Drugs for Adrenal Steroid Disease

Thianti Sylviningrum

Learning Objectives
By the end of this lectures,students will be able to : 1. Explain the anatomy,physiology and histology of adrenal glands. 2. Explain patophysiology of adrenal disease 3. Explain drug of choice for adrenal disease 4. Explain the drug mechanism for adrenal disease and its side effect

Introduction
The extracellular environment : a. must contain the correct concentrations of ions b. adequate supply of metabolic substrates for cells to generate ATP
The adrenal glands play a key role in making these adjustments

The adrenal gland

outer cortex inner medulla The cortex contains three histologically distinct zones (from outside to inside): a. Glomerulosa b. Fasciculata c. reticularis

 Hormones secreted by the adrenal cortex include glucocorticoids,aldosterone, and adrenal androgens The glucocorticoid hormones, cortisol and corticosterone adjusting the metabolism of carbohydrates, lipids, and proteins in liver, muscle, and adipose tissues during fasting, enable the body to cope with physical and emotional traumas or stresses, immune response

 The mineralocorticoid hormone : aldosterone stimulates the kidneys to conserve sodium and, hence, body fluid volume the catecholamines, epinephrine & norepinephrine, widespread effects on the cardiovascular system and muscular system,and on carbohydrate and lipid metabolism in liver, muscle,and adipose tissues.

Adrenal Steroid Hormones Are Synthesized From Cholesterol Sources of Cholesterol : lipid droplets in adrenal cortical cells contained in low-density lipoprotein

Adrenal disease
Addisons Disease : muscular weakness, low blood pressure, depression, anorexia, loss of weight and hypoglycaemia Congenital adrenal hyperplasia : genetic defects affecting the steroidogenic enzymes impair the formation of cortisol Cushings Disease : hypersecretion from the adrenal glands or by prolonged therapeutic glucocorticoid regimens

 An excessive production of mineralocorticoids results in disturbances of Na+ and K+ balance : a. hyperactivity of the adrenals or tumours of the glands (primary hyperaldosteronism, or Conn's syndrome) b. excessive renin-angiotensin action such as occurs in kidney disease, cirrhosis of the liver or congestive cardiac failure (secondary hyperaldosteronism).

GLUCOCORTICOIDS
ACTH secretion is (positively) regulated by CRF released from the hypothalamus and vasopressin from the posterior gland, and (negatively) by blood glucocorticoids highest early in the morning, gradually diminishing throughout the day and reaching a low point in the evening or night

 Both endogenous and exogenous glucocorticoids have a negative feedback effect on the secretion of CRF and ACTH. Administration of exogenous glucocorticoids depresses the secretion of CRF and ACTH, thus inhibiting the secretion of endogenous glucocorticoids and potentially causing atrophy of the adrenal cortex. If therapy is prolonged, it may take many months to return to normal function when the drugs are stopped.

 Unwanted effects : large doses or prolonged administration rather than replacement therapy. Possible unwanted effects include suppression of the response to infection or injury an opportunistic infection can be potentially very serious unless quickly treated with antimicrobial agents along with an increase in the dose of steroid. Wound healing may be impaired, and peptic ulceration may also occur.

MINERALOCORTICOIDS
Its chief action is to increase Na+ reabsorption by the distal tubules in the kidney, with concomitant increased excretion of K+ and H+

 The regulation of the synthesis and release of aldosterone is complex. Low plasma Na+ or high plasma K+ concentrations affect the zona glomerulosa cells of the adrenal directly, stimulating aldosterone release. Depletion of body Na+ also activates the reninangiotensin system. One of the effects of angiotensin II is to increase the synthesis and release of aldosterone.

 As with the glucocorticoids, the interaction of aldosterone with its receptor initiates transcription and translation of specific proteins, resulting in an increase in the number of sodium channels in the apical membrane of the cell, and subsequently an increase in the number of Na+/K+ ATPase molecules in the basolateral membrane The ensuing increased K+ excretion into the tubule results from an influx of K+ into the cell by the action of the basal Na+/K+ ATPase, coupled with an increased efflux of K+ through apical potassium channels.

Clinical use of mineralocorticoids and antagonists

Clinical use of mineralocorticoids and antagonists a. The main clinical use of mineralocorticoids is in replacement therapy b. The most commonly used drug is fludrocortisone which can be taken orally c. Spironolactone is a competitive antagonist of aldosterone, and it also prevents the mineralocorticoid effects of other adrenal steroids on the renal tubule. Side effects include gynaecomastia and impotence, because spironolactone also has some blocking action on androgen and progesterone receptors. d. Eplerenone has a similar indication and mechanism of action, although fewer side effects.