Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 39. Corticosteroids & Antagonists

Corticosteroids & Antagonists: Introduction

The corticosteroids are steroid hormones produced by the adrenal cortex. They consist of 2 major physiologic and pharmacologic groups: (1) glucocorticoids, which have important effects on intermediary metabolism, catabolism, immune responses, and inflammation; and (2) mineralocorticoids, which regulate sodium and potassium reabsorption in the collecting tubules of the kidney. This chapter reviews the glucocorticoids, the mineralocorticoids, and the adrenocorticosteroid antagonists.

High-Yield Terms to Learn

Addison's disease Partial or complete loss of adrenocortical function, including loss of glucocorticoid and mineralocorticoid function Adrenal suppression A suppression of the ability of the adrenal cortex to produce corticosteroids. Most commonly is an iatrogenic effect of prolonged exogenous glucocorticoid treatment Cushing's syndrome A metabolic disorder caused by excess secretion of adrenocorticoid steroids, which is most commonly due to increased amounts of ACTH Glucocorticoid A substance, usually a steroid, that activates glucocorticoid receptors (eg, cortisol) Mineralocorticoid A substance, usually a steroid, that activates mineralocorticoid receptors (eg, aldosterone)


Mechanism of Action

Corticosteroids enter the cell and bind to cytosolic receptors that transport the steroid into the nucleus. The steroid-receptor complex alters gene expression by binding to glucocorticoid response elements (GREs) or mineralocorticoid-specific elements (Figure 39-1). Tissue-specific responses to steroids are made possible by the presence in each tissue of different protein regulators that control the interaction between the hormone-receptor complex and particular response elements.


Mechanism of glucocorticoid action. This figure models the interaction of a steroid (S; eg, cortisol), with its receptor (R) and the subsequent events in a target cell. The steroid is present in the blood bound to corticosteroid-binding globulin (CBG) but enters the cell as the free molecule. The intracellular receptor is bound to stabilizing proteins, including heat shock protein 90 (Hsp90) and several others (X). When the complex binds a molecule of steroid, the Hsp90 and associated molecules are released. The steroid-receptor complex enters the nucleus as a dimer, binds to the glucocorticoid response element (GRE) on the gene, and regulates gene transcription. The resulting mRNA is edited and exported to the cytoplasm for the production of protein that brings about the final hormone response.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.)

Organ and Tissue Effects

Metabolic Effects

Glucocorticoids stimulate gluconeogenesis. As a result, blood glucose rises, muscle protein is catabolized, and insulin secretion is stimulated. Both lipolysis and lipogenesis are stimulated, with a net increase of fat deposition in certain areas (eg, the face and the shoulders and back).

Catabolic Effects

Glucocorticoids cause muscle protein catabolism. In addition, lymphoid and connective tissue, fat, and skin undergo wasting under the influence of high concentrations of these steroids. Catabolic effects on bone can lead to osteoporosis. In children, growth is inhibited.

Immunosuppressive Effects

Glucocorticoids inhibit cell-mediated immunologic functions, especially those dependent on lymphocytes. These agents are actively lymphotoxic and, as such, are important in the treatment of hematologic cancers. The drugs do not interfere with the development of normal acquired immunity but delay rejection reactions in patients with organ transplants.

Anti-Inflammatory Effects

Glucocorticoids have a dramatic effect on the distribution and function of leukocytes. These drugs increase neutrophils and decrease lymphocytes, eosinophils, basophils, and monocytes. The migration of leukocytes is also inhibited. The biochemical mechanisms underlying these cellular effects include the induced synthesis of an inhibitor of phospholipase A2 (Chapter 18), decreased mRNA for cyclooxygenase 2 (COX-2), decreases in interleukin-2 (IL-2) and IL-3, and decreases in platelet activating factor (PAF), an inflammatory cytokine.

Other Effects

Glucocorticoids such as cortisol are required for normal renal excretion of water loads. The glucocorticoids also have effects on the CNS. When given in large doses, these drugs may cause profound behavioral changes. Large doses also stimulate gastric acid secretion and decrease resistance to ulcer formation.

Important Glucocorticoids


The major natural glucocorticoid is cortisol (hydrocortisone; Figure 39-2). The physiologic secretion of cortisol is regulated by adrenocorticotropin (ACTH) and varies during the day (circadian rhythm); the peak occurs in the morning and the trough occurs about midnight. In the plasma, cortisol is 95% bound to corticosteroid-binding globulin (CBG). Given orally, cortisol is well absorbed from the gastrointestinal tract, is cleared by the liver, and has a short duration of action compared with its synthetic congeners (Table 39-1). Although it diffuses poorly across normal skin, cortisol is readily absorbed across inflamed skin and mucous membranes.


Outline of major pathways in adrenocortical hormone biosynthesis. The names of major adrenal secretory products are in shaded boxes. The enzymes and cofactors for the reactions progressing down each column are shown on the left and across columns at the top of the figure. When a particular enzyme is deficient, hormone production is blocked at points indicated by the shaded bars.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 39-1.)

TABLE 39-1 Properties of representative corticosteroids.

Agent Duration of Action (hours) Anti-inflammatory Potencya Salt-retaining Potencya Topical Activity Primarily glucocorticoid Cortisol 8-12 1 1 0 Prednisone 12-24 4 0.3 (+) Triamcinolone 15-24 5 0 +++ Dexamethasone 24-36 30 0 +++++ Primarily mineralocorticoid Aldosterone 1-2 0.3 3000 0 Fludrocortisone 8-12 10 125-250 0

aRelative to cortisol.

The cortisol molecule also has a small but significant salt-retaining (mineralocorticoid) effect (Table 39-1). This is an important cause of hypertension in patients with a cortisol-secreting adrenal tumor or a pituitary ACTH-secreting tumor (Cushing's syndrome).

Synthetic Glucocorticoids

The mechanism of action of these agents is identical with that of cortisol. A large number of synthetic glucocorticoids are available for use; prednisone and its active metabolite, prednisolone, dexamethasone, and triamcinolone are representative. Their properties (compared with cortisol) include longer half-life and duration of action, reduced salt-retaining effect, and better penetration of lipid barriers for topical activity (Table 39-1).

Special glucocorticoids have been developed for use in asthma (see Chapter 20) and other conditions in which good surface activity on mucous membranes or skin is needed and systemic effects are to be avoided. Beclomethasone and budesonide readily penetrate the airway mucosa but have very short half-lives after they enter the blood, so that systemic effects and toxicity are greatly reduced.

Clinical Uses

Adrenal Disorders

Glucocorticoids are essential to preserve life in patients with chronic adrenal cortical insufficiency (Addison's disease) and are necessary in acute adrenal insufficiency associated with life-threatening shock, infection, or trauma. Glucocorticoids are also used in certain types of congenital adrenal hyperplasia, in which synthesis of abnormal forms of corticosteroids are stimulated by ACTH. In these conditions, administration of a potent synthetic glucocorticoid suppresses ACTH secretion sufficiently to reduce the synthesis of the abnormal steroids.

Nonadrenal Disorders

Many disorders respond to corticosteroid therapy. Some of these are inflammatory or immunologic in nature (eg, asthma, organ transplant rejection, collagen diseases, rheumatic disorders). Other applications include the treatment of hematopoietic cancers, neurologic disorders, chemotherapy-induced vomiting, hypercalcemia, and mountain sickness. Betamethasone, a glucocorticoid with a low degree of protein binding, is given to pregnant women in premature labor to hasten maturation of the fetal lungs. The degree of benefit differs considerably in different disorders, and the toxicity of corticosteroids given chronically limits their use.


Most of the toxic effects of the glucocorticoids are predictable from the effects already described. Some are life threatening and include metabolic effects (growth inhibition, diabetes, muscle wasting, osteoporosis), salt retention, and psychosis. Methods for minimizing these toxicities include local application (eg, aerosols for asthma), alternate-day therapy (to reduce pituitary suppression), and tapering the dose soon after achieving a therapeutic response. To avoid adrenal insufficiency in patients who have had long-term therapy, additional "stress doses" may need to be given during serious illness or before major surgery. Patients who are being withdrawn from glucocorticoids after protracted use should have their doses tapered slowly, over the course of several months, to allow recovery of normal adrenal function.



The major natural mineralocorticoid in humans is aldosterone, which is discussed in connection with hypertension (see Chapter 11) and with control of its secretion by angiotensin II (see Chapter 17). The secretion of aldosterone is regulated by ACTH and by the renin-angiotensin system and is very important in the regulation of blood volume and blood pressure (see Figure 6-4). Aldosterone has a short half-life and little glucocorticoid activity (Table 39-1). Its mechanism of action is the same as that of the glucocorticoids.

Other Mineralocorticoids

Other mineralocorticoids include deoxycorticosterone, the naturally occurring precursor of aldosterone, and fludrocortisone, which also has significant glucocorticoid activity. Because of its long duration of action (Table 39-1), fludrocortisone is favored for replacement therapy after adrenalectomy and in other conditions in which mineralocorticoid therapy is needed.

Corticosteroid Antagonists

Receptor Antagonists

Spironolactone and eplerenone, antagonists of aldosterone at its receptor, are discussed in connection with the diuretics (see Chapter 15). Mifepristone (RU-486) is a competitive inhibitor of glucocorticoid receptors as well as progesterone receptors (see Chapter 40) and has been used in the treatment of Cushing's syndrome.

Synthesis Inhibitors

Several drugs inhibit adrenal steroid synthesis. The most important of these drugs are ketoconazole, aminoglutethimide, and metyraponeKetoconazole (an antifungal drug) inhibits the cytochrome P450 enzymes necessary for the synthesis of all steroids and is used in a number of conditions in which reduced steroid levels are desirable (eg, adrenal carcinoma, hirsutism, breast and prostate cancer). Aminoglutethimide blocks the conversion of cholesterol to pregnenolone (Figure 39-2) and also inhibits synthesis of all hormonally active steroids. It can be used in conjunction with other drugs for treatment of steroid-producing adrenocortical cancer. Metyrapone inhibits the normal synthesis of cortisol but not that of cortisol precursors; the drug can be used in diagnostic tests of adrenal function.

Skill Keeper: Aldosterone Antagonists and Congestive Heart Failure

(Chapters 13 and 15)

Recent clinical trials have shown that the aldosterone receptor antagonists spironolactone and eplerenone decrease morbidity and mortality in patients who are taking other standard therapies.

1. Why is aldosterone elevated in patients with congestive heart failure?

2. How does the increase in aldosterone contribute to the signs and symptoms of heart failure?

3. What happens to serum potassium concentrations in patients who are treated with aldosterone antagonists?

The Skill Keeper Answers appear at the end of the chapter.

Skill Keeper Answers: Aldosterone Antagonists and Congestive Heart Failure

(Chapters 13 and 15)

1. The reduction in cardiac output associated with heart failure decreases the effective arterial blood volume and renal blood flow. Decreased pressure in renal arterioles and increased sympathetic neural activity both stimulate renin release, which increases production of angiotensin II. Angiotensin II is a powerful stimulus of aldosterone secretion.

2. Acting through nuclear receptors in the epithelial cells that line renal collecting tubules, aldosterone promotes renal uptake of salt and water. This retention of salt and water exacerbates the peripheral and pulmonary edema associated with congestive heart failure and further overloads the weakened heart. In addition to these renal effects, aldosterone is also implicated in myocardial and vascular fibrosis and baroreceptor dysfunction.

3. The aldosterone antagonists are also known as "potassium-sparing diuretics" because, unlike other diuretics, they do not promote renal excretion of potassium. Because the excretion of potassium in the renal tubule is linked to the reuptake of sodium, the reduction in sodium uptake caused by spironolactone and eplerenone results in potassium retention and an increase in serum potassium.


When you complete this chapter, you should be able to:

 Describe the major naturally occurring glucocorticosteroid and its actions.

 List several synthetic glucocorticoids, and describe differences between these agents and the naturally occurring hormone.

 Describe the actions of the naturally occurring mineralocorticoid and 1 synthetic agent in this subgroup.

 List the indications for the use of corticosteroids in adrenal and nonadrenal disorders.

 Name 3 drugs that interfere with the action or synthesis of corticosteroids, and, for each, describe its mechanism of action.

Drug Summary Table: Corticosteroids & Antagonists

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Glucocorticoid agonists Prednisone Activation of glucocorticoid receptor leads to altered gene transcription Many inflammatory conditions, organ transplantation, hematologic cancers Duration of activity is longer than pharmacokinetic half-life of drug owing to gene transcription effects Adrenal suppression, growth inhibition, muscle wasting, osteoporosis, salt retention, glucose intolerance, behavioral changes Many other glucocorticoids available for oral and parenteral use (see Table 39-1). Cortisol is the primary endogenous glucocorticoid hormone Mineralocorticoid agonist Fludrocortisone Strong agonist of mineralocorticoid receptors and moderate activation of glucocorticoid receptors Adrenal insufficiency (Addison's disease) Long duration of action (see Table 39-1) Salt and fluid retention, congestive heart failure, signs and symptoms of glucocorticoid excess (see above) Glucocorticoid receptor antagonist Mifepristone Pharmacologic antagonist of glucocorticoid and progesterone receptors Medical abortion (see Chapter 40) and very rarely Cushing's syndrome Oral administration Vaginal bleeding in females, abdominal pain, gastrointestinal upset, diarrhea, headache Mineralocorticoid receptor antagonists Spironolactone Pharmacologic antagonist of mineralocorticoid receptor, weak antagonism of androgen receptors Aldosteronism from any cause, hypokalemia due to other diuretics, postmyocardial infarction Slow onset and offset of effect Duration: 24-48 h Hyperkalemia, gynecomastia (spironolactone, not eplerenone), additive interaction with other K-retaining drugs Eplerenone: Similar to spironolactone, more selective for mineralocorticoid receptor Synthesis inhibitorsKetoconazole Blocks fungal and mammalian CYP450 enzymes Inhibits mammalian steroid hormone synthesis and fungal ergosterol synthesis (see Chapter 48) Oral, topical administration Hepatic dysfunction, many drug-drug CYP450 interactions Other adrenal steroid synthesis inhibitors: Include aminoglutethimide and metyrapone

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