Systemic Pharmacology: Lecture 26 Drugs Acting on Endocrine System Part 4

What hormones does the outer zona glomerulosa of the adrenal cortex produce?

mineralcorticoids (e.g. aldosterone) - responsible for regulating salt and water metabolism

What hormones does the middle zona fasciculata of the adrenal cortex produce?

glucocorticoids (e.g. cortisol) - involved with metabolism and response to stress

What hormones does the inner zona reticularis of the adrenal cortex produce?

adrenal androgens

What is the secretion by the two inner zones and, to a lesser extent, the outer zone of the adrenal cortex controlled by?

pituitary adrenocroticotropic hormone (ACTH; also called corticotropin)

When is corticotropin released?

in response to hypothalamic corticotropin-releasing hormone (CRH)

What do glucocorticoids serve as feedback inhibitors for?

ACTH and CRH secretion

Corticosteroids

-they differ in their metabolic (glucocorticoid) and electrolyte-regulating (mineralcorticoid) activity

-they bind to specific intracellular cytoplasmic receptors in target tissues

Corticosteroid Receptors

-glucocorticoid receptors are widely distributed throughout the body

-mineralcorticoid receptors are confined mainly to excretory organs, such as the kidney, colon, salivary glands, and sweat glands

-both types of receptors are found in the brain

-after dimerizing, the receptor-hormone complex recruits coactivator (or corepressor) proteins and translocates into the nucleus, where it attaches to gene promoter elements

-there it acts as a transcription factor to turn genes ON (when complexed with coactivators), or OFF (when complexed with corepressors), depending on the tissue

-because of this mechanism, some effects of corticosteroids take hours to days to occur

Glucocorticoids

-cortisol is the principal human glucocorticoid

-normally, its production is diurnal, with a peak in early morning followed by a decline and then a secondary, smaller peak in late afternoon

-stress and levels of the circulating steroid influence secretion; the effects of cortisol are many and diverse

What are the actions of glucocorticoids?

-promote normal intermediary metabolism

-increase resistance to stress

-alter blood cell levels in plasma

-possess anti-inflammatory action

How do glucocorticoids promote normal intermediary metabolism?

-they stimulate hepatic glucose production by enhancing expression of enzymes involved in gluconeogensis

-they mobilize amino acids and stimulate lipolysis, thereby providing the building blocks and energy for glucose synthesis

How fo glucocorticoids increase resistance to stress?

by raising plasma glucose levels, they provide the body with energy to combat stress caused by trauma, fright, infection, bleeding, or debilitating disease

How are glucocorticoids used to alter blood cell levels in plasma?

-they cause a decrease in eosinophils, basophils, monocytes, and lymphocytes by redistributing them from the circulation to lymphoid tissue

-they also increase hemoglobin, erythrocytes, platelets, and polymorphonuclear leukocytes

What is the anti-inflammatory action of glucocorticoids?

-potent anti-inflammatory and immunosuppressive activities are their most important therapeutic properties

-they lower circulating lymphocytes and inhibit the ability of leukocytes and macrophages to respond to mitogens and antigens

-they also decrease the production and release of proinflammatory cytokines

they inhibit phospholipase A2, which blocks the release of arachidonic acid resulting in anti-inflammatory actions

-they also influence the inflammatory response by stabilizing mast cell and basophil membranes, thereby decreasing histamine release

What other systems do glucocorticoids affect?

-high levels of glucocorticoids provide negative feedback to reduce ACTH production

-they also affect the endocrine system by suppressing synthesis of glucocorticoids and thyroid-stimulating hormone

-they may adversely affect other systems

Mineralocorticoids

they help to control fluid status and concentration of electrolytes, especially sodium and potassium

Aldosterone

-acts on mineralocorticoid receptors in the distal tubules and collecting ducts in the kidney

-causes reabsorption of sodium, bicarbonate, and water

-decrease reabsorption of potassium, which, with H+, is lost in the urine

What can elevated levels of aldosterone cause?

-alkalosis and hypokalemia

-retention of sodium and water

-increased blood volume and blood pressure

What is hyperaldosteronism treated with?

spironolactone

What are the therapeutic uses of corticosteroids?

-semisynthetic derivatives of corticosteroids vary in anti-inflammatory potency, mineralocorticoid activity, and duration of action

-used in replacement therapy

-treatment of severe allergic reaction, asthma, rheumatoid arthritis, other inflammatory disorders, and some cancers

What is Addison disease caused by?

adrenal cortex dysfunction

Hydrocortisone

-identical to natural cortisol

-given to correct the deficiency

-failure to do so results in death

-2/3 of the daily dosage of hydrocortisone is administered in the morning and 1/3 in the afternoon, mimicking the normal diurnal variation in cortisol levels

Fludrocortisone

-a potent synthetic mineralocorticoid

-necessary to correct mineralocorticoid deficiency

How are corticosteroids used to diagnose Cushing syndrome?

-Cushing syndrome is caused by hypersecretion of glucocorticoids (hypercortisolism)

-results from excessive release of ACTH by the anterior pituitary or an adrenal tumor

-chronic treatment with high doses of glucocorticoids is a frequent cause of iatrogenic Cushing syndrome

-the synthetic glucocorticoid Dexamethasone suppresses cortisol release in normal individuals, but not those with Cushing syndrome

How are corticosteroids used for replacement therapy for Congenital Adrenal Hyperplasia (CAH)

-CAH is a group of diseases resulting from an enzyme defect in the synthesis of one or more of the adrenal steroid hormones

-CAH may lead to virilization in females due to overproduction of adrenal androgens

-treatment requires administration of sufficient corticosteroids to suppress release of CRH and ACTH and normalize hormone levels

-this decreases production of adrenal androgens

How are corticosteroids used to relieve inflammatory symptoms?

-they significantly reduce inflammation associated with rheumatoid arthritis and inflammatory skin conditions, including redness, swelling, heat, and tenderness

-sed to control symptoms in persistent asthma, as well as treatment of exacerbations of asthma and inflammatory bowel disease

-intraarticular corticosteroids may be used for treatment of disease flare in osteoarthritis

How are corticosteroids used in the treatment of allergies?

-corticosteroids are beneficial in the treatment of allergic rhinitis, as well as drug, serum, and transfusion allergic reactions

-Fluticasone and others are inhaled into the respiratory tract from a metered dose dispenser in the treatment of allergic rhinitis and asthma

-this minimizes systemic effects, reducing or eliminating the use of oral corticosteroids

How are corticosteroids used in the acceleration of lung maturation?

-fetal cortisol is a regulator of lung maturation

-a regimen of betamethasone or dexamethasone administered intramuscularly to the mother within 48 hours proceeding premature delivery can accelerate lung maturation in the fetus and prevent respiratory distress syndrome

What is the absorption and fate of corticosteroids like?

-are readily absorbed after oral administration

-may be administered IV, IM, intra-articularly, topically, or via inhalation or intranasal delivery

-all topical and inhaled glucocorticoids are absorbed to some extent and, therefore, have the potential to suppress the hypothalamic-pituitary-adrenal (HPA) axis

-greater than 90% bound to plasma proteins, mostly corticosteroid-binding globulin or albumin

-are metabolized by the liver microsomal oxidizing enzymes

-Prednisone is preferred in pregnancy because it minimizes steroid effects on the fetus

What is the dosage of corticosteroids like?

-factors that should be considered in determining the dosage of corticosteroids include glucocorticoid versus mineralcorticoid activity, duration of action, type of preparation, and time of day when the drug is administered

-when large doses of corticosteroids are required for more than 2 weeks, suppression of the HPA axis occurs

-alternate-day administration of corticosteroids may prevent this adverse effect by allowing the HPA axis to recover/function on days the hormone is not taken

What are the adverse effects of corticosteroids?

-osteoporosis is the most common adverse effect due to the ability of glucocorticoids to suppress intestinal Ca2+ absorption, inhibit bone formation, and decrease sex hormone synthesis

-patients are advised to take calcium and vitamin D supplements

-bisphosphonates may also be useful in the treatment of glucocorticoid-induced osteoporosis

-the classic Cushing-like syndrome (redistribution of body fat, puffy face, hirsulism, and increased appetite) is observed in excess corticosteroid replacement

-cataracts may also occur with long-term corticosteroid therapy

-hyperglycemia may develop and lead to diabetes mellitus

What is the discontinuation of corticosteroids like?

-sudden discontinuation of these drugs can cause serious consequences if the patient has suppression of the HPA axis

-abrupt removal of corticosteroids causes acute insufficiency that can be fatal

-this risk, coupled with the possibility that withdrawal could exacerbate the disease, means that the dose must be tapered slowly

-the patient must be monitored carefully

What are the therapeutically useful inhibitors of the synthesis or function of adrenal steroids?

-Ketoconazole

-Spironolactone

-Eplerenone

Ketoconazole

-an antifungal agent that strongly inhibits all gonadal and adrenal steroid hormone synthesis

-used in the treatment of patients with Cushing syndrome

Spironolactone

-competes for the mineralocorticoid receptor and, thus, inhibits sodium reabsorption in the kidney

-also antagonizes aldosterone and testosterone synthesis

-it is effective for hyperaldosteronism and hepatic cirrhosis

-used with other standard therapies for treatment of heart failure

-it is also useful in management of hirsutism in women, probably due to antiandrogen-activity on the hair follicle

What are the adverse effects of Spirinolactone?

-hyperkalemia

-gynecomastia

-menstrual irregularities, and skin rashes

Eplerenone

-specifically binds to the mineralocorticoid receptor, where it acts as an aldosterone antagonist

-this specificity avoids the adverse effect of gynecomastia that is associated with Spironolactone

-it is approved for the treatment of hypertension and for heart failure