ENDOCRINE

PHARMACOLOGY

By: Dawit Z. (B.Pharm, MSc.)

December 17, 2018
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 The Endocrine System

Major functions of hormones

Metabolism
Growth and Development
Reproduction
Homeostasis

Co-ordination

The Nervous system The Endocrine system

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 Basic Principles
 Endocrine System
 Uses chemical signals for cell to cell communication
 Coordinates the function of cells
 Response occurs within minutes to hours
 Hormones
 Cell to cell communication molecules
 Can be amino acid derivatives, peptide hormones and
lipid derivatives.
 Made in glands or cells
 Transported by blood
 Distant or local target tissue receptors
3  Activate physiological response
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 CLASSIFICATION OF HORMONES
1. Hypothalamic hormones

 Thyrotropin releasing hormone (TRH) – Tripeptide

 Corticotropin releasing hormone (CRH) – peptide (41AAs)

 Gonadotropin releasing hormone (GnRH – Gonadorelin):

LH-RH/ Follicle stimulating

 Luteinizing hormone
hormoneFSH-RH – Decapeptide
 Growth hormone releasing hormone: (GHRH) –peptide 40,44
AAs

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 CLASSIFICATION OF HORMONES…
Hypothalamic hormones……Con’d

 Prolactin release inhibitory hormone (PRIH): Dopamine

(DA)

 Somatostatin (Growth hormone release inhibitory

hormone): (GHRIH):– peptide 14 AAs

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 CLASSIFICATION OF HORMONES…
2. Pituitary hormones

a) Anterior Pituitary hormones (-tropins/-trophins)

 Growth hormone (GH) − Somatotropin, Prolactin.

 Adrenocorticotropic hormone (ACTH, Corticotropin)

 Thyroid stimulating hormones (TSH, Thyrotropin)

 Gonadotropins

- Follicle stimulating hormone (FSH)

- Luteinizing hormone (LH)

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CLASSIFICATION OF HORMONES…

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 CLASSIFICATION OF HORMONES…
2. Pituitary hormones…….Con’d

b) Posterior Pituitary hormones

 Oxytocin
 Antidiuretic hormone (ADH, Vasopressin)

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 CLASSIFICATION OF HORMONES…
3.Thyroid hormones
 Thyroxine (T4),

 Triiodothyronine (T3)

 Calcitonin

4. Parathyroid hormone: Parathormone (PTH)

5. Hormones of endocrine pancreas: Insulin, Amylin,

Glucagon

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 CLASSIFICATION OF HORMONES…
6. Adrenal hormones
a) Hormones of Adrenal cortex (Steroids)

- Glucocorticoids (GCS): Hydrocortisone, Cortisone

- Mineralocorticoids: Aldosterone
- Sex steroids: Dehydroepiandrosterone (Testost.)

b) Hormone of Adrenal medulla: Adrenaline

7. Hormone of Gonads
a) Androgens: Testosterone
b) Estrogens: Estradiol
c) Progestins: Progesterone
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 CLASSIFICATION OF HORMONES….
8. Placental hormones
 Estrogens,
 Progesterone,
 Chorionic gonadotropin

9. Hormone of Adipocytes:

 Leptin – acts on receptors in the hypothalamus of

the brain where it inhibits appetite.

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 CLASSIFICATION OF HORMONES….
10. Ghrelin

 It is a peptide hormone that is produced mainly by

the fundus of the stomach and epsilon cells of the

pancreas.

 It stimulates hunger.

 Ghrelin levels increase before meals and decrease

after meals.

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Hypothalamic and
Pituitary Hormones
Hypothalamic hormones
regulate anterior pituitary
trophic hormones that, in
turn, determine target gland
secretion.

There is a peripheral
hormones feedback which
regulates hypothalamic and
pituitary hormones.
 1. Drugs for Diabetes Mellitus(DM)
 DM is a heterogeneous group of metabolic disorders
characterized by:-
 Persistent hyperglycemia (high blood glucose levels)
 Due to alternation in metabolism of carbohydrates, lipids,
and proteins
 Related with decrease in insulin secretion or insulin
resistance
 An increased risk of complications from vascular disease
Pancreatic hormones
• Cells of Islets of Langerhans secret insulin and glucagon
 β- cells secret insulin and α- cells secrete glucagon
• Insulin is anabolic and storage hormone of the body
• Factors that controls the synthesis and release of insulin
 Blood glucose concentration (main factor )
 Amino acids, fatty acids, ANS and Drugs 15
 High blood
Low blood
glucose
glucose

Insulin released by
Glucagon
beta cells of
released by
pancreas
alpha cells of
pancreas

09-Dec-18 16
 Insulin Biosynthesis
 Insulin is a polypeptide with 51 amino acids arranged in two
chains, A- chain & B-chain linked by disulfide bridges
• Positions B-24 and 25 are important for receptor recognition
…. Substitution results in change in biological activity
 It is synthesized in β-cells as a polypeptide precursor
 The insulin is packed into granules (in a form of a hexamer
that contains 2 zinc and one calcium)

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 Insulin secretion
 Blood glucose is major stimulus for insulin secretion; glucose entry
into β-cells is facilitated GLUT 2

 Increased glucose levels results in  ATP levels

 This results in blockage of K+ channels causing membrane

depolarization which opens Ca2+ channels.

 Ca2+ influx cause pulsatile insulin secretion; continued influx of Ca2+

activates transcription factors for insulin.

 Oral glucose evokes more insulin secretion than intravenous

glucose; It elicits gut hormones that augment insulin response
 Insulin is catabolized by insulinase produced by kidney
 α-Adrenergic stimulation inhibits release (major)
 β-Adrenergic stimulation promotes release 18
Effects of Insulin

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 Effects of Insulin Cont…
Stimulates
• Glycogen synthesis
• Promotes anabolic process
• Triglyceride synthesis
• Glucose uptake
• Protein synthesis
Inhibits
• Glycogenolysis
• Ketogenesis
• Gluconeogenesis
• Protien degradation
• Lipolysis
• Catabolic process
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 Mechanism of Insulin Action:
 Insulin binds to receptors with tyrosine kinase activity
 Phosphorylation cascade results in translocation of Glut
transport proteins into the plasma membrane.
 It induces the transcription of several genes resulting in ed
glucolysis and inhibits gluconeogenesis
 Insulin promotes the uptake of K+ into cells

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Types of Diabetes mellitus
 Type 1 (Insulin dependent diabetes mellitus, IDDM)
 A T-cell mediated autoimmune disease involving
destruction of the insulin secreting β-cells
 β-Cells are destroyed which usually leading to absolute
insulin deficiency (lack of insulin secretion)
 Type 2 (Insulin Independent diabetes mellitus, NIDDM)
 Inabilities of the β-cells to produce appropriate quantities of
insulin, and reduced sensitivity to its action(insulin resistance)
 Due to a progressive insulin secretory defect
 Others, less common (e.g. Gestational, drug induced)
 Insulin resistance during pregnancy including, alterations feto-
placental hormones such as prolactin, growth hormone,
progesterone, cortisol secretion (insulin antagonists)
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Pathophysiology of Type II Diabetes mellitus 23
 Characteristic Type 1 ( 10% ) Type 2(> 90%)

Onset (Age) Usually < 30 Usually > 30

Nutritional status Usually thin Usually obese

Clinical symptoms Polydipsia, polyphagia, Often asymptomatic

polyurea, Wt loss
Endogenous insulin Absent Present, but relatively
ineffective

Related lipid Hypercholesterolemia Cholesterol and

abnormalities frequent, all lipid triglycerides often
fractions elevated in elevated; carbohydrate-
ketosis induced
hypertriglyceridemia
common

Insulin therapy Required Required in only 20 -

30% of patients
Hypoglycemic drugs Should not be used Clinically indicated
Diet Mandatory with insulin Mandatory with or
without drug 24
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 Insulin release: Daily Requirements
 Basal=1-2 Units/hr. Breakfast Lunch Evening Meal

 Food=4-6 Units/meal
Blood Sugar
 1Ux24hr+4Ux3meals
= Total 36 Units/day Mealtime Insulin

 Half life 4 to 5 min Background Insulin

 Metabolized by kidney and liver

 Biological repose to insulin can be altered by either
 A change in the receptor affinity or a change in total amount of insulin
 Obesity Daily Requirements
 Chronic exposure
to high insulin exposure
Breakfast Lunch Evening Meal

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Sign and symptoms of Diabetes mellitus
• Glycosuria
• Polyuria
• Polydipsia
• polyphagia
• Wasting
 Acute complications
 Diabetic ketoacidosis (DKA) in type I DM patients
 Hyperosmolar hyperglycemic state Type II DM patients
 Chronic Complications
 Develop as a consequence of the metabolic derangements
• Atherosclerosis, Peripheral Neuropathy , Nephropathy
and Retinopathy

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Diagnosis and Management of Diabetes mellitus
 Measurement of blood glucose on two separate occasions is usually
adequate to confirm diagnosis
 Criteria for the diagnosis of diabetes based on American
Diabetic association, 2016.

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 Goal of therapy
 To relieve the immediate signs and symptoms
 To prevent the development of /or slow the progression of the
long term complication of the disease
 To minimize the occurrence of hypoglycemia
 Recommended goals
 Glycemic control
 Glycated hemoglobin (HbA1c) <7%
 Fasting blood glucose 80-110mg/dl
 Non fasting <180mg/dl
 Blood pressure ≤130/80
 Lipids
 LDL cholesterol <100 mg/dl
 Triglycerides <150mg/dl
 HDL cholesterol >40mg/dl
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 • Differ in …………………..
• Recombinant technique employed
• Amino acid sequence
• Stability
• Solubility
• Onset of action
Insulin • Duration of action
Preparations • 4-types of insulin preparations
• Rapid acting
• Short acting
• Intermediate acting
• Long acting

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 Short acting insulin
 Clear solutions at neutral PH
 Rapid onset and short duration of action
 Prepared with Zn to increase stability
 Long acting insulin
 Turbid solution at neutral PH
 Delayed onset and sustained release
 Neutral PH in phosphate buffer or protamine Hagedorn
 Goal of insulin administration ……. To mimic Physiological
insulin secretion
• Overnight
• Fasting Basal insulin
• Between meals secretion
• Prandial Meal time insulin secretion
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 Insulin preparations
Rapid acting insulin analogues
 Insulin lispro: Produced by recombinant technology wherein
the amino acids on B28 and B29 ( proline – lysine,
respectively)have been reversed in position………….Lispro
 Insulin aspart: Created by the substitution of the B28 proline
with aspartic acid
 Insulin glulysine: formulated by substituting asparagine for
lysine at B3 and glutamic acid for lysine at B29
 Rapid-acting insulins permit more physiologic prandial insulin
replacement due to their rapid onset and early peak action
 Peak effect with in 0.5-1 hr…....duration of action …3–5 hours
 Structural modifications in the above analogues of insulin
eliminate the ability to hexamerize and enhance faster
absorption from injection site
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 Types of insulin: time course of action after Sc injection
Class Generic name Time course
Onset Peak Duration
(min) (hrs) (hrs)
Short duration: Insulin lispro 5-15 1 3-6.5
Insulin aspart 5-15 1 3-5
Regular insulin  30 2-3 5-8
Intermediate Isophane (NPH) 120-300 3-5 4-12
duration insulin
Lente insulin

Long duration Insulin glargine 60-90 4-6 11-24

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Route of Administration
• Orally inactivated by digestive enzymes
• All are given subcutaneously
– But, regular insulin (Crystalline zinc insulin) can also be given
Intravenous (IV)
Adverse Effects
1. Hypoglycemia  cause brain damage in severe cases
2. Lipodystrophy
 Lipoatrophy – loss of subcutaneous fat (due to immunologic
rxn)
 Lipohypertrophy- fat accumulates ( use rotation
administration)
3. Weight gain- during intensive insulin therapy
4. Hypersensitivity (less common in human insulin)
5. Hypokalemia: K+ drawn into the cell with glucose
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 Therapeutic uses of insulin
A. IN DIABETES MELLITUS:
1. Long term management of Type I DM
2. Short term management of Type II DM not controlled by
diet & oral hypoglycemics
3. Emergency management of Diabetic ketoacidosis
4. Control of gestational DM (refractory to diet therapy)
5. During surgery in diabetic patients.

B. IN NON-DIABETIC CONDITIONS:
 Emergency Mgt of hyperkalemia to lower extracellular K+
 eg. due to Renal failure
 Insulin when given together with glucose, promotes the
intracellular passage of potassium.
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Complications of Insulin Therapy
Hypoglycemia
 Prolonged hypoglycemia may cause permanent brain damage,
convulsions, and coma leading to death
 Most common complication of insulin therapy ….may result
from
 A delay in taking a meal
 Inadequate carbohydrate consumption
 Unusual physical exertion
 A dose of insulin that is too large for immediate
needs
 Management
– Sweet drinks or fast foods
– Glucose (10 to 15 g) given orally in conscious patients
– Dextrose IV in individuals who have lost consciousness.
– Glucagon , 1 g IM, is the treatment of choice in unconscious
patients when IV access cannot be established 36
 Managing Diabetic ketoacidosis (DKA)
 DKA is a life-threatening medical emergency caused by
inadequate or absent insulin replacement
 Occurs in people with type 1 diabetes & infrequently in
those with type 2 diabetes.
 The fundamental treatment for DKA includes aggressive IV
hydration, insulin therapy and potassium and electrolyte
maintenance
 IV fluids to rehydrate

 Potassium supplementation

 IV insulin drip with gradual lowering of blood sugars

 Judicious administration of sodium bicarbonate

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Oral anti-diabetic agents
 Diet and exercise are encouraged with oral
hypoglycemic agents as the initial pharmacological
therapy for type II diabetes mellitus
 Used to treat insulin independent diabetes mellitus

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Oral anti-diabetic agent…
 Used in type 2 DM patients who don't adequately respond to
non-pharmacologic interventions
 Newly diagnosed type 2 DM patients (< 5 years) respond well
to oral agents
 Progressive decline in β-cell function may necessitate the
addition of insulin at some time in Type II diabetes.
 There are 6 classes: (last two are novel classes)
I. Insulin secretagogues: Sulfonylureas, Meglitinides
II. Biguanides
III. Thiazolidinediones
IV. Alpha-glucosidase inhibitors
V. Incretin modulators (GLP-1 analog, DPP-4
inhibitor)
VI. Amylin analogs
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Classification of oral anti-diabetic agents

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Figure 1: Major target organs and actions of oral hypoglycemic agents
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A. Sulfonylureas
 1st generation:- Tolbutamide, tolazamide, chlorpropamide
 2nd generation: - Glibenclamide(glyburide), Glipizide,
glimepiride
Advantages of 2nd generation SUs over 1st generation SUs
• Higher specificity and affinity for the sulfonylurea receptor
– 100 times more potent
• More predictable pharmacokinetics in terms of time of onset
and duration of action,
• Fewer adverse effect and drug interaction
 Mechanism of action
• Stimulation of insulin release from the β -cells of pancreas
• May increase tissue response to insulin (↓ insulin resistant)
• May also reduce serum glucagon concentration
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 Tolbutamide : the safest sulfonylurea for elderly diabetics,
because of its short half-life. Elimination half-life of 4–5 hours
 Acetohexamide :a sulfonylurea with uricosuric activity, an
action that may be of benefit in diabetic patients who also have
gout
• Adverse effects
 The commonest adverse effect is hypoglycaemia(Glibenclamide)
 Stimulate appetite, weight gain
 Gastrointestinal upsets , allergic skin rashes
 Bone marrow suppression
 Disulfiram-like interaction with alcohol (chlorpropamide)
• Contraindecation
 Pregnancy and lactation
• Transverse the placenta and can deplete insulin from the
fetal pancreas
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B. Meglitinides
• Nateglinide, repaglinide
• They bind to ATP sensitive K+ channels to promote insulin
secretion
• Mimic prandial & postprandial insulin release
• Better used in combination than monotherapy
• Shorter onset and duration of action than sulphonylureas
 Low risk of prolonged hypoglycemia
• Cause less weight gain than conventional sulfonylureas
• Metabolized by CYP3A4 and excreted in bile

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C. Bigunides: Metformin
 Doesn’t stimulate insulin secretion
 Acts primarily
• Increasing glucose uptake and utilization in
skeletal muscle ( insulin resistance)
• Reduce hepatic glucose production ( gluconeogenesis)
 It has also anti hyperlipidemic effects (  LDL and VLDL)
 Does not cause hypoglycemia
 Used alone or in combination
• Side effects
 GI disturbance (anorexia, nausea, and diarrhea), lactic
acidosis(the most common cause of metabolic acidosis in
hospitalized patients), and metallic taste in mouth, Vitamin B 12
deficiency (prolonged use)
 Acute or chronic alcohol ingestion or iodinated contrast media
↑ risk of lactic acidosis 45
Contraindication(C/I)
 Patients with renal or hepatic disease, hypoxic
pulmonary disease, heart failure or shock
• Predisposed to lactic acidosis
 Reduced drug elimination or tissue oxygenation
 Pregnant and lactating mothers

Clinical use
 In the majority of type II patients who are obese
 It can be combined with sulfonylureas, glitazones or
insulin

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D. Thiazolidinediones (glitazones)

• Rosiglitazone and pioglitazone

• The effect on blood glucose is slow in onset
• Maximum effect achieved after 1-2 months of treatment
• Mechanism of action
 Increase production of glucose transporters
 Bind to a nuclear receptor called the peroxisome proliferator-
activated receptor-γ (PPARγ)
 Promote transcription of several genes with products that
are important in insulin signaling
  Hepatic glucose output and  glucose uptake into muscle
 Enhance effectiveness of endogenous insulin
 Reduce the amount of exogenous insulin needed
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Adverse effects
 Weight gain and fluid retention (the commonest)

 C/I in pregnant and breast feeding women

 C/I to patients with heart failure

E. α-Glucosidase inhibitors
 Acarbose and Miglitol inhibit alpha-glucosidase enzymes
(maltase, amylase, sucrase) in GI tract
• Inhibits intestinal α-glucosidase
• Delays carbohydrate absorption, reduce the postprandial
increase in blood glucose
• Used primarily as adjunctive therapy
• The commonest adverse effects
 Diarrhea, Flatulence, bloating and Abdominal pain 48
f) Incretin Modulators
a) Glucagon-like peptide-1 (GLP-1) Analogs
 GLP-1 is a member of the incretin family of peptide hormones,
released from endocrine cells in the epithelium of the bowel in
response to food
 The incretins cause insulin release from beta cells, retard
gastric emptying, inhibit glucagon secretion, and produce a
feeling of satiety.
 Exenatide: a long-acting injectable GLP-1 analog
 Combined with Metformin or a Sulfonylurea
Adverse Effects: GI disturbances, hypoglycemia
 It may cause serious and fatal acute pancreatitis.
b) Inhibitor of Dipeptidyl Peptidase-4 (DPP-4)
 Sitagliptin: is an oral inhibitor of DPP-4, the enzyme that degrades
GLP-1 and other incretins
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 Used as monotherapy or in combination with Metformin or a
Thiazolidinedione
 Sitagliptin promotes insulin release, inhibits glucagon
secretion, and has an anorexic effect.
 Adverse Effects: headache, nasopharyngitis, and upper
respiratory tract infection.
g) Amylin Analogs
 Pramlintide is an injectable synthetic analog of Amylin
 Pramlintide suppresses glucagon release, slows gastric
emptying, and works in the CNS to reduce appetite.
 It is used in combination with insulin to control postprandial
glucose levels.
 Adverse Effects: hypoglycemia and gastrointestinal
disturbance

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Summary

5151
 Diabetic Complications
The long term complications of diabetes: two groups
1. Macrovascular: Pathology of large and medium-sized vessels;
this includes Coronary Heart Disease, stroke, PVD
2. Microvascular: Pathology of small vessels and include
Neuropathy, Nephropathy, Retinopathy

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Long Term Complications

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2. Thyroid and Antithyroid Drugs

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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 to normalize growth and

development, body temperature, and energy levels

• Calcitonin is vital in the regulation of calcium metabolism

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Synthesis, Storage and Release of T3 and T4
1. Iodine trapping -Uptake of plasma iodide(I-) by follicle
cells
2. Oxidation of iodide
 Conversion of iodide to iodine (I- Io) by
thyroperoxidase enzyme and the oxidizing agent
H2O2
3. Iodination:
 Tyrosine of thyroglobulin is iodinated
 Form monoiodotyrosine (MIT) and diiodtyrosine
(DIT)
 MIT + DIT T3(Tri iodothyronine)
 DIT + DIT  T4 (Thyroxine)
4. Secretion: Enzymes act on thyroid gland (TG) then T3
and T4 are released 57
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Thyroid Hormone Synthesis and regulation
T4 is the primary product
T3 is more readily absorbed
by the GIT
 T4 absorption from intestine
is modified by factors such as
food, gastric acidity and gut
flora
About 80% of
circulating T3 comes from
deiodination of T4
• Primary pathway for the peripheral
metabolism of thyroxine is deiodination
• Most of T3 in the circulation in is
derived from peripheral metabolism of
T4
• T3 is 3-4 times more potent than T4
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Thyroid and Antithyroid Drugs….

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Thyroid Hormone Synthesis

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Thyroid Hormone Synthesis

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• Thyroid hormone (T3, T4) actions
 Have three principal actions:
1. Increasing metabolism
»  carbohydrate, protein metabolism
» Increase the use of glucose and fatty acids for ATP
production maintenance of normal body temperature
»  02 consumption and
»  Heat production
2. Stimulation of the heart
»  Heat rate
»  force of contraction  CO
3. Promotion of growth and development
» Normal growth and development of CNS
» Maturation of skeletal muscle
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Thyroid Pathophysiology

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Thyroid Pathophysiology
 Hypothyroidism
o Severe: Adult  myxedema(marked by dry skin and swellings
around lips and nose as well as mental deterioration)
o Infants  Cretinism (Severe hypothyroidism resulting in
physical and mental stunting
 Hyperthyroidism : Grave’s diseases and Toxic nodular goiter

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Hyperthyroidism (Thyrotoxicosis)
• In Thyrotoxicosis  activity of T3/T4 metabolic rate skin
temperature & sweating & sensitivity to heat
• Nervousness, tremor, tachycardia, fatigability and  appetite
associated with loss of weight occur.
• The two common types of hyperthyroidism:

1. Diffuse toxic goiter (Grave’s diseases) is characterized by the

presence of TSH receptor–stimulating antibodies (TSAB)
 TSABs mimic TSH in stimulating growth of thyroid gland
(diffuse goiter) and  secretion of T4/T3

2. Toxic nodular goiter. is caused by adenoma

• Unlike diffuse goiter, this condition doesn't usually have
concomitant exophthalmos
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Thyroid Preparations
1. L-Thyroxin
• In tablet form (0.05-0.1 mg, each). A single dose reaches its
maximal effect in about 10 days and passes off in 2-3 weeks.
2. L-Thyroxin sodium
• Is the synthetic sodium salt of L-thyroxin. This preparation is
given by IV injection in case of emergency (Myxedema
coma).
3. Liothyronine sodium
• Is the synthetic sodium salt of L-triiodothyronin. It may be
given IV in emergency. It is more potent than levothyroxine.
It has a quicker onset of action and shorter duration.
4. Liotrix (Euthroid):
• Is a preparation in tablet form containing a mixture of
levothyroxine and liothyronine in the ratio 4:1
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Therapeutic Uses of Thyroid Preparations for hypothyroidism
Replacement therapy in :
1) Hypothyroidism (Treatment: L-thyroxine)
 Myxedema, Hashimoto's disease and After therapy of thyroid tumors
with radioactive iodine.
 Levothyroxine is the usual first-line drug of choice
2) Cretinism (Treatment: L-thyroxine)
• The most critical need of the thyroid hormone is during the
myelination of the CNS that occurs about the time of birth.
3) Myxedema (T4 or T3)
• This is a medical emergency that occurs most often in elderly
• A single dose of T4 (500μg) IV or 50μg of T3 IV is life saving
• Prolonged hypothyroidism is usually associated with adrenal or
pituitary insufficiency (need for Hydrocortisone)
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Adverse Effects of Thyroid Preparations:
• Symptoms and signs of T3/T4 adverse effect are similar to
those of hyperthyroidism (except goiter and
exophthalmos)
• Adverse effects include:
Tremors  Fatigue, Weight loss, Increased appetite,
Palpitation, Nervousness, Increased liver
Insomnia
Transaminases, Cardiotoxicity….Death
 Hyperthermia
Tachycardia  Hypersensitivity (pruritits, urticaria,
Tachypnea GI intolerance)
Arrhythmias  Increase the risk of osteoporosis

Anginal pain  Increase the risk of atrial fibrillation

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Classification of Anti-thyroid drugs

Beta adrenoceptor blockers

 Propranolol DOC
 Nadolol

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Pharmacology of Antithyroid Drugs for Hyperthyroidism
I. Thioamides
• The thioamides are carbimazole, methimazole
(methylthiouracil) and propylthiouracil (PTU).
• Thioamides appear in breast milk and cross placental barrier;
caution during pregnancy
• PTU is choice of thionamide during first trimester of pregnancy.
• Given orally. Duration: 24 hr. (methimazole), 6–8 hr. (PTU)
Therapeutic Uses:
• Preparation of patients for surgery (until the patient’s thyroid
hormone level decreases before giving iodine).
• Chronic treatment of hyperthyroidism until remission.
• Management of thyrotoxic crisis (thyroid storm) along with
propranolol and other drugs

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Adverse Effects of Thioamides
 Hepatitis (more common with PTU) and cholestatic jaundice
(more common with methimazole) can be fatal; although
asymptomatic elevations in transaminase levels also occur.
 Potentially life-threatening agranulocytosis (granulocyte
count < 500 cells/mm3), and hepatotoxicity has occurred
with their use.
 The cross-sensitivity between PTU and methimazole is about
50%; therefore, switching drugs in patients with severe
reactions is not recommended
 Contraindications
 Pregnancy, since thioureas cross the placental barrier causing
fetal goiter. Propylthiouracil has the least effect in this case.

 Lactation, since the drug concentrates in milk.

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II. Anion Inhibitors
• Monovalent anions such as perchlorate (ClO 4 – ), and
thiocyanate (SCN – ) inhibit iodide uptake mechanism.

• Since these effects can be overcome by large doses of

iodides, their effectiveness is somewhat unpredictable.

• The major clinical use for potassium perchlorate is to block

thyroidal reuptake of I– in patients with iodide-induced
hyperthyroidism (e.g., amiodarone-induced
hyperthyroidism).
• However, potassium perchlorate is rarely used clinically
because it is associated with aplastic anemia.
74
74
III. Iodides
• Iodine inhibits the release of thyroid hormones.
• Lugol’s iodine (I2 + KI) is given orally.
 Lugol’s solution(Iodine 5% and Potassium Iodide
10%)
• Maximum effect is seen in 10-15 days.
• it may also inhibit iodination of thyroglobulin by inhibiting
H2O2 generation.
• Uses
 Treatment of sever thyrotoxic crisis.
 Adverse Effect
 Allergy, angioedema, rash, drug, fever, conjunctivitis.
75
75
IV. Radioactive Iodine (131I)
• Given orally
• Taken up and processed by thyroid gland (TG) in the same way
as the stable form of iodine.
• Radio active iodine emits β-particles and γ-rays which causes
destruction of thyroid follicles.
• t1/2 is 8 days and duration of action is for 2 months.
Therapeutic Uses:
 In the treatment of some cases of hyperthyroidism
 Combined with surgery in some cases of thyroid carcinoma
Adverse Effect: Hypothyroidism may occur
Contra-indicated: in children and pregnancy.

76
76
V. Drugs that Control Peripheral Effect of
Hyperthyroidism
• Unpleasant symptoms during hyperthyroidism in the heart are
due to increased tissue sensitivity to catecholamine
(Epinephrine, Norepinephrine)
• β-blockers  many of the sign and symptoms of
hyperthyroidism like tachycardia, tremor, dysrhythmia and
agitation.
• Guanethidine: antiadrenergic used in eye drops to ameliorate
exophthalmos of hyperthyroidism; relaxes sympathetically
innervated smooth muscle that causes eyelid retraction.
• Glucocorticoids (e.g. prednisolone) may be needed for the
exophthalmia of Graves' disease.
• The calcium channel blocker, Diltiazem, could be used in
patients in whom β-blockers are contraindicated. 77
78
 Growth Hormone

• Secreted by the somatotropes of the pituitary cells

• The most abundant pituitary secretion

• Released in a pulsatile fashion

• Release peaks at time of deep sleep where other body functions

sink to their lowest level

• Recombinant GH

 Somatropin
 Somatrem

79 09-Dec-18
 Regulation of Growth Hormone release

80 09-Dec-18
 Human pituitary-derived Growth Hormone

 Recombinant GH preparations used currently:

-Somatropin
Recombinant human GH (rhGH)
- Somatrem

- Sustained-release rhGH- 1 to 2 doses/month

 Somatostatin ; Acromegaly
- For decreasing excess GH secretion
 Octreotide is a synthetic analogue of somatostatin having a
longer action.
 Lanreotide is much longer acting, and is administered Only
twice a month.

81 09-Dec-18
 Growth Hormone
Mechanism of action

• Receptors belong to cytokine receptor superfamily

• Binding of GH to a homodimer receptor

 Recruits the JAK-STAT signaling pathway

o Activate downstream signaling pathways…affect gene

expression

o Enhance hepatic production of the IGFs(somatomedin C)

o IGFs mediate anabolic and growth-promoting effects

82 09-Dec-18
 Physiologic effects of Growth Hormone
• Stimulation of the longitudinal growth of bones

• Increases bone mineral density after the epiphyses have closed

and longitudinal growth ceases

• Anabolic effects in muscle and catabolic effect in lipid cells

 Amino acid uptake and protein synthesis in skeletal muscles

 Directly stimulate lipilysis in adipocytes

 Shift the balance of body composition to an increase in

muscle mass and a reduction in body fat

83 09-Dec-18
 Physiologic effects of Growth Hormone…

• Mixed effect on carbohydrate metabolism

 GH has potent anti-insulin actions in liver, adipocytes, muscle

 IGF-I has insulin-like effects on glucose transport

84 09-Dec-18
 Pathophysiology of Growth Hormone…

Excess production

 Gigantism in childhood and adolescents

 Acromegaly in adults

GH deficiency
 Short stature, delayed bone age, and a low age-adjusted

growth velocity
 Decreased muscle and bone density

 Increased mortality from cardiovascular problems in adults

85 09-Dec-18
 Growth Hormone: Therapeutic uses

Stimulation of growth in children with

• GH deficiency
• Other conditions associated with short stature
 Turner’s syndrome
o With gonadal steroids to achieve maximal height
 Chronic renal insufficiency
 Small-for-gestational-age at birth
• Idiopathic short stature

86 09-Dec-18
 Growth Hormone: Therapeutic uses…
Growth hormone deficiency in adults

• Decrease body fat, increase muscle mass, reverse asthenia,

and improve cardiac output

Wasting in patients with AIDS

• ↑ lean body mass & body weight, improve physical endurance

Malabsorption in in pts with short bowel syndrome

• Enhance growth of the intestinal mucosa and allow it to

adequately absorb nutrients

• Glutamine has also trophic effect on intestinal mucosa

87 09-Dec-18
 Growth Hormone…
Adverse effects

Children

• Intracranial hypertension with papilledema, visual changes,

headache, nausea, and/or vomiting

• Hyperglycemia

• Gynecomastia, pancreatitis

• Slipped epiphyses or scoliosis

• Upper airway obstruction or sleep apnea

88 09-Dec-18
 Growth Hormone…
Adverse effects

Adults

• Peripheral edema, myalgias, arthralgias

 Occur most frequently in older or obese pts

 Remit with dosage reduction

 GH must be contraindicated in pts with active malignancies and those

who are critically ill

89 09-Dec-18
 Insulin-Like Growth Factor 1 (IGF-1)
• Preparations

 Mecasermin (rIGF-1 )

 Mecasermin rinfabate (rIGF-1 + IGFBP-3)

 Adm. by SC injection

• Therapeutic uses

 Impaired growth secondary to mutations in the GH receptor

or GH deficiency in pts who develop antibodies against GH

 Primary IGF-1 deficiency

90 09-Dec-18
 Insulin-Like Growth Factor 1 (IGF-1)…

• Adverse effect

• Hypoglycemia and lipohypertrophy

• Lymphoid tissue hypertrophy, including enlarged tonsils

• Intracranial hypertension, slipped epiphyses, and scoliosis

91 09-Dec-18
 Growth Hormone antagonists
Pegvisomant

• GH receptor antagonist

• Approved for the treatment of acromegaly

• Adverse effects

 Hepatotoxicity with elevated liver enzyme

o Require close monitoring of liver function

 Lipohypertrophy at injection sites

 Induce antibody production(~15%)

92 09-Dec-18
 PROLACTIN
 It is a 199 amino acid, single chain peptide of MW

23000;

 quite similar chemically to GH.

 It was originally described as the hormone which

causes secretion of milk from crop glands of pigeon

and later found to be of considerable importance in
human beings as well.

93
 PROLACTIN….
Physiological function

 Prolactin is the primary stimulus which in conjunction

with estrogens, progesterone and several other

hormones,

 causes growth and development of breast during

pregnancy.

 It promotes proliferation of ductal as well as acinar

cells in the breast and induces synthesis of milk

proteins and lactose.

94
 PROLACTIN….
Physiological function

 Prolactin suppresses hypothalamo-pituitarygonadal axis

by inhibiting GnRH release.

 Continued high level of prolactin during breastfeeding is

responsible for lactational amenorrhoea, inhibition of

ovulation and infertility for several months
postpartum.

 Prolactin may affect immune response through action on

T-lymphocytes.

95
 PROLACTIN….
Regulation of secretion

 Prolactin is under predominant inhibitory control of

hypothalamus through PRIH which is dopamine that

acts on pituitary lactotrope D2 receptor.

 Dopaminergic agonists (DA, bromocriptine,

cabergoline) decrease plasma prolactin levels, while
dopaminergic antagonists (chlorpromazine,
haloperidol, metoclopramide) and DA depleter
(reserpine) cause hyperprolactinemia.

96
 PROLACTIN….
Physio-pathological involvement

 Hyperprolactinaemia is responsible for the

 Galactorrhoea

 Amenorrhoea

 Infertility syndrome in women.

 In males it causes

 Loss of libido and

 Depressed fertility.

97
 PROLACTIN….
Physio-pathological involvement……….

The causes of hyperprolactinaemia are:

(i) Disorders of hypothalamus removing the inhibitory control

over pituitary.

(ii) Antidopaminergic and DA depleting drugs- these are a frequent

cause now.

(iii) Prolactin secreting tumours- these may be microprolactinomas

or macroprolactinomas.

(iv) Hypothyroidism with high TRH levels- also increases prolactin

secretion.

Note: Use: There are no clinical indications for prolactin

98
 PROLACTIN INHIBITORS
Bromocriptine

1. Decreases prolactin release from pituitary by

activating dopaminergic receptors on lactotrope
cells: is a strong antigalactopoietic.

2. Increases GH release in normal individuals, but

decreases the same from pituitary tumours that
cause acromegaly.

3. Has levodopa like actions in CNS—antiparkinsonian

and behavioral effects.

99
 PROLACTIN INHIBITORS…..
Bromocriptine

4. Produces nausea and vomiting by stimulating

dopaminergic receptors in the CTZ.

5. Hypotension—due to central suppression of postural

reflexes and weak peripheral a adrenergic blockade.

6. Decreases gastrointestinal motility.

100
 PROLACTIN INHIBITORS…..
Bromocriptine

Uses: Bromocriptine should always be started at a low dose,

1.25 mg BD and then gradually increased till response
occurs.

 Hyperprolactinemi

 Acromegaly

 Parkinsonism

 Diabetes mellitus (DM) A new use of bromocriptine based on its

dopamine D2 agonistic action in the hypothalamus has been found in
type 2 DM, and it has been approved by US-FDA as an adjunctive drug.
101
 PROLACTIN INHIBITORS…..

Bromocriptine

Side effects: Side effects are frequent and dose related.

Early: Nausea, vomiting, constipation, nasal blockage.
Postural hypotension

Late: Behavioral alterations, mental confusion,

hallucinations, psychosis- are more prominent than with
levodopa. Abnormal movements, livedo reticularis.

102
 PROLACTIN INHIBITORS…..
Cabergoline

 It is a newer D2 agonist; more potent; more D2

selective and longer acting (t½ > 60 hours) than

bromocriptine;

 needs to be given only twice weekly.

 Incidence of nausea and vomiting is also lower;

 some patients not tolerating or not responding to

bromocriptine have been successfully treated with

cabergoline.

103
 PROLACTIN INHIBITORS…..
Cabergoline

 It is preferred for treatment of hyperprolactinemia and

acromegaly.

 Some patients who achieve total regression of

prolactinoma and normalization of prolactin levels can
stop cabergoline without recurrence.

 Dose: Start with 0.25 mg twice weekly; if needed

increase after every 4–8 weeks to max. of 1 mg twice

weekly.

104
3. ADRENOCORTICOSTEROIDS & THEIR ANTAGONISTS
• Naturally occurring steroids are synthesized and released by
the adrenal cortex
• The hormones are known as Corticosteroids.
• Based on physiological functions, they are divided in to 3:
A. Glucocorticoids: affect metabolism-hydrocortisone
B. Mineralocorticoids: regulate salt retention-aldosterone
C. Sex hormones: Corticosteroids with estrogenic and
androgenic activities (dehydroepiandrosterone)
Regulation of Adrenocortical Secretion:
• During stress, CRH released by the hypothalamus stimulates
corticotrophin (ACTH) release
• ACTH stimulates synthesis & release of cortisol from cortex
• A negative feedback relationship exists between cortisol blood
level and ACTH release 105
Glucocorticoids (Cortisol, Hydrocortisone)
• Corticosteroids control expression of corticosteroid responsive
genes changing the levels and array of proteins synthesized
• Most effect of corticosteroids aren't immediate but take longer
(time to modulate gene expression and protein synthesis
Pharmacodynamics
Sequence of activation:
Free hormone enters the cell
receptor binding  conformation change
Hormone-receptor complex form dimers
Homodimers: enter the nucleus & bind to glucocorticoid receptor
elements (GREs) of target genes
Lead to genomic effects: protein synthesized  ultimate effect
106
Action of Glucocorticoids:
I. On Metabolism:
a) Carbohydrates:
glucose utilization. gluconeogenesis  hyperglycaemia
b) Proteins: anabolism and enhances catabolism leading to:
Negative nitrogen balance with muscle wasting
Retardation of growth in children.
Skin atrophy + capillary fragility, bruising and stria.
Decreased healing power of wounds and peptic ulcer.
c) Fats
Fat deposition on shoulders, face and abdomen.
II. Inflammation:
 Inflammation is inhibited regardless of the cause
 Mechanism: inhibition of phospholipase A2  synthesis
prostaglandins inhibition of inflammatory mediators. 107
III. Allergy
 (Suppression), antigen - antibody interaction is unaffected, but
its harmful inflammatory consequences are prevented.
IV. Blood eosinophils:
 decreases in number
V. Euphoria or psychotic states:
 may occur (probably due to CNS electrolyte changes).
VI. Calcium metabolism:
 urinary excretion & intestinal absorption (antivitamin D
action)
VII. Electrolytes and water metabolism:
 Increases sodium retention by the renal tubule and potassium
excretion in urine (Mineralocorticoid effect of glucocorticoids)

108
Therapeutic Uses Of Corticosteroids:
A. Replacement therapy.
B. Anti-inflammatory and Immunosuppressant.
A. Replacement Therapy
I. Acute adrenal insufficiency (Addisonian Crisis):
 This is an emergency therefore immediate treatment based
on replacing “glucocorticoids and sodium/water deficits” is
necessary
II. Chronic primary adrenal insufficiency (Addison's disease):
 Hydrocortisone or cortisone + small amount of
mineralocorticoid (fludrocortisone, 0.1 mg orally)
III. Chronic secondary adrenal insufficiency:
 This occurs in hypopituitarism.
 Replacement therapy with hydrocortisone is essential.

109
B. Anti-inflammatory and immunosuppressant effect:
 Corticosteroids have been used in virtually every untreatable
or obscure disease.
 Drugs with high glucocorticoid effect e.g. dexamethasone or
prednisone is chosen, so that the dosage is not limited by the
mineralocorticoid effects of hydrocortisone.
 It remains essential to use only minimum doses that will
achieve the desired effect.
 Sometimes therapeutic effect must be partly sacrificed to
avoid adverse effects.

110
Glucocorticoids
i) Cortisol
 Is the major natural glucocorticoid
 Regulated by ACTH, secretion varies during the day
 In the plasma, 95% cortisol is bound to CBG.
 Given orally and has a short duration of action compared with
its synthetic congeners
 Readily absorbed across inflamed skin.
 Also has a small but significant salt retaining
(mineralocorticoid) effect
 Hypertension in patients with a cortisol secreting adrenal
tumor or with Cushing’s syndrome.

111
ii) Synthetic glucocorticoids
 Synthetic glucocorticoids available for use are:-
 Prednisone (and its metabolite, Prednisolone),
Dexamethasone, and Triamcinolone
 See the ff table for comparison with Cortisol

 Special glucocorticoids developed for use in asthma :-

 Beclomethasone and Budesonide
 Readily penetrate airway mucosa but have very short half-lives
after they enter the blood
 systemic effects and toxicity are greatly reduced
112
Adverse effects
 Minimized toxicity by
local application,
alternate-day therapy,
tapering dose
 Patients who are being
withdrawn from
glucocorticoids after
protracted use should
have their doses tapered
slowly, to allow recovery
of normal adrenal
function. 113
Mineralocorticoids
A. Aldosterone
 Aldosterone the major natural mineralocorticoid in humans
 Its secretion is regulated by ACTH and by the RAAS
 It is very important in the regulation of blood volume and BP
 Aldosterone has a short half-life & little glucocorticoid activity
 Its mechanism of action is the same as that of the glucocorticoids.
B. Other Mineralocorticoids
 Other mineralocorticoids include deoxycorticosterone (precursor
of aldosterone) and fludrocortisone (significant glucocorticoid
activity)
 Fludrocortisone: Long duration of action, favored
mineralocorticoid replacement therapy after adrenalectomy and
in other conditions

114
 Inhibitors of corticosteroid synthesis
 Metyrapone
• Reduces cortisol production to normal in patients with:
Adrenal tumor, ectopic ACTH syndromes, hyperplasia
• Major adverse effects: salt & water retention, hirsutism
 Trilostane
• Primary hyperaldosteronism, cushing’s syndrome
 Aminoglutethimide
• Reduces synthesis of all hormonally active steroids
• Used with dexamethasone to eliminate estrogen and
androgen production in patients with breast carcinoma
 Ketoconazole
• Potent, nonselective adrenal and gonadal steroid
synthesis inhibitor
• Used to treat patients with Cushing's disease

115
 Mifepristone
• Has strong progesterone receptor blocking activity
 Emergency contraceptive, abortifacient
• Block glucocorticoid receptors
• Has very long plasma half life (20 hours)
 95% is plasma albumin and 1-acid glycoprotein
bound
• Given orally to patients with Cushing's syndrome due to
ectopic ACTH production or adrenal carcinoma
• May be useful for endometriosis, breast cancer
• Adverse effect: prolonged bleeding (major)

116
4. Hormonal regulation of the female
reproductive system
• Gonadotrophin releasing hormone (GnRH) stimulates
 Follicle stimulating hormone (FSH)
 Luteinizing hormone (LH) from the anterior
pituitary gland
• FSH initiates follicular growth and the secretion of
estrogens by the growing follicles
• LH stimulates further development of ovarian follicles
and their full secretion of estrogens
• At mid cycle, LH triggers ovulation and promotes
formation of the corpus luteum
117
Phases of the female reproductive cycle
1. Menstrual phase
 Shading of the uterine lining/bleeding
 Lasts for the first 5 days of the cycle
 A few ovarian follicles begin to enlarge during the
first days of the menstrual cycle
 Through the influence of a rise in FSH

118
2. Follicular/ proliferative phase
 The time between end of menstruation and
ovulation
 A single follicle outgrows to become a dominant
follicle (Graffian follicle)
 GF continues to increase its estrogen production
under the influence of LH
 Estrogens are the main ovarian hormones before
ovulation
 Estrogen liberated by the ovarian follicles stimulates
growth of the lining of uterus

119
3. Ovulation
 Rupture of the mature follicle and release of the ovum
in to the fallopian tube
4. Luteal/secretory phase
 The time between ovulation and the first day of the
next menses
 The corpus luteum produces progesterone (dominant)
and estrogen
 Maintain the endometrium

120
121
 Estrogens
 Synthesized by ovary and placenta
 The testes and adrenal cortex also produce small
amount
 The main estrogens produced by the woman
 Estradiol
 Estrone
 Estriol
 Synthetic estrogens
 Ethinyl estradiol
 Mestranol
 Diethylstilbestrol

122
Physiological effect of estrogen
 Normal growth and sexual maturation of females
 Modest anabolic effect
 Increase circulating HDL while decreasing LDL
 Decrease bone resorption
 Enhances coagulability of blood

123
Effects of exogenous estrogen
 In primary hypogonadism; estrogen stimulates
development of secondary sexual characteristics
and accelerates growth
 In adults with primary amenorrhea, estrogen given
with progesterone induces artificial menstrual cycle
 Contraception
 In menopause; estrogen prevents menopausal
symptoms and bone loss

124
Selective Estrogen Modulators (SERMs)
• SERMs show selective agonism/antagonism for estrogen
receptors depending on tissue type (ERα & ERβ distribution)
 Tamoxiphen
 Has anti estrogenic activity on breast tissue and is used to
treat estrogen sensitive breast cancer
 Raloxifen
 Has antiestrogenic action on breast and uterus but
estrogenic effects on bone, lipid metabolism and blood
coagulation; used to treat postmenopausal osteoporosis
and as prophylactic to reduce risk of breast cancer
 Clomiphene
 Is an ER antagonist in hypothalamus and anterior
pituitary, but a partial agonist in ovaries; used in treating
infertility associated with anovulatory cycles
125
 Progestins (Progestrones)
• Progestrone is a natural progestin secreted by the
corpus luteum and placenta
• Progesterone is inactive orally because of complete first
pass effect
• There are two groups of synthetic progestin
 Progesterone derivatives: hydroxyprogesterone,
medroxyprogesterone
 Testestrone derivatives: Norethindrone, Norgestrel,
desogestrel, norgestimate, etonogestrel
• Clinical uses
 Hormonal contraception, hormone replacement
therapy, menstrual disorders
126
 Contraceptive Agents
 Pharmacologic modes of contraception
• Oral contraceptive (OCs)
• Implants
• Injectable preparations
• A progesterone- containing intrauterine device
 In addition to drugs, conception can be prevented by:
• Surgery
 Tubal ligation, Vasectomy, Hysterectomy
• Mechanical devices
 Condom, Cervical cap, Intrauterine device (IUD)
• Calendar method

127
Oral contraceptives
1.Combined OCs (estrogen + progestin)
2.Progestin only contraceptive  AKA“ minipills”

128
Combined OCs

• The estrogens : ethinyl estradiol or mestranol

• The progestin : norethindrone or norgestrel

• Mechanism of action

 Inhibition of ovulation ( LH, FSH)

 Promote thickening of cervical mucus

 Making uterus unfavourable for implantation

129
Adverse effects
 The common adverse effects are:
Mild: nausea, headache, breast pain, breakthrough
bleeding, weight gain
Skin changes (e.g. acne and/or an increase in
pigmentation)
Amenorrhoea of variable duration on cessation of taking
the pill
Others: HPT, thrombotic disorder, depression, myocardial
infarction
Hypertension
•  blood levels of angiotensin & aldosterone
 Thrombotic Disorders
•  circulating levels of clotting factors
130
Contraindicated to patients with:
 Thromboembolic phenomena, and CV and
cerebrovascular disorders or a past history of these
conditions
 Vaginal bleeding of unknown cause
 Known or suspected tumors of breast or other
estrogen dependent neoplasm
 C/I or used with caution in pts with liver disease,
migraine, eczema, hypertension, optic neuritis,
convulsion or edema

131
Progestin –only OCs (“minipills”)
 Contain a progestin (norethindrone or norgestrel)
 Less reliable & cause more menstrual irregularity
• less popular
 Mechanism of action
• Makes cervical mucus inconvenient for sperm
migration
• It also hinders implantation through its effect
on the endometrium and on the motility and
secretion of the fallopian tube
 The risk of pregnancy due to missed pills is very
much higher than the COCs

132
Long- acting contraceptives
 Subdermal progestin Implants
 Norplant
• Consists of 6 tiny nondegradable capsules each
containing 36 mg of levonorgestrel
• The capsules are surgically implanted on the side
of upper arm through a small incision
• Provide blood levels sufficient for contraception
for up to 5 years
• Following removal, blood levels become
undetectable with in 10-14 days
• The common adverse effect is menstrual
irregularity

133
  Jadelle (norplant II)
• Two rods ( norgestrel, 216 mg)
• Effective for five years
 Implanon
• A single rod (etonogestrel, 68 mg)
• Used for three years

Medroxyprogesterone Acetate (Depo-provera)

• Administered intramascularly
• provides effective contraception for 3 or more
months

134
Emergency (postcoital) contraception
 When RX begun with in 72hrs,it is effective 99% of the
times
 Often used in combination with antiemetics
 40% experience nausea or vomiting
• Levonorgestrel: 0.75 mg twice a day for one day
• Norgestrel, 0.5mg + Ethinyl estradiol, 0.05mg
 2 tabs taken with in 72 hrs &
 2 tabs 12 hrs later
• Mifepristone, 600 mg once + misoprostol, 400 mcg once
135
Uterine Stimulants and Relaxants
• Drugs used to stimulate uterine contraction are known as
oxytocics; drugs that suppress are known as tocolytics
Tocolytics(Uterine Relaxants ): Agents that Delay preterm labor
 Beta2-Adrenoceptor Agonists
 Ritodrine
o Relaxes uterine smooth muscle, so decreases frequency
and intensity of uterine contraction
o Inhibit spontaneous or oxytocin-induced contractions of
the pregnant uterus
o They can delay delivery by 48 hours
 Used to administer glucocorticoid therapy to the
mother so as to mature the lungs of the baby
o C/I for pregnant with eclampsia, preeclampsia,
hemorrhage, or maternal heart disease
136
Uterine Stimulants (Oxytocics)
• Clinical use
 Induction or augmentation of labor
 Control of postpartum bleeding
• Three groups of uterine stimulants
 Oxytocin
 Prostaglandins
 Ergot alkaloids

137
1. Oxytocin
• Synthesized in the paraventricular and supraoptic nuclei of the
hypothalamus
• Physiologic and pharmacologic effects
 Uterine stimulation—Increased force, frequency, and
duration of uterine contractions
 Milk ejection—Contracts myoepithelial cells in the mammary
gland, which causes 'milk let-down’
 Water retention—Similar to ADH, so promotes renal
retention
 Vasodilation

138
Therapeutic uses of oxytocin
 Induction of labor
 Augmentation of labor
 Control postpartum bleeding
Adverse effects
 Dose related hypotension
 Tachycardia
Precautions
 Improper use can be hazardous
Uterine rupture
Fetal distress and death

139
2. Ergot Alkaloids (Ergometrine)
• Initiates strong contraction in inappropriately relaxed uterus
• Reduce bleeding from the placental bed
• Also has a moderate degree of vasoconstrictor action
• Ergometrine can be given orally, i.m. or intravenously
• It has rapid onset of action and its effect lasts for 3-6 hrs
Clinical use:
 used to treat postpartum haemorrhage
Adverse effects
• Vomiting (D2 receptor stimulation in CTZ)
• Hypertension, blurred vision, headache, angina

140
3. Prostaglandins
• Prostaglandins of the E and F series promote
Contraction of pregnant uterus
Relaxation of the cervix
• Carboprost, dinoprostone, misoprostol

141
Clinical uses of prostaglandins
 Dinoprostone
 Induction of abortion in the second trimester of pregnancy
 Induction of labor at or near term (vaginal gel)
 Carboprost
 Control Postpartum haemorrhage
 Induce second trimester abortions
 Mifepristone (progestin antagonist) with misoprostol or..
 Termination of early pregnancy
 Increase sensitization of uterus to PGs
 Decrease the dose of PGs
Unwanted effects prostaglandins
 Uterine pain, nausea and vomiting, which occur in about
50% of patients when the drugs are used as abortifacient
142
143