USP Continuing Education - Therapeutic and Adverse Effects of Glucocorticoids

Glucocortocoids’ potency is double-edged: while critical in tempering certain disease states, they can also cause a number of complications.

Corticosteroids have been in use for over 40 years.^1-3 Over time they have become indispensable in controlling a variety of disease states. Currently, glucocorticoids are available in numerous formulations: oral, topical, ophthalmic solutions and ointments, oral inhalers, nasal formulations, parenteral and rectal preparations. Various complications associated with this drug class warrant caution and monitoring with each formulation. This article will address the therapeutic benefits of glucocorticoids as well as the consequences attributed to oral, topical and parenteral formulations.

Hypothalamic-Pituitary-Adrenal Axis
The adrenal cortex produces and secretes two types of steroid hormones: sex steroids and corticosteroids. Corticosteroids are characterized by mineralocorticoid and glucocorticoid effects, depending on the predominant pharmacologic action of the agent. There is considerable overlap in the corticosteroid classification scheme, because many glucocorticoids possess some degree of mineralocorticoid activity (Table 1). Doses of commonly used mineralocorticoids are often too small to exert any appreciable anti-inflammatory effect.⁴

Table 1 Corticosteroid Comparison
		Relative Potency		Half-Life
Agent	Equivalent Glucocorticoid Dose (mg)	Anti-inflammatory	Mineralocorticoid	Plasma (min)	Biologic (hrs)
Short-Acting Agents
Cortisone	25	0	++	30	8–12
Hydrocortisone	20	0	++	90	8–12
Intermediate-Acting Agents
Prednisone	5	+	+	60	12–36
Prednisolone	5	+	+	200	12–36
Triamcinolone	4	+	0	300	12–36
Methylprednisolone	4	+	0	180	12–36
Long-Acting Agents
Dexamethasone	0.75	++	0	200	36–54
Betamethasone	0.6	++	0	300	36–54
Reference: Adapted from Reference 8.

Table 2 Therapeutic Uses of Corticosteroids
Oral	Addison’s disease Acquired hemolytic anemia Acute mountain sickness Allergic reactions Antiemetic Asthma Chronic obstructive pulmonary disease Crohn’s disease Collagen diseases (exacerbation, maintenance) Congenital hypoplastic anemia Dermatologic disorders Drug hypersensitivity reactions Graves ophthalmopathy Exfoliative dermatitis Hepatitis Hirsutism Hypercalcemia (secondary to neoplasia) Leukemias Lymphomas Muscular dystrophy Multiple sclerosis Organ transplan Pemphigus Primary or secondary adrenal cortical insufficiency Rheumatic disorders Ulcerative colitis
Oral inhaled	Asthma
Nasal inhaled	Allergic rhinitis Nonallergic (vasomotor) rhinitis Nasal polyps
Ocular	Allergic conjunctivitis Allergic corneal marginal ulcers Corneal injury Cyclitis Diffuse posterior uveitis and choroiditis Iritis Keratitis Keratoplasty Nonspecific superficial keratitis Optic neuritis Superficial punctate keratitis
Topical	Allergic contact dermatitis Anogenital pruritus Atopic dermatitis Burns Eczema Insect bite reactions Lichen simplex chronicus Psoriasis Seborrheic dermatitis Xerosis
Parenteral	Acute spinal cord injury Allergic reactions Anemias Bacterial meningitis Cerebral edema Idiopathic thrombocytopenia purpura in adults Pneumocystis carinii Septic shock Urticarial transfusion reactions
Rectal	Cryptitis Factitial proctitis Hemorrhoids Ulcerative colitis
Reference: Adapted from References 8 and 11

Aldosterone is the principal mineralocorticoid hormone in the human body. It causes sodium and water retention in the distal tubule of the kidney and increased excretion of potassium. The increase in circulating blood volume is often the desired effect in patients with adrenal insufficiency, but it can lead to hypertension and edema in other patients.

The principal glucocorticoid hormone in humans is cortisol. The physiologic effects of glucocorticoids are diverse. These agents regulate the metabolism of proteins, carbohydrates, and lipids. Glucocorticoids cause protein and fat breakdown. They promote gluconeogenesis in the liver, which leads to increased blood glucose levels.⁴ Glucocorticoids cause a decrease in circulating lymphocytes (including T cells), eosinophils, basophils, monocytes, and macrophages. This may be due to redistribution of these cells out of the blood and into other body compartments. Glucocorticoids conversely cause an increase in the numbers of circulating neutrophils, hemoglobin, and erythrocytes. The anti-inflammatory effects of glucocorticoids are related to decreased production of prostaglandins and leukotrienes.⁵

Hormone production by the adrenal gland is influenced by many factors. Normal cortisol production follows a diurnal cycle. Levels peak in the early morning hours (6 am–8 am) and decline throughout the day with a second, lower peak in the late afternoon (4 pm–6 pm).⁴ Cortisol secretion from the adrenal gland is also increased in response to stress (physical or emotional) and low endogenous glucocorticoid levels. The response of the hypothalamus in these situations is to secrete corticotropin-releasing hormone (CRH). CRH prompts the anterior pituitary to secrete adrenocorticotrophic hormone (ACTH), which leads to increased production and secretion of cortisol by the adrenal cortex. Increased levels of cortisol or exogenously administered glucocorticoids cause a feedback inhibition of CRH and ACTH secretion.^4,6 A defect at any point along this hypothalamic-pituitary-adrenal (HPA)-axis could disrupt normal physiologic glucocorticoid levels.

Kinetics
Glucocorticoids used in therapy are synthetic preparations possessing unique pharmacokinetic characteristics. After oral administration, glucocorticoids are completely absorbed in the upper jejunum, with peak plasma levels in 30–100 minutes.⁷ Food delays the time to achieve peak concentrations, but does not affect overall bioavailability.² Corticosteroids are primarily bound to corticosteroid binding protein and albumin. Corticosteroids undergo hepatic metabolism and are renally eliminated.² However, prednisone and cortisone are converted in the liver to their active components prednisolone and hydrocortisone.^4,11

Percutaneous absorption of topical corticosteroids depends on the individual glucocorticoid, vehicle, duration of exposure, surface area, and skin condition. Absorption of topical glucocorticoids is enhanced by increased skin temperature, hydration, intertriginous areas (axilae, groin), and areas of thin or abraded skin.⁸ Ointment formulations deliver more glucocorticoid to the skin.⁹ Occlusive dressings also increase absorption.^8,9 Following topical absorption, glucocorticoids enter systemic circulation, are metabolized, exert physiological or pharmacological effects, and are excreted in the same manner as systemically administered corticosteroids.⁸

Oral inhaled glucocorticoids were designed for topical administration; therefore, bioavailability and elimination studies were not required for marketing.¹⁰ Desirable pharmacokinetic properties include retention in bronchial fluid, rapid inactivation when absorbed from lungs, and poor oral absorption along with extensive first-pass inactivation.¹⁰

Nasal formulations primarily deposit medication in the nasal passages, although a portion of the inhaled dose is swallowed. Absorption occurs rapidly from respiratory and gastrointestinal tissues. Corticosteroid levels are virtually undetectable in plasma. Absorbed drug is excreted as metabolites through bile and urine.¹¹

Following topical application into the conjunctival sac, glucocorticoids are absorbed into the aqueous humor. Systemic absorption may occur, although clinical evidence of this is rare, and severe systemic reactions are infrequent.¹¹

Intravenous and intramuscular absorption is dependent on the solubility of the agent used. Additional routes of administration for parenteral glucocorticoids include intra-articular, intrabursal, intrasynovial, intralesional and subcutaneous. Systemic absorption has been reported with all aforementioned routes of administration.¹¹

Therapeutic Uses
Numerous disease states respond to glucocorticoids. Physiologic doses of corticosteroids are used for replacement therapy in primary and secondary adrenal insufficiency, such as Addison’s disease. More commonly, glucocorticoids are used in supraphysiologic doses for their anti-inflammatory effects in arthritis, asthma, and inflammatory bowel disease. Transplant patients and those with autoimmune disorders may use corticosteroids for their immunosuppressive effects. Often overlooked uses for corticosteroids include antiemesis, mountain sickness and hirsutism (Table 2).³

Oral Glucocorticoids
The most commonly used classification scheme for glucocorticoids is based on duration of action. Glucocorticoids can generally be administered once daily, because their duration of action is significantly longer than their plasma half-life. Once-daily dosing may not apply to patients receiving glucocorticoids for replacement therapy (Addison’s disease). Anti-inflammatory and mineralocorticoid potency also differ among glucocorticoids. Short-acting agents have greater mineralocorticoid (salt-retaining) and less glucocorticoid (anti-inflammatory) potency. Long-acting agents have greater glucocorticoid activity with less mineralocorticoid potency (Table 1).⁸

Administration of exogenous glucocorticoids leads to suppression of cortisol production by the adrenal cortex via the negative feedback mechanism previously described. HPA-axis suppression is a well-known adverse effect of glucocorticoid therapy; however, considerable controversy exists over the dose and duration of glucocorticoid therapy required to suppress the HPA-axis. Some of the many factors that influence HPA-axis suppression include time of day that the doses are administered, route of administration, dose and duration of therapy, and duration of action of the agent used.⁶

In an adult who is not experiencing stress, the average amount of cortisol secreted by the adrenal gland is equivalent to 5 mg of prednisone.⁴ Any dose greater than this is considered supraphysiologic and could cause HPA-axis suppression. Streck and colleagues studied duration of HPA-axis suppression caused by 25 mg of prednisone administered twice daily for five days to healthy volunteers. In these patients, adrenal response to ACTH was still suppressed five days after discontinuing the prednisone.¹²

Musculoskeletal Complications: Glucocorticoids are the most common cause of drug-induced osteoporosis.¹³ Glucocorticoids induce osteoporosis by suppressing intestinal calcium absorption, decreasing sex hormone production, and inhibiting bone formation. Approximately one out of five patients treated for one year with 7.5–10 mg of daily prednisone will develop skeletal fractures.¹⁴ Patients at increased risk are over 50 years of age, postmenopausal, or have restricted mobility.¹³

All patients requiring long-term glucocorticoid therapy are candidates for osteoporosis prevention.¹³ Lifestyle modifications such as smoking cessation, initiating a weightbearing exercise regimen, and reducing alcohol consumption are encouraged in all patients. Calcium (1,500 mg/day) and vitamin D (800 IU/day) supplementation are also recommended.¹³ Alternate-day dosing of glucocorticoids does not prevent osteoporosis. The lowest possible steroid dose should be used, in order to minimize osteoporosis development.¹⁵

Several pharmacological agents are available for the treatment of glucocorticoid-induced osteoporosis. Thiazide diuretics may improve calcium absorption and decrease urinary calcium excretion. Postmenopausal women are encouraged to receive hormone replacement therapy, provided no contraindications are present. Men may benefit from testosterone replacement if serum testosterone levels are low.¹³ Calcitonin injection and nasal spray are effective in preventing and treating glucocorticoid-induced osteoporosis. Bisphosphonates (etidronate, pamidronate, alendronate) are also used to prevent glucocorticoid-induced osteoporosis.^13,16

Steroid-induced myopathy is a rare effect attributed most often to fluorinated agents, particularly triamcinolone.^2,7 This complication may be attributed to decreased muscle uptake of glucose and amino acid in affected muscles. Sudden muscle weakness is an initial manifestation and muscle wasting may occur.⁷ Steroid-induced myopathy is proximal and symmetrical and may involve both upper and lower extremities.² Predisposing characteristics for this complication are unknown.⁷ There is no known association between duration or dosage of steroid therapy and myopathy.² Steroid-induced myopathy usually resolves upon steroid discontinuation.²

Avascular necrosis (osteonecrosis) occurs predominantly in active patients on long-term, high-dose corticosteroids.¹⁴Avascular necrosis is probably secondary to the loading phenomenon on the hip induced by exercise.¹⁴ The most common site of avascular necrosis is the femoral head.¹⁷ Patients may complain of bone pain or discomfort in the groin.¹⁷ Treatment involves medical management and trauma avoidance in patients requiring long-term glucocorticoids.¹⁴

Ophthalmic Complications: It is estimated that over 30% of patients treated with systemic glucocorticoids develop posterior subcapsular cataracts.^2,14 The pathology of cataract formation is uncertain. Both dose and duration of glucocorticoid therapy are implicated in cataract development. Once cataracts develop, they may progress despite discontinuation of glucocorticoid therapy. Children are at increased risk for cataract formation secondary to glucocorticoid administration.⁷ Because visual difficulties do not occur until late in the cataract development, slit-lamp examinations should be performed every 6–12 months.¹⁴ Alternate-day therapy does not minimize cataract formation.7

Risk factors for increased intraocular pressure include diabetes, myopia and family history of glaucoma. Glucocorticoid discontinuation usually reverses increases in intraocular pressure.⁷ Glaucoma patients using oral glucocorticoids should have their intraocular pressure monitored regularly (every 6 months to yearly).

Gastrointestinal Complications: Peptic ulcer disease is often associated with oral glucocorticoid administration notwithstanding lack of evidence documenting a direct cause and effect relationship.^4,18 Proposed mechanisms for glucocorticoid-induced ulcers include increased gastric acid secretion, prostaglandin inhibition, and immunosuppressive effects.4 The exact incidence of glucocorticoid-induced peptic ulcer disease is unknown.

Characteristics that may signal increased risk of developing glucocorticoid-induced ulcers are coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs), >1 gram of prednisone (or equivalent) total dose, or duration of therapy >30 days.¹⁸ Alternate-day dosing has not been evaluated in association with glucocorticoid-induced ulcers. Patients are encouraged to ingest glucocorticoids with food to minimize adverse GI effects.⁸ Prophylaxis with antacids, histamine-2 receptor blockers, proton pump inhibitors, and misoprostol is debatable.¹⁸

Cardiovascular Complications: The most often recognized cardiovascular complication of glucocorticoid administration is hypertension. However, its rate of occurrence, severity, exact mechanism, and relation to dose and duration is not well defined in the literature.¹⁴ Glucocorticoid-induced hypertension is more common among the elderly, patients with a history of hypertension, and patients using glucocorticoids with enhanced mineralocorticoid activity.¹⁴ Blood pressure usually returns to patient baseline upon glucocorticoid discontinuation.¹⁹ If long-term glucocorticoid therapy is required, associated hypertension may be managed through sodium restriction and thiazide diuretics.⁷

Dermatological Complications: Various dermatological effects are associated with oral glucocorticoid use, such as subcutaneous fat redistribution, skin thinning, purpura, atrophic striae, and acneiform eruptions. Allergic reactions reported with systemic glucocorticoids include maculopapular eruptions and urticaria. Oral therapy may impair wound healing and predispose patients to cutaneous fungal infections.²

Carbohydrate and Lipid Metabolism: Glucocorticoid administration can lead to hyperglycemia through increased gluconeogenesis.⁴ The exact incidence of new onset diabetes mellitus, its severity, and relation to dose and duration are unknown. Glucose intolerance may develop early in glucocorticoid therapy, but is rarely associated with complications. The majority of patients revert to prior glucose status upon discontinuation of treatment.⁷ Diabetic patients should monitor blood glucose levels for appropriate modifications in therapy.²

Increased triglycerides and cholesterol are associated with glucocorticoid therapy. Patients with lipid abnormalities are at increased risk for glucocorticoid-associated hyperlipidemia.⁷

Central Nervous System Complications: Glucocorticoid hormone administration has been associated with a wide range of psychiatric and central nervous system (CNS) effects. Some of the commonly reported CNS effects seen with glucocorticoids include anxiety, insomnia, depression, euphoria, and mood lability.⁸

Some patients have even experienced overt psychosis. The term “steroid psychosis” has been used to describe this phenomenon, but the presentation can vary greatly from patient to patient.²⁰ Hall and colleagues found that psychotic reactions occurred at approximately equal rates in patients with and without a history of psychiatric illness.¹ All patients receiving glucocorticoids are at risk of experiencing this adverse effect. In general, studies have found a correlation between increased glucocorticoid doses (greater than 40 mg of prednisone) and risk of psychiatric symptoms. Symptoms tend to occur during the first few weeks of treatment and generally subside when the glucocorticoid is discontinued or the dose is decreased. Most patients will experience complete recovery.¹ When symptoms do not respond to dosage reduction, the symptoms must be managed medically. Phenothiazines have been effective, but tricyclic antidepressants may worsen the symptoms.^1,20

Upon discontinuation or abrupt dosage decrease of glucocorticoids, patients can experience vague CNS symptoms such as nausea, anxiety, lethargy, and sleep disturbances. This is often referred to as steroid withdrawal syndrome. The exact mechanism of steroid withdrawal syndrome is unknown, but has been reported in patients with and without documented HPA-axis suppression.²¹ This withdrawal syndrome may involve psychosis.²² When CNS symptoms are attributed to steroid withdrawal syndrome, they are usually relieved by slowing the tapering schedule.^21,22

Infections: The link between glucocorticoid use and infections is controversial.^2,7,14Although infections are more frequent in patients receiving glucocorticoids,⁵ it is not certain whether this can be attributed to the disease process itself or glucocorticoid-induced changes in lymphocytes and macrophages. Alternate-day therapy has been shown to decrease infection risk.²³ Clinicians need to be aware that the anti-inflammatory and immunosuppressant actions of the glucocorticoids can mask many of the typical signs and symptoms of infection.²

Dosing Considerations
Once-daily dosing is usually preferred for oral glucocorticoids. In clinical practice, large steroid doses are often administered in divided doses to reduce local gastrointestinal effects and diminish variations in therapeutic efficacy throughout the day. In order to mimic the normal diurnal cortisol cycle and reduce the risk of adrenal suppression, glucocorticoids should be given in the morning between 6–8 am.⁶

Alternate-day dosing minimizes HPA-axis suppression and reduces the incidence of most glucocorticoid adverse effects. By dosing glucocorticoids every other morning, the HPA-axis recovers in the last 12 hours of the off day of therapy.² Intermediate-acting glucocorticoids, such as prednisone, are most appropriate for alternate-day therapy. Long-acting agents, such as dexamethasone, do not allow the HPA-axis to recover on the off day and therefore are not used in alternate-day dosing. Short-acting agents, such as hydrocortisone, may not provide sufficient glucocorticoid effects to manage symptoms on the off day. Alternate-day dosing does not minimize the risk of osteoporosis or cataract formation.^2,7

In clinical practice, the goal of tapering glucocorticoids is usually to prevent disease flare-up, not to prevent adrenal crisis. Many tapering schedules are described in the literature. The tapering and withdrawal process selected will depend on the severity of the patient’s disease state, dose and duration of glucocorticoid use, and the potential for HPA-axis suppression.

Most tapering schedules reduce the glucocorticoid dose by 2.5–5 mg of prednisone equivalent weekly. If the patient exhibits signs and symptoms of adrenal insufficiency, steroid withdrawal syndrome or disease flare-up during tapering, the previous dose should be reinstituted and the taper should proceed more slowly. Once the glucocorticoid dose is reduced to 5 mg of prednisone equivalent, the patient may be switched to a shorter-acting agent for further tapering.¹¹

High or supraphysiologic doses of glucocorticoids used for a short duration may be discontinued without tapering. In general, patients receiving daily glucocorticoid therapy above physiological doses for two weeks or less may have therapy discontinued without tapering. Tapering should be considered after two weeks of continuous therapy.⁶ Patients on prolonged therapy with oral glucocorticoids (greater than 1 year) may need to be tapered over several months.²⁴

Disease states resulting in decreased levels of serum albumin may affect glucocorticoid dosing. Less protein binding results in an increased therapeutic effect of glucocorticoids or a greater potential for toxicity.² Hypothyroidism may lead to an increased therapeutic effect of glucocorticoids due to decreased synthesis of corticosteroid-binding globulin (CBG). Conversely, in hyperthyroidism, an increased synthesis of CBG may lead to diminished glucocorticoid effects.⁴ Liver disease may also prevent the conversion of prednisone to its active moiety, prednisolone.¹⁹

Drug Interactions
Coadministration with medications that induce cytochrome P450 enzymes—barbiturates, phenobarbital, phenytoin or rifampin—may necessitate an increase in glucocorticoid dose (Table 3). Estrogen co-administration may reduce corticosteroid clearance.⁸ Prednisolone half-life may be decreased by long-term use of other steroids.²⁵ Chronic steroid users may require prednisolone dose adjustments secondary to steroid therapy resistance.²

Administration of live attenuated or bacterial vaccines should be avoided in immunosuppressed patients (those receiving >10 mg of prednisone or equivalent for >2 weeks). An inadequate response to inactivated vaccines may occur with immunosuppression secondary to high doses of steroids. Low to moderate dose, short-term glucocorticoid therapy (<14 days) and doses used for replacement therapy are not considered contraindications for vaccine administration.¹⁴ The precise time interval from discontinuing immunosuppressive therapy to regaining the ability to respond to vaccines in unknown. Tuberculin skin test reactivity may be suppressed for up to five to six weeks in patients using glucocorticoids.⁸

Tuberculin skin test and anergy panels are sometimes recommended before long-term therapy with systemic steroids.²⁶ Long-term glucocorticoid users should avoid patients with chickenpox or measles.^8,11

Table 3 Glucocorticoid Drug Interactions
Aminoglutethimide	Possible loss of dexamethasone-induced adrenal suppression
Amphotericin B	Monitor patients for hypokalemia
Antacids	Decrease absorption of corticosteroids
Anticholinesterases	Anticholinesterase effects may be antagonized in myasthenia gravis
Anticoagulants (oral)	Anticoagulant dose requirements may be reduced. Conversely, corticosteroids may oppose anticoagulant action
Barbiturates	Decrease effects of corticosteroid
Carbamazepine	Decrease effects of corticosteroid
Cholestyramine	Decrease hydrocortisone AUC*
Contraceptives (oral)	Decrease corticosteroid clearance, Increase t1/2
Cyclosporine	Increase risk of toxicity
Digitalis glycosides	Increase risk of digitalis toxicity associated with hypokalemia
Diuretics	Monitor patients for hypokalemia
Ephedrine	Increase clearance of dexamethasone
Estrogens	Increase corticosteroid clearance
Hydantoins	Increase corticosteroid clearance, possible decrease therapeutic effects
Isoniazid	Decrease isoniazid serum concentrations
Ketoconazole	Decrease corticosteroid clearance, Increase AUC
Macrolides	Decrease methylprednisolone clearance
Phenobarbital	Increase corticosteroid clearance, possible decrease therapeutic effect
Phenytoin	Increase corticosteroid clearance, possible decrease therapeutic effect
Rifampin	Increase corticosteroid clearance, possible decrease therapeutic effect
Salicylates	Decrease serum salicylate levels, decrease salicylate effectiveness
Theophyllines	Alteration in activity of corticosteroid or theophylline may occur, monitor theophylline levels
Vitamin A	High corticosteroid doses may impair conversion of carotene to vitamin A, risk of carotenemia
*AUC: Area under the curve Adapted from references 8 and 14

Monitoring Parameters
Adverse consequences related to glucocorticoid use are minimized through appropriate patient monitoring. Hypertensive patients should have their blood pressure recorded at every doctor visit. Patients with congestive heart failure may require more frequent monitoring to assess for mineralocorticoid effects of glucocorticoids and should be encouraged to record their weight daily to assess fluctuations in weight. Baseline blood glucose, lipid panel and urinalysis should be obtained. Diabetic patients may require more frequent glucose monitoring. All patients at risk for osteoporosis should have a bone mineral density exam done at baseline and annually.¹³ Slit-lamp exams should be completed every 6–12 months to check for cataracts. Patients at risk for glaucoma should have their intraocular pressure monitored.²⁷ To minimize gastrointestinal complications, patients should avoid concomitant NSAID use and take glucocorticoids with food. Patients should be educated about signs and symptoms of steroid myopathy, avascular necrosis, infection, and CNS effects.

Topical Glucocorticoids
Topical glucocorticoids possess anti-inflammatory and antimitotic activity. They are effective in a variety of acute and chronic inflammatory diseases.⁹ Topical corticosteroids are classified according to vasoconstrictor assay and/or clinical efficacy in alleviating signs and symptoms of inflammatory dermatoses.^9,28 Therapeutic efficacy may be increased by augmenting corticosteroid concentration, using occlusive dressings, or changing the vehicle (creams to ointments, augmented formulations). The more potent the glucocorticoid, the greater the risk of adverse effects.

Adverse effects produced by topical glucocorticoids are considered local or systemic. Common local effects include skin atrophy, epidermal thinning, acneiform eruption, hypertrichosis, telangiectasia, striae, delayed wound healing, and hypersensitivity reactions.²⁹ Skin atrophy is often reversible upon steroid discontinuation. Striae most commonly occur in intertriginous areas and are usually not reversible. The steroid, vehicle, or both may cause hypersensitivity reactions.^9,28

Systemic effects from topical glucocorticoids depend on several factors: the amount of steroid applied, surface area, application frequency, potency, and occlusion.^8,9,28 Potent topical glucocorticoids or less potent steroids with occlusion display laboratory evidence of adrenal sup-pression.⁹ These aberrations are not of clinical significance in patients with sufficient adrenal reserve to handle stress.⁹ Iatrogenic topical glucocorticoid-induced adrenal insufficiency may develop when long-term therapy with a potent topical steroid is discontinued.⁹ Iatrogenic topical glucocorticoid-induced Cushing’s syndrome may also occur.^9,30 Hyperglycemia and hypertension may occur or be aggravated with topical glucocorticoids. Growth suppression has been associated with chronic use.⁹

Pharmacists should be aware of general guidelines for proper use of topical glucocorticoids. The lowest-potency steroid should be selected and used for the shortest possible time. Lower-potency steroids are for routine use, with higher-potency agents reserved for resistant areas. Combinations of topical steroids and anti-infectives may prevent proper diagnosis and should therefore be avoided. In general, topical steroids should not be used on healing ulcers.²⁸ The face is particularly susceptible to local adverse effects and systemic effects. Fluorinated agents applied to the face may produce a rosacea-like eruption.³¹

Vehicle formulation should match the application site to minimize adverse events and improve percutaneous absorption. Aerosol sprays and foams are preferred for intertriginous and hair-bearing skin. Creams and lotions are used in glabrous (hairless), intertriginous, and hair-bearing skin. If the hair is short or sparse, ointments may be utilized. Impregnated tape is reserved for glabrous skin; gels are reserved for hair-bearing skin.⁹

Newer vehicles have enhanced percutaneous absorption. Compounding pharmacists should be aware that uncontrolled extemporaneous manipulation of these optimized vehicles might alter the steroid/vehicle balance, compromising optimal effects.⁹

Oral Inhaled Glucocorticoids
Inhaled glucocorticoids are the drugs of choice for managing persistent asthma.³² The relative anti-inflammatory potency of inhaled glucocorticoids is as follows: flunisolide = triamcinolone acetonide < beclomethasone dipropionate = budesonide < fluticasone.¹⁰ Currently, no evidence exists for greater efficacy of one inhaled product over another in relative equipotent doses.¹⁰ Direct administration to the respiratory tract minimizes the risk for adverse effects seen with oral therapy. Common adverse effects include dysphonia, cough, and localized fungal infections with Candida albicans. Using spacer devices and rinsing the mouth after administration may minimize these adverse effects.^8,11,32

Unfortunately, growth suppression in children using oral inhaled products has been documented. The Food and Drug Administration (FDA) recently met to discuss the development of a class label warning about growth suppression.³³ It is unknown whether dosing schedules such as continuous or intermittent dosing will influence growth suppression. It is also not known if there is a possibility of “catch up” growth or the impact of growth suppression on final adult height.³³ Dry powder and metered dose inhalers used with spacers have similar risks of systemic effects.¹⁰

The following recommendations may minimize potential adverse effects from inhaled glucocorticoids:

Nasal Glucocorticoids
Intranasal steroids are effective in treating seasonal or perennial rhinitis and nasal polyps. Common adverse reactions with the nasal steroids include mild nasopharyngeal irritation and nasal burning, stinging, dryness, and irritation.^8,11 Less burning and stinging is reported with the aqueous formulation of nasal steroids.^8,11,34 Epistaxis, sneezing attacks, and insomnia have occurred with their use. Rare reports of nasal mucosa ulceration and localized infections have been documented.^8,11

Ocular
Ocular steroids are effective in treating ocular allergy disorders. Significant adverse effects limit their use. Although systemic steroids are often implicated in cataract formation, topical ocular agents may also lead to cataract development.²⁷ Glaucoma may also result from prolonged ocular administration. Steroid-induced glaucoma may result in optic nerve damage and defects in the visual field.²⁷ New modified steroids, rimexolone and loteprednol etabonate, may lessen the increase in intraocular pressure.⁸ Fluorometholone may lessen cataract formation.¹¹

Rapid tapering and abrupt discontinuation of ocular steroids may result in rebound inflammation. Symptoms of rebound inflammation include decreased visual acuity and photophobia. Ocular steroids make the eye more vulnerable to bacterial, viral and fungal infection. Ocular steroids are contraindicated with concomitant contact lens use and in herpes simplex keratitis.²⁷

Monitoring for cataract formation and increased intraocular pressure is the same as with oral glucocorticoid recommendations. Ocular rebound inflammation is best avoided with gradual tapering. Ophthalmologic evaluation is indicated if a patient treated with an ocular steroid develops ocular discharge, pain, photophobia, or redness.²⁷

Parenteral
Patients receiving parenteral glucocorticoids are susceptible to the same adverse effects mentioned for other routes of administration. Monitoring parameters should be based on the dose and duration of parenteral therapy. These patients should be monitored for fluid and electrolyte disturbances, changes in vital signs (especially blood pressure), hypersensitivity reactions, and injection site reactions. These patients may be more susceptible to CNS effects due to the large doses of glucocorticoids given parenterally.¹

Summary
Glucocorticoids are among the most commonly prescribed agents in clinical practice. Their varied physiologic effects make them ideal agents for treating several disease states. However, serious complications associated with their use make it crucial for pharmacists to be familiar with monitoring parameters and dosing strategies to minimize these adverse effects. Regardless of the formulation used, pharmacists must provide timely and complete counseling to patients receiving glucocorticoids.