04.

01-02
February 5, 2014
Rene Luis F. Filarca, M.D. Endocrine I:
"I saw a woman wearing a sweatshirt with Guess on it. I said, thyroid problem?" Thyroid Pharmacology
– Arnold Schwarzenegger

Based on the lecture by Dr. Filarca. THYROID HORMONE BIOSYNTHESIS

Italicized text lifted from book.
THYROID PHYSIOLOGY
 Thyroid hormones
o Triiodothyronine (T3) and tetraiodothyronine (T4
or thyroxine)
 Secreted in sufficient amounts by the normal
thyroid gland
 Normalize:
‒ Growth and development
‒ Body temperature
‒ Energy levels
 Contain 59% and 65% iodine respectively

IODIDE
 RDA in adults: 150 mcg (200 mcg during pregnancy)
 Rapidly absorbed and enters extracellular fluid pool
o Thyroid gland removes 75 mcg/day from this pool
 Balance excreted in the urine

STEP EVENTS INHIBITORS

Transport of iodide into the thyroid gland via sodium-iodide  Thiocyanate
symporter or NIS (intrinsic follicle cell basement membrane protein)  Pertechnate
IODIDE TRAPPING  Perchlorate
Pendrin (apical cell membrane I- transporter) controls flow of iodide
across membrane
Iodide oxidized by thyroidal peroxidase (TPO) to iodine which  Transiently blocked by high levels of intrathyroidal I-
ORGANIFICATION OR OXIDATION rapidly iodinates tyrosine residues within thyroglobulin molecule to  Blocked more persistently by thioamides
form monoiodotyrosine (MIT) and diiodotyrosine (DIT)
DIT + DIT = T4
COUPLING
DIT + MIT = T3
T3 and T4 released by exocytosis and proteolysis of thyroglobulin at  High levels of intrathyroidal I-
HYDROLYSIS OR PROTEOLYSIS
apical colloid border
MIT and DIT deiodinated in the gland to reutilize iodine  Amiodarone
 Iodinated contrast media
DEIODINATION  Beta blockers
 Corticosteroids
 Severe illness or starvation
PERIPHERAL CONVERSION Yields T3 (active form) from peripheral metabolism of thyroxine

Figure 1. Chemical structures of thyroid hormones.

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 Endocrine I: Thyroid Pharmacology

SUMMARY OF THYROID HORMONE KINETICS AUTOREGULATION OF THYROID GLAND

 Uptake of iodide and thyroid hormone synthesis
o Regulated by intrathyroidal mechanisms which are
independent of TSH and are primarily related to level of
iodine in the blood
o Wolff-Chaikoff block (woolf' cha'kof)
 Large doses of iodine  inhibit iodide organification
 Result in hypothyroidism of Hashimoto's thyroiditis
 Loss of Wolff-Chaikoff block  hyperthyroidism in
susceptible individuals (e.g. multinodular goiter)

ABNORMAL THYROID STIMULATORS

 Graves' disease
o Lymphocytes secrete TSH receptor-stimulating
antibody (TSH-R Ab [stim]) or thyroid-stimulating
immunoglobulin (TSI)
 TSH-R in orbital fibrocytes
o Stimulation by TSH-R Ab [stim]  ophthalmopathy

THYROID HORMONES
CHEMISTRY
(refer to Figure 1 in p. 1)
 T4, T3, and reverse T3 naturally exist as levo (L) isomers
 Synthetic dextro (D) isomers
o ~4% biologic activity of L-isomers

PHARMACOKINETICS
 T4 best absorbed in duodenum and ileum
HYPOTHALAMIC-PITUITARY-THYROID AXIS  Oral bioavailability of current preparations (refer to
summary of thyroid hormone kinetics):
o LT4: 80%
o T3: 95%
 Severe myxedema with ileus   absorption
 Route for parenteral therapy: IV (preferred)

FACTORS INCREASING THYROID HORMONE CLEARANCE

HYPERTHYROIDISM
  metabolic clearances of T4 and T3
  t1/2 of T4 and T3
 Opposite occurs in hypothyroidism

HEPATIC MICROSOMAL ENZYME INDUCERS

 Rifampin, phenobarbital, carbamazepine, phenytoin,
imatinib, HIV protease inhibitors   metabolism of T4
and T3
 Dosing of T4 may need to be increased in patients
dependent on T4 replacement medication to maintain
clinical effectiveness

TBG BINDING SITES

 Increased by pregnancy, estrogens, oral contraceptives
  concentration of total and bound hormone
 Concentration of free hormone and steady-state elimination
remain normal

MECHANISM OF ACTION
 T4 enters cell by active transport  T4 converted to T3
by 5'-deiodinase  T3 enters nucleus and binds to a
specific T3 receptor protein (member of c-erboncogene
family that also includes steroid hormone receptors and
receptors for vitamins A and D)

THYROID HORMONE RECEPTORS

 Most hormone-responsive tissues:

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 Endocrine I: Thyroid Pharmacology

o Pituitary, liver, kidney, heart, skeletal muscle, lung,

and intestine LIOTHYRONINE (T3)
 Hormone-unresponsive tissues:  3-4 times more potent than levothyroxine
o Spleen, testes  Not recommended for routine replacement therapy
because of:
EFFECTS OF THYROID HORMONE o Shorter half-life (24 hours)
 Critical for the development and functioning of the following o Multiple daily doses
tissues: o Higher cost
o Nervous o Greater difficulty of monitoring
o Skeletal o Greater risk of cardiotoxicity
o Reproductive  Clinical uses
 Depend on protein synthesis o Best used in short-term suppression of TSH
 Potentiates secretion and action of growth hormone  Contraindications
o Patients with cardiac disease
THYROID DEPRIVATION EARLY IN LIFE
 Irreversible mental retardation and dwarfism LEVOTHYROXINE (T4) LIOTHYRONINE (T3)
 Congenital cretinism POTENCY 3-4 times more potent
than levothyroxine
METABOLISM AND ENDOCRINE EFFECTS t1/2 Longer (7 days) Shorter (24 hours)
 Pervasive influence on metabolism of drugs, carbohydrates, DOSING Once-daily administration Multiple daily doses
fats, proteins, and vitamins COST Lower Higher
 Affects secretion and degradation rates of virtually all other SERUM Easier More difficult
hormones including catecholamines, cortisol, estrogens, MONITORING
testosterone, and insulin CLINICAL DOC for long-term thyroid Short-term suppression
USES hormone replacement and of TSH
THYROID HYPERACTIVITY suppression therapy
 Resemble sympathetic nervous system overactivity TOXICITY No allergenic foreign protein Greater risk of
(especially in the cardiovascular system) cardiotoxicity
 Increase in catecholamine-stimulated adenylyl cyclase
activity may be explained by: LIOTRIX
o  numbers of receptors  More expensive
o Enhanced amplification of receptor signal  Mixture of thyroxine and liothyronine
 Clinical symptoms of excessive epinephrine activity
(partially alleviated by adrenoceptor antagonists) DESICCATED THYROID
o Lid lag and retraction
 Disadvantages
o Tremor
o Protein antigenicity
o Excessive sweating
o Product instability
o Anxiety
o Variable hormone concentrations
o Nervousness
o Difficulty in laboratory monitoring
o Far outweigh advantage of lower cost
THYROID PREPARATIONS

ORIGIN PREPARATIONS SHELF LIFE EQUI-EFFECTIVE DOSES

SYNTHETIC Levothyroxine ~2 years particularly if stored in dark  100 mg of desiccated thyroid
Liothyronine bottles to minimize spontaneous  100 mcg of levothyroxine
Liotrix iodination  37.5 mcg of liothyronine
ANIMAL Desiccated thyroid Unknown;  potency if kept dry
ANTITHYROID AGENTS
 Reduction of thyroid activity and hormone effects can be
THYROID HORMONE
accomplished by:
 Not effective and can be detrimental in the management
o Antithyroid agents
of obesity, abnormal vaginal bleeding, or depression due to
 Interfere with production of thyroid hormones
hypothyroidism if thyroid hormone levels are normal
 Modify tissue response to thyroid hormones
o Glandular destruction with radiation or surgery
SYNTHETIC LEVOTHYROXINE (T4)  Goitrogens
 DOC of thyroid replacement and suppression therapy o Suppress secretion of T3 and T4 to subnormal levels
because of: o Increase TSH
o Stability o Produce glandular enlargement (goiter)
o Content uniformity  Antithyroid compounds used clinically:
o Low cost o Thioamides
o Lack of allergenic foreign protein o Iodides
o Easy laboratory measurement of serum levels o Radioactive iodine
o Long t1/2 (7 days) permitting once-daily administration
 Administration produces both hormones THIOAMIDES
o T4  converted intracellularly to T3
 Propylthiouracil (PTU)
 Generic levothyroxine preparations
 Methimazole (thiamazole, MMI)
o Comparable in efficacy and more cost-effective than
o Ten times more potent than propylthiouracil
branded preparations

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 Endocrine I: Thyroid Pharmacology

 Carbimazole  Rapidly reversible when drug is discontinued

o Converted to methimazole in vivo  Broad-spectrum antibiotic therapy may be necessary for
 Thiocarbamide group essential for antithyroid activity complicating infections
 Colony-stimulating factors (G-CSF) may hasten recovery
PHARMACOKINETICS  Cross-sensitivity between propylthiouracil and
methimazole: ~50%
PROPYLTHIOURACIL (PTU) METHIMAZOLE (MMI) o Switching drugs not recommended in patients with
 Rapidly absorbed  Completely absorbed severe reactions
 Plasma t1/2: 1.5 hours  Plasma t1/2: 6 hours
 Peak levels in 1 hour  Excretion slower than with ANION INHIBITORS (MONOVALENT ANIONS)
 50-80% bioavailability propylthiouracil  Perchlorate (ClO4–), pertechnetate (TcO4–), thiocyanate
 Excreted by the kidney as inactive (SCN–)
glucuronide within 24 hours o Block uptake of iodide by thyroid gland
 Preferred in pregnancy  Associated with rare congenital  Competitive inhibition of iodide transport
o More strongly protein-bound malformations (MMI o Can be overcome by large doses of iodides
embryopathy)  Effectiveness unpredictable
 Both accumulated by the thyroid gland
 Pregnancy and lactation POTASSIUM PERCHLORATE
o Cross placental barrier  Clinical uses
o Caution in pregnancy o Iodide-induced hyperthyroidism (e.g. amiodarone-
 Risk of fetal hypothyroidism induced hyperthyroidism)
 Classified as pregnancy category D (evidence of human fetal  Rarely used clinically because of its association with
risk based on adverse reaction data from investigational or aplastic anemia
marketing experience)
o Secreted in low concentrations in breast milk but are considered safe IODIDES
for the nursing infant  Major antithyroid agents prior to introduction of thioamides
in the 1940s
PHARMACODYNAMICS  Now rarely used as sole therapy
 Multiple mechanisms
o Major action: prevent hormone synthesis PHARMACODYNAMICS
 Inhibit thyroid peroxidase-catalyzed reactions  Inhibit organification and coupling
 Block iodine organification  Inhibit hormone release
 Block coupling of iodotyrosines  Decrease size and vascularity of hyperplastic gland
o Do not block uptake of iodide by the gland  In susceptible individuals:
o Inhibit peripheral deiodination of T4 o Induce iodide-induced hyperthyroidism (Jod-
 Propylthiouracil >>> methimazole Basedow phenomenon
 Slow onset o Precipitate hypothyroidism (via Wolff-Chaikoff block)
o Affect synthesis but not release of hormones  In pharmacologic doses (>6 mg/d):
 3–4 weeks before stores of T4 become depleted o Major action: inhibit hormone release through
inhibition of thyroglobulin proteolysis
TOXICITY o Improvement in thyrotoxic symptoms occurs rapidly
 3–12% of treated patients (within 2-7 days)
 Nausea and gastrointestinal distress  Valuable in thyroid storm
 Altered sense of taste or smell o  vascularity, size, and fragility of hyperplastic gland
o May occur with methimazole  Preoperative preparation for surgery
 Maculopapular pruritic rash (4–6%)
o Most common adverse reaction CLINICAL PHARMACOLOGY
o Accompanied by systemic signs (e.g. fever)  Increase in intraglandular stores of iodine may delay onset
 Severe hepatitis of thioamide therapy or prevent use of radioactive iodine
o More common with propylthiouracil therapy for several weeks
o Can be fatal  Iodides
 Cholestatic jaundice o Initiate after onset of thioamide therapy
o More common with methimazole o Avoided if treatment with radioactive iodine seems
 Rare: urticarial rash, vasculitis, lupus-like reaction, likely
lymphadenopathy, hypoprothrombinemia, exfoliative o Should not be used alone
dermatitis, polyserositis, acute arthralgia  Gland will escape iodide block in 2-8 weeks
 Asymptomatic elevations in transaminase can also occur  Withdrawal may produce severe exacerbation of
thyrotoxicosis in iodine-enriched gland
AGRANULOCYTOSIS o Chronic use of iodides in pregnancy should be
 Granulocyte count <500 cells/mm3 avoided
 Most dangerous complication  Cross placenta and can cause fetal goiter
 Infrequent but potentially fatal  Use of iodides in radiation emergencies
o Occurs in 0.1–0.5% of patients taking thioamides o Thyroid-blocking effects of potassium iodide protect the
o Risk may be increased in: gland from subsequent damage if administered before
 Older patients radiation exposure
 Patients on high-dose methimazole therapy (>40
mg/d)

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 Endocrine I: Thyroid Pharmacology

TOXICITY MANAGEMENT OF HYPOTHYROIDISM

 Iodism LEVOTHYROXINE
o Uncommon  Administration
o Reversible upon discontinuance o Infants and children:
o Manifestations:  Require more T4/kg of body weight than adults
 Acneiform rash (similar to that of bromism)  1–6 months of age: 10–15 mcg/kg/d
 Swollen salivary glands o Adults:
 Mucous membrane ulcerations, conjunctivitis,  1.7 mcg/kg/d
rhinorrhea  >65 years of age: may require less thyroxine
 Drug fever  Absorption
 Metallic taste o Administered on an empty stomach
 Bleeding disorders  30 minutes before meals or 1 hour after meals
 Anaphylactoid reactions (rare)  Metabolism
o t1/2: 7 days
RADIOACTIVE IODINE (131I) o qd dosing
 Adminsitered PO in solution as sodium 131I  Monitoring
 Therapeutic effects depend on emission of  rays with: o Serum TSH and FT4 measured at regular intervals
o Effective t1/2 of 5 days o TSH maintained within 0.5-2.5 mU/L (optimal)
o Penetration range of 400–2000 μm o 6–8 weeks to reach steady-state levels in bloodstream
 Destruction of thyroid parenchyma within a few weeks as o Dosage changes should be made slowly
evidenced by:  Reduce dosage in long-standing hypothyroidism, older
o Epithelial swelling and necrosis patients, underlying cardiac disease
o Follicular disruption o 12.5-25 mcg/d for 2 weeks  increase daily dose by 25
o Edema mcg every 2 weeks until euthyroidism or drug toxicity
o Leukocyte infiltration observed
 Advantages o If angina pectoris or cardiac arrhythmia develops:
o Easy administration  Stop or reduce dose of thyroxine STAT
o Effectiveness  Toxicity
o Low expense o In children:
o Absence of pain  Restlessness, insomnia, accelerated bone
 No increased risk of radiation-induced genetic damage, maturation and growth
leukemia, and neoplasia based on more than 50 years of o In adults:
clinical experience with radioiodine therapy for  Increased nervousness, heat intolerance, episodes
hyperthyroidism of palpitation and tachycardia, or unexplained
 Should not be administered to pregnant women or weight loss
nursing mothers  Chronic overtreatment with T4 in elderly patients
o Crosses placenta to destroy fetal thyroid gland increases risk of:
o Excreted in breast milk ‒ Atrial fibrillation
‒ Accelerated osteoporosis
ADRENOCEPTOR-BLOCKING AGENTS
SPECIAL PROBLEMS INMANAGEMENT OFHYPOTHYROIDISM
 Metoprolol, propranolol, atenolol
MYXEDEMA AND CORONARY ARTERY DISEASE
o Beta blockers without intrinsic sympathomimetic
activity  Frequently occurs in older persons
o Therapeutic adjuncts  Low thyroid hormone levels  cardioprotective
 Management
o Correction of myxedema must be done cautiously
PROPRANOLOL
to avoid provoking arrhythmia, angina, or AMI
 Beta blocker most widely studied and used o Coronary artery revascularization prioritized if needed
 Clinical improvement of hyperthyroid symptoms
 Do not typically alter thyroid hormone levels
MYXEDEMA COMA
 Doses greater than 160 mg/d may also reduce T3 levels by
approximately 20%  Medical emergency
 Inhibits peripheral conversion of T4 o ICU admission
 End state of untreated hypothyroidism associated with:
o Progressive weakness, stupor, hypothermia,
CLINICAL PHARMACOLOGY
hypoventilation, hypoglycemia, hyponatremia, water
HYPOTHYROIDISM
intoxication, shock, and death
 Reversible slowing down of all body functions  Management
 In infants and children: o Associated illnesses (infection or heart failure) must be
o Retardation of growth and development treated accordingly
o Dwarfism and irreversible mental retardation o Give all preparations intravenously
 Can occur with or without goiter  Patients absorb drugs poorly from other routes
 Hashimoto's thyroiditis  Levothyroxine IV
o Most common cause of hypothyroidism in USA ‒ Initial loading dose: 300–400 mcg initially
o Immunologic disorder in genetically predisposed followed by 50–100 mcg/d
individuals  Intravenous T3
o Evidence of humoral immunity in the presence of ‒ May be more cardiotoxic and more difficult
antithyroid antibodies and lymphocyte sensitization to monitor
to thyroid antigens

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 Endocrine I: Thyroid Pharmacology

 Intravenous hydrocortisone if associated with  Methimazole or propylthiouracil

adrenal or pituitary insufficiency o Given until spontaneous remission
o Opioids and sedatives must be used with extreme o Only therapy leaving an intact thyroid gland
caution o Long period of treatment and observation (12-18
months)
HYPOTHYROIDISM AND PREGNANCY o 50-68% incidence of relapse
 Hypothyroid women o Begin with divided doses  shift to maintenance
o Frequently have anovulatory cycles therapy with qd doses when clinically euthyroid
o Relatively infertile until euthyroid state  Best clinical guide to remission: reduction in
o Led to widespread use of thyroid hormone for infertility goiter size
 Management of pregnant hypothyroid patients METHIMAZOLE PROPYLTHIOURACIL
o Daily dose of thyroxine must be adequate  Preferred over  Inhibits conversion of T4 to T3
 Early fetal brain development depends on maternal propylthiouracil (except o Faster decrease in
thyroxine
in pregnancy and thyroid activated thyroid
o Increase thyroxine dose (about 30–50%) to normalize NOTES
storm) hormone level
serum TSH level during pregnancy
 Once daily
 Adequate maternal thyroxine dosages warrant
 Enhanced adherence
maintenance of TSH between 0.5 and 3.0 mU/L
and total T4 at or above the upper range of normal 20-40 mg x 4-8 weeks 100-200 mg q6-8  gradual
to offset elevated maternal TBG levels and total T4 DOSING (10-20 mg bid-tid) reduction to maintenance of 50-
levels Maintenance: 5-15 mg qd 150 mg qd or divided doses
 Minor rash
SUBCLINICAL HYPOTHYROIDISM o Administer antihistamines
 Agranulocytosis
 Elevated TSH but normal thyroid hormone levels
TOXICITY o Often heralded by sore throat or high fever
 Found in 4-10% of general population
o Discontinue drug and seek immediate medical attention
 Increases to 20% in women >50 years old
o White cell and differential counts and a throat culture
 Management
followed by appropriate antibiotic therapy
o Close TSH monitoring
o Thyroid hormone therapy "BLOCK-AND-REPLACE" REGIMEN
 Considered if TSH >10 mIU/L  Levothyroxine 50-100 mcg
o Prevents hypothyroidism and suppress TSH
DRUG-INDUCED HYPOTHYROIDISM o Adjusted according to FT4
 Blocking dose of antithyroid kept constant
 Levothyroxine if offending agent cannot be stopped
 In amiodarone-induced hypothyroidism:  TSH levels can be used to monitor therapy if TSH suppression is alleviated
o Levothyroxine therapy may be necessary even after  Compared to titration regimen
discontinuance because of very long t1/2 of amiodarone o Superior remission in some studies
o 6 months vs. 18 months
o Higher antithyroid dosage
HYPERTHYROIDISM
o Not used in pregnancy
GRAVES' DISEASE
o TSH often remain suppressed
 Diffuse toxic goiter  Not a sensitive index of treatment response
 Most common form of hyperthyroidism  Less preferred
 Spontaneous remission occurs but some require years of
TITRATION REGIMEN
antithyroid therapy
 Preferred to minimize dose of antithyroid drugs and provide an index of
treatment response
PATHOPHYSIOLOGY
 Thyroid function tests and clinical manifestations reviewed 3–4 weeks
 Autoimmune disorder after starting treatment
 Helper T lymphocytes stimulate B lymphocytes to  Dose titrated based on unbound T4 levels
synthesize Ab to thyroidal antigens
 Most patients do not achieve euthyroidism until 6–8 weeks after initiation
 TSH-R Ab [stim]
of treatment
o Stimulate growth and biosynthetic activity of thyroid
 Usual daily maintenance doses of antithyroid drugs in titration regimen:
cell
o 2.5-10 mg of carbimazole or methimazole
o 50-100 mg of propylthiouracil
LABORATORY DIAGNOSIS
  T3, T4, FT4, FT3 SURGICAL THYROIDECTOMY
 TSH suppressed  Near-total thyroidectomy
 Radioiodine uptake elevated  Treatment of choice for patients with very large
 Presence of antithyroglobulin, thyroid peroxidase, TSH-R Ab glands or multinodular goiters
[stim] antibodies  Pre-operative:
o Antithyroid drugs for ~6 weeks until euthyroid
o Saturated solution of potassium iodide
MANAGEMENT  10- 14 days prior to surgery
 5 drops bid
ANTITHYROID DRUG THERAPY  Diminishes vascularity of gland and simplifies
 Most useful in: surgery
o Young patients  Post-operative:
o Small glalnds o 80-90% will require thyroid supplementation
o Mild disease

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RADIOACTIVE IODINE  Destruction of thyroid parenchyma

 Preferred treatment for most patients >21 years of age  Transient release of stored thyroid hormones
o 80-120 Ci/g of estimated thyroid weight corrected for  May occur in patients with Hashimoto's thyroiditis
uptake  Spontaneously resolving hyperthyroidism
 In patients with underlying heart disease, severe
thyrotoxicosis, elderly patients: SUPPORTIVE THERAPY
o Antithyroid drugs (preferably methimazole) until  Beta blocking agents without intrinsic sympathomimetic
euthyroid activity (e.g. propranolol) for tachycardia
o Medication stopped 5-7 days before RAI  Aspirin or NSAID to control local pain and fever
 Iodides should be avoided to ensure maximal uptake  Corticosteroids in severe cases to control inflammation
 6-12 weeks after 131I administration:
o Gland will shrink in size THYROID STORM (THYROTOXIC CRISIS)
o Patient will usually become euthyroid or hypothyroid
 Sudden acute exacerbation of all of the symptoms of
o Second dose may be required in some patients
thyrotoxicosis
o Hypothyroidism occurs in about 80% of patients
 Life-threatening syndrome
o Regularly monitor serum FT4 and TSH levels
ANTITHYROID RADIOACTIVE IODINE MANAGEMENT
IMPROVES 2 weeks 2 months  Propranolol
SYMPTOMS o 1-2 mg slow IV or 40-80 mg PO q6
EUTHYROID 6 weeks 6 months o Control severe cardiovascular manifestations
NOTES 18-24 months  Repeat TSH and FT4 after 6-8 weeks  Diltiazem
treatment  Hyperthyroidism can persist for 2-3 o Severe heart failure or asthma
months before radioiodine takes full o 90-120 mg PO tid-qid or 5-10 mg/hour IV infusion
effect (give adrenergic blockers or (asthmatic patients only)
antithyroid drugs to control symptoms  Saturated solution of potassium iodide (KISS)
during this interval) o Retards release of thyroid hormones from the gland
 Contraindications: pregnancy and o 10 gtts (drops) OD PO
breastfeeding (but patients can  Propylthiouracil
conceive safely 6 months after o Blocks hormone synthesis
treatment) o 250 mg PO q6
o If unable to take orally:
 Rectal formulation: 400 mg q6 as retention enema
ADJUNCTS TO ANTITHYROID THERAPY
 Methimazole rectal administration
 Acute phase of thyrotoxicosis
o 60 mg qd
o Beta blockers
 Hydrocortisone
 Propranolol 20-40 mg PO q6
o Protect the patient against shock
‒ Control tachycardia, hypertension, atrial
o Block conversion of T4 to T3
fibrillation
o 50 mg IV every 6 hours
 Gradually withdraw as serum thyroxine levels
 Supportive therapy
return to normal
o Control fever, heart failure, and any underlying disease
 If contraindicated:
process
‒ Diltiazem 90-120 mg tid-qid to control
o Plasmapheresis or peritoneal dialysis
tachycardia
 Lowers levels of circulating thyroxine
o Adequate nutrition and vitamin supplements
o Barbiturates
 Accelerate T4 breakdown by hepatic enzyme OPHTHALMOPATHY
induction  Rare but difficult to treat
 May be helpful as sedative and to lower T4 levels
o Bile acid sequestrants (e.g. cholestyramine) MANAGEMENT
 Rapidly lower T4 levels  Usually by total thyroidectomy or 131I ablation of the gland
 Increase fecal excretion of T4 + oral prednisone
 Local therapy may be necessary
TOXIC UNINODULAR AND MULTINODULAR GOITERS  Head elevation to diminish periorbital edema
 Often in older women with nodular goiter  Artificial tears to relieve corneal drying
 FT4 moderately elevated or normal  Smoking cessation
 FT3 or T3 markedly elevated  Short course of prednisone for severe acute inflammatory
reaction
o 60-100 mg PO qd for ~1 week then 60-100 mg every
SINGLE TOXIC ADENOMAS
other day (tapering dose over a period of 6-12 weeks)
 Surgical excision or radioiodine therapy  Radioiodine treatment to prevent exacerbation
o 40 mg/d tapered over 2-3 months
TOXIC MULTINODULAR GOITER  Irradiation of posterior orbit if steroid therapy fails or is
 Usually associated with a large goiter contraindicated
 Preparation with methimazole or propylthiouracil followed  Surgical decompression of the orbit for threatened loss
by subtotal thyroidectomy of vision
 Eyelid or eye muscle surgery to correct residual problems
SUBACUTE THYROIDITS after acute process has subsided
 Acute phase of a viral infection of thyroid gland

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 Endocrine I: Thyroid Pharmacology

DERMOPATHY OR PRETIBIAL MYXEDEMA  Treated with thioamides

 Often respond to topical corticosteroids applied to o Inflammatory thyroiditis (type II) due to leakage
involved area and covered with occlusive dressing of thyroid hormone into circulation
 Responds to glucocorticoids
 Management
THYROTOXICOSIS IN PREGNANCY
o Thioamides and glucocorticoids often administered
 Women in childbearing period with severe disease ideally together
should have definitive therapy with 131I or subtotal o Discontinue amiodarone if possible
thyroidectomy prior to pregnancy
 Propylthiouracil
NONTOXIC GOITER
o Less placental transfer and T4-T3 conversion
o Fewer teratogenic risks than methimazole  Often due to TSH stimulation from inadequate thyroid
o Can be given in first trimester hormone synthesis
o Dosage kept to the minimum necessary for control of
disease (<300 mg/d) ETIOLOGIES
o May affect fetal thyroid gland function  Iodide deficiency (most common cause worldwide)
 Methimazole  Hashimoto's thyroiditis (most common cause in USA)
o Can be given for the remainder of pregnancy to avoid  Other causes:
potential liver damage o Germline or acquired mutations in genes involved in
o Potential alternative hormone synthesis, dietary goitrogens, neoplasms
o Possible risk of fetal scalp defects
 Thyroidectomy in mid-trimester MANAGEMENT
 Thyroid supplement  Goiter due to iodide deficiency
 Definitive therapy after delivery o Best managed by prophylactic administration of iodide
 Optimal daily iodide intake: 150-200 mcg
NEONATAL GRAVES' DISEASE  Iodized salt and iodate
 Occurs due to: ‒ Used as preservatives in flour and bread
o Transplacental passage of maternal TSH-R Ab [stim]  Alternative: solution of iodized poppy-seed oil IM
o Genetic transmission of the trait to the fetus  Goiter due to ingestion of goitrogens
 If caused by maternal TSH-R Ab [stim]: o Elimination of goitrogen
o Usually self-limited o Adding sufficient thyroxine
o Subsides over a period of 4-12 weeks  Hashimoto's thyroiditis and dyshormonogenesis
o Thyroxine therapy of 150–200 mcg/d PO
LABORATORY DIAGNOSIS  Suppresses pituitary TSH
 Elevated FT4  Induces slow regression of goiter
 Markedly elevated T3  Corrects hypothyroidism
 Low TSH
o TSH normally elevated at birth MANAGEMENT OF THYROID NEOPLASMS
 Primary diagnostic test: FNAB
MANAGEMENT  Benign lesions
 Treatment necessary because of severe metabolic stress o Monitored for growth or symptoms of local obstruction
 Propylthiouracil  Thyroid carcinoma
o 5–10 mg/kg/d in divided doses q8 o Total thyroidectomy
 Lugol's solution o Post-operative radioiodine therapy in selected
o 8 mg of iodide per drop (1 drop q8) instances
 Propranolol o Lifetime replacement with levothyroxine
o 2 mg/kg/d in divided doses  Evaluation for tumor recurrence
 Careful supportive therapy essential o Involves withdrawal of thyroxine for 4-6 weeks or
o Oral prednisone for very ill infants administering recombinant human TSH (Thyrogen)
 2 mg/kg/d in divided doses qd IM for 2 days
 Helps block conversion of T4 to T3  Can produce comparable TSH elevations without
 Medications gradually reduced as patient improves and can discontinuing thyroxine
be discontinued by 6-12 weeks o Rise in serum thyroglobulin or positive 131I scan if
TSH elevated  recurrence
SUBCLINICAL HYPERTHYROIDISM
 Suppressed TSH level with normal thyroid hormone
levels
 Greatest concern: cardiac toxicity (e.g. atrial fibrillation)
especially in older persons
 Treat if TSH <0.1 mIU/L
 Close monitoring of TSH level appropriate for those with
less TSH suppression

AMIODARONE-INDUCED THYROTOXICOSIS (AAT)

 Occurs in 3% of patients receiving amiodarone
 Types
o Iodine-induced (type I) in patients with underlying
thyroid disease (e.g. multinodular goiter)

Martin, Pesky, Ron, Cla, Barbs, Nikka Page 8 of 8