Endocrine Pharmacology

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 Introduction
• The endocrine pancreas in the adult human consists of
approximately 1 million islets of Langerhans

• Within the islets, there are hormone producing cells

 Their hormone products include;

 Insulin,
 Islet amyloid polypeptide (IAPP, or amylin),
 Glucagon,
 Somatostatin,
 Pancreatic peptide, and
 Ghrelin
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 Introduction
Pancreatic islet cells and their secretory products

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The effect of hormones on blood glucose

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Structure of human proinsulin

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Factors regulating insulin secretion

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Control of insulin release from the pancreatic beta cell by glucose and by sulfonylurea drugs

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Diabetes Mellitus

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 Diabetes Mellitus
 Diabetes mellitus is defined as an elevated blood glucose
associated with absent or inadequate pancreatic insulin
secretion,

o with or without concurrent impairment of insulin

action.

• The disease states underlying the diagnosis of diabetes

mellitus are now classified into four categories:

– type 1, type 2, other, and gestational diabetes

mellitus. 9
 Diabetes Mellitus
Types of DM

 Type 1(Insulin dependent diabetes mellitus, IDDM)

β-Cells are destroyed which results in absolute deficiency

 Type 2 (None Insulin dependent diabetes mellitus, NIDDM)

 Inabilities of the β-cells to produce appropriate quantities

of insulin, and reduced sensitivity to its action(insulin resist.)

 Others* and Gestational Diabetes Mellitus

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SOME DRUGS THAT MAY PROMOTE HYPERGLYCEMIA OR HYPOGLYCEMIA

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 Diagnostic criteria for diabetes

• Pre-Diabetic
Impaired fasting glucose (IFG): FPG of 100 - 125 mg/dL (5.6
to 6.9 mmol/L).
 Impaired glucose tolerance (IGT): 2-hour postload oral
glucose tolerance test of 140 - 199 mg/dL (7.8 to 11.0
mmol/L)

• Diagnosis of DM*
– Symptoms + RBS(random blood sugare) ≥ 200mg/dl or
– FBS(fasting blood sugare) ≥ 126mg/dl or
– OGTT ≥ 200mg/dl – 2 hr post 75gm oral glucose load

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Drugs for Diabetes Mellitus

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 • Differ in …………………..
• Recombinant technique employed
• a.a sequence
• Stability
• Solubility
• Onset of action
Insulin • Duration of action
• 4-types of insulin preparations
preparations • Rapid acting
• Short acting
• Intermediate acting
• Long acting

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 Pharmacokinetics of various insulin
Type of Onset Peak Duration Maximum Appearance
Insulin (Hours) (Hours) (Hours) Duration
(Hours)
Rapid-acting
Aspart 15–30 min 1–2 3–5 5–6 Clear
Lispro 15–30 min 1–2 3–4 4–6 Clear
Glulisine 15–30 min 1–2 3–4 5–6 Clear
Short-acting
Regular 0.5–1.0 2–3 3–6 6–8 Clear
Intermediate-actinga
NPH 2–4 4–6 8–12 14–18 Cloudy
Long-acting
Detemir 2 hours 6–9 14–24 24 Clear
Glargine 4–5 — 22–24 24 Clear

NPH, neutral protamine Hagedorn.

a others: lente and ultralente insulin 15
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Insulin analogues

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 Drugs for diabetes mellitus
 Route of administration
• Orally inactivated by digestive enzymes

• All are given subcutaneously

• Regular insulin can also be given IV

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 Drugs for Diabetes Mellitus
Clinical uses of insulin
 Patients with type 1 diabetes require long-term insulin
 DKA and hyperosmolar hyperglycemic state
 Soluble insulin is used (iv) in emergency treatment
 Many patients with type 2 diabetes ultimately need insulin
 Gestational diabetes not controlled by diet alone
 Emergency treatment of hyperkalaemia: insulin is given
with glucose to lower extracellular K+ via redistribution into
cells

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 Drugs for diabetes mellitus
Adverse Effects
1. Hypoglycemia  cause brain damage in severe
cases

2. Lipodystrophy

»lipoatrophy – loss of subcutaneous fat (due to

immunologic rxn)

»lipohypertrophy- fat accumulates

3. Weight gain- during intensive insulin therapy

4. Hypersensitivity (less common in human insulin) 20

 Complications of Insulin Therapy
HYPOGLYCEMIA
 Most common complication of insulin therapy
may result from;
A delay in taking a meal

Inadequate carbohydrate consumpiton

Unusual physical exertion

A dose of insulin that is too large for immediate needs

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 Drugs for diabetes mellitus
Oral antidiabetic agents
 Used to treat NIDDM
a) The sulphonylureas, Meglitinides
b) Biguanides, Thiazolidinediones
c) - glucosidase inhibitors
d) GLP-1 receptor agonists, dipeptidyl peptidase 4
[DPP-4] inhibitors
e) sodium-glucose co-transporter inhibitors [SGLTs]
f) agents that act by other or ill-defined mechanisms
(pramlintide, bromocriptine, colesevelam) 22
 Drugs for diabetes mellitus
Sulfonylureas
 1st generation:- Tolbutamide, tolazamide, chlorpropamide

 2nd generation: - Glibenclamide(glyburide), Glipizide, glimepiride

 More potent than 1st generation

 Have fewer adverse effect and drug interaction

 Mechanism of actions

• Stimulation of insulin release from the β -cells of pancreas

• May also increase tissue response to insulin (↓ insulin resist.)

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Mechanism of Action

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Sulfonylureas

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 Drugs for diabetes mellitus
 Adverse effects

 The commonest adverse effect is hypoglycaemia

 Stimulate appetite, weight gain

 Gastro-intestinal upsets

 Allergic skin rashes

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 Drugs for diabetes mellitus
 Meglitinides
 Repaglinide, Mitiglinide

• Enhances insulin secretion

• These drugs modulate beta-cell insulin release;

o by regulating potassium efflux through the potassium channels

• Shorter onset and duration of action than sulphonylureas

 Low risk of prolonged hypoglycemia

• Cause less weight gain than conventional sulfonylureas

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 Drugs for diabetes mellitus
 Biguanides
 Metformin
 Doesn’t stimulate insulin secretion
 Acts primarily;
• Reduce hepatic glucose production (gluconeogenesis)
• through AMPK activation
 It has also anti hyperlipidemic effects (  LDL and VLDL)
 Less hypoglycemic risk….―euglycemic‖ agents
 Used alone or in combination
• Side effects
 GI disturbance (anorexia, nausea, and diarrhea), lactic acidosis
 Vitamin B12 deficiency

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 Drugs for diabetes mellitus
Bigunides…
Contraindication
 Patients with renal or hepatic disease, hypoxic pulmonary
disease, heart failure or shock
o Predisposed to lactic acidosis
 Reduced drug elimination or tissue oxygenation
Clinical use
 DOC in the majority of type 2 patients who are obese
 Can be combined with sulfonylureas, glitazones or insulin29
 Drugs for diabetes mellitus
 Thiazolidinediones (glitazones)
 Rosiglitazone and pioglitazone
Troglitazone, the first member of the class,
o was withdrawn as a consequence of liver failure.
• They are insulin sensitizers and increase insulin-mediated
glucose uptake;
• by 30%–50% in patients with type 2 diabetes.
• Mechanism of action
  hepatic glucose output & glucose uptake into
muscle
 Enhance effectiveness of endogenous insulin
 Reduce the amount of exogenous insulin needed 30
They are ligands of peroxisome proliferator-
activated receptor gamma (PPAR-γ),
o part of the steroid and thyroid superfamily of nuclear
receptors.

Observed effects of the thiazolidinediones include;

– increased glucose transporter expression (GLUT 1 and
GLUT 4),

– Decreased hepatic glucose output

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 Drugs for diabetes mellitus
Thiazolidinediones (glitazones)…
 Unwanted effects
 Weight gain and fluid retention (commonest)
 C/I to patients with heart failure

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 Drugs for diabetes mellitus

 α-Glucosidase inhibitors
 Acarbose, Miglitol, Voglibose
• Inhibits intestinal α-glucosidase enzymes
• Delays carbohydrate absorption,
o reduce the postprandial increase in blood glucose
• Used primarily as adjunctive therapy in patients who cannot
achieve their glycemic goals with other medications
• The commonest adverse effects;
o Diarrhea
o Flatulence, bloating
o Abdominal pain
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 DRUGS THAT MIMIC INCRETIN EFFECT OR PROLONG
INCRETIN ACTION
1) GLP-1 RECEPTOR AGONISTS
 When GLP-1 is infused in patients with type 2 diabetes,
o it stimulates insulin release and lowers glucose levels.
 GLP-1 analogs; Exenatide, liraglutide, albiglutide,
and dulaglutide are available for clinical use
 ADR:
 All may increase the risk of pancreatitis.
oRenal impairment (Exenatide)
oThe drugs, however, should not be used in persons
with a past medical or FHx of medullary thyroid
cancer
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2) DIPEPTIDYL PEPTIDASE 4 (DPP-4) INHIBITORS

GLP-1 is rapidly degraded by DPP-4.

 Then, inhibitors of DPP-4 can be used to prolong the action of
endogenously released GLP-1

DPP-4 inhibitors; sitagliptin, saxagliptin, linagliptin,

alogliptin, and vildagliptin, are available.

Common adverse effects include nasopharyngitis, upper

respiratory infections, and headaches, hypersensitivity
reactions
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 SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2)
INHIBITORS

 Glucose is freely filtered by the renal glomeruli and,

 reabsorbed in the proximal tubules by the action of SGLTs

 SGLT2 inhibition causes glycosuria and lowers glucose levels

in patients with type 2 diabetes.

 The SGLT2 inhibitors; canagliflozin, dapagliflozin, and

empagliflozin, are approved for clinical use.

 The main adverse effects are increased incidence of

genital infections and urinary tract infections.
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THANK YOU!!!

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 Thyroid and antithyroid drugs
Thyroid Hormones
 The thyroid gland secrets three types of hormones:
 Thyroxine (T4)
 Triiodothyronine (T3)
 Calcitonin
 T3 and T4 are important for normal growth and development
and for energy metabolism
 Calcitonin controls blood calcium level
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Biosynthesis of thyroid hormones and the sites of action of various drugs that
interfere with thyroid hormone biosynthesis

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Peripheral metabolism of thyroxine

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 Thyroid and antithyroid drugs
Synthesis, storage and release of TH
 Iodine trapping -Uptake of plasma iodide(I-) by the follicle
cells
 Oxidation of iodide
Conversion of iodide to iodine (I- Io)
Thyroperoxidase requires H2O2 as oxidizing agent
 Iodination:
Tyrosine of thyroglobulin is iodinated
 Form monoiodotyrosine (MIT) and diiodtyrosine (DIT)
 MIT + DIT T3(Triiodothyronine)
 DIT + DIT T4 (Thyroxine)
 Secretion: proteolytic enzymes act on TG then T3 & T4 are
released to the plasma
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 Thyroid and antithyroid drugs

 Thyroid hormone (T3, T4) actions

 Have three principal actions:
1. Increasing metabolism
»  carbohydrate, protein metabolism
» stimulate protein synthesis
» increase the use of glucose and fatty acids for ATP
production
»  O2 consumption &
»  Heat production
2. Stimulation of the heart
»  Heat rate
»  force of contraction and  CO
3. Promotion of growth & development
» Normal growth and development of CNS
» Maturation of skeletal muscle
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 Inadequate secretion of thyroid hormone
(hypothyroidism) results in;
– bradycardia, poor resistance to cold, mental and physical
slowing.

– In children, this can cause mental retardation and

dwarfism.
 In contrast, excess secretion of thyroid hormones
(hyperthyroidism) can cause;
o tachycardia and cardiac arrhythmias, body wasting,
nervousness, tremor, and heat intolerance.

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Thyroid & Antithyroid Drugs

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Etiology and pathogenesis of hypothyroidism

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 Thyroid and antithyroid drugs
 Treatment of hypothyroidism
 Levothyroxine (T4) and liothyronine(T3)
• Administered orally
• Levothyroxine is the usual first-line drug of choice
• T1/2 of T4 7 days  About 1 month is required to reach plateau
(onset delayed)
• Liothyronine has a faster onset but a shorter duration of action
• T3; plasma t1/2 is 18–24 h,
» relatively short duration of action, T3 is less desirable
than T4 for long-term use
» Superior than T4 in a situation that requires speedy
results (e.g., myxedema coma)
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 Thyroid and antithyroid drugs
• Adverse Effects
– If dosage is excessive:
• Thyrotoxicosis
–tachycardia
–angina
–tremor
–nervousness
–hyperthermia

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 Thyroid and antithyroid drugs

Drugs used to treat hyperthyroidism

1) Thioamides
» Propylthiouracil
» Methimazole
» Carbimazole
2) Iodides
»Lugol’s solution
»KI tablets
3) Radioactive iodine
4) Adrenoreceptor blocking agents
– imp’t in controlling the peripheral manifestation of thyrotoxicosis

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 Thyroid and antithyroid drugs
 Thioamides (thioureylenes)
• Propylthiouracil (PTU), carbimazole, methimazole
• MoA
 inhibiting the thyroid peroxidase-catalyzed reactions and
blocking iodine organification.
 PTU has additional effect of decreasing deiodination of T4
to T3 in peripheral tissues
• Therapeutic uses
1. For therapy of Graves’s disease
2. As adjunct to radiation therapy (to control
hyperthyroidism until radiation effects manifest)
3. Part of the treatment of thyroid storm (very severe
hyperthyroidism)
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 Thioamides

 Because of the risk of fetal hypothyroidism, both

thioamides are classified as
– FDA pregnancy category D

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PHARMACOKINETIC FEATURES OF ANTITHYROID DRUGS

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 Methimazole is about ten times more potent
than PTU and;
– is the drug of choice in adults and children.

 Due to a black box warning about severe hepatitis,

– PTU should be reserved for use during the first
trimester of pregnancy,
• in thyroid storm, and in those experiencing ADR to
methimazole (other than agranulocytosis or hepatitis).
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 Thyroid and antithyroid drugs

Adverse effects
• Agranulocytosis (granulocyte count < 500 cells/mm 3 )
• Rash (most common)

• Headache, nausea, jaundice and pain in the joints

• Cholestatic jaundice is more common with methimazole

than propylthiouracil.

• An increased risk of severe hepatitis is reported with

PTU.

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 Thyroid and antithyroid drugs
Iodide
 MOA – when present in high concentration:

 Inhibit iodination

 Inhibit hormone release

 Improvement in thyrotoxic symptoms occurs rapidly,

 within 2–7 days

 Decrease the size and vascularity of the hyperplastic gland

» With long-term iodide administration suppressant effects
become weaker rarely used alone
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 Thyroid and antithyroid drugs
 Therapeutic uses
 In preparation of hyper thyroid patients for surgery
 Treatment of severe thyrotoxic crisis
• Preparation
1. Lugols solution – contains;
Iodine ---- 5%
Potassium Iodide 10%
2. Potassium iodide
 Adverse effects
 Allergy; angioedema, rashes, drug fever
 lacrimation, conjunctivitis
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 Thyroid and antithyroid drugs
Radioiodine
• The isotope used is 131I (usually as the sodium salt)
• Emits a combination of β-particles &  rays
• Concentrated in the thyroid gland
 Destruction of the thyroid tissue is produced primarily by
emission of β-rays
• T1/2 is 8 days and duration of 2 months
• Given orally as one single dose

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 Thyroid and antithyroid drugs

Therapeutic uses

 Rx of hyperthyroidism

 In the Rx of thyroid cancer

Adverse effects

 Delayed hypothyroidism

 Contraindicated in pregnancy & nursing mothers

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 Thyroid and antithyroid drugs
β-adrenoceptor antagonists
 Propranolol, metoprolol, atenolol
• Useful for decreasing many of the signs and symptoms of
hyperthyroidism
 Tachycardia, dysrhythmias, tremor and agitation
 Clinical use
 During the preparation of thyrotoxic patients for surgery
 Initial treatment period while the thioamides or radioiodine
take effect
 As part of the treatment of acute hyperthyroid crisis
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 Thyroid and antithyroid drugs
Guanethidine
 A noradrenergic-blocking agent
 Used in eye drops to ameliorate the exophthalmos of
hyperthyroidism (which is not relieved by antithyroid drugs)
 Acts by relaxing the sympathetically innervated smooth
muscle that causes eyelid retraction

 Glucocorticoids (e.g. prednisolone

or hydrocortisone) or surgical
decompression may be needed to
mitigate severe exophthalmia in
Graves’ disease.

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 AGENTS THAT DISRUPT THYROID
HORMONE SYNTHESIS, RELEASE, AND METABOLISM

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Thank you…

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