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Chapter 60

Drugs for Disorders of the Adrenal Cortex

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Adrenal Cortex Hormones

Affect multiple processes Maintenance of glucose availability Regulation of water and electrolyte balance Development of sex characteristics Life-preserving responses to stress

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Physiology of the Adrenocortical Hormones

Three classes of steroid hormones from the adrenal cortex:1. Glucocorticoids2. Mineralocorticoids3. Androgens

Two most familiar forms of adrenocortical dysfunction:1. Adrenal hormone excess

• Cushing’s syndrome2. Adrenal hormone deficiency

• Addison’s disease

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Glucocorticoids: Physiologic Effects

Physiologic effects (occur at low levels) Carbohydrate metabolism Protein metabolism Fat metabolism Cardiovascular system Skeletal muscle Central nervous system Stress Respiratory system in neonates

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Fig. 60–2. Negative feedback regulation of glucocorticoid synthesis and secretion.

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Mineralocorticoids

Influence renal processing of sodium, potassium, and hydrogen

Aldosterone Promotes sodium and potassium hemostasis Maintains intravascular volume Harmful cardiovascular effects with high levels Regulated by renin-angiotensin-aldosterone

system (RAAS)

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Adrenal Androgens

Androstenedione Minimal physiologic effects at normal levels In excess (congenital adrenal hyperplasia)

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Adrenal Hormone Excess

Cushing’s syndrome Causes

• Hypersecretion of adrenocorticotropic hormone (ACTH)• Hypersecretion of glucocorticoids• Administering glucocorticoids in large doses

Clinical presentation• Obesity• Hyperglycemia• Glycosuria• Hypertension• Fluid and electrolyte disturbances

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Adrenal Hormone Excess

Cushing’s syndrome (cont’d) Treatment

• Carcinoma/adenoma: surgical removal of adrenal gland• Replacement therapy with glucocorticoids and

mineralocorticoids for bilateral adrenalectomy• Drugs are adjunct for surgical treatment

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Primary Hyperaldosteronism

Excessive secretion of aldosterone Causes

Hypokalemia, metabolic alkalosis, hypertension Treatment

Based on underlying cause Surgery or aldosterone antagonist

(spironolactone)

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Adrenal Hormone Insufficiency

General therapeutic considerations Replacement therapy with glucocorticoids

• Should mimic normal patterns of corticosteroid secretion• 2/3 in the morning and 1/3 in the afternoon• Doses for endocrine disorders are much smaller than for

nonendocrine disorders• Increase dosage in times of stress

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Adrenal Hormone Insufficiency

Addison’s disease (primary adrenocortical insufficiency) Clinical presentation and causes

• Weakness and hypotension• Emaciation• Hypoglycemia, hyperkalemia, hyponatremia• Increased pigmentation of skin and mucous membranes

Treatment• Replacement therapy with adrenocorticoids• Hydrocortisone is the drug of choice

Both glucocorticoid and mineralocorticoid

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Adrenal Hormone Insufficiency

Secondary adrenocortical insufficiency results from decreased secretion of ACTH

Tertiary insufficiency results from decreased secretion of CRH

In both cases, adrenal secretion of glucocorticoids is diminished, whereas secretion of mineralocorticoids is usually normal

Treatment consists of replacement therapy with a glucocorticoid (eg, hydrocortisone)

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Adrenal Hormone Insufficiency

Acute adrenal insufficiency (adrenal crisis) Can lead to death

Clinical presentation Hypotension Dehydration Weakness Lethargy GI symptoms (vomiting and diarrhea)

Causes Adrenal failure Pituitary failure Inadequate doses of corticosteroids or abrupt withdrawal

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Adrenal Hormone Insufficiency

Acute adrenal insufficiency (cont’d) Treatment

• Rapid replacement of fluid, salt, and glucocorticoids (hydrocortisone)

• Glucose: normal saline with dextrose

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Adrenal Hormone Insufficiency

Congenital adrenal hyperplasia Clinical presentation and causes Treatment—glucocorticoids employed—

hydrocortisone, dexamethasone, prednisone Screening

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Agents for Replacement Therapy in Adrenocortical Insufficiency

Require replacement therapy with corticosteroids

Glucocorticoid is always required Some patients require a mineralocorticoid

as well The principal glucocorticoids employed are

hydrocortisone, dexamethasone, and prednisone

Fludrocortisone is the only mineralocorticoid available

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Hydrocortisone

Synthetic steroid with structure identical to cortisol

Therapeutic uses Adrenal insufficiency Allergic reactions to inflammation Cancer

Adverse effects of high-dose therapy Adrenal suppression Cushing’s syndrome

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Fludrocortisone (Florinef)

Potent mineralocorticoid Therapeutic uses

Addison’s disease Primary hypoaldosteronism Congenital adrenal hyperplasia

Adverse effects Hypertension Edema Cardiac enlargement Hypokalemia

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Diagnostic Testing ofAdrenocortical Function

ACTH is used primarily for diagnostic tests Cosyntropin

• Synthetic polypeptide whose structure corresponds to the first 24 amino acids of ACTH

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Dexamethasone

Synthetic steroid Primarily glucocorticoid properties; very little

mineralocorticoid activity Overnight dexamethasone test to diagnose

Cushing’s syndrome Prolonged dexamethasone suppression test