Pharmacology of Hydrocortisone

Introduction/Overview

Hydrocortisone, also known as cortisol, represents the primary endogenous glucocorticoid hormone secreted by the zona fasciculata of the adrenal cortex. As a pharmaceutical agent, it serves both as replacement therapy in deficiency states and as an anti-inflammatory and immunosuppressive drug. Its pharmacology is fundamental to understanding both endocrine physiology and the therapeutic application of corticosteroids across numerous medical disciplines. The clinical relevance of hydrocortisone extends from life-saving intervention in adrenal crisis to the management of chronic inflammatory and autoimmune conditions. Its dual role as a hormone and a drug necessitates a thorough comprehension of its physiological actions and pharmacotherapeutic implications.

Learning Objectives

• Describe the chemical classification of hydrocortisone and its relationship to endogenous cortisol.
• Explain the genomic and non-genomic mechanisms of action through which hydrocortisone exerts its physiological and pharmacological effects.
• Analyze the pharmacokinetic profile of hydrocortisone, including factors influencing its absorption, distribution, metabolism, and excretion.
• Identify the approved therapeutic indications for hydrocortisone and evaluate its role in both replacement and pharmacotherapeutic contexts.
• Recognize the spectrum of adverse effects associated with hydrocortisone therapy, particularly distinguishing between those seen with replacement dosing versus supraphysiological dosing.

Classification

Hydrocortisone is systematically classified within multiple hierarchical frameworks based on its chemical structure, physiological role, and therapeutic application.

Chemical and Therapeutic Classification

Chemically, hydrocortisone is a steroid hormone, specifically a pregnane derivative. Its systematic name is 11β,17α,21-trihydroxypregn-4-ene-3,20-dione. It is the pharmaceutical preparation of the naturally occurring hormone cortisol. Therapeutically, it is classified as a corticosteroid, falling under the subclass of glucocorticoids. Unlike many synthetic analogs, hydrocortisone possesses significant mineralocorticoid activity in addition to its glucocorticoid effects, with an approximate glucocorticoid to mineralocorticoid potency ratio of 1:1. This contrasts with agents like dexamethasone, which have virtually no mineralocorticoid activity.

Regulatory and Formulary Classification

From a regulatory perspective, hydrocortisone is available in multiple formulations, including oral tablets, intravenous and intramuscular injections, topical creams and ointments, rectal foams and suppositories, and ophthalmic preparations. It is typically categorized as an essential medicine by global health organizations due to its critical role in managing adrenal insufficiency. In most formularies, it is listed as a glucocorticoid replacement agent, an anti-inflammatory agent, and an immunosuppressant, depending on the dosage and indication.

Mechanism of Action

The pharmacological effects of hydrocortisone are mediated through complex molecular interactions that can be broadly categorized into genomic and non-genomic pathways. These mechanisms underpin both its physiological regulatory functions and its therapeutic anti-inflammatory and immunosuppressive actions.

Genomic Mechanisms

The predominant mechanism involves diffusion of the lipophilic hydrocortisone molecule across the plasma membrane and binding to the cytosolic glucocorticoid receptor (GR). In the unliganded state, the GR is part of a multiprotein complex that includes heat shock proteins (HSPs) 70 and 90, which maintain the receptor in a conformation with high affinity for the hormone. Upon binding, the receptor undergoes a conformational change, dissociates from the chaperone proteins, and dimerizes. The ligand-receptor complex then translocates to the nucleus.

Within the nucleus, the complex exerts its effects primarily through two mechanisms: transactivation and transrepression. Transactivation involves binding of the dimerized receptor to specific DNA sequences known as glucocorticoid response elements (GREs) located in the promoter regions of target genes. This binding typically recruits coactivator proteins and histone acetyltransferases, facilitating gene transcription. Genes upregulated via transactivation include those encoding anti-inflammatory proteins such as lipocortin-1 (which inhibits phospholipase A2), interleukin-10, and IκBα (the inhibitor of nuclear factor kappa B, NF-κB).

Transrepression, considered more critical for the anti-inflammatory and immunosuppressive effects, involves protein-protein interactions that inhibit the activity of key transcription factors. The glucocorticoid receptor complex can directly interact with and suppress pro-inflammatory transcription factors such as NF-κB and activator protein-1 (AP-1). This interaction prevents these factors from binding to their response elements on DNA, thereby repressing the transcription of genes encoding cytokines (e.g., interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor-alpha), chemokines, adhesion molecules, and inflammatory enzymes like cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS).

Non-Genomic Mechanisms

Rapid effects of hydrocortisone, occurring within minutes, are believed to be mediated through non-genomic pathways. These may involve interaction with membrane-bound glucocorticoid receptors or other non-specific physicochemical interactions with cellular membranes. Proposed mechanisms include modulation of second messenger systems, such as reducing intracellular calcium concentrations and inhibiting the release of arachidonic acid from membrane phospholipids. These rapid effects can contribute to the immediate symptomatic relief sometimes observed in acute inflammatory settings, though their clinical significance relative to genomic effects is a subject of ongoing investigation.

Cellular and Physiological Effects

The molecular mechanisms translate into several key cellular and systemic effects. Hydrocortisone inhibits the recruitment and function of inflammatory cells (neutrophils, eosinophils, macrophages, and lymphocytes). It induces apoptosis in certain lymphocyte subsets. Metabolically, it promotes gluconeogenesis, lipolysis, and proteolysis, while antagonizing the action of insulin. Its mineralocorticoid activity, mediated through binding to the mineralocorticoid receptor in the distal nephron, promotes sodium reabsorption and potassium excretion, contributing to fluid and electrolyte homeostasis.

Pharmacokinetics

The pharmacokinetic profile of hydrocortisone is influenced by its formulation, route of administration, and individual patient factors such as hepatic function and albumin concentration. Understanding these parameters is essential for optimizing therapeutic regimens and minimizing toxicity.

Absorption

Absorption characteristics vary significantly with the route of administration. Oral hydrocortisone is well absorbed from the gastrointestinal tract, with a bioavailability typically ranging from 70% to 90%. Peak plasma concentrations (C_max) are generally achieved within 1 to 2 hours post-ingestion. Absorption may be slightly delayed but not significantly reduced by food. For parenteral administration, intravenous injection provides immediate and complete bioavailability, with plasma concentrations rising rapidly. Intramuscular administration results in a more delayed and variable absorption profile, depending on the injection site and local blood flow. Topical and rectal absorption is generally low but can become systemic with prolonged use on large surface areas, broken skin, or under occlusive dressings.

Distribution

Following absorption, hydrocortisone is extensively distributed throughout body tissues. Its volume of distribution is approximately 0.3 to 0.5 L/kg. In the plasma, approximately 90% of the drug is bound to proteins, primarily corticosteroid-binding globulin (CBG, or transcorrin) with high affinity and low capacity, and to albumin with low affinity and high capacity. Only the unbound, free fraction (approximately 5-10%) is biologically active. Conditions that decrease plasma protein concentrations, such as liver cirrhosis, nephrotic syndrome, or critical illness, can increase the free fraction and potentiate the drug’s effects and toxicity. Hydrocortisone readily crosses the placenta and is distributed into breast milk.

Metabolism

Hydrocortisone undergoes extensive hepatic metabolism, which is the primary determinant of its systemic clearance. The major metabolic pathways involve sequential reduction of the A-ring (forming tetrahydro metabolites) and conjugation with glucuronic acid or sulfate to form water-soluble, inactive compounds. The initial step is catalyzed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which can interconvert cortisol and its inactive metabolite cortisone, and type 2 (11β-HSD2), which predominantly inactivates cortisol to cortisone in mineralocorticoid target tissues. The cytochrome P450 enzyme system, particularly CYP3A4, also plays a role in its oxidative metabolism. Hepatic impairment can significantly reduce the clearance of hydrocortisone, necessitating dose adjustment.

Excretion

The metabolites of hydrocortisone are primarily excreted by the kidneys, with approximately 90% of an administered dose appearing in the urine as conjugated metabolites. Less than 1% is excreted unchanged in the urine. The elimination half-life (t_1/2) of hydrocortisone in plasma is relatively short, ranging from 1.5 to 2 hours. However, the biological half-life, reflecting the duration of its physiological effects, is considerably longer, typically 8 to 12 hours. This discrepancy is due to the time required for the genomic effects to reverse after plasma concentrations have declined. Renal impairment does not significantly alter the pharmacokinetics of hydrocortisone itself, though accumulation of sodium and water due to its mineralocorticoid activity may be problematic.

Dosing Considerations

The short plasma half-life necessitates multiple daily doses for replacement therapy to mimic the physiological diurnal rhythm of cortisol secretion. A common regimen involves two-thirds of the daily dose in the morning and one-third in the late afternoon. During periods of physiological stress (e.g., surgery, infection, trauma), doses must be increased significantly, often to 200-300 mg per day in divided doses, to replicate the appropriate adrenal response. For anti-inflammatory or immunosuppressive indications, dosing is typically supraphysiological and must be carefully tapered to avoid adrenal suppression upon discontinuation.

Therapeutic Uses/Clinical Applications

Hydrocortisone has a broad range of clinical applications, which can be divided into physiological replacement and pharmacological therapy. The dose and regimen differ fundamentally between these two categories.

Approved Indications

Adrenal Insufficiency: This is the primary indication for physiological replacement. Hydrocortisone is the drug of choice for both primary adrenal insufficiency (Addison’s disease) and secondary/tertiary adrenal insufficiency due to pituitary or hypothalamic dysfunction. It corrects glucocorticoid deficiency while its inherent mineralocorticoid activity often suffices for patients with primary disease, though some may require additional fludrocortisone.

Congenital Adrenal Hyperplasia (CAH): In classic forms of CAH (e.g., 21-hydroxylase deficiency), hydrocortisone provides glucocorticoid replacement and suppresses the excessive secretion of adrenocorticotropic hormone (ACTH), thereby reducing the overproduction of adrenal androgens.

Anti-inflammatory and Immunosuppressive Therapy: Hydrocortisone is used systemically and locally to treat a wide array of inflammatory and immune-mediated conditions. These include, but are not limited to:

• Rheumatologic diseases: Acute flares of rheumatoid arthritis, polymyalgia rheumatica.
• Allergic and hypersensitivity reactions: Severe allergic reactions, anaphylaxis (as an adjunct to epinephrine), angioedema.
• Dermatological conditions: Severe contact dermatitis, pemphigus vulgaris.
• Gastrointestinal diseases: Inflammatory bowel disease (particularly ulcerative colitis) via rectal formulations, autoimmune hepatitis.
• Hematologic/Oncologic conditions: As part of chemotherapy regimens to reduce inflammation and emesis, in the management of lymphoid malignancies.
• Neurologic conditions: Cerebral edema associated with brain tumors, acute exacerbations of multiple sclerosis.
• Pulmonary diseases: Severe asthma exacerbations, chronic obstructive pulmonary disease (COPD) exacerbations, aspiration pneumonitis.
• Septic Shock: Adjunctive therapy with vasopressors in adults with septic shock refractory to fluid resuscitation.

Topical and Local Applications: A multitude of dermatological, ophthalmic, otic, and rectal inflammatory conditions are managed with topical hydrocortisone formulations.

Off-Label Uses

Several off-label applications are supported by clinical evidence and are commonly employed in practice. These include the prevention of antiemetic regimens for chemotherapy-induced nausea and vomiting, treatment of acute spinal cord injury, management of hypercalcemia of malignancy, and as a component of therapy for certain types of refractory hypotension. Its use in the critically ill patient beyond septic shock, such as in acute respiratory distress syndrome (ARDS) or severe community-acquired pneumonia, remains an area of active research and debate.

Adverse Effects

The adverse effect profile of hydrocortisone is dose- and duration-dependent. Effects observed with physiological replacement doses differ in frequency and severity from those associated with high-dose, long-term pharmacotherapy.

Common Side Effects

Even at replacement doses, some effects related to the drug’s physiological actions may be observed. These can include weight gain, fluid retention, hypertension, hypokalemia, mood changes (euphoria, irritability, insomnia), and dyspepsia. With higher pharmacologic doses, a wider array of effects becomes common:

• Metabolic: Hyperglycemia and glucose intolerance (steroid-induced diabetes), central obesity, moon facies, dorsocervical fat pad (buffalo hump).
• Musculoskeletal: Proximal myopathy, muscle weakness, osteoporosis, vertebral compression fractures, osteonecrosis (particularly of the femoral head), growth suppression in children.
• Dermatological: Skin thinning, easy bruising, purple striae, impaired wound healing, acne, hirsutism.
• Ophthalmic: Posterior subcapsular cataracts, increased intraocular pressure (glaucoma).
• Gastrointestinal: Peptic ulcer disease, pancreatitis, abdominal distension.
• Neuropsychiatric: Anxiety, depression, psychosis, cognitive dysfunction.

Serious/Rare Adverse Reactions

Serious adverse events often relate to immunosuppression and metabolic derangements. These include opportunistic infections (e.g., Pneumocystis jirovecii pneumonia, fungal infections, reactivation of tuberculosis or viral hepatitis), severe hyperglycemia leading to diabetic ketoacidosis or hyperosmolar state, and adrenal suppression or crisis upon rapid withdrawal after prolonged therapy. Avascular necrosis of bone is a particularly debilitating complication. Cases of anaphylactoid reactions to intravenous hydrocortisone, though rare, have been documented.

Adrenal Suppression and Withdrawal

This is a critical consideration not classified as a typical “side effect” but as a predictable physiological consequence of exogenous glucocorticoid administration. Suppression of the hypothalamic-pituitary-adrenal (HPA) axis occurs with doses exceeding approximately 20-30 mg of hydrocortisone per day (or equivalent) for more than three weeks. Abrupt cessation can lead to a withdrawal syndrome characterized by malaise, fatigue, arthralgias, and, in severe cases, adrenal crisis with hypotension, hyponatremia, and hyperkalemia. Therefore, tapering is mandatory after prolonged therapy.

Drug Interactions

Hydrocortisone participates in numerous pharmacokinetic and pharmacodynamic drug interactions that can alter its efficacy or toxicity, or the effects of concomitant medications.

Major Pharmacokinetic Interactions

Agents that induce hepatic cytochrome P450 enzymes, particularly CYP3A4, can accelerate the metabolism of hydrocortisone, reducing its plasma concentration and therapeutic effect. Key inducers include phenytoin, phenobarbital, carbamazepine, rifampin, and St. John’s wort. Conversely, drugs that inhibit CYP3A4 may increase hydrocortisone levels and the risk of toxicity. Potent inhibitors include ketoconazole, itraconazole, clarithromycin, ritonavir, and grapefruit juice. The clinical significance of these interactions is greatest with long-term oral therapy.

Major Pharmacodynamic Interactions

• Antidiabetic Agents: Hydrocortisone antagonizes the effect of insulin and oral hypoglycemics, necessitating dose adjustments and close glucose monitoring.
• Diuretics: Concurrent use with potassium-wasting diuretics (e.g., thiazides, loop diuretics) can potentiate hypokalemia. The mineralocorticoid effects of hydrocortisone may antagonize the efficacy of diuretics used for hypertension or edema.
• Anticoagulants: Glucocorticoids may alter the response to coumarin anticoagulants (e.g., warfarin), potentially increasing or decreasing the International Normalized Ratio (INR); close monitoring is required.
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Concurrent use significantly increases the risk of gastrointestinal ulceration and bleeding.
• Vaccines: The immunosuppressive effects of hydrocortisone can diminish the efficacy of live attenuated vaccines (e.g., MMR, varicella) and increase the risk of vaccine-associated infection. Administration of live vaccines is generally contraindicated in patients receiving immunosuppressive doses.
• Other Immunosuppressants: Additive immunosuppression increases the risk of infection and possibly lymphoproliferative disorders.

Contraindications

Absolute contraindications to systemic hydrocortisone are relatively few but critical. These include systemic fungal infection (unless used for the management of adrenal insufficiency in such patients) and known hypersensitivity to hydrocortisone or any component of the formulation. Live virus vaccination is contraindicated in individuals receiving immunosuppressive doses. Administration of hydrocortisone via the intrathecal route is contraindicated due to the risk of severe adverse events. Caution is warranted in patients with active or latent tuberculosis, active peptic ulcer disease, uncontrolled hypertension, congestive heart failure, diabetes mellitus, osteoporosis, and psychotic disorders.

Special Considerations

The use of hydrocortisone requires careful adjustment and monitoring in specific patient populations due to altered physiology, pharmacokinetics, or risk-benefit profiles.

Pregnancy and Lactation

Hydrocortisone crosses the placenta. When used in physiological replacement doses for adrenal insufficiency, it is considered essential and safe. High-dose pharmacologic therapy during pregnancy, particularly in the first trimester, has been associated with a small increased risk of oral clefts in the fetus. However, the benefits of treating serious maternal disease often outweigh this potential risk. Chronic use may be associated with intrauterine growth restriction. During labor, stress-dose steroids are required for mothers with adrenal insufficiency. Hydrocortisone is excreted in breast milk in low concentrations, but the amounts are unlikely to cause significant systemic effects in the nursing infant, especially at replacement doses. With high maternal doses, monitoring the infant for signs of glucocorticoid excess may be prudent.

Pediatric Considerations

Children are particularly susceptible to the growth-suppressing effects of glucocorticoids. Long-term therapy can impair linear growth. Strategies to minimize this effect include using the lowest effective dose, administering alternate-day therapy when possible, and ensuring adequate nutrition. Dosing for replacement therapy in children is typically based on body surface area (approximately 8-10 mg/m² per day in divided doses). Close monitoring of growth velocity and bone health is mandatory. The risk of certain adverse effects, such as benign intracranial hypertension, may be higher in the pediatric population.

Geriatric Considerations

Elderly patients may be more susceptible to certain adverse effects of hydrocortisone, including hypertension, osteoporosis, hyperglycemia, and psychosis. Age-related reductions in hepatic and renal function can potentially alter drug metabolism and excretion, though significant dose adjustment for replacement therapy is not routinely required. The increased baseline risk of osteoporosis and fracture in this population necessitates proactive assessment and consideration of bone-protective strategies (e.g., calcium, vitamin D, bisphosphonates) when initiating long-term therapy.

Renal and Hepatic Impairment

Renal impairment does not significantly alter the clearance of hydrocortisone itself. However, dose adjustment may be necessary due to the drug’s effects on electrolyte balance and fluid status, which can exacerbate the metabolic disturbances of renal disease. Hepatic impairment is a more significant concern. As the liver is the primary site of hydrocortisone metabolism, severe liver disease (e.g., cirrhosis) can reduce its clearance, prolong its half-life, and increase its bioavailability due to reduced first-pass metabolism and lower synthesis of binding proteins like albumin and CBG. Consequently, dose reduction may be required to avoid signs of Cushing’s syndrome. Monitoring of clinical response and signs of toxicity is essential.

Summary/Key Points

• Hydrocortisone is both the endogenous glucocorticoid cortisol and a versatile therapeutic agent used for physiological replacement and pharmacological anti-inflammatory/immunosuppressive effects.
• Its mechanism of action is predominantly genomic, involving cytosolic glucocorticoid receptor binding, nuclear translocation, and modulation of gene transcription via transactivation and transrepression.
• Pharmacokinetically, it has good oral bioavailability, a short plasma half-life (1.5-2 hours), a longer biological half-life (8-12 hours), and is metabolized primarily in the liver by enzymes subject to induction and inhibition.
• Therapeutic applications are dichotomized: replacement therapy for adrenal insufficiency and CAH, and higher-dose therapy for a broad spectrum of inflammatory, allergic, and autoimmune conditions.
• The adverse effect profile is extensive and correlates with dose and duration. Common effects include metabolic disturbances (hyperglycemia, weight gain), musculoskeletal issues (osteoporosis, myopathy), and dermatological changes. Adrenal suppression with prolonged use necessitates gradual tapering.
• Significant drug interactions occur with hepatic enzyme inducers/inhibitors, antidiabetic agents, diuretics, NSAIDs, and anticoagulants. Careful review of concomitant medications is required.
• Special populations require tailored management: physiological replacement is safe in pregnancy; children are sensitive to growth suppression; the elderly are prone to metabolic and bone complications; and hepatic impairment necessitates potential dose reduction.

Clinical Pearls

• For adrenal insufficiency, mimic the diurnal rhythm: give two-thirds of the daily dose upon waking and one-third in the late afternoon.
• Always consider “stress-dose” steroids (typically 50-100 mg IV every 8 hours) for patients on chronic therapy undergoing surgery, trauma, or serious infection to prevent adrenal crisis.
• The mineralocorticoid activity of hydrocortisone is often sufficient for patients with primary adrenal insufficiency, but some will still require fludrocortisone.
• When tapering after prolonged supraphysiological therapy, reduce the dose slowly and monitor for symptoms of adrenal insufficiency. The rate of taper is more critical than the specific regimen.
• Topical hydrocortisone, especially high-potency formulations, can cause significant systemic absorption if used over large body surface areas, on thin skin, or under occlusion.

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