Adrenal Insufficiency: What Pharmacists Should Know

Pharmacy Times
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The adrenal gland is divided intothe adrenal medulla, which producescatecholamines such asepinephrine and norepinephrine, and theadrenal cortex, which produces corticalsteroids such as cortisol, aldosterone,and androgens, all of which are neededto maintain homeostasis in the body. Theadrenal cortex is further subdivided into3 regions: the zona glomerulosa, which isresponsible for producing mineralocorticoids(eg, aldosterone); the zona fasciculata,which secretes glucocorticoids (eg,cortisol); and the zona reticularis, whichreleases androgens (eg, testosterone).1,2

The levels of these cortical steroids areregulated through the hypothalamuspituitary-adrenal (HPA) axis (Figure). Inresponse to inadequate levels of corticalsteroids in the body, the hypothalamuswill secrete corticotropin-releasing hormone(CRH), which exerts a positivefeedback on the anterior pituitary glandto release adrenocorticotropic hormone(ACTH). ACTH then stimulates the releaseof cortical steroids from the adrenalgland. The cortical steroids have the abilityto inhibit the release of both CRH andACTH from the hypothalamus and thepituitary gland, respectively, through anegative feedback loop.1,2

Cortisol is the principal glucocorticoidproduced by the zona fasciculata. Therelease of this hormone results in proteinand fat catabolism, gluconeogenesis inthe liver to increase blood glucose levels,increased bone resorption with decreasedbone formation, inhibition of theimmune system, and a reduction inprostaglandins leading to an anti-inflammatoryresponse.

Aldosterone is the predominantmineralocorticoid releasedfrom the zona glomerulosa. Itsrelease will lead to hypernatremiaand hypokalemia, oncestimulated by ACTH, elevatedpotassium levels, and/or therenin-angiotensin-aldosteronesystem (RAAS). Ultimately, aldosteronerelease can lead tohypertension and edema.

Androgens produced fromthe zona reticularis are responsiblefor the expression of sexcharacteristics such as axillaryand pubic hair.1

Adrenal insufficiency resultswhen there is an inadequatelevel of glucocorticoids to regulatenormal body functions.Primary adrenal insufficiencyis due to a disorder of theadrenal glands, whereas secondaryadrenal insufficiency resultsfrom diminished secretion of ACTHfrom the anterior pituitary gland.1,2

Primary Adrenal Insufficiency

The most common cause of primaryadrenal insufficiency, also known asAddison's disease, is an autoimmunedestruction of the adrenal cortex. Itaccounts for 70% of cases. The estimatedprevalence of Addison's disease is 60to 110 cases per 1 million people.3

Because the entire adrenal cortex hasbeen destroyed by the body's own antibodies,deficiencies in cortisol, aldosterone,and androgens occur. In a patientwith Addison's disease, plasma ACTH andpotassium levels typically are elevated,and plasma cortisol levels are reduced.

Other causes of primary adrenal insufficiencyinclude infections such as tuberculosisand polyendocrine deficiencysyndrome.4 Signs and symptoms ofAddison's disease result when approximately90% of the adrenal cortex hasbeen destroyed.1-3

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency ismore common than primary adrenalinsufficiency. It typically results fromabrupt withdrawal from chronic steroiduse. Because the exogenous administrationof steroids has resulted in suppressionof the HPA axis, there is a reductionin cortisol and androgen levels as well asplasma ACTH levels. Aldosterone levelstypically remain normal because of stimulationfrom the RAAS.5

Symptoms and Diagnosis

Patients with adrenal insufficiencygenerally present with flu-like symptomssuch as fever, shaking, chills, headache,diarrhea, cramping, vomiting, weakness,and fatigue. Other symptoms includevertigo, hypotension, depression, saltcraving, and vitiligo (depigmentedpatches of skin). Hyperpigmentationoften is seen in patients with Addison'sdisease because ACTH can stimulatemelanocytes to produce excessive levelsof melatonin. Patients with secondaryadrenal insufficiency have low levelsof ACTH and generally do not experiencehyperpigmentation.1-3,6,7

The diagnosis of adrenal insufficiencycan be confirmed through the use of acosyntropin-stimulation test. During thistest, 250 ?g of synthetic ACTH is givenintravenously or intramuscularly. Plasmacortisol levels are assessed at baselineand at 30 and 60 minutes after administrationof the hormone. If cortisol levelsrise above 18 ?g/dL, generally there is noadrenal insufficiency.2,6


The treatment of choice for a patientwith primary adrenal insufficiency isexogenous replacement with glucocorticoidssuch as prednisone, hydrocortisone,or cortisone. They typically areadministered in doses that mimic physiologicpatterns. Normally, there is a diurnalvariation in cortisol secretions, withthe highest peak occurring between 6and 8 AM and a decline throughout theday. A second smaller peak occurs in thelate evening or early morning. Therefore,in order to mimic endogenous secretions,the glucocorticoids are given twicedaily. The starting dose generally is prednisone2.5 mg or hydrocortisone 15 mgor cortisone 20 mg in the morningbetween 6 and 8 AM, with a subsequentevening dose of ~33% to 50% of themorning dose.

Common adverse drug reactions associatedwith glucocorticoids include sodiumretention, which can lead to edema,hyperglycemia, increased susceptibilityto infections, osteoporosis, cataracts,seizures, peptic ulcer disease, and hypokalemia.Drugs such as phenobarbital,phenytoin, and rifampin can enhance theclearance of glucocorticoids, which maynecessitate higher doses of steroids tomaintain homeostasis. Estrogens, pregnancy,increasing age, and liver diseasecan lead to a reduction in glucocorticoidclearance, allowing lower doses ofsteroids to be used. In addition, anyunderlying conditions that have led toadrenal insufficiency, such as tuberculosis,should be treated adequately.1-3,6,8

To avoid the development of secondaryadrenal insufficiency, patients treatedwith chronic steroids, usually for >14days of consecutive therapy, shouldundergo a taper of the glucocorticoid. Inpatients receiving chronic steroid administrationfor conditions such as rheumatoidarthritis, alternate-day dosing is preferredto reduce the risk of HPA axis suppression,once the patient has beenstabilized.1

The exogenous replacement of mineralocorticoidsis warranted in Addison'sdisease due to the destruction of thezona glomerulosa. Fludrocortisone acetate(Florinef) may be used in doses of0.05 to 0.2 mg per day to reduce elevatedpotassium levels, increase serumsodium levels, and/or treat posturalhypotension. Patients with secondaryadrenal insufficiency typically do notrequire therapy with a mineralocorticoidbecause aldosterone levels have beenpreserved due to stimulation by theRAAS. Patients receiving fludrocortisoneacetate may experience gastrointestinalupset, edema, hypertension, hypokalemia,insomnia, and excitability.Therefore, judicious monitoring of electrolytes,blood pressure, and weight iswarranted.1,8

Stress, abrupt withdrawal from glucocorticoids,trauma, infection, surgery, anddehydration are potential triggers foracute adrenal insufficiency, also knownas an addisonian crisis. Early signs of thismedical emergency include malaise,weakness, and myalgias. As cortisol levelsremain low, patients may developsevere hypotension, vascular collapse,acute renal failure, and hypothermia.

This acute condition should be treatedimmediately with 100 mg of intravenoushydrocortisone, followed by a continuousinfusion for 24 to 48 hours. Fluid replacementto correct hyponatremia shouldoccur during the first 4 hours. After 24 to48 hours, the dose of hydrocortisoneshould be tapered to 50 mg by mouthevery 8 hours for an additional 48 hours.The dose should then be tapered over 2to 3 days to a maintenance dose of 30 to50 mg per day. If the patient remainshyperkalemic once on hydrocortisonemaintenance therapy, the addition of fludrocortisoneacetate should be considered.1,2,6

Patient Education

Patient education is the key to successfulmanagement of adrenal insufficiency.Pharmacists should advise patientsnever to stop therapy with a glucocorticoidor a mineralocorticoid withoutseeking their health care provider'sadvice. Patients also should be encouragedto wear medical-alert braceletsindicating, in case of an emergency, thatthey are receiving chronic therapy with aglucocorticoid.

Counseling regarding the anticipatedadverse effects of glucocorticoids shouldbe emphasized. Recommendations for acalcium and vitamin D supplement maybe warranted to minimize the risk forosteoporosis. Patients with diabetes mellitusmay be advised to monitor theirblood sugar levels more frequently untilglycemic control is achieved and maintained.

In the event of a missed dose of theglucocorticoid, patients should be instructedto take the dose as soon as possiblebut to skip the dose if it is almosttime for the next dose. They should notdouble the dose of the glucocorticoid.Refill reminders for patients with adrenalinsufficiency can possibly increaseadherence to glucocorticoid therapy.2

Dr. Brown is an assistant professor ofpharmacy practice at Palm BeachAtlantic University, West Palm Beach,Fla.

For a list of references, send a stamped,self-addressed envelope to: ReferencesDepartment, Attn. A. Rybovic, PharmacyTimes, Ascend Media Healthcare,103 College Road East, Princeton, NJ 08540;or send an e-mail request

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