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Chapter: Modern Pharmacology with Clinical Applications: Adrenocortical Hormones and Drugs Affecting the Adrenal Cortex

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Therapeutic Uses of Steroid Hormones

Adrenal insufficiency may result from hypofunction of the adrenal cortex (primary adrenal insufficiency, Addison’s disease) or from a malfunctioning of the hypothalamic–pituitary system (secondary adrenal in-sufficiency).

THERAPEUTIC USES OF STEROID HORMONES

 

Replacement Therapy

 

Adrenal insufficiency may result from hypofunction of the adrenal cortex (primary adrenal insufficiency, Addison’s disease) or from a malfunctioning of the hypothalamic–pituitary system (secondary adrenal in-sufficiency). In treating primary adrenal insufficiency, one should administer sufficient cortisol to diminish hy-perpigmentation and abolish postural hypotension; these are the cardinal signs of Addison’s disease.

 

Although patients may require varying amounts of replacement steroid, 20 to 30 mg/day of cortisol supple-mented with the mineralocorticoid 9- -fluorocortisol (0.1 mg/day) is generally adequate. A doubling of the cortisol dose may be required during minor stresses or infections. In patients who require high-dose supple-mentation, prednisone can be substituted for cortisol to avoid fluid retention.

 

In the treatment of secondary adrenocortical insuf-ficiency, lower doses of cortisol are generally effective, and fluid and electrolyte disturbances do not have to be considered, since patients with deficient corticotrophin secretion generally do not have abnormal function of the zona glomerulosa. Since cortisol replacement ther-apy is required for life, adequate assessment of patients is critical to avoid the serious long-term consequences of excessive or insufficient treatment. In many cases, the doses of glucocorticoid used in replacement therapy are probably too high. Patients should ideally be adminis-tered three or more doses daily. To limit the risk of osteoporosis, replacement therapy should be carefully assessed on an individual basis and overtreatment avoided.

Inflammatory States

 

Since glucocorticoids possess a wide range of effects on virtually every phase and component of the inflamma-tory and immune responses, they have assumed a major role in the treatment of a wide spectrum of diseases with an inflammatory or immune-mediated component. Rheumatoid arthritis is the original condition for which antiinflammatory steroids were used, and they remain a mainstay of therapy. Intraarticular glucocorticoid injec-tions have proven to be efficacious, particularly in chil-dren. However, the detrimental effects of glucocorti-coids on growth are significant for children with active arthritis. Although steroids offer symptomatic relief from this disorder by abolishing the swelling, redness, pain, and effusions, they do not cure. Progressive deteri-oration of joint structures continues, and the disease process may be exacerbated after steroid therapy is ter-minated .

 

Based on the concept that asthma is an inflamma-tory disease that leads to airway obstruction, inhaled glucocorticoids are the first-line treatment for moderate to severe asthma. Inhaled preparations are particularly effective when used to prevent recurrent attacks. This therapy is often combined with an inhaled bron-chodilator such as a β-adrenergic agonist. The use of β-adrenergic agonists or theophylline enables use of a lower dose of glucocorticoid, especially in patients rela-tively resistant to therapy .

 

Steroids are used in other collagen diseases, such as lupus erythematosus; in hypersensitivity or allergic states, such as nephrotic syndrome, ulcerative colitis, and Crohn’s disease; in granulomatous disease, such as sarcoid; and in a wide range of dermatological and ophthalmological conditions. Glucocorticoids may also be used at lower doses in combination with other drugs for the treatment of vasculitis, lupus nephritis, and amyloidosis. Steroids are valuable in the prevention and treatment of organ transplant rejec-tion and in the improvement of muscle function in polymyositis.

 

Corticosteroids are the mainstay of therapy for in-flammatory demyelinating polyneuropathies. In Guillain-Barré syndrome glucocorticoids reduce the inflamma-tory attack and improve final outcome, while in chronic inflammatory demyelinating polyneuropathy glucocor-ticoids suppress the immune reaction but may not re-tard the progression of the disease. Glucocorticoids also exert a facilitatory action on neuromuscular transmis-sion that may contribute to their efficacy in certain neu-romuscular disorders. The fact that acetylcholine recep-tor antibodies are responsible for the neuromuscular transmission defect in myasthenia gravis has provided a rationale for exploiting the immunosuppressive effects of glucocorticoids .

Although infections are generally thought to be particularly frequent and possibly severe in patients treated with steroids, they have been used as short-term adjunctive therapy to reduce the severe symptoms asso-ciated with such bacterial infections as acute H. influen-zae and miliary tuberculosis and in viral infections, such as hepatitis and infectious mononucleosis.

 

Glucocorticoids are also used in the treatment of a number of HIV-related disorders, including Pneumo-cystis carinii pneumonia, demyelinating peripheral neu-ropathies, tuberculous meningitis, and nephropathy. Glucocorticoids are used as adjunctive therapy in Pneumo cystitis carinii pneumonia to decrease the in-flammatory response and allow time for antimicrobial agents to exert their effects. In patients who are im-munocompromised because of HIV infection, adjunctive steroids may be less beneficial in promoting survival.

 

Leukemia

 

Steroids are important components in the treatment of hematopoietic malignancies. Their efficacy in chronic lymphocytic leukemia and multiple myeloma stems from their lympholytic effects to reduce cell prolifera-tion, promote cell cycle arrest, and induce cell death by apoptosis. A complication of chronic lymphocytic leukemia, that is, autoimmune hemolytic anemia, also responds favorably to steroids. However, the develop-ment of resistance may limit the effectiveness of steroid therapy.

 

 

Shock

 

Prompt intensive treatment with corticosteroids may be lifesaving when an excessive inflammatory reaction has resulted in septic shock. A massive infusion of cortico-steroids can restore cardiac output and reverse hy-potension by sensitizing the response of adrenoceptors in the heart and blood vessels to the stimulating action of catecholamines. This protective role of steroids may be due to a direct effect on vascular smooth muscle. The combination of glucocorticoids and dopamine therapy preserves renal blood flow during shock.

 

Congenital Adrenal Hyperplasia

 

Congenital enzymatic defects in the adrenal biosyn-thetic pathways lead to diminished cortisol and aldo-sterone production and release. In these conditions, corticotrophin secretion is increased, and adrenal hy-perplasia occurs, accompanied by enhanced secretion of steroid intermediates, especially adrenal androgens. More than 90% of cases of congenital adrenal hyper-plasia are due to 21-hydroxylase deficiency, which is cre-ated by mutations in the CYP21 gene encoding the en-zyme. Overproduction of androgens causes virilization, accelerated growth, and early epiphysial fusion. Treat-ment of this condition requires administration of gluco-corticoid in amounts adequate to suppress adrenal an-drogen secretion but insufficient to compromise bone growth and mineralization. Approximately 75% of pa-tients have concomitant mineralocorticoid deficiency and therefore cannot synthesize sufficient aldosterone to maintain sodium balance. These patients may de-velop potentially fatal salt-wasting if not treated.

 

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