a disorder in which the adrenal glands do not produce enough steroid hormones.
a benign (noncancerous) tumor of glandular origin.
a term referring to a deficiency in the levels of adrenal hormones.
Adrenocorticotropic hormone (ACTH)
a hormone produced by the pituitary gland that stimulates the adrenal cortex to produce glucocorticoids, mineralocorticoids, and androgens.
a hormone produced by the adrenal glands that regulates the balance of sodium, water, and potassium concentrations in the body.
any of the male sex hormones that regulate the development and maintenance of male characteristics.
Corticotropin-releasing hormone (CRH)
a hormone released by the hypothalamus that regulates the release of ACTH from the pituitary gland.
any of the steroid hormones made by the cortex of the adrenal gland.
the primary glucocorticoid produced by the adrenal cortex.
a hormonal disorder caused by prolonged exposure of the body to a higher cortisol concentration than the body normally requires.
produced or synthesized from within an organism.
originating from outside an organism.
a steroid hormone that has anti-inflammatory and immunosuppressive properties.
an excess amount of aldosterone.
an insufficient amount or impaired function of aldosterone.
an excess amount of circulating cortisol.
an insufficient amount of circulating cortisol.
a steroid hormone that affects fluid and electrolyte balance in the body.
a synthetic process that produces steroids (glucocorticoids and mineralocorticoids).
After completing this chapter, you should be able to
Identify the hormones produced by the adrenal glands.
Describe the functions of mineralocorticoids and glucocorticoids in the body.
Recognize the signs and symptoms of adrenal insufficiency.
List the pharmacological treatment of patients with acute and chronic adrenal insufficiency.
Recognize the signs and symptoms of Cushing’s syndrome and the result of too much cortisol.
List the pharmacologic and nonpharmacologic management of patients with Cushing’s syndrome.
List the pharmacologic management of primary aldosteronism.
List management strategies for the administration of glucocorticoid and mineralocorticoid therapy to avoid the development of adrenal disorders.
The adrenal glands are an integral part of the endocrine system, secreting hormones that act throughout the body to regulate functions and promote homeostasis. In addition to the neurotransmitters epinephrine and norepinephrine, the corticosteroids secreted by the adrenal glands are vital to various physiological processes. Pharmacologic agents that resemble the adrenal hormones in chemistry and action are essential in treating many conditions.
Mrs. Smith is a 30-year-old woman who presents to the emergency department with complaints of fatigue, muscle weakness, anorexia, and dizziness for the last few days. She also states that she has a bad cold, has been coughing, and had a fever of 101°F. She has a history of autoimmune disease and has been treated for it with prednisone 10 mg daily and hydroxychloroquine 400 mg daily for the past 5 years.
Her vital signs include blood pressure 108/64 mm Hg and pulse 96 beats per minute (bpm) lying down, blood pressure 80/45 mm Hg and pulse 110 bpm sitting, respiration rate of 26 breaths per minute, and temperature of 99.8°F. Laboratory data show low serum sodium and blood glucose (sugar) levels along with high calcium and potassium levels.
ANATOMY AND PHYSIOLOGY OF THE ADRENAL GLANDS
The adrenal glands are small triangular-shaped organs located on top of both kidneys (Figure 9-1). Each adrenal gland consists of two main regions: the adrenal cortex, which makes up the outer region of the gland, and the adrenal medulla, which makes up the inner region of the gland. The inner medulla is responsible for secreting the hormones epinephrine and norepinephrine (also known as adrenaline and noradrenaline, respectively). These hormones are involved in the activities of the sympathetic nervous system, which regulates the body’s responses to stress (eg, the fight-or-flight response). See Chapter 4 for a more detailed discussion of epinephrine and norepinephrine. The outer adrenal cortex secretes three major classes of hormones: glucocorticoids, mineralocorticoids, and androgens.1 These three major classes of hormones control many important functions in the body. This chapter focuses on the actions and pharmacologic uses of glucocorticoids and mineralocorticoids.
The adrenal glands work interactively with the hypothalamus and pituitary gland, and this is referred to as the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus releases corticotropin-releasing hormone (CRH), which in turn stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH then stimulates the adrenal cortex, which is made up of three distinct zones: the outer zona glomerulosa, the middle zona fasciculata, and the inner zona reticularis. When stimulated, these zones produce and release mineralocorticoids (from the zona glomerulosa), glucocorticoids (from the zona fasciculata), and androgens (from the zona reticularis).1
Cortisol is the primary glucocorticoid and its main functions are to regulate blood glucose concentrations, maintain normal blood pressure, promote protein and lipid (fat) breakdown while preventing protein synthesis, and regulate inflammation. Cortisol also affects wound healing and normal immune activity. Aldosterone is the primary mineralocorticoid and is responsible for maintaining the balance of sodium (salt), potassium, and water in the body. Adrenal androgens control sexual maturation during childhood and puberty.
A disorder of the adrenal cortex may result in decreased production of glucocorticoids. This is known as hypocortisolism or adrenal insufficiency. When the adrenal cortex produces too much cortisol, hypercortisolism results. This can lead to the development of a condition called Cushing’s syndrome. These are the two most common disorders of the adrenal glands and are discussed in detail later in this chapter.
Abnormal aldosterone concentration can reveal disorders of the adrenal glands. Hyperaldosteronism results from the overproduction of aldosterone, whereas the shortage or impaired function of aldosterone results in hypoaldosteronism. These conditions may occur together with the cortisol abnormalities or by themselves as primary disorders.
Pharmacologic Uses of Corticosteroids
Corticosteroids are steroid hormones that are further classified as glucocorticoids (eg, cortisol) or mineralocorticoids (eg, aldosterone) based on their biologic activity. Glucocorticoids bind to receptors in the body to suppress the immune response and provide anti-inflammatory effects. Mineralocorticoids also bind to receptors but cause sodium and water retention and potassium depletion.
Corticosteroids may be produced and secreted naturally by the body (endogenous) or administered to the body (exogenous). Exogenous glucocorticoid medications, such as prednisone, can be prescribed for a multitude of indications, such as adrenal insufficiency, inflammatory conditions (eg, skin conditions, asthma, allergic rhinitis), and autoimmune diseases (eg, rheumatoid arthritis). Corticosteroids are commonly prescribed for their glucocorticoid activity, but some patients require medications with mineralocorticoid effects.
Mineralocorticoids may be prescribed for conditions such as primary adrenal insufficiency or low blood pressure. Fludrocortisone is a synthetic mineralocorticoid, which is available as an oral tablet. It is typically administered once daily in the morning. Adequacy of the mineralocorticoid dose is dependent on blood levels of sodium and potassium, symptoms of dizziness upon standing, and blood pressure in the sitting, standing, and lying down positions.2,3
What steroid medication has Mrs. Smith been taking? Besides suppressing her autoimmune disease what else might you expect this medication to do?
Exogenous corticosteroids are differentiated on the basis of their half-life, glucocorticoid potency, and mineralocorticoid activity (see Table 9-1).3 Hydrocortisone has fairly significant mineralocorticoid activity and is closely related to endogenous cortisol. Prednisone and prednisolone have minimal mineralocorticoid activity. For situations in which mineralocorticoid activity is to be avoided, methylprednisolone and dexamethasone are good alternatives.4
Mineralocorticoid (Sodium and Water-Retaining) Activity
Equivalent Dose (mg)
Short-acting (duration 8–12 hr)
Intermediate-acting (duration 12–36 hr)
Long-acting (duration 36–72 hours)
Source: Data adapted from Liu D, Ward AA, Krishnamoorthy P, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30.
While glucocorticoid medications are commonly (and properly) referred to as steroids, they are not to be confused with the anabolic steroids (similar in chemical structure), which have been the subject of abuse by athletes seeking to build muscle mass and enhance athletic performance. This type of steroid is discussed inChapter 11.
Prednisone is the most commonly prescribed oral corticosteroid due to its widespread availability, many dosage strengths, and low cost. In general, selecting a glucocorticoid medication for a medical condition depends on its half-life, glucocorticoid potency, and mineralocorticoid activity.
Inhaled corticosteroids are typically used for respiratory disorders (such as asthma, bronchitis, and emphysema) and are available as single-ingredient products or in combination with other medications. These treatments are discussed extensively inChapter 19. (See MedicationTable 19-1for information about inhaled corticosteroids.)
Since corticosteroids can be prescribed for a vast number of conditions, a variety of different formulations are available to facilitate optimal drug delivery (eg, oral, inhaled, nasal, topical, intravenous [IV], intramuscular [IM], intra-articular, or intravitreal injections). Oral and IV corticosteroids are usually prescribed in situations where systemic (throughout the body) anti-inflammatory effects are desired, such as severe asthma attacks and severe allergic reactions. IV administration of corticosteroids results in the highest concentration of the medication in the blood. IM and intra-articular preparations have lower systemic absorption and, therefore, fewer systemic side effects.5 They can be used in patients with musculoskeletal disorders or inflammatory joint disorders, such as arthritis, to provide localized relief of pain and inflammation at the site of administration. For example, an intra-articular injection to the knee can provide pain relief for a patient with osteoarthritis in this joint. Medication Table 9-1 lists the corticosteroids that are available in oral and injectable formulations. (Medication Tables are located at the end of the chapter).
Intranasal corticosteroids (covered in Chapter 36) are typically prescribed for patients with allergic rhinitis (hay fever). Their effects are localized in the nasal pathway, and the side effects can include nasal dryness and crusting, nosebleeds, sneezing bouts, and irritation of the nose and throat. In some instances, intranasal administration may lead to systemic absorption of the drug if a large portion of the dose is swallowed.6
Dermatologic corticosteroids are used for a variety of skin conditions, including allergic reactions, and are available as creams, ointments, lotions, gels, and aerosols. Creams can be used on most body surfaces, while ointments may be beneficial for dry or scaly lesions because of their occlusive properties. Other dosage forms, such as lotions, gels, and aerosols, can be applied to areas with hair. Local side effects include drying and cracking of the skin, thinning of the skin, and pinkish or purplish scar-like lesions on the skin. Systemic side effects with topical administration can occur when large skin areas are involved, prolonged use occurs, occlusive dressings are used, or if the skin is broken.7
Topical corticosteroids are often available in a variety of salts (propionate, diacetate, etc.) and dosage forms (creams, ointments, gels), as well as different strengths. These are not interchangeable, and it is important to recognize the appropriate salt, strength, and dosage form from the prescription or medication order.
Topical corticosteroids vary in potency and are listed in Medication Table 9-2.8 High-potency agents are reserved for resistant conditions or for use on areas of the skin that are harder to penetrate (eg, palms or soles). Medium-potency agents can be used on the trunk, arms, and legs. Low-potency agents are recommended for use in children or for patients requiring that the medication be applied over large areas of the body. They are preferred for use on the face, genitals, armpits, and skin folds.7,8
Major Systemic Side Effects Associated with Corticosteroid Therapy4
Thinning of the bones (osteopenia or osteoporosis)
Death of a bone or part of a bone (avascular necrosis)
Growth retardation of long bones
Muscle weakness and pain
Bulging of one or both eyes
Ulcers in the lining of the stomach
Inflammation of the pancreas
Inflammation of the esophagus
High blood sugars
Weight gain due to increased appetite and/or fluid retention
Source: Data adapted from Jackson S, Gilchrist H, Nesbitt LT, Jr. Update on the dermatologic use of systemic glucocorticosteroids. Dermatol Ther. 2007;20:187-205.
Hydrocortisone is the only topical corticosteroid available over the counter (OTC) but only at strengths up to 1%. Higher strengths of hydrocortisone, other topical corticosteroids, and corticosteroids for other routes of administration are available only by prescription.
Ophthalmic corticosteroids are used to treat inflammatory eye conditions. They are also available in combination with an ophthalmic antibiotic to treat eye infections. These preparations are covered in Chapter 34.
Side Effects of Corticosteroid Therapy
Regardless of the formulation used, corticosteroids can result in a multitude of systemic effects if absorbed into the circulation (see Table 9-2).4 While some of the effects are related to therapeutic effectiveness of the medications, they may also become unwanted side effects that may limit the use of these drugs. For example, immunosuppressant, anti-inflammatory, and antiproliferative effects of corticosteroids are beneficial for conditions such as psoriasis, atopic dermatitis, and arthritis but potentially harmful in patients with serious infections.
In general, side effects may be minimized by using localized formulations (eg, inhalers, nasal sprays, creams, ointments, lotions, gels, intra-articular injections), but overuse of these medications in any formulation can lead to an increased risk of side effects. Corticosteroids administered in routes that lead to the highest blood concentration (eg, IV, oral) pose the greatest risk for side effects.6 The dose and duration of corticosteroid use can also affect the risk for systemic side effects. The most common side effects related to corticosteroid therapy are osteoporosis, high blood glucose, weight gain, anxiety, and insomnia.4 Two serious complications associated with exogenous corticosteroid administration are adrenal insufficiency and Cushing’s syndrome.
In contrast to those associated with other corticosteroids, side effects from fludrocortisone are mainly related to its powerful mineralocorticoid activity and typically result from overtreatment. These side effects include high blood pressure, low potassium level, and fluid retention. If any of these occur, the fludrocortisone dose is usually reduced, and the patient is monitored for resolution of symptoms.3
Weight gain associated with corticosteroid therapy can be due to increased appetite or fluid retention.
Adrenal Insufficiency or Hypocortisolism
Adrenal insufficiency (AI) occurs when the adrenal glands are unable to produce enough cortisol to satisfy the needs of the body. AI is classified as primary, secondary, or tertiary. Primary AI occurs as a result of the destruction of the adrenal glands. Secondary AI occurs when there is dysfunction of the pituitary gland, while tertiary AI is the result of dysfunction in the hypothalamus.9
Primary AI (also known as Addison disease) occurs infrequently in Western populations. It is more common in women than men and peaks in the fourth decade of life.9 Primary AI occurs as a consequence of destruction of greater than 90% of the adrenal glands. The majority of primary AI cases are caused by the patient’s own immune system (autoimmune disease) destroying the adrenal glands. Infections, such as tuberculosis, human immunodeficiency virus (HIV), and acquired immunodeficiency syndrome (AIDS), can also cause primary AI. Other less-common causes include bleeding or a decrease in blood supply to the adrenal glands, cancers that may have spread to the adrenal glands, and side effects from some medications.10 In primary AI, there is a decrease in production of both glucocorticoids and mineralocorticoids.9
In secondary AI, dysfunction of the pituitary gland causes a decrease in the production of ACTH. This results in less stimulation of the adrenal gland to produce its hormones by ACTH. Cancers, infection, head trauma, or radiation of the pituitary gland can cause secondary AI.10 Secondary AI occurs more frequently than primary AI but is still rare. It is also more common in women and peaks in the sixth decade of life.9
Based upon Mrs. Smith’s medical history, what is a possible cause of her current problem?
Drug therapy with corticosteroids for various medical conditions is a common contributor to the development of both secondary and tertiary AI.10 Administration of exogenous corticosteroids can suppress the HPA axis by inhibiting the secretion of CRH from the hypothalamus and ACTH from the pituitary gland. As a result, secretion of endogenous corticosteroids by the adrenal gland is suppressed, resulting in AI.4 In secondary and tertiary AI, mineralocorticoid function is preserved, and only the glucocorticoid production is decreased.
The clinical manifestations of AI depend on multiple factors. The onset of chronic AI is slow and gradual over time with nonspecific symptoms, including persistent fatigue, weakness, lethargy, loss of appetite, weight loss, postural hypotension (sudden drop in blood pressure upon standing, which may result in dizziness or feeling faint), and gastrointestinal complaints, such as nausea, vomiting, and abdominal pain. Hyperpigmentation or development of dark spots, especially in skin areas unexposed to sunlight, is another characteristic symptom of chronic AI.11Acute AI (also known as adrenal crisis) is mainly caused by glucocorticoid deficiency and is dramatic in onset.11 In adrenal crisis, patients usually have a combination of the following signs or symptoms: low sodium level (hyponatremia), high potassium level (hyperkalemia), high calcium level (hypercalcemia), low fasting blood glucose level (hypoglycemia), fever, abdominal pain, and hypotensive shock that does not correct with fluid supplementation.10,11 Adrenal crisis can be the end result of chronic AI, where the overwhelmed adrenal glands are not able to meet the increased glucocorticoid demand in physiologic stress situations, such as severe infections, trauma, or surgical procedures.10 Adrenal crisis can also result from abrupt withdrawal of chronic corticosteroid medication use, which is the most common cause of adrenal crisis.10
Which of Mrs. Smith’s signs and symptoms are consistent with adrenal insufficiency?
Diagnosis of Adrenal Insufficiency
A number of tests are used to diagnose AI. The most widely used is the ACTH (cosyntropin) stimulation test. This test evaluates the ability of the adrenal glands to secrete cortisol after administration of cosyntropin, a synthetic form of ACTH. In patients with AI, the blood concentration of cortisol measured during the test is low since their adrenal glands are unable to respond to ACTH stimulation. Several other blood tests, including the insulin tolerance test, overnight metyrapone test, plasma aldosterone concentration, and plasma renin concentration, can be used to determine whether the patient has the primary, secondary, or tertiary form of AI.
Metyrapone is an oral drug supplied in 250-mg capsules and used for diagnostic testing of adrenal-related disorders. For a single-dose test, a dose of 30 mg/kg (up to 3 g or 12 capsules) is administered at midnight, and the patient’s blood is sampled the following morning. In a multiple-dose test, a dose of 750 mg (3 capsules) is administered every 4 hours for 6 doses.
Treatment of Chronic Adrenal Insufficiency
Supplementation with glucocorticoids and mineralocorticoids is the treatment of choice for AI. The healthy body produces cortisol in the amount approximately equivalent to 20–30 mg/day of oral hydrocortisone or 5–7.5 mg/day of oral prednisone. Corticosteroid supplementation is available in tablet and injectable formulations, where the IV formulation is given only when patients are not able to swallow or are critically ill. Therapy for chronic AI is individualized for each patient and usually requires oral hydrocortisone dosed at 20–30 mg in two to three divided doses a day to maintain normal glucocorticoid balance, with the last dose no later than 4–6 hours before bedtime. Patients are treated to normalize their blood pressure, heart rate, and temperature. Treatment with corticosteroid can also achieve improvement in sense of well-being and eliminate other symptoms. In primary AI, supplementation with a mineralocorticoid, such as fludrocortisone at 0.05–0.1 mg/day, is also required to correct the low sodium concentration and prevent orthostatic hypotension.
The pharmacy has received an order to send a stat dose of 100 mg IV hydrocortisone for Mrs. Smith in the emergency room. For what condition do you think they are treating her?
Prevention and Treatment of Acute Adrenal Insufficiency
Patients with chronic AI require supplemental doses of corticosteroid in addition to their normal corticosteroid doses in situations of severe physiologic stress, such as acute severe illness, surgery, or trauma, to prevent adrenal crisis. The supplemental corticosteroid stress dose depends on the severity of the stress situation. For example, during a major surgery or for diseases that require intensive care, doses of IV hydrocortisone will be approximately 100–200 mg/day, plus fludrocortisone if needed.12
After a patient has recovered from the physiologic stress, the dose of supplemental corticosteroid should be gradually tapered off and not abruptly discontinued.
Therapy for adrenal crisis is intended to stabilize the patient as quickly as possible and consists of IV fluid and hydrocortisone replacement as soon as the diagnosis is made.11 IV hydrocortisone at 100–400 mg/day should be administered immediately and continued for at least 2–3 days or until full recovery. Once the patient is stable, the hydrocortisone dose is tapered over 1–4 days and converted to oral maintenance therapy. Fluid replacement with 0.9% sodium chloride injection solution (“normal saline”) may be administered at rates of up to 1 liter/hr to treat the hypotension. Patients with low blood glucose may also receive supplemental dextrose solution.11,12
Since the most common cause of adrenal crisis is the abrupt withdrawal of corticosteroid therapy, patient education is an important way to prevent adrenal crisis in patients who are on a long-term corticosteroid therapy. The pharmacist should educate these patients about the importance of adherence to glucocorticoid therapy and advise them to contact their providers if they become ill as they may need higher doses of glucocorticoids.
Patients who are on long-term systemic glucocorticoids or frequently placed on high-dose, short courses of systemic glucocorticoids (eg, for recurrent asthma exacerbation) are at risk for adrenal crisis if they experience an acute episode of physiologic stress, such as surgery, trauma, or severe illness. They should be advised to carry documentation (eg, medical bracelet, wallet card) that they take glucocorticoid medications regularly.
Cushing’s Syndrome or Hypercortisolism
Hypercortisolism, also known as Cushing’s syndrome, is a consequence of long-term exposure to excessive amounts of glucocorticoids circulating in the body. The source of the glucocorticoid may be exogenous or endogenous. Endogenous Cushing’s syndrome is classified as ACTH-dependent or ACTH-independent. In ACTH-dependent Cushing’s syndrome, the rise in glucocorticoid concentrations is either due to pituitary adenomas that produce excess amounts of ACTH or from the ectopic (located away from the normal location) of ACTH from outside the pituitary gland, such as in small cell lung cancer or cancers of various endocrine glands.13 ACTH-independent Cushing’s syndrome is the result of abnormalities with the adrenal gland. Adenoma of the adrenal gland accounts for approximately 60% of ACTH-independent Cushing’s syndrome, and the remaining 40% is due to cancer of the adrenal glands. The most common cause of exogenous Cushing’s syndrome is the long-term administration of glucocorticoids in doses that are higher than is normally needed in the healthy body.13 Note that occasionally the terms Cushing’s syndrome and Cushing’s disease may be used interchangeably but Cushing’s syndrome is a more general term, while Cushing’s disease refers specifically to hypercortisolism due to an ACTH-secreting pituitary adenoma.
Cushing’s syndrome involves multiple organs and systems in the body. The classic cutaneous (skin) presentation of Cushing’s syndrome is facial plethora (swollen and red face), oily skin and acne, purpura (patches of purplish discoloration on the skin), hirsutism (excessive hair growth), and wide purplish striae (stretch marks) over the abdomen, flanks, and upper arms. The skin is thin, bruises easily, and heals slowly from wounds or abrasions. Women with adrenal tumors may develop male pattern baldness and/or excess hair on the face, upper lip, chin, or abdomen. Hyperpigmentation occurs in some patients. Weight gain is common in Cushing’s syndrome. The pattern of weight gain is described as central, with fat deposits in the abdomen, chest, face, and neck that leads to the description of moon face and buffalo hump. Muscle weakness in the legs and arms and low blood potassium levels can occur. There is an increased risk of bone fractures (breaks) because of low bone density. Emotional status may range from depression to mania, and some patients experience mood swings, decreased concentration, and impaired memory. There are also dysfunctions of the reproductive system, loss of sexual drive, and menstrual abnormalities in women. High blood glucose levels can occur in Cushing’s syndrome. Patients with Cushing’s syndrome are also at higher risk of developing hypertension (high blood pressure) and cardiovascular disease (diseases that involve the heart and blood vessels). Thromboembolism (the blockage of a blood vessel from a blood clot) and increased risk of infections, especially with fungal or opportunistic microorganisms may also occur. The diagnosis of Cushing’s syndrome is made by evaluating the signs and symptoms, with confirmation by laboratory values. An endocrinologist is usually consulted to make a definitive diagnosis of Cushing’s syndrome.
Treatment of Cushing’s Syndrome
Therapy for Cushing’s syndrome is intended to reduce the cortisol concentration in the body to normal levels and avoid causing pituitary or adrenal insufficiency. Treating the hypercortisolism will also prevent or delay complications and deaths from hypercortisol-related disorders, such as diabetes, cardiovascular abnormalities, thromboembolism, and infections. The treatment method selected depends on the reason for the hypercortisolism. Surgical removal of the benign or malignant tumor in the pituitary or adrenal gland is the treatment of choice for patients with pituitary or adrenal adenomas or cancers. If removal is incomplete, radiation or chemotherapy may be required. In extreme cases, one or both adrenal glands must be removed.
Pharmacologic therapy is not indicated as the primary therapy for Cushing’s syndrome but instead is used while a patient is preparing for surgery or as additive therapy after surgery or radiation. Pharmacologic therapy is also selected for patients who are unable or unwilling to undergo surgery.13 Several classes of medications are used in the pharmacologic management of Cushing’s syndrome: steroidogenesis inhibitors, somatostatin agonist (pasireotide, subcutaneous injection), peripheral glucocorticoid antagonist (mifepristone, oral), dopamine agonist (cabergoline, oral). Most of these medications are used off-label for the management of Cushing’s syndrome. The most commonly prescribed medications are the steroidogenesis inhibitors, which prevent glucocorticoid production in the adrenal glands. Metyrapone, ketoconazole, etomidate, mitotane, and osilodrostat are steroidogenesis inhibitors. Osilodrostat is a recently available medication approved by the Food and Drug Administration for adults with Cushing’s disease who are not candidates for pituitary surgery or who still have hypercortisolism after undergoing the surgery. Metyrapone and ketoconazole inhibit enzymes that are involved with cortisol synthesis. Metyrapone is also used as a diagnostic test for hypothalamic-pituitary ACTH function. Etomidate is a general anesthetic agent that also inhibits enzymes involved in cortisol synthesis. Etomidate (the only steroidogenesis inhibitor that is available as an injectable formulation) is used in situations where rapid control of cortisol levels is necessary or the patient is not able to take medications by mouth. Mitotane inhibits the production of cortisol by destroying the adrenal gland.14,15 See Medication Table 9-3 for common dosing, side effects, and preparations of these drugs.16,17
Ketoconazole administration may increase the concentration of other drugs in the body and may result in drug toxicities due to this drug–drug interaction. Whenever a drug–drug interaction warning occurs upon ketoconazole being entered in a patient’s medication profile, a technician must be sure to notify the pharmacist. Examples of drug–drug interactions with ketoconazole include alprazolam, midazolam, triazolam, simvastatin, apixaban, dabigatran, certain HIV medications, dasatinib, fluticasone, and sirolimus, along with many others.
Metyrapone has drug interactions with phenytoin and acetaminophen. Phenytoin increases the inactivation of metyrapone, resulting in a lower concentration of metyrapone in the body. The metabolism of acetaminophen may be decreased by metyrapone, leading to an increased risk of acetaminophen toxicity. Notify the pharmacist if the patient is taking either of these drugs and is prescribed metyrapone.
LOOK-ALIKE/SOUND-ALIKE—Do not confuse etomidate with edetate disodium.
Mitotane is an anticancer drug and is considered a biohazard. Gloves should be worn not only when handling the tablets, but during receiving, unpacking, and placing the item in storage. The manufacturer cautions that these tablets should not be crushed.
Mitotane may increase the metabolism of many medications, including glucocorticoids such as prednisone and dexamethasone. Notify the pharmacist when a drug–drug interaction alert appears when mitotane is added to a patient’s medication regimen that contains these drugs.
Prevention of Drug-Induced Adrenal Insufficiency and Cushing’s Syndrome
Several strategies have been employed to minimize the risk for AI and Cushing’s syndrome associated with corticosteroid administration. To mimic the physiologic release of cortisol in the body, corticosteroid preparations with intermediate-acting duration, such as prednisone, are typically preferred and administered as a single dose after waking in the morning. This regimen causes less profound and shorter-lived adrenal suppression than divided doses or doses given at other times of the day.4,18 When patients take systemic corticosteroids for more than 7–14 days, slowly decreasing the dose (dosage tapering) can minimize the risk for adrenal suppression. In practice, most physicians develop their own withdrawal regimens based on previous experience. Pharmacy personnel must be careful with dosage calculations for these situations. Alternate-day dosing can minimize the risk for adrenal suppression by allowing the HPA axis to recover during the off days.18 Minimizing the corticosteroid dose to 7.5 mg or less and for the shortest duration of time needed for clinical benefit can help to prevent the development of drug-induced Cushing’s syndrome.
Some oral glucocorticoids (methylprednisolone and dexamethasone) are available in a “dose pack” package, which allows for ease of tapering the dose.
An excess amount of aldosterone in the blood is termed hyperaldosteronism, which can be classified as primary or secondary. Primary hyperaldosteronism, also known as primary aldosteronism (PA), is a result of overproduction of aldosterone due to stimulation within the adrenal glands, whereas secondary hyperaldosteronism results from stimulation coming from outside the adrenal glands.
The most common causes of PA are bilateral adrenal hyperplasia (enlargement of both adrenal glands) and aldosterone-producing adenoma. The diagnosis of PA involves evaluation of the aldosterone-to-renin ratio, aldosterone suppression test, genetic testing, computed tomography (CT) scan of the adrenal glands, and adrenal vein sampling (measurement of aldosterone from both adrenal veins). It is important that these tests are utilized to identify the exact cause of PA because treatment options are different depending on the cause. Bilateral adrenal hyperplasia is generally treated with drugs that inhibit aldosterone receptors, whereas aldosterone-producing adenoma needs surgical removal.19
PA is a common cause of resistant hypertension (high blood pressure despite being adherent on three or more blood pressure drugs at maximum doses). Patients with PA typically present with high blood pressure, as well as low potassium level and water retention. Additional signs and symptoms of PA include muscle weakness, fatigue, headache, and increased thirst. Additionally, patients with hypertension and sleep apnea, a family history of early onset of hypertension or stroke (at an age less than 40 years), and a first-degree family member diagnosed with PA are at higher risk for PA. If patients with PA are left untreated for a long time, they are at increased risk of cardiovascular disease and cerebrovascular disease (diseases that involve the blood vessels of the brain).20
Treatment of Hyperaldosteronism
The aldosterone receptor inhibitors spironolactone and eplerenone are the treatment of choice in patients with PA due to bilateral adrenal hyperplasia. They bind to aldosterone receptor to block the effects of endogenous aldosterone. Their effects also include an increase in blood potassium level and a decrease in blood pressure. Unlike eplerenone, which only binds to aldosterone receptors, spironolactone also binds to androgen and progesterone (a sex hormone involved in the menstrual cycle and pregnancy) receptors as well, causing additional side effects, such as gynecomastia (enlarged male breasts) and menstrual irregularities. The alternative to aldosterone receptor inhibitors is the potassium-sparing diuretic amiloride. Amiloride is reserved for patients who cannot tolerate either spironolactone or eplerenone because it is less effective than the aldosterone receptor inhibitors. These medications are discussed in detail in Chapter 15 and included in Medication Table 15-4.
As mentioned earlier, hyperaldosteronism due to aldosterone-producing adenomas requires surgical removal of the affected adrenal gland. The surgical removal improves blood pressure control and cures the disease in the majority of patients. If a patient is not a candidate for the surgery, an aldosterone receptor inhibitor is recommended as medical management.
Low aldosterone production causes hypoaldosteronism, which is a rare condition, seen more in patients with diabetes, postural hypotension, or a surgical history of adrenal gland removal. As noted earlier in this chapter, hypoaldosteronism can be part of an overall insufficiency of the adrenal gland (Addison disease) or a stand-alone disorder. Patients typically present with low sodium and high potassium concentrations in the body. Because the disorder is mainly due to deficiency in mineralocorticoid production, replacement with fludrocortisone is the treatment of choice.21
Disorders of the adrenal gland result in decreased or increased production of glucocorticoids or mineralocorticoids, and the clinical presentations differ significantly depending on the production level and the type of steroid hormones involved. Treatment for disorders of hypocortisolism involves administering glucocorticoids such as hydrocortisone, prednisone, or dexamethasone, and in some instances, also the mineralocorticoid fludrocortisone. In situations of physiologic stress, such as during surgery or severe illness, giving supplemental glucocorticoids is necessary to prevent adrenal crisis. Treatment for hypercortisolism involves eliminating the source of excessive cortisol. Long-term administration of glucocorticoid at higher doses than the body needs is the most common cause of AI and Cushing’s syndrome. Therefore, patient education and monitoring are needed when these medications are dispensed.
Aldosterone abnormalities can also occur together with disorders of glucocorticoids or by themselves as primary disorders. Treatment options for hyperaldosteronism depend on the cause, and aldosterone receptor inhibitors are the main pharmacological therapy for PA. Fludrocortisone is an effective therapy for hypoaldosteronism.
The authors wish to acknowledge and thank Jennifer Lee, PharmD, and Trinh Pham, PharmD, coauthors of this chapter in the first edition of this book.
What are the three major types of hormones that the adrenal glands secrete? What are the characteristics of each?
Catherine Jones is a 76-year-old female with rheumatoid arthritis who comes to your pharmacy every month to pick up her prescription for prednisone. You know that long-term corticosteroid use can increase the risk for osteoporosis. What counseling should the pharmacist provide to Mrs. Jones to minimize this risk?
Which route of administration of glucocorticoid can lead to the highest blood concentration?
What is the most common cause of adrenal insufficiency and Cushing’s syndrome? How can this be avoided?
Nancy Smith is a 40-year-old female with newly diagnosed Cushing’s syndrome based upon high blood cortisol level and a low-dose dexamethasone suppression test (LD-DST). She is prescribed ketoconazole for treatment of her hypercortisolism. The patient also has a diagnosis of anxiety and is on alprazolam. What should you do if a drug–drug interaction alert appears when you type ketoconazole into the patient’s medication profile?
Contains 30% alcohol; contains propylene glycol; dye-free and sugar-free; can be mixed with liquids or semisolid foods; use only the calibrated dropper provided with the product; do not store for future use; do not freeze
Dxevo, HiDex, TaperDex
Tablet therapy pack: 1.5 mg
21, 27, 35, 49, or 51 scored tablets on a taper dose card
Injectable solution: 4 mg/mL, 10 mg/mL
May need further dilution; prefilled syringe available at 10 mg/mL; protect from light, heat, and freezing
TopiDex, Active Injection D, DoubleDex, MAS Care-Pak, ReadySharp Dexamethasone
Augmented betamethasone dipropionate (bay ta METH a sone)
Not to exceed 2-wk use; avoid occlusive dressings; avoid use on face, groin, armpits, skin folds; higher risk for systemic absorption
Clobetasol propionate (kloe BAY ta sol)
Clobex, Cormax, Olux-E, Temovate, Temovate E, Tovet, generics
0.05% emollient cream
0.05% solution for scalp application
Fluocinonide (floo oh SIN oh nide)
Halobetasol propionate (hal oh BAY ta sol)
Amcinonide (am SIN oh nide)
Use occlusive dressings with caution; avoid use of occlusive dressings with augmented betamethasone dipropionate or betamethasone dipropionate; may use on scalp, trunk, hands, and feet; avoid use on face and skin folds
Betamethasone dipropionate (bay ta METH a sone)
Diprolene AF, generics
0.05% cream (augmented formulation)
Desoximetasone (des ox i MET a sone)
Diflorasone diacetate (dye FLOR a sone)
ApexiCon E, generics
Fluocinonide (floo oh SIN oh nide)
Halcinonide (hal SIN oh nide)
Triamcinolone acetonide (trye am SIN oh lone)
Betamethasone dipropionate (bay ta METH a sone)
May be used on scalp, trunk, or extremities; do not use occlusive dressings with mometasone
Betamethasone valerate (bay ta METH a sone)
Beta-Val, Luxiq, generics
Clocortolone pivalate (kloe KOR toe lone)
Desoximetasone (des ox i MET a sone)
Fluocinolone acetonide (floo oh SIN oh lone)
0.01% body oil
0.01% scalp oil
Flurandrenolide (flure an DREN oh lide)
Fluticasone propionate (floo TIK a sone)
Hydrocortisone butyrate (hye droe KOR ti sone)
Hydrocortisone probutate (hye droe KOR ti sone)
Hydrocortisone valerate (hye droe KOR ti sone)
Mometasone furoate (moe MET a sone)
Prednicarbate (pred ni KAR bate)
Triamcinolone acetonide (trye am SIN oh lone)
Kenalog®, Triderm®, Trianex®, generics
0.147 mg/g spray
Alclometasone dipropionate (al kloe MET a sone)
Low potency agents preferred in children; low potency agents preferred when large areas are to be covered; low potency agents preferred on the face and skin folds; hydrocortisone is available by prescription or over the counter (nonprescription) based on strength and formulation; maximum strength of nonprescription hydrocortisone available is 1%