pharmacology-iii 452 (2)

7/28/2019 Pharmacology-III 452 (2)

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PHARMACOLOGY-III

PHL- 452 (2+0)

FIRST LECTUREAdrenocorticosteroids and Antagonists

Objectives:

After listening to the lecture (s), and studying the textbook the student shoud be able

to

1. Explain the molecular mechanism of action of corticosteroids

2. Explain the difference between direct and indirect, pharmacological

and permissive effects of corticosteroids

3. Describe the effects of glucocorticoids upon different organ systems

4. describe the primary features of the anti-inflammatory action of

glucocorticoids

5. Explain the mechanism of the anti-inflammatory, immunosuppressive

and antineoplastic action of glucocorticoids

6. List several synthetic glucocorticoids and the difference between these

agents and the naturally occurring hormones

7. Classify the main glucocorticoids of clinical use according to their

duration of action

8. List the routes of administration for glucocorticoids

9. Describe the adverse effects of glucocorticoids after acute or long-

term administration

10.List the main microorganisms that can cause an infection in patients

receiving glucocorticoids

11.describe the interactions between glucocorticoids and other drugs


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12.Outline the therapeutic uses of glucocorticoids in adrenal and in non-

adrenal disorders

13.list the main contraindications to the use of glucocorticoids

14.Explain the basic principles for using glucocorticoids in clinical

practice

15.describe the factors that regulate aldosterone secretion

16.Describe the effects, toxicity and main therapeutic uses of

mineralocorticoids

17.Describe the mechanism of action and therapeutic uses of theantagonists of glucocorticoids

Classification of adrenocorticosteroids:1. Natural and synthetic.


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2. Glucocorticoids and mineralocorticoids.

Glucocorticoids: concerned with CH metabolism and may include

natural glucocorticoid as Hydrocortisone (cortisol) and Cortisone

and synthetic ones including Prednisone, Prednisolone, Methyl-

prednisolone,Triamcinolone, Betamethasone and Dexamethasone.

Mineralocorticoids: concerned with salt and water metabolism and

may include natural mineralocorticoid as Aldosterone and

Desoxycorticosterone (DOC) and synthetic ones including

Fludrocortisone.

Mechanism of Action of Glucocorticoids:

1) Diffusion of glucocorticoid across the membrane of the target

cell to bind to a glucocorticoid receptor-heat-shock protein

complex in the cytoplasm.

2) Release of the heat-shock protein and transport of the hormone-

receptor complex into the nucleus.

3) Binding of the hormone-receptor complex to specific nucleotidesequence along the DNA called glucocorticoid response elements

(GREs).

4) Decreased or increased accumulation of mRNA within the target

cell (alteration of transcription).

5) Changes in the rate of synthesis of specific proteins that carry

the biological actions of the hormones.

Mechanism of action (some details)

1. Enter cells where they combine with steroid receptors in

cytoplasm.


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2. Combination enters nucleus where it controls synthesis of

protein, including enzymes that regulate vital cell activities over a

wide range of metabolic functions including all aspects of

inflammation.

3. Formation of a protein that inhibits the enzyme phospholipase

A2 which is needed to allow the supply of arachidonic acid. The

latter is essential for the formation of inflammatory mediators.

4. Also act on cell membranes to alter ion permeability

5. Also modify the production of neurohormones

Effects of glucocorticoids may be:

A) Direct effects: Direct actions in the cell.

B) Indirect effects: the results of the homeostatic responses (e.g. by

insulin, glucagon, PTH).

A) Physiologic (or pharmacologic) effect: dose-dependent effect.

B) Permissive effect: dose-independent effect

Important to distinguish between physiological effects

(replacement therapy) and pharmacological effects (occur at

higher doses).

1. Metabolic Effects:

A) Carbohydrate Metabolism

1. Increased gluconeogenesis in liver and kidney.

2. Increased glycogen synthesis and storage.


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3. Inhibition of glucose uptake and utilization by both adipose

tissue and skeletal muscle.

4. The hyperglycemia stimulates insulin secretion

B) Lipid Metabolism:

1. Increased lipolysis which leads to an increased in plasma levels

of

free fatty acids.

2. Insulin secretion stimulates lipogenesis leading to a net increase

in fat deposition.

3. Increased fat absorption from the intestine.

4. Redistribution of body fat (increased in the back of the neck andface, decreased in the extremities).

C) Protein Metabolism

1. Increased protein synthesis in the liver.

2. Decreased synthesis (anabolism is decreased).

3. Increased breakdown of proteins in lymphoid and connective

tissue, muscle, fat and skin. Catabolism continues unabated or is

increased resulting in negative N balance and muscle wasting.Osteoporosis occurs, growth slows in children, skin atrophies

(together with increased fragility leads to brusing and striae),

healing and fibrosis delayed.

D) Salt and Water Metabolism:

1. Salt and water retention

2. Less than mineralocorticoids.

3. Negligible with some synthetic glucocorticoids.

4. Mineralocorticoids cause:

A) Na retention by renal tubule

B) Increased K excretion in urine


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2. Cardiovascular Effects:

A. Permissive Effects: maintenance of:

1. A normal capillary permeability.

2. A normal vasomotor response to CAs.

3. A normal heart contractility.

4. A normal cardiac output.

B. Direct effect:

1. Direct vasoconstriction on small vessels.

2. Hypertension.

3. Renal Effects:A) Permissive Effects: maintenance of:

1. A normal glomerular filtration.

2. A normal water permeability in the distal collecting tubules due

to inhibition of vasopressin secretion.

B) Increased excretion of Ca++.

C) Renal urate excretion increased

4. Gastrointestinal Effects:

1. Maintenance of normal function of visceral smooth muscle(permissive Effect).

2. Increased production of gastric acid and pepsin.

3. Decreased cytoprotection of gastric mucosa.

4. Decreaed Ca++ absorption from the intestine (also, due to

blockade of vitamin D action).

5. Antiemetic effects.

6. General depressive effects on intestinal functions after high

doses.


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5. Central Nervous System Effects:

1. Decreased cortical threshold for convulsions.

2. Behavioural disturbances after high doses.

3. Increased intracranial pressure after high doses.

Euophoria or psychotic states may occur probably due to CNS

electrolyte changes

6. Endocrine Effects:

1. Decreaed release of CRH, ACTH and beta-lipotropin, TSH,

FSH, and ADH.

2. Increased release of GH.

7. Hematopoietic Effects:

1. Decreased concentration of lymphocytes, monocytes, basophils

and eosinophils in blood due to increased efflux of these cells from

blood to the lymphoid tissue.

2. Increaed concentration of neutrophils in blood due both to 1)

increased efflux from bone marrow and to decreased migration

from the blood vessels.

3. Increased concentration of red blood cells and platelets.

8. Locomotor System Effects:

1. Permissive effect: Maintenance of normal function of striatal

muscle (Permissive effect).2. Decreased muscle mass after high doses.

3. Decreased bone formation (direct effect due to iinhibition of

osteoblasts.

4. Increased bone resorption (indirect effect due to increased

secretion of PTH and decreased secretion of calcitonin.

5. Negative total body Ca++ balance.

9. Antineoplastic action due to:


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1. Dissolution of pathologic lymphocytes and lymphoid tissue

(lympholythic action).

2. Inhibition of growth of mesenchymal cancer tissue.

3. In many tumors, the effect is the consequence of their anti-

inflammatory action.

10. Anti-Inflammatory action:

Have two important characters:

1. All types of inflammatory reactions are affected.

2. Both early and late phases of inflammation are inhibited.

Inlammatory response depressed

Main mechanisms of anti-inflammatory actions are:

1) Alteration of number, distribution and function of peripheral

leukocytes and tissue macrophages.

2. Inhibition of PG and leukotriene synthesis.

3) Additional mechanisms.

Alteration of number, distribution and function of peripheral

leukocytes and tissue macrophages includes:

For leukocytes:

1. Decreased migration of neutrophils from the blood vessels.

2. Increased movements of lymphocytes, monocytes, basphils andeosinophils from vascular bed to the lymphoid tissue.

3. Decreased production of Interleukins (mainly I 2). TNF, and

interferon gamma.

4. Inhibition of histamine release from basophils and mast cells.

5. Inhibition of fibroblast proliferation both due to the decrease in

growth factor production and the decreae in interleukin 1.

For macrophages:


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1. Decreased accumulation of macrophages at the site of

inflammation.

2. Decreased macrophage ability to phagocytose and kill

microorganisms.

3. Decreased production of interleukins (mainly I 1), TNF,

interferon gamma and pyrogens.

4. Decreased activation of T cells.

Inhibition of PG and leukotriene synthesis.

1. Inhibition of phospholipase A2 production.

2. Inhibition of COX-II production.

Additional mechanisms of anti-inflammatory action include

Decrease in postcapillary permeability due to

1. Inhibition of histamine release and kinin activity.

2. Inhibition of the effects of complement system.

11. Immunosuppressive action:

Have two important characters:

1. Humoral immunity is slightly affected as the antibody

production is reduced only after high doses.

2. Cellular immunity is strongly inhibited as the distribution and

function of immune cells are deeply modified.

Mechanisms of immunosuppressive action are:

A) Most of the effects on leukocytes and macrophages mentioned

above can impair immunity. Especially in this regard are:

1. Inhibition of interlekin 1 production which in turn decreases the

proliferation of T cells and impairs the responses of both T and B

cell to antigen.

2. The direct lympholythic effect on certain subset of T cells

(cytotoxic T cells and inflammatory T cells).


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B) Additional mechanisms include:

1. Inhibition of antigen release from grafted tissue.

2. Stimulation of the catabolism of IgG antibodies thus lowering

the effective concentration of specificantibodies.

Relative potencies of corticosteroids

Drug AI SR EOD(mg)

Hydrocortisone 1 1 20

Prednisone 4 0.3 5

Prednisolone 5 0.3 5

Triamcinolone 5 0 4

Betamethasone 25-40 0 0.6

Dexamethasone 30 0 0.7

Fludrocortisone 10 250 2

Desoxycorticosterone 0 20 -

AI: Antiinflammatory activity

SR: Salt-retaining activity.

EOD: Equivalent oral dose (mg)

Duration of action of corticosteroids


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Group Plasma t1/2 Biological t1/2 Examples

Short-Acting 0.5-2 hrs 8-12 hrs Hydrocortisone,

cortisone,

Fludrocortisone

Intermediate

Acting

2-5 hrs 12-36 hrs Prednisone,

prednisolone,

Triamcinolone

Long Acting 3-6 hrs 36-72 hrs Betamethasone,

Dexamethasone

Routes of administration of corticosteroids

Route Dosage form

Oral Tablets, syrups, etc.

Rectal Suppositories, enemas

Intramuscular Solutions, suspensions

Intra-articular Solutions, suspensions

Intravenous SolutionsRespiratory Oral aerosol

Topical Cream, lotions, sprays, eye

drops

Note: Some absorption of topical preparations always occurs

and may be high.


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Toxicity of glucocorticoids

1. Adrenal suppression

2. Iatrogenic Cushings syndrome

3. Other toxic effects: subdivided into:

A) Early toxic effects (days, weeks)

B) Later toxic effects (months, years)

Adrenal suppression:

1. The degree and duration of adrenal suppression

depend

on the dose and duration of glucocorticoid therapy

2. It takes at least 2-3 months for the pituitary and

adrenals to become responsive, after chronic steroid

therapy is discontinued

3. If therapy is to be stopped, corticosteroid dosage

should

be tapered slowly.

4. If the dose of glucocorticoid is reduced too rapidly,

acute

or chronic adrenal insufficiency could ensue.


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What are the symptoms of acute or chronic adrenal

insufficiency?

A) Nausea and vomiting

B) Weight loss

C) Lethargy

D) Fever

E) Muscle pain

F) Circulatory collapse

G) Renal failure

N.B. Steroid suppressed adrenal continues to secrete

aldosterone.

Iatrogenic Cushings syndrome:

Treatment with high dose for more than 2-3 weeks

Symptoms of Cushings syndrome include:

1. Moon face: rounding and puffiness of the face

2. Buffalo hump: Redistribution of fat to the face andtrunk

3. Thin limbs

4. Thin and atrophic skin

5. Acne

6. Hypertrichosis

Early Toxic effects (days or weeks after administration)

1. Weight gain2. Mood changes

3. Retarded wound healing

4. Glucose intolerance

5. Allergic contact dermatitis when given

6. Rare early toxic effects:

- Hypertriglyceridemia

- Peptic ulcer

- Acute pancreatitis


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Later toxic effects (months or years after administration)

1. Central obesity

2. Cutaneous fragility

3. Ecchymosis

4. Osteoporosis

5. Myopathy

6. Opportunistic infections

7. Growth failure in children (Growth reduction occurs

where new cells are being added (as in children) but not

where they are replacing cells as in adult tissues.

8. Raised intracranial pressure (pseudotumor cerebri)

9. Diabetes mellitus in risk patients

10. Hypertension (rare with synthetic glucocorticoids)

11. Rare late toxic effects:

12. Aseptic necrosis in bone

13. Posterior subcapsular cataracts, glaucoma

Infections occurring with increased frequency and severity

in patients receiving glucocorticoids

Bacterial infection caused by:

Mycobacterium tuberculosis

Proteus Vulgaris

Pseudomonas aeruginosa

Staphylococcus species

Viral infection caused by:

Herpes simplex virus

Varicella-Zoster virus

Fungal infection caused by:


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Aspergillus fumigatus

Candida albicans

Parasitic infection caused by;

Entamoeba histolytica, Toxoplasma gondii

Contraindications and Cautions of Glucocorticoids

1. Diabetes mellitus

2. Hypertension

3. Heart failure

4. Renal failure

5. Osteoporosis

6. Osteoarthritis7. Glaucoma

8. Bacterial infections

9. Herpes simplex infection

10. Acute viral hepatitis

11. Schizophrenic or depressive psychosis

12. Pregnancy

Drug interactions with corticosteroids:1. with ethacrynic acid (high clinical relevance)

Increased K+ loss

Increased risk of gastric hemorrhage

2. with cyclosporine (high clinical relevance)

Decreased metabolism of cyclosporine

3. with estrogens (high clinical relevance):Decreased metabolism of corticosteroids

4. with enzyme inducers as barbiturates, phenytoin.

Rifampin and carbamazepine (medium clinical relevance):

Increased metabolism of corticosteroids

5. with salicylates (medium clinical relevance):

Increased salicylate excretion

Enhancement of gastric effects


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6. Among the drugs that interact with corticosteroids are:

* Insulin and diabetes medicines

* Heart medicines such as digitalis

* Diuretics

* Medicines containing potassium or sodium

* Immunization (vaccination)

* Blood thinners such as warfarin

Clinical uses of glucocorticoids:

1. Diagnostic uses2. Therapeutic uses

A. Endocrine disorders

B. Non-endocrine disorders

Diagnostic uses:

Dexamethazone suppression test is used for:

A) Differential diagnosis in patients with Cushings

syndromeB) Differential diagnosis of psychiatric states (the test is

abnormal in the presence of severe mental disorder)

Uses of glucocorticoids in endocrine disorders:

1. Replacement or supplementation therapy in:

A. Acute and chronic adrenal insufficiency

B. During and after surgical removal of a pituitary or

adrenal adenomaC. Feed-back inhibition of ACTH as in congenital adrenal

hyperplasia


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Uses of glucocorticoids in non-endocrine disorders:

1. Musculoskeletal and connective tissue diseases

* Rheumatoid arthritis

* Gout arthritis

* Bursitis

* Polymyalgia rheumatica

* Polymyositis

* Polyarteritis nodosa

* Lupus erythematosus

Neoplastic diseases*n Leukemias

*n Lymphomas

* Multiple myeloma

* Complications of malignancy

Hematologic diseases:

* Acquired hemolytic anemia

* Autoimmune hemolytic anemia* Some forms of aplastic anemias

* Idiopathic thrombocytopenic purpura

* Acute allergic purpura

* Transfusion reactions

Gastrointestinal diseases

* Ulcerative colitis

* Crohns disease* Chronic active hepatitis

* Subacute hepatic necrosis

Pulmonary diseases

* Bronchial asthma* Aspiration pneumonia


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* Prevention of infant respiratory distress syndrome

(administered to the mother during pregnancy)

* Idiopathic pulmonary fibrosis

Cardiovascular diseases

* Myocarditis and pericarditis

* Rheumatic carditis

* Temporal arteritis

Renal disease

*Nephrotic syndrome

Neurologic diseases

* Acute cerebral edema

* Meningitis

* Multiple sclerosis

* Myasthenia gravis

* Spinal cord injury

Eye diseases*Anterior uveitis

* Posterior uveitis

* Optic neuritis

* Malignant thyroid exophthalmos

Allergic and immune diseases

*Subacute thyroiditis

* Allergic conjunctivitis

* Allergic rhinitis

* Angioneurotic edema


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* Serum sickness

* Insect venom allergy

* Drug reactions

* Anaphylaxis

* Transplantation rejection (host-versus-graft disease

and graft-versus-host disease)

Skin diseases

* Urticaria

* Various types of dermatitis

* Erythema multiforme

* Psoriasis

**Normal daily secretion of hydrocortisone is 10-30 mg.

exogenous daily dose that completely suppresses cortex is 40-

80 mg (or prednisolone 10-20 mg).

**Prednisolone is standard choice for anti-inflammatory

therapy and can be given orally or IM

**Methylprednisolone used for IV pulsed therapy

**Dexamethazone longer acting

**Fludrocortisone used to replace aldosterone where the

adrenal cortex has been destroyed

**Beclomethazone and budesonide used by inhalation forasthma.

Principles for using glucocorticoids

1. for any disease, in any patient, the appropriate dose to

achieve a given therapeutic effect must be determined by

trial and error


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2. The dosage should be kept flexible, being raises or

lowered according to the activity of the disease or the

development of unwanted effects

3. The synthetic analogs are generally preferable to natural

steroids because of their negligible sodium-retaining effects

4. a single dose of corticosteroids, even if very large, is

virtually without harmful effects

5. in the absence of specific contraindications, a few days of

corticosteroid therapy are unlike to produce harmful effects,

except at the most extreme dosage

6. as corticosteroid therapy is prolonged over periods of

weeks or months, with doses exceeding the equivalent of

substitution therapy, the incidence of adverse effects is

greatly increased

7. Committing a patient to long-term corticosteroid therapy

should be considered only when there is an undisputed

therapeutic indication or after other therapeutic measures

have failed

8. The lowest effective dose should be prescribed for the

shortest possible time. Moderation of symptoms with

minimal untoward effects is preferable to complete

palliation with major complications

9. in stable treatment programs, use of the alternate daydosage schedule should be considered. With this regimen,

unwanted effects are fewer and less severe

10. Abrupt cessation of prolonged, high dosage

corticosteroid therapy is associated with significant risk of

adrenal insufficiency that can be threatening to life


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11. Patients who have received cortisone 50 mg or more per

day (or equivalent amount of other corticosteroids) for more

than one month should be considered to have some degree of

pituitary adrenal suppression for at least one year after

corticosteroid withdrawal

12. except in adrenal insufficiency, the administration of

corticosteroids is neither an etiological nor a curative

therapy but only a symptomatic one

Mineralocorticoids

Mechanism of action:

A mineralocorticoid receptor is present in the cytoplasm of

target cells and regulation of gene expression is the same as

described for glucocorticoids.

Pharmacological effects:

1. Stimulation of absorption of Na+ in:

* Distal renal tubules (the main effect)* Salivary glands


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* Gastrointestinal mucosa

* Across cell membranes in general

2. Increased renal excretion of of K+ and H+

Members:

*Aldosterone: plasma half life is 20 min

* DOC and fludrocortisone : plasma half life is 1.5 hrs

Therapeutic uses:

1.Acute adrenal insufficiency

2. Chronic adrenal insufficiency (Addisons disease)

In both cases, cortisone must always be given concomitantly)

Adverse effects:

1.Hypernatremia

2. Hypervolemia

3. Hypokalemic alkalosis

4. Hypertension5. Rare side effects in the form of:

* Mood changes

* Hyperglycemia

Symptoms of hypokalemic alkalosis:

1.Episodic weakness

2. Paralytic ileus

3. Paresthesias

4. Transient paralysis and tetany


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Regulation of aldosterone secretion:

Aldosterone secretion can be stimulated by 4 main factors:

1. The increased concentration of K+ in the extracellular

fluid (small changes in K+ conc. Can increase aldosterone

secretion several fold).

2. The activation of the rennin-angiotensin system (the

system can be activated by a decrease of mean arterial

pressure, renal blood flow, or plasma Na+ conc.).

3. The decreased conc. Of Na+ in the extracellular fluid (this

stimulation is not dependent on activation of RAS

4. ACTH (stimulation is modest and not sustained for more

than a few days in normal subject)

N.B. the first two factors are by far the most important.

Glucocorticoid inhibitors and antagonists

A. Glucocorticoid synthesis inhibitors:

Mitotane:

1.Irreversible inhibition of several steps of steroidogenesis.2. Adrenocortical necrosis

3. Used clinically in inoperable adrenal carcinoma

Metyrapone

1. Reversible blockade of 11B-hydroxylase enzyme leading

to inhibition of both cortisol and aldosterone synthesis

2. Used clinically in severe cushings syndrome and in tests

of adrenal function

Aminoglutethimide


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1. Reversible blockade of conversion of cholesterol to

pregnenolone leading to inhibition of production of of all

adrenal steroids

2. Used clinically in Cushings syndrome and in

ovariectomized women with metastatic breast cancer to

eliminate adrenal estrogen production

Ketoconazole (high doses)

1. Reversible blockade of several steps of steroidogenesis

requiring cytochrome P450 enzymes

2. The drug of choice when a reversible inhibition of steroid

production is needed.

Trilostane

3B-17hydroxysteroid dehydrogenase inhibitor that

interferes with the synthesis of adrenal and gonadal

hormones and is comparable to aminoglutethimide

B. Receptor antagonists

Mifepristone (high dose)

1. Blockade of glucocorticoid receptor

2. Also, it is an antiprogestin

Spironolactone

1. Blockade of mineralocorticoid receptor

2. Used clinically in hyperaldosteronism and hirsutism in

women


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PHARMACOLOGY-III

PHL- 452 (2 + 0)

SECOND LECTURE

Ovarian Hormones and Inhibitors

Objectives:After listening to the lecture (s), and studying the textbook the student shoud be able

to:

1. List natural and synthetic estrogens available for clinical use

2. Explain the mechanism of action of estrogens

3. Describe the effects of estrogens upon different organ systems

4. Outline the main clinical uses &contraindications of estrogens

5. Explain the benefits and hazarsds of postmenopausal estrogen

6. List the progestins available for clinical uses

7. Describe effects of progesterone upon different organ systems

8. Explain how various progestins differ one from another

9. Outline main clinical uses and contraindications of progestins

10. Describe different types of hormonal contraceptives

11. Explain mechanisms of action of hormonal contraceptives

12. Describe main adverse effects of hormonal contraceptives

13. List absolute & relative contraindication of contraceptives


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14. Outline the benefit of hormonal contraceptives

15. Describe the effects, mechanism of action and clinical uses of

antiestrogens

16. Describe the effects, mechanism of action and clinical uses of

antiprogestins

Ovarian Hormones

1. Estrogens (Estradiol, Estrone, Estriol).

2. Progestins (Progesterone).

3. Others (Androgens, Inhibin, Activin).

Secretion of ovarian hormones:

1. Estrogens and progestins are produced by the ovary, placenta,

adrenals, and testes.

2. Several tissues can produce estrogens from testosterone.

3. Androgens are produced in small amounts by the ovary.


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4. Inhibin and activin are powerful inhibitor and stimulator of

FSH biosynthesis and secretion and are produced by the ovary.

5. In the ovary, theca and granulose cells secrete estrogens while

corpus luteum cells secrete progesterone.

Classification of Estrogens:

1. Natural Estrogens:

Estradiol

Estrone

Estriol.

2. Synthetic (steroidal)

Ethinylestradiol

Mestranol.

3. Synthetic (nonsteroidal)

Diethylstilbestrol

Dienestrol.

Advantages of synthetic estrogens over the natural products:

1. Greater oral bioavailability

2. Longer duration of action


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Classification of Progestins:

1.Progesterone derivatives:

Progesterone

Hydroxyprogesterone,

Medroxyprogesterone

Megesterol.

2. Nortestosterone derivatives

Norethindrone

Norethindrone acetate

Norethynodrel

Norgestrel

L-Norgestrel.

Synthetic progestins differ from progesterone in:

1. The degree of androgenic and estrogenic activity.

2. The effects on protein, salt and water metabolism

3. The degree of inhibition upon gonadotropin secretion.

4. The extent of oral bioavailability.


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Mechanism of action of estrogens:

1. Specific estrogen receptors are located in the cytoplasm in a

complex with heat-shock proteins.

2. Estrogen response elements (EREs) are present on the DNA of

estrogen target cells.

3. The ultimate effect of the hormone-receptor interaction in an

activation of gene transcription.

Mechanism of action of progestins:

1. Specific progesterone receptors are located in the cytoplasm

in a complex with heat-shock proteins.

2. Progesterone response elements (PREs) are present on the

DNA of progesterone target cells.

3. The ultimate effect of the hormone-receptor interaction in an

activation of gene transcription.


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Pharmacodynamics of estrogen and progesterone:

I. Genital system effects of estrogen:

A. Estrogen at puberty:

Stimulation of the development of vagina, uterus, uterine tubes.

B. Estrogen after puberty:

1. Stimulation of endometrial growth during the first 10-12

days of menstrual cycle.

2. Increased uterine blood flow.

3. Decreased viscosity and increased alkalinity of cervical

mucus.

4. Sensitization of the uterus to the action of progesterone and

oxytocin.

5. Continuous and prolonged exposure to estrogens leads to

abnormal endometrial hyperplasia and bleeding.

C. Progesterone:

1. Stimulation of endometrial secretion during the last 10-14

days of menstrual cycle.

2. Increased viscosity of cervical mucus.

3. Decreased sensitivity of the uterus to the action of estrogens

and oxytocin.


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II. Effects on breast, skin and appendages:

A. Estrogen at puberty:

1. Development of ductal and stromal growth of the breast.

2. Control of growth of the axillary and pubic hair.

3. Stimulation of skin pigmentation in nipples areolae and

genital region.

4. Control of distribution of subcutaneous fat.

B. Estrogen after puberty:

Maintenance of the normal structure of female skin

C. Progesterone:

Development of alveolobular and secretary apparatus of thebreast during puberty or pregnancy.


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III. Locomotor system effects:

A. Estrogen

1. Stimulation of female epiphysis closure of the long bones at

puberty.

2. Maintenance of bone mass in

Postmenopausal women due to:

* Inhibition of bone resorption.

* Slight stimulation of bone formation.

* Increased production of calcitriol by the

Kidney due to increased levels of 1-

Hydroxylase.

B. Progesterone:

No effect.

IV. Cardiovascular effects:

A. Estrogen

Maintenance of normal structure and function of blood vessels

in women.

B. Progesterone

No effect.

V. Metabolic effects:

A. Estrogen

1. CH metabolism:


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Mild decrease in glucose tolerance.

2. Lipid metabolism:

Increased concentration of HDL and plasma triglycerides,

Decreased concentration of LDL and cholesterol.

3. Protein metabolism:

Increased circulating levels of plasma globulins and slight

positive nitrogen balance.

4. Salt and water metabolism:

salt and water retention (the moderate fluid retention in the

latter half of the menstrual cycle).

B. Progesterone

1. CH metabolism:

* Increased basal insulin levels, * Increased glycogen storage.

* No change, or decrease, in glucose tolerance.

2. Lipid metabolism:* Reduction of HDL. * Stimulation of fat deposition.


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3. Protein metabolism:

Decreased circulating levels of amino acids (negative nitrogen

balance).

4. Salt and water metabolism:

Decreased salt and water reabsorption by the kidney due to

inhibition of aldosterone effects.

VI. Endocrine system effects:

A. Estrogen

1. Inhibition of FSH secretion and LH secretion (if constant

and sufficiently high doses are given).

2. Stimulation of FSH and LH secretion (if a suitable dose is

given at midcycle).

3. Induction of synthesis of progesterone receptors.4. Stimulation of cortical secretion.

B. Progesterone

Decreased frequency and increased amplitude of pulses of LH

release from the pituitary.

VII. Gastrointestinal effects:

A. Estrogen

1. Reduction of motility of the bowel.

2. Alteration of liver function.

3. Increased production of the bile.

4. Increased viscosity of the bile.


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5. decreased intestinal absorption of folates.

B. Progesterone :

No effect.

VIII. Central nervous system effects:

A. Estrogen

1. Increased cortical excitability.

2. Stimulation of estrous behavior, in animals.

3. Various influences on feminine behavior, in humans.

B. Progesterone

1. Decreased cortical excitability.

2. Stimulation of thermoregulatory center in the hypothalamus

(increased body temperature).

3. Increased sensitivity of respiratory center to CO2

(stimulation of respiration).

IX. Hematological effects:

A. Estrogen

1. Increased circulating levels of factor II, V, VII, VIII, IX, X,and XII.

2. Decreased circulating levels of antithrombin III.

3. Increased platelet aggregation

B. Progesterone:

No effect.


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X. Carcinogenic and anticancer effects:

A. Estrogen

1. Carcinogenic effects in animals.

2. Increased incidence of certain tumors in humans.

3. Anticancer effects in some hormone-dependent tumors.

B. Progesterone:

No effect.

Therapeutic uses

A. Estrogen

1. Postmenopausal hormone replacement results in:

* Reduction in myocardial infarction.

* Reduction in fatal strokes.

* Relieve of hot flushes, sweating and insomnia.* Decreased atrophic changes of vagina and vulva.

* Reduction of bone fractures

2. Hormonal contraception in combination with progestins.

3. Dysmenorrhea and menorrhagia in combination with

progestins.


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4. Amenorrhea and hirsutism (due to excessive secretion of

androgen from the ovary or adrenal).

5. Prostatic cancer (the therapeutic effect is due to suppression

of androgen production).

B. Progesterone

I. Diagnostic uses

As a test for estrogen secretion

Withdrawal bleeding after 5-7 days of progesterone therapy

occurs only when the endometrium has been stimulated by

estrogens).

II. Therapeutic uses1. Hormonal contraception in combination with estrogens.

2. Endometriosis: the beneficial effects after 6-9 months of

treatment, fertility returns in 50% of cases).

3. Dysmenorrhea combined with estrogens.

4. To increase fertility in women with inadequate luteal

response to gonadotropins.


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5. Prostatixc carcinoma (megestrol).

6. Advanced breast and endometrial carcinoma (megestrol,

palliative therapy).

Contraindicationa and cautions of estrogen:

1. Estrogen-dependent neoplasms.

2. Endometriosis.

3. Liver disease.

4. Gallbladder disease.

5. Undiagnosed vaginal bleeding.

6. History of thromboembolic disorders.

7. Coronary artery disease.

8. Severe hypertension.

9. Depressive disorders.

10. Migraine.


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11. Severe diabetes.

12. Porphyria.

13. Smoking.

14. Pregnancy.

Contraindicationa and cautions of estrogen:

1. Breast carcinoma except for palliative therapy.

2. Cerebrovascular disease.

3. Undiagnosed vaginal bleeding.

4. Cervical carcinoma.

5. Pregnancy.

6. Cardiac disease.

7. Hepatic disease.

8. Severe hypertension.

9. Serious hyperlipidemia.

10. All contraindications of estrogens for the compounds that

have estrogenic activity.


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11. All contraindications of androgens for the compounds that

have androgenic activity.

Drug G.I. P E A

Progesterone derivatives:

Progesterone + 1 0 0

Medroxyprogesterone + 2 0 0

Megestrol + 3 0 0

Nortestesterone derivatives:

Norethindrone ++ 2.3 + ++

Norethindrone acetate ++ 3.7 + ++

Norethynodrel + 2.7 ++ +

Ethynodiol acetate ++ 20 ++ 0

Levo-norgesterel ++ 40 0 +

G.I. = Gonadotropin inhibition.

P = Progestational activity (potency relative to progesterone).

E = estrogenic activity.

A = Androgenic activity.


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Hormonal contraceptivesHormonal contraceptive formulations:

A. Monophasic combination:

1. Estrogen (0.02-0.1 mg) + progestin (0.5-2.5 mg)

2. Ethinyl estradiol + Norethindrone

3. Mestranol + Norethynodrel.

B. Biphasic combination:

Ethinyl estradiol + Norethindrone

C. Triphasic combination:

Ethinyl estradiol + Norethindrone.

Combination tablets are the most frequently usedpreparation.

D. Daily progestin

Norethindrone, Norgestrel.

To be used when estrogens are contraindicated or

undesirable

E. Implantable preparation:

L-Norgestrel (6 tubes of 36 mg each).

The capsules slowly release their content over 5 years.

F. Postcoital administration:

Administered within 72 hrs of coitus.

1. High dose of Ethinyl estradiol

(owing to the high dose used, nausea and vomiting,

headache, dizziness and abdominal cramps are common).


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2. Ethinyl estradiol + norgestrel (to be repeated 12 hrs late

r, failure rate = 1%).

3. Mifepriston e (failure rate 0.5%).

Mechanism of action of hormonal contraceptives:

1. Inhibition of ovulation due to the direct negative feed-back at the hypothalamus where they inhibit GnRH

secretion and at the pituitary gland where estrogens mainly

inhibit FSH secretion and progestins mainly inhibit LH

secretion. Progestins alone do not always inhibit ovulation.

2. Changes in cervical mucus (the increased viscosity may

decrease sperm penetration).

3. Changes in motility of the uterine tubes which may speed

up the tubal transport of the ovum so decreasing the time

available for fertilization in the tubes.

4. Histological and functional changes of the endometrium

which can prevent egg nidation


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Adverse effects of estrogen-progestin combination pill

1. Represent the algebraic sum of the effects of each.

Because of this, some effects cancel each other as the effects

on lipid metabolism and or the risk of endometrial cancer).

2. The risk of many adverse effects increases by increasing

the dose or the duration of treatment.

3. Low-dose preparations pose minimal health risk in

women who have no predisposing risk factors,

4. The existence of an increased risk of some potentially

serious adverse effects as breast cancer, uterine cervical

cancer is still controversial but it seems that a small increase

in the incidence of these tumors may occur with long-term

use.


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Mild or moderate adverse effects of hormonal

contraceptives:

A) Mainly due to the estrogen in the preparation:

1. Galactorrhea.

2. Cholelithiasis.

3. Endometrial hyperplasia.

4. Vaginal infection.

5. Nausea, vomiting, abdominal pain.

6. Headache, worsening of migraine.

7. Fluid retention, edema.

8. Megaloblastic anemia.

9. Increased skin pigmentation (chloasma).

B) Mainly due to the progesterone in the preparation:


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1. Breakthrough bleeding.

2. Weight gain.

3. Acne, hirsutism, alopecia.

4. Prolonged amenorrhea following pill cessation.

C) Due to estrogen and progestin in the preparation:

1. Mastalgia, breast tenderness.

2. Lack of withdrawal bleeding.

3. Impaired glucose tolerance.

4. Altered lipid metabolism.

5. Urticaria, maculopapular rash.

Severe adverse effects:

1. Venous thromboembolic disease (E):

the risk is three-fold higher than in normal population).


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2. Myocardial infarction (E) (P)

The risk is negligible in women below 35 who do not smoke,

but there is a small increase in risk in women over 35 who

smoke or have other risk factors.

3. Cerebrovascular disease (E)

There is a small increase in risk in women over 35 who

smoke.

4. Hypertension (E) (P).

Three to six-fold increase in the incidence of hypertension in

women taking oral contraceptives.

5. Hepatic and gallbladder disease (E).

Jaundice, cholecystitis, cholelithiasis, hepatic adenomas.

6. Ocular disorders (E)

Retinal thrombosis, optic neuritis, diplopia, loss of vision.

7. Depression (E) (P)

Depression may be of sufficient degree to require cessation

of treatment.

8. Cancer (E) (P).

Small increase in risk of hepatic carcinoma.

Increased risk of breast cancer and uterine cervical cancer

in women without risk factors is questionable.

9. Fetal malformations (E) (P).

The risk is increased when the hormonal contraceptives are

taken during pregnancy.

Absolute contraindications of hormonal contraceptives:

1- Presence or history of cerebrovascular disease.

thromboembolic disease, myocardial infarction andcoronary artery disease.


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2- Serious congenital hyperlipidemia.

3- Known or suspected cancer of the breast, carcinoma of

the female reproductive tract or other hormone dependent /

responsive neoplasms.

4- Optic neuritis.

5- Known or suspected pregnancy

6- Past or present liver tumors or impaired liver function.

7- Adolescents in whom epiphysial closure has not been

developed.

Relative contraindications of hormonal contraceptives:

1. Migraine headache.

2. Diabetes mellitus.

3. Hypertension.

4. Congestive heart failure.


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5. Jaundice.

6. Depressive disorders.

7. Uterine fibrosis.

8. Gallbladder disease.

9. Heavy smoking (more than 15 cigarettes per day).

10. Surgery (Discontinuation of oral contraceptives for

several weeks is recommended).

Health benefits of hormonal contraceptives:

1- Significant reduction of ovarian and endometrial cancer

within 6 months of use. This protective effect persists for up

to 15 years after discontinuation of oral contraceptive use.

2- Significant decrease of ovarian cysts and benignfibrocystic breast disease.

3- More regular menstruation.

4- Reduced menstrual blood loss.

5- Less menstrual tension.

6- Decreased frequency of dysmenorrheal.


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7- Decreased incidence of pelvic inflammatory disease and

endometriosis.

8- Decreased risk of thyroid disease.

9- Avoided risk of unwanted pregnancy.

Antiestrogen Compounds

Tamoxifen and clomiphene


1. Both act as competitive partial agonists with weak activityat estrogen receptors.

2. Tamoxifen seems also to act as agonist at estrogen

receptors in bone so reducing osteoporosis.

Pharmacodynamics:

1. Estrogen action is diminished both along the

hypothalamic-hypophyseal axis and in peripheral tissues.

2. Secretion of GnRH, gonadotropins and estrogens isincreased.


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Pharmacokinetics:

Half-lives: Tamoxifen = 7 days, Clomiphene = 5 days.

Toxicity:

1. Hot flushes.

2. Nausea, vomiting.

3. Headache.

4. Vaginal bleeding.

5. Nervous tension.

6. Ovarian enlargement, ovarian cysts (clomiphene).

7. transient worsening of symptoms of breast cancer (flare

reaction).

8. The incidence of multiple pregnancy (clomiphene) is

about 10%.

Therapeutic uses:1. To treat estrogen-dependent tumors of the breast

(Tamoxifen and clomiphene), the effects result from

estrogen receptor blockade).

2. To treat infertility due to anovulation in women with an

intact hypothalamic-pituitary-ovarian axis. The stimulation

of ovulation is due to the increase in the amplitude of FSH

and LH pulses by blocking the inhibitory effect of estrogenon hypothalamus and pituitary (Clomiphene).

Antiprogestins: Mifepristone.



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It acts as competitive antagonist at both progesterone and

glucocorticoid receptors.

Pharmacodynamics:

1. Inhibition of ovulation by blocking hypothalamic-

pituitary progesterone receptors which suppresses midcycle

gonadotropin release

2. During the luteal phase inhibition of progesterone actions

upon the uterus, which leads to PG release from the

endometrium.

3. Termination of pregnancy by facilitating luteolysis,menstruation, uterine motility and detachment of the embryo.

Half-life:

20-40 hours.

Adverse effects:

1. Nausea, vomiting, diarrhea, abdominal pain.

2. Vaginal bleeding.

Therapeutic uses:

1. As an abortifacient (either alone or in combination with

an oral oxytocic PG).

2. As a postcoital contraceptive.

3. To induce labor after fetal death.

4. In progesterone-sensitive tumors (investigational).


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PHARMACOLOGY III

PHL-452 (2 + 0)

THIRD LECTURE

Gonadotropin releasing hormone (GnRH) &

Gonadotropins

Objectives:

After listening to the lecture (s), and studying the textbook the student shoud be ableto:

1. Describe the mechanism of action, effects , and diagnostic

and therapeutic uses of GnRH

2. List the main synthetic analogues of GnRH

3. Describe the mechanism of action, effects, and diagnostic

and therapeutic uses of gonadotropins

4. List the main gonadotropin preparations available for

clinical uses


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5. Describe the mechanism of action and effects of prolactin

6. List the main factors that influence prolactin secretion in

humans

7. Describe the mechanism of action, effects, and therapeutic

uses of bromocriptine

Gonadotropin releasing hormone (GnRH)

Members:

1. Human GnRH (Gonadorelin) (decapeptide)

2. Synthetic analogues:

Leuprolide

Nafarelin.

Buserelin.

Goserelin

Histrelin.

1. GnRh: t1/2: 4 min. Administered IV by IV portable

pump.


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2. Synthetic analogues: t1/2: 3 hours, administered

intranasal, IM, SC (depot formulations).


Activation of a receptor on gonadotroph pituitary cells

increases the production of cAMP which in turn stimulates

exocytotic release of FSH and LH but inhibits the release of

prolactin

Therapeutic uses:

1. Pulsatile IV administration (every 1-4 hours) stimulates

FSH and LD secretion. So, they are use to achieve a gonadal

stimulation in hypogonadotropic hypogonadism in both

sexes and Cryptorchidism.

2. Continuous administration (IV infusion, depot

formulation) inhibits FSH and LH secretion (due to receptordesensitization or down-regulation). So, they are used to

achieve a gonadal suppression. (A temporary biochemical

castration can be useful in case of:

1- Prostate cancer.

2- Breast cancer (estrogen positive).

3- Uterine fibrosis.


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4- Endometriosis.

5- Polycystic ovarian syndrome.

6- Precocious puberty in children.

Adverse effects:

1- Hot flushes.

2- Headache.

3- Initial worsening of bone pain in patients with prostate

cancer.

3- When used for gonadal suppression these drugs can cause

all adverse effects related to hypoestrogenism in females and

hypotestosteronism in males.


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Gonadotropins

1. Protein hormones secreted by gonadotrophe cells of the

pituitary gland of vertebrates.

2. The principal gonadotropins are LH and FSH

3. Both hormones consist of two peptide chains, an alpha

chain and a beta chain linked by disulfide bonds.

4. LH and FSH share nearly identical alpha chains, while the

beta chain provides specificity for receptor interactions.

5. A third gonadotropin is human chorionic gonadotropin

(hCG) produced by the placenta during pregnancy.

6. Gonadotropins are released under the control of GnRH

from the arcuate nucleus of the hypothalamus.

7. The gonads testes and ovaries are the primary target

organs for LH and FSH.

8. LH stimulates the Leydig cells of the testes and the theca

cells of the ovaries to produce testosterone and indirectly

estradiol, while FSH stimulates the spermatogenic tissue of

the testes and the granulose cells of ovarian follicles.

9. Gonadotropin deficiency due to pituitary disease results in

hypogonadism.


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10. Failure or loss of the gonads usually results in elevated

levels of LH and FSH in the blood.

Members:

1- Natural hormone: FSH and LH (glycoproteins in nature)

2- Human menopausal gonadotropins (hMG)

Obtained from the urine of menopausal women

3- Menotropins: mixture of FSH and LH

4- Urofolitropin: contains only FSH.

5- Human chorionic gonadotropin (hCG)

* Produced by human placenta.

* Extracted from urine.

* Structure and actions are very similar to LH

6. FSH and LH: half life = 2 hours.

HCG: half-life = 6 hours.

Administration routes: IM, SC.


FSH and LH activate a specific receptor located only on

gonadal tissue. This activation increases the synthesis of

cAMP which in turn stimulates the cAMP-dependent

protein kinase activity.


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Pharmacodynamics:

1. In men:

1- FSH stimulates spermatogenesis.

2- LH stimulates Leydig cells to produce testosterone.

2. In women:

1- FSH stimulates:

* Gametogenesis.

* Follicular development.

* Ovarian steroidogenesis.

2- LH stimulates:

* Follicular development.

* Induction of ovulation.

* Stimulation of corpus luteum to produce progesterone and

androgens.

Therapeutic uses:

1. in women to induce ovulation in case of sterility due to

pituitary insufficiency.

2. in men to achieve fertility in case of hypogonadotropic

3. Diagnostic use:


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In prepuberal boys to distinguish a truly retained testis (no

testicular descent during therapy) from a retracted one

(testis descends during therapy).

Adverse effects of Gonadotropins:

1- Simple ovarian enlargement.

2- Hyperstimulation syndrome consists of:

* Ovarian enlargement.* Hydrthorax.

* Hypovolemia.

3- Rupture of ovarian cyst (rare).

4- Thromboembolism (rare).

5- Spontaneous abortion.

6- Gynecomastia.

PHARMACOLOGY III

PHL-452 (2 + 0)

Fourth LECTURE

Prolactin & Fertility Drugs


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1. Prolactin is a peptide secreted by mammotroph cells of

pituitary gland.

2- Somatomammotropin:

* Placental lactogen.

* Similar to prolactin and Gh.

* produced by placenta.

* secreted into amniotic fluid.

What is Prolactin?

1. Prolactin is a chemical that is secreted by pituitary gland.

This is the pea-sized gland found in the middle of the brain,

which is responsible for triggering many of body's processes.

2. Prolactin is found in both men and women and is released

at various times throughout the day and night.

3. Prolactin is generally released in order to stimulate milk

production in pregnant women. It also enlarges a women's

mammary glands in order to allow her to prepare for

breastfeeding.

Pharmacodynamics:

1. Prolactin stimulates mammary tissue growth and milk

production when appropriate levels of estrogens, progestins,

corticosteroids and insulin are present.


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2. Prolactin inhibits ovulation by decreasing the frequency

and amplitude of LH pulses.

Hormones that affect Prolactin:

1. The release of prolactin is triggered by other hormones as

dopamine, serotonin, thyroid-producing hormone.

2- When a woman becomes pregnant, prolactin changes arecompletely normal. prolactin must increase in order to

encourage the production of milk in mammary glands.

During pregnancy, estrogen levels begin to rise and this

what stimulates the increase in prolactin levels. After birth,

as baby breastfeeds, nipple stimulation will trigger a further

increase in prolactin. Prolactin is what allows to continue

breastfeeding for an extended period of time.

Prolactin and infertility:

1. Prolactin increases milk production.

2. It also affects ovulation and menstrual cycles, this is why

it is nearly impossible to become pregnant when you are

breastfeeding.


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3. In fact, prolactin is 90% effective against pregnancy in the

first months after birth.

4. Prolactin inhibits two hormones necessary to ovulation,

FSH and GnRH. Both hormones are responsible for helping

the eggs to develop and mature in the ovaries, so that they

can be released during ovulation.

5. when the woman has excess prolactin in bloodstream,

ovulation is not triggered and she will be unable to become

pregnant.

6. Prolactin may also affect menstrual cycle and the

regularity of periods.

Difficulties in pregnancy may be attributed to irregularity in

prolactin levels. Elevated prolactin can inhibit ovulation and

menstruation.

7. Normal prolactin level in women is between 30 and 600

mIU/L.

Types of irregularities:

1. Galactorrhea: a condition in which the woman begins to

produce milk spontaneously, without being pregnant or

having given birth recently. It is a result of high prolactin

levels. Other symptoms include: enlarged breasts, painful or

tender breasts, irregular menstruation, loss of sex drive,

infertility.


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2. Hyperprolactinemia: too much prolactin in the blood.

Symptoms of high prolactin levels include: prolactin levels at

or abve 600 mIU/L, infertility, irregular menstruation,

headache, reduced sex drive.

3. Prolactinoma: Prolactinoma causes a tumor to grow on

the pituitary gland. It secretes excess prolactin into the body.

4. Some drugs can cause excess secretion of prolactin. Some

anti-depressants, painkillers, and opiates block dopamine,

preventing prolactin secretion from being inhibited. This

can cause prolactin levels to rise.

5. Other more rare causes of prolactin irregularities

include:thyroid disease, polycystic ovarian syndrome

(PCOS).

Bromocryptine and Pergolide


1- Direct activation of D-receptors in mammotroph cells of

the pituitary.

2- Decreased dopamine turnover in the arcuate nucleus

which in turn increases dopamine levels.

Effects of Bromocryptine:


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1- Reduction of plasma prolactin levels within hours from

administration.

2- Stimulation of GH release in normal subjects

3- Blockade of GH release in acromegalic ones

Therapeutic uses:

1- Physiologic lactation to prevent breast engorgement when

breast feeding is not indicated.

2- Prolactin-secreting adenomas (unfortunately expansion ofthe tumor occurs if the drug is discontinued).

3- Idiopathic hyperprolactinemia and associated

dysfunctions as amenorrhea, galactorrhea, infertility).

4- Parkinsson's disease.

5) Acromegaly (still investigational).

6- Cocaine withdrawal (still investigational)

Adverse effects:

1- Dyspepsia, anorexia, nausea and vomiting.

2- Postural hypotension, cardiac dysrhythmias, vasospasm(after long term use).

3- Headache, insomnia, confusion.

Fertility drugs

Drugs that induce, enhance, or regulate ovulation.


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1. FSH is an injected fertility medication that stimulates andsupports the development of multiple eggs.

2. Clomid: can establish normal ovulation in some women.

3. Metformin: is an effective fertility drug for lowering insulinlevels in some women with PCOS. Normalizing insulin levelsallows normal ovulation to occur.

4. Human chorionic gonadotropin (hCG) is an injectedhormone used to induce ovulation.

5. Progesterone is used to promote the development of theendometrium to adequately support the growing embryo.

6. Corticosteroids sometimes are used to treat immunedisorders that can cause the production of antispermantibodies.

7. Antibiotics are used to treat reproductive tract infectionsin male and female.8. Medications that may be used to treat diseases that canaffect fertility such as insulin for diabetes.

PHARMACOLOGY III

PHL-452 (2 + 0)

FIFTH LECTUREThyroid Hormones & Antithyroid drugs

Thyroid gland

The thyroid gland is located in the front of the neck attached

to the lower part of the voicebox (or larynx) and to the

upper part of the windipipe (or trachea). It has two sides or

lobes. These lobes are connected by a narrow neck (or

isthmus). Each lobe is about 4cm long and 1 to 2cm wide.

The thyroid gland produces thyroid hormones. These

hormones are peptides containing iodine. The two important

hormones are tetraiodothyronine (thyroxine or T4) and


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triiodothyronine (T3). These hormones are essential for life

and have many effects on body metabolism, growth, and

development.

Thyroid Gland facilitates normal growth and maturation by

maintaining the level of metabolism in the tissues that is

optimal for their normal function.

2. The two major thyroid hormones are

T3 (triiodothyronine, the most active form), and T4

(thyroxine).

3. Inadequate secretion of thyroid hormone

(hypothyroidism) results in bradycardia, poor resistance to

cold, and mental and physical slowing (in children, this can

cause mental retardation and dwarfism).

If an excess of thyroid hormones is secreted

(hyperthyroidism), tachycardia and cardiac dysrhythmias,

body wasting, nervousness, tremor and excess heat

production can occur.

In mammals, the thyroid gland also secretes the hormone

calcitonin, a serum calcium- lowering hormone.

Iodine

Plays an important role in the function of the thyroid

gland.It is the chief component of thyroid hormones, and is

essential for their production. Iodine is obtained from the

water we drink and the food we eat. In areas where ther is

an iodine deficiency, iodine must be added to the salt or

bread.Taking excess amounts of iodine in foods will

aggravate autoimmune thyroid disease.


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Hypothalamic-Pituitary-Thyroid Axis

The throid gland is influenced by hormones produced by

two other organs:

1-The pituitary gland, located at the base of the brain,produces thyroid stimulating hormone (TSH).

2- The hypothalamus, a small part of the brain above the

pituitary, produces thyrotropin releasing hormone (TRH).

3. Low levels of thyroid hormones in the blood are detected

by the hypothalamus and the pituitary, TRH is released,

stimulating the pituitary to release TSH, increasing levels ofTSH, in turn stimulates the thyroid to produce more thyroid

hormone in the blood back to normal.

Thyroid disorders:

1. Too much thyroid hormone production or

hyperthyroidism.

2. Too little thyroid hormone production or hypothyroidism.

3. The state of normal thyroid function is called euthroidism.

Graves' Disease or thyrotoxicosis

Due to a unique antibody called thyroid stimulating

antibody which stimulates the thyroid cells to grow largerand to produce excessive amounts of thyroid hormones. In

this disease, the goiter is due not to TSH but to this unique

antibody.

Hashimoto's Thyroiditis

The goiter is caused by an accumulation of white blood cells

and fluid (inflammation) in the thyroid gland. This leads to

destruction of the thyroid cells and, eventually, throid


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failure (Hypothyroidism). As the gland is destroyed, thyroid

hormone production decreases; as a result, TSH increases,

making the even larger.

Thyroid Nodules

Sometimes, thyroid enlargement is restricted to one part of

the gland; the rest of the gland being normal. The most

common cause of this is a cyst or nodule, which may be

benign or malignant. Occasionally there are many nodules.

The so called " multinodular goiter" is probably caused by

mutations of follicular cells.

Common symptoms of hypothyroidism are:

1. Fatigue or lack of energy.

2. Weight gain.3. Feeling cold.

4. Dry skin and hair.

5. Heavy menstrual periods.

6. Constipation.

7. Slowed thinking.

Diagnosis

Patients with hypothyroidism due to Hashimoto's thyroiditishave an elevated level of serum TSH. However, the rare

patient with hypothyroidism due to a pituitary or

hypothalamic condition may have a normal or low serum

TSH

Treatment

Of hypothyroidism consists of taking thyroid hormone in pill

form on a daily basis. Symptoms of hypothyroidism shouldclear up within a few months of starting treatment.


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Adjustment of the dose of thyroid pills is based upon

measurements of serum TSH. Most patients need to take

thyroid hormone for life.

Common symptoms of hyperthyroidism are:

1- Increased nervousness or irritability.2- Rapid heart beat or palpitations.

3- Feeling hot.

4- Weight loss.

5- Fatigue, feeling exhausted

6- more frequent bowel movements.

7- Shorter or lighter menstrual periods.

8- Some patients with Graves' disease develop eye symptoms

as eye irritation, double vision or loss of vision.

Diagnosis:

1- Finding an elevated level of free T4 and low level of TSH

in the blood. A thyroid scan should then be performed to

determine whether the hyperthyroidism is due to

Graves'disease or another conditions such as toxic

multinodular goiter, hot nodule, subacute thyroiditis, or

silent thyroiditis.

Treatment

The popular method is radioactive iodine. The main side

effect is the development of an underactive thyroid.

Medications can also be used for treatment. These drugs

slow down the working of thyroid and restore normal levels.

However, they are usually needed to be taken for 6-12

months and 60-80% of patients have a relapse when they

stop taking them. These drugs are associated with serious


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side effects in a small percentage of patients taking them.

Surgical removal of a part of the thyroid is occasionally used

as a treatment.

Thyroid hormone synthesis and secretion

1. The thyroid gland is made up of multiple follicles that

consist of a single layer of epithelial cells surrounding a

lumen filled with colloid (thyroglobulin), the storage form ofthroid hormone.

2. The steps in thyroid hormone synthesis and secretion

involve the following:

1- Uptake of iodide ion.

2- Synthesis of thyroglobulin in the thyroid cell.

3- Iodination.

4- Condensation.5- Proteolytic release of hormones.

Regulation of synthesis:

1. Thyroid function is controlled by a tropic hormone,

thyroid-stimulating hormone (TSH, thyrotropin), a

glycoprotein synthesized by the anterior pituitary.

2. TSH generation is governed by the hypothalamic

thyrotropin-releasing hormone (TRH). TSH action is

mediated by cAMP and leads to stimulation of iodide

uptake.

3. Oxidation of iodine by a peroxidase is followed by

iodination of tyrosines on thyroglobulin.


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4. Condensation of two diiodotyrosine residues gives rise to

t4 or T3 still bound to the protein.

5. The hormones are released following proteolytic cleavage

of the throglobulin.

Regulation of secretion

1. Secretion of TSH by the anterior pituitary is stimulated

by the hypothalamic TRH.

2. Feedback inhibition of both TRH and TSH secretion

occurs with high levels of circulating thyroid hormone or

iodide.

3. Most of the hormone (T3 and T4) is bound to thyroxine-

binding globulin in the plasma.

Pharmacokinetics

1. Both T4 and T3 are absorbed after oral administration.

2. T4 is converted to T3 by one of two distinct deiodinases,

depending on the tissue.

3. T3 combines with a receptor to stimulate subsequent

protein synthesis necessary for normal metabolism.

4. The hormones are metabolized through the microsomal P-

450 system.

5. Drugs such as phenytoin, rifampin, Phenobarbital, that

induce the P-450 enzymes accelerate metabolism of thyroid

hormones.

Treatment of hypothyroidism

Hypothyroidism is treated with levothyroxine (T4). The

drug is given once daily because of its long half-life. Steady

state is achieved at 6-8 weeks. Toxicity is directly related to


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thyroxine levels and manifests itself as nervousness, heart

palpitations and tachycardia, intolerance to heat and weight

loss.

Treatment of hyperthyroidism (thyrotoxicosis)

1. Excessive amounts of thyroid hormones in the circulation

are associated with a number of disease states , including

Graves' disease, toxic adenoma, and goiter.

2. The goal of the therapy is to decrease synthesis and/or

release of additional hormone. This can be accomplished byremoving part or all of the thyroid gland, by inhibiting

synthesis of the hormones, or by blocking release of the

hormones from the follicle.

3. Removal of part or the entire thyroid can be accomplished

either surgically or by destruction of the gland by beta

particles emitted by radioactive iodine (131I), which is

selectively taken up by the thyroid follicular cells.


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Inhibition of throid hormone synthesis

1- The thionamides, propylthiouracil (PTU) and

methimazole are concentrated in the thyroid where they

inhibit both the oxidative processes required for iodination

of tyrosyl groups and the coupling of iodotyrosines to form

T3 and T4.

PTU can also block the conversion of T4 to T3.

** These drugs have no effect on the thyroglobulin already

stored in the gland; therefore observation of any clinical

effect of these drugs may be delayed until thyroglobulin

stores are depleted.

2. The thionamides are well absorbed from the GIT, but

they have short half-lives.

3. Several doses of PTU are required per day, whereas a

single dose of methimazole suffices due to the duration of its

antithyroid effect.

4. The effect of these drugs is slow in onset and thus they are

not effective in the treatment of thyroid storm.

5. Relatively rare adverse effects include agranulocytosis,

rash, and edema.


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6. B- Blockers as propranolol are effective in blunting the

widespread sympathetic stimulation that occurs in

hyperthyroidism.

Blockade of hormone release1. Pharmacologic dose of iodide inhibits the iodination of

tyrosines, thus decreasing the supply of stored

thyroglobulin.

Iodide also inhibits thyroid hormone release by mechanisms

not yet understood.

Today, iodide is rarely used as sole theapy. However, it isemployed to treat potentially fatal thyrotoxic crisis (thyroid

storm), or prior to surgery.

2. Since, it decreases the vascularity of the thyroid gland,

iodide is not useful for long-term therapy, because the

thyroid ceases to respond to the drug after a few weeks.

3. Iodide is administered orally.

Adverse effects are relatively minor and include sore mouth

and throat, rashes, ulcerations of mucous membranes, and a

metallic taste in the mouth.


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Thyroid hormone tests

1. Total thyroxine (T4).

Most of the thyroxine (T4) in the blood is attached to a

protein called the thyroxine-binding globulin. Less than 1%

of the T4 is unattached. A total of T4 blood test measures

both bound and free thyroxine. Free thyroxine affects tissue

function in the body, but bound thyroxine does not.

2. Free throxine index (FTI or FT4).

Free throxine (T4) can be measured directly (FT4) or

calculated as the free thyroxine index (FTI). The FTI tells

how much T4 is present compared to the thyroxine-binding

globulin. The FTI can help tell if abnormal amounts of T4

are present because of abnormal amounts of thyroxin-

binding globulin.

3. Triiodothyronine(T3)

Most of the T3 in the blood is attached to thyroxin-binding

globulin. Less than 1% of the T3 is unattached. A T3 blood

test measures both bound and free triiodothyronine. T3 has

a greater effect on the way the body uses energy than T4,

even though T3 is normally present in smaller amounts than

T4.

4. Thyroid-stimulating hormone )TSH)

Mesures the amount of TSH in the blood and is considered

the most reliable way to find a thyroid problem. If the TSH

test is abnormal, other thyroid hormone tests such as a T3 or

T4 may be done.


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5. Thyroid antibodies test

Measures the presence of antibodies against thyroid tissue.Antibodies may mean that you have an autoimmune disease

such as Hasimoto's thyroditis or Graves' disease.

6.Thyroxine-binding globulin (TBG) test

TBG is an important protein in the blood that carries the

thyroid hormones T3 and T4. TBG is not done very often.

7. Other tests used to investigate problems include: thyroid

scan, ultrasound or biopsy, Radioactive iodine uptake.

N.B. Because false positive results can occur when testing a

newborn for congenital hypothyroidism, the thyroid

hormone tests may be repeated a few days after initial

testing. If the results are still abnormal and congenital

hypothyroidism is suspected, additional testing is done.


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Antithyroid Drugs

Although the condition of hyperthyroidism can be controlled

with antithyroid drugs, the disease is not "cured" since the

drugs do not alter the underlying autoimmune mechanisms,

Furthermore; there is little evidence that these drugs affect

the course of the exophthalmoses associated with Graves,

disease.

1. Radioiodine

1. The first-line treatment for hyperthyroidism.

2. The isotope used is 131I.

3. Given orally, it incorporated into thyroglobulin.

* It emits both -particles and -rays. The -rays pass

through the tissue, but the -radiation has a very short

range and exerts a cytotoxic action restricted to the cells of

the thyroid follicles resulting in significant destruction.

4. Iodine-131 has a half-life of 8 days; by 2 months its

radioactivity has effectively disappeared.

It is used in one single dose, but its cytotoxic effect on the

gland is delayed for 1-2 months and does not reach its

maximum for a further 2 months.

5. Hypothyroidism will occur after treatment with

radioiodine particularly in patients with Graves' disease, but

it is easily managed by replacement therapy with thyroxine.

6. Radioiodine is best avoided in children and also in

pregnant patients because of potential damage to the fetus.


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7. The uptake of131I and other isotopes of iodine may be used

as a test of thyroid function. A tracer dose of isotope is given

orally or intravenously and the amount accumulated by the

thyroid is measured by a gamma scintillation counter placed

over the thyroid.

8. Because radioactive iodine takes several weeks to take its

full effect, thyroid tablets are also sometimes given until

such time as the full effect occurs. More often than this ,

patients end up hypothyroid due to the radioactive iodine,

and have to take thyroxine for life.

II- Thioureylenenes

1. Carbimazole, methimazole and propylthiouracil all are

related to thiourea.

2. The thiocarbamide group (S-C-N) being essential for

antithyroid activity.

3. Thioureylenes:

A) Decrease the output of thyroid hormones from the gland

B) Cause a gradual reduction in the signs and symptoms of

thyrotoxicosis, the basal metabolic rate and pulse rate

returning to normal over a period of 3-4 weeks.

4. Their mode of action is not completely understood, but

there is evidence that they inhibit the iodination of tyrosyl

residues in thyroglobulin. It is thought that they inhibit the

thyroperoxidase-catalyzed oxidation reactions by acting as

substrates for the postulated peroxidase-iodinium complex,

thus competitively inhibiting the interaction with tyrosine.


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Propylthiouracil has the additional effect of reducing the de-

iodination of T4 and T3 in peripheral tissues.

5. Thiourylenes are given orally. Carbimazole is rapidly

converted to methimazole. Methimazole is distributed

throughout the body water and has a plasma half-life of 6-15

hours.

6. The clinical response to methimazole and other

antithyroid drugs may take several weeks. This is not only

because T4 has a long half-life but also because the thyroid

may have large stores of hormone which need to be depleted

before the drug's action can be manifest.

7. Propylthiouracil is thought to act more rapidly because of

its effect in inhibiting peripheral conversion of T4 to T3.

8. Both methimazole and propylthiouracil cross the placenta

and also appear in milk but this effect is less pronounced

with propylthiouracil because it is more strongly bound to

plasma proteins. After degradation, the metabolites are

excreted in the urine, propylthiouracil being excreted more

rapidly than methimazole. The thioureylenes are not

concentrated in the thyroid.

9. Unwanted effects:

* Granulocytopenia (relatively rare and being reversible if

the drug is stopped).

* Rashes are more common.

* Other symptoms such as headaches, nausea, jaundice and

pain in the joints can occur


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III- Iodine/Iodide

1. Iodine is converted in vivo to iodide which temporarily

inhibits the release of thyroid hormones.

2. When high doses of iodine are given to thyrotoxic patients,

the symptoms subside within 1-2 days. There is inhibition of

the secretion of thyroid hormones and over a period of 10-14

days, a marked reduction in vascularity of the gland, which

becomes smaller and firmer.

3. Iodine solution in potassium iodide (Lugol's iodine) is

given orally. Its effect is reaches maximum within 10-15 days

and then decreases.

4. Iodine may inhibit iodination of thyroglobulin, possibly by

inhibiting the H2O2 generation that is necessary for this

process.

5. The main uses are for the preparation of hyperthyroid

subjects for surgery and as part of the treatment of severe

thyrotoxic crisis (thyroid storm).

6. Allergic reactions can occur. These include angio-edema,

rashes, drug fever, lacrimation, conjunctivitis, pain in the

salivary glands and a cold-like syndrome.

IV- Other drugs used:

1. The -adrenoceptor antagonists as propranolol

A) Useful for decreasing many of the signs and symptoms of

hyperthyroidism- the tachycardia, dysrhythmias, tremor

and agitation.

B) Used in preparation for surgery.


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C) Used for the initial treatment of most hyperthyroid

patients while the thioureylenes or radioiodine are taking

effect.

D) Used as part of the treatment of thyroid storm (acute

hyperthyroid crisis).

2. Guanethidine is used in eye drops to ameliorate the

exophthalmos of hyperthyroidism which is not relieved by

antithyroid drugs.

It acts by relaxing the sympathetically innervated smooth

muscle that causes eyelid retraction.

3- Glucocorticoids as prednisolone or surgical

decompression may be needed for the exophthalmia of

Graves' disease.

Summary:

1. Thyroid hormones are synthesized by iodination of

tyrosine residues on thyroglobulin within the lumen of the

thyroid follicle.

2. The thyroglobulin is endocytosed and thyroxine (T4) and

triiodothyronine (T3) are secreted.


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3. Synthesis and secretion of T3 and T4 are regulated by

TSH and influenced by plasma iodide.

4. T3 and T4 actions are:

A) To stimulate metabolism

B) Generally causing increased oxygen consumption and

increased metabolic rate

C) To influence growth and development.

5. within cells, the T4 is converted to T3, which interacts

with a nuclear receptor; the receptor represses basal

transcription when not bound to T3 and activates

transcription when bound.

6. Concerning T4:

A) There is a large pool of T4 in the body

B) It has a low turnover rate

C) Found mainly in the circulation

7. Concerning T3

A) There is a small pool of T3 in the body

B) It has a fast turnover rate

C) Found mainly intracellularly.

Drugs in thyroid diseases

Drugs for hyperthyroidism

1. Radioiodine

A) Given orally

B) Selectively taken up by thyroid and damages cells

C) It emits short-range -radiation, which affects only

thyroid follicle cells

D) Hypothyroidism will eventually occur.

2. Thioureylenes as propylthiouracil


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A) Decreases the synthesis of thyroid hormones

B) The mechanism is through inhibition of thyroperoxidase,

thus reducing iodination of thyroglobulion

C) They are given orally.

3. Iodine

A) Given orally in high doses

B) Transiently reduces throid hormone secretion

C) Decreases vascularity of the gland.

Drugs for hypothyroidism

1. Thyroxine has all the actions of endogenous throxine. It is

given orally.

2. Liothyronine has all the actions of endogenous

triiodothyronine given intravenously.

Important points about antithyroid drugs

1. Carbimazole

1. Used to treat hyperthyroidism

2. It prevents the peroxidase enzyme from coupling and

iodinating the tyrosine residues on thyroglobulin, hence

reducing the T3/T4.

3. Therapy for hyperthyroidism generally starts at a high

dose of 15-40mg continued until the patient has normal

thyroid function, and then reduced to a maintenance dose of

5-15mg. Treatment is usually given for 12-18 months

followed by a trial withdraw.

4. Rashes and pruritis are common and can often be treatedwith antihistamines without stopping carbimazole. For those


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patients where sensitivity reactions can bot be controlled,

propylthiouracil may be used as an alternative.

5. Serious side effects (although rare) is bone marrow

suppression causing neutropenia and agranulocytosis.

Patients are advised to report symptoms of infection

especially sore throat. In this case, a full blood count test

may be arranged. If this confirms a low neutrophil count

then the drug must be discontinued immediately, allowing

for a prompt recovery. Otherwise, fatalities may occur.

2. Propylthiouracil

1. Thionamide drug used to treat hyperthyroidism.

2. It is a medicine that is used to decrease the amount of

thyroid hormone produced by the thyroid gland. PTU

inhibits many steps in the synthesis of thyroid hormones,

including the addition of iodide to thyroglobulin by the

enzyme thyroperoxidase, a necessary step in the synthesis of

thyroxine, and by inhibiting the enzyme 5'-deiodinase which

converts T4 to T3.

3. PTU does not inhibit the action of sodium-dependent

iodide transporter located on follicular cells' basolateral

membranes. Inhibition of this step requires competitive

inhibitors as perchlorate and thiocyanate.

4. Side effects include agranulocytosis, allergic reactions,

whitening and loss of hair.


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3. Methimazole

1. Used to treat hyperthyroidism and taken before thyroid

surgery or radioactive iodine therapy to lower thyroid

hormone levels and minimize the effects of thyroid

manipulation.

2. Mechanism of action: exactly like propylthiouracil.

3. Side effects; the same as propylthiouracil

Important Questions:

Q1: Classify antithyroid drugs according to their

mechanism of action:

1. Drugs that interfere directly with thyroid hormone

synthesis: thiourea drugs (thionamides or thiocarbamides).

2. Drugs which block the iodide transport mechanism as K.

perchlorate.

3. Drugs which inhibit the release of thyroid hormones and

in large dose suppress the thyroid function as iodides.

4. Drugs which damage the gland with ionizing radiation as

radioactive iodine.

5. Drugs which impair the tissue response to thyroid

hormones as B-adrenoceptor blockers.

Q2: Mechanism of action of thiocarbamides e.g.

propylthiouracil:


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1- Inhibit iodide oxidation, iodine organification and

coupling of monoiodotyrosine and diiodotyrosine.

2. Divert peripheral conversion of T4 into rT3 and decrease

thyroid autoantibody levels

3. Their onset of action is slow (3-4 weeks) after T4 stores

become depleted.

Q3: Preparation and doses of thionamides in treatment of

hyperthyroidism

1. Propylthiouracil (300-600 mg/day), Methimazole and

carbimazole (30-60 mg/day) till euthyroid then maintains on

smaller doses.

2. Treatment is given for 1-2 years, then slowly withdrawn.

3. If relapse occurs, continue treatment.

Q4: Adverse reactions of thiocarbamides:

1. Maculopapular rash.

2. Arthralgia.

3. Jaundice.

4. Lymphadenopathy.

5. Nausea and vomiting.6. Drug fever.

7. The most serious is agranulocytosis or aplastic anemia.

8. Carbimazole and methimazole can cause goiter in fetus or

nursing infants of thyrotoxic mothers.

Q5; Mechanism of action of iodides in thyrotoxicosis:

1. Iodides act rapidly within 2-7 days but the effect can notbe maintained for more than few weeks.


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2. They inhibit the releaseof thyroid hormones.

3- They decrease the size and vascularity of hyperplastic

gland.

4. In large doses, they inhibit iodine organification.

Q6: Precautions during iodide therapy in hyperthyroidism:

1. Iodide should not be used alone.

2. Iodide should

pharmacology-iii 452 (2)

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