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Endocrine Pharmacology


Endocrine Pharmacology


Endocrine Pharmacology

Endocrine Pharmacology
Mechanism of action of Hormones:

Mechanism of Action

1-Polypeptide hormones
3-Steroid hormones
4-Vitamin D.

Activation of cell membrane receptors (G-protein linked)

increased synthesis of 2ry messenger as c-AMP.
The onset of action is immediate.

5-Thyroid hormones.

Activation of nuclear receptors synthesis of m-RNA and

proteins. They have intermediate onset of action.

6-Insulin (polypeptide

Activation of specific "tyrosine kinase-linked" receptors.

Insulin has very rapid onset of action.

Activation of cytoplasmic receptors activation of the

hormone-receptor complex which enters the nucleus and
binds to DNA (nuclear receptors) synthesis of m-RNA
synthesis of specific proteins (gene expression) and/or
inhibition of other proteins (gene repression).
They have delayed onset of action (lag period of several

N.B.: All polypeptide hormones are never given orally because they are destroyed by
proteolytic enzymes in GIT whereas steroid and thyroid hormones are given orally.

Endocrine Pharmacology


Definition: Diabetes Mellitus (D.M.) is a chronic metabolic disorder affecting carbohydrate,
fat, and protein metabolism and is characterized by hyperglycemia and glucosuria, due to
absolute or relative insulin deficiency, or decreased sensitivity of insulin receptors.

Types of D.M.:
Type I: Insulin-Dependent D.M. (IDDM): known as (Juvenile) D.M.-it occurs in
young age (< 30 years) and is characterized by severe or absolute insulin deficiency- patients
are non obese (underweight)- and diadetic ketoacidosis (DKA) is common.
Treatment is by insulin replacement for life.
Type II: Non Insulin Dependent D.M.: known as (Maturity onset) D.M.- it occurs in
older patients (> 40 years) and is characterized by relative insulin deficiency or a defect in the
biological effect of insulin (insensitivity)-85% of patients are obese and only 15 % are nonobese and DKA is rare.
Treatment does not necessarily require insulin.
Type III (secondary D.M.): it occurs due to:
1- Drugs (iatrogenic D.M.) as thiazides, diazoxide, phenytoin, and CCBs as verapamil. These
drugs inhibit insulin release.
2- Counter-regulatory hormones (anti-insulins) including glucagon, growth hormone,
glucocorticoids, thyroxin, and catecholamines (adrenaline and noradrenalin).
3- Immunosuppressive drugs (inhibit insulin synthesis).
4- Pancreatic diseases as pancreatitis, or after pancreatectomy.
5- Cytotoxic drugs that destroy B-cells as streptozotocin and alloxan.
Type IV (gestational D.M.): which occurs for the first time during pregnancy, and is mostly
due to placental hormones with anti-insulin effect.

Anti-Diabetic Drugs
Anti-diabetic drugs can be classified into the following groups:
I-Insulin: given S.C. in all type I patients and in some type II patients. Only soluble regular
insulin can be given I.V. only in emergencies as diabetic ketoacidosis (D.K.A.) and
hyperosmolar non-ketotic coma.
II-Oral anti-diabetic drugs: these drugs are given orally in treatment of type II D.M. They
are subdivided into:
A-Insulin secretagogues: their main action is to stimulate insulin release from B-cells of islets
of Langerhan. That is why they may cause hypoglycemia and are sometimes referred to as
"oral hypoglycemics". According to their chemical structure they are classified as:
1. Sulfonylureas (SU): these drugs are chemically related to sulfonamides, and are divided
into 2 generations:

Endocrine Pharmacology


First generation SU: as Tolbutamide (short acting)- Acetohexamide (intermediate acting)Chlorpropamide (long acting).
Second generation SU: as Glibenclamide (Glyburide)- Glipizide- Gliclazide- Glimepiride.
They have the following advantages over the first generation:
a. Less adverse effects (better tolerated).
b. More potent.
c. Intermediate duration of action (12-24 hours) and can be given once or twice daily.
2. Meglitinides: as Repaglinide.
3. D-phenylalanine derivatives: as Nateglinide.
B-Insulin sensitizers: they improve the action of insulin on insulin receptors in the liver,
adipose tissue, and skeletal muscles mainly.
They do not stimulate insulin release and never induce hypoglycemic when used alone; that is
why they are referred to as "oral euglycemics".
Insulin sensitizers include:
1-Biguanides: only Metformin is available (phenformin was withdrawn because of severe
lactic acidosis).
2-Thiazolidinediones (Tzds) = Glitazones: as Rosiglitazone and Pioglitazone (Troglitazone
was withdrawn due to serious hepatotoxicity).
C-Alpha Glucosidase Inhibitors:
These drugs inhibit -glucosidase enzymes in the brush border of intestinal mucosa leading to
inhibition digestion of dietary carbohydrates (poly-, oligo- and di-saccharides) into glucose.
They are used to reduce "post-prandial" increase in blood glucose.
Examples are Acarbose and Miglitol (which is about 5 times more potent than acarbose).

III-New Antidiabetic Drugs:

A- GLP-1* receptor agonists: Exenatide and Liraglutide (given S.C.).
B- DPP-IV** inhibitors: Sitagliptin, Vildagliptin, and Saxagliptin (given orally).
C- Synthetic Amylin*** analogues: Pramlintide (given S.C.).
Important notes:
1. GLP-1: Glucagon-Like Peptide 1 which is an incretin (GIT hormone released after
2. DPP-IV: Di-Peptidyl Peptidase-4 which is the enzyme responsible for degradation of


Endocrine Pharmacology

3. Amylin: is a polypeptide hormone (37 amino acids) stored and released with insulin
from B-cells.
GLP-1 receptor agonists

Mechanism and

DPP-IV inhibitors

1-Sitagliptin (Januvia).
S.C. injection.
Stimulate Glucagon-Like
Inhibit Di-PeptidylPeptide-1 (GLP-1) receptors
Peptidase-4 (DPP-IV)
leading to:
enzyme endogenous
1. Stimulation of insulin
GLP-1 stimulation of
release from B-cells.
GLP-1 receptors leading to:
2. Decrease glucagon release 1. Stimulation of insulin
release from B-cells.
from A-cells.
3. Delay gastric emptying (to 2. Decrease glucagon
release from A-cells.
prevent sudden elevation of
blood glucose after meals). 3. Delay gastric emptying
(to prevent sudden
4. Suppress appetite (CNS
elevation of blood
glucose after meals).
4. Suppress appetite (CNS
1-Exenatide (short duration).
2-Liraglutide (long duration).


Type II D.M.step 4.

Adverse effects

1. Hypoglycemia (when
combined with SU).
2. Nausea is very common.
3. Decreased absorption of
some drugs as paracetamol
due to delayed gastric
4. Given only by injection.

Type II D.M. step3 and 4

(Sitagliptin is available in
combination with metformin
and is known as Janumet).

Amylin analogues

S.C. injection.
Stimulates amylin
receptors leading to:
1. Decrease glucagon
release from A-cells.
2. Delay gastric
emptying (to prevent
sudden elevation of
blood glucose after
3. Suppress appetite
(CNS action).
N.B. amylin does not
stimulate insulin release
(it may even reduce
insulin release but this is
Type I and Type II D.M.
to prevent post-prandial

1. Animal insulin: from animal pancreatic extracts and is either:
Bovine: differs from human insulin in 3 amino acids and is highly antigenic.

Endocrine Pharmacology


Porcine: differs from human insulin in 1 amino acid and is less antigenic than bovine
2. Human insulin: obtained by 2 different techniques:
Synthesis by recombinant DNA technology (Bio-synthetic insulin).
Enzymatic modification of animal insulins (Semi-synthetic insulin).
Human insulin is the least antigenic but is much more expensive.

Insulin is composed of 2 polypeptide chains: A chain made up of 21 amino acids, and B chain
made up of 30 amino acids. Both chains are connected by 2 disulphide links which are
essential for the biological activity of insulin.

Factors Affecting Insulin Release:

Factors Stimulating Insulin Release

Factors Inhibiting Insulin Release

1. Glucose (the most potent stimulus): glucose

enters B-cells by GLUT 2 and undergoes
glycolysis to form ATP, which in turn
blocks ATP-sensitive K+ channels
depolarization opening to voltagedependent Ca2+ channels influx of Ca2+
insulin release.
2. Amino acids (leucine and arginine) and
fatty acids in diet.
3. GIT hormones (incretins) as Glucagon-like
peptide 1 (GLP-1) and Gastrin inhibitory
peptide (GIP).
4. Systemic Hormones: Glucagon and growth
hormone (secondary to increased blood
5. Autonomic innervation and receptors:
Muscarinic stimulation, 2 stimulation, and
2 block increase insulin release.
6. Insulin secretagogues (Oral hypoglycemic
drugs, e.g. sulfonylureas and meglitinides).

1. Fasting and starvation: increase sympathetic

activity leading to release of adrenaline and
noradrenaline which stimulate 2-receptors
thus inhibit insulin release.
2. Somatostatin (inhibits glucagon release
more than its inhibitory action on insulin).
2-PG E1.
3. Autonomic innervation and receptors:
2 stimulation, 2 block, and muscarinic
4. Drugs:
Thiazides, Loop diuretics, and Diazoxide:
open ATP-sensitive K+ channels in B-cells
leading to hyperpolarization.
Phenytoin (Na+ channel blocker).
CCBs as Verapamil.


Insulin is never given orally because it is a polypeptide; i.e. it is destroyed by proteolytic

enzymes in GIT.
All insulin preparations are given by S.C. injection.
Only regular (soluble) insulin is given IV Only in case of diabetic ketoacidosis (D.K.A.).
Insulin is distributed to all tissues.
Fate: insulin is metabolized by glutathione insulin transhydrogenase (insulinase) in liver
and kidney which breaks the disulphide links, then the polypeptide chains are degraded
by polypeptidases.


Endocrine Pharmacology


Mechanism of action:
Insulin acts by stimulation of specific insulin receptors.
Insulin receptors are "Tyrosine Kinase linked".
Each receptor is composed of 2 -subunits on the cell membrane, and 2 -subunits that
transfix the cell membrane (partly extracellular and partly intracellular). These subunits are
linked by disulphide links.
Insulin molecule binds to -subunits of insulin receptors which then activate -subunits
leading to activation of tyrosine kinase and phosphorylation of different enzymes which
initiate the biological actions of insulin; e.g. glucose transporters (GLUT) which glucose
The insulin receptor then undergoes "conformational change" and "internalization", then it
is either degraded or "recycled" to the cell membrane.
Pharmacological actions:
"Remember that insulin is an anabolic hormone".
1. Action on Carbohydrate Metabolism:
Insulin tends to reduce blood glucose by the following mechanisms:
Stimulation of glucose uptake by formation of "glucose transporters" as GLUT 4 which
is responsible for glucose uptake into skeletal muscles and adipose tissue.
Stimulation of glucose utilization by glycolysis (glucose by glucokinase glucose 6
phosphate ATP).
Stimulation of glycogenesis and inhibition of hepatic glycogenolysis.
Inhibits gluconeogenesis.
2. Action on Protein metabolism:
Amino acid transport and stimulates synthesis of proteins.
Inhibits gluconeogenesis ( protein degradation).
3. Action on Fat Metabolism:
Stimulates lipogenesis by stimulating lipoprotein lipase andadipocyte fat storage.
Inhibits lipolysis by inhibition of triglyceride lipase.
Free fatty acids in blood.
Fatty acid oxidation and inhibits ketone bodies synthesis (inhibits ketogenesis).
4. Stimulates transport of K+, Mg2+, and phosphate and decreases their plasma level.
Insulin deficiency in D.M. is characterized by:
1. Hyperglycemia and glucosuria due to:
Glucose uptake and utilization.
2. Free fatty acids in blood due to:


Endocrine Pharmacology
3. Oxidation of free fatty acids and formation of ketone bodies (ketogenesis).
4. Amino acid uptake and protein synthesis and protein catabolism.
5. Weakness, immunocompromization and recurrent infections.

Indications of insulin:
A- Diabetic indications:

1. Treatment of Type I (IDDM): replacement therapy from the time of diagnosis and
throughout life.
2. Treatment of Diabetic Keto-Acidosis (DKA) by soluble insulin IV.
3. Temporarily in Type II (NIDDM) in cases of "stress" due to: infections surgery
pregnancy -trauma.
4. Permanently in Type II (NIDDM) in cases of:
Failure to control hyperglycemia by diet + exercise + oral anti-diabetics.
Development of renal or hepatic impairment.
After recovery from DKA.
B- Indications of insulin in "non-diabetic cases":
Treatment of hyperkalemia due to renal impairment (glucose should be given with insulin to
avoid hypoglycemia).

Adverse effects:
A-Local Adverse Effects:
1- Lipodystrophy: either hypertrophy (more common due to insulin-induced lipogenesis) or
atrophy of subcutaneous fats. It is prevented by changing (rotating) the site of injection.
2- Local allergic reactions; they are rare nowadays due to the use of human insulin instead of
animal insulin.
3- Localized infections (very rare).
B-Systemic Adverse Effects:
Hypoglycemia is the most dangerous adverse effect of insulin therapy.
1- Insulin overdose (too much insulin).
2- Ommission of meals (too little food).
3- Exhaustive physical exercise (too much exercise).
Sympathetic stimulation: tachycardia and palpitations (the most important warning
symptoms) tremors sweating pallor.
Neuroglycopenia: headache blurred vision and diplopia confusion convulsions,
coma and may end in death.
If the patient is conscious: treatment by oral glucose or sweets (candy, juice, chocolate,


Endocrine Pharmacology

If the patient is comatose: treatment by IV glucose (50-100 mL. of 25-50% glucose) or

by glucagon (1mg.) given IM or SC followed by oral glucose. Adrenaline SC is used
only if there is no alternative and no contraindication (as hypertension, angina,
2- Systemic allergic reactions (uncommon because human insulin has largely replaced animal
insulins). Allergy may be due to protamine-containing isulins as N.P.H and P.Z.I., and they
should be replaced by zinc-containing insulins (as Lente insulin).
3- Insulin resistance (daily insulin requirements exceed 200 Units, common in obese nonexercising patients, and may improve by adding insulin sensitizers as metformin or
glitazones). Insulin resistance was also common with animal insulin due to the formation of
insulin antibodies.
4- Hypokalemia may occur especially with IV insulin therapy in DKA.

Methods of Administration:
1- Disposable plastic syringes.
2- Insulin pen (more accurate dosage and less painful).
3- Insulin pump.
N.B.: insulin in the form of nasal inhalation will be available soon.

Insulin Preparations:
Insulin Preparation:
Rapid acting insulin analogs (Ultrashort acting): rapid onset + short
1- Insulin Lispro.
2- Insulin Aspart.
3- Insulin Glulisine.

Short acting: (slower onset + longer

duration than ultra-short)
1- Soluble = Regular =Crystalline
insulin zinc.
2- Semilente (prompt insulin zinc
Intermediate acting:
1- Isophane insulin (NPH).
2- Lente (insulin zinc suspension).




5-15 min.
5-15 min.
5-15 min.

30-90 min.
30-90 min.
30-90 min.

5 hours.
5 hours.
1-2 hours.

30-60 min.

2-3 hours.

5-8 hours.

30-60 min.

4-6 hours.

12-16 hours.

2-4 hours.
2-4 hours.

4-10 hours.
4-10 hours.

10-18 hours.
10-18 hours.


Endocrine Pharmacology

Long acting:
1- Protamine zinc insulin (PZI).
2- Ultralente (insulin zinc
3- Insulin Glargine (peakless
4- Insulin Detemir.
70% NPH/30% regular (Humulin

4-6 hours.
6-10 hours.
2-4 hours.
1-4 hours.

16-18 hour
10-16 hour
No peak.

20-36 hours.
18-24 hours.
18-24 hours.
6-23 hours

30-60 min.

2 Peaks (1-3
hours and 410 hours).

24 hours.

Insulin analogs:
Prepared by recombinant DNA technology.
Synthesized by substitution of one or more amino acids in insulin molecule (modified
amino acid sequence or composition).
They show different pharmacokinetic properties and accordingly have different onset and
Examples include: insulin glargine- insulin lispro- insulin aspart-insulin detemir-insulin

Oral Anti-Diabetic Drugs

Oral anti-diabetic (anti-hyperglycemic) drugs are classified into:

I- Insulin Secretagogues:
These drugs stimulate insulin release from pancreas in Type II diabetes and accordingly may
cause "Hypoglycemia" in large doses and are called "Oral Hypoglycemic drugs". They include:
A- Sulphonylureas: sulphonamide derivatives and accordingly may cause severe allergic
reactions, and there is an incidence of acute myocardial infarction causing sudden death.
B- Meglitinides: they have the same mechanism of action as sulphonylureas but are nonsulphonamides and are less allergic and not associated with risk of acute myocardial
infarction. They include Repaglinide and Nateglinide.

II- Insulin Receptor Sensitizers:

These drugs do not stimulate insulin release but increase sensitivity of insulin receptors and
never cause hypoglycemia but "normalize high blood sugar" so they are known as
"Euglycemics".They include:


Endocrine Pharmacology


A- Biguanides: only Metformin(Glucophage) is available and phenphormin is obsolete

because it may cause fatal "lactic acidosis".
B- Thiazolidinediones: also known as "Glitazones", for example:Rosiglitazone, Pioglitazone,
and Troglitazone which was withdrawn due to hepatic toxicity.
Mechanism of action: They stimulate Perixosome Proliferator Activated Receptor -Gamma
(PPAR- ) which is a nuclear receptor that stimulates synthesis of lipoprotein lipase and
GLUT-4 in skeletal muscles and adipose tissues, thus increasing glucose uptake and utilization.
Indications: Indicated in type 2 diabetes in addition to dietary control
and exercise, either alone (monotherapy) or in combination with sulphonylureas,
metformin, or insulin.


Adverse effects:
Na+ and water retention leading to edema, weight gain, and may cause CHF.
Hepatitis and elevation of liver enzymes (transaminases). Hepatotoxicity is rare but may be
fatal and frequent monitoring by liver function tests is needed (troglitazone was withdrawn).
Mild anemia.
May increase the risk of: osteoporosis and bone fractures, myocardial infarction and sudden
death, and cancer bladder.

Contraindications: pregnancy- liver impairment-hypertension and heart failure.

III- Alpha Glucosidase Inhibitors:

They act by inhibition of -glucosidase enzymes in the brush border of intestinal mucosa
leading to inhibition of digestion of complex carbohydrates and accordingly inhibition of
dietary glucose absorption.
They are used to control=blunt "Post-Prandial hyperglycemia" in type II DM, they can be
given with SU but not with metformin (see later).
They cause GIT disturbances: bloating, flatulence, abdominal pain, diarrhea, malabsorption
of dietary carbohydrates, and decrease absorption of metformin.
N.B.: in case of hypoglycemia, they will interfere with oral absorption of sucrose, and glucose
should be given.
They include: Acarbose and Miglitol (5-6 times more potent).

Sulfonylureas (SU)
Source: synthetic.
Chemistry: sulfonamide derivatives.

Endocrine Pharmacology



First Generation: they are less potent than the second generation and not used clinically
anymore in D.M.:
Tolbutamide: metabolized mainly by the liver and is "short acting".
Acetohexamide: metabolized into active metabolite and excreted mainly in urine and is
"intermediate acting".
Chlorpropamide: about 80% excreted in urine and 20% metabolized by the liver, and is
"long acting" (action lasts up to 60 hours).
It stimulates secretion and action of ADH and is used in pituitary (central) diabetes
Second Generation: they are more potent and well tolerated (less adverse effects) than the
first generation and all are "intermediate acting", i.e. act for about 12 to 24 hours. They
Glibenclamide (also known as Glyburide and is contraindicated in patients with creatinine
clearance less than 50 ml. / min.) -Glipizide Gliclazide- Glimeperide (most potent).


Well absorbed orally.

Bound to plasma proteins, and may be displaced by many drugs as NSAIDs and
Pass BBB and may cause CNS adverse effects.
Pass placental barrier and may cause teratogenicity and fetal hypoglycemia.
Fate: extensive hepatic metabolism, metabolites are excreted in urine.
They are partly excreted in breast milk.

Mechanism of action:
Sulfonylureas block ATP-sensitive K+-channels in pancreatic cells depolarization and influx
of Ca2+ release of insulin from pancreatic B cells of islets of Langerhans.
(SU act on specific receptors in ATP-sensitive K+ channels, known as SUR).

Pharmacological actions:
1. Stimulation of insulin release from pancreas. This is the main action of sulphonylureas, and
depends on the presence of some insulin in the pancreas.
2. Inhibition of glucagon release from pancreas.
3. Increase sensitivity of -cells to glucose.
4. (Actions 1, 2, and 3 are known as "Pancreatic actions").
5. Increase tissue sensitivity to insulin.
6. Suppress hepatic gluconeogenesis.
(Actions 4 and 5 are known as "Extra-pancreatic action".



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1-NIDDM: alone in non-obese patients, or in combination with metformin if one drug can not
control hyperglycemia.
2-Chlorpropamide is used in pituitary diabetes insipidus because it has an antidiuretic action
(may be through stimulation of ADH release).

Adverse effects:
1- Hypoglycemia: is the most serious adverse effect. The causes, manifestations, and treatment
are identical to insulin-induced hypoglycemia.
2- Hypersensitivity reactions: skin rash and photosensitivity, and cross allergy with
sulphonamides and thiazides.
3- Gut upsets: nausea, vomiting, diarrhea.
4- Stimulation of appetite and weight gain.
5- Cholestaic jaundice especially with chlorpropamide.
6- Disulfiram-like action (alcohol-intolerance) especially with chlorpropamide.
7- Edema and dilutional hyponatremia with chlorpropamide due to its antidiuretic action.
8- Teratogenicity and fetal hypoglycemia.
9- High incidence of acute myocardial infarction and sudden death especially with first
generation sulphonylureas.
10- CNS disturbances: drowsiness, confusion, and ataxia.
11- Bone marrow depression (blood dyscrasias).
12- Failure of therapy: either "primary" failure (no response to sulphonylureas from the start
of therapy), or "secondary" failure (failure to control hyperglycemia after 1-2 years of initial
improvement, which may be due to refractoriness of -cells or loss of dietary compliance).


Type I D.M.
Pregnancy and lactation.
Renal and hepatic impairment.
After recovery from DKA.
NIDDM in conditions of stress: pregnancy-infections-surgery.
N.B.: SU are contraindicated whenever insulin is indicated + allergy to sulfa.

*Drug interactions:
Pharmacokinetic interactions:
1- Sulphonylureas displace oral anticoagulants as warfarin from plasma proteins leading to
2- Sulphonylureas are displaced by NSAIDs as aspirin and phenylbutazone, and
sulphonamides from plasma proteins and may augment the hypoglycemic effect of



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3- Dicoumarol (oral anticoagulant) decreases renal excretion of chlorpropamide and may

augment its hypoglycemic effect.
4- Alcohol may cause hypoglycemia and thus augments the effect of sulfonylureas.
Pharmacodynamic interactions:
1- Thiazide diuretics, loop diuretics, diazoxide, CCBs as Verapamil, and phenytoin antagonize
the hypoglycemic effect of sulphonylureas because they inhibit insulin release (thiazides,
loop diuretics, and diazoxide open ATP-sensitive K+-channels and phenytoin blocks Na+channels).
2- Glucocorticoids (cortisol), Catecholamines (adrenaline) and oral contraceptives (estrogen)
cause hyperglycemia and antagonize the hypoglycemic effect of sulphonylureas.
3- Non-selective -blockers as propranolol inhibit 2-mediated hepatic glycogenolysis thus
may augment the hypoglycemic effect of sulphonylureas by inhibition of compensatory
glycogenolysis, and all -blockers mask the warning symptoms of hypoglycemia
especially tachycardia and palpitations- and may lead to "silent hypoglycemia". They do not
inhibit sweating, which is a cholinergic action not mediated by -receptors.
4- Sympathomimetics cause hyperglycemia by stimulation of hepatic glycogenolysis (2).
1- Enumerate drugs that augment the hypoglycemic action of sulphonylureas.
2- Enumerate drugs that antagonize the hypoglycemic action of sulphonylureas.
Drugs that Augment the
hypoglycemic action of SU

Drugs that Antagonize the

hypoglycemic action of SU

1- NSAIDs as salicylates (aspirin),

indomethacin, phenylbutazone
2- Sulfonamide.
3- HME inhibitors as Cimetidine,
Allopurinol, Chloramphenicol, MAO
4- Beta blockers as Propranolol.
5- Alcohol.
6- Dicoumarol (augemts chlorpropamideinduced hypoglycemia).

1- Thiazide diuretics
(Hydrochlorothiazide), and to a less
extent loop diuretics (Frusemide).
2- Diazoxide.
3- Phenytoin.
4- HME inducers as Phenytoin,
Rifampicin, Phenobarbitone
5- Estrogen (oral contraceptives).
6- Glucocorticoids (cortisol).
7- Catecholamines as Adrenaline.

Biguanides = Metformin
Pharmacokinetics: absorbed orally and excreted unchanged in urine.
Mechanism of action: unclear but may act through:
1. Increases insulin sensitivity by stimulation of binding to its receptors.
2. Decreases oral absorption of glucose from GIT.



Endocrine Pharmacology

3. Decreases glucagon release from pancreas.

4. Increases action of insulin in peripheral tissues and thus stimulates glucose uptake and
utilization by skeletal muscles and adipose tissues.
5. Stimulates anaerobic glycolysis.
6. Inhibits hepatic gluconeogenesis ( hepatic glucose output).
7. Decreases appetite leading to weight reduction.
(Remember that metformin does not stimulate insulin release, this is why it is euglycemic not

1. NIDDM especially in obese patients, and may be combined with sulphonylureas.
2. Treatment of diabetes insipidus.
3. Polycystic ovary with anovulatory cycles (often in obese diabetic females).

Adverse effects:
1. Lactic acidosis: it is the most serious adverse effect and may lead to coma and death in 50%
of cases. It is common in cases of: renal impairment-hepatic insufficiency and alcoholismcongestive heart failure (CHF)-chronic obstructive pulmonary disease (COPD)-old age.
2. GIT upsets (most common): anorexia, nausea, vomiting, bloating, colics and diarrhea.
3. Prolonged use decreases GIT absorption of vitamin B12 and may lead to macrocytic
hyperchromic anemia.

Metformin is contraindicated in conditions that increase lactic acidosis:
1. Renal impairment (elimination of metformin and lactic acid).
2. Hepatic insufficiency and alcoholism (elimination of lactic acid).
3. CHF (causes hypoxia).
4. COPD (causes hypoxia).
5. Old age (associated with renal and hepatic dysfunction).

Diabetic Keto-Acidosis (DKA)

Too little insulin-Too little exercise-Too much food-Poor patient's compliance.
DKA is more common in type 1 D.M. and may be the first manifestation.



1-Marked insulin deficiency.

1. Soluble insulin IV (20-50 units).

2. KCl IV infusion to avoid insulin-induced
2-Hyperglycemia and glucosuria.
hypokalemia (with ECG monitoring to
avoid arrhythmias).
3. NaHCO3 IV infusion to correct acidosis.
3-Ketone bodies in blood
(ketonemia) leading to acidosis and 4. Isotonic saline (0.9% NaCl) by IV



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acetone odor, and ketonuria.
4-Dehydration due to glucosuria
and ketonuria.
5-Infections especially RTI.

infusion; followed by glucose 5% IV

infusion when blood glucose is less than
300 mg. % to avoid insulin-induced
5. Antibiotics as Azithromycin.

Adrenocortical Hormones (Corticosteroids)

The adrenal (suprarenal) gland is formed of cortex and medulla. The adrenal medulla secretes
catecholamines (adrenaline and noradrenaline) and the cortex secretes steroid hormones
1. Glucocorticoids: cortisone (corticosterone) and cortisol (hydrocortisone).
2. Mineralocorticoids: aldosterone and desoxycorticosterone (DOC).
3. Sex hormones: estrogens and androgens are secreted in small amounts.
Glucocorticoids are synthesized by the adrenal cortex from cholesterol (steroidogenesis)
under control of "Hypothalamic-Pituitary-Adrenocortical Axis" (HPA axis).

HPA Axis:
1. Corticotropin releasing hormone (CRH): synthesized and released from the
2. Adrenocorticotrophic hormone (ACTH): synthesized and released from the anterior
pituitary under the influence of CRH.
3. Cortisol (active) and cortisone (inactive and converted by the liver into active cortisol):
synthesized and released from the adrenal cortex under the influence of ACTH.
4. Cortisol exerts negative feed-back effect on CRH and ACTH and causes suppression of
HPA axis.
5. HPA axis is
Stimulated by:
1. Stress (infection, surgery, trauma, and pregnancy).
2. Day-light (circadian rhythm).
3. Hormones: A.D.H., adrenaline, and estrogen.
4. Low plasma cortisol level.
Inhibited by:
1. Negative feedback effect of cortisol.
2. Night.
3. Hormones: androgens.
4. Opiopeptides (endorphins and enkephalins).


Polypeptide released from the anterior pituitary.


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Release is controlled by CRH, negative feed-back by cortisol, stress, and circadian rhythm
(see before).
Mechanism of action: stimulates membrane receptors activation of adenylyl cyclase
synthesis of c-AMP.
Action: stimulates synthesis and release of cortisol (steroidogenesis) but minimal action on
mineralocorticoid synthesis and release.
1. Diagnostic: diagnosis of adrenocortical function: ACTH release of cortisol from
"healthy" cortex eosinopenia and increased metabolites as 17-keto-steroids in urine.
2. Therapeutic: same indications as cortisol with the advantage of less catabolic effect in
old patients and less growth retardation in children.
3. During gradual withdrawal of steroids after long use to avoid acute addisonian
1. ACTH (corticotrophin) prepared from animals and is highly antigenic.
2. Synthetic tetracosactrin which is less antigenic.

Glucocorticoids (Cortisol)
Chemistry: steroid.
Well absorbed orally.
Given also: IV, IM, intra-thecal, topical on skin, eye, ear, and nose, intra-articular, by
inhalation, and as rectal retention enema.
Pass BBB.
Pass placental barrier and cause teratogenicity.
Highly bound to plasma proteins; mainly to globulin known as corticosteroid binding
globulin = CBG (75%), and to albumin (20%), only 5% is in the free form.
Cortisol (= Hydrocortisone) is active whereas cortisone is inactive and is converted by
the liver into cortisol.
Give reason: cortisol is used locally (as skin cream or intra-articular injection) and
systemically but cortisone is used only systemically?
Glucocorticoids are metabolized in the liver by reduction and conjugation with
glucuronic acid and sulfate.
Metabolites are excreted in urine and may be measured to assess function of HPA axis.

Mechanism of action:
1- Genomic mechanism:
Cortisol passes easily the cell membrane by simple diffusion being lipophilic. Then cortisol


Endocrine Pharmacology


binds to cytoplasmic receptors activation of the hormone-receptor complex which enters

the nucleus and binds to nuclear receptors (a specific site on DNA strands) leading to:
a. Gene expression: synthesis of m-RNA (transcription) synthesis of specific proteins (
after translation) as Lipocortin I (Annexin 1) and catabolic enzymes.
b. Gene repression: inhibition of synthesis of certain proteins as COX-II, Nitric oxide
synthase (NOS), and antibodies (immunoglobulins).
The genomic mechanism shows a delayed onset of action (lag period of several hours).
2- Non-genomic mechanism: few actions of cortisol are due to stimulation membrane
receptors, such as the action on HPA axis. These actions are rapid in onset.
Pharmacological actions:
1. Negative feed-back inhibition of hypothalamic-pituitary-adrenal cortical axis leading to
inhibition of CRH and ACTH, with suppression of endogenous glucocorticoid synthesis.
Long use of exogenous glucocorticoids may lead to atrophy of the adrenal cortex may occur
due to inhibition of ACTH.
2. Metabolic Actions:
A- On Carbohydrate metabolism:
Anti-insulin actions: stimulate gluconeogenesis (mobilization of amino acids from
skeletal muscles to the liver and synthesis of carbohydrates) and inhibit glucose uptake
and utilization by tissues.
Stimulate synthesis of glycogen from pyruvate (glycogenesis) in the liver, and prevent
glucose output from the liver.
The net result is Hyperglycemia and glucosuria (glucose intolerance).
B- On Protein metabolism:
Glucocorticoids cause protein catabolism in most tissues except few tissues as the liver- as
skeletal muscles, bone, lymphoid tissue, and connective tissue leading to muscle wasting
and myopathy, osteoporosis, growth retardation in children, and delayed wound healing.
Amino acids are converted into urea which is excreted in urine, this is known as "negative
nitrogen balance".
C- On Fat metabolism:
Lipolysis of fats in limbs, thighs, and buttocks.
Lipemia: cortisol increases free fatty acids (FFA) in blood.
Lipogenesis in face, back, and trunk leading to "moon face", "buffalo hump", and
trunkal obesity. This is known as Fat Redistribution.
3. Mineralocorticoid action: glucocorticoids have aldosterone-like action causing Na+ and
water reabsorption and hypokalemia. This may lead to edema, elevation of ABP, and may
dangerous in patients with CHF. Severe hypokalemia occurs if given with thiazides and
loop diuretics.
In addition; they are essential for diuresis of excess water (may be through inhibition of ADH).
N.B.: Cortisol is essential to get rid of excess water and prevention of water intoxication.
This is a "glucocorticoid" not a "mineralocorticoid" action and may be due to antagonism of
ADH effect on the nephrons, and this action is known as "free water clearance".


Endocrine Pharmacology


4. On vitamin D and Ca2+: glucocorticoids have anti-vitamin D action and accordingly

decrease Ca2+ absorption from GIT and increase Ca2+ excretion by the kidney, leading to
Hypocalcemia (negative calcium balance).
5. Anti-inflammatory action:
By inhibition of phospholipase A2 (through synthesis of lipocortin I also known as
-by neutrophils and macrophages leading to inhibition of synthesis of inflammatory
mediators: PGs, leukotrienes, and platelet activating factor (PAF).
Gene repression leading to inhibition of synthesis of COX-II, NOS, adhesion molecules,
and complement components.
Inhibit migration of neutrophils.
Decrease circulating lymphocytes, eosinophils, monocytes, basophils.
Decrease synthesis of inflammatory cytokines as interleukins, TNF, and colony
stimulating factor (CSF).
Stabilize lysosomal membrane and inhibit release of lysosomal enzymes thus preventing
cell death and tissue destruction.
Decrease capillary permeability thus decreasing inflammatory edema and joint effusion.
N.B.: Cortisol is a non-specific anti-inflammatory, and is sometimes described as a
"deceiver" as it masks the signs of infection and inflammation without treating the cause.
6. Immunosuppression and Anti-allergic actions:
Through inhibition of antibody (immunoglobulins) formation, inhibition of antigen-antibody
reaction, and tissue response to inflammatory mediators.
7. Actions on blood:
Increased number of RBCs due to increased release from bone marrow (polycythemia).
Increased number of neutrophils (PMNLs)due to inhibition of migration and increase
output from the bone marrow (neutrophilia).
Increased number of platelets (thrombocytosis).
Increased blood coagulability.
Decreased number of lymphocytes due to catabolic effect on lymphoid tissue
Decreased number of eosinophils (eosinopenia).
8. Action on Serum Uric Acid:
Uricosuric action and decrease serum uric acid.
9. Action on CNS: cortisol has a stimulant action on the CNS causing euphoria and may even
lead to psychosis.
10.Action on Respiratory system:
Anti-inflammatory and stabilization of the membrane of mast cells to prevent the release
of "allergotoxins" in bronchial asthma.
Increase number of 2-receptors and prevents down regulation by 2-agonists as
Stimulate production of surfactant in neonates.


Endocrine Pharmacology


11.Action on GIT: inhibit synthesis of cytoprotective PGE2 and

PGI2and accordingly increase HCl and decrease mucus leading to peptic ulcer. This iatrogenic
ulcer is best prevented and treated by misoprostol.
12.Anti-stress and Anti-shock: (by increasing blood volume and BP by hypernatremia, by
increasing blood sugar, and by CNS action).
13.Action on CVS: cortisol elevates blood pressure by the following mechanisms:
1. I-Sodium and water retention by its mineralocorticoid (aldosterone-like) action which
increases cardiac output.
2. Potentiation of the vasoconstrictor action of noradrenaline and angiotensin II, which
increases total peripheral resistance.
3. Decrease in capillary permeability thus maintaining blood volume.
14.Antiemetic action.

Therapeutic uses:
A- Replacement Therapy:

Physiological doses of glucocorticoids are used which minimizes the adverse effects.
1. Acute adrenocortical insufficiency (acute Addisonian crisis) due to sudden withdrawal
of exogenous steroid therapy, or due to stress (trauma or infection). Treatment by
Hydrocortisone sodium succinate IV +
0.9% NaCl IV infusion + glucose 5% IV infusion. Blood transfusion and vasopressor
drugs are sometimes needed.
2. Chronic adrenocortical insufficiency (chronic Addison's disease): treated by oral steroids
having both gluco- and mineralocorticoid actions as cortisol or fludrocortisone (see
(Gluco: cortisone acetate orally + generous salt and sugar diet.
Mineralo: DOCA SL, IM, or SC implantation).
B- Suppressive and Supplementary Therapy:
Pharmacological (supra-physiological)doses are used, which may lead to many and serious
adverse effects. Glucocorticoids with no mineralocorticoid activity are needed
1. Suppression of ACTH in treatment of adrenogenital hyperplasia.
2. Anti-allergic in angioneurotic edema, dermatitis, allergic rhinitis, allergic conjunctivitis,
anaphylactic shock.
3. Anti-inflammatory and anti-allergic in bronchial asthma (inhaled steroids as
beclomethasone in prophylaxis, and hydrocortisone sodium succinate IV in status
4. Anti-inflammatory and immunosuppressive in auto-immune diseases (collagen diseases)
as rheumatic carditis, R.A., S.L.E., nephrotic syndrome, chronic hepatitis, and ulcerative
colitis (may be given as retention enema).
5. Anti-inflammatory in: acute gouty arthritis resistant to NSAIDs, osteoarthritis (may be
given intra-articular), and cerebral edema (avoid glucocorticoids with salt-retaining
6. Immunosuppressive after organ transplantation to prevent rejection.



Endocrine Pharmacology

7. Blood diseases as: leukemia (acute lymphocytic leukemia), thrombocytopenic purpura,

agranulocytosis, and hemolytic anemia.
8. Hypercalcemia and hypervitaminosis D (vitamin D intoxication).
9. Shock.
10.Hypertrophic scars and keloids.
11.Respiratory distress syndrome in neonates.


Short acting glucocorticoids:

1. Cortisone (inactive converted
into active cortisol).
2. Cortisol = Hydrocortisone.
Intermediate acting
1. Prednisone (inactive converted
by the liver into active
2. Prednisolone and
3. Triamcinolone.
4. Paramethasone.
Long acting glucocorticoids:
1. Betamethasone.
2. Dexamethasone.
Inhaled Steroids:
1. Beclomethasone.
2. Fluticasone.
3. Budesonide.
1. Aldosterone.
2. Fludrocortisone.
3. Desoxycorticosterone (DOC).
4. Desoxycorticosterone acetate
DOC and DOCA are ineffective
orally (extensively metabolized);
given IM and SL and DOCA is



(Salt retaining) action










Endocrine Pharmacology


given by SC implantation.

1. Cortisone and Prednisone are used only systemicall. Hydrocortisone, prednisolone,

methylprednisolone, triamcinolone, betamethasone, and dexamethasone are given orally,
topically, and by injection.
2. Triamcinolone, Paramethasone, Betamethasone, and Dexamethasone are fluorinated
prednisolone derivatives with very potent anti-inflammatory action and almost no Na+ and
water retention.

Adverse Effects
Toxic effects from sudden withdrawal:
1. Suppression of HPA axis and adrenal atrophy which
leads to acute adrenocortical insufficiency if
exogenous steroids are suddenly stopped after
prolonged therapy.
2. Corticosterone withdrawal syndrome: fever, myalgia,
arthralgia, and malaise.
Toxic effects due to continued use of large doses:
1. Iatrogenic Cushing' syndrome: moon face-buffalo
hump-trunkal obesity- wasting of limbs.
2. Iatrogenic peptic ulcer and acute pancreatitis.
3. Hyperglycemia and glucosuria.
4. Skeletal muscle wasting and myopathy- osteoporosissublaxation of joints-delayed wound healing-growth
retardation in children.
5. Na+ and water retention leading to edema and weight
gain, elevation of ABP, and may cause HF.
6. Hypokalemia (hypokalemic alkalosis).
7. Hypocalcemia.
8. Immunosuppression and masking of inflammation
leading to infection by T.B., viral and fugal infections
(as candidiasis). Inhaled steroids cause oropharyngeal
candidiasis and dysphonia.

1. Sudden withdrawal of
glucocorticoids after
prolonged use.
2. Cushing syndrome.
3. Peptic ulcer.
4. Diabetes mellitus.
5. Osteoporosis.
6. Repeated intra-articular
7. Hypertension.
8. CHF.
9. In digitalis toxicity and
with K+ losing
13.Psychotic patients.

9. Increased blood coagulability and thrombo-embolic

10. Catarct and glaucoma.
11. Hirsutism and menstrual disturbances.


Endocrine Pharmacology


12. CNS manifestations: psychosis.

13. Teratogenicity.

*Precautions during long-term therapy:

1. Never stop glucocorticoids suddenly after long term therapy to avoid acute adrenal
insufficiency. Glucocorticoids should be gradually withdrawn; the longer the duration of
therapy the slower must be the withdrawal.
2. Increase the dose during periods of stress as infections.
3. Diet should be rich in proteins, Ca2+, and K+ but low in Na+.
Anabolic steroids may be added.
4. Follow up:
Body weight.
Glucose in blood and urine.
Hidden infections.
Peptic ulcer (ask about heartburn and other symptoms).
Osteoporosis (X-ray of the spine every 6 months).
5. Use the smallest effective dose.

1. Aldosterone:

Synthesized by the adrenal cortex (zona glomerulosa).

Synthesis and release are not controlled by HPA but is controlled by:
1. Renin-Angiotensin system.
2. Na+ and K+ levels in blood (low Na+ and high K+ stimulate aldosterone release
Mechanism of action: as steroid hormones.
1. On the kidney: aldosterone acts on the distal convoluted tubules (D.C.T.) leading to salt
and water reabsorption (retention) and excretion of potassium (and to a less extent H+
and Mg2+) in urine.
2. On GIT, salivary glands, and sweat glands: the same action as on the kidney but much
In cases of prolonged hypervolemia due to hyperaldosteronism there is decreased
sensitivity of D.C.T. to the salt-retaining action of aldosterone (as a compensatory
mechanism to correct hypervolemia) but K+ excretion persists. Escape phenomenom
does not occur in other tissues (GIT, salivary and sweat glands).


Endocrine Pharmacology


The action of aldosterone is potentiated by Cortisol and Estrogen, and is antagonized by

Progesteron and Spironolactone.
Aldosterone has no therapeutic uses but aldosterone-like drug "Carbenoxolone" is a
mucosal protective agent in treatment of peptic ulcer, and aldosterone antagonists as
"Spironolactone and Eplerenone" are used as K+-sparing diuretics (spironolactone is
steroid in structure and may cause sexual dysfunction in males and females).

2. Synthetic Mineralocorticoids:

Fludrocortisone. -DOC -DOCA (see table of preparations).

Inhibitors of Steroid Synthesis (Adrenostatics)

Adrenostatics are used mainly for treatment of Cushing\s disease, which is either ACTHdependent or ACTH-independent.
A- ACTH-dependent Cushing: treated by drugs that inhibit release of ACTH from the anterior
1. Bromocriptine:
Direct Dopaminergic (D2) agonist.
Therapeutic uses:
1. Parkinsonism.
2. Hyperprolactinemia.
3. Suppression of lactation (much safer than estrogen).
4. ACTH-dependent Cushing's disease.
5. Acromegaly (bromocriptine inhibits release of growth hormone).
2. Cyproheptadine: it has additional antihistaminic (antiallergic) and antiserotonin actions.
B- ACTH-independent Cushing's disease:

1. Metyrapone (metopyrone):
Inhibits synthesis of cortisol by inhibition of 11- hydroxylase.
1. Treatment of ACTH-independent Cushing's disease.
2. To test the ability of the anterior pituitary to secrete ACTH.
2. Mitotane: antimitotic used in inoperable tumors of the adrenal cortex.
3. Aminoglutethimide and 4-Ketoconazole inhibit conversion of cholesterol into
pregnenolone which is the first step in steroidogenesis. Ketoconazole is used mainly as
an antifungal drug, it also inhibits androgen synthesis (may cause gynecomastia) and is a
potent HME inhibitor and may markedly decrease metabolism of other drugs as
theophylline leading to toxicity.
The most serious adverse effect of ketoconazole is hepatotoxicity.



Endocrine Pharmacology

Thyroid Hormones and Antithyroid Drugs

Thyroid Hormones
Thyroid gland secretes thyroid hormones (thyroxin) from follicular cells, and calcitonin from
parafollicular C cells.

Steps of synthesis of thyroid hormones:

1. Dietary iodine is absorbed as iodide.
2. Iodide trapping: active uptake of iodide into follicular cells which requires energy obtained
by Na+ / K+ ATPase. Iodide trapping is stimulated by TSH and is inhibited by cardiac
glycosides as ouabain, and by ionic inhibitors as thiocyanate and perchlorate.
3. Oxidation: Iodide is oxidized into iodine by peroxidase enzyme.
4. Organification of iodine: iodine binds to tyrosine in thyroglobulin to form "monoiodotyrosine" (MIT) and "di-iodotyrosine" (DIT) which are biologically inactive.
5. Coupling: MIT is coupled to DIT to form "tri-iodothyronine" =T3, and DIT is coupled to
DIT to form "tetra-iodothyronine" =T4.
6. Storage: T3 and T4 are stored within thyroglobulin of thyroid follicles in a ratio of 1:5.
7. Proteolysis and release: proteolysis of thyroglobulin by protease enzyme and free T3 and T4
are released into the circulation. MIT and DIT are also released from thyroglobulin into
follicular cells where they are de-iodinated by thyroid de-iodinase and iodine is re-utilized
to synthesize T3 and T4 (congenital deficiency of thyroid de-iodinase may lead to

Control of thyroid hormones:

1. Thyrotropin releasing hormone (TRH) from the hypothalamus stimulates the anterior
pituitary to synthesize thyroid stimulating hormone (TSH).
2. TSH is a polypeptide acting on cell membrane receptors and increases c-AMP leading to
stimulation of iodide trapping and synthesis of thyroid hormones, and increases the size and
vascularity of the gland.
3. T3 and T4 exert a negative feed-back inhibition on TRH and TSH.
4. Autoregulation: the thyroid gland regulates iodide uptake and hormone synthesis by an
"intrathyroid mechanism" according to the level of iodide in the blood: excess iodide
decreases iodide uptake (trapping) and inhibits organification if the gland is exposed to such
excess iodide for a period not more than 2 weeks.
If the gland is exposed to iodide excess for longer periods this autoregulatory mechanism
"wears off" (thyroid adaptation).


Endocrine Pharmacology


5. Thyroid stimulating immunoglobulin (TSI): is synthesized by lymphocytes in patients with

hyperthyroidism and it stimulates TSH receptors on thyroid gland leading to release of huge
amounts of thyroid hormones. It was known as "long acting thyroid stimulator" (LATS).

Absorption: thyroid hormones are well absorbed orally; about 95% of T3 and 65% of T4 are
absorbed orally. Absorption of both T3 and T4 is reduced in myxedema, and absorption of T4 is
reduced in the presence of food, antacids, and iron.
Thyroid hormones are distributed to all tissues.
They are highly bound to plasma proteins (>99%) mainly to globulin known as
thyroxine binding globulin (TBG) and to a lesser extent to thyroxine binding prealbumin
Only 0.04% of T4 and 0.4% of T3 are free.
TBG increases by estrogen therapy and during pregnancy and is reduced by
Drugs as salicylates and phenytoin displace thyroid hormones from plasma globulin and
may increase free hormones which reduces TSH by negative feed-back and may
interfere with radioactive iodine uptake test.
1. Peripheral (Tissue) De-iodination: is the primary pathway.
T4 is de-iodinated into more active T3 (30%) into reverse T3 (40%) which is biological inactive,
and the liberated iodine is re-trapped by the thyroid gland.
N.B.: peripheral de-iodination is inhibited by:
Ipodate sodium: iodinated contrast medium used in radio-diagnosis. It also inhibits
release of T4 and T3.
2. Conjugation: with glucuronic acid and sulphate, and the conjugated metabolites are
excreted partly in bile (and undergo entero-hepatic circulation) and partly in urine.

Mechanism of action:
Thyroid hormones enter the cell and bind to nuclear receptors, and thyroid hormone-receptor
complex binds to DNA and induce transcription of DNA into m-RNA thus inducing synthesis
of various enzymes.
Pharmacological actions:
1. Calorigenic action: increase oxygen consumption, heat production, basal metabolic rate, and
sweating (as adrenaline but more potent and slower onset of action).
2. Growth: essential for mental, physical, and sexual development both directly and indirectly
by stimulation of release and effect of growth hormone.


Endocrine Pharmacology


3. CVS: increase number and sensitivity of 1-receptors (supersensitivity and upregulation)

leading to cardiac stimulation.
4. GIT: increase cholinergic activity of GIT leading to stimulation of motility and secretion.
5. CNS stimulation.
6. Metabolic actions: glycogenolysis and increase glucose absorption, uptake and utilization,
decrease lipogenesis, and decrease cholesterol level in blood.

Therapeutic uses:
1. Replacement therapy in hypothyroidism: myxedema and myxedema coma in adults, and
cretinism in children. Treatment of cretinism should be started as early as possible.
2. Suppressive therapy: to suppress TSH to reduce size of the gland in puberty goiter and
Hashimoto's disease, and to inhibit growth of TSH-dependent follicular carcinoma.
3. Treatment of hypercholesterolemia in euthyroid patients by D-thyroxine which is
biologically inactive.

1. Levothyroxine =synthetic L-T4: less potent than T3-delayed onset because of long t 1/2 (7
days)-low cost- and not antigenic.
It is the preparation of choice: cheap stable well absorbed long acting.
2. Liothyronine = synthetic L-T3: 4 times as potent as T4-rapid onset because of shorter t 1/2
(1.5 days) so it is used in emergencies as myxedema coma I.V. and acute psychosis -high
cost-and not antigenic.
3. Liotrix = synthetic mixture of T4 and T3 in a ratio of 4:1, it is potent, high cost, and not
4. Dried thyroid extract obtained from animals is obsolete as it was highly antigenic.

Adverse effects:
1. Tachycardia, palpitation, arrhythmia, and anginal pains.
2. Diarrhea.
3. Nervousness, tremors, and insomnia.

1. Angina pectoris.
2. Arrhythmias.

Antithyroid Drugs
Antithyroid drugs are used in treatment of hyperthyroidism (thyrotoxicosis) which results from
a hyperplastic thyroid nodule or due to diffuse hyperplasia of the gland (Grave's disease). It is
not controlled by TSH but is controlled by TSI (LATS).


Endocrine Pharmacology


Hyperthyroidism is more common in females and is characterized by: nervousness, tremors,

insomnia, tachycardia, palpitations, anginal pains, increased appetite with weight loss,
sweating and heat intolerance, and exophthalmos in Grave' disease.

Antithyroid drugs: they include the following groups:

1. Thioamides: Carbimazole-Methimazole-Propylthiouracil (PTU).
2. Ionic Inhibitors: Potassium Perchlorate- Thiocyanate. They inhibit iodide trapping and
are obsolete due to the high incidence of fatal aplastic anemia.
3. Iodides: Potassium iodide- Lugol's iodine.
4. Radioactive Iodine: I131.
5. Adjuvant Drugs: -Blockers especially Propranolol. It is used to control CVS and CNS
symptoms of hyperthyroidism. Propranolol is also given IV in treatment of thyrotoxic crisis
(storm) and is "life-saving".
Advantages of Propranolol:
1. It is given both orally and parenterally (in thyrotoxic crisis).
2. It inhibits peripheral de-iodination.
3. It has no ISA (proranolol is a pure antagonist).
4. It is lipophilic, i.e. it can pass BBB and controls CNS manifestations of thyrotoxicosis as
tremors and insomnia.

1. Thioamides
Carbimazole Methimazole -Propylthiouracil (PTU).
Source: synthetic.
Chemistry: thiourea derivatives.

Absorbed orally. PTU is incompletely absorbed and can also be given IV in thyrotoxic crisis.
Highly bound to plasma proteins.
Concentrated in thyroid gland.
Pass BBB.
Pass placental barrier and may cause fetal goiter or cretinism. PTU is the safest thioamide in
pregnancy (PTU does not cross placental barrier).
Carbimazole is a prodrug and is metabolized into active methimazole.
Thioamides are metabolized by the liver by conjugation and metabolites are excreted in
urine. They are excreted in breast milk and affect suckling infants.

Mechanism of action:


Endocrine Pharmacology


1. Inhibit peroxidase enzyme and accordingly inhibit oxidation of iodide into iodine.
2. Inhibit organification of iodine and formation of MIT and DIT.
3. Inhibit coupling of MIT with DIT and DIT with DIT thus inhibiting synthesis of T3 and T4.
4. PTU also inhibits peripheral de-iodination.
5. Inhibition of iodine absorption from GIT.
Pharmacological actions:
Inhibition of synthesis of "new" thyroid hormones but no effect on iodide uptake and no effect
on release of already formed and stored hormones. That is why they have delayed onset of
action (about 2 weeks) until the stored hormones are depleted and due to long t1/2 of thyroid

Therapeutic uses:
1. Treat mild cases of hyperthyroidism. They are given until the patient is "euthyroid" then a
smaller maintenance dose is given to prevent recurrence.
2. Temporary control of hyperthyroidism in patients treated by radioactive iodine which has
very delayed onset of action (about 2-3 months).
3. Pre-operative preparation before subtotal thyroidectomy to decrease the stored hormones
before operation, but they have the disadvantage of increasing the size and vascularity of
the gland (corrected by iodides before thyroidectomy).
4. PTU is also used in thyrotoxic crisis.

Adverse effects:
1. Allergy: is common and may manifest as skin rash, pruritis, fever, cholestatic hepatitis and
jaundice, or nephritis.
2. Bone marrow depression (blood dyscrasias): is the most dangerous and is usually in the
form of toxic (dose-dependent) agranulocytosis. Frequent blood count should be performed
to detect agranulocytosis. Low-grade fever and sore throat are the earliest manifestations of
agranulocytosis which is treated by: Stopping the drug- fresh blood transfusion-broad
spectrum penicillins-anabolic steroids.
3. Arthralgia and joint stiffness.
4. Gut upsets: anorexia, nausea, vomiting, and diarrhea.
5. Increase size and vascularity of the gland: thioamides T3 and T4 TSH (reduced
negative feed-back inhibition) increased size and vascularity of the gland.
6. Goitre and hypothyroidism in fetus and suckling infants if given during pregnancy and
7. Other adverse effects: headache-depigmentation and loss of hair aggravate exophthalmos.

1. Pregnancy and lactation.
2. Allergy to thioamides.

2. Iodides

Endocrine Pharmacology


Include: potassium iodide and Lugol's iodine (5% iodine in 10% potassium iodide).
Mechanism of action and actions:
1. Antagonizes the action of TSH and decreases iodide trapping and reduces the size and
vascularity of the gland if given for 10-15 days (see autoregulation).
2. Iodide also inhibits protease enzyme and inhibits release of stored hormones and so it has a
rapid onset of action.
3. Inhibition of iodide organification.
Therapeutic uses:
1. Pre-operative preparation before subtotal thyroidectomy.
2. Treatment of thyrotoxic crisis (with PTU and Propranolol).
3. Prophylaxis of goiter (added to salt, bread, and water).
N.B.: iodine is also used as "saline expectorant" in treatment of productive cough.
Adverse effects:
1. Allergy: skin rash, angioedema, and anaphylaxis.
2. Iodism: iodide is concentrated in exocrine glands as the salivary glands, nasal glands,
lacrimal glands, and bronchial glands leading to irritation and increased secretion which
causes: metallic taste-sialadenitis and salivation-rhinorrhea (runny nose)- lacrimationproductive cough.
It also causes nausea, vomiting, and diarrhea.
3. Long use may lead to goiter.

3- Radioactive Iodine (I131)

I131: given orally and is trapped by -and stored in- the thyroid gland.
It emits destructive - and particles which have low penetrability and lead to
destruction of follicular cells without damaging surrounding tissues.
The onset of action is very delayed (1-2 months) and maximal response appears after
another 2 months, and the patient is temporarily treated by thioamides and propranolol
until its effect appears.
1. Hyperthyroidism in patients who are unfit for surgery as old patients and cardiac patients.
2. Recurrence of hyperthyroidism after surgery.
3. Failure to control hyperthyroidism by long term therapy with thioamides.
4. Metastatic follicular carcinoma of the thyroid gland. Radioactive iodine uptake can be
increased by TSH or by decreasing the size of the gland by surgery or irradiation.
5. I132 is used only for diagnosis of thyroid function.
Adverse effects:
1. Hypothyroidism due to excessive destruction of thyroid follicles (the main adverse effects).
2. Induces fetal and neonatal hypothyroidism (cretinism) if given in pregnancy and lactation as
it passes placental barrier and is excreted in breast milk.
3. Induce carcinogenicity in thyroid gland after several years (15-20 years).
4. Delayed onset of action.


Endocrine Pharmacology


5. Thyroid storm due to release of thyroid hormones.

6. Leukemia.
7. Repeated doses may be required.
1. Pregnancy and lactation.
2. Young patients (below 40 years).

Treatment of thyrotoxic crisis (storm):

It usually occurs in patients undergoing thyroidectomy who are not adequately prepared.
Manifestations include CVS stimulation, CNS stimulation (convulsions), hyperpyrexia, and
1. Propranolol IV (life saving).
2. PTU IV.
3. Potassium iodide IV.
4. Hydrocortisone IV (antistress and inhibits peripheral de-iodination).
5. Symptomatic treatment: IV fluids as 0.9% NaCl to correct dehydration cold fomentationsanticonvulsants as diazepam IV.

Pre-operative Preparation:
1. Thioamides until the patient is "euthyroid".
2. Iodide for 10-15 days to reduce size and vascularity of the gland.
3. Propranolol.

Sex Hormones
All sex hormones are steroid in nature and act on "nuclear" receptors.

I. I-Androgens:
Testosterone and androsterone. Used as replacement therapy in male hypogonadism.
Contraindicated in cancer prostate.

Anabolic steroids:
Examples: nandrolone methandrostenolone.
1. Aplastic anemia.
2. Anemia associated with acute renal failure .
3. Osteoporosis.
4. General wasting.
Adverse effects:
1. Precocious puberty in children.
2. Virilization in females (deepening of voice, hirsutism, and acne).
3. Testicular atrophy in adult males.



Endocrine Pharmacology

1. Flutamide and Cyproterone: competitive antagonists on androgen receptors. Used in: cancer
prostate-hirsutism-male hypersexuality.
2. Finasteride: inhibits 5- reductase and thus inhibits conversion of testosterone into more
active dihydrotestosterone in prostate and other tissues except skeletal muscles. Used in
benign prostatic hyperplasia (BPH).
3. Ketoconazole: Antifungal and also inhibits synthesis of androgens and cortisol.
4. Spironolactone: K+-sparing diuretic-aldosterone antagonist.
5. Cimetidine: H2-antagonist.
Male contraceptives:
1. Gossypol: it destroys seminiferous tubules and decreases sperm count. The main adverse
effect is hypokalemia (may cause transient paralysis).
2. Testosterone in large doses.
3. Cyproterone (anti-androgen) + levonorgestrel (progestogen).

II. II-Progestogens:
Therapeutic uses:
1. Contraception; either alone (minipill) or combined with estrogen.
2. Dysmenorrhea and premenstrual tension.
3. Endometriosis and endometrial carcinoma.
4. Threatened and habitual abortion.
Adverse effects:
1. Sodium and water retention.
2. Weak androgenic effect of some preparations leading to acne vulgaris, hirsutism, and
deepening of voice.
3. Psychic depression.
4. Elevation of LDL-cholesterol and atherosclerosis.

1. Mifepristone:
Blocks progesterone receptors and in large doses it blocks also glucocorticoid (cortisol)
1. Termination of early pregnancy given with PG analog as misoprostol, as it sensitizes
the uterus to prostaglandins.
2. Post-coital contraceptive as it inhibits implantation.
2. Danazol:
Binds to progesterone, androgen, and glucocorticoid (cortisol) receptors.
It inhibits the mid-cycle surge of FSH and LH.


Endocrine Pharmacology


It inhibits steroid synthesis in the ovaries leading to reduced ovarian function and
endometrial atrophy.
Uses: Endometriosis Fibrocystic disease of breast Menorrhagia-Gynecomastia.
Adverse effects:
1. Deepening of voice, decrease breast size, and changes in libido in females.
2. Edema and weight gain due to salt and water retention.
3. Hot flushes and headache.
4. Hepatic impairment.
5. Teratogenic.
6. GIT disturbances.
Contraindications: Pregnancy Liver diseases.

III. Estrogens:
Mechanism of action:
Being a steroid; estrogen is lipid soluble and crosses the cell membrane by simple diffusion.
Estrogen binds to "nuclear" estrogen receptors (ER) which are of 2 subtypes: ER and ER.
ER stimulates gene transcription whereas ER inhibits transcription.
(The actions of estrogen are mostly due to stimulation of ER).

1. Replacement therapy in primary hypogonadism.
2. Hormonal Replacement Therapy (HRT) in postmenopausal syndrome (climacteric
syndrome) to prevent osteoporosis, hot flushes, atrophic or senile vaginitis, and
hyperlipidemia causing atherosclerosis and ischemic heart diseases.
3. Dysmenorrhea (with progestins to suppress ovulation).
4. Endometriosis.
5. Oral Contraception.
6. Suppression of lactation (bromocriptine is safer).
7. Functional uterine bleeding.
8. Postmenopausal cancer breast (some cases).
9. Acne vulgaris and Hirsutism.
10.Cancer prostate.
N.B.: Treatment of dysmenorrhea: 1-oral contraceptives 2-NSAIDs (avoid aspirin as it may
increase bleeding) 3-2-agonists as ritodrine
4-CCBs as nifedipine.

1. Steroidal preparations:
Estradiol (most potent), estriol, and estrone (natural): ineffective orally due to extensive
hepatic metabolism. Estradiol is given by IM injection.
Premarin is a sulphate-conjugated estrogen which is effective orally


Endocrine Pharmacology


Ethinyl estradiol and Mestranol (semisynthetic): effective orally.

2. Non-Steroidal: Diethylstilbosterol (synthetic) effective orally.
N.B.: estrogens may be given as vaginal pessaries or creams, and also as transdermal patches
as they are well absorbed from the skin.

Adverse effects:
1. Nausea mainly and less commonly vomiting.
2. Breast tenderness (mastalgia).
3. Salt and water retention leading to edema, weight gain, hypertension, and heart failure.
4. Decreased libido (corrected by adding progestins).
5. Headache and increased frequency of migraine.
6. Increase TBG and CBG, and elevate sedimentation rate.
7. Failure of withdrawal bleeding (misinterpreted as pregnancy).
8. Hyperglycemia and impaired glucose tolerance.
9. Fibroids and Endometrial carcinoma (corrected by adding progestins).
10.Premenopausal breast carcinoma (estrogen-dependent tumors).
11.Vaginal carcinoma in females whose mothers received estrogen (diethylstilbestrol) as postcoital pills (see later).
12.Thromboembolism and antagonizes the action of oral anticoagulants as warfarin due to
increase in hepatic synthesis of coagulation factors II (prothrombin), VII, IX, and X. This
may cause deep venous thrombosis (DVT) leading to pulmonary embolism. Acute
myocardial infarctions and cerebrovascular strokes may also occur.
The risk of thromboembolism is higher in females over 35 years and in smoker females.
13.Cholestatic hepatitis and jaundice, gall stones, cholangitis, and cholecystitis.
15.Feminization in males with cancer prostate treated by estrogen.


Hypertension, ischemic heart disease, and heart failure.

Diabetes mellitus.
Fibroids and endometrial carcinoma (estrogen-dependent).
Pre-menopausal breast carcinoma (estrogen-dependent).
Thromboembolic diseases.
Liver and gall bladder diseases.
Females over 35 years to avoid thromboembolism, hypertension, DM, especially in obese
and smokers.
10.Undiagnosed vaginal bleeding (which may be due to endometrial carcinoma).

Drug interactions:
A-Pharmacokinetic interactions:
1. HME inducers as rifampicin, phenytoin, and phenobarbitone increases clearance of
estrogens (contraceptives) and cause failure of therapy (conception).


Endocrine Pharmacology


2. HME inhibitors as cimetidine decrease clearance of estrogens and may increase adverse
3. Estrogens have mild HME inhibitory action and may reduce clearance of other drugs as
digitoxin and aminophylline.
4. Mineral oils as paraffin oil (lubricant purgative used in treatment of constipation) reduce
oral absorption of steroid hormones.
B-Pharmacodynamic interactions:
1. Estrogens antagonize the action of: anticoagulants, diuretics, antihypertensives and
2. Tobacco smoking and anti-fibrinolytics (as aminocaproic acid and tranexamic acid)
increase the incidence of thromboembolism in patients receiving estrogens.

I-Selective Estrogen Receptor Modulators (SERMs):
These drugs are "tissue-selective", i.e they stimulate ER in the bone, lipoproteins, blood
coagulation, and endometrium leading to "estrogen-like actions" in these tissues. On the other
hand; they stimulate ER in the anterior pituitary and breast leading to "anti-estrogen" actions.
1. Clomiphen: was previously considered a "partial agonist" on estrogen receptors in
anterior pituitary, but mow it is considered a SERM that stimulates ER in the anterior
pituitary inhibition of negative feed-back inhibition on FSH and LH increase in FSH
and LH induction of ovulation.
It may cause multiple ovulations and multiple twins hot flushes nausea constipation
headache reversible hair loss visual disturbances.
2. Tamoxifen: was also considered as a "partial agonist" on estrogen receptors in the breast,
but now it is regarded as a SERM that stimulates ER in the breast and is accordingly used
in treatment of estrogen-dependent (pre-menopausal) breast carcinoma.
It may cause hot flushes and nausea.
3. Raloxifen: a SERM which stimulates ER in bone and lipids and is accordingly used in
prevention and treatment of postmenopausal osteoporosis and hyperlipidemia without
inducing breast carcinoma.
4. Toremifene: a SERM used in cancer breast.

II-Aromatase inhibitors (AIs): inhibit synthesis of estrogen from androgen precursor by

inhibition of aromatase enzyme.
They are classified into:
A- A-Steroids: irreversible aromatase inhibitors (suicide inhibitors) as Exemestane. Used in
cancer breast resistant to tamoxifen.
B- B-Non-steroids: reversible aromatase inhibitors used to induce ovulation, as Letrozole.


Endocrine Pharmacology


Methods of contraception:

Hormonal contraceptives: either orally or parenterally.

Intrauterine device (IUD).
Mechanical contraceptives (male condom and vaginal diaphragm).
Chemical contraceptives (spermicides).
Physiological methods (safe period).
Sterilization in females or males.

1-Hormonal Contraceptives:
They are administered either: orally, IM, or by S.C. implantation.

They contain estrogen alone, progestin alone, or more commonly combination of estrogen and
progestin in the same "pill".
A- Combined Method:
Pills contain combination of estrogen (ethinyl estradiol) and progestin (norethindrone,
levonorgestrel, or desogestrel which is less androgenic). They are started at the 5th day of the
menstrual cycle and used continuously for 21 days then stopped to allow menstruation and are
subdivided into:
1. Monophasic pills:
Pills contain fixed amount of estrogen (0.035 mg. ethinyl estradiol) and progesterone (0.5 mg.
2. Biphasic pills:
There are 2 types of pills:
Pills containing 0.035 mg. ethinyl estradiol + 0.5 mg. norethindrone given for 10 days
(from day 1 till day 10).
Pills containing 0.035 mg. ethinyl estradiol + 1 mg. norethindrone for the next 11 days
(from day 11 till day 21).
3. Triphasic pills:
There are 3 types of pills:
Pills containing 0.03 mg = 30 g. ethinyl estradiol + 0.05mg. = 50 g. norgestrel given
from day 1 till day 6 (for 6 days).
Pills containing 0.04 mg. =40 g. ethinyl estradiol + 0.075 mg. =75g. norgestrel given
from day 7 till day 11 (for 5 days).
Pills containing 0.03 mg. =30 g. ethinyl estradiol + 0.125 mg. =125 g.
norgestrel given from day 12 till day 21 (for 10 days).
1. Most effective.
2. Lower amounts of hormones are used.
3. Similar to the natural menstrual cycle.
4. Less adverse effects than other oral contraceptive methods.


Endocrine Pharmacology


B- Minipill:

Pills contain progestogen only (norethindrone or levonorgestrel) given continuously without

Disadvantages: "Break-through bleeding" is common, irregular menstrual cycles, and less
effective than combined method.
N.B.: Continous progestin only contraceptives include:
1- Minipills orally.
2- Medroxyprogesterone 150 mg. is given IM every 3 months (depot therapy), used in
lactating females as it does not suppress lactation.
3- L-norgestrel is given as SC implant which lasts about 5 years (6 capsules are placed SC in
upper arem).
a. Advantages: effective cheap-does not depend on patient's compliance-reversible.
b. Disadvantages: irregular menstruation-headache.
4- I.U.D.: release progestin locally.
C-Post-Coital Pills (Emergency Pills =Morning after = Rape pills):
1. Estrogen only (diethylstilbestrol) is given within 72 hours after coitus (sexual intercourse)
and for 5 days.
2. Estrogen + progestogen given twice (every 12 hours) within 72 hours after intercourse.
3. Mifepristone + Misoprostol once (see before).

Mechanism of action:
1. Inhibition of FSH release by estrogen and inhibition of ovarian follicle development.
2. nhibition of LH release by progestins mainly and accordingly inhibition of ovulation.
3. ncrease the viscosity of cervical mucus which prevents sperm penetration (by progestins
4. Induce endometrial changes which interfere with implantation (by both estrogen and
5. Interfere with coordinated contraction of the uterus, cervix, and Fallopian tubes which
interferes with fertilization and implantation (by both estrogen and progestins).

Adverse effects:
1. Nausea.
2. Breast tenderness (mastalgia).
3. Salt and water retention leading to edema and weight gain.
4. Decreased libido (corrected by adding progestins).
5. Headache and increased frequency of migraine.
6. Increase TBG and CBG, and elevate sedimentation rate.
7. Failure of withdrawal bleeding.
8. Break-through bleeding due to using progestin only or small doses of combination pills.
9. Skin pigmentation, hirsutism, and acne due to progestins having androgenic effects.
10.Vaginal infections and bacteruria.


Endocrine Pharmacology


12.Hyperglycemia and impaired glucose tolerance.

13.Fibroids and Endometrial carcinoma.
14.Premenopausal breast carcinoma.
15.Thromboembolism (due to inhibition of anti-thrombin III) which may cause deep venous
thrombosis (DVT), acute myocardial infarctions, and cerebrovascular strokes. Progestins
increase LDL-cholesterol and triglycerides and increase the risk of atherosclerosis.
16.Cholestatic hepatitis and jaundice, gall stones, cholangitis, and cholecystitis.


Hypertension, ischemic heart diseases, and heart failure.

Diabetes mellitus.
Fibroids and Endometrial carcinoma.
Pre-menopausal breast carcinoma.
Thromboembolic diseases.
Liver and gall bladder diseases.
Females over 35 years to avoid thromboembolism, hypertension, DM, especially in obese
and smokers.
10.Undiagnosed vaginal bleeding (which may be due to endometrial carcinoma).
Drug interactions: see estrogen.

Pituitary Hormones
Anterior Pituitary Hormones
1. Growth Hormone (GH) = Somatotropin: polypeptide synthesized by recombinant
DNA technology-used in treatment of dwarfism (replacement therapy, given before closure
of epiphyses).
2. Gonadotrophins = FSH and LH: used to induce ovulation. They are prepared as
human menopausal gonadotrophoins (hMG contains both FSH and LH) and human
chorionic gonadotrophins (hCG contains LH).
3. Prolactin: inhibited by the action of hypothalamic dopamine on D2-receptors (dopamine =
PIF). D2-agonists as bromocriptine are used in treatment of hyperprolactinemia and to
suppress lactation. D2-antagonists as chlorpromazine and metoclopramide, and drugs
reducing dopamine level in CNS as - methyldopa and reserpine cause hyperprolactinemia.
Drugs used to induce ovulation:
1. Clomiphen (anti-estrogen).
2. Bromocriptine.


Endocrine Pharmacology


3. Gonadotrophins (hMG and hCG).

4. Gonadotrophin releasing hormone = GnRH (released from hypothalamus) and its synthetic
analogues (leuprolide and nafarelin). GnRH are also used to induce spermatogenesis.
They should be given "intermittently" or as "pulsatile" therapy to induce release of
It should be noted that "continous" administration of GnRH causes "desensitization" of the
anterior pituitary leading to inhibition of gonatrophins, androgens, estrogens and progesterone,
and endometrial atrophy. That is why continous GnRH analogues are used in treatment of
endometriosis, ovarian cysts, uterine fibroids, central precocious puberty, as well as in cancer
N.B.: Cancer prostate is treated by:
1. Anti-androgens as Flutamide and Cyproterone.
2. GnRH analogues as Leuprolide and nafarelin (continuously).
3. estrogen.

4. T.S.H.
5. A.C.T.H.

Posterior Pituitary Hormones

1-Oxytocin: polypeptide- causes uterine contraction and contraction of myo-epithelial cells
of breast.
Uses: induction of labor in uterine inertia control post partum hemorrhage-milk ejection in
breast engorgement.
Syntocinon is a synthetic drug.
Oxytocic Drugs= Uterine Stimulants:
1. Oxytocin and syntocinon.
2. PG analogs as misoprostol and dinaprostone.
3. Ergometrine and methylergometrine.
They are used in induction of labor and abortion, and to control postpartum hemorrhage.
Tocolytic Drugs= Uterine Relaxants:
1. NSAIDs.
2. 2-agonists as ritodrine.
3. CCBs as nifedipine.
They are used in dysmenorrhea, premature labor, threatened abortion, and contraction ring of
the uterus.

2-Anti-Diuretic Hormone (ADH) = Vasopressin:

Polypeptide- acts on specific V-receptors:



Endocrine Pharmacology

V1-receptors in smooth muscles contraction (as V.C. and spasmogenic on smooth

muscles of GIT).
V2-receptors in collecting tubules facultative water reabsorption.
1. Replacement therapy in pituitary (central) type of diabetes insipidus.
2. To stop bleeding in esophageal varices in patients with portal hypertension.
3. Paralytic ileus.
It is given by injection or by nasal spray (may cause nasal ulcers).

N.B.: Types and treatment of diabetes insipidus:

1. Pituitary type: treated by ADH- carbamazepine-chlorpropamide-metformin.
2. Nephrogenic type: caused by ADH antagonists as demeclocycline-lithiummethoxyflurane, and treated by thiazides (amiloride is used in treatment of lithiuminduced nephrogenic diabetes insipidus).

Hypothalamic Hormones
1. Gonadotrophin releasing hormones: see before.
2. Somatostatin (GH inhibitory hormone): also secreted in gut and pancreas. In addition to
its inhibitory effect on GH; it also inhibits insulin, glucagon, HCl, and gut motility.
Octreotide is a synthetic analog used in treatment of bleeding esophageal varices.

Factors Affecting Calcium Homeostasis

Serum calcium (Ca2+) is maintained at a normal range of 9-11 mg. % by the action of
parathyroid hormone (parathormone), calcitonin, and vitamin D mainly and to a less extent by
the effect of glucocorticoids and estrogen. Some and drugs as thiazide and loop diuretics,
biphosphonates may affect serum calcium.

1. Parathormone


Activation of
Gs coupled
receptors and
increase cAMP.
serum Ca2+
and decreases


Routes of

1. Treatment of
I.M. (ineffective
hypoparathyroidism orally).
hypocalcemia and
2. Intermittent use of
small doses
stimulates bone
growth in


Endocrine Pharmacology
(Teriparatide is a

2. Calcitonin

3. Vitamin D

Activation of
serum Ca2+
and phosphate.
As steroid
serum Ca2+
and phosphate.

1. treatment of
2. Post-menauposal
3. Paget's disease of
1. Hypocalcemia and
2. Rickets and
3. Post-menauposal
osteoporosis with
dietary Ca2+.

I.M., S.C., nasal

spray (ineffective

Oral and I.M.

Other Factors Affecting Calcium Homeostasis:

1. Bisphosphonates: inhibit bone resorption- used in: osteoporosis- Paget's disease
hypercalcemia associated with malignancy. Examples: sodium etidronate , alendronate,
risedronate and pamidronate.
2. Estrogens and SERM as Raloxifen: inhibit parathormone-induced bone resorption in
menopause, used it treatment and prophylaxis of postmenopausal osteoporosis.
3. Thiazide diuretics: decrease Ca2+ excretion in urine and cause hypercalcemia, used in
hypocalcemia and idiopathic hypercalciuria.
4. Loop diuretics: decrease blood Ca2+ and are used in hypercalcemia.
5. Glucocorticoids: antagonize vitamin D and decrease Ca2+ absorption from GIT leading
to hypocalcemia, and are used in hypercalcemia.
6. Fluoride: increases bone Ca2+ deposition and prevents dental caries, and is used in
postmenopausal osteoporosis.
7. Mithramycin (Plicamycin): cytotoxic antibiotic that prevents bone resorption, used in
hypercalcemia due to malignancy and Paget's disease.

Treatment of Osteoporosis:
Osteoporosis occurs in post-menopausal females- due to long treatment with glucocorticoids,
hyperparathyroidism, thyrotoxicosis, and alcoholism. Treatment includes:
1. Ca+ and vitamin D.


Endocrine Pharmacology


2. Bisphosphonates.
3. Estrogen and Raloxifen (better than estrogen to reduce the risk of breast and endometrial
4. Calcitonin.
5. Fluoride sustained release.
6. Teriparatide: recombinant parathormone given in small pulse doses.

Treatment of Hypocalcemia:
1. Ca2+ and vitamin D.
2. Parathormone.
3. Thiazides.

Treatment of Hypercalcemia:

Calcitonin and phosphate.
Ca2+-chelating agents as disodium edetate IV.

Treatment of hypoparathyroidism:
Hypoparathyroidism is either idiopathic or following thyroidectomy. It is characterized by low
serum calcium and high phosphate leading to tetany.
Treatment by:
1. Parathormone (resistance occurs).
2. Calcium gluconate slowly IV.
3. Vitamin D.
4. Dihydrotachysterol (AT 10) to elevate serum calcium.