.1 A 20-year girl was diagnosed as a case of recent onset Graves’ disease with mild diffuse
pulsatile thyroid enlargement. She was treated with tab. Carbimazole 5 mg 2 tab 3 times a day.
Her symptoms started subsiding after 2 weeks and were fully controlled after 3 months. The
thyroid swelling also subsided and she was maintained on a dose of carbimazole 5 mg twice
daily. After one year she noticed that the neck swelling was reappearing and her body weight
increased by 2 kg in the last one month, but without recurrence of her earlier symptoms. She
rather felt dull, sleepy and depressed. The serum TSH was 12 μU/ml and free thyroxine (FT4)
was 9 pmol/L.
(a) Why was the initial response to carbimazole delayed? Could any additional medicine be given
to her initially to afford more rapid symptomatic relief?
(b) What was the cause of reappearance of the neck swelling and her condition after 1 year?
What measures need to be taken at this stage?
(see Appendix-1 for solution)

CHAPTER 18
Chapter 19 Insulin, Oral Hypoglycaemic
Drugs and Glucagon

Diabetes mellitus (DM) It is a metabolic dis- circulating insulin levels are low or very low,
order characterized by hyperglycaemia, glycosuria, and patients are more prone to ketosis. This type
hyperlipidaemia, negative nitrogen balance and is less common and has a low degree of genetic
sometimes ketonaemia. A widespread pathological predisposition.
change is thickening of capillary basement
Type II Noninsulin-dependent diabetes mellitus
membrane, increase in vessel wall matrix and
(NIDDM)/maturity onset diabetes mellitus:
cellular proliferation resulting in vascular comp-
There is no loss or moderate reduction in β cell
lications like lumen narrowing, early atheroscle-
mass; insulin in circulation is low, normal or even
rosis, sclerosis of glomerular capillaries, retino-
high, no anti-β-cell antibody is demonstrable; has
pathy, neuropathy and peripheral vascular
a high degree of genetic predisposition; generally
insufficiency.
Enhanced nonenzymatic glycosylation of tissue proteins has a late onset (past middle age). Over 90%
due to persistent exposure to high glucose concentrations cases of diabetes are type 2 DM. Causes may
and the accumulation of larger quantities of sorbitol (a reduced be:
product of glucose) in tissues are believed to be causative • Abnormality in gluco-receptor of β cells so
in the pathological changes of diabetes. The concentration
of glycosylated haemoglobin (HbA1c) is taken as an index that they respond at higher glucose concen-
of protein glycosylation: it reflects the state of glycaemia tration or relative β cell deficiency. In either
over the preceding 2–3 months. way, insulin secretion is impaired; may progress
Two major types of diabetes mellitus are: to β cell failure.
• Reduced sensitivity of peripheral tissues to
Type I Insulin-dependent diabetes mellitus insulin: reduction in number of insulin recep-
(IDDM)/juvenile onset diabetes mellitus: tors, ‘down regulation’ of insulin receptors.
There is β cell destruction in pancreatic islets; Many hypertensives are hyperinsulinaemic, but
majority of cases are autoimmune (type 1A) normoglycaemic; and have associated dyslipi-
antibodies that destroy β cells are detectable in daemia, hyperuricaemia, abdominal obesity
blood, but some are idiopathic (type 1B)—no (metabolic syndrome). Thus, there is relative
β cell antibody is found. In all type 1 cases insulin resistance, particularly at the level of

Approaches to drug therapy in type 2 DM

Improve insulin availability Overcome insulin resistance

Exogenous insulin Biguanides
Sulfonylureas Thiazolidinediones
Meglitinide/phenylalanine analogues α glucosidase inhibitors
Dipeptidyl peptidase-4 inhibitors (DPP-4Is)

Major limitations (except for DPP-4Is) Major limitations

Hypoglycaemic episodes Inability to achieve normoglycaemia by themselves
Weight gain in many patients, especially moderate-to-severe cases
Concern about premature atherosclerosis
due to hyperinsulinaemia
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 259

Thus, pork insulin is more homologous to human

insulin than is beef insulin. The A and B chains
are held together by two disulfide bonds.
Insulin is synthesized in the β cells of
pancreatic islets as a single chain peptide
Preproinsulin (110 AA) from which 24 AAs are
first removed to produce Proinsulin (Fig. 19.1).
The connecting or ‘C’ peptide (35 AA) is split
off by proteolysis in Golgi apparatus; both insulin
and C peptide are stored in granules within the
cell. The C peptide is secreted in the blood along
with insulin.
Fig. 19.1: Human proinsulin; simplified structure depicting Assay Insulin is bioassayed by measuring blood sugar
the main features. The connecting peptide, having 35 depression in rabbits (1 U reduces blood glucose of a fasting
amino acids, is split off leaving insulin molecule with two rabbit to 45 mg/dl) or by its potency to induce hypoglycaemic
chains joined by two disulfide bridges convulsions in mice. 1 mg of the International Standard of
insulin = 28 units. With the availability of pure preparations,
it can now be assayed chemically and quantity expressed
liver, muscle and fat. Hyperinsulinaemia per by weight. Plasma insulin can be measured by radio-
immunoassay or enzyme immunoassay.
se has been implicated in causing angiopathy.
• Excess of hyperglycaemic hormones (glucagon,
Regulation of insulin secretion
etc.)/obesity: cause relative insulin defi-
ciency—the β cells lag behind. Under basal condition ~1U insulin is secreted
Other rare forms of DM are those due to specific genetic per hour by human pancreas. Much larger quantity
defects (type-3) like ‘maturity onset diabetes of young’ is secreted after every meal. Secretion of insulin
(MODY), other endocrine disorders, pancreatectomy and
‘gestational diabetes mellitus’ (GDM, type-4).
from β cells is regulated by chemical, hormonal
and neural mechanisms.
INSULIN Chemical The β cells have a glucose sensing
Insulin was discovered in 1921 by Banting and mechanism dependent on entry of glucose into

CHAPTER 19
Best who demonstrated the hypoglycaemic action β cells (through the aegis of a glucose transporter
of an extract of pancreas prepared after degene- GLUT1) and its phosphorylation by glucokinase.
ration of the exocrine part due to ligation of Glucose entry and metabolism leads to activation
pancreatic duct. It was first obtained in pure of the glucosensor which indirectly inhibits the
crystalline form in 1926 and the chemical structure ATP-sensitive K+ channel (K+ATP) resulting in
was fully worked out in 1956 by Sanger. partial depolarization of the β cells (see Fig. 19.6).
Insulin is a two chain polypeptide having 51 This increases intracellular Ca2+ availability (due
amino acids and MW about 6000. The A-chain to increased influx, decreased efflux and release
has 21 while B-chain has 30 amino acids. There from intracellular stores) → exocytotic release
are minor differences between human, pork and of insulin storing granules. Other nutrients that
beef insulins: can evoke insulin release are—amino acids, fatty
acids and ketone bodies, but glucose is the
Species A-chain B-chain principal regulator and it stimulates synthesis of
8th AA 10th AA 30th AA
insulin as well. Glucose induces a brief pulse
Human THR ILEU THR of insulin output within 2 min (first phase)
Pork THR ILEU ALA followed by a delayed but more sustained second
Beef ALA VAL ALA phase of insulin release.
260 HORMONES AND RELATED DRUGS

Glucose and other nutrients are more effective in invoking

insulin release when given orally than i.v. They generate
chemical signals ‘incretins’ from the gut which act on β
cells in the pancreas to cause anticipatory release of insulin.
The incretins involved are glucagon-like peptide-1 (GLP-
1), glucose-dependent insulinotropic polypeptide (GIP),
vasoactive intestinal peptide (VIP), pancreozymin-cholecys-
tokinin, etc.; but different incretin may mediate signal from
different nutrient. Glucagon and some of these peptides enhance
insulin release by increasing cAMP formation in the β cells.

Hormonal A number of hormones, e.g. growth

hormone, corticosteroids, thyroxine modify insu-
lin release in response to glucose. PGE has been Fig. 19.2: Paracrine modulation of hormone secretion
within the pancreatic islets of Langerhans
shown to inhibit insulin release. More important
are the intra-islet paracrine interactions between
the hormones produced by different types of islet These neural influences appear to govern
cells. The β cells constitute the core of the islets both basal as well as evoked insulin secretion,
and are the most abundant cell type. The α cells, because the respective blocking agents have effects
comprising 25% of the islet cell mass, surround opposite to that mentioned above. The primary
the core and secrete glucagon. The δ cells central site of regulation of insulin secretion is
(5–10%) elaborating somatostatin are interspersed in the hypothalamus: stimulation of ventrolateral
between the α cells. There are some PP (pancreatic nuclei evokes insulin release, whereas stimulation
polypeptide containing) cells as well.
of ventromedial nuclei has the opposite effect.
• Somatostatin inhibits release of both insulin
and glucagon.
• Glucagon evokes release of insulin as well as ACTIONS OF INSULIN
somatostatin. The overall effects of insulin are to dispose meal
• Insulin inhibits glucagon secretion. Amylin, derived glucose, amino acids, fatty acids and
another β cell polypeptide released with insulin, favour storage of fuel. It is a major anabolic
inhibits glucagon secretion through a central hormone: promotes synthesis of gylcogen, lipids
site of action in the brain. and protein. The actions of insulin and the results
SECTION 5

The three hormones released from closely situa- of its deficiency can be summarized as:
ted cells influence each other’s secretion and 1. Insulin facilitates glucose transport across cell
appear to provide fine tuning of their output in membrane; skeletal muscle and fat are highly
response to metabolic needs (Fig. 19.2). sensitive. The availability of glucose intracellu-
Neural The islets are richly supplied by sympa- larly is the limiting factor for its utilization in
thetic and vagal nerves. these and some other tissues. However, glucose
• Adrenergic α2 receptor activation decreases entry in liver, brain, RBC, WBC and renal medullary
insulin release (predominant) by inhibiting β cells is largely independent of insulin. Ketoacidosis
cell adenylyl cyclase. interferes with glucose utilization by brain and
• Adrenergic β2 stimulation increases insulin contributes to diabetic coma. Muscular activity
release (less prominent) by stimulating β cell induces glucose entry in muscle cells without the
adenylyl cyclase. need for insulin. As such, exercise has insulin
• Cholinergic—muscarinic activation by ACh or sparing effect.
vagal stimulation causes insulin secretion The intracellular pool of vesicles containing
through IP3/DAG-increased intracellular Ca2+ glucose transporter glycoproteins GLUT4 (insulin
in the β cells. activated) and GLUT1 is in dynamic equilibrium
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 261

with the GLUT vesicles inserted into the mem- sed in blood—partly used up by muscle and heart
brane. This equilibrium is regulated by insulin as energy source, but when their capacity is
to favour translocation to the membrane. exceeded, ketonaemia and ketonuria result.
Moreover, on a long-term basis, synthesis of 5. Insulin enhances transcription of vascular
GLUT4 is upregulated by insulin. endothelial lipoprotein lipase and thus increases
2. The first step in intracellular utilization of clearance of VLDL and chylomicrons.
glucose is its phosphorylation to form glucose- 6. Insulin facilitates AA entry and their synthesis
6-phosphate. This is enhanced by insulin through into proteins, as well as inhibits protein breakdown
increased production of glucokinase. Insulin in muscle and most other cells. Insulin deficiency
facilitates glycogen synthesis from glucose in liver, leads to protein breakdown → AAs are released in
muscle and fat by stimulating the enzyme glycogen blood → taken up by liver and converted to pyruvate,
synthase. It also inhibits glycogen degrading glucose and urea. The excess urea produced is
enzyme phosphorylase → decreased glyco- excreted in urine resulting in negative nitrogen
genolysis in liver. balance. Thus, catabolism takes the upper hand over
3. Insulin inhibits gluconeogenesis (from pro- anabolism in the diabetic state.
tein, FFA and glycerol) in liver by gene mediated Most of the above metabolic actions of insulin
decreased synthesis of phosphoenol pyruvate are exerted within seconds or minutes and are
carboxykinase. In insulin deficiency, proteins and called the rapid actions. Others involving DNA
amino acids are funneled from peripheral tissues mediated synthesis of glucose transporter and
to liver where these substances are converted to some enzymes of amino acid metabolism have
carbohydrate and urea. Thus, in diabetes there a latency of few hours—the intermediate actions.
is underutilization and over production of glucose In addition insulin exerts major long-term effects
→ hyperglycaemia → glycosuria. on multiplication and differentiation of many types
of cells.
4. Insulin inhibits lipolysis in adipose tissue
Mechanism of action Insulin acts on specific receptors
and favours triglyceride synthesis. In diabetes located on the cell membrane of practically every cell, but their
increased amount of fat is broken down due to density depends on the cell type: liver and fat cells are very rich.
unchecked action of lipolytic hormones (gluca- The insulin receptor is a receptor tyrosine kinase (RTK) which
gon, Adr, thyroxine, etc.) → increased FFA and is heterotetrameric glycoprotein consisting of 2 extracellular

CHAPTER 19
α and 2 transmembrane β subunits linked together by disulfide
glycerol in blood → taken up by liver to produce bonds. It is oriented across the cell membrane as a heterodimer
acetyl-CoA. Normally acetyl-CoA is resynthesized (Fig. 19.3). The α subunits carry insulin binding sites, while
to fatty acids and triglycerides, but this process the β subunits have tyrosine protein kinase activity.
Binding of insulin to α subunits induces aggregation
is reduced in diabetics and acetyl CoA is diverted
and internalization of the receptor along with the bound insulin
to produce ketone bodies (acetone, acetoacetate, molecules. This activates tyrosine kinase activity of the β
β-hydroxy-butyrate). The ketone bodies are relea- subunits → pairs of β subunits phosphorylate tyrosine residues

Actions of insulin producing hypoglycaemia

Liver Muscle Adipose tissue

▲ Increases glucose uptake ▲ Increases glucose uptake ▲ Increases glucose uptake and
and glycogen synthesis and utilization storage as fat and glycogen
▲ Inhibits glycogenolysis ▲ Inhibits proteolysis and ▲ Inhibits lipolysis and
and glucose output release of amino acids, release of FFA + glycerol
▲ Inhibits gluconeogenesis pyruvate, lactate into blood which form substrate
from protein, pyruvate, FFA which form the substrate for for gluconeogenesis
and glycerol gluconeogenesis in liver in liver
262 HORMONES AND RELATED DRUGS

Fig. 19.3: A model of insulin receptor and mediation of its metabolic and cellular actions.
T—Tyrosine residue; GLUT4—Insulin dependent glucose transporter; IRS—Insulin receptor substrate proteins;
PIP3—Phosphatidyl inositol trisphosphate; MAP kinase—Mitogen-activated protein kinase; T-PrK—Tyrosine protein
kinase; Ras—Regulator of cell division and differentiation (protooncogene product).
SECTION 5

on each other → expose the catalytic site to phosphorylate exerted by generation of transcription factors promoting
tyrosine residues of Insulin Receptor Substrate proteins (IRS1, proliferation and differentiation of specific cells.
IRS2, etc). In turn, a cascade of phosphorylation and The internalized receptor-insulin complex is either
dephosphorylation reactions is set into motion which amplifies degraded intracellularly or returned back to the surface from
the signal and results in stimulation or inhibition of enzymes where the insulin is released extracellularly. The relative
involved in the rapid metabolic actions of insulin. preponderance of these two processes differs among different
Certain second messengers like phosphatidyl inositol tissues: maximum degradation occurs in liver, least in vascular
trisphosphate (PIP3) which are generated through activation endothelium.
of a specific PI3-kinase also mediate the action of insulin on
metabolic enzymes. Fate of insulin Insulin is distributed only extra-
Insulin stimulates glucose transport across cell membrane cellularly. It is a peptide; gets degraded in the
by ATP dependent translocation of glucose transporter GLUT4 g.i.t. if given orally. Injected insulin or that released
to the plasma membrane. The second messenger PIP3and certain
tyrosine phosphorylated guanine nucleotide exchange proteins from pancreas is metabolized primarily in liver
play crucial roles in the insulin sensitive translocation of GLUT4 and to a smaller extent in kidney and muscles.
from cytosol to the plasma membrane, especially in skeletal Nearly half of the insulin entering portal vein
muscle and adipose tissue. Over a period of time insulin also from pancreas is inactivated in the first passage
promotes expression of the genes directing synthesis of GLUT4.
Genes for a large number of enzymes and carriers are regulated through liver. Thus, normally liver is exposed to
by insulin through Ras/Raf and MAP-Kinase as well as through a much higher concentration (4–8 fold) of insulin
the phosphorylation cascade. Long-term effects of insulin are than are other tissues. As noted above, degradation
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 263

TABLE 19.1 Types of insulin preparations and insulin analogues

Type Appearance Onset Peak Duration Can be mixed

(hr) (hr) (hr) with
Rapid acting
Insulin lispro Clear 0.2–0.3 1–1.5 3–5 Regular, NPH
Insulin aspart Clear 0.2–0.3 1–1.5 3–5 Regular, NPH
Insulin glulisine Clear 0.2–0.4 1–2 3–5 Regular, NPH
Short acting
Regular (soluble) insulin Clear 0.5–1 2–3 6–8 All preparations
(except insulin
glargine/detemir)
Intermediate acting
Insulin zinc suspension or Lente* Cloudy 1–2 8–10 20–24 Regular
Neutral protamine hagedorn Cloudy 1–2 8–10 20–24 Regular
(NPH) or isophane insulin
Long acting
Insulin glargine Clear 2–4 — 24 None
Insulin detemir Clear 1–4 — 20–24 None
* Lente insulin is a 7:3 mixture of ultralente (crystalline) and semilente (amorphous) insulin zinc suspension.
Ultralente (long-acting) and semilente (short-acting) are not separately marketed. The older protamine zinc insulin
is also not marketed.

of insulin after receptor mediated internalization MC insulin is similar to that of recombinant human
occurs to variable extents in most target cells. insulin.
During biotransformation the disulfide bonds are
reduced—A and B chains are separated. These Types of insulin preparations
are further broken down to the constituent amino Regular (soluble) insulin It is a buffered
acids. The plasma t½ is 5–9 min. neutral pH solution of unmodified insulin stabili-
zed by a small amount of zinc. At the concentration
Preparations of insulin of the injectable solution, the insulin molecules

CHAPTER 19
The older commercial preparations were produced self aggregate to form hexamers around zinc ions.
from beef and pork pancreas. They contained ~1% After s.c. injection, insulin monomers are released
(10,000 ppm) of other proteins (proinsulin, other gradually by dilution, so that absorption occurs
polypeptides, pancreatic proteins, insulin deriva- slowly. Peak action is produced only after
tives, etc.) which were potentially antigenic. They 2–3 hours and action continues upto 6–8 hours.
are no longer produced and have been totally The absorption pattern is also affected by dose;
replaced by highly purified pork/beef insulins/ higher doses act longer. When injected s.c. just
recombinant human insulins/insulin analogues. before a meal, this pattern often creates a mismatch
between need and availability of insulin to result
Highly purified insulin preparations in early postprandial hyperglycaemia and late
In the 1970s improved purification techniques like postprandial hypoglycaemia. It is generally
gel filtration and ion-exchange chromatography injected ½-1 hour before a meal. Regular insulin
were applied to produce ‘single peak’ and injected s.c. is also not suitable for providing a
‘monocomponent (MC)’ insulins which contain low constant basal level of action in the interdiges-
<10 ppm proinsulin. The MC insulins are more tive period. The slow onset of action is not appli-
stable and cause less insulin resistance or injection cable to i.v. injection, because insulin hexamer
site lipodystrophy. The immunogenicity of pork dissociates rapidly to produce prompt action.
264 HORMONES AND RELATED DRUGS

To overcome the above problems, some long- inj., WOSULIN-R 40 U/ml inj vial and 100 U/ml pen
acting ‘modified’ or ‘retard’ preparations of insulin injector cartridge.
2. HUMAN MONOTRAD, HUMINSULIN-L: Human lente
were soon developed. Recently, both rapidly acting insulin; 40 U/ml, 100 U/ml.
as well as peakless and long-acting insulin analogues 3. HUMAN INSULATARD, HUMINSULIN-N: Human
have become available. isophane insulin 40 U/ml. WOSULIN-N 40 U/ml inj.
For obtaining retard preparations, insulin is vial and 100 U/ml pen injector cartridge.
4. HUMAN ACTRAPHANE, HUMINSULIN 30/70,
rendered insoluble either by complexing it with HUMAN MIXTARD: Human soluble insulin (30%) and
protamine (a small molecular basic protein) or isophane insulin (70%), 40 U/ml. and 100 U/ml vials.
by precipitating it with excess zinc and increasing WOSULIN 30/70: 40 U/ml vial and 100 U/ml cartridge.
the particle size. 5. ACTRAPHANE HM PENFIL: Human soluble insulin
30% + isophane insulin 70% 100 U/ml pen injector.
Lente insulin (Insulin-zinc suspension): Two 6. INSUMAN 50/50: Human soluble insulin 50% +
isophane insulin 50% 40 U/ml inj; HUMINSULIN 50:50,
types of insulin-zinc suspensions have been HUMAN MIXTARD 50; WOSULIN 50/50 40 U/ml vial,
produced. The one with large particles is 100 U/ml cartridge.
crystalline and practically insoluble in water
In the USA pork and beef insulins are no longer
(ultralente). It is long-acting. The other has smaller
manufactured, but they are still available in U.K.,
particles and is amorphous (semilente), is short-
India and some European countries. In Britain now
acting. Their 7:3 ratio mixture is called ‘Lente
> 90% diabetics who use insulin are taking human
insulin’ and is intermediate-acting.
insulins or insulin analogues. In India also human
Isophane (Neutral Protamine Hagedorn or insulins and analogues are commonly used, except
NPH) insulin: Protamine is added in a quantity for considerations of cost. Human insulin is more
just sufficient to complex all insulin molecules; water soluble as well as hydrophobic than porcine
neither of the two is present in free form and or bovine insulin. It has a slightly more rapid s.c.
pH is neutral. On s.c. injection, the complex absorption, earlier and more defined peak and
dissociates slowly to yield an intermediate duration slightly shorter duration of action. Human insulin
of action. It is mostly combined with regular is also modified similarly to produce isophane
insulin (70:30 or 50:50) and injected s.c. twice (NPH) and lente preparations. Lente human insulin
daily before breakfast and before dinner (split- is no longer prepared in the USA.
mixed regimen). The allegation that human insulin produces more
SECTION 5

1. Highly purified (monocomponent) pork regular insulin: hypoglycaemic unawareness has not been substantiated.
ACTRAPID MC, RAPIDICA 40 U/ml inj. However, after prolonged treatment, irrespective of the type
2. Highly purified (MC) pork lente insulin: LENTARD, of insulin, many diabetics develop relative hypoglycaemic
MONOTARD MC, LENTINSULIN-HPI, ZINULIN 40 unawareness/change in hypoglycaemic symptoms, because of
U/ml autonomic neuropathy, changes in perception/attitude and
3. Highly purified (MC) pork isophane (NPH) insulin: other factors.
INSULATARD 40 U/ml inj. Clinical superiority of human insulin over pork MC insulin
4. Mixture of highly purified pork regular insulin (30%) has not been demonstrated. Though new patients may be started
and isophane insulin (70%): RAPIMIX, MIXTARD on human insulins, the only indication for transfer from purified
40 U/ml inj. pork to human insulin is allergy to pork insulin. It is unwise to
transfer stabilized patients from one to another species insulin
Human insulins In the 1980s, the human insu-
without good reason.
lins (having the same amino acid sequence as
human insulin) were produced by recombinant Insulin analogues
DNA technology in Escherichia coli—‘proinsulin
recombinant bacterial’ (prb) and in yeast— Using recombinant DNA technology, analogues
‘precursor yeast recombinant’ (pyr), or by of insulin have been produced with modified
‘enzymatic modification of porcine insulin’ (emp). pharmacokinetics on s.c. injection, but similar
1. HUMAN ACTRAPID: Human regular insulin; 40 U/ pharmacodynamic effects. Greater stability and
ml, 100 U/ml, ACTRAPID HM PENFIL 100 U/ml pen consistency are the other advantages.
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 265

Insulin lispro: Produced by reversing proline and injection. It is mostly injected at bed time. Lower
lysine at the carboxy terminus B 28 and B 29 incidence of night-time hypoglycaemic episodes
positions, it forms very weak hexamers that compared to isophane insulin has been reported.
dissociate rapidly after s.c. injection resulting in However, it does not control meal-time glycaemia,
a quick and more defined peak as well as shorter for which a rapid acting insulin or an oral
duration of action. Unlike regular insulin, it needs hypoglycaemic is used concurrently. Because of
to be injected immediately before or even after acidic pH, it cannot be mixed with any other
the meal, so that dose can be altered according insulin preparation; must be injected separately.
to the quantity of food consumed. A better control LANTUS OPTISET 100 U/ml in 5 ml vial and 3 ml prefilled
of meal-time glycaemia and a lower incidence pen injector.
of late post-prandial hypoglycaemia have been Insulin detemir Myristoyl (a fatty acid) radical is attached
obtained. Using a regimen of 2–3 daily meal- to the amino group of lysine at B29 of insulin chain. As
time insulin lispro injections, a slightly greater a result, it binds to albumin after s.c. injection from which
reduction in HbA1c compared to regular insulin the free form becomes available slowly. A pattern of insulin
action almost similar to that of insulin glargine is obtained,
has been reported. Fewer hypoglycaemic episodes but twice daily dosing may be needed.
occurred.
HUMALOG 100 U/ml, 3 ml cartridge, 10 ml vial.
REACTIONS TO INSULIN
Insulin aspart: The proline at B 28 of human
insulin is replaced by aspartic acid. This change 1. Hypoglycaemia This is the most frequent
reduces the tendency for self-aggregation, and a and potentially the most serious reaction. It is
time-action profile similar to insulin lispro is commonly seen in patients of ‘labile’ diabetes
obtained. It more closely mimics the physiological in whom insulin requirement fluctuates unpredic-
insulin release pattern after a meal, with the same tably. Hypoglycaemia can occur in any diabetic
advantages as above. following inadvertent injection of large dose, by
NOVOLOG, NOVORAPID 100 U/ml inj; Biphasic insulin missing a meal after injection or by performing
aspart - NOVO MIX 30 FEXPEN injector. vigorous exercise. The symptoms can be divided
Insulin glulisine: Another rapidly acting insulin analogue into those due to counter-regulatory sympathetic
with lysine replacing asparagine at B 23 and glutamic acid stimulation—sweating, anxiety, palpitation,
replacing lysine at B 29. Properties and advantages are similar tremor; and those due to deprivation of the brain

CHAPTER 19
to insulin lispro. It has been particularly used for continuous of its essential nutrient glucose (neuroglucopenic
subcutaneous insulin infusion (CSII) by a pump.
symptoms)—dizziness, headache, behavioural
Insulin glargine: This long-acting biosynthetic changes, visual disturbances, hunger, fatigue,
insulin has 2 additional arginine residues at the weakness, muscular incoordination and sometimes
carboxy terminus of B chain and glycine replaces fall in BP. Generally, the reflex sympathetic
asparagine at A 21. It remains soluble at pH4 symptoms occur before the neuroglucopenic, but
of the formulation, but precipitates at neutral pH the warning symptoms of hypoglycaemia differ
encountered on s.c. injection. A depot is created from patient to patient and also depend on the
from which monomeric insulin dissociates slowly rate of fall in blood glucose level. After long-
to enter the circulation. Onset of action is delayed, term treatment about 30% patients lose adrenergic
but relatively low blood levels of insulin are symptoms. Diabetic neuropathy can abolish the
maintained for upto 24 hours. A smooth ‘peakless’ autonomic symptoms. Hypoglycaemic unaware-
effect is obtained. Thus, it is suitable for once ness tends to develop in patients who experience
daily injection to provide background insulin frequent episodes of hypoglycaemia.
action. Fasting and interdigestive blood glucose Finally, when blood glucose falls further (to
levels are effectively lowered irrespective of time < 40 mg/dl) mental confusion, abnormal
of the day when injected or the site of s.c. behaviour, seizures and coma occur. Irreversible
266 HORMONES AND RELATED DRUGS

neurological deficits are the sequelae of prolonged Insulin is effective in all forms of diabetes
hypoglycaemia. mellitus and is a must for type 1 cases, as well
as for post pancreatectomy diabetes and
Treatment Glucose must be given orally or i.v.
gestational diabetes. Many type 2 cases can be
(for severe cases)—reverses the symptoms rapidly.
controlled by diet, reduction in body weight and
Glucagon 0.5–1 mg i.v. or Adr 0.2 mg s.c. (less
appropriate exercise supplemented, if required,
desirable) may be given as an expedient measure
by oral hypoglycaemics. Insulin is needed by such
in patients who are not able to take sugar orally
patients when:
and injectable glucose is not available.
• Not controlled by diet and exercise or when
2. Local reactions Swelling, erythema and stinging these are not practicable.
sometimes occur at the injected site, especially in the begin- • Primary or secondary failure of oral hypo-
ning. Lipodystrophy of the subcutaneous fat around the
injection site may occur if the same site is injected repeatedly. glycaemics or when these drugs are not
This is rare with the newer preparations. tolerated.
3. Allergy This is due to contaminating proteins, and
• Under weight patients.
is very rare with human/highly purified insulins. • Temporarily to tide over infections, trauma,
Urticaria, angioedema and anaphylaxis are the manifestations. surgery, pregnancy. In the perioperative period
4. Edema Some patients develop short-lived dependent and during labour, monitored i.v. insulin
edema (due to Na + retention) when insulin therapy is started. infusion is preferable.
• Any complication of diabetes, e.g. ketoacidosis,
Drug interactions nonketotic hyperosmolar coma, gangrene of
1. β adrenergic blockers prolong hypoglycaemia extremities.
by inhibiting compensatory mechanisms opera- When instituted, insulin therapy has to be tailored
ting through β2 receptors (β1 selective blockers according to the requirement and convenience of
are less liable). Warning signs of hypoglycaemia each patient. A tentative regimen is instituted and
like palpitation, tremor and anxiety are masked. the insulin requirement is assessed by testing urine
Rise in BP can occur due to unopposed α action or blood glucose levels (glucose oxidase based
of released Adr. spot tests and glucometers are available). Most
2. Thiazides, furosemide, corticosteroids, type 1 patients require 0.4–0.8 U/kg/day. In type
oral contraceptives, salbutamol, nifedipine tend 2 patients, insulin dose varies (0.2–1.6 U/kg/day)
SECTION 5

to raise blood sugar and reduce effectiveness of with the severity of diabetes and body weight:
insulin. obese patients require proportionately higher doses
3. Acute ingestion of alcohol can precipitate due to relative insulin resistance.
hypoglycaemia by depleting hepatic glycogen. Any satisfactory insulin regimen should provide
4. Lithium, high dose aspirin and theophylline basal control by inhibiting hepatic glucose output,
may also accentuate hypoglycaemia by enhancing lipolysis and protein breakdown, as well as supply
insulin secretion and peripheral glucose utilization. extra amount to meet postprandial needs for
disposal of absorbed glucose and amino acids.
USES OF INSULIN A single daily injection of any long/intermediate/
Diabetes mellitus The purpose of therapy in short-acting insulin or a mixture of these cannot
diabetes mellitus is to restore metabolism to fulfil both these requirements. Either multiple
normal, avoid symptoms due to hyperglycaemia (2-4) injections daily of long and short acting
and glucosuria, prevent short-term complications insulins or a single injection daily of long-acting
(infection, ketoacidosis, etc.) and long-term seque- insulin supplemented by oral hypoglycaemics for
lae (cardiovascular, retinal, neurological, renal, meal time glycaemia is used. A frequently selected
etc.) regimen utilizes mixture of regular with lente/
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 267

isophane insulin. The total daily dose of a 30:70

or 50:50 mixture of regular and NPH insulin is
usually split into two (split-mixed regimen) and
injected s.c. before breakfast and before dinner.
Several variables, viz. site and depth of s.c.
injection, posture, regional muscular activity,
injected volume and type of insulin can alter the
rate of absorption of s.c. injected insulin, so that
the anticipated time-course of insulin action may
not be obtained each time. The advantage is that
only two daily injections are required, but the
post-lunch glycaemia may not be adequately
covered (see Fig. 19.4 A), and late postprandial
hypoglycaemia may occur.
A more intensive regimen termed the ‘basal-
bolus regimen’ that is now advised needs 3–4
daily injections (see Fig. 19.4B). A long-acting
insulin (glargine) is injected once daily either
before breakfast or before bed-time for basal Fig. 19.4: Diagrammatic depiction of pattern of insulin
action obtained with two commonly employed insulin
coverage along with 2–3 meal-time injections of regimens.
a rapid acting preparation (insulin lispro or aspart). Arrow indicates subcutaneous insulin injection.
Such intensive regimens more completely meet I. Ana—Insulin analogue (rapid acting); I. Glar—Insulin
glargine; R.I—Regular insulin; NPH—Neutral protamine
the objective of achieving round-the-clock
Hagedorn (isophane) insulin
euglycaemia, but are more demanding and
expensive. The large multicentric Diabetes Control
and Complications Trial (DCCT) among type 1 of severe hypoglycaemic episodes. Moreover,
patients has established that intensive insulin injected insulin fails to reproduce the normal
therapy markedly reduces the occurrence of pattern of increased insulin secretion in response
primary diabetic retinopathy, neuropathy, to each meal, and liver is exposed to the same

CHAPTER 19
nephropathy and slows progression of these concentration of insulin as other tissues, while
complications in those who already have them, normally it receives much higher concentration
in comparison to conventional regimens which through portal circulation. As such, the overall
attain only intermittent euglycaemia. Thus, the desirability and practicability of intensive insulin
risk of microvascular disease appears to be related therapy has to be determined in individual patients.
to the glycaemia control. The ‘UK prospective Intensive insulin therapy is best avoided in young
diabetes study’ (UK PDS, 1998) has extended children (risk of hypoglycaemic brain damage)
these observations to type 2 DM patients as well. and in the elderly (more prone to hypoglycaemia
Since the basis of pathological changes in both and its serious consequences).
type 1 and type 2 DM is accumulation of Diabetic ketoacidosis (Diabetic coma)
glycosylated proteins and sorbitol in tissues as Ketoacidosis of different grades generally occurs
a result of exposure to high glucose concentrations, in insulin dependent diabetics. It is infrequent
tight glycaemia control can delay end-organ in type 2 DM. The most common precipitating
damage in all diabetic subjects. cause is infection; others are trauma, stroke,
However, regimens attempting near normo- pancreatitis, stressful conditions and inadequate
glycaemia are associated with higher incidence doses of insulin.
268 HORMONES AND RELATED DRUGS

Fig. 19.5: Schematic depiction of the development of diabetic ketoacidosis due to insulin lack.
Symptoms produced are shown within boxes

The development of cardinal features of diabetic L/4 hours depending on the volume status. Once
ketoacidosis is outlined in Fig. 19.5. Patients may BP and heart rate have stabilized and adequate
present with varying severity. Typically they are renal perfusion is assured change over to ½N
dehydrated, hyperventilating and have impaired saline. After the blood sugar has reached 300
consciousness. The principles of treatment remain mg/dl, 5% glucose in ½N saline is the most appro-
the same, irrespective of severity, only the vigour priate fluid because blood glucose falls before
with which therapy is instituted is varied. ketones are fully cleared from the circulation. Also
SECTION 5

glucose is needed to restore the depleted hepatic

1. Insulin Regular insulin is used to rapidly
glycogen.
correct the metabolic abnormalities. A bolus dose
of 0.1–0.2 U/kg i.v. is followed by 0.1 U/kg/hr 3. KCl Though upto 400 mEq of K+ may be
infusion; the rate is doubled if no significant fall lost in urine during ketoacidosis, serum K+ is
in blood glucose occurs in 2 hr. Fall in blood usually normal due to exchange with intracellular
glucose level by 10% per hour can be considered stores. When insulin therapy is instituted ketosis
adequate response. subsides and K+ is driven back intracellularly—
Usually, within 4–6 hours blood glucose dangerous hypokalemia can occur. After 4 hours
reaches 300 mg/dl. Then the rate of infusion is it is appropriate to add 10–20 mEq/hr KCl to
reduced to 2–3 U/hr. This is maintained till the the i.v. fluid. Further rate of infusion is guided
patient becomes fully conscious and routine by serum K+ measurements and ECG.
therapy with s.c. insulin is instituted.
4. Sodium bicarbonate It is not routinely
2. Intravenous fluids It is vital to correct dehy- needed. Acidosis subsides as ketosis is controlled.
dration. Normal saline is infused i.v., initially at However, if arterial blood pH is < 7.1, acidosis
the rate of 1 L/hr, reducing progressively to 0.5 is not corrected spontaneously or hyperventilation
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 269

is exhausting, 50 mEq of sod. bicarbonate is added have fewer insulin receptors. However, in most
to the i.v. fluid. Bicarbonate infusion is continued type 2 diabetics the transducer mechanism linking
slowly till blood pH rises above 7.2. insulin receptor to the response appears to be
faulty, rather than the receptor itself. Exercise
5. Phosphate When serum PO4 is in the low-
increases insulin sensitivity and lack of it
normal range, 5–10 m mol/hr of sod./pot. phos-
phate infusion is advocated. However, routine use contributes to insulin resistance.
of PO4 in all cases is still controversial. Pregnancy and oral contraceptives often induce
relatively low grade and reversible insulin resis-
6. Antibiotics and other supportive measures tance. Other rare causes are—acromegaly,
and treatment of precipitating cause must be Cushing’s syndrome, pheochromocytoma, lipo-
instituted simultaneously. atrophic diabetes mellitus. Hypertension is often
Hyperosmolar (nonketotic hypergly- accompanied with relative insulin resistance as
caemic) coma This usually occurs in elderly part of metabolic syndrome.
type 2 patients. Its cause is obscure, but appears Acute insulin resistance This form of insulin
to be precipitated by the same factors as keto- resistance develops rapidly and is usually a short
acidosis, especially those resulting in dehydration. term problem. Causes are—
Uncontrolled glycosuria of DM produces diure- (a) Infection, trauma, surgery, emotional stress
sis resulting in dehydration and haemoconcen- induce release of corticosteroids and other
tration over several days → urine output is finally hyperglycaemic hormones which oppose insulin
reduced and glucose accumulates in blood rapidly action.
to > 800 mg/dl, plasma osmolarity is > 350 mOsm/ (b) Ketoacidosis—ketone bodies and FFA inhibit
L → coma, and death can occur if not vigorously glucose uptake by brain and muscle. Also insulin
treated. binding may increase resulting in insulin
The general principles of treatment are the resistance.
same as for ketoacidotic coma, except that faster
Treatment is to overcome the precipitating
fluid replacement is to be instituted and alkali
cause and to give high doses of regular insulin.
is usually not required. These patients are prone
The insulin requirement comes back to normal
to thrombosis (due to hyperviscosity and sluggish
once the condition has been controlled.
circulation), prophylactic heparin therapy is

CHAPTER 19
Treatment is to overcome the precipitating
recommended.
cause and to give high doses of regular insulin.
Despite intensive therapy, mortality in
The insulin requirement comes back to normal
hyperosmolar coma remains high. Treatment of
once the condition has been controlled.
precipitating factor and associated illness is vital.
Newer insulin delivery devices A number of innova-
Insulin resistance tions have been made to improve ease and accuracy of insulin
administration as well as to achieve tight glycaemia control.
Insulin resistance refers to suboptimal response These are:
of body tissues, especially liver, skeletal muscle
and fat to physiological amounts of insulin. As 1. Insulin syringes Prefilled disposible syringes contain
specific types or mixtures of regular and modified insulins.
already stated, relative insulin resistance is integral
to type 2 DM. Advanced age, obesity and 2. Pen devices Fountain pen like: use insulin cartridges
for s.c. injection through a needle. Preset amounts
sedentary life-style promote insulin resistance. (in 2 U increments) are propelled by pushing a plunger;
Insulin sensitivity has been found to decline convenient in carrying and injecting.
with age. Glucose entry into muscle and liver
3. Inhaled insulin An inhaled human insulin preparation
in response to insulin is deficient in individuals was marketed in Europe and the USA, but withdrawn due
with large stores of body fat. Bigger adipocytes to risk of pulmonary fibrosis and other complications. The
270 HORMONES AND RELATED DRUGS

fine powder delivered through a nebulizer controlled meal- 2. Meglitinide/phenylalanine analogues

time glycaemia, but was not suitable for round-the-clock Repaglinide, Nateglinide
basal effect. Attempts are being made to overcome the 3. Glucagon-like peptide-1 (GLP-1) receptor
shortcomings.
agonists (Injectable drugs)
4. Insulin pumps Portable infusion devices connected Exenatide, Liraglutide
to a subcutaneously placed cannula—provide ‘continuous 4. Dipeptidyl peptidase-4 (DPP-4) inhibitors
subcutaneous insulin infusion’ (CSII). Only regular insulin
Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin,
or a fast acting insulin analogue is used. The pump can
be programmed to deliver insulin at a low basal rate (approx. Linagliptin
1 U/hr) and premeal boluses (4–15 times the basal rate) B. Overcome Insulin resistance
to control post-prandial glycaemia. Though, theoretically more 1. Biguanide (AMPK activator)
appealing, no definite advantage of CSII over multidose s.c. Metformin
injection has been demonstrated. Moreover, cost, strict 2. Thiazolidinediones (PPARγ activator)
adherence to diet, exercise, care of the device and cannula, Pioglitazone
risk of pump failure, site infection, are too demanding on
C. Miscellaneous antidiabetic drugs
the patient. The CSII may be appropriate for selected type
1. α-Glucosidase inhibitors
2 DM cases only.
Acarbose, Miglitol, Voglibose
5. Implantable pumps Consist of an electromechanical 2. Amylin analogue
mechanism which regulates insulin delivery from a percu-
taneously refillable reservoir. Mechanical pumps, propellant
Pramlintide
driven and osmotic pumps have been utilized. 3. Dopamine-D2 receptor agonist
Bromocriptin
6. Other routes of insulin delivery Intraperitoneal, oral
4. Sodium-glucose cotransport-2 (SGLT-2)
(by complexing insulin into liposomes or coating it with
inhibitor
impermeable polymer) and rectal routes are being tried. These
have the advantage of providing higher concentrations in Dapagliflozin
the portal circulation, which is more physiological.
Sulfonylureas (KATP Channel blockers)
ORAL HYPOGLYCAEMIC DRUGS The generic formula of sulfonylureas (SUs) is—
These drugs lower blood glucose levels and are
effective orally. The chief draw back of insulin
is—it must be given by injection. Orally active
drugs have always been saught. All SUs have similar pharmacological profile, their
SECTION 5

The early sulfonamides tested in 1940s produced hypo- sole significant action being lowering of blood
glycaemia as side effect. Taking this lead, the first clinically
acceptable sulfonylurea tolbutamide was introduced in 1957.
glucose level in normal subjects and in type 2
Others followed soon after. In the 1970s many so called diabetics, but not in type 1 diabetics. Being more
‘second generation’ sulfonylureas were developed which are potent and clinically superior, only the second
20–100 times more potent. Clinically useful biguanide generation SUs are employed now. All first
phenformin was produced parallel to sulfonylureas in 1957. generation compounds have been discontinued
Newer approaches have constantly been explored and
except tolbutamide which is infrequently used.
have lately yielded thiazolidinediones, meglitinide analogues,
α-glucosidase inhibitors and the latest are dipeptidyl Mechanism of action Sulfonylureas provoke
peptidase-4 (DPP-4) inhibitors. a brisk release of insulin from pancreas, the
mechanism of which is detailed in Fig. 19.6. The
CLASSIFICATION rate of insulin secretion at any glucose concen-
A. Enhance Insulin secretion tration is increased, i.e. insulin release is provoked
1. Sulfonylureas (KATP Channel blockers) even at low-glucose concentration risking
First generation: Tolbutamide production of severe and unpredictable hypo-
Second generation: Glibenclamide (Glyburide), glycaemia. In type 2 DM the kinetics of insulin
Glipizide, Gliclazide, Glimepiride release in response to glucose or meals is delayed
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 271

and subdued. The SUs primarily augment the 2nd (b) Inhibit metabolism/excretion: Cimetidine
phase insulin secretion with little effect on the ketoconazole, sulfonamides, warfarin, chloram-
1st phase. That they do not cause hypoglycaemia phenicol, acute alcohol intake (also synergises
in pancreatectomised animals and in type by causing hypoglycaemia).
1 diabetics (presence of at least 30% functional (c) Synergise with or prolong pharmacodynamic
β cells is essential for their action), confirms their action: Salicylates, propranolol (cardioselective
indirect action through pancreas. β 1 blockers are less liable), sympatholytic
A minor action reducing glucagon secretion, antihypertensives, lithium, theophylline, alcohol
probably by increasing insulin and somatostatin (by inhibiting gluconeogenesis).
release has been demonstrated. Hepatic
degradation of insulin is also slowed. Drugs that decrease SU action (vitiate
diabetes control) are—
Extrapancreatic action After few months of
(a) Induce metabolism: Phenobarbitone, pheny-
administration, the insulinaemic action of SUs
declines, probably due to down regulation of toin, rifampicin, chronic alcoholism.
sulfonylurea receptors (SUR1) on β cells, but (b) Opposite action/suppress insulin release:
improvement in glucose tolerance is maintained. Corticosteroids, thiazides, furosemide, oral
In this phase, they sensitize the target tissues contraceptives.
(especially liver) to the action of insulin. This Adverse effects Incidence of adverse effects
is due to increase in number of insulin receptors is quite low (3–7%).
and/or a postreceptor action—improving trans-
lation of receptor activation. It is hypothesized 1. Hypoglycaemia It is the commonest prob-
that long-term improvement in carbohydrate lem, may occasionally be severe and rarely fatal.
tolerance leads to overall lowering of circulating It is more common in elderly, liver and kidney
insulin concentration which reverses the down disease patients and when potentiating drugs are
regulation of insulin receptors. An apparent added. Tolbutamide carries lowest risk due to its
increase in their number occurs. A direct low potency and short duration of action.
extrapancreatic action of SUs to increase insulin Treatment of hypoglycaemic episode is to give
receptors on target cells and to inhibit gluco- glucose, may be for a few days because hypogly-
neogenesis in liver has been proposed, but appears caemia may recur.

CHAPTER 19
to have little clinical relevance.
2. Nonspecific side effects Majority of
Pharmacokinetics All SUs are well absorbed diabetics started on SUs tend to gain 1–3 kg
orally, and are 90% or more bound to plasma weight. This may be a consequence of their
proteins: have low volumes of distribution insulinaemic action. Nausea, vomiting, flatulence,
(0.2–0.4 L/kg). They are primarily metabolized— diarrhoea or constipation, headache and pares-
may produce active metabolite. The metabolites thesias are generally mild and infrequent.
(active/inactive) are excreted in urine. As such,
they should be used cautiously in patients with 3. Hypersensitivity Rashes, photosensitivity,
liver or kidney dysfunction. purpura, transient leukopenia, rarely agranulo-
The distinctive features of different SUs are cytosis.
given in Table 19.2. Flushing and a disulfiram-like reaction after
alcohol is reported to occur in some individuals
Interactions taking SUs.
Drugs that enhance SU action (may Tolbutamide reduces iodide uptake by thyroid
precipitate hypoglycaemia) are— but hypothyroidism does not occur.
(a) Displace from protein binding: Phenylbuta- Safety of SUs during pregnancy is not
zone, sulfinpyrazone, salicylates, sulfonamides. established. Change over to insulin is advised.
 272
SECTION 5

TABLE 19.2 Important features of oral hypoglycaemics

Drug Preparations Plasma Duration Clearance Daily No. of Remarks

t½ (hr) of action route* dose doses per
(hr) day
SULFONYLUREAS
1. Tolbutamide RASTINON, 6 6–8 L 0.5–3 g 2–3 Weaker, shorter acting, flexible dosage, safer in
0.5 g tab. elderly and in those prone to hypoglycaemia.
2. Glibenclamide DAONIL, 2–4 24 L 2.5–15 mg 1–2 Potent but slow acting, higher incidence of
(Glyburide) EUGLUCON, BETANASE hypoglycaemia, single daily dose despite short t½
2.5, 5 mg tab. due to active metabolite and sequestration in β cells.
3. Glipizide GLYNASE, GLIDE 3–5 12 L 5–20 mg 1–2 Fast and shorter acting, higher daily dose to be
MINIDIAB 5 mg tab devided, hypoglycaemia and weight gain less likely,
preferable in elderly.
4. Gliclazide DIAMICRON 80 mg tab. 8–20 12–24 L 40–240 mg 1–2 Has antiplatelet action, generates only inactive
DIAZIDE 20, 80 mg tab metabolite, daily dose > 80mg to be divided.
GLIZID 30, 40, 80 mg tab
5. Glimepiride AMARYL, GLYPRIDE 5–7 24 L 1–6 mg 1–2 Long acting, only inactive metabolite. Stronger extra-
GLIMER 1, 2 mg tab pancreatic action. Lower incidence of hypoglycaemia.
MEGLITINIDE / PHENYLALANINE ANALOGUES
1. Repaglinide EUREPA, RAPLIN <1 3–5 L 1–8 mg 3–4 Given ½ hr before each meal for limiting p.p.
REGAN 0.5, 1, 2 mg tab hyperglycaemia.
2. Nateglinide GLINATE, NATELIDE 1.5 2–4 L 180–480 3–4 Stimulates 1st phase insulin secretion, less likely
60,120 mg tab mg to cause delayed hypoglycaemia.
DPP-4 INHIBITORS
1. Sitagliptin JANUVIA 100 mg tab. ~12 24 K 100 mg 1 Non-covalent binding to DPP-4; excreted unchanged in
HORMONES AND RELATED DRUGS

urine. Low risk of hypoglycaemia. Body weight neutral.

2. Vildagliptin GALVUS, JALRA, 2–4 12–24 L,K 50–100 mg 1–2 Covalent binding to DPP-4; Metabolized in liver.
ZOMELIS 50 mg cap Hepatotoxicity reported.
BIGUANIDE
1. Metformin GLYCIPHAGE, GLYCOMET 1.5–3 6–8 K 0.5–2.5 g 1–2 No hypoglycaemia. Not metabolized. Lactic acidosis
0.5, 0.85 g tab, 0.5 g rare, only in kidney disease.
and 1.0 g SR tabs
THIAZOLIDINEDIONE
1. Pioglitazone PIONORM, PIOREST, 3–5 24 L 15–45 mg 1 May improve lipid profile. Reverses insulin resis-
PIOZONE 15, 30 mg tab tance. No hypoglycaemia, C/I in liver and heart disease.
*L—Metabolized in liver; K—Excreted unchanged by kidney; p.p.—postprandial
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 273

Sulfonylureas are secreted in milk: should not used in type 2 DM along with other antidiabetics,
be given to nursing mothers. to control postprandial rise in blood glucose.
Chlorpropamide is one of the first SUs which has been
discontinued because of long duration of action (> 2 days) Glucagon-like peptide-1 (GLP-1) receptor
and frequent hypoglycaemia. It was also prone to cause agonists
dilutional hyponatraemia (by sensitizing kidney to ADH
action), cholestatic jaundice and alcohol flush. GLP-1 is an important incretin released from the
gut in response to ingested glucose. It induces
Meglitinide / D-phenylalanine analogues insulin release from pancreatic β cells, inhibits
(KATP Channel blockers) glucagon release from α cells, slows gastric
emptying and suppresses appetite by activating
These are KATP channel blockers with a quick
specific GLP-1 receptors, which are cell surface
and short lasting insulinemic action.
GPCRs (see Fig. 19.6) expressed on β and α
Repaglinide This meglitinide analogue oral cells, central and peripheral neurones, gastro-
hypoglycaemic is designed to normalise meal- intestinal mucosa, etc. Characteristically GLP-1
time glucose excursions. Though not a sulfonyl- induces insulin release only at high glucose
urea, it acts in an analogous manner by binding concentration. The incretin system appears to
to SUR → closure of ATP dependent K+ channels promote β cell health as well. Failure of incretins
→ depolarisation → insulin release (see Fig. 19.6). has been implicated in the pathogenesis of β cell
Repaglinide is quickly absorbed and rapidly dysfunction of type 2 DM, particularly progression
metabolized. It induces fast onset short-lasting of the disease. GLP-1 based therapy appears to
insulin release. Because of this characteristic its be the most effective measure for preserving β
pattern of use is different from that of SUs. It cell function in type 2 DM.
is administered before each major meal to control GLP-1 itself is not suitable for clinical use
postprandial hyperglycaemia; the dose should be because of rapid degradation by the enzyme
omitted if a meal is missed. Because of short dipeptidyl peptidase-4 (DPP-4) which is expressed
lasting action it may have a lower risk of serious on the luminal membrane of capillary endothelial
hypoglycaemia. Side effects are mild headache, cells, kidney, liver gut mucosa and immune cells.
dyspepsia, arthralgia and weight gain. Another incretin glucose-dependent insulinotropic
Repaglinide is indicated only in selected peptide (GIP) also induces insulin release, but in

CHAPTER 19
type 2 diabetics who suffer pronounced post human beings GLP-1 is the more important incre-
prandial hyperglycaemia, or to supplement tin and GIP has poor action in type 2 diabetics.
metformin/long-acting insulin. It should be The GIP receptor is distinct from GLP-1 receptor,
avoided in liver disease. but mediates mostly similar responses. Some more
stable analogues of GLP-1 have been produced
Nateglinide It is a D-phenylalanine derivative
for clinical use in type-2 DM.
which principally stimulates the 1st phase insulin
secretion by closing β cell KATP channels resulting Exenatide It is a synthetic DPP-4 resistant analogue which
activates GLP-1 receptors (Fig. 19.6) and produces the same
in faster onset and shorter lasting hypoglycaemia
responses. Being a peptide, it is inactive orally. After s.c.
than repaglinide. Ingested 10 min before meal, injection its plasma t½ is ~ 3 hours and duration of action
it limits postprandial hyperglycaemia in type 2 6–10 hours. It is marketed in USA, UK, Europe for use
diabetics without producing late phase hypo- mainly as add-on drug to metformin/SU or a combination
glycaemia. There is little effect on fasting blood of these or pioglitazone in poorly controlled type 2 diabetics.
Benefits noted are lowering of postprandial as well as fasting
glucose level. Episodes of hypoglycaemia are less blood glucose, HbA1c and body weight. The most important
frequent than with SUs. Side effects are dizziness, side effect is nausea and vomiting occurring in ~ 50%
nausea, flu like symptoms and joint pain. It is recipients, but tolerance develops later.
274 HORMONES AND RELATED DRUGS

Fig. 19.6: Mechanism of action of insulin secretagogues

The sulfonylureas (SU) and meglitinide analogues (Megli) block the sulfonylurea receptor (SUR1) which constitutes a
subunit of the inwardly rectifying ATP-sensitive K + channel (KATP) in the membrane of pancreatic β cells. The inward
flow of K+ ions is thereby restricted, intracellular K+ concentration falls and the membrane is partially depolarized
augmenting Ca2+ channel opening as well as release of Ca2+ from intracellular stores. The Ca2+ ions promote fusion
of insulin containing intracellular granules with the plasma membrane and exocytotic release of insulin.
Incretins such as glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) act
upon their own G-protein coupled receptors on the β cell membrane to activate adenylyl cyclase and generate cAMP,
which also promotes exocytosis of insulin. Exenatide (Exe) and liraglutide (Lira) are GLP1 receptor agonists—produce
the same response as GLP1. The incretins GLP1 and GIP are rapidly inactivated by the capillary endothelial enzyme
dipeptidyl peptidase-4 (DPP-4). Their action is enhanced by DPP-4 inhibitors sitagliptin (sita) and vildagliptin (vilda).
The DPP-4 inhibitors thus markedly accentuate the insulin response to ingested glucose/meal and attenuate post-
prandial glycaemia.
SECTION 5

Liraglutide This recently developed long-acting GLP-1 have emerged as important adjunctive drugs in
agonist is closely related to the native peptide but its tight
type 2 DM.
binding to plasma proteins extends t½ to > 12 hours and
duration of action to > 24 hours. Injected s.c. once daily, Sitagliptin This is the first DPP-4 inhibitor
alone or added to oral metformin ± SU or pioglitazone, it
has achieved improved glycaemic control in type 2 diabetics. introduced in USA in 2006 and now available
Nausea and diarrhoea are the frequent side effects, but world wide. It is a competitive and selective
decrease in incidence over time. Use of liraglutide is attended DPP-4 inhibitor which potentiates the action of
by weight loss, and it is being evaluated as an antiobesity
drug even for nondiabetics.
GLP-1 (Fig. 19.6) and GIP, boosts post prandial
Hypoglycaemia is rare with exenatide/liraglutide mono- insulin release, decreases glucagon secretion and
therapy, but can occur when combined with SUs/metformin. lowers meal-time as well as fasting blood glucose
in type 2 diabetics. No effect on gastric emptying
Dipeptidyl peptidase-4 (DPP-4) inhibitors
and appetite have been noted. It is body weight
Realizing the key role of the enzyme DPP-4 in neutral and carries low risk of hypoglycaemia
rapid degradation of endogenous GLP-1, orally unless combined with SUs or insulin. The HbA1c
active inhibitors of this enzyme have been lowering caused by sitagliptin is equivalent to
developed as indirectly acting insulin secreta- that with metformin. Further lowering of HbA1c
gogues. In the past few years, DPP-4 inhibitors occurs when it is added to pioglitazone/SUs/insulin
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 275

with or without metformin. However, sitagliptin hours. It is metabolized by CYP3A4 and generates
monotherapy is recommended only when an active metabolite that has a t½ of 3–7 hours.
metformin cannot be used. Most professional Drug interactions with CYP3A4 inhibitors are
guidelines recommend DPP-4 inhibitors primarily possible.
as adjuvant drugs in type 2 diabetics not well Dose: 5 mg OD; reduce by half in moderately severe renal
controlled by metformin/SUs/pioglitazone or failure, but not in liver disease.
ONGLYZA 2.5, 5 mg tabs
insulin. Though clinical efficacy of all DPP-4
inhibitors is comparable, one metaanalysis has Alogliptin is marketed in Japan and Linagliptin has been
recently approved in USA.
found sitagliptin to cause greater reduction of
fasting blood glucose than vildagliptin.
Biguanide (AMPK activator)
Sitagliptin is well absorbed orally, is little
metabolized and is largely excreted unchanged Two biguanide antidiabetics, phenformin and
in urine with a t½ averaging 12 hours. Dose metformin were introduced in the 1950s. Because
reduction is needed in renal impairment, but not of higher risk of lactic acidosis, phenformin was
in liver disease. Sitagliptin is well tolerated, side withdrawn and has been banned in India since
effects are nausea, loose stools, headache, rashes, 2003.
allergic reactions and edema. Nasopharyngitis and
H — N — C — N — C — N — CH3
cough occurs in some patients, which has been
| || | || |
ascribed to prevention of substance P degradation.
H NH H NH CH3
Pancreatitis is rare.
METFORMIN
Vildagliptin This is the second DPP-4 inhibitor
available in Europe and India which binds to the Metformin It differs markedly from SUs:
enzyme covalently. The complex dissociates very causes little or no hypoglycaemia in nondiabetic
slowly resulting in persistent DPP-4 inhibition subjects, and even in diabetics, episodes of
even after the free drug has been cleared from hypoglycaemia are rare. It does not stimulate
circulation. This explains the longer duration of pancreatic β cells. Metformin is reported to
action (12–24 hours) despite short plasma t½ improve lipid profile as well in type 2 diabetics.
(2–4 hours). The major route of elemination is Mechanism of action Biguanides do not
by hepatic metabolism; only 20–25% is excreted

CHAPTER 19
cause insulin release, but presence of insulin is
unchanged in urine. Dose reduction is needed essential for their action. Metformin is not effective
in moderately severe liver and kidney disease. in pancreatectomized animals and in type 1
No significant drug interactions have been diabetics. Though the details are not clear, recent
reported. Vildagliptin is less selective than studies have recognized activation of AMP-
sitagliptin for DPP-4; causes some inhibition of dependent protein kinase (AMPK) to play a crucial
DPP-8, DPP-9 as well, but the clinical significance role in mediating the actions of metformin, the
of this feature is not known. The tolerability of key features of which are:
vildagliptin is similar to that of sitagliptin, but 1. Suppresses hepatic gluconeogenesis and
hepatotoxicity has been reported. Vildagliptin may glucose output from liver. This is the major
require twice daily dosing; though single daily action responsible for lowering of blood
dose suffices in most cases when combined with
glucose in diabetics.
another hypoglycaemic.
2. Enhances insulin-mediated glucose uptake and
Saxagliptin It has been available in USA since disposal in skeletal muscle and fat. Insulin
2009, and is recently marketed in India. Like resistance exhibited by type-2 diabetics is thus
vildagliptin, it binds covalently with DPP-4 and overcome. This translates into—
acts for 24 hours despite a plasma t½ of 2–4 • glycogen storage in skeletal muscle
276 HORMONES AND RELATED DRUGS

• reduced lipogenesis in adipose tissue and • weight loss promoting

enhanced fatty acid oxidation. • has potential to prevent macrovascular as well
3. Interferes with mitochondrial respiratory chain as microvascular complications of diabetes
and promotes peripheral glucose utilization • no acceleration of β cell exhaustion/ failure
through anaerobic glycolysis. in type 2 DM.
AMPK activation by metformin appears to be • antihyperglycaemic efficacy (HbA1c reduction
an indirect consequence of interference with by 0.8–1.2%) equivalent to other oral drugs.
cellular respiration and lowering of intracellular • can be combined with any other oral or
ATP and other energy sources. injectable antidiabetic, if one drug is not
Metformin also retards intestinal absorption adequate.
of glucose, other hexoses, amino acids and The limiting feature is g.i. intolerance,
Vit B12. especially at higher doses, but lack of serious
toxicity is well established by decades of use.
Pharmacokinetics The important features of
metformin pharmacokinetics are given in Table Infertility: Metformin has been found to improve ovulation
19.2. Clearance of metformin approximates g.f.r. and fertility in some infertile women with polycystic ovary.
This benefit is observed irrespective of the glycaemic status
It accumulates in renal failure and increases the of the woman. It may be due to mitigation of insulin resistance
risk of lactic acidosis. and lowering of circulating insulin levels.

Adverse effects Side effects with metformin

are frequent, but generally not serious. Abdominal Thiazolidinedione (PPARγ agonist)
pain, anorexia, bloating, nausea, metallic taste, Pioglitazone Only one thiazolidinedione
mild diarrhoea and tiredness are the usual Pioglitazone is currently available. Rosiglitazone,
complaints, which tend to subside with time. the other member, is banned in India since 2010
Metformin does not cause hypoglycaemia except and has been withdrawn in Europe due to
in overdose. unacceptable increase in risk of myocardial
Lactic acidosis Small increase in blood lactate occurs with infarction, CHF, stroke and death. This class of
metformin, but lactic acidosis is rare (<1 per 10,000 patient oral antidiabetic drugs are selective agonists for
years) because it is poorly concentrated in hepatic cells.
Alcohol ingestion can precipitate lactic acidosis.
the nuclear peroxisome proliferator-activated
receptor γ (PPARγ) which is expressed mainly
Vit B12 deficiency due to interference with its absorption
SECTION 5

can occur with high dose of metformin.

in fat cells, but also in muscle and some other
cells. It enhances the transcription of several
In addition to general restrictions for use of insulin responsive genes. Glitazones tend to
oral hypoglycaemics (see below), metformin is reverse insulin resistance by enhancing GLUT4
contraindicated in hypotensive states, heart failure, expression and translocation. Entry of glucose
severe respiratory, hepatic and renal disease, as into muscle and fat is improved. Hepatic gluconeo-
well as in alcoholics because of increased risk genesis is also suppressed. Activation of genes
of lactic acidosis. regulating fatty acid metabolism and lipogenesis
Drugs like cimetidine, furosemide may in adipose tissue contributes to the insulin
compete with metformin excretion and enhance sensitizing action. Lipolysis and plasma fatty acid
its toxicity. levels are reduced. Adipocyte turnover and
Uses Metformin is now established as a first differentiation is accelerated by glitazones. Thus,
choice drug for all type 2 DM patients, except fatty tissue is a major site of their action. The
when not tolerated or contraindicated. magnitude of blood glucose reduction is somewhat
less than SUs and metformin. Improved glycae-
Advantages of metformin are: mic control results in lowering of circulating
• nonhypoglycaemic HbA1C and insulin levels in type 2 DM patients.
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 277

Pioglitazone, in addition, lowers serum trigly- enzymes for the digestion of carbohydrates in
ceride level and raises HDL level without much the brush border of small intestine mucosa. It
change in LDL level, probably because it acts slows down and decreases digestion and absorption
on PPARα as well to induce expression of reverse of polysaccharides (starch, etc.) and sucrose. In
cholesterol transporter and some apoproteins. addition, GLP-1 release is promoted which may
Pioglitazone is well tolerated; adverse contribute to the effect. Postprandial glycaemia
effects are plasma volume expansion, edema, is reduced without significant increase in insulin
weight gain, headache, myalgia and mild anaemia. levels. Regular use lowers HbA1c modestly (by
Monotherapy with glitazones is not associated
0.4–0.8%), but change in body weight and lipid
with hypoglycaemic episodes. Few cases of
levels is minimal. The stop-NIDDM trial (2002)
hepatic dysfunction have been reported; CHF may
has shown that long-term acarbose treatment in
be precipitated or worsened. Monitoring of liver
function is advised. It is contraindicated in liver prediabetics reduces occurrence of type 2 DM
disease and in CHF. Glitazones increase the risk as well as hypertension and cardiac disease. In
of fractures, especially in elderly women. diabetics, it reduces cardiovascular events.
Pioglitazone is metabolized by both CYP2C8 Acarbose is a mild antihyperglycaemic and
and CYP3A4. Failure of oral contraception may not a hypoglycaemic; may be used as an adjuvant
occur during pioglitazone therapy. Ketoconazole to diet (with or without metformin/SU) in obese
inhibits and rifampin induces metabolism of diabetics. Dose 50–100 mg TDS is taken at the
pioglitazone. beginning of each major meal. Only a small
Pioglitazone is indicated in type 2 DM, but fraction of the dose is absorbed. Flatulence,
not in type 1 DM. It reduces blood glucose and abdominal discomfort and loose stool are
HbA1c (by 0.5–1.2%) without increasing circula- produced in about 50% patients due to
ting insulin. About 25% patients may not respond fermentation of unabsorbed carbohydrates. Patient
(nonresponders), probably due to low baseline acceptability of α-glucosidase inhibitors is poor
insulin levels. It should be stopped if HbA1c due to uncomfortable g.i. symptoms. Hepatic
reduction is < 0.5% at 6 months. Pioglitazone transaminases may rise, but liver damage is rare.
is primarily used to supplement SUs/metformin GLUCOBAY 50, 100 mg tabs, ASUCROSE, GLUCAR 50
and in case of insulin resistance. However, it is mg tabs.
not likely to be effective when β cell failure has

CHAPTER 19
Miglitol It has a smaller molecule than acarbose,
set in, which may be the cause of loss of efficacy
and it is a stronger inhibitor of sucrase. Potency
to a combination of SUs + metformin. It may
also be used as monotherapy (along with diet for other α-glucosidases is equivalent to acarbose.
and exercise) in mild cases. Absorption of miglitol is substantial, but variable.
Several reports describe greater fluid retention, The absorbed drug is excreted by the kidney. No
weight gain and precipitation of CHF after systemic toxicity is known.
combined use of glitazones with insulin. Experts Dose: 25–100 mg TDS at beginning of each meal.
MIGTOR, DIAMIG, ELITOX 25, 50 mg tabs.
advise avoiding such combination. Pioglitazone
should not be used during pregnancy. The Diabetes Voglibose Has properties, use and side effects
Prevention Programme (2005) has shown that similar to that of acarbose.
glitazones have the potential to delay progression Dose: 200–300 mg TDS just before meals.
of prediabetics to overt type 2 DM. They may VOGLITOR, VOLIX, VOLIBO 0.2, 0.3 g tabs.
help to conserve β cell function in diabetics.
Amylin analogue
Amylin, also called ‘islet amyloid polypeptide’ (IAP), is
α Glucosidase inhibitors
produced by pancreatic β cells and acts in the brain to reduce
Acarbose It is a complex oligosaccharide which glucagon secretion from α cells, delay gastric emptying, retard
reversibly inhibits α-glucosidases, the final glucose absorption and promote satiety.
278 HORMONES AND RELATED DRUGS

Pramlintide It is a synthetic amylin analogue which on Related to degree of glycaemia control, both
s.c. injection before meal attenuates postprandial glycaemia insulin and SUs reduced microvascular complica-
and exerts a centrally mediated anorectic action. The duration
of action is 2–3 hours. It has been used as an adjuvant tions (retinopathy, neuropathy, nephropathy) in
to meal time insulin injection to suppress the glycaemic peak type 2 DM, but did not have significant effect
in both type 1 and type 2 diabetics. Reduction in body weight on macrovascular complications (coronary artery
is an additional benefit. disease, stroke, etc). Metformin, however, could
reduce macrovascular complications as well; it
Dopamine D2 agonist
decreased risk of death and other diabetes related
Bromocriptine Recently (2009) a quick release oral
formulation of bromocriptine has been approved by US-FDA endpoints in overweight patients. This may be
for adjunctive treatment of type 2 DM. Taken early in the related to the fact that both SUs and exogenous
morning it is thought to act on the hypothalamic dopaminergic insulin improve glycaemic control by increasing
control of the circadian rhythm of hormone (GH, prolactin, insulin supply rather than by reducing insulin
ACTH, etc.) release and reset it to reduce insulin resistance.
Bromocriptin can be taken alone to supplement diet+exercise resistance, while metformin can lower insulin
or added to metformin or SU or both. Started at 0.8 mg resistance which is a pathogenic factor in type 2
OD and increased upto 4.8 mg OD (as needed) it has been DM. All oral hypoglycaemics do however control
shown to marginally improve glycaemic control and lower symptoms that are due to hyperglycaemia and
HbA1c by upto 0.5%.
glycosuria, and are much more convenient than
Sodium-glucose co-transport-2 (SGLT-2) inhibitor insulin.
Practically all the glucose filtered at the glomerulus is Oral hypoglycaemics are indicated only in
reabsorbed in the proximal tubules. The major transporter type 2 diabetes, in addition to diet and exercise.
which accomplishes this is SGLT-2, whose inhibition induces They are most effective in patients with—
glucosuria and lowers blood glucose in type 2 DM, as well 1. Age above 40 years at onset of disease.
as causes weight loss.
2. Obesity at the time of presentation.
Dapagliflozin This SGLT-2 inhibitor has been recently 3. Duration of disease < 5 years when starting
tested in type 2 DM patients. After single daily dose it
produces round-the-clock glucosuria and lowers blood glucose
treatment.
levels. The concerns which appear inbuilt due to its 4. Fasting blood sugar < 200 mg/dl.
mechanism of action are—glycosuria which can predispose 5. Insulin requirement < 40 U/day.
to urinary and genital infections, electrolyte imbalance and 6. No ketoacidosis or a history of it, or any other
increased urinary frequency. Tolerability and safety of this
complication.
drug is yet to be established.
SECTION 5

The Diabetes Prevention Programme (2002)

Status of oral hypoglycaemics in has established that in middle aged, obese predia-
diabetes mellitus betics metformin prevented progression to type
After 8 years of prospective study involving large 2 DM, but not in older nonobese prediabetics.
number of patients, the University Group Diabe- Glitazones also appear to have prophylactic
tes Programme (UGDP) of USA (1970) presented potential. Long-term acarbose therapy as well can
findings that cardiovascular mortality was higher delay type 2 DM.
in patients treated with biguanides and SUs than Oral hypoglycaemics should be used to sup-
in those treated with diet and exercise alone or plement dietary management and not to replace
with insulin. A decline in their use followed. it. In view of the prophylactic and outcome
Subsequent studies both refuted and supported benefits, current recommendation is to institute
these conclusions. metformin therapy right at the diagnosis of type
The controversy has been settled by the UK 2 DM, along with dietary and other lifestyle
PDS trial which found that both SUs and measures, without waiting to see if the latter alone
metformin did not increase cardiovascular are sufficient. Metformin may delay progression
mortality over > 10 years observation period. of diabetic severity by favourably affecting β cell
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 279

health and retarding β cell failure. It is especially The latest hypoglycaemics gaining popularity
valuable for obese patients; may also aid weight are the DPP-4 inhibitors. Their favourable features
reduction. Further, it has the potential to reduce are:
the risk of myocardial infarction and stroke. Thus, • Insulin release is glucose dependent; therefore
unless contraindicated/not tolerated, metformin is not likely to induce hypoglycaemia.
prescribed to all type 2 diabetics, despite its • Suppress glucagon release, thus lowering
inferior patient acceptability due to g.i. side effects. fasting blood glucose as well.
Many type 2 DM patients do not attain desired • Improve β cell health and retard progression
level of glycaemia control and HbA1c reduction of β cell failure.
(to < 7%) with metformin alone, and a second • Body weight neutral.
drug is needed. SUs are the most commonly • Mostly single daily dose, well tolerated with
selected 2nd drug. They have good patient few side effects, no serious toxicity, no drug
acceptability, convenient dosing and high efficacy, interactions, except with saxagliptin.
but can cause weight gain and hypoglycaemia. However, they are new drugs and have not
There is some evidence that SUs given over long- withstood the test of time yet. Their impact on
term (2–10 years) expedite β cell apoptosis and cardiovascular mortality and other outcomes is
failure. Receptor desensitization may also be a
yet to be measured. As such, most professional
cause, and SUs tend to lose efficacy in few years
guidelines place them as second line/add on
(5–10% per year failure rate). There is no
antidiabetic drugs. They are especially valuable
difference in the clinical efficacy of different 2nd
for patients having body weight problem and those
generation SUs. However, this does not indicate
experiencing frequent episodes of hypoglycaemia.
that choice among them is irrelevant. Differences
Upto 50% patients of type 2 DM initially
among them are mainly in dose, onset and duration
of action which govern flexibility of regimens. treated with oral hypoglycaemics ultimately need
Some specific features of various SUs are given insulin. Moreover, when a diabetic on oral
in Table 19.2. If a particular SU proves inadequate hypoglycaemics presents with infection, severe
in a given patient, another one may still work. trauma or stress, pregnancy, ketoacidosis or any
Patients with near normal fasting blood other complication, or has to be operated upon—
glucose but prominent post-prandial hypergly- switchover to insulin (see Flow chart in Fig. 19.7).
caemia, or those experiencing late postmeal Metformin and/or SUs or DPP-4 inhibitors can

CHAPTER 19
hypoglycaemia may do better with a premeal also be combined with insulin, particularly when
meglitinide/phenyl alanine analogue. a single daily injection of long-acting (e.g.
Pioglitazone is usually the 3rd choice drug; glargine) insulin is used to provide basal control.
may be added to metformin or a combination The oral drug given before meals serves to check
of metformin + SU. Though it reduces insulin postprandial glycaemia.
resistance, tends to preserve β cell function and Epalrestat Sorbitol is a minor metabolite of glucose
does not cause hypoglycaemia, it is infrequently generated by the enzyme aldose reductase. In diabetics, excess
selected for monotherapy. Its major limitations sorbitol is produced and gets deposited in nerves and other
are—tendency to fluid retention, weight gain, tissues. This is involved in the pathogenesis of diabetic
neuropathy and other complications. Epalrestat is an aldose
increased risk of heart failure and fractures, need reductase inhibitor developed in Japan which has been found
to monitor liver function and inefficacy in a to delay sorbitol accumulation in sciatic nerve/other tissues
significant number of patients. of diabetics imparting potential to delay progression of
Acarbose-like drugs are mild antihypergly- diabetic neuropathy. In trials it has caused modest
caemics, mostly used as supplementary drugs to improvement in nerve conduction, neuropathic pain and other
symptoms. However, magnitude of benefit and safety are
a combination hypoglycaemic regimen. They are yet to be defined. Nausea, vomiting and elevation of liver
disliked by many patients because of bloating, enzymes are the adverse effects.
indigestion and other abdominal symptoms. Dose: 50 mg TDS before meals; ALRISTA 50 mg tab.
280 HORMONES AND RELATED DRUGS

Fig. 19.7: Simplified flow chart of management approaches in diabetes mellitus.

Met—Metformin; SU—Sulfonylurea; Megli—Meglitinide/d-phenylalanine analogue; DPP-4i—Dipeptidyl peptidase-4
inhibitor; α Gli—α Glucosidase inhibitor; Pio—Pioglitazone
Note: A meglitinide drug is indicated only in patients with predominant postprandial hyperglycaemia.
An α glucosidase inhibitor can be additional add on drug.
SECTION 5

GLUCAGON Actions Glucagon is hyperglycaemic; most of its actions

A hyperglycaemic principle was demonstrated to be present are opposite to that of insulin. Glucagon causes hyperglycaemia
in the pancreatic islets just two years after the discovery primarily by enhancing glycogenolysis and gluconeogenesis
of insulin in 1921. It was named ‘glucagon’. Glucagon is in liver; suppression of glucose utilization in muscle and fat
a single chain polypeptide containing 29 amino acids, MW contributes modestly. Glucagon is considered to be the hormone
3500. It is secreted by the α cells of the islets of Langerhans of fuel mobilization. Its secretion is increased during fasting,
and commercially produced now by recombinant DNA and is largely responsible for the high fasting blood glucose
technology. levels in type 2 diabetics. It plays an essential role in the
development of diabetic ketoacidosis. Increased secretion of
Regulation of Secretion Like insulin, glucagon is also glucagon has been shown to attend all forms of severe tissue
derived by cleavage of a larger peptide prohormone. Its injury.
secretion is regulated by glucose levels, other nutrients, Glucagon increases the force and rate of cardiac contraction
paracrine hormones and nervous system. Glucose has opposite and this is not antagonized by β blockers. It has a relaxant
effects on insulin and glucagon release, i.e. high glucose action on the gut and inhibits gastric acid production.
level inhibits glucagon secretion. The incretin GLP-1, FFA Mechanism of action Glucagon, through its own receptor
and ketone bodies also inhibit glucagon release. Amino acids, and coupling Gs protein activates adenylyl cyclase and
however, induce both insulin and glucagon secretion. Insulin, increases cAMP in liver, fat cells, heart and other tissues;
amylin and somatostatin, elaborated by the neighbouring β most of its actions are mediated through this cyclic nucleotide.
and δ cells, inhibit glucagon secretion. Sympathetic Glucagon is inactive orally; that released from pancreas
stimulation consistently and parasympathetic stimulation is broken down in liver, kidney, plasma and other tissues.
under certain conditions evokes glucagon release. Its t½ is 3–6 min.
 INSULIN, ORAL HYPOGLYCAEMIC DRUGS AND GLUCAGON 281

Uses Other hyperglycaemics

1. Hypoglycaemia due to insulin or oral hypoglycaemics; Diazoxide Chemically related to thiazides, it inhibits insulin
use of glucagon is; only an expedient measure for the release from β cells and causes hyperglycaemia lasting
emergency, and must be followed by oral glucose/sugar given 4–8 hours. Its action on ATP sensitive K+ channels of
repeatedly till the blood glucose level stabilizes. It may not β cells is opposite to that of SUs. Other actions which may
work if hepatic glycogen is already depleted. contribute to hyperglycaemia are decreased peripheral
Dose: 0.5–1.0 mg i.v. or i.m. utilization of glucose and release of catecholamines. It has
GLUCAGON 1 mg inj. been used to prevent hypoglycaemia in insulinomas. Other
actions are vasodilatation, fall in BP and antidiuresis.
2. Cardiogenic shock to stimulate the heart in β
adrenergic blocker treated patients. However, action is not Somatostatin It causes hyperglycaemia primarily by
very marked. inhibiting insulin release.

3. To facilitate radiographic examination of upper/lower Streptozocin It is obtained from Streptomyces achromo-

g.i. tract by relaxing stomach and intestines. genes. Causes selective damage to insulin secreting
β cells. It has been used to produce experimental diabetes
in animals and to treat insulin secreting tumours of pancreas.

) PROBLEM DIRECTED STUDY

19.1 During routine medical checkup a 50-year male office executive with sedentary lifestyle
was diagnosed to have developed type 2 diabetes mellitus. His fasting and post-meal blood glucose
was 130 mg/dl and 190 mg/dl respectively, HbA1C was 7.8%, BP was 130/82 mm Hg and body
mass index was 27 kg/m2. He was asymptomatic and investigations revealed no end organ damage.
He was advised suitable diet, exercise and other lifestyle modifications.
(a) Should he be prescribed an antidiabetic medication as well? If so, which drug/combination
of drugs should be selected, and why?
(see Appendix-1 for solution)

CHAPTER 19
Chapter 20 Corticosteroids

The adrenal cortex secretes steroidal hormones steroidogenesis takes place under the influence
which have glucocorticoid, mineralocorticoid and of ACTH which makes more cholesterol available
weakly androgenic activities. Conventionally, the for conversion to pregnenolone and induces steroi-
term ‘corticosteroid’ or ‘corticoid’ includes natural dogenic enzymes. Since adrenal cortical cells store
gluco- and mineralo-corticoids and their synthetic only minute quantities of the hormones, rate of
analogues. release is governed by the rate of biosynthesis.
By the middle of 19th century it was demonstrated that The circulating corticosteroids inhibit ACTH
adrenal glands were essential for life. Later it was appreciated release from pituitary as well as CRH production
that the cortex was more important than the medulla. A number
of steroidal active principles were isolated and their structures from hypothalamus (see Ch. 17) and thus provide
were elucidated by Kendall and his coworkers in the 1930s. negative feed back regulation of the hypothalamo-
However, the gate to their great therapeutic potential was pituitary-adrenal (HPA) axis.
opened by Hench (1949) who obtained striking improvement
in rheumatoid arthritis by using cortisone. The Nobel Prize The normal rate of secretion of the two principal
was awarded the very next year to Kendall, Reichstein and corticoids in man is—
Hench.
Hydrocortisone—10–20 mg daily (nearly half of
BIOSYNTHESIS this in the few morning hours).
The corticoids (both gluco and mineralo) are 21 Aldosterone — 0.125 mg daily.
carbon compounds having a cyclopentanoper-
hydro-phenanthrene (steroid) nucleus. They are
ACTIONS
synthesized in the adrenal cortical cells from
cholesterol. A simplified version of the biosyn- The corticoids have widespread actions. They
thetic pathways is presented in Fig. 20.1. Adrenal maintain fluid-electrolyte, cardiovascular and

Fig. 20.1: Simplified depiction of the pathways of adrenal steroid hormone biosynthesis
 CORTICOSTEROIDS 283

Fig. 20.2: Hypothalamo-pituitary-adrenal (HPA) axis; regulation of corticosteroid production and

response to stress which overrides the negative feedback regulation of ACTH release

energy substrate homeostasis and functional status Mineralocorticoid Effects on Na+, K+ and fluid

CHAPTER 20
of skeletal muscles and nervous system. They balance.
prepare the body to withstand effects of all kinds Marked dissociation between these two types
of noxious stimuli and stress. The involvement of actions is seen among natural as well as synthetic
of hypothalamo-pituitary-adrenal axis in stress corticoids. Accordingly, compounds are labelled
response is depicted in Fig. 20.2. as ‘glucocorticoid’ or ‘mineralocorticoid’.
Corticoids have some direct and some
permissive actions. By permissive action is meant Mineralocorticoid actions
that while they do not themselves produce an
The principal mineralocorticoid action is enhan-
effect, their presence facilitates other hormones
cement of Na+ reabsorption in the distal convo-
to exert that action, e.g. they do not have any
luted tubule in kidney. There is an associated
effect on BP but the pressor action of Adr is
increase in K+ and H+ excretion. Its deficiency
markedly blunted in their absence. Actions of
results in decreased maximal tubular reabsorptive
corticoids are divided into:
capacity for Na+; kidney is not able to retain Na+
Glucocorticoid Effects on carbohydrate, protein even in the Na + deficient state → Na + is
and fat metabolism, and other actions that are progressively lost: kidneys absorb water without
inseparably linked to these. the attendant Na+ (to maintain e.c.f. volume which
284 HORMONES AND RELATED DRUGS

nevertheless decreases) → dilutional hyponatrae- peripheral tissues. This is responsible for side
mia → excess water enters cells → cellular effects like muscle wasting, lympholysis, loss of
hydration: decreased blood volume and raised osteoid from bone and thinning of skin. The amino
haematocrit. Hyperkalaemia and acidosis accom- acids so mobilized funnel into liver → used up
pany. These distortions of fluid and electrolyte in gluconeogenesis, excess urea is produced →
balance progress and contribute to the circulatory negative nitrogen balance. Glucocorticoids are
collapse. As such, these actions make adrenal thus catabolic. Their function appears to be aimed
cortex essential for survival. at maintaining blood glucose levels during
Similar action on cation transport is exerted starvation—so that brain continues to get its
in other tissues as well. The action of aldosterone nutrient. When food is withheld from an
is exerted by gene mediated increased transcrip- adrenalectomized animal—liver glycogen is
tion of m-RNA in renal tubular cells which directs rapidly depleted and hypoglycaemia occurs.
synthesis of proteins (aldosterone-induced Glucocorticoids also increase uric acid excretion.
proteins—AIP). The Na+K+ ATPase of tubular
2. Fat metabolism The action of glucocor-
basolateral membrane responsible for generating
ticoids on fat metabolism is primarily permissive
gradients for movement of cations in these cells
in nature. They promote lipolysis due to glucagon,
is the major AIP (see Fig. 41.3). Synthesis of
growth hormone, Adr and thyroxine. cAMP
β subunit of amiloride sensitive Na+ channel is
induced breakdown of triglycerides is enhanced.
also induced. Because of the time taken to induce
Fat depots in different areas of the body respond
protein synthesis, aldosterone action has a latency
differently—redistribution of body fat occurs.
of 1–2 hours. In addition, aldosterone rapidly
Subcutaneous tissue over extremities loses fat
induces phosphorylation and activation of
which is deposited over face, neck and shoulder
amiloride sensitive Na+ channel.
producing ‘moon face’, ‘fish mouth’ and ‘buffalo
The main adverse effect of excessive mine-
hump’. Explanation offered is—because
ralocorticoid action is fluid retention and hyper-
peripheral adipocytes are less sensitive to insulin
tension. The natural and some of the synthetic
and more sensitive to corticosteroid-facilitated
glucocorticoids have significant mineralocorticoid
lipolytic action of GH and Adr, break down of
activity responsible for side effects like edema,
fat predominates, whereas truncal adipocytes
progressive rise in BP, hypokalemia and alkalosis.
respond mainly to raised insulin levels caused
SECTION 5

The diuretic induced hypokalemia is aggravated

by glucocorticoid induced hyperglycaemia.
by mineralocorticoid excess.
Aldosterone has been shown to promote CHF Difference in the sensitivity of adipocytes at different locations
associated myocardial fibrosis and progression to glucocorticoids is believed to arise from different levels
of expression of the isoenzyme 11β-hydroxysteroid dehydroge-
of the disease (see Ch. 37). nase type 1 (11β HSD1) which generates active hydrocortisone
from inactive cortisone in the target tissues. Greater expression
Glucocorticoid actions of 11βHSD1 in peripheral adipocytes than in truncal
adipocytes would direct glucocorticoid-facilitated lipolysis
1. Carbohydrate and protein metabolism to the subcutaneous fat in the limbs.
Glucocorticoids promote glycogen deposition in
11βHSD1
liver (they are assayed on the basis of this action) Cortisone Hydrocortisone
by inducing hepatic glycogen synthase and 11βHSD2
promoting gluconeogenesis. They inhibit glucose On the other hand, high expression of the type 2 isoenzyme
utilization by peripheral tissues. This along with (11βHSD2) in the kidney tubule (also colon and salivary
increased glucose release from liver results in gland) which express mineralocorticoid receptor (MR) is
believed to account for only weak mineralocorticoid activity
hyperglycaemia, resistance to insulin and a
of hydrocortisone whose inherent potency on MR is similar
diabetes-like state. They also cause protein to that of aldosterone. As shown above, 11βHSD2 catalyses
breakdown and amino acid mobilization from the reverse reaction inactivating hydrocortisone.
 CORTICOSTEROIDS 285

3. Calcium metabolism Glucocorticoids is a direct effect on brain, independent of relief

inhibit intestinal absorption and enhance renal of disease symptoms, and sometimes progresses
excretion of Ca2+. Loss of osteoid (decreased to cause increased motor activity, insomnia, hypo-
formation and increased resorption) indirectly mania or depression. On the other hand, patients
results in loss of Ca2+ from bone, producing of Addison’s disease suffer from apathy,
negative calcium balance. Spongy bones depression and occasionally psychosis.
(vertebrae, ribs, pelvis, etc.) are more sensitive. Glucocorticoids also maintain the level of
4. Water excretion The effect on water sensory perception and normal level of excita-
excretion is independent of action on Na + bility of neurones. High doses lower seizure
transport; hydrocortisone and other glucocorti- threshold. Use in epileptics requires caution. This
coids, but not aldosterone, maintain normal g.f.r. action is independent of electrolyte changes in
In adrenal insufficiency, the capacity to excrete the brain and is not shared by aldosterone.
a water load is markedly reduced—such patients 8. Stomach Secretion of gastric acid and pep-
are prone to water intoxication from i.v. infusions. sin is increased—may aggravate peptic ulcer.
Glucocorticoids also enhance secretory acti-
vity of renal tubules. 9. Lymphoid tissue and blood cells
Glucocorticoids enhance the rate of destruction
5. CVS Glucocorticoids restrict capillary per-
of lymphoid cells (T cells are more sensitive than
meability, maintain tone of arterioles and myo-
B cells); but in man the effect on normal lymphoid
cardial contractility. Applied topically, they cause
tissue is modest. However, a marked lytic response
cutaneous vasoconstriction. They have a permis-
sive role for the pressor action of Adr and is shown by malignant lymphatic cells. This is
angiotensin. They also play a permissive role in the basis of their use in lymphomas.
development of hypertension—should be used Glucocorticoids increase the number of RBCs,
cautiously in hypertensives. platelets and neutrophils in circulation. They
Adrenal insufficiency is attended by low car- decrease lymphocytes, eosinophils and basophils.
diac output, arteriolar dilatation, poor vasocons- This is not due to destruction of the concerned
trictor response to Adr (repeated doses of Adr cells, but due to their sequestration in tissues.
cause destructive changes in blood vessels) and Blood counts come back to normal after 24 hours.
increased permeability of capillaries. These

CHAPTER 20
10. Inflammatory responses Irrespective of
changes along with hypovolemia (due to lack of
the type of injury or insult, the attending inflamma-
mineralocorticoid) are responsible for cardio-
tory response is suppressed by glucocorticoids.
vascular collapse.
This is the basis of most of their clinical uses.
6. Skeletal muscles Optimum level of The action is nonspecific and covers all compo-
corticosteroids is needed for normal muscular nents and stages of inflammation. This includes
activity. Weakness occurs in both hypo- and attenuation of—increased capillary permeability,
hypercorticism, but the causes are different. local exudation, cellular infiltration, phagocytic
Hypocorticism: diminished work capacity and activity and late responses like capillary prolife-
weakness are primarily due to hypodynamic ration, collagen deposition, fibroblastic activity
circulation. and ultimately scar formation. This action is
Hypercorticism: excess mineralocorticoid action direct and can be restricted to a site by local
→ hypokalaemia → weakness;
administration. The cardinal signs of inflam-
Excess glucocorticoid action → muscle wasting
mation—redness, heat, swelling and pain are
and myopathy → weakness.
suppressed.
7. CNS Mild euphoria is quite common with Glucocorticoids interfere at several steps
pharmacological doses of glucocorticoids. This in the inflammatory response (see cellular
286 HORMONES AND RELATED DRUGS

mechanism below), but the most important overall with practically every step of the immunological
mechanism appears to be limitation of recruitment response, but at therapeutic doses in vivo there
of inflammatory cells at the local site and is no impairment of antibody production or comp-
production of proinflammatory mediators like lement function. The clinical effect appears to
PGs, LTs, PAF through indirect inhibition of be due to suppression of recruitment of leukocytes
phospholipase A2. at the site of contact with antigen and of
Corticoids are only palliative; do not remove inflammatory response to the immunological injury.
the cause of inflammation; the underlying disease Glucocorticoids cause greater suppression of
continues to progress while manifestations are CMI in which T cells are primarily involved, e.g.
dampened. They favour spread of infections because delayed hypersensitivity and graft rejection. This
capacity of defensive cells to kill microorganisms is the basis of their use in autoimmune diseases
is impaired. They also interfere with healing and and organ transplantation (see Ch. 63). Factors
scar formation: peptic ulcer may perforate asymp- involved may be inhibition of IL-1 release from
tomatically. Indiscriminate use of corticoids is macrophages; inhibition of IL-2 formation and
hazardous. action → T cell proliferation is not stimulated;
11. Immunological and allergic responses suppression of natural killer cells, etc.
Glucocorticoids impair immunological compe- The broad action seems to be interruption of
tence. They suppress all types of hypersensitization communication between cells involved in the
and allergic phenomena. At high concentrations immune process by interfering with production
and in vitro they have been shown to interfere of or action of lymphokines.

Gene mediated cellular actions of glucocorticoids

Mechanism Action
• Translocation of glucose transporters from plasma • ↓ glucose uptake and utilization in peripheral
membrane to deeper sites. tissues.
• Induction of hepatic gluconeogenetic enzymes. • ↑ production of glucose from amino acids.
• Induction of hepatic glycogen synthase. • Deposition of glycogen in hepatocytes.
• Site specific changes in sensitivity of adipocytes • Altered distribution of body fat.
to GH, Adr, insulin.
• ↑ expression of vascular adrenergic and AT1 receptor. • Enhanced reactivity to vasopressor substances.
SECTION 5

• ↓ expression of POMC gene in pituitary corticotropes • ↓ production of ACTH.

Antiinflammatory and Immunosuppressant actions
• Induction of annexins in macrophages, • Annexins inhibit phospholipase A2 → decreased
endothelium and fibroblasts. production of PGs, LTs & PAF.
• Negative regulation of COX-2 • ↓ inducible PG production.
• Negative regulation of genes for cytokines in • ↓ production of IL-1, IL-2, IL-3, IL-6, TNFα,
macrophages, endothelial cells and lymphocytes. GM-CSF, γ interferon → fibroblast proliferation
and T-lymphocyte function are suppressed,
chemotaxis interfered.
• ↓ production of acute phase reactants from • Complement function is interfered.
macrophages and endothelial cells
• ↓ production of ELAM-1 and ICAM-1 in • Adhesion and localization of leukocytes is interfered.
endothelial cells.
• ↓ expression of transcription factors • ↓ histone acetylation
AP-1, NF-κB • ↓ MAP kinase
• ↓ production of collagenase and stromolysin • Prevention of tissue destruction
POMC—Proopiomelanocortin; IL—Interleukin; TNFα—Tumour necrosis factor α; GM-CSF—Granulocyte macrophage
colony stimulating factor; ELAM-1—Endothelial leukocyte adhesion molecule-1; ICAM-1—Intracellular adhesion
molecule-1; AP-1–Activator protein-1; NF-κB–Nuclear factor κB; MAP kinase–Mitogen activated protein kinase.
 CORTICOSTEROIDS 287

Mechanism of action at cellular level or i.m., act rapidly and achieve high concentra-
Corticosteroids penetrate cells and bind to a high tions in tissue fluids. Insoluble esters, e.g. hydro-
affinity cytoplasmic receptor protein → a struc- cortisone acetate, triamcinolone acetonide cannot
tural change occurs in the steroid receptor comp- be injected i.v., but are slowly absorbed from
lex that allows its migration into the nucleus and i.m. site and produce more prolonged effects.
binding to glucocorticoid response elements Hydrocortisone undergoes high first pass meta-
(GRE) on the chromatin → transcription of bolism, has low oral: parenteral activity ratio. Oral
specific m-RNA → regulation of protein synthesis bioavailability of synthetic corticoids is high.
(see Fig. 4.10). This process takes at least 30– Hydrocortisone is 90% bound to plasma
60 min : effects of corticosteroid are not protein, mostly to a specific cortisol-binding
immediate, and once the appropriate proteins are globulin (CBG; transcortin) as well as to albumin.
synthesized—effects persist much longer than the Transcortin concentration is increased during
steroid itself. In many tissues, the overall effect pregnancy and by oral contraceptives—corticoid
is catabolic, i.e. inhibition of protein synthesis. levels in blood are increased but hypercorticism
This may be a consequence of steroid directed does not occur, because free cortisol levels are
synthesis of an inhibitory protein. normal.
The glucocorticoid receptor (GR) is very The corticosteroids are metabolized primarily
widely distributed (in practically all cells). It has by hepatic microsomal enzymes. Pathways are—
been cloned and its structure determined. It is (i) Reduction of 4, 5 double bond and hydroxy-
made up of ~ 800 amino acids. lation of 3-keto group.
Several coactivators and corepressors modulate the interaction (ii) Reduction of 20-keto to 20-hydroxy form.
of liganded GR with the GREs, altering the intensity of (iii) Oxidative cleavage of 20C side chain (only
response. in case of compounds having a 17-hydroxyl
Because the GR largely maintains uniformity throughout the
body, tissue specificity is not exhibited by different
group) to yield 17-ketosteroids.
glucocorticoids, and all members produce the same These metabolites are further conjugated with
constellation of effects. glucuronic acid or sulfate and are excreted in
The functional scheme of GR is presented in Fig. urine.
4.10. Direct evidence of gene expression mediated The plasma t½ of hydrocortisone is 1.5 hours.
action has been obtained for actions listed in the However, the biological t½ is longer because of

CHAPTER 20
box (see p. 286). action through intracellular receptors and regu-
Some actions of corticoids are exerted more lation of protein synthesis—effects that persist
rapidly (like inhibition of ACTH release from long after the steroid is removed from plasma.
pituitary). These may be mediated by a cell The synthetic derivatives are more resistant
membrane receptor or a different mechanism not to metabolism and are longer acting.
involving protein synthesis. Phenobarbitone and phenytoin induce meta-
bolism of hydrocortisone, prednisolone and dexa-
methasone, etc. to decrease their therapeutic effect.
PHARMACOKINETICS
All natural and synthetic corticoids, except DOCA
CHEMISTRY AND RELATIVE ACTIVITY
are absorbed and are effective by the oral route.
OF CORTICOIDS
Absorption into systemic circulation occurs from
topical sites of application as well, but the extent Fig. 20.3 depicts the chemical structure of desoxy-
varies depending on the compound, site, area of corticosterone in blue line. It is a selective mineralo-
application and use of occlusive dressing. Water corticoid. Chemical modifications that result in
soluble esters, e.g. hydrocortisone hemisuccinate, clinically useful compounds are also indicated.
dexamethasone sod. phosphate can be given i.v. Fluorination at position 9 or 6 has resulted in
288 HORMONES AND RELATED DRUGS

Fig. 20.3: Chemical structure of corticosteroids. The structure in blue is desoxycorticosterone.

Important substitutions which yield other useful compounds are shown in red
+ OH at 11 — Corticosterone
+ OH at 11 + OH at 17 — Hydrocortisone
(if O at 11) + OH at 17 — Cortisone
+ OH at 11 + OH at 17 + Δ 1, 2 — Prednisolone
+ OH at 11 + OH at 17 + Δ 1, 2 + F at 9 + OH at 16 — Triamcinolone
+ OH at 11 + OH at 17 + Δ 1, 2 + F at 9 + CH3 α at 16 — Dexamethasone
+ OH at 11 + OH at 17 + Δ 1, 2 + F at 9 + CH3 β at 16 — Betamethasone
Hydrocortisone + F at 9 — Fludrocortisone
Corticosterone + CHO at 18 — Aldosterone

highly potent compounds. Synthetic steroids have LYCORTIN-S, EFCORLIN SOLUBLE 100 mg/2 ml inj. (as
largely replaced the natural compounds in hemisuccinate for i.v. inj.) WYCORT, EFCORLIN 25 mg/ml
inj (as acetate for i.m./intraarticular inj.). PRIMACORT 100,
therapeutic use, because they are potent, longer 200, 400 mg/vial inj.
acting, more selective for either glucocorticoid
or mineralocorticoid action and have high oral 2. Prednisolone It is 4 times more potent
activity. than hydrocortisone, also more selective gluco-
SECTION 5

corticoid, but fluid retention does occur with high

DISTINCTIVE FEATURES doses. Has intermediate duration of action: causes
The relative potency and activity of different less pituitary-adrenal suppression when a single
natural and synthetic corticosteroids employed morning dose or alternate day treatment is given.
systemically is compared in Table 20.1. Used for allergic, inflammatory, autoimmune
diseases and in malignancies: 5–60 mg/day oral,
1. Hydrocortisone (cortisol) Acts rapidly 10–40 mg i.m., intraarticular; also topically.
but has short duration of action. In addition to DELTACORTRIL, HOSTACORTIN-H, 5, 10 mg tab, 20 mg/
primary glucocorticoid, it has significant minera- ml (as acetate) for i.m., intraarticular inj., WYSOLONE,
NUCORT, 5, 10, 20, 30, 40 mg tabs.
locorticoid activity as well. Used for:
Replacement therapy—20 mg morning + 10 mg 3. Methylprednisolone Slightly more potent
afternoon orally. and more selective than prednisolone: 4–32 mg/
Shock, status asthmaticus, acute adrenal insuf- day oral. Methylprednisolone acetate has been
ficiency—100 mg i.v. bolus + 100 mg 8 hourly used as a retention enema in ulcerative colitis.
i.v. infusion. Pulse therapy with high dose methylpredni-
Topically (see Ch. 64) and as suspension for solone (1 g infused i.v. every 6–8 weeks) has
enema in ulcerative colitis (see Ch. 48). been tried in nonresponsive active rheumatoid
 CORTICOSTEROIDS 289

TABLE 20.1 Relative activity of systemic corticosteroids

Compound Gluco Mineralo Equiv. dose

(antiinflammatory)
Short acting 1. Hydrocortisone 1 1 20 mg
(Biological (cortisol)
t½ < 12 hr)
GLUCOCORTICOIDS

Intermediate 2. Prednisolone 4 0.8 5 mg

acting 3. Methyl- 5 0.5 4 mg
(Biological prednisolone
t½ 12–36 hr) 4. Triamcinolone 5 0 4 mg
5. Deflazacort 3–4 0 6 mg
Long acting 6. Dexamethasone 25 0 0.75 mg
(Biological 7. Betamethasone 25 0 0.75 mg
t½ > 36 hr)

Equiv. salt
CORTICOIDS

retaining dose
MINERALO-

8. Desoxycortico- 0 100 2.5 mg

sterone acetate (DOCA) (sublingual)
9. Fludrocortisone 10 150 0.2 mg
10. Aldosterone 0.3 3000 not used clinically

arthritis, renal transplant, pemphigus, etc. with DECADRON, DEXONA 0.5 mg tab, 4 mg/ml (as sod.
phosphate) for i.v., i.m. inj., 0.5 mg/ml oral drops;
good results and minimal suppression of pituitary-
WYMESONE, DECDAN 0.5 mg tab, 4 mg/ml inj.
adrenal axis.
SOLU-MEDROL Methylprednisolone (as sod. succinate) 6. Betamethasone Similar to dexamethasone,
4 mg tab; 40 mg, 125 mg, 0.5 g (8 ml) and 1.0 g (16
ml) inj, for i.m. or slow i.v. inj, DEESOLONE 4, 16 mg
0.5–5 mg/ day oral, 4–20 mg i.m., i.v. injection
tabs, 0.5 g and 1.0 g. inj. or infusion, also topical.
BETNESOL, BETACORTRIL, CELESTONE 0.5 mg, 1 mg
The initial effect of methylprednisolone pulse therapy (MPPT)
tab, 4 mg/ml (as sod. phosphate) for i.v., i.m. inj., 0.5 mg/ml
is probably due to its antiinflammatory action, while long

CHAPTER 20
oral drops. BETNELAN 0.5 mg, 1 mg tabs.
term benefit may be due to temporary switching off of the
immunodamaging processes as a consequence of lymphopenia Dexamethasone or betamethasone are prefer-
and decreased Ig synthesis. red in cerebral edema and other states in which
fluid retention must be avoided.
4. Triamcinolone Slightly more potent than
prednisolone but highly selective glucocorticoid: 7. Deflazacort The glucocorticoid potency of
4–32 mg/day oral, 5–40 mg i.m., intraarticular this newer steroid is somewhat less than of
injection. Also used topically. prednisolone, but it lacks mineralocorticoid
KENACORT, TRICORT 1, 4, 8 mg tab., 10 mg/ml, 40 mg/ml
(as acetonide) for i.m., intraarticular inj., LEDERCORT 4 mg tab. activity. It is claimed to produce fewer adverse
effects, but that may be due to its lower potency.
5. Dexamethasone Very potent and highly In some trials it caused lesser growth retardation
selective glucocorticoid. It is also long-acting, in children; has been particularly recommended
causes marked pituitary-adrenal suppression, but for pediatric patients. It is used mainly for
fluid retention and hypertension are not a problem. inflammatory and immunological disorders.
It is used for inflammatory and allergic condi- Dose: 60–120 mg/day initially, 6–18 mg/day for maintenance;
tions 0.5–5 mg/day oral. For shock, cerebral children 0.25–1.5 mg/kg daily or on alternate days.
edema, etc. 4–20 mg/day i.v. infusion or i.m. DEFGLU 6, 30 mg tabs, DEFLAR, DEFZA, DFZ 1, 6, 30 mg
injection is preferred. It can also be used topically. tabs.
290 HORMONES AND RELATED DRUGS

8. Desoxycorticosterone acetate (DOCA) It has only 3. Congenital adrenal hyperplasia (Adreno-

mineralocorticoid activity. Used occasionally for replacement
genital syndrome) It is a familial disorder due
therapy in Addison’s disease: 2–5 mg sublingual,
10–20 mg i.m. once or twice weekly. to genetic deficiency of steroidogenic enzymes,
In DOCABOLIN 10 mg/ml inj (along with nandrolone). mostly 21-hydroxylase. As a result the synthesis
of hydrocortisone and aldosterone suffers. There
9. Fludrocortisone A potent mineralocorti- is compensatory increase in ACTH secretion—
coid having some glucocorticoid activity as well, adrenals hypertrophy; enzyme deficiency being
orally active, used for: only partial in most cases, normal amounts of
Replacement therapy in Addison’s disease 50–200 µg daily.
Congenital adrenal hyperplasia in patients with salt wasting gluco- and mineralocorticoids are produced along
50–200 µg/day. with excessive amounts of weak androgens →
Idiopathic postural hypotension 100–200 µg/day. virilization and/or precocious sexual development.
FLORICORT 100 µg tab.
If the deficiency is severe, salt wasting also occurs.
10. Aldosterone It is the most potent mineralocorticoid. Treatment is to give hydrocortisone 0.6 mg/
Not used clinically because of low oral bioavailability and kg daily in divided doses round the clock to
difficulties in regulating doses. maintain feed back suppression of pituitary. If
In addition a number of topically active salt wasting persists—fludrocortisone 50–200 µg/
glucocorticoids have been developed. day may be added.
Beclomethasone dipropionate budesonide,
fluticasone, etc. are used by inhalation in asthma, B. Pharmacotherapy
as spray in nasal allergy, as well as for skin and (for nonendocrine diseases)
mucous membrane lesions (see Ch. 16).
Fluocinolone acetonide, fluocortolone, clo- Systemic as well as topical corticosteroids have
one of the widest spectrum of medicinal uses for
betasol propionate and esters of betamethasone,
their antiinflammatory and immunosuppressive
dexamethasone, triamcinolone are described in
properties. Corticosteroids are powerful drugs.
Ch. 64.
They have the potential to cause dramatic
improvement in many severe diseases as well as
USES
produce equally dramatic adverse effects if not
A. Replacement therapy properly used. The use in nonendocrine diseases
1. Acute adrenal insufficiency It is an emer- is empirical and palliative, but may be life saving.
SECTION 5

gency. Hydrocortisone or dexamethasone are The following general principles must be

given i.v., first as a bolus injection and then as observed.
infusion, along with isotonic saline and glucose (a) A single dose (even excessive) is not harmful:
solution. The amount of fluid infused i.v. is guided can be used to tide over mortal crisis, even when
benefit is not certain.
by monitoring central venous pressure, because
(b) Short courses (even high dose) are not likely
these patients have reduced capacity to excrete
to be harmful in the absence of contraindications;
water load. Short-term i.v. infusion of a
starting doses can be high in severe illness.
vasopressor (dopamine) may be needed. The cause
(c) Long-term use is potentially hazardous: keep
of adrenal insufficiency should be treated.
the duration of treatment and dose to minimum,
2. Chronic adrenal insufficiency (Addison’s which is found by trial and error; even partial
disease) Hydrocortisone given orally is the relief may have to be tolerated.
most commonly used drug along with adequate (d) Initial dose depends on severity of the disease;
salt and water allowance. Some patients who start with a high dose in severe illness—reduce
continue to excrete excess Na+ need additional gradually after symptoms subside, while in mild
mineralocorticoid: fludrocortisone is added. cases start with the lowest dose and titrate upwards
 CORTICOSTEROIDS 291

to find the correct dose. The dose should be 3. Severe allergic reactions Corticoids may
reassessed from time-to-time. be used for short periods in anaphylaxis, angioneu-
(e) No abrupt withdrawal after a corticoid has rotic edema, urticaria and serum sickness.
been given for > 2 to 3 weeks: may precipitate However, even i.v. injection of a glucocorticoid
adrenal insufficiency. takes 1–2 hours to act and is not a substitute
(f) Infection, severe trauma, surgery or any stress for Adr (which acts immediately) in anaphylactic
during corticoid therapy—increase the dose. shock and angioedema of larynx. Topical use is
(g) Use local therapy (cutaneous, inhaled, intra- made in allergic conjunctivitis and rhinitis.
nasal, etc) wherever possible.
4. Autoimmune diseases Autoimmune
1. Arthritides haemolytic anaemia, idiopathic thrombocytopenic
(i) Rheumatoid arthritis: Corticosteroids are purpura, active chronic hepatitis respond to
indicated only in severe cases as adjuvants to corticoids. Prednisolone 1–2 mg/kg/day is given
NSAIDs when distress and disability persists till remission, followed by gradual withdrawal or
despite other measures, or to suppress exacer- low-dose maintenance depending on the response.
bations, or when there are systemic manifestations Remission may also be induced in severe cases
(see Ch. 15). of myasthenia gravis, in which their use is
(ii) Osteoarthritis: It is treated with analgesics adjunctive to neostigmine. Patients requiring long
and NSAIDs; systemic use of corticoids is rare. term maintenance therapy are better shifted to
Intraarticular injection of a steroid may be used
other immunosuppressants.
to control an acute exacerbation. Injections may
be repeated 2–3 times a year, but have the potential 5. Bronchial asthma Early institution of
to cause joint destruction. inhaled glucocorticoid therapy is now recom-
(iii) Rheumatic fever: Corticoids are used only mended in most cases needing inhaled β2 agonists
in severe cases with carditis and CHF with the almost daily (see Ch. 16). Systemic corticosteroids
aim of rapid suppression of symptoms, because are used only for:
they act faster than aspirin, or in patients not • Status asthmaticus: give i.v. glucocorticoid;
responding to aspirin. Aspirin is given in addition withdraw when emergency is over.
and is continued after corticoids have been • Actue asthma exacerbation: short-course of
withdrawn. high dose oral corticoid, followed by gradual

CHAPTER 20
(iv) Gout: Corticoids (short course) should only withdrawal.
be used in acute gouty arthritis when NSAIDs • Severe chronic asthma not controlled by
have failed to afford relief and colchicine is not inhaled steroids and bronchodilators: add low
tolerated. Intraarticular injection of a soluble dose prednisolone daily or on alternate days.
glucocorticoid is preferable to systemic therapy
(see p. 214). 6. Other lung diseases Corticosteroids
Though they are uricosuric—use in chronic benefit aspiration pneumonia and pulmonary
gout is not recommended. edema from drowning. Given during late
pregnancy, corticoids accelerate lung maturation
2. Collagen diseases Most cases of systemic
and surfactant production in the foetal lung and
lupus erythematosus, polyarteritis nodosa, derma-
prevent respiratory distress syndrome at birth. Two
tomyositis, nephrotic syndrome, glomerulo-
doses of betamethasone 12 mg i.m. at 24 hour
nephritis and related diseases need corticosteroid
interval may be administered to the mother if
therapy. They may be life saving in these diseases.
premature delivery is contemplated.
Therapy is generally started with high doses which
are tapered to maintenance dose when remission 7. Infective diseases Administered under
occurs. Later other immunosuppressants may be effective chemotherapeutic cover, corticosteroids
added or substituted. are indicated only in serious infective diseases
292 HORMONES AND RELATED DRUGS

to tideover crisis or to prevent complications. They tic and poststroke cerebral edema is questionable.
are indicated in conditions like severe forms of Large doses given i.v. soon after spinal injury
tuberculosis (miliary, meningeal, renal, etc.), may reduce the resulting neurological sequelae.
severe lepra reaction, certain forms of bacterial A short course (2–4 weeks) of oral
meningitis and Pneumocystis carinii pneumonia prednisolone can hasten recovery from Bell’s palsy
with hypoxia in AIDS patients. and acute exacerbation of multiple sclerosis. In
the latter, methyl prednisolone 1 g i.v. daily for
8. Eye diseases Corticoids are used in a large 2–3 days may be given in the beginning.
number of inflammatory ocular diseases—may
prevent blindness. Topical instillation as eye Neurocysticercosis: When albendazole/prazi-
drops or ointment is effective in diseases of the quantel is used to kill cysticerci lodged in the
anterior chamber—allergic conjunctivitis, iritis, brain, prednisolone 40 mg/day or equivalent is
iridocyclitis, keratitis, etc. Ordinarily, steroids given for 2–4 weeks to suppress the reaction to
should not be used in infective conditions. But the dying larvae.
if inflammation is severe, they may be applied
12. Malignancies Corticoids are an essential
in conjunction with an effective antibiotic.
component of combined chemotherapy of acute
Steroids are contraindicated in herpes simplex
lymphatic leukaemia, Hodgkin’s and other
keratitis and in ocular injuries. Posterior segment
lymphomas, because of their marked lympholytic
afflictions like retinitis, optic neuritis, uveitis action in these conditions. They have a secondary
require systemic steroid therapy. Retrobulbar place in hormone responsive breast carcinoma—
injection is occasionally given to avoid systemic act probably by causing HPA suppression so as
side effects. to reduce production of adrenal androgens which
9. Skin diseases (see Ch. 64) Topical are converted to estrogens in the body (see Ch.
corticosteroids are widely employed and are highly 62).
effective in many eczematous skin diseases. Corticoids also afford symptomatic relief in
Systemic therapy is needed (may be life-saving) other advanced malignancies by improving
in pemphigus vulgaris, exfoliative dermatitis, appetite and controlling secondary hypercalcae-
Stevens-Johnson syndrome and other severe mia. For hypercalcaemia, however, bisphos-
afflictions. phonates are more effective and have superseded
SECTION 5

corticosteroids.
10. Intestinal diseases Ulcerative colitis,
13. Organ transplantation and skin allograft
Crohn’s disease, coeliac disease are inflammatory
High dose corticoids are given along with other
bowel diseases with exacerbations and remissions.
immunosuppressants to prevent the rejection
Corticoids are indicated during acute phases—
reaction. Low maintenance doses are generally
may be used orally or as retention enema (for
continued over long term + maintenance doses
colonic involvement). They are particularly
of companion drugs. (see Ch. 63).
valuable for patients with systemic manifestions,
and are given in addition to sulfasalazine/ 14. Septic shock High-dose corticosteroid
mesalazine + other measures (see Ch. 48). Some therapy for septic shock has been abandoned,
specialists advocate small maintenance doses to because it worsens the outcome. However, many
prevent relapses. such patients have relative adrenal insufficiency.
Recent studies have documented beneficial effects
11. Cerebral edema due to tumours, tubercular of low-dose (hydrocortisone 100 mg 8 hourly i.v.
meningitis, etc., responds to corticoids. Dexa-or infusion for 5–7 days) therapy in patients who
betamethasone are preferred because they donot are adrenal deficient and do not respond
have Na+ retaining activity. Their value in trauma- adequately to fluid replacement and vasopressors.
 CORTICOSTEROIDS 293

15. Thyroid storm Many patients in thyroid 6. Delayed healing: of wounds and surgical
storm have concomitant adrenal insufficiency. incisions.
Moreover, corticosteroids reduce peripheral T4 7. Peptic ulceration: risk is doubled; bleeding
to T3 conversion. Hydrocortisone 100 mg i.v. 8 and silent perforation of ulcers may occur.
hourly may improve outcome. Dyspeptic symptoms are frequent with high
16. To test pituitary-adrenal axis function dose therapy.
Dexamethasone suppresses pituitary-adrenal axis 8. Osteoporosis: especially involving vertebrae
at doses which do not contribute to steroid and other flat spongy bones. Compression
metabolites in urine. Responsiveness of the axis fractures of vertebrae and spontaneous frac-
can be tested by measuring daily urinary steroid ture of long bones can occur, especially in
metabolite excretion after dosing with the elderly. Radiological evidence of osteo-
dexamethasone. porosis is an indication for withdrawal of
corticoid therapy. Corticosteroid induced
ADVERSE EFFECTS osteoporosis can be prevented/arrested by
calcium supplements + vit D, and by
These are extension of the pharmacological action estrogen/raloxifene or androgen replacement
which become prominent with prolonged therapy, therapy in females and males respectively.
and are a great limitation to the use of corticoids However, bisphosphonates are the most
in chronic diseases. effective drugs in this regard.
A. Mineralocorticoid Sodium and water Avascular necrosis of head of femur,
retention, edema, hypokalaemic alkalosis and a humerous, or knee joint is an occasional
abrupt onset complication of high dose
progressive rise in BP. These are now rare due
to availability of highly selective glucocorticoids. corticosteroid therapy.
Gradual rise in BP occurs due to excess 9. Posterior subcapsular cataract may develop
after several years of use, especially in
glucocorticoid action as well.
children.
B. Glucocorticoid 10. Glaucoma: may develop in susceptible
1. Cushing’s habitus: characteristic appearance individuals after prolonged topical therapy.
with rounded face, narrow mouth, supra- 11. Growth retardation: in children occurs even
clavicular hump, obesity of trunk with with small doses if given for long periods.

CHAPTER 20
relatively thin limbs. Large doses do inhibit GH secretion, but
2. Fragile skin, purple striae—typically on growth retardation may, in addition, be a
thighs and lower abdomen, easy bruising, direct cellular effect of corticoids. Recombi-
telangiectasis, hirsutism. Cutaneous atrophy nant GH given concurrently can prevent
localized to the site occurs with topical growth retardation, but risk/benefit of such
application as well. use is not known.
3. Hyperglycaemia, may be glycosuria, preci- 12. Foetal abnormalities: Cleft palate and other
pitation of diabetes. defects are produced in animals, but have
4. Muscular weakness: proximal (shoulder, not been encountered on clinical use in
arm, pelvis, thigh) muscles are primarily pregnant women. The risk of abortion, still-
affected. Myopathy occurs occasionally, birth or neonatal death is not increased, but
warrants withdrawal of the corticoids. intrauterine growth retardation can occur
5. Susceptibility to infection: this is nonspeci- after prolonged therapy, and neurological/
fic for all types of pathogenic organisms. behavioral disturbances in the offspring are
Latent tuberculosis may flare; opportunistic feared. Prednisolone appears safer than dexa/
infections with low grade pathogens beta methasone, because it is metabolized
(Candida, etc.) set in. by placenta, reducing foetal exposure. There
294 HORMONES AND RELATED DRUGS

is no evidence of foetal growth retardation operative and postoperative i.v. hydrocortisone

occurring after short term use in the mother. till the condition stabilizes, followed by oral
Prolonged corticosteroid therapy during prednisolone.
pregnancy increases the risk of gestational Measures that minimise HPA axis suppression are:
diabetes, pregnancy induced hypertension (a) Use shorter acting steroids (hydrocortisone,
and preeclampsia. prednisolone) at the lowest possible dose.
13. Psychiatric disturbances: mild euphoria (b) Use steroids for the shortest period of time
frequently accompanies high dose steroid possible.
treatment. This may rarely progress to manic (c) Give the entire daily dose at one time in the
psychosis. Nervousness, decreased sleep and morning.
mood changes occur in some patients. (d) Switch to alternate-day therapy if possible.
Rarely a depressive illness may be induced It has been found that moderate dose of a short acting steroid
after long-term use. (e.g. prednisolone) given at 48 hr interval did not cause
14. Suppression of hypothalamo-pituitary-adre- HPA suppression, whereas the same total amount given in
4 divided 12 hourly doses produced marked HPA suppression.
nal (HPA) axis: occurs depending both on Alternate-day therapy also resulted in less immunological
dose and duration of therapy. In time, suppression—lower risk of infection. The longer acting
adrenal cortex atrophies and stoppage of steroids (dexamethasone, etc.) are not suitable for alternate-
exogenous steroid precipitates withdrawal day therapy. Only problem with alternate-day therapy is that
many steroid dependent patients are incapacitated on the
syndrome consisting of malaise, fever, ‘off day’.
anorexia, nausea, postural hypotension,
electrolyte imbalance, weakness, pain in (e) If appropriate, use local (dermal, inhaled, ocu-
muscles and joints and reactivation of the lar, nasal, rectal, intrasynovial) preparations
disease for which they were used. Subjected of a steroid with poor systemic availability
to stress, these patients may go into acute (beclomethasone, triamcinolone acetonide,
fluticasone, etc.)
adrenal insufficiency leading to cardiovas-
cular collapse.
Any patient who has received > 20–25 mg/ CONTRAINDICATIONS
day hydrocortisone, or ≥ 5 mg prednisolone/day The following diseases are aggravated by corti-
or equivalent for longer than 2–3 weeks should costeroids. Since corticosteroids may have to be
SECTION 5

be put on a scheme of gradual withdrawal: 20 used as a life-saving measure, all of these are
mg hydrocortisone/ day reduction every week and relative contraindications in the presence of which
then still smaller fractions once this level has been these drugs are to be employed only under
achieved. Such patients may need protection with compelling circumstances and with due
a corticosteroid (oral or i.v.) if a stressful situation precautions.
develops up to one year after withdrawal. 1. Peptic ulcer
Administration of ACTH during withdrawal does 2. Diabetes mellitus
not hasten recovery because it has been found 3. Hypertension
that adrenals recover earlier than pituitary and 4. Viral and fungal infections
hypothalamus. 5. Tuberculosis and other infections
If a patient on steroid therapy develops an 6. Osteoporosis
infection—the steroid should not be discontinued 7. Herpes simplex keratitis
despite its propensity to weaken host defence and 8. Psychosis
delay healing. Rather, the dose may have to be 9. Epilepsy
increased to meet the stress of infection. Surgery 10. CHF
is such a patient should be covered by intra- 11. Renal failure
 CORTICOSTEROIDS 295

Combination of any other drug with cortico- enzymes—can be used to treat Cushing’s disease when surgery
steroids in fixed dose formulation for internal use or other measures are not an option. Ketoconazole reduces
gonadal steroid synthesis as well.
is banned.
Glucocorticoid antagonist The antiprogestin mifepri-
Metyrapone Inhibits 11-β hydroxylase in adrenal cortex
stone (see p. 319–20) acts as a glucocorticoid receptor
and prevents synthesis of hydrocortisone so that its blood
antagonist as well. In Cushing’s syndrome, it can suppress the
level falls → increased ACTH release → increased synthesis,
manifestations of corticosteroid excess, but blockade of feedback
release and excretion of 11-desoxycortisol in urine. Thus,
ACTH inhibition leads to oversecretion of ACTH → more
it is used to test the responsiveness of pituitary and its ACTH
hydrocortisone is produced, which tends to annul the GR
producing capacity.
blocking action of mifepristone. It is indicated only for
Aminoglutethimide, trilostane and high doses of the anti- inoperable cases of adrenal carcinoma and in patients with
fungal drug Ketoconazole also inhibit steroidogenic ectopic ACTH secretion.

) PROBLEM DIRECTED STUDY

20.1 A 35-year female patient of inflammatory bowel disease was treated with prednisolone
40 mg/day and mesalazine 800 mg TDS. After 4 weeks, the symptoms subsided and prednisolone
dose was tapered at the rate of 10 mg every 2 weeks. When she was taking 10 mg prednisolone/
day, she met with a road-side accident and suffered compound fracture of both bones of the
right leg. Internal fixation of the fracture and suturing of wounds under general anaesthesia
is planned.
(a) Whether any additional measure needs to be taken during surgery in view of her corticosteroid
therapy?
(b) Does the prednisolone therapy need discontinuation or any alteration in the postoperative
period? Give reasons.
(see Appendix-1 for solution)

CHAPTER 20
Chapter 21 Androgens and Drugs for
Erectile Dysfunction

ANDROGENS produce significant quantity of testosterone. In

(Male Sex Hormones) women ovary produces small quantity of testo-
sterone; this together with that derived indirectly
These are substances which cause development
from adrenals amounts to 0.25–0.5 mg/day.
of secondary sex characters in the castrated male.
That testes are responsible for the male characters Androsterone It is a metabolite of testosterone
is known since prehistoric times. Its endocrine which is excreted in urine. It has 1/10 the activity
function was established by Berthold in 1849. of testosterone.
Testosterone was isolated as the testicular
Synthetic androgens Methyltestosterone and
hormone, its structure was worked out and it was
fluoxymesterone are 17-alkyl substituted deriva-
synthetically prepared by the year 1935.
tives of testosterone which are orally active
Natural androgens Testes of adult male pro- because of resistance to first pass metabolism,
duce 5–12 mg of testosterone daily, a part of but have submaximal androgenic efficacy and
which is converted in extraglandular tissues to potential to cause cholestatic jaundice. Other
the more active dihydrotestosterone (DHT); by orally active compounds are testosterone
the enzyme steroid 5 α-reductase; cholesterol is undecanoate which is administered as oily solution
the starting material and the same pathway to be absorbed through lymphatics bypassing the
depicted in Fig. 20.1 is utilized. Adrenal cortex liver, and mesterolone. A number of lipid-soluble
produces small quantities of dehydroepiandro- esters of testosterone have been produced, suitable
sterone and androstenedione which are called for injection in oily vehicle, from which they are
‘weak androgens’ (potency 1/20 to 1/30), but are absorbed slowly and exert prolonged action after
infact inactive as such and derive their weak deesterification in the body.
activity from partial conversion to testosterone
in peripheral tissues. Adrenals themselves do not Regulation of secretion
Testosterone is secreted by the interstitial (Leydig)
cells of the testes under the influence of pulsatile
secretion of LH from pituitary. FSH is mainly
responsible for promotion of spermatogenesis in
tubular (Sertoli) cells. The mediator of feedback
relationship with pituitary is uncertain. While
relatively high concentration of testosterone
inhibits LH secretion and in time causes atrophy
of interstitial cells, it has only weak inhibitory
action on FSH secretion. Estrogens are more
potent inhibitors of Gn secretion even in males,
and it is believed that the small amount of estradiol
produced by testes as well as that resulting from
conversion of testosterone to estradiol in liver
and fat plays a role in feedback inhibition. Inhibin,
 ANDROGENS AND DRUGS FOR ERECTILE DYSFUNCTION 297

ACTIONS
1. Sex organs and secondary sex
characters (Androgenic) Testosterone is
responsible for all the changes that occur in a
boy at puberty:
Growth of genitals—penis, scrotum, seminal
vesicles, prostate.
Growth of hair—pubic, axillary, beard, moust-
ache, body hair and male pattern of its distribution.
Thickening of skin which becomes greasy due
to proliferation and increased activity of seba-
ceous glands—especially on the face. The duct
often gets blocked and infection occurs resulting
in acne. Subcutaneous fat is lost and veins look
prominent.
Larynx grows and voice deepens.
Behavioral effects are—increased physical vigour,
aggressiveness, penile erections. Male libido
appears to be activated by testosterone directly,
and probably to a greater extent by estradiol
produced from testosterone.
Testosterone is also important for the intrauterine
development of the male phenotype. Relatively
large amounts of testosterone are produced by
the foetal testes during the first half of intrauterine
life.
Fig. 21.1: Regulation and production of sex steroids in
the male. 2. Testes Moderately large doses cause testi-
In liver and many target cells 5α-reductase enzyme cular atrophy by inhibiting Gn secretion from

CHAPTER 21
converts testosterone to the more potent androgen
dihydrotestosterone (DHT) which combines more avidly
pituitary. Still larger doses have a direct sustain-
with the androgen receptor (AR). The aromatase enzyme ing effect and atrophy is less marked. Testoste-
in testes, liver and adipose tissue converts some rone is needed for normal spermatogenesis and
testosterone into estradiol which exerts certain actions maturation of spermatozoa. High concentration
in male target cells by combining with estrogen receptor
(ER) and is probably important for feedback inhibition of
of testosterone is attained locally in the spermato-
gonadotropins (LH/FSH) as well as that of gonadotropin genic tubules by diffusion from the neighbouring
releasing hormone (GnRH) from hypothalamus. Leydig cells and stimulates spermatogenesis.
(a protein) produced by Sertoli cells, has strong 3. Skeleton and skeletal muscles
FSH inhibitory action and may be mediating the (Anabolic) Testosterone is responsible for the
feedback inhibition. Testosterone and estradiol act pubertal spurt of growth in boys and to a smaller
on hypothalamus to reduce GnRH as well as act extent in girls. There is rapid bone growth, both
directly on pituitary. The plasma level of in thickness as well as in length. After puberty,
testosterone in adult males ranges from 0.3 to the epiphyses fuse and linear growth comes to
1 µg/dl. In women, small amounts of testosterone a halt. Estradiol produced from testosterone, and
are produced by corpus luteum and adrenal cortex; not testosterone itself, is responsible for fusion
blood levels remain low (20–60 ng/dl). of epiphyses in boys as well as in girls. Moreover,
298 HORMONES AND RELATED DRUGS

estradiol largely mediates the effect of testosterone tract of male contains 5α- reductase-2 which is more sensitive
on bone mineralization. Testosterone also promotes to inhibition by finasteride. Genetic deficiency of this isoenzyme
causes male pseudohermaphroditism because of inability of
muscle building, especially if aided by exercise. male genitalia to produce the active hormone dihydro-
There is accretion of nitrogen, minerals (Na, K, testosterone from circulating testosterone. 5α-reductase-1
Ca, P, S) and water—body weight increases rapidly, has a wider distribution in the body including nongenital
more protoplasm is built. Appetite is improved skin and liver; and is inhibited by finasteride to a lesser
extent.
and a sense of well being prevails. Testosterone
Testosterone itself appears to be the active
given to patients prone to salt and water retention
hormone at certain sites, such as—
may develop edema.
• foetal genital rudiments
4. Erythropoiesis Testosterone accelerates • hypothalamus/pituitary site involved in feed
erythropoiesis by increasing erythropoietin pro- back regulation
duction and probably direct action on haeme • erythropoietic cells
synthesis. Men have higher hematocrit than women. • spermatogenic cells in testes.

Mechanism of action PHARMACOKINETICS

Testosterone can largely be regarded as the circu- Testosterone is inactive orally due to high first
lating prohormone. In most target cells, the pass metabolism in liver. The duration of action
4–5 double bond is reduced producing dihydro- after i.m. injection is also very short. Therefore,
testosterone—which binds more avidly with the slowly absorbed esters of testosterone are used
cytoplasmic androgen receptor (AR), and this by this route—are hydrolysed to the active free
complex is more active than testosterone-receptor form. Testosterone in circulation is 98% bound
complex in combining with DNA. No subtypes to sex hormone binding globulin (SHBG) and
of AR are known; both genital and nongenital to albumin. The SHBG bound testosterone is
(muscle, bone) cells express the same AR. After unavailable for action due to tight binding.
combining with androgen response elements of The major metabolic products of testosterone
the target genes, DNA transcription is enhanced/ are androsterone and etiocholanolone which are
repressed with the help of coactivators or excreted in urine, mostly as conjugates with
corepressors, which may be tissue specific. The glucuronic acid and sulfate. Small quantities of
SECTION 5

effects are expressed through modification of estradiol are also produced from testosterone
protein synthesis. by aromatization of A ring in extraglandular tissues
The 5α-reductase enzyme exists in two isoforms: 5α-reductase-1 (liver, fat, hypothalamus). Plasma t½ of
and 5α-reductase-2. The genital skin of both sexes and urogenital testosterone is 10–20 min.

Principal androgen for different target tissue actions

Testosterone Dihydrotestosterone
Pituitary: LH inhibition • External genitalia (scrotum, penis, male urethra)
Testes: Spermatogenesis formation in foetus and maturation during puberty
Internal genitalia (epididymis, • Pubertal changes, sexual maturity, male behaviour
vas deferens, seminal vesicle) • Prostate growth; hypertrophy in elderly
development in foetus • Hair follicles: growth during puberty,
scalp hair loss in adults
Erythropoiesis

Bone and skeletal muscle: increase in mass and strength

 ANDROGENS AND DRUGS FOR ERECTILE DYSFUNCTION 299

Methyltestosterone and fluoxymesterone are 3. Frequent, sustained and often painful erec-
metabolized slowly and have a longer duration tions in males in the beginning of therapy; subside
of action, but are weaker androgens. Estrogens spontaneously after sometime.
are not produced from fluoxymesterone and 4. Oligozoospermia can occur with moderate
dihydrotestosterone. doses given for a few weeks to men with normal
testosterone levels. Prolonged use may produce
Preparations and Dose testicular atrophy.
1. Testosterone (free): 25 mg i.m. daily to twice weekly; 5. Precocious puberty, premature sexual
AQUAVIRON 25 mg in 1 ml inj. behaviour, and stunting of stature due to early
2. Testosterone propionate: 25–50 mg i.m. daily to twice closure of epiphysis—if testosterone is given
weekly: TESTOVIRON, PARENDREN, TESTANON 25, 50
mg/ml inj.
continuously to young boys for increasing stature.
3. TESTOVIRON DEPOT 100: testo. propionate 25 mg 6. Salt retention and edema: especially when
+ testo. enanthate 100 mg in 1 ml amp; 1 ml i.m. weekly. large doses are used in patients with heart or
4. TESTOVIRON DEPOT 250: testo. propionate 250 mg kidney disease. It is rare with the doses used for
+ testo. enanthate 250 mg in 1 ml amp; i.m. every 2–4 hypogonadism.
weeks.
5. SUSTANON ‘100’: testo. propionate 20 mg + testo. 7. Cholestatic jaundice: occurs with methyltes-
phenyl propionate 40 mg + testo. isocaproate 40 mg in 1 tosterone and other 17-alkyl substituted derivatives
ml amp; 1 ml i.m. every 2–3 weeks. (fluoxymesterone and some anabolic steroids like
6. SUSTANON ‘250’: testo. propionate 30 mg + testo. oxymetholone, stanozolol) in a dose dependent
phenylpropionate 60 mg + testo. isocaproate 60 mg + testo.
decanoate 100 mg in 1 ml amp; 1 ml i.m. every 3–4 weeks.
manner, but not with parenterally used esters of
7. NUVIR, ANDRIOL; Testosterone undecanoate 40 mg testosterone. For this reason, the latter are prefer-
cap, 1–3 cap daily for male hypogonadism, osteoporosis. red. However, jaundice is reversible on
8. Mesterolone: Causes less feedback inhibition of Gn secre- discontinuation.
tion and spermatogenesis, and has been promoted for treatment 8. Hepatic carcinoma: incidence is higher in
of male infertility PROVIRONUM, RESTORE, MESTILON
25 mg tab; 1–3 tab daily for androgen deficiency, oligozoo-
patients who have received long-term methyl-
spermia and male infertility. testosterone or other oral androgens.
9. Gynaecomastia: may occur, especially in
Transdermal androgen Recently delivery of children and in patients with liver disease. This
androgen across skin has been achieved by is due to peripheral conversion of testosterone
developing suitable solvents and absorption to estrogens. Dihydrotestosterone does not cause

CHAPTER 21
facilitators. By cutaneous delivery, testosterone/ gynaecomastia because it is not converted to
dihydrotestosterone circumvent hepatic first pass estradiol.
metabolism; uniform blood levels are produced 10. Lowering of HDL and rise in LDL levels,
round the clock. A gel formulation has been especially with 17α-alkylated analogues.
marketed for once daily application which has
become the preferred method of androgen Contraindications Androgens are contraindi-
replacement for hypogonadism and impotence. cated in carcinoma of prostate and male breast,
ANDRACTIM: Dihydrotestosterone 25 mg/g gel (100 g tube); liver and kidney disease and during pregnancy
5–10 g gel to be applied over nonscrotal skin once daily. (masculinization of female foetus). They should
Fixed dose combinations of testosterone with yohimbine,
not be given to men aged >65 years, and to those
strychnine and vitamins are banned in India. with coronary artery disease or CHF. Androgen
therapy can worsen sleep apnoea, migraine and
SIDE EFFECTS epilepsy.
1. Virilization, excess body hair and menstrual
irregularities in women. Many effects, e.g. voice USES
change may be permanent after prolonged therapy. 1. Testicular failure It may be primary—in
2. Acne: in males and females. children, resulting in delayed puberty. Treatment
300 HORMONES AND RELATED DRUGS

with parenteral testosterone esters or transdermal ANABOLIC STEROIDS

testosterone/dihydrotestosterone in courses of
These are synthetic androgens with supposedly
4–6 months at a time is highly satisfactory.
higher anabolic and lower androgenic activity.
Secondary testicular failure occurring later in life Drugs are Nandrolone, Oxymetholone, Stanozolol
manifests mainly as loss of libido, muscle mass and Methandienone.
and energy, feminization, mild anaemia and impo- The anabolic : androgenic activity ratio is
tence. These are corrected gradually over months determined by injecting the drug in castrated rats
by androgen treatment. However, impotence due and measuring the increase in weight of levator
to psychological and other factors, and not ani muscles to that of ventral prostate. The
testosterone deficiency, does not respond. anabolic : androgenic ratio of testosterone is
2. Hypopituitarism Hypogonadism is one of considered as 1; The anabolic selectivity of these
the features of hypopituitarism. Androgens are steroids is modest with ratios between 1 to 3
added at the time of puberty to other hormonal in the rat model, and probably still lower in man.
replacement. The anabolic effects are similar to that of testo-
sterone and are mediated through the same
3. AIDS related muscle wasting Testosterone receptor as the androgenic effects. For all practical
therapy has been shown to improve weakness and purposes, they are androgens.
muscle wasting in AIDS patients with low
testosterone levels. Preparations and dose
1. Methandienone: 2–5 mg OD–BD oral; children 0.04
4. Hereditary angioneurotic edema This is mg/kg/day, 25 mg i.m. weekly; ANABOLEX 2, 5 mg tab,
a genetic disorder. The attacks can be prevented 2 mg/ml drops, 25 mg/ml inj.
by 17α-alkylated androgens (methyltestosterone, 2. Nandrolone phenyl propionate: 10–50 mg; children
10 mg; i.m. once or twice weekly; DURABOLIN 10, 25 mg/
stanozolol, danazol) but not by testosterone. These ml inj.
drugs act by increasing synthesis of complement 3. Nandrolone decanoate: 25–100 mg i.m. every 3 weeks,
(C1) esterase inhibitor. DECADURABOLIN, 25, 100 mg/ml inj.
4. Oxymetholone: 5–10 mg, children 0.1 mg/kg, OD;
5. Ageing Because testosterone levels decline in old age, ADROYD 5 mg tab.
it has been administered to elderly males to improve bone 5. Stanozolol: 2–6 mg/day, MENABOL, NEURABOL,
mineralization and muscle mass. However, safety of such TANZOL 2 mg tab.
SECTION 5

therapy in terms of metabolic, cardiovascular and prostatic Combination of anabolic steroids with any other drug is
complications is not known. banned in India.
Occasionally small amount of androgen is added to
postmenopausal hormone replacement. Side effects Anabolic steroids were developed
6. Idiopathic male infertility Since high intratesticular
with the idea of avoiding the virilizing side effects
level of testosterone is essential for spermatogenesis, it is of androgens while retaining the anabolic effects.
presumed that exogenous androgens will stimulate But the same adverse effect profile applies to
spermatogenesis or improve sperm maturation in epididymis. these compounds.
On the other hand, androgens can adversely affect The 17-alkyl substituted compounds oxymetho-
spermatogenesis by suppressing Gn secretion. Since
mesterolone causes less feedback inhibition of Gn (probably
lone, stanozolol, can produce jaundice and worsen
due to restricted entry into brain) it is believed that moderate lipid profile.
doses will predominantly stimulate testis directly. Contraindications are same as for testosterone.
A recent metaanalysis of 11 clinical trials has found
that oral androgens (mesterolone and testosterone
undecanoate) had no effect on sperm count or sperm motility Uses
as well as on subsequent pregnancy rate when given to oligo-
astheno-spermic subfertile men. As such, use of these
1. Catabolic states Acute illness, severe
androgens for improving male fertility is unjustified. trauma, major surgery, etc. are attended by
 ANDROGENS AND DRUGS FOR ERECTILE DYSFUNCTION 301

negative N balance. Anabolic steroids can reduce Danazol It is an orally active ethisterone
N2 loss over short periods, but long-term benefits derivative having weak androgenic, anabolic and
are questionable. They may cause a transient progestational activities. Though labelled as an
response in the elderly, under-nourished or impeded/attenuated androgen, because it binds to
debilitated individuals, but controlled studies have the AR and induces some androgen-specific mRNA
failed to demonstrate a difference in the total production, the most prominent action is
weight gained. However, short-term use may be suppression of Gn secretion from pituitary in both
made during convalescence for the sense of men and women → inhibition of testicular/ovarian
wellbeing and improvement in appetite caused function. In addition, it suppresses gonadal
by such treatment. function directly by inhibiting steroidogenic
2. Osteoporosis In elderly males and that occurring due
enzymes. In women endometrial atrophy occurs
to prolonged immobilization may respond to anabolic steroids, over few a weeks and amenorrhoea may supervene.
but bisphosphonates are more effective and are the preferred Danazol is metabolized with a t½ of 12–18 hours.
drugs. Dose: 200–600 mg/day; DANAZOL, LADOGAL,
DANOGEN, GONABLOK 50, 100, 200 mg cap.
3. Suboptimal growth in boys Use is controversial;
somatropin is a better option. Brief spurts in linear growth Uses are:
can be induced by anabolic steroids, but this probably does
not make a difference in the final stature, except in
1. Endometriosis Danazol causes impro-
hypogonadism. Use for more than 6 months is not recom- vement in ~75% cases by inhibiting ovarian
mended—premature closure of epiphyses and shortening of function. Relief of dysmenorrhoea is prompt. Pain,
ultimate stature may result. dyspareunia and excessive bleeding regress slowly.
4. Hypoplastic, haemolytic and malignancy associated Estrogen-progestin combination contraceptive is
anaemia Majority of properly selected patients respond the first line drug. Non-responsive cases are treated
to anabolic steroids/androgens by an increase in RBC
count and Hb%. However, erythropoietin therapy is more
by a high dose progestin alone. Danazol is
effective. infrequently used now because of androgenic side
effects and risk of liver damage.
5. To enhance physical ability in athletes When
administered during the period of training androgens/anabolic 2. Menorrhagia Danazol reduces menstrual
steroids can increase the strength of exercised muscles. blood loss. Usually complete amenorrhoea does
However, effects are mostly short-lived and the magnitude
of improvement in performance is uncertain except in women. not occur with 200 mg/day. It is a second line
This is considered illegal and anabolic steroids are included drug to an oral progestin.

CHAPTER 21
in the list of ‘dope test’ performed on athletes before
3. Fibrocystic breast disease (chronic cystic
competitive games.
mastitis): 3–6 months danazol treatment causes
IMPEDED ANDROGENS/ improvement with decrease in pain, nodularity
ANTIANDROGENS and engorgement in ~ 75% cases.
4. Hereditary angioneurotic edema Danazol
Superactive GnRH agonists are the most potent inhibitors
of gonadal function. Administered over a few days, they is a 17α alkylated steroid: has prophylactic effect
markedly inhibit LH and FSH release, resulting in loss of in this condition by inducing complement (C1)
androgen secretion (see Ch. 17). esterase inhibitor (see above).
Ketoconazole at high doses inhibits steroidogenic CYP 450
enzymes: testosterone as well as adrenal steroid production Side effects are frequent and dose related.
is interfered. Plasma protein binding of testosterone is also Complete amenorrhoea occurs with higher doses.
reduced. However, toxicity of high doses precludes its use Androgenic side effects are acne, hirsutism,
to suppress androgens.
Cimetidine and spironolactone have weak antiandrogenic
decreased breast size, deepening of voice, edema
action which manifests as side effects. Progesterone has weak and weight gain. Loss of libido in men, hot flashes
androgen receptor blocking action. in women and night sweats, muscle cramps, g.i.
Drugs that have been clinically used to modify upset, elivation of hepatic enzymes are the other
androgen action are: problems.
302 HORMONES AND RELATED DRUGS

Cyproterone acetate This relatively weak AR antagonist When used along with a GnRH agonist or
is chemically related to progesterone. In contrast to flutamide castration, 50 mg OD affords marked relief in bone
which increases LH release by blocking feedback inhibition,
cyproterone inhibits LH release by its progestational activity. pain and other symptoms due to the metastasis. Side
Lowering of serum testosterone (consequent to LH inhibition) effects are hot flashes, chills, edema and loose
supplements the direct antiandrogenic action of cyproterone. stools, but it is better tolerated and less hepatotoxic
Given to boys in relatively higher doses, it prevents than flutamide. Elevation of hepatic transaminase
pubertal changes, while in adult men libido and androgenic
anabolism are suppressed. Its clinical indications are— above twice normal is a signal for stopping the
precocious puberty in boys, inappropriate sexual behaviour in drug.
men, acne and hirsutism in women (usually in combination BIPROSTA, CALUTIDE, TABI 50 mg tab.
with an estrogen). Its efficacy in metastatic prostate carcinoma
is inferior to other forms of androgen deprivation. 5 α-REDUCTASE INHIBITOR
Hepatotoxicity limits its use.
Dose: 2 mg OD; GINETTE-35, DINAC-35; cyproterone Finasteride A competitive inhibitor of the
acetate 2 mg + ethinyl estradiol 35 μg tab. enzyme 5 α-reductase which converts testosterone
Flutamide A nonsteroidal AR antagonist with into more active DHT responsible for androgen
no other hormonal activity. Its active metabolite action in many tissues including the prostate gland
2-hydroxyflutamide competitively blocks andro- and hair follicles. It is relatively selective for 5
gen action on accessory sex organs as well as α-reductase type 2 isoenzyme which predominates
on pituitary. Thus, it increases LH secretion by in male urogenital tract. Circulating and prostatic
blocking feedback inhibition. Plasma testosterone DHT concentration are lowered, but plasma LH
levels increase in males which partially overcome and testosterone levels remain unchanged because
the direct antiandrogenic action. This limits utility testosterone itself mediates feedback pituitary LH
of monotherapy with antiandrogens in carcinoma inhibition.
prostate. They are now used only in conjunction Treatment with finasteride has resulted in
with a GnRH agonist (to suppress LH and decreased prostate size and increased peak urinary
testosterone secretion) or after castration to block flow rate in ~50% patients with symptomatic
the residual action of adrenal androgens as benign hypertrophy of prostate (BHP). The bene-
combined androgen blockade (CAB) therapy of ficial effects are typically delayed needing ~6
metastatic carcinoma prostate (also see p. 872). months for maximum symptomatic relief. Patients
It is preferably started 3 days before the GnRH with large prostate (volume > 40 ml) obtain greater
SECTION 5

agonist to block the initial flare up that may occur relief than those with smaller gland. Upto 20%
due to excess release of LH and testosterone in reduction in prostate size may be obtained.
the beginning (before GnRH receptors are Withdrawal of the drug results in regrowth of
desensitized). However, long-term benefit of CAB prostate, but with continued therapy benefit is
over GnRH agonist alone is not established. Along maintained for 3 years or more. The relief of
with oral contraceptives it has been tried in female obstructive symptoms, however, is less marked
hirsutism, but its hepatotoxic potential may not compared to surgery and adrenergic α1 blockers
justify such use. Though gynaecomastia and breast (see p. 143). It primarily reduces the static compo-
tenderness occur frequently, libido and potency nent of obstruction, while α1 blockers overcome
are largely preserved during flutamide treatment. the dynamic component. Concurrent treatment with
Reports of liver damage have restricted its use. both produces greater symptomatic relief.
Dose: 250 mg TDS Finasteride has also been found effective in
PROSTAMID, FLUTIDE, CYTOMID 250 mg tab. male pattern baldness, though hair follicles have
Bicalutamide This more potent and longer primarily type 1 enzyme. In such subjects it
acting (t½ 6 days) congener of flutamide is suitable promotes hair growth and prevents further hair
for once daily administration in metastatic carci- loss. Observable response takes 3 or more months
noma of prostate as a component of CAB therapy. therapy and benefit is reversed within 1 year of
 ANDROGENS AND DRUGS FOR ERECTILE DYSFUNCTION 303

treatment cessation. However, 20–30% cases do 1. Androgens

not improve. Hypogonadism is an infrequent cause of ED.
Finasteride is effective orally, extensively Parenteral testosterone esters or transdermal
metabolized in liver—metabolites are excreted in testosterone therapy is effective only when
urine and faeces; plasma t½ 4–8 hours (elderly androgen deficiency is proven to be responsible
6–15 hours). It is well tolerated by most patients; for the loss of libido and ED.
side effects are decreased libido, impotence and
decreased volume of ejaculate (each in 3–4% 2. Phosphodiesterase-5 (PDE-5) inhibitors
patients). Gynaecomastia, skin rashes, swelling
This class of drugs have become the first line
of lips are rare.
therapy for ED.
Dose for BHP 5 mg OD, review after 6 months;
for male pattern baldness 1 mg/day. Nitric oxide causes smooth muscle relaxation
FINCAR, FINAST, FINARA 5 mg tab; FINPECIA, ASTIFINE by generating cGMP intracellularly which then
1 mg tab. promotes dephosphorylation of myosin light chain
Dutasteride This newer congener of finasteride kinase (MLCK) so that myosin fails to interact
inhibits both type 1 and type 2 5α-reductase with actin (see Fig. 39.3). Inhibition of
and reduces DHT levels. It is metabolized by PDE-5, the cGMP degrading isoenzyme in
CYP3A4 and is very long-acting (t½ is ~ 9 weeks). cavernosal and vascular smooth muscle, results
It is approved for use in BHP and can benefit in accumulation of cGMP and marked potentiation
male pattern baldness. In clinical trias, both of NO action. Sildenafil, Tadalafil and vardenafil
finasteride and dutasteride have been found to are selective PDE-5 inhibitors found effective in
reduce the risk of developing carcinoma prostate a majority of patients with ED.
by upto 25%. Interactions with CYP3A4 inducers cGMP
and inhibitors are possible. PDE-5
Dose: 0.5 mg OD; DUPROST, DURIZE 0.5 mg tab. Inhibited by
5-GMP sildenafil
DRUGS FOR ERECTILE DYSFUNCTION
Erectile dysfunction (ED) refers to the inability Sildenafil It is an orally active drug, marketed
of men to attain and maintain an erect penis with in the USA in 1998 and 2 years later in India,

CHAPTER 21
sufficient rigidity to allow sexual intercourse. It for treatment of ED. It became an instant hit,
occurs mainly past middle-age and is common and evoked worldwide response. Sildenafil acts
after the age of 65 years. A variety of vascular, by selectively inhibiting PDE-5 and enhancing
neurogenic, hormonal, pharmacologic or psycho- NO action in corpus cavernosum. Penile
genic causes may underlie the disorder. tumescence during sexual arousal is improved,
Sexual arousal increases blood flow to the but it has no such effect in the absence of sexual
penis and relaxes the cavernosal sinusoids so that activity. It does not cause priapism in most
they fill up with blood, making the penis rigid, recipients.
elongated and erect. Nitric oxide (NO) released Oral bioavailability of sildenafil is ~40%, peak
from parasympathetic nonadrenergic noncholi- blood levels are attained in 1–2 hr; it is metabolized
nergic (NANC) nerves and vascular endothelium largely by CYP3A4 and an active metabolite is
is the major transmitter causing relaxation of produced; t½ in men <65 years averages 4 hours.
smooth muscle in corpus cavernosum and the It is recommended in a dose of 50 mg (for men
blood vessels supplying it; ACh and PGs also > 65 years 25 mg), if not effective then 100 mg
play a role. A variety of mechanical/prosthetic 1 hour before intercourse. Duration and degree
devices and surgery have been used for ED, but of penile erection is increased in 74–82% men
drug therapy has made a big impact recently. with ED including diabetic neuropathy cases. Over
304 HORMONES AND RELATED DRUGS

20 controlled trials have confirmed its efficacy. selective for pulmonary circulation than vardenafil,
However, sildenafil is ineffective in men who have and has been shown to improve arterial oxyge-
lost libido or when ED is due to cord injury or nation in pulmonary hypertension. It significantly
damaged nervi eregantis. increases exercise capacity. Sildenafil 20 mg TDS
has now become the drug of choice for PAH.
Adverse effects Side effects are mainly due
to PDE-5 inhibition related vasodilatation— Tadalafil It is a more potent and longer acting
headache, nasal congestion, dizziness, facial congener of sildenafil; t½ 18 hours and duration
flushing and fall in BP, loose motions. Relaxation of action 24–36 hours. Peak plasma levels are
of lower esophageal sphincter may cause gastric attained between 30–120 min; time to onset of
reflux and dyspepsia. Sildenafil, in addition, action may be longer. Side effects, risks,
weakly inhibits the isoenzyme PDE-6 which is contraindications and drug interactions are similar
involved in photoreceptor transduction in the to sildenafil. In addition, back pain is reported,
retina. As such, impairment of colour vision, which has been ascribed to some degree of
especially blue-green discrimination, occurs in PDE II inhibition by tadalafil. Because of its
some recipients. Few cases of sudden loss of vision longer lasting action, nitrates are contraindicated
due to nonarteritic ischaemic optic neuropathy for upto 3 days after tadalafil. Due to its lower
(NAION) among users of PDE-5 inhibitors have affinity for PDE-6, visual disturbances occur less
been reported. frequently.
Sildenafil markedly potentiates the vasodilator Dose: 10 mg at least 30 min before intercourse (max.
action of nitrates; precipitous fall in BP; MI can 20 mg)
MEGALIS, TADARICH, TADALIS 10, 20 mg tabs,
occur. After >6 million prescriptions dispensed MANFORCE 10 mg tab.
in USA, the FDA received reports of 130 deaths
Vardenafil Another congener of sildenafil with similar
related to sildenafil use by the year 2002. Most time-course of action; peak levels in 30–120 min and t½
deaths occurred in patients with known risk 4–5 hours. Side effects, contraindications and interactions
factors, drug interactions or contraindications, and are also the same. It prolongs Q-T interval; should be avoided
in hyperkalaemia and in patients with long Q-T or those
were timed either during or within 4–5 hours of
receiving class IA and class III antiarrhythmics.
sex. Sildenafil is contraindicated in patients of Dose: 10 mg (elderly 5 mg), max 20 mg.
coronary heart disease and those taking nitrates.
3. Papaverine/Phentolamine induced penile
Though sildenafil remains effective for <8 hours, erection (PIPE) therapy
SECTION 5

it is advised that nitrates be avoided for 24 hours. Injection of papaverine (3–20 mg) with or without phento-
Caution is advised in presence of liver or kidney lamine (0.5–1 mg) in the corpus cavernosum produces penile
disease, peptic ulcer, bleeding disorders. Inhibitors tumescence to permit intercourse. However, the procedure
requires skill and training. Priapism occurs in 2–15% cases,
of CYP3A4 like erythromycin, ketoconazole,
which if not promptly treated leads to permanent damage. This
verapamil, cimetidine potentiate its action. Caution is reversed by aspirating blood from the corpus cavernosum
is required also in patients of leukaemia, sickle or by injecting phenylephrine locally. Repeated injections can
cell anaemia or myeloma which predispose to cause penile fibrosis. Other complications are—local haema-
priapism. toma, infection, paresthesia and penile deviation. In view of
the availability of PDE-5 inhibitors, it is rarely used now; only
Sildenafil is erroneously perceived as an in cases not responding to sildenafil and alprostadil.
aphrodisiac. Men even without ED are going for
4. Prostaglandin E1
it to enhance sexual satisfaction/pleasure.
Alprostadil (PGE1) injected directly into the corpus cavernosum
PENEGRA, CAVERTA, EDEGRA 25, 50, 100 mg tabs.
using a fine needle produces erection lasting 1–2 hours to
Pulmonary arterial hypertension (PAH) Since permit intercourse. Alprostadil injections are less painful than
papaverine, but local tenderness may occur. Penile fibrosis and
NO is an important regulator of pulmonary priapism are rare. It is now the most commonly used drug in
vascular resistance, PDE-5 inhibitiors lower patients not responding to PDE-5 inhibitors, such as neurogenic
pulmonary arterial pressure. Sildenafil is more and psychogenic ED.
 ANDROGENS AND DRUGS FOR ERECTILE DYSFUNCTION 305

A transurethral pellet termed ‘medicated urethral which avoids intracavernosal injection, but is less
system for erection’ (MUSE) has been developed effective and may cause urethral burning.

) PROBLEM DIRECTED STUDY

21.1 A 65-year-old man presented with severe pain in the left shoulder region. The pain has
progressively increased over the last 4 weeks, is not relieved by analgesics or NSAIDs and is
worsened by pressure or movement. He also has increasing micturition difficulty for the last
6 months. Shoulder X-ray showed osteolytic lesion in the head of humerus. Rectal examination
was consistent with prostate cancer which was confirmed by needle biopsy and raised serum
PSA level (30 ng/ml). He refused orchidectomy and was prescribed injection triptorelin 3.75 mg
i.m. to be repeated after one week and then every 4 weeks. After 1 week of 1st injection, he
reported increased bone pain and greater bladder voiding difficulty. The serum PSA level was
34 ng/ml.
(a) What is the cause of the increase in bone pain and urinary obstructive symptoms? Is the
choice of the drug incorrect?
(b) Could this flaring of symptoms be avoided; if so how?
(c) Can any other drug be given to relieve the bone pain?
(see Appendix-1 for solution)

CHAPTER 21
Chapter 22 Estrogens, Progestins and
Contraceptives

ESTROGENS males also from aromatization of testosterone in

(Female Sex Hormones) the testes and extraglandular tissues. In mare, large
quantity of equilin is produced which has 1/5
These are substances which can induce estrus in
estrogenic potency of estradiol.
spayed (ovariectomized) animals.
It was established in the year 1900 that ovaries Synthetic estrogens Natural estrogens are
control female reproductive function through a inactive orally and have a short duration of action
hormonal mechanism. Allen and Doisy (1923) due to rapid metabolism in liver. To overcome
found that an alcoholic extract of ovaries was this, synthetic compounds have been produced:
capable of producing estrus and devised a simple
Steroidal Ethinylestradiol, Mestranol,
bioassay method. The active principle estradiol
Tibolone.
was obtained in pure form in 1929 and soon its
Nonsteroidal Diethylstilbestrol (stilbestrol)
chemical structure was worked out.
Hexestrol, Dienestrol
The nonsteroidal compounds assume a trans
configuration as depicted below and sterically
resemble natural estrogens.

Natural estrogens Estradiol is the major estro-

gen secreted by the ovary. It is synthesized in
the graafian follicle, corpus luteum and placenta
from cholesterol. Steps depicted on the right hand
side in Fig. 20.1 are carried out. Further steps
are shown below.

Regulation of secretion The daily secretion

of estrogens in menstruating women varies from
10–100 µg depending on the phase of the cycle.
Its secretion starts from the graafian follicle under
the influence of FSH and the blood level rises
gradually during the follicular phase. Due to the
Estradiol is rapidly oxidized in liver to estrone modest preovulatory FSH surge, estrogens further
which is hydroxylated to form estriol. All three rise transiently. After ovulation, corpus luteum
are active and circulate in blood, but estradiol continues to secrete estrogens till about two
is the most potent estrogen. Small quantity days before menstruation. Estrogens exercise
(2–20 µg/day) of estradiol is derived in human feedback inhibition of FSH (also of LH at higher
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 307

concentrations) by direct action on pituitary as estrogens to suppress pituitary-gonadal axis causes

well as through hypothalamus (see p. 240). regression of acne.
During pregnancy, placenta secretes large
3. Metabolic effects Estrogens are anabolic,
quantities of estrogens, (mainly estrone and estriol)
similar to but weaker than testosterone. There-
reaching a peak of upto 30 mg/day at term. Their
fore, small amount of androgen may be contri-
level declines sharply after delivery. In the
buting to the pubertal growth spurt even in girls,
postmenopausal women, daily production of
as estrogens do in boys. Continued action of
estrogen has been estimated as 2–10 µg—derived
estrogen promotes fusion of epiphyses both in
primarily by extraglandular aromatization of
girls and boys.
adrenal androgens.
Estrogen is important in maintaining bone
ACTIONS mass primarily by retarding bone resorption.
Osteoclast pit formation is inhibited and there
1. Sex organs The estrogens bring about is increased expression of bone matrix proteins
pubertal changes in the female including growth such as osteonectin, osteocalcin, collagen and
of uterus, fallopian tubes and vagina. Vaginal alkaline phosphatase. It promotes positive calcium
epithelium gets thickened, stratified and corni- balance, partly by inducing renal hydroxylase
fied. They are responsible for the proliferation enzyme which generates the active form of
of endometrium in the preovulatory phase, and Vit D3.
it is only in concert with estrogens that proges- Both osteoblasts and osteoclasts express estrogen receptors
terone brings about secretory changes. (ERs). The major action of estrogens is to reduce maturation
In the absence of progesterone (anovulatory and activity of osteoclasts by modifying regulatory cytokine
signals from osteoblasts (see Ch. 24 for bone remodeling
cycles) withdrawal of estrogens alone produces mechanisms). Estrogens enhance elaboration of OPG from
menstruation. If modest doses of estrogen are osteoblasts which binds RANKL and prevents activation of
given continuously without added progesterone osteoclast-precursors from fusing and maturing into osteoclasts.
—menstruation is delayed but breakthrough The direct action on osteoclasts is to accelerate their apoptosis.
bleeding occurs at irregular intervals. However, Pharmacological doses of estrogens can cause
the normal event which triggers menstruation is mild salt and water retention—edema occurs in
progesterone withdrawal. The progesterone with- predisposed patients, but it can be treated with
drawal bleeding cannot be suppressed even by diuretics. BP may rise after prolonged use.

CHAPTER 22
high doses of estrogens. Combination contraceptives containing higher
Estrogens augment rhythmic contractions of doses of estrogens and progestins impair glucose
the fallopian tubes and uterus, and induce a watery tolerance. Normal blood sugar is not affected but
alkaline secretion from the cervix. This is favou- diabetes may be precipitated or its control vitiated.
rable to sperm penetration. They also sensitize However, amounts used for HRT and low dose
the uterus to oxytocin. Deficiency of estrogens contraception do not affect carbohydrate meta-
is responsible for atrophic changes in the female bolism.
reproductive tract that occur after menopause. Estrogens decrease plasma LDL cholesterol
2. Secondary sex characters Estrogens while HDL and triglyceride levels are raised. The
produced at puberty cause growth of breasts— raised HDL : LDL ratio is probably responsible
proliferation of ducts and stroma, accumulation for rarity of atherosclerosis in premenopausal
of fat. The pubic and axillary hair appear, feminine women. However, blood coagulability is increa-
body contours and behaviour are influenced. sed due to induction of synthesis of clotting factors
Acne is common in girls at puberty as it is (factors II, VII, IX and X). Fibrinolytic activity
in boys—probably due to small amount of andro- in plasma also tends to increase due to lowering
gens produced simultaneously. Administration of of plasminogen-activator inhibitor-1 (PAI-1).
308 HORMONES AND RELATED DRUGS

Estrogens induce nitric oxide synthase and the oral route due to rapid metabolism in liver.
PGI2 production in vascular endothelium. The Estradiol esters injected i.m. are slowly absorbed
increased availability of NO and PGI2 could and exert prolonged action. Natural estrogens in
promote vasodilatation. They increase lithogeni- circulation are largely plasma protein bound—
city of bile by increasing cholesterol secretion to SHBG as well as to albumin.
and reducing bile salt secretion. Plasma levels Estradiol is converted to estrone and vice versa
of sex hormone binding globulin (SHBG), in liver. Estriol is derived from estrone. All three
thyroxine binding globulin (TBG) and cortisol are conjugated with glucuronic acid and sulfate—
binding globulin (CBG) are elevated—but without excreted in urine and bile. Considerable entero-
any change in hormonal status. hepatic circulation occurs due to deconjugation
in intestines and reabsorption—ultimate disposal
Mechanism of action occurs mostly in urine.
Estrogens bind to specific nuclear receptors in Ethinylestradiol is metabolized very slowly
target cells and produce effects by regulating (t½ 12–24 hours). It is orally active and more
protein synthesis. Estrogen receptors (ERs) have potent.
been demonstrated in female sex organs, breast,
pituitary, liver, bone, blood vessels, heart, CNS Preparations and dose
and in certain hormone responsive breast
All estrogen preparations have similar action. Their equivalent
carcinoma cells. The ER is analogous to other
parenteral doses are—
steroid receptors: agonist binding to the ligand Estradiol 0.1 mg = Ethinylestradiol 0.1 mg = Mestranol 0.15
binding domain brings about receptor dimerization mg = Conjugated estrogens 10 mg = Estriol succinate 16
and interaction with ‘estrogen response elements’ mg = Diethylstilbestrol 10 mg.
(EREs) of target genes. Gene transcription is The oral potencies differ from the above due to differing
extents of first pass metabolism. Estradiol is inactive orally,
promoted through certain coactivator proteins. conjugated estrogens and estriol succinate undergo partial
On binding an estrogen antagonist the receptor presystemic metabolism, while in case of ethinylestradiol,
assumes a different conformation and interacts mestranol and diethylstilbestrol the oral and parenteral doses
with other corepressor proteins inhibiting gene are practically the same.
The preferred route of administration of estrogens is
transcription.
oral. Intramuscular injection is resorted to only when large
Two distinct ERs designated ERα and ERβ doses have to be given, especially for carcinoma prostate.
have been identified, cloned and structurally 1. Estradiol benzoate/cypionate/enanthate/valarate: 2.5–10
SECTION 5

characterized. Most tissues express both subtypes, mg i.m.; OVOCYCLIN-P 5 mg inj, PROGYNON DEPOT
but ERα predominates in uterus, vagina, breast, 10 mg/ml inj.
2. Conjugated estrogens: 0.625–1.25 mg/day oral;
bone, hypothalamus and blood vessels, while ERβ PREMARIN 0.625 mg, 1.25 mg tab, 25 mg inj (for
predominates in prostate gland of males and dysfunctional uterine bleeding).
ovaries in females. Estradiol binds to both ERα 3. Ethinylestradiol: for menopausal syndrome 0.02–0.2 mg/
and ERβ with equal affinity, but certain ligands day oral; LYNORAL 0.01, 0.05, 1.0 mg tab, PROGYNON-
C 0.02 mg tab.
have differing affinities. More importantly ERα
4. Mestranol: acts by getting converted to ethinylestradiol
and ERβ may have a different pattern of by demethylation in the liver: 0.1–0.2 mg/day oral; in
interaction with coactivators and corepressors. OVULEN 0.1 mg tab, with ethynodiol diacetate 1 mg.
Few nongenomic rapid actions of estrogens 5. Estriol succinate: 4–8 mg/day initially, maintenance dose
in certain tissues mediated through the same ERs in menopause 1–2 mg/day oral: EVALON 1, 2 mg tab, 1
mg/g cream for vaginal application in atrophic vaginitis 1–
but located on the cell membrane have also been 3 times daily.
observed. 6. Fosfestrol tetrasodium: initially 600–1200 mg slow i.v.
inj for 5 days, maintenance 120–240 mg/day oral or 300
PHARMACOKINETICS mg 1–3 times a week i.v. HONVAN 120 mg tab, 60 mg/
ml inj 5 ml amp.
Estrogens are well absorbed orally and trans- 7. Dienestrol: 0.01% topically in vagina: DIENESTROL
dermally, but natural estrogens are inactive by 0.01% vaginal cream.
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 309

Transdermal estradiol A transdermal patch 3. In postmenopausal women, estrogens can

(Estradiol-TTS) is available in 3 sizes, viz. 5, increase the risk of irregular bleeding and
10 and 20 cm2 delivering 0.025 mg, 0.05 mg endometrial carcinoma (5–15 fold). A progestin
and 0.1 mg respectively in 24 hr for 3–4 days. given concurrently blocks the risk.
The usual dose in menopause is 0.05 mg/day 4. Estrogens can accelerate the growth of existing
which produces plasma estradiol levels seen in breast cancer, but low-dose estrogen only HRT
premenopausal women in the early or mid does not appear to increase the risk of developing
follicular phase. Cyclic therapy (3 weeks on, 1 new breast cancer (see p. 311).
week off) with estradiol-TTS is advised with an 5. Long-term estrogen therapy doubles the
oral progestin added for the last 10–12 days. incidence of gallstones. Benign hepatomas are
Beneficial effects of estradiol-TTS on menopausal more common in women taking estrogens in their
symptoms, bone density, vaginal epithelium and teens and twenties.
plasma Gn levels are comparable to those of oral 6. Migraine, epilepsy and endometriosis may be
therapy, but improvement is serum lipid profile worsened by estrogens.
is less marked. 7. Stilbestrol given to pregnant women, especially during
Systemic side effects of estradiol-TTS are the first trimester (as test of pregnancy or otherwise)—increased
the incidence of vaginal and cervical carcinoma in the female
same as with oral estrogens, but are milder. Oral offspring in childhood or early adulthood. Other genital
therapy delivers high dose of the hormone to the abnormalities are possible in the female as well as male
liver and increases synthesis of several proteins. offspring. Estrogens are contraindicated during pregnancy.
Estradiol-TTS avoids high hepatic delivery:
consequently plasma levels of TBG, CBG, angio- USES
tensinogen and clotting factors are not elevated— Currently, the two most common uses of estrogens
risk of thromboembolic phenomena may not be are as contraceptives and for hormone replace-
increased. ment therapy in postmenopausal women, but there
ESTRADERM-MX: Estradiol 25, 50 or 100 µg per 24 hr are some other indications as well.
transdermal patches; apply to nonhairy skin below waist,
replace every 3–4 days using a different site; add an oral 1. Hormone replacement therapy (HRT)
progestin for last 10–12 days every month.
Recently a combined estradiol 50 µg + norethisterone Due to cessation of ovarian function at meno-
acetate 0.25 mg patch has become available in some countries pause women suffer a number of physical,

CHAPTER 22
(ESTRAGEST-TTS). Two weeks of estraderm-TTS followed psychological and emotional consequences.
by 2 weeks estragest-TTS with patches changed twice weekly
is used for total transdermal HRT. Medical problems related to menopause are:
A gel formulation of estradiol for application over skin • Vasomotor disturbances Hot flushes, chilly sensation,
is also available. OESTRAGEL, E2 GEL 3 mg/5 g in inappropriate sweating, faintness, paresthesias, aches and
80 g tube, SANDRENA 1 mg/g gel; apply over the arms pains.
and spread to cover a large area once daily for HRT. • Urogenital atrophy Change in vaginal cytology and pH,
vaginal dryness, vulval shrinkage, dyspareunia, vaginitis,
ADVERSE EFFECTS itching, urinary urgency, predisposition to urinary tract
infection.
Most of the adverse effects of estrogens are • Osteoporosis Loss of osteoid as well as calcium →
described with HRT and with oral contraceptives thinning and weakening of bone → minimal trauma
(see p. 325). fractures especially of femur, hip, radius, vertebrae.
In addition, dose dependent adverse effects noted • Dermatological changes Thinning, drying and loss of
when use is made for other indications are— elasticity of skin, wrinkles, thin and listless hairs.
1. Suppression of libido, gynaecomastia and • Psychological/Cognitive disturbances Irritability, depres-
sed mood, loss of libido and self confidence, anxiety
feminization when given to males. and dementia.
2. Fusion of epiphyses and reduction of adult • Increased risk of cardiovascular diseases Coronary artery
stature when given to children. disease, myocardial infarction, stroke.
310 HORMONES AND RELATED DRUGS

The vasomotor symptoms tend to subside over a few years, estrogen’ trial (2002) has shown that even lower doses of
but the other changes progress continuously. conjugated estrogens (0.3, 0.45 mg/day) increased bone
Estrogen ±progestin HRT or ‘menopausal mineral density in postmenopausal women, though 0.625
hormone therapy’ (MHT) is highly efficacious mg/day was more effective.
Not withstanding the above, appreciation of the other
in suppressing the perimenopausal syndrome of risks of HRT (see below) has dislodged estrogen from its
vasomotor instability, psychological disturbances prime position in the treatment of osteoporosis.
as well as in preventing atrophic changes and Bisphosphonates are more effective and the drugs of choice.
osteoporosis. However, several recent findings If prevention and treatment of osteoporosis is the goal, HRT
is not the best option, and is not recommended beyond 5
have emphasized a number of risks and limitations years of use.
of long-term HRT, so that the whole outlook has c. Cardiovascular events Since hypertension and cardio-
changed. vascular disease are rare in premenopausal women, and
estrogens improve HDL : LDL ratio, retard atherogenesis,
The dose of estrogen used in HRT is sub-
reduce arterial impedance, increase NO and PGI2 production
stantially lower than that for contraception. and prevent hyperinsulinaemia, it was believed that estrogen
Typically conjugated estrogens are used at 0.625 therapy in postmenopausal women will have a protective
mg/day dose (equivalent to ethinylestradiol 10 cardiovascular influence. This was supported by early reports
relying mainly on retrospective/epidemiological studies and
μg) either cyclically (3 weeks treatment 1 week
those using surrogate markers to indicate that HRT in
gap) or continuously, but there is a trend now otherwise healthy women reduced risk of coronary artery
to use lower doses (0.3–0.45 mg/day). A progestin disease (CAD), myocardial infarction (MI) and stroke. This
(medroxy progesterone acetate/norethisterone lead to the extensive use of HRT; a segment of doctors
contended that menopausal women should take HRT for the
2.5 mg daily) is added for the last 10–12 days rest of their lives.
each month. Though the progestin may attenuate In the past decade many large scale placebo controlled
the metabolic and cardiovascular benefits of randomized interventional trials and cohort studies have
estrogen, it is needed to block the increased risk yielded opposite results. The ‘Heart and estrogen/progestin
replacement study’ (HERS and HERS II) conducted in older
of dysfunctional uterine bleeding and endometrial women with preexisting cardiovascular disease found that
carcinoma due to continuous estrogenic HRT triples the risk of venous thromboembolism, increases
stimulation of endometrium. Estrogen alone is risk of MI in the 1st year and affords no secondary prophylaxis
used in hysterectomised women and when a of CAD in the long-term. The larger ‘women’s health initiative’
(WHI) study conducted in over 16000 younger women without
progestin is not tolerated or is contraindicated. CAD found 24% increase in CAD, 40% increase in stroke
Transdermal estradiol (with oral or transdermal and doubling of venous thromboembolism with the use of
progestin) appears to have certain advantages (see combined HRT. The study was terminated prematurely in
SECTION 5

above) and is preferred by some. 2002. The increased risk of MI was attributed to the progestin
component, since women who took estrogen alone had no
The benefits and risks of HRT are considered increase in the incidence of MI. Reexamination of the data
below: has revealed ~30% reduction in incidence of MI among
a. Menopausal symptoms and atrophic changes The women who took HRT within 10 years of menopause. As
vasomotor symptoms respond promptly and almost such, a few years of HRT just after menopause may be
completely. They are the primary indication for using HRT protective. The committee on safety of medicines (CSM)
which also improves general physical, mental and sexual of UK has estimated that ~20 out of 1000 women aged
well being. HRT should be discontinued once the vasomotor 60–69 years and not using HRT develop venous
symptoms abate. Estrogens also arrest genital and dermal thromboembolism over 5 years; 4 extra cases occur in those
atrophic changes; vulval and urinary problems resolve. Vaginal taking estrogen alone, while 9 extra cases occur in those
application of estrogen is effective in relieving local symptoms taking combined HRT. Thus, progestin use adds to the risk.
and should be preferred when this is the only aim of HRT. d. Cognitive function and dementia: Contrary to earlier
b. Osteoporosis and fractures HRT restores Ca 2+ belief, the ‘women’s health initiative memory study’ (WHIMS)
balance; further bone loss is prevented and the excess fracture conducted among older women (65–79 years) has failed to
risk is nullified. When used for this purpose, HRT should detect any protection against cognitive decline by either
be initiated before significant bone loss has occurred, because estrogen alone or combined HRT. There was in fact a slight
reversal of osteoporosis is none or slight. Calcium + global deterioration. Surprisingly, the incidence of dementia
vit D supplements and exercise aid the beneficial effect of (Alzheimer’s) was doubled.
HRT. However, accelerated bone loss starts again on cessation e. Cancer: That estrogens enhance the growth of breast
of HRT. The ‘Women’s health, osteoporosis, progestin- cancer has been well recognized. However, it was contended
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 311

that small replacement doses of estrogens will not induce tissues. In a dose of 2.5 mg daily, it suppresses
new cancer. This appears to be supported by the estrogen menopausal symptoms and lowers the raised Gn
alone arm of WHI study in hysterectomized women, as the
occurrence of breast cancer was actually lower (but
levels. No endometrial stimulation has been noted.
insignificantly). However, in the combined HRT group, a Urogenital atrophy, psychological symptoms,
significantly higher incidence of cancer breast occurred, libido and osteoporosis are improved similar to
indicating that medroxyprogesterone was the culprit. The other forms of HRT. Contraindications are the
prospective observational cohort ‘Million women study’ same as for conventional HRT, but long term
(MWS) in the UK found a marginally higher incidence of
breast cancer with estrogen alone, but a clearly higher one
benefits and risks are not defined.
with estrogen + progestin. Some other studies have also Weight gain, increased facial hair and
implicated the progestin, and the CSM of UK has drawn occasional vaginal spotting may be noted.
similar conclusions. Thus, the protective effect of progestin LIVIAL 2.5 mg tab, one tab daily without interruption; institute
on endometrial cancer appears to be counter balanced by therapy only after the women has been menopausal for atleast
the procarcinogenic effect on the breast. 12 months.
Estrogen is well known to induce endometrial hyperplasia
and its continuous use unopposed by progestin results in 2. Senile vaginitis Estrogens change vaginal
irregular uterine bleeding. In the long-term it predisposes cytology to the premenopausal pattern and are
to endometrial carcinoma. The MWS has supported this effective in preventing as well as treating atrophic
contention. The standard practice is to give combined HRT vaginitis that occurs in elderly women. Oral
to women with an intact uterus. However, a Cochrane
therapy can be given but more commonly a topical
Database Review has concluded that lower dose unopposed
estrogen does not increase endometrial carcinoma risk; may preparation is used; an antibacterial may be
be used in women with intact uterus when a progestin is combined. Estrogens help in overcoming infection
contraindicated. and relieve symptoms of Kraurosis vulvae.
A small protective effect of combined HRT on colorectal
carcinoma has been detected by the WHI study, but this 3. Delayed puberty in girls It may be due
needs to be confirmed. to ovarian agenesis (Turner’s syndrome) or
f. Gallstone, migraine: Estrogens slightly increase the hypopituitarism. In both, pubertal changes are
risk of developing gallstones, while progestins may trigger
brought about by estrogen treatment, except the
migraine.
rapid gain in height for which growth hormone
Tibolone It is a 19-norsteroid developed speci- and/or a small dose of androgen may be added.
fically to be used for HRT. It is converted into Usually cyclic treatment is given; some prefer
3 metabolites which exert estrogenic, progesta- to start with a lower dose and gradually attain

CHAPTER 22
tional and weak androgenic actions in specific the full replacement dose.

Current conclusions regarding HRT

1. The main indication of HRT is vasomotor and other symptoms in the perimenopausal period. It should be
used at the smallest effective dose and for the shortest duration.
2. Young women with premature menopause clearly deserve HRT.
3. Hysterectomized women should receive estrogen alone, while those with intact uterus be given estrogen +
progestin.
4. Perimenopausal women should be given cyclic HRT rather than continuous HRT.
5. HRT is not the best option to prevent osteoporosis and fractures.
6. HRT affords protection against coronary artery disease only in early postmenopausal women. Combined
HRT at conventional dose may even increase the risk of venous thromboembolism, MI and stroke in elderly
women.
7. HRT does not protect against cognitive decline; may increase the risk of dementia.
8. Combined HRT increases the risk of breast cancer, gallstones and migraine.
9. Transdermal HRT may have certain advantages over oral HRT.
10. The need for HRT should be assessed in individual women, and not prescribed routinely.
312 HORMONES AND RELATED DRUGS

4. Dysmenorrhoea While PG synthesis inhibitors are all human tissues, but the racemate displays weak
the first line drugs, cyclic estrogen therapy (with added
agonistic action in rats. It induces Gn secretion
progestin to ensure withdrawal bleeding) benefits by inhibiting
ovulation (anovular cycles are painless) and decreasing in women by blocking estrogenic feedback
prostaglandin synthesis in endometrium; but this should be inhibition of pituitary. The amount of LH/FSH
reserved for severe cases. released at each secretory pulse is increased. In
5. Acne It occurs at puberty due to increased androgen response, the ovaries enlarge and ovulation occurs
secretion in both boys and girls. Estrogens benefit by
if the ovaries are responsive to Gn. Antagonism
suppressing ovarian production of androgen by inhibiting
Gn release from pituitary. Cyclic treatment (with added of peripheral actions of estrogen results in hot
progestin) is quite effective. Use of estrogen in boys is out flushes. Endometrium and cervical mucus may
of question. Even in girls, topical therapy with antimicrobials, be modified.
tretinoin and other drugs is preferred (see Ch. 64).
The chief use of clomiphene is for infertility
6. Dysfunctional uterine bleeding A progestin given due to failure of ovulation: 50 mg once daily
cyclically is the rational and effective therapy. Estrogens have
adjuvant value. for 5 days starting from 5th day of cycle.
7. Carcinoma prostate Estrogens are palliative; produce Treatment is given monthly. Conception occurs
relief in primary as well as metastatic carcinoma prostate in many women who previously were amenor-
by suppressing androgen production (through pituitary). rhoeic or had anovular cycles. If 1–2 months
GnRH agonists with or without androgen antagonist are treatment does not result in conception—the daily
preferred.
dose may be doubled for 2–3 cycles. No more
ANTIESTROGENS AND SELECTIVE than 6 treatment cycles should be tried. The
ESTROGEN RECEPTOR MODULATORS antiestrogenic effect of clomiphene on developing
(SERMs) follicle, endometrium or cervical mucus can be
counterproductive. Luteal phase dysfunction has
Two nonsteroidal compounds clomiphene citrate also been blamed for therapeutic failures. Addition
and tamoxifen citrate previously grouped as of menotropins or chorionic gonadotropin on the
estrogen antagonists have been in use since 1970s, last 2 days of the course improves the success
but their differing antagonistic and agonistic rate.
actions depending on species, target organ and Clomiphene is well absorbed orally, gets depo-
hormonal background could not be explained. The sited in adipose tissue and has long t½ of ~6
recent discovery of two estrogen receptors (ERα
days. It is largely metabolized and excreted in
and ERβ) and that ligand binding could change
SECTION 5

bile.
their configuration in multiple ways allowing inter-
action with different coactivators and corepres- Adverse effects Polycystic ovaries, multiple
sors in a tissue specific manner has paved the pregnancy, hot flushes, gastric upset, vertigo,
way for development of compounds with unique allergic dermatitis. Risk of ovarian tumour may
profile of agonistic and antagonistic actions be increased.
in different tissues. These drugs have been
designated ‘selective estrogen receptor Other uses To aid in vitro fertilization Clomi-
modulators’ (SERMs), and two new compounds phene given with Gns causes synchronous matu-
Raloxifene and Toremifene are in clinical use. It ration of several ova—improves their harvesting
has been demonstrated that the conformation of for in vitro fertilization.
ER after binding tamoxifen or raloxifene is Oligozoospermia: In men also clomiphene inc-
different from that after binding estradiol.
reases Gn secretion → promotes spermatogenesis
and testosterone secretion. For male infertility—
Antiestrogens
25 mg daily given for 24 days in a month with
Clomiphene citrate It binds to both ERα and 6 days rest for upto 6 months has been recom-
ERβ and acts as a pure estrogen antagonist in mended. However, success rates are low.
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 313

CLOMID, FERTOMID. CLOFERT, CLOME 25, 50, 100 mg suggesting additional nonhormonal mechanism of
tab. action. Tamoxifen is the only drug approved for
Fulvestrant It is the first member of a distinct class of ER primary as well as metastatic breast carcinoma
ligands called ‘selective estrogen receptor down-regulators’ in premenopausal women. It is also effective in
(SERDs) or ‘pure estrogen antagonists’ that has been
surgically treated cancer of male breast.
introduced for the treatment of metastatic ER positive breast
cancer in postmenopausal women which has stopped Based on large epidemiological studies which
responding to tamoxifen. In contrast to tamoxifen, it inhibits have shown 45% reduction in the incidence of
ER dimerization so that ER interaction with DNA is prevented ER-positive breast cancer, tamoxifen has been
and receptor degradation is enhanced. The ER is thus down approved for primary prophylaxis of breast cancer
regulated resulting in more complete suppression of ER
responsive gene function. This feature along with its higher
in high-risk women. Recurrence rate in ipsilateral
affinity for the ER probably accounts for its efficacy in as well as contralateral breasts is reduced by
tamoxifen resistant cases. tamoxifen, but benefits of prophylactic therapy
Fulvestrant is administered as (250 mg) monthly i.m. beyond 5 years are not proven; outcomes may
injections in the buttock. It is slowly absorbed and has an
elimination t½ of more than a month.
even be worse. Adjuvant therapy of breast carcinoma
with tamoxifen when used in postmenopausal
Selective estrogen receptor modulators women is now generally replaced after 2 years
(SERMs) by an aromatase inhibitor, while in premenopausal
women, tamoxifen itself is continued till 5 years
These are drugs which exert estrogenic as well
postmastectomy.
as antiestrogenic actions in a tissue selective
Improvement in bone mass due to anti-
manner.
resorptive effect, and in lipid profile are the other
Tamoxifen citrate Though chemically related benefits of tamoxifen therapy. However, endo-
to clomiphene, it has complex actions; acts as metrial thickening occurs and risk of endometrial
potent estrogen antagonist in breast carcinoma carcinoma is increased 2–3 fold due to estrogenic
cells, blood vessels and at some peripheral sites, action.
but as partial agonist in uterus, bone, liver and Tamoxifen is effective orally; has a biphasic
pituitary. Inhibition of human breast cancer cells plasma t½ (10 hours and 7 days) and a long
and hot flushes reflect antiestrogenic action, while duration of action. Some metabolites of tamoxifen
the weak estrogen agonistic action manifests as are more potent antiestrogens. The drug is excreted
stimulation of endometrial proliferation, lowering

CHAPTER 22
primarily in bile.
of Gn and prolactin levels in postmenopausal Dose 20 mg/day in 1 or 2 doses, max. 40 mg/day;
women as well as improvement in their bone TAMOXIFEN, MAMOFEN, TAMODEX 10, 20 mg tabs.
density. Male infertility: May be used as alternative to
A decrease in total and LDL cholesterol clomiphene.
without any change in HDL and triglyceride level
reflects estrogenic action. Similar to estrogen HRT, Side effects Hot flushes, vomiting, vaginal
it increases the risk of deep vein thrombosis by bleeding, vaginal discharge, menstrual irregula-
2–3 times. rities are the side effects. Increased risk of venous
Till recently tamoxifen has been the standard thromboembolism is due to estrogenic action on
hormonal treatment of breast cancer in both pre- clotting mechanism.
and post-menopausal women, but aromatase Dermatitis, anorexia, depression, mild leucopenia
inhibitors have now gained prominence. In early and ocular changes are infrequent.
cases tamoxifen is given as postmastectomy Tamoxifen is much less toxic than other anticancer
adjuvant therapy, while in advanced cases, it is drugs.
a constituent of palliative treatment. Response Toremifene It is a newer congener of tamoxifen with similar
rates are high in ER-positive breast carcinomas, actions, but is a weaker ER agonist. Uses and adverse effects
but some ER-negative tumours also respond are also similar.
314 HORMONES AND RELATED DRUGS

Raloxifene This SERM has a different pattern of vertebral fractures, i.e. in those who have
of action than tamoxifen. It is an estrogen partial already suffered a fracture. It has no use in men.
agonist in bone and cardiovascular system, but Dose: 60 mg/day;
an antagonist in endometrium and breast. It has BONMAX, RALOTAB, ESSERM 60 mg tab.
high affinity for both ERα and ERβ, and has
a distinct DNA target the ‘raloxifene response AROMATASE INHIBITORS
element’ (RRE). Aromatization of ‘A’ ring of testosterone and
Several long-term multicentric studies have androstenedione is the final and key step in the
shown that raloxifene prevents bone loss in production of estrogens (estradiol/estrone) in the
postmenopausal women; bone mineral density body. In addition to the circulating hormone,
(BMD) may even increase by 0.9–3.4% over years locally produced estrogens appear to play an
in different bones, particularly the lumbar important role in the development of breast cancer.
vertebrae. However, accelerated bone loss occurs Though some aromatase inhibitors (AIs) were
when raloxifene is stopped. The risk of vertebral produced in the past, three recent ‘third generation’
fracture is reduced to half, but not that of long AIs Letrozole, Anastrozole and Exemestane have
bones. Reloxifene is less efficacious than demonstrated clinical superiority and are widely
bisphosphonates in preventing fractures. used now in the treatment of breast cancer.
In postmenopausal women raloxifene reduces Properties of AIs are compared with that of
LDL cholesterol, probably by upregulating hepatic tamoxifen in Table 22.1.
LDL receptors. In contrast to estrogen HRT there
is no increase in HDL and triglyceride levels. Follow Letrozole It is an orally active nonsteroidal
up studies have shown that raloxifene reduces the (type 2) compound that reversibly inhibits
risk of breast cancer by 65%, though the protection aromatization all over the body, including that
was confined to ER-positive breast cancer. within the breast cancer cells, resulting in nearly
Raloxifene does not stimulate endometrial total estrogen deprivation. Proliferation of estrogen
proliferation and there is no increase in the risk dependent breast carcinoma cells is suppressed
of endometrial carcinoma. No relief of menopausal to a greater extent than with tamoxifen. Letrozole
vasomotor symptoms occurs; rather hot flushes is rapidly absorbed with 100% oral bioavailability,
may be induced in some women. large volume of distribution, slow metabolism and
Raloxifene is absorbed orally but has low a t½ of ~40 hours. Randomized clinical trials
SECTION 5

bioavailability due to extensive first pass glucuro- have established its utility in:
nidation. The t½ is 28 hours and major route (a) Early breast cancer: Letrozole is a first line
of excretion is faeces. drug for adjuvant therapy after mastectomy in
ER+ive postmenopausal women. Extended
Side effects Hot flushes, leg cramps are gene- adjuvant therapy with letrozole beyond the
rally mild; vaginal bleeding is occasional. The standard 5 year tamoxifen treatment continues to
only serious concern is 3-fold increase in risk afford protection, whereas continuation of
of deep vein thrombosis and pulmonary embolism. tamoxifen is not useful. Replacement of tamoxifen
However, similar risk attends estrogen HRT. by an AI is now recommended after 2 years
Use Raloxifene is a second line drug for (sequential therapy). Survival is prolonged in
prevention and treatment of osteoporosis in patients who have positive axillary lymph nodes.
postmenopausal women; Ca 2+ and vit D (b) Advanced breast cancer: Current guidelines
supplements enhance the benefit. According to recommend letrozole as first line therapy because
British guidelines, raloxifene is not recommended of longer time to disease progression and higher
for primary prophylaxis of osteoporotic fractures response rate obtained with it compared to
in postmenopausal women, but is an alternative tamoxifen. It is also effective as second line
option for secondary prevention and treatment treatment when tamoxifen has failed.
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 315

TABLE 22.1 Comparative properties of tamoxifen (SERM) and letrozole/anastrozole (AIs)

Tamoxifen Letrozole/Anastrozole
1. Estrogen antagonist in breast and blood vessels, 1. Inhibits production of estrogens in all tissues.
but agonist in uterus, bone, liver and pituitary. Nearly total estrogen deprivation.
2. Can be used for breast Ca. in premenopausal 2. Not to be used in premenopausal women.
women as well.
3. Less effective in delaying recurrence when 3. More effective in delaying recurrence of early stage
used as adjuvant therapy after surgery. breast Ca. (adjuvant therapy)
4. Prophylactic use for breast Ca. recurrence 4. Continues to exert prophylactic effect beyond 5 years.
limited to 5 years.
5. Less delay in disease progression and lower 5. Greater delay in disease progression and greater
survival advantage in advanced/metastatic survival advantage in palliative treatment of advanced/
breast Ca. than AIs. metastatic breast Ca.
6. Not effective in failure cases. 6. Effective in tamoxifen failure cases of advanced
breast Ca.
7. Causes endometrial hyperplasia, predisposes to 7. No endometrial hyperplasia/cancer predisposition.
endometrial carcinoma
8. No bone losss, no increase in fractures or 8. Accelerates bone loss, predisposes to fractures,
arthritic symptoms arthritic symptoms.
9. Increases risk of venous thromboembolism 9. No increase in thromboembolic risk
10. Improves lipid profile; small lowering of LDL Ch. 10. No effect on lipid profile.
SERM—Selective estrogen receptor modulate; AIs—aromatase inhibitors; Ca.—Carcinoma; LDL Ch—Low density
lipoprotein cholesterol

Adverse effects Hot flushes, nausea, diarrhoea, was also lower with anastrozole. A longer time
dyspepsia and thinning of hair are the side effects. to disease progression compared to tamoxifen has
Joint pain is common and bone loss may be been obtained in advanced ER+ive breast cancer.
accelerated. However, there is no endometrial Many tamoxifen resistant cases responded with
hyperplasia or increased risk of endometrial increased survival. Like letrozole, it is also a first
carcinoma. Risk of venous thromboembolism is line drug for early as well as advanced breast
also not increased, and there is no deterioration carcinoma in postmenopausal women. Side effects

CHAPTER 22
of lipid profile. are hot flushes, vaginal dryness, vaginal bleeding,
Dose: 2.5 mg OD oral. nausea, diarrhoea, thinning of hair. Arthralgia and
LETOVAL, LETROZ, FEMARA, ONCOLET 2.5 mg tab. acceleration of osteoporosis are prominent.
Though contraindicated in premenopausal women, letrozole However, it does not predispose to endometrial
was clandestinely promoted and tested as an ovulation carcinoma or to venous thromboembolism.
inducing fertility drug. Use of letrozole for inducing ovulation Dose: 1 mg OD.
in infertile women has been banned in India since Oct. 2011. ALTRAZ, ARMOTRAZ, ANABREZ 1 mg tab.
Anastrozole Another nonsteroidal and reversi- Exemestane: This steroidal and irreversible (Type 1)
ble (Type 2) AI, more potent than letrozole and inhibitor of aromatase acts like a suicide substrate by covalent
suitable for single daily dosing. It accumulates binding to the enzyme. As a result >90% suppression of
estradiol production is obtained. However, it has weak
in the body to produce peak effect after 7–10 androgenic activity similar to androstenedione. Exemestane
days. Anastrozole is useful as adjuvant therapy has been found beneficial in early breast cancer by reducing
in early ER+ive breast cancer as well as for the risk of disease progression when it was substituted for
palliation of advanced cases in postmenopausal tamoxifen as adjuvant therapy. In advanced breast cancer,
longer survival, increased time to disease progression and
women. In early cases, tumor recurrence time was fewer treatment failures have been obtained with exemestane.
found to be longer than with tamoxifen. Risk of It is administered orally and is well tolerated. Adverse effects
new tumor appearing in the contralateral breast are similar to other AIs.
316 HORMONES AND RELATED DRUGS

PROGESTINS are used primarily as adjuvants to estrogens for

HRT in postmenopausal women, threatened
These are substances which convert the estrogen
abortion, endometriosis, etc. for selective proges-
primed proliferative endometrium to secretory
tational effect. The older 19-nortestosterone
and maintain pregnancy in animals spayed after
derivatives developed in the 1950-60s have
conception (Progestin = favouring pregnancy).
additional weak estrogenic, androgenic, anabolic
At the turn of the last century it became
and potent antiovulatory action: are used primarily
apparent that ovaries secrete two hormones, and
in combined contraceptive pills. Estranes with a
that corpus luteum was essential for maintenance
13-ethyl substitution are called ‘gonanes’, e.g.
of pregnancy. Progesterone was isolated in
norgestrel. Gonanes are more potent (especially
1929, but its full therapeutic potential has been
the levoisomers, e.g. levonorgestrel) and have
exploited only after the 1950s when a large number
reduced androgenic activity.
of orally active synthetic progestins were
In the 1980-90s a number of other gonane
developed.
compounds were introduced, of which desogestrel
Natural progestin Progesterone, a 21 carbon has been marketed in India. Desogestrel and
steroid, is the natural progestin and is derived norgestimate are prodrugs. In addition to being
from cholesterol (see Fig. 20.1). It is secreted very potent progestins they have strong
by the corpus luteum (10–20 mg/day) in the later antiovulatory action (gestodene inhibits ovulation
half of menstrual cycle under the influence of at as low as 40 µg/day dose), and little or no
LH. Its production declines a few days before androgenic property. Therefore, they do not
the next menstrual flow. If the ovum gets fertilized antagonise the beneficial action of estrogens on
and implants—the blastocyst immediately starts lipid profile and are preferable in women with
producing chorionic gonadotropin which is hyperandrogenemia. High antiovulatory potency
absorbed into maternal circulation and sustains allows reduction of ethinylestradiol dose when
the corpus luteum in early pregnancy. Placenta these are combined in oral contraceptives.
starts secreting lots of estrogens and progesterone The newer 19-norprogesterone derivative
from 2nd trimester till term. Men produce 1– nomegestrol has weak antiandrogenic property, is
5 mg progesterone per day from adrenals and less antiovulatory, but has strong antiestrogenic
testes; its role if any, in males is not known. effect on endometrium. Adverse effects on lipid
SECTION 5

profile and glucose tolerance appear to be lacking.

Synthetic progestins A number of synthetic
progestins with high oral activity have been
PROGESTERONE DERIVATIVES
produced. These are either progesterone deri-
vatives (21 C) or 19-nortestosterone derivatives, Medroxyprogesterone acetate
also called ‘estranes’ (18 C). Megestrol acetate
Dydrogesterone
The progesterone derivatives are almost pure Hydroxyprogesterone caproate
progestins, have weaker antiovulatory action and
Newer compound
Nomegestrol acetate

19-NORTESTOSTERONE DERIVATIVES
Older compounds Newer compounds
Norethindrone (Gonanes)
(Norethisterone) Desogestrel
Lynestrenol Norgestimate
(Ethinylestrenol) Gestodene
Allylestrenol
Levonorgestrel (Gonane)
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 317

ACTIONS 7. Respiration Progestins in relatively higher

doses stimulate respiration, as occurs during
The main function of progesterone is preparation
pregnancy.
of the uterus for nidation and maintenance of
pregnancy. The latter is due to prevention of 8. Metabolism Prolonged use of oral contra-
endometrial shedding, decreased uterine motility ceptives impairs glucose tolerance in some
and inhibition of immunological rejection of the women. This has been ascribed to the progesta-
foetus: progesterone depresses T-cell function and tional component. Progestins, especially those with
cell-mediated immunity (CMI). androgenic activity (19-nortestosterone deriva-
tives) tend to raise LDL and lower HDL
1. Uterus Progesterone brings about secretory
cholesterol levels. This may reduce the beneficial
changes in the estrogen primed endometrium:
effect of estrogen used concurrently for HRT or
hyperemia, tortuocity of glands and increased
secretion occurs while epithelial proliferation is in contraceptives. Micronized oral progesterone
halted. It is lack of progestational support which formulation (referred to as ‘natural progesterone’)
causes mucosal shedding during menstruation. has been shown not to counteract the beneficial
Continued action of progesterone (when effect of estrogen on LDL and HDL cholesterol.
pregnancy occurs) brings about decidual changes 9. Pituitary Progesterone is a weak inhibitor
in endometrium—stroma enlarges and becomes of Gn secretion from pituitary. It exerts negative
spongy, glands atrophy, and sensitivity of feedback primarily at the level of hypothalamic
myometrium to oxytocin is decreased. pulse generator—reducing the frequency of GnRH
2. Cervix Progesterone converts the watery pulses. However, the amount of LH at each pulse
cervical secretion induced by estrogens to viscid, may increase. Administration of progestin during
scanty and cellular secretion which is hostile to follicular phase suppresses the preovulatory LH
sperm penetration. surge and prevents ovulation. It synergises with
estrogen for this action. The gonanes markedly
3. Vagina Progesterone induces pregnancy like suppress GnRH and are potent antiovulatory
changes in the vaginal mucosa: leukocyte drugs.
infiltration of cornified epithelium occurs.
4. Breast Progesterone causes proliferation of Mechanism of action

CHAPTER 22
acini in the mammary glands. Cyclic epithelial Unlike other steroid receptors, the progesterone
proliferation and turnover occurs during luteal receptor (PR) has a limited distribution in the
phase, but continuous exposure to progesterone body: confined mostly to the female genital tract,
during pregnancy halts mitotic activity and breast, CNS and pituitary. The PR is normally
stabilizes mammary cells. Acting in concert with present in the nucleus of target cells. Analogous
estrogens, it prepares breast for lactation. to ER, upon hormone binding the PR undergoes
Withdrawal of these hormones after delivery dimerization, attaches to progesterone response
causes release of prolactin from pituitary and milk element (PRE) of target genes and regulates
secretion starts. transcription through coactivators. The anti-
5. CNS High circulating concentration of pro- progestins also bind to PR, but the conformation
gesterone (during pregnancy) appears to have a assumed is different from agonist bound receptor
sedative effect. It can also affect mood. and opposite effects are produced by interaction
6. Body temperature A slight (0.5oC) rise in with corepressors.
body temperature by resetting the hypothalamic The PR exists in a short (PR-A) and a longer (PR-B)
isoforms. The two have differing activities, but because the
thermostat and increasing heat production is ligand binding domain of both is identical, all agonists and
induced. This is responsible for the higher body antagonists display similar binding properties for them. Tissue
temperature seen during the luteal phase. selective modulation of PR has not yet been possible, as has
318 HORMONES AND RELATED DRUGS

been in the case of ER. Progesterone also acts on cell membrane HRT); NORISTERAT 200 mg/ml inj (as enanthate) for
receptors in certain tissues and produces rapid effects, like contraception 1 ml i.m every 2 months; has androgenic, anabolic
Ca2+ release from spermatozoa and oocyte maturation, but their and antiestrogenic activity.
physiological significance is not clear. 6. Lynestrenol (Ethinylestrenol): 5–10 mg OD oral;
Estrogens have been shown to increase PR ORGAMETRIL 5 mg tab. Has additional androgenic, anabolic
density, whereas progesterone represses ER and and estrogenic activity.
7. Allylestrenol: 10–40 mg/day; GESTANIN, FETUGARD,
enhances local degradation of estradiol. MAINTANE 5 mg tab. Has been especially used for threatened/
habitual abortion, PROFAR 25 mg tab.
8. Levonorgestrel: 0.1–0.5 mg/day; DUOLUTON-L,
PHARMACOKINETICS OVRAL 0.25 mg+ ethinylestradiol 0.05 mg tab. Has
Progesterone, unless specially formulated, is androgenic, anabolic and antiestrogenic property.
9. Desogestrel 150 µg + ethinylestradiol 30 µg (NOVELON)
inactive orally because of high first-pass meta- tab, 1 tab OD 3 week on 1 week off cyclic therapy.
bolism in liver. It is mostly injected i.m. in oily (Other preparations are given with oral contraceptives).
solution. Even after an i.m. dose it is rapidly
cleared from plasma, has a short t½ (5–7 min).
ADVERSE EFFECTS
Nearly complete degradation occurs in the liver—
major product is pregnanediol which is excreted • Breast engorgement, headache, rise in body
in urine as glucuronide and sulfate conjugates. temperature, edema, esophageal reflux, acne
However, effects of progesterone last longer than and mood swings may occur with higher doses.
the hormone itself. • Irregular bleeding or amenorrhoea can occur
A micronized formulation of progesterone if a progestin is given continuously.
has been developed for oral administration. • The 19-nortestosterone derivatives lower
Microfine particles of the drug are suspended in plasma HDL levels—may promote atheroge-
oil and dispensed in gelatin capsules. Absorption nesis, but progesterone and its derivatives have
occurs through lymphatics bypassing liver. Though no such effect.
bioavailability is low, effective concentrations are • Long-term use of progestin in HRT may
attained in the body. increase the risk of breast cancer.
Most of the synthetic progestins are orally • Blood sugar may rise and diabetes may be
active and are metabolized slowly; have plasma precipitated by long-term use of potent agents
t½ ranging from 8–24 hours. like levonorgestrel.
• Intramuscular injection of progesterone is
SECTION 5

Preparations and dose

painful.
1. Progesterone: 10–100 mg i.m. (as oily solution) OD; • Given in early pregnancy, progestins can cause
PROGEST, PROLUTON, GESTONE 50 mg/ml inj., 1 and
2 ml amp; 100–400 mg OD oral: NATUROGEST,
masculinization of female foetus and other
DURAGEST, OGEST 100, 200, 400 mg caps containing congenital abnormalities.
micronized oily suspension. Use of a progestin for diagnosis of pregnancy
2. Hydroxyprogesterone caproate: 250–500 mg i.m. at is contraindicated.
2–14 days intervals; PROLUTON DEPOT, MAINTANE INJ,
PROCAPRIN 250 mg/ml in 1 and 2 ml amp.
3. Medroxyprogesterone acetate: 5–20 mg OD–BD oral, USES
50–150 mg i.m. at 1–3 month interval; FARLUTAL 2.5,
5, 10 mg tab., PROVERA, MEPRATE, MODUS 2.5, 10 1. As contraceptive Most common use (see
mg tab, DEPOT-PROVERA 150 mg in 1 ml inj. (as contra- later).
ceptive). Has weak androgenic and antiestrogenic property.
4. Dydrogesterone: 5–10 mg OD/TDS oral; DUPHASTON 2. Hormone replacement therapy (HRT)
5 mg tab. It has poor antiovulatory action: may be preferred In nonhysterectomised postmenopausal women
when contraceptive effect is not required.
estrogen therapy is supplemented with a progestin
5. Norethindrone (Norethisterone): 5–10 mg OD–BD oral;
PRIMOLUT-N, STYPTIN, REGESTRONE, NORGEST 5 mg for 10–12 days each month to counteract
tab; REGESTRONE HRT, NORETA HRT 1 mg tab (for the risk of inducing endometrial carcinoma.
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 319

A progesterone derivative lacking androgenic given daily on symptom days dampen irritability
activity is preferred. and mood changes in majority of women. If severe,
premenstrual syndrome requires suppression of
3. Dysfunctional uterine bleeding It is often
ovulation by combined estrogen-progesterone
associated with anovular cycles. Continued
treatment given cyclically. Relatively higher dose
estrogenic action on endometrium (causing
of progestin is generally used. Progestins are
hyperplasia) without progesterone induction and
added to estrogen when it is used for severe dys-
withdrawal resulting in incomplete sloughing leads
to irregular, often profuse bleeding. A progestin menorrhoea.
in relatively large doses (medroxyprogesterone 6. Threatened/habitual abortion In most such
acetate/norethindrone 10–20 mg/day or equi- patients there is no progesterone deficiency;
valent) promptly stops bleeding and keeps it in administration of excess hormone is of no benefit.
abeyance as long as given. Subsequently cyclic Progestin therapy may be considered in those
treatment at lower doses regularizes and norma- patients who have established deficiency.
lizes menstrual flow. A progestin with inherent However, progestins are briskly promoted and
estrogenic action is preferred; often supplemental almost routinely prescribed in India. There is some
dose of estrogen is combined, or a combination recent evidence of its efficacy in preventing
oral contraceptive pill is given cyclically for premature delivery in high risk pregnancy. If such
3–6 months. use is made—a pure progestin without estrogenic
4. Endometriosis This condition results from or androgenic activity should be employed.
presence of endometrium at ectopic sites. 7. Endometrial carcinoma Progestins are pal-
Manifestations are dysmenorrhoea, painful pelvic liative in about 50% cases of advanced/ metastatic
swellings and infertility. Continuous administration endometrial carcinoma. High doses are needed.
of progestin induces an anovulatory, hypo-
estrogenic state by suppressing Gn release. The
direct action on endometrium prevents bleeding ANTIPROGESTIN
in the ectopic sites by suppressing menstruation. Mifepristone It is a 19-norsteroid with potent
Treatment for a few months causes atrophy and antiprogestational and significant antigluco-
regression of the ectopic masses. Therapy can corticoid, antiandrogenic activity.
be withdrawn in many cases after 6 months without

CHAPTER 22
Given during the follicular phase, its antipro-
reactivation. Fertility returns in some patients. gestin action results in attenuation of the midcycle
Progestin treatment of endometriosis is cheap and Gn surge from pituitary → slowing of follicular
generally well tolerated, but not all cases respond development and delay/failure of ovulation. If
and recurrences are frequent. Initial progestin given during the luteal phase, it prevents secretory
therapy is often replaced by cyclic tratment with changes by blocking progesterone action on the
an estrogen-progestin contraceptive pill given for endometrium. Later in the cycle, it blocks
3–6 months. GnRH agonist and danazol are progesterone support to the endometrium,
alternatives used in nonresponsive cases. unrestrains PG release from it—this stimulates
Aromatase inhibitors are being tried in resistant uterine contractions. Mifepristone also sensitizes
cases. the myometrium to PGs and induces menstruation.
5. Premenstrual syndrome/tension Some If implantation has occurred, it blocks
women develop headache, irritability, fluid decidualization, so that conceptus is dislodged,
retention, distention and breast tenderness a few HCG production falls, secondary luteolysis
days preceding menstruation. When depression occurs–endogenous progesterone secretion decrea-
predominates, it has been labelled ‘premenstrual ses and cervix is softened. All these effects lead
dysphoric disorder’. Fluoxetine and other SSRIs to abortion.
320 HORMONES AND RELATED DRUGS

Mifepristone is a partial agonist and com- 2. Cervical ripening 24–30 hours before
petitive antagonist at both A and B forms of PR. attempting surgical abortion or induction of labour,
In the absence of progesterone (during anovulatory mifepristone 600 mg results in softening of cervix;
cycles or after menopause) it exerts weak the procedure is facilitated.
progestational activity—induces predecidual
3. Postcoital contraceptive Mifepristone 600
changes. Therefore, it is now regarded as
mg given within 72 hr of intercourse interferes
‘progesterone receptor modulator’ rather than
with implantation and is a highly effective method
‘pure antagonist.’ The weak agonistic action is
of emergency contraception. The subsequent
not manifest in the presence of progesterone.
menstrual cycle, however, is disturbed.
The antiglucocorticoid action of usual doses
is also not manifest in normal individuals because 4. Once-a-month contraceptive A single 200 mg dose
blockade of the negative feedback at hypothalamic- of mifepristone given 2 days after midcycle each month
prevents conception on most occasions. Administering
pituitary level elicits ACTH release → plasma mifepristone in late luteal phase to dislodge the embryo (if
cortisol rises and overcomes the direct antigluco- present) and to ensure menstruation irrespective of concep-
corticoid action. Amelioration of Cushing’s tion, has also been tried. These alternative methods of
symptoms has been obtained with large doses contraception, though attractive, may prolong/disrupt the next
menstrual cycle, and thus cannot be used continuously. There
(see p. 295). is little experience and little justification to use these methods
on regular basis.
Pharmacokinetics Mifepristone is active orally,
but bioavailability is only 25%. It is largely 5. Induction of labour By blocking the relaxant action
metabolized in liver by CYP 3A4 and excreted of progesterone on uterus of late pregnancy, mifepristone
can promote labour. It may be tried in cases with intrauterine
in bile; some enterohepatic circulation occurs; t½ foetal death and to deliver abnormal foetuses.
20–36 hr.
6. Cushing’s syndrome Mifepristone has palliative effect
Interaction with CYP 3A4 inhibitors (erythro- due to glucocorticoid receptor blocking property. May be
mycin, ketoconazole) and inducers (rifampin, used for inoperable cases.
anticonvulsants) has been reported. Other proposed uses are—in endometriosis, uterine fibroid,
certain breast cancers and in meningioma.

Uses MIFEGEST, MIFEPRIN 200 mg tab.

T-PILL + MISO: Mifepristone 200 mg (3 tabs) + Misoprostol
1. Termination of pregnancy of up to 7 200 μg (2 tabs); for medical termination of pregnancy of
SECTION 5

weeks: 600 mg as single oral dose causes complete upto 49 days: take 3 tablets of T-PILL on day 1, followed
on day 3 by 2 tablets of MISO.
abortion in 60–85% cases. To improve the success
rate, current recommendation is to follow it up Ulipristal It is a recently approved ‘selective
48 hours later by a single 400 mg oral dose of progesterone receptor modulator’ (SPRM) for use
misoprostol. This achieves >90% success rate and as emergency contraceptive. It inhibits ovulation
is the accepted nonsurgical method of early first by suppressing LH surge as well as by direct
trimester abortion. In place of oral misoprostol, effect on follicular rupture. In addition, its action
a 1 mg gemeprost pessary can be inserted intra- on endometrium can interfere with implantation.
vaginally. Mifepristone administered within 10 In clinical trials the efficacy of ulipristal (30 mg)
days of a missed period results in an apparent as emergency contraceptive has been rated equal
late heavy period (with dislodged blastocyst) in to that of levonorgestrel (1.5 mg) when taken
upto 90% cases. within 72 hours of unprotected intercourse, and
This procedure is generally safe, but prolonged to extend for 2 more days. Thus, it may have
bleeding and failed abortion are the problems an advantage, if the woman misses to take the
in some cases. Anorexia, nausea, tiredness, drug within 3 days.
abdominal discomfort, uterine cramps, loose Headache, nausea, vomiting, abdominal pain
motions are the other side effects. and menstrual delay are the side effects, as they
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 321

are with levonorgestrel. Few cases of ovarian TYPES OF METHODS

cysts are reported. Oral
The antiglucocorticoid activity of ulipristal is
1. Combined pill It contains an estrogen and
weaker than that of mifepristone.
a progestin in fixed dose for all the days of a
Onapristone (a pure progesterone antagonist) and Gestinone treatment cycle (monophasic). With accumulated
(more efficacious in endometriosis) are the other experience, it has been possible to reduce the
antiprogestins.
amount of estrogen and progestin in the ‘second
generation’ OC pills without compromising
HORMONAL efficacy, but reducing side effects and
CONTRACEPTIVES complications. ‘Third generation’pills containing
These are hormonal preparations used for newer progestins like desogestrel with improved
reversible suppression of fertility. Because of our profile of action have been introduced in the
alarming population trends, antifertility drugs are 1990s. Ethinylestradiol 30 µg daily is considered
the need of the day. In developing countries threshold but can be reduced to 20 µg/day if a
progestin with potent antiovulatory action is
particularly, the mortality rate has declined and
included. The progestin is a 19-nortestosterone
birth rate has increased due to urbanization. In
because these have potent antiovulatory action.
the earlier part of 20th century, methods of
Used alone the ovulation inhibitory dose (per day)
contraception used (condoms, diaphragms, sper- of the currently used progestins is estimated to
micidal creams, foam tablets, etc.) were intimately be—levonorgestrel 60 µg, desogestrel 60 µg,
related to sexual intercourse, therefore, despised norgestimate 200 µg, gestodene 40 µg, but the
by most couples. These also have higher failure amount in the pill is 2–3 times higher to attain
rate. Rock and Pincus (1955) announced the suc- 100% certainty. While both estrogens and
cessful use of an oral progestin for contraception, progestins synergise to inhibit ovulation, the
separating fertility control from coitus. progestin ensures prompt bleeding at the end of
It was soon discovered that addition of a small a cycle and blocks the risk of developing
quantity of an estrogen enhanced their efficacy; endometrial carcinoma due to the estrogen. One
combined pills have become the most popular tablet is taken daily for 21 days, starting on the
method of contraception, particularly because the 5th day of menstruation. The next course is started

CHAPTER 22
hormone content of the pills has been reduced, after a gap of 7 days in which bleeding occurs.
minimizing the potential harm and affording other Thus, a cycle of 28 days is maintained. Calendar
health benefits. packs of pills are available (Table 22.2). This
is the most popular and most efficacious method.
FEMALE CONTRACEPTION 2. Phased pill Triphasic regimens have been
introduced to permit reduction in total steroid
Over 100 million women worldwide are currently dose without compromising efficacy by mimicking
using hormonal contraceptives. With these drugs, the normal hormonal pattern in a menstrual cycle.
fertility can be suppressed at will, for as long The estrogen dose is kept constant (or varied slightly
as desired, with almost 100% confidence and between 30–40 µg), while the amount of progestin
complete return of fertility on discontinuation. is low in the first phase and progressively higher
The efficacy, convenience, low cost and overall in the second and third phases.
safety of oral contraceptives (OCs) has allowed Phasic pills are particularly recommended for
women to decide whether and when they want women over 35 years of age and for those with
to become pregnant and to plan their activities. no withdrawal bleeding or breakthrough bleeding
A variety of oral and parenteral preparations are while on monophasic pill, or when other risk
now available offering individual choices. factors are present.
322 HORMONES AND RELATED DRUGS

TABLE 22.2 Oral contraceptive preparations

PROGESTIN ESTROGEN TRADE NAME

COMBINED PILLS
1. Norgestrel 0.3 mg Ethinylestradiol 30 μg MALA–D (21 tabs + 7
ferrous sulfate 60 mg tabs.)
2. Norgestrel 0.5 mg Ethinylestradiol 50 µg OVRAL-G 20 tabs.
3. Levonorgestrel 0.25 mg Ethinylestradiol 50 µg OVRAL, DUOLUTON-L 21 tabs.
4. Levonorgestrel 0.15 mg Ethinylestradiol 30 µg OVRAL-L, OVIPAUZ 21 tabs.
5. Levonorgestrel 0.1 mg Ethinylestradiol 20 µg LOETTE, OVILOW, COMBEE
21 tabs
6. Desogestrel 0.15 mg Ethinylestradiol 30 µg NOVELON 21 tabs.
7. Desogestrel 0.15 mg Ethinylestradiol 20 µg FEMILON 21 tabs.

PHASED PILL
1. Levonorgestrel 50–75 Ethinylestradiol 30–40 TRIQUILAR (6 + 5 + 10
–125 µg –30 µg tablets)
2. Norethindrone 0.5–0.75 Ethinylestradiol 35–35 ORTHONOVUM 7/7/7
–1.0 mg –35 µg (7+7+7 tabs)

POSTCOITAL PILL
1. Levonorgestrel 0.25 mg Ethinylestradiol 50 µg OVRAL, DUOLUTON-L
(2+2 tabs)
2. Levonorgestrel 0.75 mg -Nil- — NORLEVO, ECEE2 (1+1 tab)
1.5 mg -Nil- — iPILL, NOFEAR-72, OH GOD (1 tab)
MINI PILLS
1. Norethindrone 0.35 mg -Nil- — MICRONOR*, NOR-QD*
2. Norgestrel 75 µg -Nil- — OVRETTE*

*Not marketed in India.

3. Progestin-only pill (Minipill) It has been • Levonorgestrel 0.75 mg two doses 12 hours
devised to eliminate the estrogen, because many apart, or 1.5 mg single dose taken as soon
of the long-term risks have been ascribed to this as possible, but before 72 hours of unprotected
SECTION 5

component. A low-dose progestin-only pill is an intercourse.

alternative for women in whom an estrogen is Trials conducted globally by a WHO task
contraindicated. It is taken daily continuously force on postovulatory methods of fertility
without any gap. The menstrual cycle tends to control have found this regimen to be 2–3 times
become irregular and ovulation occurs in 20–30% more effective and better tolerated than the
women, but other mechanisms contribute to the earlier ‘Yuzpe method’ which used levonor-
contraceptive action. The efficacy is lower (96– gestrel 0.5 mg + ethinylestradiol 0.1 mg, two
98%) compared to 98–99.9% with combined pill. doses at 12 hour interval within 72 hours of
Pregnancy should be suspected if amenorrhoea exposure. Incidence of nausea and vomiting
of more than 2 months occurs. This method is is ~6% in the progestin only regimen compared
less popular. to 20–50% with the estrogen+progestin
4. Emergency (postcoital) pill These are for regimen. Headache and other side effects are
use in a woman not taking any contraceptive who also milder. However, the next period may be
had a sexual intercourse risking unwanted delayed or disrupted with either regimen.
pregnancy. The most commonly used and standard Recently (2010) a SPRM ulipristal has been
regimen is— approved for emergency contraception.
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 323

• Ulipristal 30 mg single dose as soon as Gn suppression. This may also produce

possible, but within 120 hours of intercourse. menopause-like symptoms (hot flushes, vaginal
It is an equally effective (failure rate dryness, reduced libido).
1–3% compared to levonorgestrel 2–4%) and Only the long-acting progestin only injections
equally well tolerated alternative method now are in use now. They are injected once in
available with an extended window of 2–3 months depending on the steroid and its dose.
protective action (see p. 320). Two compounds have been marketed:
Another antiprogestin that has been used, (a) Depot medroxyprogesterone acetate
particularly in Europe and China, with high (DMPA) 150 mg at 3-month intervals. After
success rate and few side effects is— i.m. injection peak blood levels are reached
• Mifepristone 600 mg single dose taken within in 3 weeks and decline with a t½ of ~ 50 days.
72 hours of intercourse. DEPOT-PROVERA 150 mg in 1 ml vial for deep i.m.
Emergency postcoital contraception should be injection during first 5 days of menstrual cycle. Repeat
every 3 months.
reserved for unexpected or accidental exposure
(b) Norethindrone (Norethisterone) enanthate
(rape, condom rupture) only, because all
(NEE) 200 mg at 2-month intervals.
emergency regimens have higher failure rate and
NORISTERAT 200 mg in 1 ml vial for deep i.m.
side effects than regular low-dose combined pill. injection during first 5 days of menstrual cycle. Repeat
every 2 months.
Injectable
The most important drawback is complete
These have been developed to obviate the need disruption of menstrual bleeding pattern or total
for daily ingestion of pills. They are given i.m. amenorrhoea (more common with DMPA). It is
as oily solution; are highly effective; over 50 not suitable for adolescent girls and lactating
million women have used them so far. Their major mothers. Use of DMPA is generally restricted to
limitations are: women who are unlikely to use other contra-
(a) Animal data has indicated carcinogenic ceptives effectively. NEE is shorter acting and
potential, but there is no proof from human studies failure rates have been higher than with DMPA.
despite >30 years of experience. No increase in All fixed dose combination injectable preparations of synthetic
estrogens and progestins are not allowed in India and
overall risk of cervical, ovarian or hepatic cancer
discontinued in most countries.
has been noted by a WHO sponsored study.

CHAPTER 22
Breast cancer risk may be slightly increased in Implants These are drug delivery systems implanted under
the skin, from which the steroid is released slowly over a
younger women (< 35 yr). The logistics of period of 1–5 years. They consist of either—
administration and supervision for mass use are (a) Biodegradable polymeric matrices—do not need to be
considered inadequate in developing countries removed on expiry.
and use–effectiveness in field conditions is low. (b) Non-biodegradable rubber membranes—have to be
removed on expiry.
In India approval has been granted for use only NORPLANT: A set of 6 capsules each containing 36 mg
under close supervision, but not on mass scale levonorgestrel (total 216 mg) for subcutaneous implantation
under the National Programme. is available in some countries, but has been discontinued
in the USA. Works for up to 5 years.
(b) Menstrual irregularities, excessive bleeding or
A progesterone impregnated intrauterine insert
amenorrhoea are very common; incidence of (PROGESTASERT) has been introduced in some countries.
amenorrhoea increases with increasing duration It contains 52 mg of levonorgestrel which primarily acts
of use. Return of fertility may take 6–30 months locally on endometrium. The device remians effective
for 5 years, but efficacy is rated lower.
after discontinuation; permanent sterility may
occur in some women. Weight gain and headache
occur in >5% subjects. Bone mineral density may MECHANISM OF ACTION
decrease after 2–3 years of use (especially with Hormonal contraceptives interfere with fertility
DMPA) due to low estrogen levels caused by in many ways; the relative importance depends
324 HORMONES AND RELATED DRUGS

on the type of method. This is summarized in with fertilization—not suitable for nidation. This
Table 22.3. action appears to be the most important in case
1. Inhibition of Gn release from pituitary by of minipills and postcoital pill.
reinforcement of normal feedback inhibition. The 4. Uterine and tubal contractions may be
progestin reduces frequency of LH secretory modified to disfavour fertilization. This action
pulses (an optimum pulse frequency is required is uncertain but probably contributes to the
for tiggering ovulation) while the estrogen efficacy of minipills and postcoital pill.
primarily reduces FSH secretion. Both synergise 5. The postcoital pill may dislodge a just
to inhibit midcycle LH surge. When the combi- implanted blastocyst or may interfere with
ned pill is taken both FSH and LH are reduced fertilization/implantation.
and the midcycle surge is abolished. As a result,
follicles fail to develop and fail to rupture— Practical considerations
ovulation does not occur. 1. Discontinuation of all OCs results in full return
The minipill and progestin only injectable regi- of fertility within 1–2 months. There may even
men also attenuate LH surge but less consis- be a rebound increase in fertility—chances of
tently—ovulation may occur irregularly in ~ 1/3 multiple pregnancy are more if conception occurs
cycles. Postcoital pill when taken before ovulation within 2–3 cycles. With injectable preparations,
can dampen LH surge and inhibit ovulation in return of fertility is delayed. The cycles take
some cases. However, pregnancy is still prevented several months to normalize or may not do so
by direct actions on the genital tract. at all. They are to be used only if the risk of
2. Thick cervical mucus secretion hostile to permanent infertility is acceptable.
sperm penetration is evoked by progestin action. 2. If a woman on combined pills misses to take
As such, this mechanism can operate with all a tablet, she should be advised to take two tablets
methods except postcoital pill. the next day and continue as usual. If more than
3. Even if ovulation and fertilization occur, the 2 tablets are missed, then the course should be
blastocyst may fail to implant because endomet- interrupted, an alternative method of contracep-
rium is either hyperproliferative or hypersecre- tion used and next course started on the 5th day
tory or atrophic and in any case out of phase of bleeding.
SECTION 5

TABLE 22.3 Effects of different forms of hormonal contraception

Oral pills Injections

Combined Minipill Postcoital Progestin
E+P only P only P only
1. FSH inhibition ++ – – +
2. LH inhibition +++ + + +++
3. Antiovulatory effect +++ + +,– ++
4. Hostile cervical mucus +++ +++ – +++
5. Endometrium Hyper- Out of Unfavourable Atrophic
secretory phase
6. Failure rate 0.1–0.3 2–3 2–4% < 0.5
(pregnancy/100 women years)
7. Contraceptive efficacy ++++ +++ ++ ++++
E—Estrogen; P—Progestin
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 325

3. If pregnancy occurs during use of hormonal 2. Chloasma: pigmentation of cheeks, nose and
contraceptives—it should be terminated by forehead, similar to that occurring in pregnancy.
suction-aspiration, because the risk of malforma- 3. Pruritus vulvae is infrequent.
tions, genital carcinoma in female offspring and 4. Carbohydrate intolerance and precipitation of
undescended testes in male offspring is increased. diabetes in few subjects taking high dose
4. While for most women a pill containing preparations; but this is unlikely with the present
30 µg ethinylestradiol is sufficient, the obese may pills. Many large studies have found no link
require a pill containing 50 µg, and only 20 µg between OC use and development of diabetes.
may be appropriate/sufficient for those with 5. Mood swings, abdominal distention are
cardiovascular risk factor, as well as for those occasional; especially reported with progesterone
above 40 yr age. only contraceptives.
5. If breakthrough bleeding occurs—switch
C. Serious complications
over to a pill containing higher estrogen dose.
1. Leg vein thrombosis and pulmonary
6. In women with contraindications for estrogen
embolism: The older preparations increased the
(see below), a progestin only contraceptive may
incidence of venous thromboembolism, but this
be used.
is found to be only marginal with the newer
reduced steroid content pills. Those who develop
ADVERSE EFFECTS
such complication, generally do it in the 1st year
Since contraceptives are used in otherwise healthy of use. However, even low-dose pills pose
and young women, adverse effects, especially significant risk in women >35 years of age,
long-term consequences assume great significance. diabetics, hypertensives and in those who smoke.
The adverse effects are dose dependent; most of The excess risk normalizes shortly after stopping
the past data with high-dose preparations cannot the OC.
be directly extrapolated to the present-day low- 2. Coronary and cerebral thrombosis resulting
dose preparations which carry relatively minor in myocardial infarction or stroke: A 2 to 6-fold
risk. The following applies primarily to combined increase in risk was estimated earlier, but recent
oral pill which has been most extensively used. studies have found no increased incidence with
the low dose pills in the absence of other risk
A. Nonserious side effects These are
factors.

CHAPTER 22
frequent, especially in the first 1–3 cycles, and
The estrogen component of OC has been
then disappear gradually.
mainly held responsible for venous thromboembo-
1. Nausea and vomiting: similar to morning
lism, while both estrogen and progestin have been
sickness of pregnancy.
blamed for the arterial phenomena. The
2. Headache is generally mild; migraine may be
mechanisms involved may be:
precipitated or worsened.
• Increase in blood clotting factors (coagulabi-
3. Breakthrough bleeding or spotting: especially
lity is enhanced).
with progestin only preparations. Rarely bleeding
• Decreased antithrombin III.
fails to occur during the gap period. Prolonged
• Decreased plasminogen activator in endo-
amenorrhoea or cycle disruption occurs in few thelium.
women taking injectables or minipill. • Increased platelet aggregation.
4. Breast discomfort. 3. Rise in BP: occurred in 5–10% women taking
B. Side effects that appear later the earlier pills. This again is less frequent and
1. Weight gain, acne and increased body hair smaller in magnitude with the low-dose pills of
may be noted due to androgenic action of older today. If the BP rises, best is to stop OCs—BP
19-nortestosterone progestins. The newer ones like normalizes in the next 3–6 months. Both
desogestrel are relatively free of this effect. the estrogen and progestin components are
326 HORMONES AND RELATED DRUGS

responsible for this effect, probably by increasing 4. Suspected/overt malignancy of genitals/

plasma angiotensinogen level and renin activity breast.
which induces salt and water retention. 5. Prophyria.
4. Estrogen tends to raise plasma HDL/LDL ratio 6. Impending major surgery—to avoid excess
(beneficial), but the progestin nullifies this benefit. risk of postoperative thromboembolism.
Lipid profile is not significantly altered by low
Relative contraindications (requiring avoidance/
dose OCs, except that triglyceride level may rise
cautious use under supervision)
marginally which poses no excess risk.
1. Diabetes: control may be vitiated.
5. Genital carcinoma: an increased incidence of
2. Obesity
vaginal, cervical, and breast cancers was feared
3. Smoking
on the basis of animal data, but extensive
epidemiological data over the past 30 years has 4. Undiagnosed vaginal bleeding
repeatedly shown that oral as well as injected 5. Uterine leiomyoma: may enlarge with estro-
contraceptives do not increase the occurrence of genic preparations; progestin only pills can
these cancers in the general population. However, be used.
risk is increased in predisposed individuals. 6. Mentally ill
Growth of already existing hormone dependent 7. Age above 35 years
tumour may be hastened. 8. Mild hypertension
Epidemiological data has recorded minor 9. Migraine
increase in breast cancer incidence among current 10. Gallbladder disease
OC users, but not among past users. Since breast Interactions Contraceptive failure may occur
cancer is rare in young women, this finding is if the following drugs are used concurrently:
considered inconsequential. (a) Enzyme inducers: phenytoin, phenobarbitone,
A protective effect against endometrial carci- primidone, carbamazepine, rifampin, ritonavir.
noma has been shown for the progestin Metabolism of estrogenic as well as progestational
component. Prolonged suppression of gonado- component is increased.
tropic stimulation of ovary may account for the (b) Suppression of intestinal microflora: tetracyc-
lower incidence of ovarian malignancy noted in lines, ampicillin, etc. Deconjugation of estrogens
contraceptive users. excreted in bile fails to occur → their entero-
SECTION 5

6. Benign hepatomas: which may rupture or turn

hepatic circulation is interrupted → blood levels
malignant; incidence of this rare tumour appears
fall.
to be slightly higher in OC users.
With both types of interacting drugs, it is wise
7. Gallstones: Estrogens increase biliary choles-
to switch over to a preparation containing 50 µg
terol excretion; incidence of gallstones is slightly
of ethinylestradiol or to use alternative method
higher in women who are taking OCs, or after
of contraception. Rifampin is usually taken for
long-term use.
a long time and is such a potent enzyme inducer
Contraindications that alternative contraception should be advised.
The combined oral contraceptive pill is absolu- Other health benefits Apart from benefits
tely contraindicated in: due to prevention of unwanted pregnancy and
1. Thromboembolic, coronary and cerebrovas- the risks during delivery, use of oral
cular disease or a history of it. contraceptives affords certain other beneficial
2. Moderate-to-severe hypertension; hyperlipi- effects as a bonus:
daemia. • Lower risk of developing endometrial and
3. Active liver disease, hepatoma or h/o jaun- ovarian carcinoma; probably colorectal cancer
dice during past pregnancy. as well.
 ESTROGENS, PROGESTINS AND CONTRACEPTIVES 327

• Reduced menstrual blood loss and associated 1. Complete suppression of spermatogenesis is

anaemia; cycles if irregular become regular; relatively difficult without affecting other tissues:
premenstrual tension, dysmenorrhoea and millions of spermatozoa are released at each
menorrhagia are ameliorated. ejaculation vs a single ovum per month in women.
• Endometriosis and pelvic inflammatory disease
are improved. 2. Spermatogenesis takes 64 days. A drug which
• Reduced incidence as well as symptomatic relief even completely inhibited spermatogenesis will
of fibrocystic breast disease and ovarian cysts. take a long latent period to produce infertility.
Accordingly, return of fertility will be slow.
Ormeloxifene (Centchroman) It is a non-
steroidal SERM developed at CDRI India as an 3. Gonadotropin suppression inhibits testos-
oral contraceptive. It has predominant estrogen terone secretion as well, resulting in loss of libido
antagonistic action in uterus and breast with little and impotence: unacceptable to all men and to
action on vaginal epithelium and cervical mucus. most spouses.
Endometrial proliferation is suppressed by down 4. Risk of adverse effects.
regulation of endometrial ER. Contraceptive action
is probably due to utero-embyonic asynchrony 5. Most importantly—men don’t get pregnant:
and failure of implantation. Pituitary, ovarian and few would be ready to bear the contingency of
other endocrine functions remain practically regular medication so that their sexual partners
unaffected. Menstrual cycle is not disrupted, but do not become pregnant.
in some women it may be lengthened irregularly.
Excessive bleeding attending anovulatory cycles Drugs and approaches tried are—
(that generally occurs near menopause) is 1. Antiandrogens Depress spermatogenesis, but raise
diminished; ormeloxifene is approved for use in Gns; cause unacceptable loss of libido.
dysfunctional uterine bleeding. 2. Estrogens and progestins Act by suppressing Gns—
The plasma t½ of ormeloxifene is long cause unacceptable feminization.
(~1 week). It prevents conception as long as taken 3. Androgens They inhibit Gns but have poor efficacy.
Even combination with progestin is not reliable.
with return of fertility few months after stoppage.
Failure rate is considered acceptable, but it has 4. Superactive Gn RH analogues They inhibit Gn release
by continuous action; inhibit testosterone secretion as well;
failed to gain popularity for widespread use. Side

CHAPTER 22
produce impotence, loss of libido.
effects are nausea, headache, fluid retention,
5. Cytotoxic drugs Cadmium, nitrofurans and indoles
weight gain, rise in BP and prolongation of suppress spermatogenesis, but are toxic.
menstrual cycles.
6. Gossypol It is a nonsteroidal compound, obtained from
Dose: For contraception—30 mg twice a week for 12 weeks
cotton seed; has been studied in China. It is effective orally—
followed by once a week.
causes suppression of spermatogenesis and reduces sperm
For dysfunctional uterine bleeding—60 mg twice a week
motility—infertility develops after a couple of months. Fertility
for 12 weeks, then once a week for 12 weeks.
is restored several months after discontinuation. However,
CENTRON 30 mg tab, SAHELI 60 mg tab.
about 10% men remain oligozoospermic. During treatment
serum LH and testosterone levels do not change: libido and
MALE CONTRACEPTIVE potency are not affected. The mechanism of action is
uncertain; probably involves direct toxicity on seminiferous
The only way to suppress male fertility by drugs epithelium.
is to inhibit spermatogenesis. Though consider-
Most important adverse effect is hypokalaemia (due to renal
able effort has been made in this direction and
loss of K +) with its attendant muscular weakness (even
effective drugs have been found, no satisfactory/ paralysis). Other side effects are—edema, diarrhoea,
acceptable solution is yet tangible. Reasons are— breathlessness and neuritis.
328 HORMONES AND RELATED DRUGS

) PROBLEM DIRECTED STUDY

22.1 A 55-year-old postmenopausal woman developed a cancerous lump in the left breast for
which radical mastectomy was performed. The tumour was ER positive and only one of the excised
axillary lymph nodes had metastasis. She was put on adjuvant therapy with tamoxifen 20 mg
per day. On her checkup visit one year later, she was found to be asymptomatic with no sign
of local recurrence or lymph node enlargement, but ultrasound examination of the uterus revealed
thickening of endometrium.
(a) What could be the cause and implication of the increase in endometrial thickness?
(b) Should the same adjuvant therapy continue, or should it be stopped altogether, or be replaced
by another drug? Give reasons.
22.2 A 28-year-old mother with a 9 month baby wants to space out her next child and consults
you for taking oral contraceptive.
(a) What questions will you ask, what physical examination will you perform and what investigations
will you order before advising her whether she should take oral contraceptive or not, as well
as for selecting the contraceptive preparation most suitable for her?
(see Appendix-1 for solutions)
SECTION 5
Chapter 23 Oxytocin and Other Drugs
Acting on Uterus

Drugs acting on uterus can primarily affect the tricular nuclei of hypothalamus; are transported
endometrium or the myometrium. The most down the axon and stored in the nerve endings
important drugs affecting endometrium are within the neurohypophysis. They are stored in
estrogens, progestins and their antagonists. separate neurones as complexes with their specific
Myometrium receives both sympathetic and binding proteins (neurophysins) to form granules.
parasympathetic innervation: autonomic drugs can Both are released by stimuli appropriate for
affect its motility. However, directly acting drugs oxytocin, i.e. coitus, parturition, suckling; or for
are more important and have more selective action. ADH, i.e. hypertonic saline infusion, water depri-
The responsiveness of myometrium to drugs is vation, haemorrhage, etc., or nonspecific, i.e. pain
markedly affected by the hormonal and gestational and apprehension. However, the proportion of
status. oxytocin to ADH can vary depending upon the
nature of the stimulus.
UTERINE STIMULANTS
(Oxytocics, Abortifacients)
ACTIONS
These drugs increase uterine motility, especially
at term. 1. Uterus Oxytocin increases the force and
1. Posterior pituitary hormone Oxytocin, frequency of uterine contractions. With low doses,
Desamino oxytocin full relaxation occurs inbetween contractions;
2. Ergot alkaloids Ergometrine (Ergonovine), basal tone increases only with high doses.
Methylergometrine Increased contractility is due to hightened elec-
3. Prostaglandins PGE2, PGF2α, 15-methyl trical activity of the myometrial cell membrane—
PGF2α, Misoprostol burst discharges are initiated and accentuated.
4. Miscellaneous Ethacridine, Quinine. Estrogens sensitize the uterus to oxytocin; increase
oxytocin receptors. Nonpregnant uterus and that
OXYTOCIN during early pregnancy is rather resistant to
oxytocin; sensitivity increases progressively in the
Oxytocin is a nonapeptide secreted by the posterior third trimester; there is a sharp increase near term
pituitary along with vasopressin (ADH). Pituitary and quick fall during puerperium. Progestins
extract was first used in labour in 1909. decrease the sensitivity, but this effect is not
Controversy as to whether the antidiuretic and marked in vivo.
uterine stimulating activities were due to one At term the increased contractility is restricted
substance or two separate substances was finally to the fundus and body; lower segment is not
resolved by du Vigneaud in 1953 when he contracted; may even be relaxed.
separated Oxytocin and Vasopressin, determined
their chemical structure and synthesized them. Mechanism of action Action of oxytocin on
Both are nonapeptides which differ at positions myometrium is independent of innervation. There
3 and 8. are specific G-protein coupled oxytocin receptors
Both oxytocin and ADH are synthesized within which mediate the response mainly by depo-
the nerve cell bodies in supraoptic and paraven- larization of muscle fibres and influx of Ca2+ ions
330 HORMONES AND RELATED DRUGS

as well as through phosphoinositide hydrolysis ejection reflex is absent in the hypophysectomized

and IP3 mediated intracellular release of Ca2+ ions. animal.
The number of oxytocin receptors increases
3. Neurotransmission Oxytocin appears to
markedly during later part of pregnancy. Oxytocin
function as a peptide neurotransmitter of
increases PG synthesis and release by the
oxytocinergic neurones in the hypothalamus and
endometrium which may contribute to the
brainstem to regulate autonomic outflow.
contractile response. Distinct subtypes of oxytocin
receptors have been shown on the myometrium
PHARMACOKINETICS
and the endometrium.
Being a peptide, oxytocin is inactive orally and
2. Breast Oxytocin contracts the myoepi- is generally administered by i.m. or i.v. routes,
thelium of mammary alveoli and forces milk into rarely by intranasal spray. It is rapidly degraded
the bigger milk sinusoids—‘milk ejection reflex’ in liver and kidney; plasma t½ 6–12 min, and
(milk letdown in cattle) is initiated by suckling is still shortened at term. Pregnant uterus and
so that it may be easily sucked by the infant. placenta elaborate a specific aminopeptidase
Oxytocin has been used in milch cattle to facilitate called oxytocinase—which can be detected in
milking. maternal plasma.
3. CVS Conventional doses used in obstetrics Unitage and preparations 1 IU of oxytocin = 2 µg
have no effect on BP, but higher doses cause of pure hormone. Commercially available oxytocin is produced
vasodilatation → brief fall in BP, reflex synthetically.
OXYTOCIN, SYNTOCINON 2 IU/2 ml and 5 IU/ml inj.,
tachycardia and flushing. This action is most PITOCIN 5 IU/0.5 ml inj.
marked in chicken and is used for bioassay of
oxytocin. The umbilical vessels are markedly USE
constricted; oxytocin may help in their closure
at birth. 1. Induction of labour Labour needs to be
induced in case of postmaturity or prematurely
4. Kidney Oxytocin in high doses exerts in toxaemia of pregnancy, diabetic mother, erythro-
ADH-like action—urine output is decreased: blastosis, ruptured membranes or placental
pulmonary edema can occur if large amounts of insufficiency. For this purpose oxytocin is given
i.v. fluids and oxytocin are infused together.
SECTION 5

by slow i.v. infusion: 5 IU is diluted in 500 ml

Conventional doses are without any effect. of glucose or saline solution (10 milli IU/ml)—
infusion is started at a low rate and progressively
Physiological role accelerated according to response (0.2–2.0 ml/
1. Labour Oxytocin is released during labour min). Before starting infusion, confirm that:
and the uterus is highly sensitive to it at this • presentation is correct
time. However, it does not appear to be obligatory • foetal lungs are adequately mature
for initiating parturition—delivery occurs even • there is no cephalopelvic disproportion
in hypophysectomized animals and humans, • no placenta previa
though labour may be prolonged in its absence. • no foetal distress and
A facilitatory role is more plausible. PGs and • no uterine scar (due to previous surgery).
PAF are complementary to oxytocin. Uterine contractions are then closely monitored:
the drug is discontinued when they are strong
2. Milk ejection reflex Suckling induces
enough. Usually a total of 2–4 IU is needed.
oxytocin release from pituitary which contracts
the myoepithelial cells. These cells in breast are 2. Uterine inertia When uterine contrac-
more sensitive than myometrium to oxytocin. Milk tions are feeble and labour is not progressing
 OXYTOCIN AND OTHER DRUGS ACTING ON UTERUS 331

satisfactorily—oxytocin can be infused i.v. (as the presenting part through incompletely dilated
described above) to augment contractions. It birth canal, causing maternal and foetal soft tissue
should not be used to hasten normally progressing injury, rupture of uterus, foetal asphyxia and death.
labour. Before deciding to use an oxytocic for (ii) Water intoxication: This occurs due to ADH
strengthening uterine contractions, all the like action of large doses given along with i.v.
conditions as setout above (for induction of labour) fluids, especially in toxaemia of pregnancy and
must be fulfilled. Too strong contraction can be renal insufficiency. It is a serious (may be fatal)
catestrophic: use should only be made in selected complication.
cases and by experienced people. Desamino-oxytocin It has been developed as a buccal
Oxytocin is the drug of choice and is preferred formulation; action is similar to injected oxytocin, but less
consistent. Its indications are:
over ergometrine/PGs for the above two purposes:
Induction of labour: 50 IU buccal tablet repeated every 30
(a) Because of its short t½ and slow i.v. infusion, min, max 10 tabs.
intensity of action can be controlled and action Uterine inertia: 25 IU every 30 min.
can be quickly terminated. Promotion of uterine involution 25–50 IU 5 times daily for
7 days.
(b) Low concentrations allow normal relaxation Breast engorgement 25–50 IU just before breast feeding.
inbetween contractions—foetal oxygenation does BUCTOCIN 50 IU tab
not suffer. Carbetocin It is a long-acting analogue of oxytocin that
(c) Lower segment is not contracted: foetal has been introduced recently for prevention of uterine atony
descent is not compromised. after caesarean section and to control PPH.
(d) Uterine contractions are consistently
augmented. ERGOMETRINE, METHYLERGOMETRINE
3. Postpartum haemorrhage, Caesarean The pharmacology of ergot alkaloids is described
section Oxytocin 5 IU may be injected i.m. in Ch. 12. Only the amine ergot alkaloid ergo-
or by i.v. infusion for an immediate response, metrine (ergonovine) and its derivative methyl-
especially in hypertensive women in whom ergometrine are used in obstetrics. Both have
ergometrine is contraindicated. It acts by forcefully similar pharmacological property.
contracting the uterine muscle which compresses 1. Uterus They increase force, frequency and
the blood vessels passing through its mesh work duration of uterine contractions. At low doses,

CHAPTER 23
to arrest haemorrhage from the inner surface contractions are phasic with normal relaxation in
exposed by placental separation. between, but only moderate increase in dose raises
4. Breast engorgement It may occur due to the basal tone, contracture occurs with high doses.
inefficient milk ejection reflex. Oxytocin is effec- Gravid uterus is more sensitive, especially at term
tive only in such cases; an intranasal spray may and in early puerperium. Their stimulant action
be given few minutes before suckling. It does involves the lower segment also. The uterotonic
not increase milk production. action is believed to result from partial agonistic
action on 5-HT2 and α adrenergic receptors.
5. Oxytocin challenge test It is performed to determine
uteroplacental adequacy in high risk pregnancies. Oxytocin 2. CVS Ergometrine and methylergometrine
is infused i.v. at very low concentrations till uterine are much weaker vasoconstrictors than ergotamine
contractions are elicited every 3–4 mins. A marked increase
in foetal heart rate indicates uteroplacental inadequacy. The
and have low propensity to cause endothelial
test is risky and is rarely performed. damage. Though they can raise BP, this is not
significant at doses used in obstetrics.
Adverse effects 3. CNS No overt effects occur at usual doses.
(i) Injudicious use of oxytocin during labour can However, high doses produce complex actions—
produce too strong uterine contractions forcing partial agonistic/antagonistic interaction with
332 HORMONES AND RELATED DRUGS

adrenergic, serotonergic and dopaminergic recep- with oxytocin 5 IU i.m./i.v. may be used in severe
tors in the brain have been shown. bleeding.
These drugs produce sustained tonic uterine
4. GIT High doses can increase peristalsis.
contraction: perforating uterine arteries are
Methylergometrine is 1½ times more potent than compressed by the myometrial meshwork—
ergometrine on the uterus, but other actions are bleeding stops.
less marked. It has thus replaced ergometrine at 2. After caesarean section/instrumental delivery
many obstetric units. —to prevent uterine atony.
Pharmacokinetics In contrast to the amino acid 3. To ensure normal involution: A firm and active
ergot alkaloids, ergometrine and methylergomet- uterus involutes rapidly. To ensure this: 0.125
rine are rapidly and nearly completely absorbed mg of ergometrine or methylergometrine has been
from the oral route. The onset of uterine action given TDS orally for 7 days. However, routine
is: Oral—15 min; i.m.—5 min; i.v.—almost imme- use in all cases is not justified because normal
diate. involution is not hastened. Multipara and others
They are partly metabolized in liver and in whom slow involution is apprehended, these
excreted in urine. Plasma t½ is 1–2 hours. drugs may be given prophylactically.
Effects of a single dose last 3–4 hours. 4. Diagnosis of variant angina: A small dose of ergometrine
injected i.v. during coronary angiography causes prompt
Adverse effects Ergometrine and methylergo- constriction of reactive segments of coronary artery that are
responsible for variant angina.
metrine are less toxic than ergotamine. When
ERGOMETRINE 0.25, 0.5 mg tab, 0.5 mg/ml inj.
correctly used in obstetrics—hardly any compli- Methylergometrine: METHERGIN, METHERONE,
cations arise. Nausea, vomiting and rise in BP ERGOMET 0.125 mg tab, 0.2 mg/ml inj.
occur occasionally. They can decrease milk
secretion if higher doses are used for many days PROSTAGLANDINS
postpartum; this is due to inhibition of prolactin
release (dopaminergic action). PGE2, PGF2α and 15-methyl PGF2α are potent
Ergometrine should be avoided in— uterine stimulants, especially in the later part of
(i) patients with vascular disease, hypertension, pregnancy and cause ripening of cervix. Their
toxaemia. actions and use in obstetrics is described in
(ii) presence of sepsis—may cause gangrene. Ch. 13. Since misoprostol (a PG analogue used
SECTION 5

(iii) liver and kidney disease. for peptic ulcer) produces less side effects, it is
They are contraindicated during pregnancy and being used for obstetric indications as well.
before 3rd stage of labour. Ethacridine Available as 50 mg/50 ml solution
(EMCREDIL, VECREDIL) for extra-amniotic infusion:
Use 150 ml (containing 150 mg) is injected slowly for medical
termination of pregnancy in the 2nd trimester. This is an
1. The primary indication for ergometrine/ alternative method used occasionally.
methylergometrine is to control and prevent
postpartum haemorrhage (PPH): 0.2–0.3 mg i.m.
at delivery of anterior shoulder reduces blood UTERINE RELAXANTS
loss attending delivery and prevents PPH. (Tocolytics)
However, routine use in all cases is not justified— These are drugs which decrease uterine motility.
only in those expected to bleed more, e.g. grand They have been used to delay or postpone labour,
multipara, uterine inertia. Multiple pregnancy arrest threatened abortion and in dysmenorrhoea.
should be excluded before injecting. Prevention of premature labour in those at higher
If PPH is occurring—0.5 mg i.v. is recom- risk due to past history has been attempted by
mended. A combination of 0.5 mg ergometrine administration of high dose progesterone in the
 OXYTOCIN AND OTHER DRUGS ACTING ON UTERUS 333

later half of pregnancy, with some success. YUTOPAR, RITROD 10 mg/ml inj (5 ml amp), 10 mg tab.
Suppression of premature labour may be needed RITODINE 10 mg tab, 10 mg in 1 ml inj.
to allow the foetus to mature, to allow time for Salbutamol and terbutaline can be used as
initiating glucocorticoid therapy for foetal lung alternatives to ritodrine. Isoxsuprine oral/i.m. has
maturation or to transfer the mother in labour to been used to stop threatened abortion, but efficacy
a centre with proper facilities. However, no clearly is uncertain.
satisfactory drug is available since none of them
has been shown to improve foetal outcome. An 2. Calcium channel blockers Because
attempt to delay premature labour is likely to influx of Ca2+ ions plays an important role in
succeed only if cervical dilatation is < 4 cm and uterine contractions, Ca2+ channel blockers (see
‘taking up’ of lower segment is minimal. Measures Ch. 39) reduce the tone of myometrium and
to delay labour should not be undertaken if oppose contractions. These drugs, especially
membranes have ruptured, antepartum nifedipine, which has prominent smooth muscle
haemorrhage is occurring, in severe toxaemia of relaxant action, can postpone labour if used early
pregnancy, intrauterine infection or foetal death. enough. Efficacy comparable to β2 adrenergic
agonists has been demonstrated and side effects
1. Adrenergic agonists (see Ch. 9) are fewer. Oral nifedipine 10 mg repeated once
Ritodrine, the β2 selective agonist having more or twice after 20–30 min, followed by 10 mg
prominent uterine relaxant action is approved to 6 hourly has been used. Tachycardia and
suppress premature labour and to delay delivery hypotension are prominent at doses which
in case of some exigency or acute foetal distress. suppress uterine contractions. Reduced placental
For dependable action it is started as 50 µg/min perfusion causing foetal hypoxia is apprehended.
i.v. infusion, the rate is increased every 10 min However, fewer babies delivered after nifedipine
till uterine contractions cease or maternal HR rises needed intensive care.
to 120/min. Contractions are kept suppressed by
continuing i.v. infusion or by 10 mg i.m. 4–6 3. Oxytocin antagonist Atosiban is a peptide analogue
of oxytocin that acts as antagonist at the oxytocin receptors.
hourly followed by 10 mg oral 4–6 hourly. In clinical trials, it has been found to suppress premature
However, treatment beyond 48 hours is not uterine contractions and postpone preterm delivery with fewer
recommended, since risk to mother increases and cardiovascular and metabolic complications than β2 adrenergic

CHAPTER 23
benefit is uncertain. Delivery can be postponed in agonists. In Europe and UK it is available for inhibition
of labour between 24–33 weeks of gestation, and may offer
about 70% cases by few hours to few weeks. better benefit: risk ratio than other tocolytics. However, it
However, cardiovascular (hypotension, tachycar- is not yet approved in USA and India.
dia, arrhythmia, pulmonary edema) and metabolic
4. Magnesium sulfate Infused i.v. it is a first line drug
(hyperglycaemia, hyperinsulinaemia, hypo- for prevention and treatment of seizures in preeclampsia and
kalaemia) complications and anxiety, restlessness, eclampsia. It also acts as a tocolytic by competing with Ca2+
headache occur frequently. Use of ritodrine to ions for entry into myometrium through both voltage sensitive
as well as ligand gated Ca2+ channels. However, its use to
arrest labour has been found to increase maternal delay premature labour is risky, may increase perinatal
morbidity. Foetal pulmonary edema can develop; mortality and is not recommended now.
volume of i.v. infusion should be kept to a 5. Miscellaneous drugs Ethyl alcohol, nitrates, proges-
minimum to avoid fluid overload. The neonate terone, general anaesthetics and indomethacin (PG synthesis
inhibitors) are the other drugs, which can depress uterine
may develop hypoglycaemia and ileus. It should
contractions. However, their effect is not dependable and
not be used if mother is diabetic, having heart they are not used clinically as tocolytics.
disease, or receiving β blockers or steroids. Halothane is an efficacious uterine relaxant that has been
Ritodrine has been discontinued in the USA, but is still used as the anaesthetic when external or internal version is
available in UK and India. attempted.
334 HORMONES AND RELATED DRUGS

) PROBLEM DIRECTED STUDY

23.1 A full term primigravida aged 26 years is brought to the hospital with the complaint of
having labour pains for the past 24 hours without making much progress. Two hours ago she
had passed meconium stained liquor. The lady is in distress, mildly dehydrated and looks exhausted.
The presentation is vertex and head is engaged, but cervix is incompletely dilated and uterine
contractions are relatively weak. Foetal tachycardia is noted with irregularity during contractions.
(a) What course of action is appropriate?
(b) Can she be administered a uterine stimulant to strengthen the contractions? If yes, which
drug should be given and how? If no, then why?
(see Appendix-1 for solution)
SECTION 5
Chapter 24 Drugs Affecting Calcium Balance

CALCIUM Influences affecting bone turnover

After C, O, H and N, calcium is the most abun- ↑ Resorption ↓ Resorption

dant body constituent, making up about 2% of
Corticosteroids Androgens/Estrogens
body weight, or 1–1.5 kg in an adult. Over 99% Parathormone Calcitonin
of this is stored in bones, the rest being distributed Thyroxine (excess) Growth hormone
in plasma and all tissues and cells. Calcium serves Hypervitaminosis D Bisphosphonates
Prostaglandin E2 Fluoride
important physiological roles.
Interleukin 1 & 6 Gallium nitrate
Alcoholism Mithramycin
Physiological roles Loop diuretics Thiazide diuretics
1. Calcium controls excitability of nerves and
muscles and regulates permeability of cell mem- to albumin; 10% is complexed with citrate, phos-
branes. It also maintains integrity of cell phate and carbonate in an undissociable form;
membranes and regulates cell adhesion. the remaining (about 50%) is ionized and physio-
2. Ca2+ ions are essential for excitation-contrac- logically important. For example, in hypoalbu-
tion coupling in all types of muscle and excitation- minemia, total plasma calcium may be low but
secretion coupling in exocrine and endocrine the concentration of Ca2+ ion is usually normal.
glands, release of transmitters from nerve ending Acidosis favours and alkalosis disfavours ioniza-
and other release reactions. tion of calcium. As such, hyperventilation (by
3. Ca 2+ is an intracellular messenger for raising plasma pH) precipitates tetany and
hormones, autacoids and transmitters. laryngospasm in calcium deficiency by reducing
4. Ca2+ controles impulse generation in heart; ionization.
determines level of automaticity and A-V Calcium turnover Major fraction of calcium in the bone
conduction. is stored as crystalline hydroxyapatite deposited on the organic
bone matrix osteoid, while a small labile pool is in dynamic
5. Ca2+ is essential for coagulation of blood.
equilibrium with plasma. Even the fully laid down parts
6. Calcium serves structural function in bone of the bone undergo constant remodeling by way of two
and teeth. closely coupled but directionally opposite processes of
resorption and new bone formation (Fig. 24.2). Millions of
Plasma calcium level It is precisely regulated tiny remodeling units are working on the surface of bone
by 3 hormones almost exclusively devoted to this trabeculae and Haversian canals to dig micropits by
function, viz. parathormone (PTH), calcitonin and osteoclastic activity and then repair by osteoblastic activity
in which first collagen and other proteins (osteoid) are
calcitriol (active form of vit D). These regulators deposited followed by mineralization; the full cycle taking
control its intestinal absorption, exchange with 4–6 months. Diet, exercise, several hormones and drugs
bone and renal excretion as summarized in Fig. regulate the number and efficiency of bone remodeling units
24.1. In addition, several other hormones, meta- at any given time. Remodeling deficits accumulate over life-
time to account for age related bone loss, the pace of which
bolites and drugs influence calcium homeostasis can be retarded or accelerated by modulating the above listed
(see box). influences. Estrogen lack after menopause mainly causes loss
of trabecular bone, particularly affecting vertebrae, wrist bones
Normal plasma calcium is 9–11 mg/dl. Of this and femoral neck. Minimal trauma/compression fractures are
about 40% is bound to plasma proteins—chiefly most common at these sites.
336 HORMONES AND RELATED DRUGS

Fig. 24.1: Regulation of plasma level of calcium.

————→ stimulation, - - - - - - → Inhibition; Bold arrow indicates—major action.
PTH—Parathormone; 25-OHD3—Calcifediol; 1,25 (OH)2D3—Calcitriol.

Absorption and excretion Calcium is absor- Preparations

bed by facilitated diffusion from the entire small 1. Calcium carbonate (40% Ca): It is an insoluble, tasteless
and nonirritating salt. Reacts with gastric HCl to form chloride,
intestine as well as from duodenum by a carrier- and can be used as antacid. It is the most common salt
mediated active transport under the influence present in calcium supplements, but gastric acid is required
of vit D. Phytates, phosphates, oxalates and for converting it into the absorbable form. Calcium availability
from it is poor in patients taking proton pump inhibitors
tetracyclines complex with Ca2+ in an insoluble (PPIs), H2 blockers, and in elderly.
form in the intestines and interfere with its 2. Calcium citrate (as tetrahydrate, 21% Ca2+): Slightly
SECTION 5

absorption. Glucocorticoids and phenytoin also soluble in water, but dissolves well in presence of HCl. It
is nonirritating and is used in supplements; absorption in
reduce calcium absorption. patients taking PPIs/H2 blockers and elderly is satisfactory.
Ionized calcium is totally filtered at the glome- 3. Calcium gluconate (9% Ca): is available as 0.5 g and
rulus and most of it is reabsorbed in the tubules. 1 g tablets and 10% injection (5 ml amp.). It is nonirritating
to g.i.t. and the vascular endothelium. A sense of warmth
Vit D and PTH increase, while calcitonin decreases
is produced on i.v. injection: extravasation should be guarded.
tubular reabsorption of Ca2+. About 300 mg of It is the preferred injectable salt.
endogenous calcium is excreted daily: half in urine 4. Calcium lactate: (13% Ca) is given orally, nonirritating
and half in faeces. To maintain calcium balance, and well tolerated.
5. Calcium dibasic phosphate (23% Ca): is insoluble,
the same amount has to be absorbed in the small reacts with HCl to form soluble chloride in the stomach.
intestine from the diet. Because normally only 1/3rd It is bland; used orally as antacid and to supplement calcium.
of ingested calcium is absorbed, the dietary Availability of calcium from it is reduced by PPIs and H2
blockers.
allowance for calcium is 0.8–1.5 g per day. However, 6. Calcium chloride (27% Ca): It is freely soluble in water,
fractional calcium absorption is greater in presence but highly irritating to gastric mucosa and tissues; therefore
of calcium deficiency and low dietary calcium. not used.
Thiazide diuretics impede calcium excretion Side effects Calcium supplements are
by facilitating tubular reabsorption. usually well tolerated; only g.i. side effects like
 DRUGS AFFECTING CALCIUM BALANCE 337

constipation, bloating and excess gas (especially given to fracture patients, but if diet is adequate
with cal. carbonate) have been reported. this does not accelerate healing.
Some combined formulations 3. Osteoporosis In the prevention and treat-
CALCINOL-RB: Cal. carb 0.375 g, Cal. Phos 75 mg + vit ment of osteoporosis with alendronate/HRT/
D3 250 IU tab. raloxifene, it is important to ensure that calcium
MILICAL: Cal. citrate 1 g + vit D3 200 IU tab. deficiency does not occur. Calcium + vit D3 have
CALCIBONE: Cal. citrate 1 g + vit D3 200 IU tab and susp.
CALSHINE: Cal. citrate 0.5 g + vit D3 500 IU tab. adjuvant role to these drugs in prevention and
CALCIUM-SANDOZ: Cal. gluco-bionate 137.5 mg/ml inj. treatment of osteoporosis.
10 ml amp., also tabs containing cal. carbonate 650 mg. However, the efficacy of calcium ± vit D
KALZANA: Cal. dibasic phos 430 mg + Vit C and D3 200 supplements alone in increasing bone mass or
IU tab, also syrup: Cal. gluconate 300 mg, Cal. lactobionate
1.1 g, Cal. phos. 75 mg per 5 ml, containing Vit A, C, preventing fractures among menopausal women/
niacinamide and D3 200 IU. elderly men is controversial. It does not appear to
OSTOCALCIUM: Cal. phos 380 mg + Vit D3 400 IU tab, reduce fracture risk in otherwise healthy subjects
also syrup: Cal. phos 240 mg per 5 ml containing Vit D3 taking adequate diet. In the recently concluded
200 IU and B12.
SHELCAL: Cal. carb. 625 mg (eq 250 mg elemental cal), 7 year prospective WHI study involving >36000
Vit D3 125 IU tab and per 5 ml syr. postmenopausal women (51–79 years), the overall
MACALVIT: Cal. carb. 1.25 g, cholecalciferol 250 IU tab; risk of fractures was the same in the calcium
Cal. gluconate 1.18 g, Cal. lactobionate 260 mg + Vit D3 (1 g/day) + vit D (400 IU/day) group as in the
100 IU per 5 ml syr.
CALCIMAX: Cal. carb. (150 mg cal), dibasic cal. phos. placebo group, though the bone mineral density
(23.3 mg cal) with magnesium, zinc and vit D3 200 IU at the hip was 1% higher in the treated group.
tab.; also syrup cal. carb. (150 mg cal) with magnesium, Certain subgroups of osteoporotic subjects may
zinc and vit D3 200 IU per 5 ml syrup. benefit from calcium supplements, but the benefit
Use appears to be marginal and limited to cortical
bone loss only. On the other hand, a metaanalysis
1. Tetany For immediate treatment of severe has shown that subjects receiving calcium
cases 10–20 ml of Cal. gluconate (elemental supplements had a 27% higher incidence of MI.
calcium 90–180 mg) is injected i.v. over 10 min, Thus, calcium supplements should be given only
followed by slow i.v. infusion. A total of 0.45- to subjects taking diet low in calcium.
0.9 g calcium (50 to 100 ml of cal. gluconate 4. Empirically, Cal. gluconate i.v. has been used

CHAPTER 24
solution) over 6 hours is needed for completely in dermatoses, paresthesias, weakness and other
reversing the muscle spasms. Supportive treatment vague complaints. Any benefit is probably psy-
with i.v. fluids and oxygen inhalation may be chological due to warmth and other subjective
required. Long-term oral treatment to provide 1– effects produced by the injection.
1.5 g of calcium daily is instituted along with 5. As antacid (see Ch. 46).
vit. D. Milder cases need oral therapy only.
2. As dietary supplement especially in growing PARATHYROID HORMONE
children, pregnant, lactating and menopausal (Parathormone)
women. The dietary allowance recommended by
Vassale and Generali (1900) were the first to perform selective
National Institute of Health (1994) is— parathyroidectomy (without removing thyroids) and found
• Children 1–10 yr : 0.8–1.2 g that it produced tetany and death. MacCallum and Voegtlin
• Young adult 11–24 yr, pregnant in 1909 established this to be due to decrease in plasma
and lactating women : 1.2–1.5 g calcium levels; parathormone (PTH) was isolated in 1925.
• Men 25–65 yr, women 25–50 yr
PTH is a single chain 84 amino acid poly-
and 51–65 yr if taking HRT : 1.0 g
• Women 51–65 yr not taking HRT, peptide, MW 9500. It is synthesized as prepro-
every one > 65 yr : 1.5 g PTH, the excess amino acids are split off in two
Calcium supplement can reduce bone loss in steps and it is then stored in intracellular vesicles.
predisposed women as well as men. It is often Secretion of PTH is regulated by plasma Ca2+
338 HORMONES AND RELATED DRUGS

concentration through a calcium-sensing receptor of vit D) in the kidney by activating 1α-

(CaSR), that is a G-protein coupled receptor on hydroxylase. Calcitriol then promotes intestinal
the surface of parathyroid cells. There is no trophic absorption of calcium.
hormone for it. Fall in plasma Ca2+ induces PTH
4. PTH decreases calcium levels in milk, saliva
release and rise inhibits secretion by decreasing
and ocular lens. This may be responsible for
cAMP in the parathyroid cells. Agents that increase
development of cataract in hypoparathyroidism.
cAMP cause PTH release, but direct activation
of protein kinase C by fall in Ca2+ concentration Mechanism of action The PTH receptor is
is more important physiologically. Prolonged a G protein coupled receptor which on activation
hypocalcaemia causes hypertrophy and increases cAMP formation and intracellular Ca2+
hyperplasia of parathyroids, while sustained in target cells. In bone, the target cell is the osteo-
hypercalcaemia has the opposite effect. Changes blast because PTH receptors are not expressed
in phosphate concentration in plasma affect PTH on the surface of osteoclasts. Acting on the
secretion indirectly by altering Ca2+ concentration. osteoblast, PTH induces a factor ‘Receptor for
The active form of vit. D calcitriol inhibits activation of nuclear factor-κB-ligand’ (RANKL)
expression of PTH gene in parathyroid cells which diffuses and combines with RANK on
reducing PTH production. PTH is rapidly osteoclast precursors and transforms them into
degraded in liver and kidney; its plasma t½ is osteoclasts as well as activates osteoclasts (Fig.
2–5 min. 24.2). In addition, birth rate of bone remodeling
units into which osteoclasts are recruited is
Actions enhanced. Formation of the remodeling pit is
followed by osteoblastic deposition of new bone
PTH increases plasma calcium levels by:
into it. PTH enhances proliferation and
1. Bone PTH promptly increases resorption of differentiation of preosteoblasts and deposition
calcium from bone. This is the most prominent of osteoid as well. Bone resorption predominates
action of PTH—exerted by increasing the number when high concentrations of PTH are present
of bone remodeling units and activating osteo- continuously, but intermittent exposure to low
clasts when high concentrations are present concentrations has the opposite effect.
continuously. Since bone resorption is followed Hypoparathyroidism Manifestations are:
SECTION 5

by new bone deposition, this is also promoted Low plasma calcium levels, tetany, convulsions, laryngospasm,
by PTH: increased bone formation occurs when paresthesias, cataract and psychiatric changes. Pseudohypo-
PTH is given intermittently and in low doses. parathyroidism occurs due to reduced sensitivity of target
cells to PTH caused by a mutant G protein that couples
2. Kidney PTH increases calcium reabsorption PTH receptor activation to cAMP generation in target cells.
in the distal tubule and provides moment to Hyperparathyroidism It is mostly due to parathyroid
tumour. It produces—
moment regulation of calcium excretion. It also Hypercalcaemia, decalcification of bone—deformities and
promotes phosphate excretion which tends to fractures (osteitis fibrosa generalisata), metastatic calcification,
supplement the hypercalcaemic effect. However, renal stones, muscle weakness, constipation and anorexia.
grossly increased plasma calcium level occurring Treatment is surgical removal of the parathyroid tumour.
in hyperparathyroidism overrides the direct action When this is not possible—low calcium, high phosphate diet
on tubules and calcium excretion in urine is with plenty of fluids is advised.
actually increased. The converse occurs in Cinacalcet It activates the Ca2+ sensing receptor (CaSR) in
hypoparathyroidism. the parathyroids and blocks PTH secretion. It is indicated in
secondary hyperparathyroidism due to renal disease and in
3. Intestines PTH has no direct effect on parathyroid tumour.
calcium absorption but increases it indirectly by Use PTH is not used in hypoparathyroidism because plasma
enhancing the formation of calcitriol (active form calcium can be elevated and kept in the normal range more
 DRUGS AFFECTING CALCIUM BALANCE 339

Fig. 24.2: Hormonal regulation of bone remodeling unit

The monocyte osteoclast precursor cells in the marrow near the bony surface are activated to proliferate and fuse to
form multinucleated osteoclasts. The osteoclast-precursors express a ‘receptor for activation of nuclear factor-κ B’
(RANK) on their surface. The osteoblasts on activation release a protein RANK-ligand (RANKL). When RANKL is
bound to RANK on the surface of osteoclast-precursors they are transformed into mature osteoclasts and develop
bone lysing ruffled surface. A bone resorption pit is dug out by secretion of acid and proteolytic acid hydrolases.
Osteoblasts produce another protein osteoprotegerin (OPG) as well, which can bind RANKL and prevent it from
combining with RANK to activate osteoclasts. Thus, osteoblasts by producing RANKL and OPG regulate bone
resorption.
After formation of the remodeling pit, preosteoblasts from bone marrow stem cells proliferate, migrate to the base
of the pit, transform into mature osteoblasts and laydown new osteoid, which is later mineralized.
Parathormone (PTH) acts on PTH-receptor located on the osteoblast membrane and induces RANKL production—
indirectly activating osteoclast differentiation and function. Subsequently PTH promotes new bone formation as well.
Calcitriol also induces RANKL in osteoblasts to indirectly activate osteoclasts. Similarly, it promotes laying of
osteoid as well as bone mineralization.
Calcitonin directly inhibits osteoclast function and probably enhances osteoblastic new bone formation.

CHAPTER 24
conveniently by vit D therapy. PTH has to be given intermittent action is produced and the bone forming action
parenterally, while vit D can be given orally. Vit D is cheap. predominates over bone resorbing action. High cost and need
However, recombinant human PTH (1–84 amino acid) has for daily s.c. injections are the limitations. Its use may be
been produced and is being clinically evaluated for use in justified in severely osteoporotic women, those who have
hypoparathyroidism. already suffered osteoporotic fractures or have multiple risk
factors for fracture. Treatment beyond 2 years is not
Teriparatide This recombinant preparation of 1–34 residues
recommended. Side effects include dizziness and leg
of amino terminal of human PTH has been recently introduced
cramps. Pagets disease and hypercalcaemia are the contraindi-
for the treatment of severe osteoporosis. It duplicates all
cations.
the actions of long (1–84) PTH. Injected s.c. 20 μg once
daily, it acts only for 2–3 hours, and has been found to Diagnostic use To differentiate pseudo from true hypopara-
increase bone mineral density in osteoporotic women. The thyroidism: teriparatide is given i.v.: if plasma calcium level
effect was faster and more marked than that produced by fails to rise, then it is pseudohypoparathyroidism.
estrogens and bisphosphonates (BPNs). Teriparatide is the
only agent which stimulates bone formation, whereas the
other two only check bone resorption. In clinical trials it CALCITONIN
was found to be equally or more effective than estrogens
and BPNs in reducing risk of vertebral as well as non-vertebral Calcitonin is the hypocalcaemic hormone dis-
fractures in osteoporotic women as well as men. After s.c. covered by Copp in 1962. It is a 32 amino acid
injection its plasma t½ is 1 hr; given once daily only single chain polypeptide (MW 3600) produced
340 HORMONES AND RELATED DRUGS

by parafollicular ‘C’ cells of thyroid gland. Therefore, used only to supplement BPNs initially, because
Parathyroids, thymus and cells of medullary BPNs take 24–48 hours to act.
2. Postmenopausal osteoporosis Though i.m. or s.c.
carcinoma of thyroid also contain calcitonin. calcitonin can be used, a nasal spray formulation delivering
Synthesis and secretion of calcitonin is regu- 200 IU per actuation is employed. MIACALCIN NASAL
lated by plasma Ca2+ concentration itself: rise in SPRAY, OSTOSPRAY 2200 IU metered dose vial,
plasma Ca2+ increases, while fall in plasma Ca2+ CALCINASE 200 IU per actuation nasal spray. One spray
in alternate nostril daily has been shown to increase bone
decreases calcitonin release. However, circulating mineral density in menopausal women and to reduce vertebral,
level of calcitonin is low and its physiological but not nonvertebral, fractures. It is less effective than BPNs/
role in regulating plasma Ca2+ appears to be minor. HRT. Calcitonin is indicated only when other drugs cannot
The plasma t½ of calcitonin is 10 min, but its be given and in women who are menopausal for at least
5 years with definite evidence of osteoporosis. Though nausea
action lasts for several hours.
and flushing are less with nasal spray, rhinitis, epistaxis,
nasal ulceration and headache are produced frequently.
Actions
3. Paget’s disease 100 IU i.m./s.c. daily or on alternate
The actions of calcitonin are generally opposite days produces improvement for few months. Later, resistance
to that of PTH. It inhibits bone resorption by usually develops due to production of antibodies.
Bisphosphonates are preferred; calcitonin may be used as
direct action on osteoclasts—decreasing their adjuvant or 2nd line drug.
ruffled surface which forms contact with the
4. Diagnosis of medullary carcinoma of thyroid Detection
resorptive pit. Whether it also promotes calcium
of high blood level of calcitonin is diagnostic of this tumour,
deposition by osteoblasts is not certain. The which arises from the calcitonin producing parafollicular cells
hypocalcaemic action of calcitonin lasts ~8 hours. of thyroid.
Calcitonin inhibits proximal tubular
reabsorption of calcium and phosphate by direct VITAMIN D
action on the kidney. However, hypocalcaemia
Vitamin D is the collective name given to
overrides the direct action by decreasing the total
antirachitic substances synthesized in the body
calcium filtered at the glomerulus—urinary Ca2+
is actually reduced. and found in foods activated by UV radiation.
The actions of calcitonin are mediated through D3 : cholecalciferol — synthesized in the skin
a G-protein coupled calcitonin receptor (CTR) under the influence of UV rays.
and increase in cAMP formation, but its target D2 : calciferol—present in irradiated food—
yeasts, fungi, bread, milk.
SECTION 5

cells are different from that of PTH.

D1 : mixture of antirachitic substances found in
Preparation and unitage Synthetic salmon calcitonin
is used clinically, because it is more potent and longer acting food—only of historic interest.
due to slower metabolism. Human calcitonin has also been In 1919 it was established that rickets was due to deficiency
produced. of a dietary factor as well as lack of exposure to sunlight.
1 IU = 4 µg of the standard preparation. McCollum (1922) showed that this fat soluble dietary factor
CALSYNAR, ZYCALCIT: Synthetic salmon calcitonin 100 was different from vit A and its structure was determined
IU/ml amp. for i.m. or s.c. injection. in 1935. The interrelation between calciferol and
Nausea, flushing and tingling of fingers is frequent after cholecalciferol and their activation in the body has been
calcitonin injection. Bad taste, flu-like symptoms, allergic fully understood only in the 1970s.
reactions and joint pain are the other adverse effects.
Activation of vit D It takes place in the
Uses
1. Hypercalcaemic states Hyperparathyroidism, hyper-
following manner—
vitaminosis D, osteolytic bony metastasis and hypercalcaemia Ergosterol differs from 7-dehydrocholesterol in
of malignancy; 4–8 IU/kg i.m. 6–12 hourly only for 2 days. having an extra double bond between C22–23
It acts rapidly within 4 hours, the response peaks at 48 hours and a methyl group at C24. In man vit D2 and
and then refractoriness develops. It also relieves bone pain.
For emergency treatment of hypercalcaemia 5–10
D3 are equally active and calcitriol (active form
IU/kg may be diluted in 500 ml saline and infused i.v. over of D3) is more important physiologically; 25-OH
6 hours. Calcitonin is a relatively weak hypocalcaemic drug. D3 is released in blood from the liver and binds
 DRUGS AFFECTING CALCIUM BALANCE 341

7-DEHYDROCHOLESTEROL ERGOSTEROL
(Synthesized in skin) (yeast, bread, milk)
UV Light
CHOLECALCIFEROL (Vit D 3) CALCIFEROL (Vit D2)
Liver microsomes
CALCIFEDIOL (25-OH-D3) 25-OH-D2
Kidney mitochondria
CALCITRIOL (1,25 (OH)2D3) 1,25 (OH) 2D2
ACTIVE FORMS

loosely to a specific vit D binding globulin. The by mechanisms not involving gene regulation.
final 1α-hydroxylation in kidney is rate limiting 2. Calcitriol enhances resorption of calcium and
and is controlled by many factors. This step is phosphate from bone by promoting recruitment
activated or induced by calcium/vit D deficiency and differentiation of osteoclast precursors in the
as well as by PTH, estrogens and prolactin, while bone remodeling units, but mature osteoclasts lack
calcitriol inhibits it in a feedback manner. VDR. Like PTH, calcitriol induces RANKL in
Thus, vit D should be considered a hormone osteoblasts which may then activate the
because: osteoclasts. Osteoblastic cells express VDR and
(a) It is synthesized in the body (skin); under respond to calcitriol by laying down osteoid, but
ideal conditions it is not required in the diet. it mainly appears to help bone mineralization
(b) It is transported by blood, activated and then indirectly by maintaining normal plasma calcium
acts on specific receptors in the target tissues. and phosphate concentration. Its action is indepen-
(c) Feedback regulation of vit D activation dent of but facilitated by PTH.
occurs by plasma Ca2+ level and by the active 3. Calcitriol enhances tubular reabsorption of
form of vit D itself. calcium and phosphate in the kidney, but the
action is less marked than that of PTH. However,
Actions in hypervitaminosis D, influence of hypercal-

CHAPTER 24
caemia overrides the direct action and more
1. Calcitriol enhances absorption of calcium and
calcium is excreted in urine.
phosphate from intestine. This is brought about
4. Other actions Actions of calcitriol on immu-
by increasing the synthesis of calcium channels
nological cells, lymphokine production, prolifera-
and a carrier protein for Ca2+ called ‘calcium
tion and differentiation of epidermal and certain
binding protein’ (Ca BP) or Calbindin. The action
malignant cells, neuronal and skeletal muscle
of calcitriol is analogous to that of steroid
function have also been demonstrated.
hormones. It binds to a cytoplasmic vitamin D
receptor (VDR) → translocate to the nucleus → Vit D deficiency Plasma calcium and phos-
increase synthesis of specific mRNA → regulation phate tend to fall due to inadequate intestinal
of protein synthesis. Another line of evidence absorption. As a consequence, PTH is secreted
suggests that activation of VDR promotes → calcium is mobilized from bone in order to
endocytotic capture of calcium, its transport restore plasma Ca2+. The bone fails to mineralize
across the duodenal mucosal cell and finally its normally in the newly laid area, becomes soft
active extrusion through the serosal membrane. → rickets in children and osteomalacia in adults.
At least part of vit D action is quick (within However, in contrast to osteoporosis, the organic
minutes) and, therefore, appears to be exerted matrix (osteoid) is normal in these conditions.
342 HORMONES AND RELATED DRUGS

Hypervitaminosis D It may occur due to chronic ingestion 4. Alfacalcidol It is 1 α-OHD3—a prodrug that is rapidly
of large doses (~50,000 IU/day) or due to increased sensi- hydroxylated in the liver to 1,25 (OH)2 D 3 or calcitriol.
tivity of tissues to vit D. Manifestations are due to elevated Therefore, it does not require hydroxylation at position 1 which
plasma calcium and its ectopic deposition. These are: is the limiting step in the generation of active form of vit D,
hypercalcaemia, weakness, fatigue, vomiting, diarrhoea, and which takes place in the kidney. As such, it is effective
sluggishness, polyuria, albuminuria, ectopic Ca2+ deposition in renal bone disease, vit D dependent rickets, vit D resistant
(in soft tissues, blood vessels, parenchymal organs), renal rickets, hypoparathyroidism, etc. i.e. indications for which
stones or nephrocalcinosis, hypertension, growth retardation calcitriol is needed. It is also being used in osteoporosis.
in children. Even coma has been reported. Alfacalcidol is orally active and clinically equally effective
Treatment: consists of withholding the vitamin, low calcium on long term basis to calcitriol. Its metabolic activation in liver
diet, plenty of fluids and corticosteroids. Recovery may be does not pose a problem even in severe liver disease.
incomplete in many cases. Dose: 1–2 µg/day, children < 20 kg 0.5 µg/day. Repeated
serum calcium measurements are essential for regulation of
maintenance dose. Hypercalcaemia should be watched for
Pharmacokinetics and therapy promptly interrupted for few days when it
develops.
Vit D is well absorbed from the intestines in the ONE ALPHA, ALPHA D3, ALPHADOL 0.25 and 1 µg caps,
presence of bile salts, mainly through lymphatics. ALFACAL 0.25, 0.5 µg caps.
Absorption of the D3 form is somewhat better 5. Dihydrotachysterol A synthetic analogue of vit D2 that
than that of D2. Malabsorption and steatorrhoea is much less active in antirachitic tests, but directly mobilizes
calcium from bone after 25-hydroxylation in liver, and does
interfere with its absorption. not require PTH dependent activation in the kidney. It is
In the circulation, it is bound to a specific particularly useful in hypoparathyroidism and renal bone
α globulin and is stored in the body, mostly in disease.
adipose tissues, for many months. It is hydroxy- Dose: 0.25–0.5 mg/day.
Combination preparations of vit D are listed on p. 337 and in
lated in the liver to active and inactive metabolites. Table 67.2.
The t½ of different forms varies from 1–18 days:
25-OHD3, having the longest t½ , constitutes the Use
primary circulating form. Calcitriol is cleared
rapidly. 1. Prophylaxis (400 IU/day) and treatment
Metabolites of vit D are excreted mainly in bile. (3000–4000 IU/day) of nutritional vit D
deficiency This is given to prevent and treat
rickets in children and osteomalacia in adults.
Unitage and preparations
1 µg of cholecalciferol = 40 IU of vit D. Alternatively 300,000–600,000 IU can be given
SECTION 5

The daily requirement varies, depending on exposure to orally or i.m. once in 2–6 months. Prophylactic
sunlight. It is estimated that if no vit D3 is synthesized treatment may be given in obstructive jaundice,
in the body, a dietary allowance of 400 IU/day will prevent steatorrhoea and other conditions which
deficiency symptoms. However, higher amounts (upto 1000
IU/day) are also recommended. The forms in which vit D
predispose to vit D deficiency.
is supplied are— 2. Metabolic rickets These are a group of
1. Calciferol (Ergocalciferol, vit D2) As solution in oil,
filled in gelatin capsules 25,000 and 50,000 IU caps.
conditions in which tissues do not respond to
2. Cholecalciferol (vit D3) As granules for oral ingestion normal doses of vit D.
and oily solution for i.m. injection. (a) Vit D resistant rickets: X-linked hereditary
ARACHITOL 300,000 IU (7.5 mg) and 600,000 IU (15 mg) disease in which vit D metabolism is normal but
per ml inj.
calcium and phosphate metabolism is deranged.
CALCIROL, CALCIBEST SACHET 60,000 IU in 1 g
granules—suspended in milk/water and taken at 3–4 weeks Administration of phosphate with high dose of
intervals, and then every 2–6 months. calcitriol or alfacalcidol is beneficial.
3. Calcitriol 0.25–1 µg orally daily or on alternate days; (b) Vit D dependent rickets: Another genetic
CALTROL, ROLSICAL, ROCALTROL 0.25 µg cap. CALCI- disorder due to deficiency of renal hydroxylating
BEST 1 μg in 1 ml aqueous inj; 0.5–1 μg i.v. on alternate
days.
mechanism which converts 25-OHD3 into calci-
Hypercalcaemia is the main adverse effect; must be watched triol. Administration of calcitriol or alfacalcidol
for and therapy promptly stopped if plasma Ca2+ rises. is effective in normal doses.
 DRUGS AFFECTING CALCIUM BALANCE 343

(c) Renal rickets: Conversion of 25-OHD3 into drugs enhance degradation of vit D. However,
calcitriol does not occur due to chronic renal now it has been shown that plasma level of
disease. Calcitriol/alfacalcidol or dihydrotachys- calcitriol is normal, but its effect on intestine and
terol are needed in usual doses. bone is diminished.
3. Senile or postmenopausal osteoporosis
BISPHOSPHONATES
Age-related decrease in calcium absorption from
gut has been noted. Vit D3 + calcium have been Bisphosphonates (BPNs) are analogues of pyro-
shown to improve calcium balance in osteoporotic phosphate: carbon atom replacing oxygen in
females and elderly males. However, benefit in the P-O-P skeleton. They inhibit bone resorption
terms of improved bone mass or reduced fracture and have recently attracted considerable attention
risk is controversial or marginal (see p. 337). But because of their ability to prevent osteoporosis
this does not apply to active therapy with calcitriol/ in addition to their usefulness in metabolic bone
alfacalcidol for patients with established osteo- diseases and hypercalcaemia. They are the most
porosis, treated with BPNs, etc. because calcitriol effective antiresorptive drugs. Chronologically and
suppresses parathyroids and reduces bone according to potency, the BPNs can be grouped
remodeling. Vit D deficiency results in secondary into 3 generations (see box). The first generation
hyperparathyroidism which contributes to compounds have simpler side chains, are the least
osteoporosis. Calcitriol therapy carries the risk potent and seldom used now. The second and
of hypercalcaemia, calcium stones and metastatic third generation compounds have an amino or
calcification which should be watched for. nitrogenous ring substitution in the side chain,
are more potent, have higher efficacy and additional
4. Hypoparathyroidism Dihydrotachysterol or
mode of action.
calcitriol/alfacalcidol are more effective than vit,
D2 or D3, because they act quickly and directly Bisphosphonate Relative potency
without requiring hydroxylation in kidney which First generation BPNs
needs PTH. Alternatively, conventional
Etidronate 1
preparations of vit D3 may be given in high doses *Tiludronate 10
(25000-100,000 IU/day). Second generation BPNs
Pamidronate 100
5. Fanconi syndrome Vit D can raise the

CHAPTER 24
Alendronate 100–500
lowered phosphate levels that occur in this *Ibandronate 500–1000
condition. Third generation BPNs
Risedronate 1000
6. A nonhypercalcaemic analogue of vit D Zoledronate 5000
Calcipotriol (DAIVONEX 0.005% oint) is used * Not marketed in India
locally in plaque type psoriasis, and has yielded
good results (see Ch. 64). Systemically it has O R1 O
been tried in skin cancer and immunological HO || | || OH
disorders. P—C—P
NaO | ONa
R2
Interactions
Bisphosphonate
1. Cholestyramine and chronic use of liquid
O OH O
paraffine can reduce vit D absorption. HO || | || OH
2. Phenytoin and phenobarbitone reduce the P—C—P
responsiveness of target tissues to calcitriol; their NaO | ONa
prolonged use (for epilepsy) can cause rickets/ CH2 — CH 2 — NH2
osteomalacia. It was believed earlier that these Pamidronate
344 HORMONES AND RELATED DRUGS

The mechanism of action of BPNs is not fully are effective in preventing and treating post-
understood, but two facets of action have been menopausal osteoporosis in women as well as
delineated: age related, idiopathic and steroid-induced
(a) BPNs have strong affinity for calcium osteoporosis in both men and women. Alendronate
phosphate and have selective action in calcified is equally or more effective than HRT or raloxifene
tissue. The two main components of bone are in conserving bone mineral density and has
protein matrix and the solid mineral phase reduced the risk of vertebral as well as hip fracture
(hydroxyapatite). On the surface of resorptive pits by 47–56%.
the mineral phase is solubilized in the clear acidic Estrogens prevent vertebral but not other
zone created at the ruffled border of osteoclasts, fractures. BPNs are more effective than calcitonin
followed by resorption of protein matrix in this and continue to afford protection for at least 5
area by acid hydrolases secreted from osteoclasts. years of continuous use. Thus, they are the first
BPNs localise in the acidic zone under the choice drugs now for osteoporosis. Since the t½
osteoclasts due to their high affinity for Ca2+ ions. of alendronate in bone is ~ 10 years, treatment
When Ca2+ ions are released from the bone surface beyond 5 years is considered unnecessary.
due to high acidity, the BPNs are also released
and are internalized into osteoclasts by 2. Paget’s disease This disease due to abnor-
endocytosis. This results in: mal osteoclast function producing disordered bone
• Accelerated apoptosis of osteoclasts reducing remodeling and honeycomb-like bone architecture
their number. is benefited by BPNs. They arrest osteolytic
• Disruption of cytoskeleton and ruffled border lesions, reduce bone pain and improve secondary
of osteoclasts. symptoms. Long-lasting remissions may be
In addition, BPNs appear to affect osteoclast induced. Alendronate, risedronate, pamidronate
precursors and inhibit their differentiation by and zoledronate are used now. They are more
suppressing IL-6. convenient, more effective and cheaper than
(b) It has been shown now that BPNs, especially calcitonin. Combined use of BPNs and calcitonin
the second and third generation potent amino- further increases efficacy. Treatment with BPNs
derivatives like alendronate, zoledronate, have should not exceed 6 months; but courses may
important metabolic effects in the mevalonate be repeated after a gap.
SECTION 5

pathway for isoprenoid lipid synthesis. They 3. Hypercalcaemia of malignancy Severe

inhibit prenylation of certain GTP-binding proteins hypercalcaemia, a common complication of
involved in cytoskeletal organization, membrane malignancy, is a medical emergency with altered
ruffling and vesicle movement. The net result is consciousness. Pamidronate (60–90 mg i.v. over
inactivation of osteoclasts, impaired vesicle fusion 2–4 hours) or zoledronate (4 mg i.v. over 15 min)
and enhanced apoptosis. Interference with are the most effective drugs, but take 24–48 hours
mevalonate pathway may also impart antitumor to act. They may be supplemented by i.m.
action on bony metastasis. calcitonin 6–12 hourly for 2 days to achieve rapid
All oral BPNs are poorly absorbed, and produce action. Vigorous i.v. hydration is instituted first.
gastric irritation, esophagitis as the major side
After volume repletion, furosemide is added to
effect. They are contraindicated in gastroesophageal
enhance Ca2+ excretion and to prevent volume
reflux, peptic ulcer and renal impairment.
overload. This is followed by BPN infusion. This
The BPNs are useful in conditions characteri-
therapy reduces serum calcium within few hours
zed by enhanced bone turnover.
and corrects the attending dehydration. Oral BPNs
1. Osteoporosis The second and third are not useful. Corticosteroids also lower plasma
generation BPNs (e.g. alendronate, risedronate) Ca2+, but are slow to act, take 1–2 weeks.
 DRUGS AFFECTING CALCIUM BALANCE 345

4. Osteolytic bone metastasis Parenteral unchanged mainly by the kidney. The terminal
pamidronate/zoledronate arrests osteolytic lesions elimination t½ of alendronate has been measured
and reduces bone pain. as 10.5 years.
Etidronate This is the first BPN to be used clinically, Risedronate It is an oral 3rd generation BPN,
employed in hypercalcaemia and Paget’s disease. However, more potent than alendronate, but equally
it also interferes with bone mineralization: continuous therapy
produces osteomalacia. Therefore, it has been largely replaced
efficacious. Oral bioavailability of 1% and other
by zoledronate for hypercalcaemia and alendronate/risedronate features are similar to alendronate. It is indicated
for Paget’s disease. Etidronate is administered both orally in the treatment of osteoporosis and Paget’s
and i.v., but is not preferred now. disease.
Dose: 5–7.5 mg/kg/day. Dose: 35 mg/week oral in the morning with a full glass
DRONATE-OS 200 mg tab, 300 mg inj. of water.
RISOFO 5, 35, 70 mg tabs. GEMFOS, ACTONEL 35 mg
Pamidronate A second generation potent BPN tab.
which is administered only by i.v. infusion in a
dose of 60–90 mg over 2–4 hours weekly or Zoledronate This parenteral highly potent 3rd
monthly depending on the condition. It is used generation BPN is indicated for hypercalcaemia,
in Paget’s disease, hypercalcaemia of malignancy bony metastasis, osteolytic lesions, and Paget’s
and in bony metastasis. Adverse effects are disease. Osteoclastic activity is markedly
thrombophlebitis of injected vein, bone pain, fever suppressed and an additional antitumor effect may
be exerted by interference with mevalonate
and leukopenia. A flu-like reaction may occur
pathway. Proliferation of bony metastasis of
initially due to cytokine release.
AREDIA 15, 30, 60 mg inj; AREDRONET 30, 90 mg inj.
prostate/breast cancer and multiple myeloma cells
BONAPAM 30, 60, 90 mg inj. may be arrested. For hypercalcaemia, it is more
effective, faster acting than pamidronate and
Alendronate This potent orally effective
therefore the drug of choice now. Another
second generation amino-BPN is used primarily advantage is that it can be infused over 15 min
for prevention and treatment of osteoporosis both (because of less venous irritation), whereas
in women and men, as well as for Paget’s disease. pamidronate needs 2–4 hours. Flu-like symptoms
It is to be taken on empty stomach in the morning due to cytokine release attend the i.v. infusion.
with a full glass of water and patient is instructed Nausea, vomiting, bodyache, dizziness are also

CHAPTER 24
not to lie down or take food for at least 30 min. common. Renal toxicity has been encountered.
These measures are needed to prevent contact Osteonecrosis of the jaw is a rare complication
of the drug with esophageal mucosa which results of i.v. high dose BPN therapy.
in esophagitis. Calcium, iron, antacids, mineral Zoledronate 4 mg infused i.v. once every 12
water, tea, coffee, fruit juice interfere with months has been used for osteoporosis in
alendronate absorption. NSAIDs accentuate postmenopausal women who do not tolerate oral
gastric irritation caused by alendronate. Other alendronate/risedronate.
adverse effects are gastric erosion, retrosternal Dose: 4 mg diluted in 100 ml saline/glucose solution and
pain, flatulence, headache, bodyache and initial infused i.v. over 15 min; may be repeated after 7 days and
then at 3–4 week intervals.
fall in serum Ca2+ level. ZOBONE, ZOLDRIA, ZOLTERO 4 mg/vial inj.
Dose: 5–10 mg OD; or 35–70 mg weekly; weekly treatment is
as effective, more convenient and better tolerated.
OSTEOPHOS, DENFOS 5, 10, 35, 70 mg tab. RESTOFOS, Other drugs for hypercalcaemia
DRONAL 10, 70 mg tab. 1. Gallium nitrate: It is a potent inhibitor of bone resorption;
acts by depressing ATP-dependent proton pump at the ruffled
Oral bioavailability of alendronate is ~1%. membrane of osteoclasts. Indicated in resistant cases of hyper-
Up to 50% of the drug entering the body is calcaemia, it is given by continuous i.v. infusion daily for 5
sequestrated in bone while the rest is excreted days. It is nephrotoxic and only a reserve drug.
346 HORMONES AND RELATED DRUGS

2. Glucocorticoids: High doses of prednisolone (and others) a reserve drug for elderly women >75 years age who have
enhance calcium excretion, decrease calcium absorption and already suffered osteoporotic fracture and are unable to tolerate
have adjuvant role in hypercalcaemia due to lymphoma, BPNs.
myeloma, leukaemia, carcinoma breast, etc. 2. Denosumab: It is a human monoclonal antibody which
inhibits osteoclast differentiation and function as well as
Other drugs for osteoporosis promotes their apoptosis. It is a treatment option for
1. Strontium ranelate: It suppresses bone resorption as well postmenopausal osteoporosis when no other drug is
as stimulates bone formation, and has been introduced as appropriate.
SECTION 5