Mineralocorticoids

• They help to control body water and electrolytes, particularly sodium and potassium.

• The main endogenous Min Cor is ALDOSTERONE, which produced by Zona Glomerulosa in the adrenal medulla.

Aldosterone• The main actions are:

1.Increase in the Na+ reabsorption in the distal tubules of the kidneys.

2. Increase in excretion of K+ and H+ ions in the urine.

3. Increase in water and bicarbonate reabsorption.

It is stimulated by:It is stimulated by:

a. Low plasma sodium and high plasma potassium concentration.

b. Depleting the body Na+ activates renin-angiotensin system - increase in plasma angiotensin II level stimulates aldosterone level.

• Increase aldosterone level causes:

• Conn’s syndrome

1.Enhance sodium reabsorption by the renal tubule (site IV)

2.Potassium and hydrogen loss causing hypokalaemia and metabolic alkalosis.

3. Increase in total body Na++ and H2O leading to an increase in extracellular fluid volume and a rise in B.P.

Decrease in Decrease in aldosterone level aldosterone level causes:causes:

• Addison’s disease:1. Increase Na+ loss, which

is more pronounced than water loss.

2. Reduced the osmotic pressure in the extracellular fluid, resulting in a shift of fluids into intracellular compartment.

3. Decrease in the excretion of K+ resulting in hyperkalaemia.

Mechanism of action of Mechanism of action of aldosteronealdosterone

It binds to specific intracellular receptors in the kidneys ,colon and bladder, resulting in initiation of DNA transcription of specific proteins, resulting in an early increase in the number of sodium channels with a later an increase in Na+/K+-ATPase molecules.

• The increase K+ excretion produced by aldosterone results from influx of K+ into cell by the action of Na+/K+-ATPase .

• There is also an action on the Na+---H+ exchanger in the apical membrane on the Na+ influx.

• It is rapidly absorbed from the bowel.

•10% plasma bound.

• Undergo extensive first –

pass effect (only small amount reaches the circulation), so it cannot be given orally.

• Given IM

• Half-life 20 min

• Used in acute adrenal insufficiency.

• Has no place in routine therapy.

Fludrocortisone• Synthetic preparation

• Has glucocorticoid and minerCor. activity.

• Has very great Na+ retaining effect.

• Used to replace aldosterone

( Addisons disease).

• Drug of choice in patients with autonomic neuropathy , in whom volume expansion is easy to occur than a sustained increase in vasoconstrictor tone.

• Is active orally and has a longer

duration of action and more powerful than aldosterone.

• Half-life 90 min, given once daily.

• Used in adrenal failure.

Spironolactone• Is competitive antagonist of

aldosterone.

• It also prevent the minerCor. activity of other adrenal steroids on the renal tubules.

• Has antihypertensive effect by inhibiting Na+ reabsorption in the kidneys.

• Antagonize the synthesis of testosterone.

• Used in primary primary hyperaldosteronism,hyperaldosteronism, and as a diuretic in CCF and cirrhosis of the liver.

• Useful in the treatment of hirsutism in women( interfere at the androgen receptors of the hair follicles, and progesterone receptors).

Adverse effects1.1. GIT upsetGIT upset

2.2. Hyperkalemia.Hyperkalemia.

3.3. Gynecomastia Gynecomastia

4.4. Impotence.Impotence.

5.Menstrual irregularities

6. Skin rash.

7. Headache, confusion

8. High K+ and low Na+

9. Hepatotoxicity(. Osteomalacia.

EplerenoneSelective blocker of aldosterone at mineralcorticoid receptor.

Aldosterone play important role in the pathophysiology of heart failure, it:–promotes Na+ retention, K+

and magnesium loss –sympathetic activation, –parasympathetic inhibition.

–Myocardial and vascular fibrosis.

–Barareceptor dysfunction.

–Impaired arterial compliance and vascular damage.

–Its effects on K+ and Magnesium contributes to the cardiac arrythmias and sudden death.

Adverse effectsCommon:• High K+, Dizziness

• Low BP

• Diarrhoea and nausea

• Increase in urination.

Uncommon:• Dehydration

• High cholesterol and Trig.

• Low Na+ in the blood

• Headache, insomnia

• Arrythmias, dizziness

• Vomiting and flatulence.

Sex Hormones The testis

Testesterone: Is the principal hormone of the testis. Secreted by the interstitial (Leyding) cells into blood and lymphotics. Bound (95%) to globulin.Inactivated by the liver.

Actions:1. Development of male

secondary sex characteristics.

2. Nitrogen retention, growth, and bone maturation, muscle development.

3. Temporal recession of hair.

4. Sebum secretion.

5. Spermatogenesis and seminal fluid formation.

Testicular functions is controlled by:

A.Follicle – stimulating hormone (FSH)-

promote spermatogenesis.

B. Luteinising hormone (LH).

• Stimulate testosterone production.

FSH and LH release is mediated by gonadotrophin – releasing hormone (GRH).

Pharmacokinetics• Rapidly absorbed orally • Considerable first – pass

metabolism • Given I.M.

• Metabolised by the liver

Clinical uses: 1. Replacement therapy for

primary and secondary hypogonadism .

2. Delayed puberty.

3. Anabolic effect – in ostesporosis, renal failure.

4. In breast cancer.

5. Anemia of neoplastic disease.

6. Itch in jaundice.

Adverse effects: 1. Virilisation in women and

increased libido in men .

2. In women: Acne, growth of facial hair, deepening of Voice, menstrual irregularity.

3. MaleMale: Excessive musculinisation.

4.Young children: premature fusion of epiphyses.

5. Jaundice ( cholestatic).

6. Impotence and azoaspermia.

7.Hypercalcaemia.

The Ovary Three main hormones Three main hormones areare secretedsecreted:Oestradiol – 17β, oestrone, progesterone

(Oestrogens, progesterone, androgens).

Oestrogens

1. Causes enlargement of the breasts, external genitalia, uterus, female fat distribution (Female secondary sex characteristics).

2. Anabolic effects: epiphyseal fusion.

3.3. MenstruationMenstruation: proliferation in the endometrium (withdrawal of oestrogens causes a shedding of the endometrium and vaginal bleeding).

4. FSH release is inhibited.

5.Increase in the rate of tumour growth of the breast.

6.Blood and arterial disease: Increase in alpha and beta lipoproteins (low incidence of coronary artery disease).

7.Uricosuric effect: Increase u. acid excretion.

Drug fate :

–Oestrogens rapidly absorbed from GIT.

–Rapidly metabolised in the liver (MFO).

– Excreted in urine.

Adverse effects:1. Nausea and vomiting .

2.2.FeminisationFeminisation: Gynaecomastia testicular atrophy in men.

3. Fluid retention.

4.Hypercoagulability: shorten PT by increasing the plasma conc. Of factors II, VII, VIII, IX, X.

5.Carcinogenesis: Vaginal carcinoma in early adult life if given during early pregnancy,

Uses:1. Replacement therapy: at

menarche or in menopause. Menopausal symptoms may improve as hot flushes, heat intolerance, atrophy of the uterus and vagina, loss of sense of well-being.

2. prevent ostesporosis.

3. Carcinoma of the prostate and breast .

4. Menstrual disorders – to normalize menses and in dysmenorrhoea.

5.Oral contraceptives.

6. Suppression of lactation

Preparations :• Ethinyloestradiol – effective

orally Mestranol, Stilboesterol, Oestradiol

ProgesteroneAction 1.Menses and pregnancy: Causes

secretory changes in endometrium and vagina, which eacilitate implantation of the fertilized ovum. Low prog. May precipitate menstruation.Prog. decrease smooth muscle activity in the uterus. In high dose-prevent LH release.

2.Androgenic effect – mild verilisation

3.Anti – oestrogenic effect .

4.Suppress tumour growth in the endometrium.

Drug fate:Absorbed orally, rapidly metabolised, undergo enterohepatic circulation. More effective I.M or S.L.

Uses 1. Oral contraceptives (alone or

with oestrogens).

2. Endometriosis.

3. Threatened or habitual abortion.

4. Dysmenorrhoea.

5. Carcinoma of the endometrium, breast.

Adverse Effects

1. Acne and hirsutism.

2. Depression .

3. Teratogenic effect.

Preparation

Progesterone, Megestrol, Norethynodrel, Norethisterone.