The adrenal gland is divided into the adrenal medulla, which produces catecholamines such as epinephrine and norepinephrine, and the adrenal cortex, which produces cortical steroids such as cortisol, aldosterone, and androgens, all of which are needed to maintain homeostasis in the body. The adrenal cortex is further subdivided into 3 regions: the zona glomerulosa, which is responsible for producing mineralocorticoids (eg, aldosterone); the zona fasciculata, which secretes glucocorticoids (eg, cortisol); and the zona reticularis, which releases androgens (eg, testosterone).1,2
The levels of these cortical steroids are regulated through the hypothalamuspituitary-adrenal (HPA) axis (Figure). In response to inadequate levels of cortical steroids in the body, the hypothalamus will secrete corticotropin-releasing hormone (CRH), which exerts a positive feedback on the anterior pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH then stimulates the release of cortical steroids from the adrenal gland. The cortical steroids have the ability to inhibit the release of both CRH and ACTH from the hypothalamus and the pituitary gland, respectively, through a negative feedback loop.1,2
Cortisol is the principal glucocorticoid produced by the zona fasciculata. The release of this hormone results in protein and fat catabolism, gluconeogenesis in the liver to increase blood glucose levels, increased bone resorption with decreased bone formation, inhibition of the immune system, and a reduction in prostaglandins leading to an anti-inflammatory response.
Aldosterone is the predominant mineralocorticoid released from the zona glomerulosa. Its release will lead to hypernatremia and hypokalemia, once stimulated by ACTH, elevated potassium levels, and/or the renin-angiotensin-aldosterone system (RAAS). Ultimately, aldosterone release can lead to hypertension and edema.
Androgens produced from the zona reticularis are responsible for the expression of sex characteristics such as axillary and pubic hair.1
Adrenal insufficiency results when there is an inadequate level of glucocorticoids to regulate normal body functions. Primary adrenal insufficiency is due to a disorder of the adrenal glands, whereas secondary adrenal insufficiency results from diminished secretion of ACTH from the anterior pituitary gland.1,2
Primary Adrenal Insufficiency
The most common cause of primary adrenal insufficiency, also known as Addison's disease, is an autoimmune destruction of the adrenal cortex. It accounts for 70% of cases. The estimated prevalence of Addison's disease is 60 to 110 cases per 1 million people.3
Because the entire adrenal cortex has been destroyed by the body's own antibodies, deficiencies in cortisol, aldosterone, and androgens occur. In a patient with Addison's disease, plasma ACTH and potassium levels typically are elevated, and plasma cortisol levels are reduced.
Other causes of primary adrenal insufficiency include infections such as tuberculosis and polyendocrine deficiency syndrome.4 Signs and symptoms of Addison's disease result when approximately 90% of the adrenal cortex has been destroyed.1-3
Secondary Adrenal Insufficiency
Secondary adrenal insufficiency is more common than primary adrenal insufficiency. It typically results from abrupt withdrawal from chronic steroid use. Because the exogenous administration of steroids has resulted in suppression of the HPA axis, there is a reduction in cortisol and androgen levels as well as plasma ACTH levels. Aldosterone levels typically remain normal because of stimulation from the RAAS.5
Symptoms and Diagnosis
Patients with adrenal insufficiency generally present with flu-like symptoms such as fever, shaking, chills, headache, diarrhea, cramping, vomiting, weakness, and fatigue. Other symptoms include vertigo, hypotension, depression, salt craving, and vitiligo (depigmented patches of skin). Hyperpigmentation often is seen in patients with Addison's disease because ACTH can stimulate melanocytes to produce excessive levels of melatonin. Patients with secondary adrenal insufficiency have low levels of ACTH and generally do not experience hyperpigmentation.1-3,6,7
The diagnosis of adrenal insufficiency can be confirmed through the use of a cosyntropin-stimulation test. During this test, 250 ?g of synthetic ACTH is given intravenously or intramuscularly. Plasma cortisol levels are assessed at baseline and at 30 and 60 minutes after administration of the hormone. If cortisol levels rise above 18 ?g/dL, generally there is no adrenal insufficiency.2,6
The treatment of choice for a patient with primary adrenal insufficiency is exogenous replacement with glucocorticoids such as prednisone, hydrocortisone, or cortisone. They typically are administered in doses that mimic physiologic patterns. Normally, there is a diurnal variation in cortisol secretions, with the highest peak occurring between 6 and 8 AM and a decline throughout the day. A second smaller peak occurs in the late evening or early morning. Therefore, in order to mimic endogenous secretions, the glucocorticoids are given twice daily. The starting dose generally is prednisone 2.5 mg or hydrocortisone 15 mg or cortisone 20 mg in the morning between 6 and 8 AM, with a subsequent evening dose of ~33% to 50% of the morning dose.
Common adverse drug reactions associated with glucocorticoids include sodium retention, which can lead to edema, hyperglycemia, increased susceptibility to infections, osteoporosis, cataracts, seizures, peptic ulcer disease, and hypokalemia. Drugs such as phenobarbital, phenytoin, and rifampin can enhance the clearance of glucocorticoids, which may necessitate higher doses of steroids to maintain homeostasis. Estrogens, pregnancy, increasing age, and liver disease can lead to a reduction in glucocorticoid clearance, allowing lower doses of steroids to be used. In addition, any underlying conditions that have led to adrenal insufficiency, such as tuberculosis, should be treated adequately.1-3,6,8
To avoid the development of secondary adrenal insufficiency, patients treated with chronic steroids, usually for >14 days of consecutive therapy, should undergo a taper of the glucocorticoid. In patients receiving chronic steroid administration for conditions such as rheumatoid arthritis, alternate-day dosing is preferred to reduce the risk of HPA axis suppression, once the patient has been stabilized.1
The exogenous replacement of mineralocorticoids is warranted in Addison's disease due to the destruction of the zona glomerulosa. Fludrocortisone acetate (Florinef) may be used in doses of 0.05 to 0.2 mg per day to reduce elevated potassium levels, increase serum sodium levels, and/or treat postural hypotension. Patients with secondary adrenal insufficiency typically do not require therapy with a mineralocorticoid because aldosterone levels have been preserved due to stimulation by the RAAS. Patients receiving fludrocortisone acetate may experience gastrointestinal upset, edema, hypertension, hypokalemia, insomnia, and excitability. Therefore, judicious monitoring of electrolytes, blood pressure, and weight is warranted.1,8
Stress, abrupt withdrawal from glucocorticoids, trauma, infection, surgery, and dehydration are potential triggers for acute adrenal insufficiency, also known as an addisonian crisis. Early signs of this medical emergency include malaise, weakness, and myalgias. As cortisol levels remain low, patients may develop severe hypotension, vascular collapse, acute renal failure, and hypothermia.
This acute condition should be treated immediately with 100 mg of intravenous hydrocortisone, followed by a continuous infusion for 24 to 48 hours. Fluid replacement to correct hyponatremia should occur during the first 4 hours. After 24 to 48 hours, the dose of hydrocortisone should be tapered to 50 mg by mouth every 8 hours for an additional 48 hours. The dose should then be tapered over 2 to 3 days to a maintenance dose of 30 to 50 mg per day. If the patient remains hyperkalemic once on hydrocortisone maintenance therapy, the addition of fludrocortisone acetate should be considered.1,2,6
Patient education is the key to successful management of adrenal insufficiency. Pharmacists should advise patients never to stop therapy with a glucocorticoid or a mineralocorticoid without seeking their health care provider's advice. Patients also should be encouraged to wear medical-alert bracelets indicating, in case of an emergency, that they are receiving chronic therapy with a glucocorticoid.
Counseling regarding the anticipated adverse effects of glucocorticoids should be emphasized. Recommendations for a calcium and vitamin D supplement may be warranted to minimize the risk for osteoporosis. Patients with diabetes mellitus may be advised to monitor their blood sugar levels more frequently until glycemic control is achieved and maintained.
In the event of a missed dose of the glucocorticoid, patients should be instructed to take the dose as soon as possible but to skip the dose if it is almost time for the next dose. They should not double the dose of the glucocorticoid. Refill reminders for patients with adrenal insufficiency can possibly increase adherence to glucocorticoid therapy.2
Dr. Brown is an assistant professor of pharmacy practice at Palm Beach Atlantic University, West Palm Beach, Fla.
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