Drugs for Adrenal Steroid Disease-2009

8/13/2019 Drugs for Adrenal Steroid Disease-2009

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Drugs for Adrenal Steroid Disease

Thianti Sylviningrum


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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


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Introduction

The extracellular environment :

a. must contain the correct concentrations of ions

b. adequate supply of metabolic substrates for cellsto generate ATP

The adrenal glands play a key role in making

these adjustments


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The adrenal gland

outer cortex

inner medulla

The cortex contains three histologically distinctzones (from outside to inside):

a. Glomerulosa

b. Fasciculata

c. reticularis


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Hormones secreted by the adrenal cortex include

glucocorticoids,aldosterone, and adrenal androgens

The glucocorticoid hormones, cortisol and

corticosterone adjusting the metabolism ofcarbohydrates, 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


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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.


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Adrenal Steroid Hormones Are Synthesized

From Cholesterol

Sources of Cholesterol : lipid droplets in adrenal

cortical cells

contained in low-density lipoprotein


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Adrenal disease

Addisons Disease : muscular weakness, low blood

pressure, depression, anorexia, loss of weight and

hypoglycaemia

Congenital adrenal hyperplasia : genetic defectsaffecting the steroidogenic enzymes impair the formation

of cortisol

Cushings Disease : hypersecretion from the adrenal

glands or by prolonged therapeutic glucocorticoidregimens


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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).


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Both endogenous and exogenous glucocorticoids have a

negative feedback effect on the secretion of CRF and

ACTH.

Administration of exogenous glucocorticoids depressesthe 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 toreturn to normal function when the drugs are stopped.


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Unwanted effects : large doses or prolongedadministration rather than replacement therapy.

Possible unwanted effects include suppression of theresponse to infection or injury

an opportunistic infection can be potentially very seriousunless quickly treated with antimicrobial agents alongwith an increase in the dose of steroid.

Wound healing may be impaired, and peptic ulceration

may also occur.


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The regulation of the synthesis and release of aldosterone

is complex.

Low plasma Na+ or high plasma K+ concentrations

affect thezona glomerulosacells of the adrenal directly,stimulating aldosterone release.

Depletion of body Na+ also activates the renin-

angiotensin system. One of the effects of angiotensin II is

to increase the synthesis and release of aldosterone.


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As with the glucocorticoids, the interaction ofaldosterone with its receptor initiates transcription andtranslation of specific proteins, resulting in an increase inthe number of sodium channels in the apical membrane

of the cell, and subsequently an increase in the number ofNa+/K+ ATPase molecules in the basolateral membrane

The ensuing increased K+ excretion into the tubuleresults from an influx of K+ into the cell by the action of

the basal Na+/K+ ATPase, coupled with an increasedefflux of K+ through apical potassium channels.


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Clinical use of mineralocorticoids

and antagonists

Clinical use of mineralocorticoids and antagonists

a. The main clinical use of mineralocorticoids is in replacementtherapy

b. The most commonly used drug is fludrocortisonewhich can betaken orally

c. Spironolactone is a competitive antagonist of aldosterone, and italso prevents the mineralocorticoid effects of other adrenalsteroids on the renal tubule. Side effects include gynaecomastiaand impotence, because spironolactone also has some blockingaction on androgen andprogesterone receptors.

d. Eplerenone has a similar indication and mechanism of action,although fewer side effects.


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Drugs for Adrenal Steroid Disease-2009

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