Pharmacology of Corticosteroids

Introduction/Overview

Corticosteroids represent a cornerstone class of therapeutic agents with profound and diverse physiological effects. These synthetic analogues of hormones produced by the adrenal cortex are among the most widely prescribed drugs globally due to their potent anti-inflammatory and immunosuppressive properties. The clinical introduction of cortisone in the late 1940s marked a therapeutic revolution, transforming the management of previously untreatable inflammatory and autoimmune conditions. The subsequent development of numerous synthetic derivatives has refined their therapeutic profile, allowing for targeted application across virtually every medical specialty.

The clinical relevance of corticosteroids cannot be overstated. Their ability to modulate the immune response and suppress inflammation provides therapeutic benefit in conditions ranging from asthma and rheumatoid arthritis to organ transplantation and hematologic malignancies. However, this broad efficacy is counterbalanced by a similarly wide spectrum of potential adverse effects, which are often dose- and duration-dependent. A thorough understanding of corticosteroid pharmacology is therefore essential for optimizing therapeutic outcomes while minimizing harm. This balance between profound benefit and significant risk defines the clinical challenge of corticosteroid use.

The primary learning objectives for this chapter are:

• To classify corticosteroids based on their chemical structure, relative potency, and duration of action.
• To explain the genomic and non-genomic molecular mechanisms underlying corticosteroid effects.
• To describe the pharmacokinetic principles governing corticosteroid absorption, distribution, metabolism, and excretion.
• To identify the major therapeutic applications of corticosteroids and the rationale for their use in specific clinical contexts.
• To recognize the spectrum of adverse effects associated with corticosteroid therapy and strategies for their mitigation.

Classification

Corticosteroids are systematically classified according to their origin, chemical structure, biological activity, and clinical duration of action. This classification informs therapeutic selection and dosing strategies.

Chemical and Biological Classification

All corticosteroids are derived from the cyclopentanoperhydrophenanthrene steroid nucleus. Modifications to this core structure, particularly at the C-1, C-6, C-9, C-16, and C-21 positions, profoundly alter receptor affinity, metabolic stability, and mineralocorticoid activity. The two primary endogenous classes are glucocorticoids and mineralocorticoids.

• Glucocorticoids: Primarily influence carbohydrate, protein, and fat metabolism, and possess potent anti-inflammatory and immunosuppressive activity. The principal endogenous glucocorticoid is cortisol (hydrocortisone).
• Mineralocorticoids: Primarily regulate electrolyte and water balance by promoting sodium retention and potassium excretion in the distal renal tubule. The principal endogenous mineralocorticoid is aldosterone.

Most synthetic agents are designed to maximize glucocorticoid effects while minimizing mineralocorticoid activity, although some retain significant mineralocorticoid potency for specific indications.

Classification by Duration of Action

A clinically useful classification system categorizes corticosteroids based on their biological half-life and duration of hypothalamic-pituitary-adrenal (HPA) axis suppression following a single dose.

1. Short-Acting (Biological t_1/2 8–12 hours): Hydrocortisone (cortisol), cortisone. These agents have significant mineralocorticoid activity.
2. Intermediate-Acting (Biological t_1/2 18–36 hours): Prednisone, prednisolone, methylprednisolone, triamcinolone. This group is most commonly used for chronic anti-inflammatory and immunosuppressive therapy.
3. Long-Acting (Biological t_1/2 36–54 hours): Dexamethasone, betamethasone. These are highly potent glucocorticoids with negligible mineralocorticoid activity.

Topical, inhaled, and intra-articular preparations are formulated from derivatives across these categories, with selection based on desired potency and penetration.

Mechanism of Action

The pharmacological effects of corticosteroids are mediated through complex genomic and non-genomic pathways. The classical and most significant mechanism involves modulation of gene transcription.

Genomic Mechanisms: Intracellular Receptor Mediation

Being lipophilic, glucocorticoids passively diffuse across the plasma membrane and bind to the cytosolic glucocorticoid receptor (GR). The unliganded GR exists in a multiprotein complex with chaperone proteins, including heat shock proteins 90 and 70. Upon ligand binding, a conformational change occurs, causing dissociation of the chaperone complex. The activated glucocorticoid-GR complex then translocates to the nucleus.

Within the nucleus, the complex exerts its effects via two primary mechanisms:

1. Transactivation: The dimerized GR complex binds to specific DNA sequences known as glucocorticoid response elements (GREs) in the promoter regions of target genes. This binding typically recruits co-activators and enhances the transcription of anti-inflammatory proteins. Examples include:
   • Lipocortin-1 (annexin-1), which inhibits phospholipase A₂, reducing the production of prostaglandins and leukotrienes.
   • IκBα, an inhibitor of the nuclear factor-kappa B (NF-κB) pathway, a master regulator of pro-inflammatory gene expression.
   • Interleukin-10, an anti-inflammatory cytokine.
2. Transrepression: This mechanism is primarily responsible for the anti-inflammatory and immunosuppressive effects. The GR monomer interacts with and inhibits the activity of key transcription factors, such as NF-κB and activator protein-1 (AP-1), which drive the expression of pro-inflammatory genes. This interaction prevents the transcription of cytokines (e.g., IL-1, IL-2, IL-6, TNF-α), chemokines, adhesion molecules, and inflammatory enzymes like cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS).

Non-Genomic Mechanisms

Rapid effects of corticosteroids, occurring within seconds to minutes, are likely mediated through non-genomic pathways. These may involve:

• Interaction with membrane-associated GRs or other membrane receptors.
• Non-specific physicochemical interactions with cellular membranes, affecting ion channel activity and signaling cascades.
• Inhibition of arachidonic acid release through non-transcriptional effects on phospholipase A₂.

The genomic mechanisms are considered predominant for the therapeutic anti-inflammatory effects, while non-genomic mechanisms may contribute to some rapid metabolic and cardiovascular effects.

Pharmacokinetics

The pharmacokinetic profile of corticosteroids varies significantly between agents and formulations, influencing their dosing regimens, therapeutic applications, and side effect profiles.

Absorption

Most synthetic glucocorticoids are well absorbed from the gastrointestinal tract, with oral bioavailability typically exceeding 70-90% for agents like prednisone and dexamethasone. Absorption can be influenced by food, with a high-fat meal potentially increasing the bioavailability and C_max of some agents like prednisone. Topical absorption is highly variable and depends on the chemical nature of the steroid, the vehicle, the integrity of the epidermal barrier, and the site of application. Occlusive dressings can increase percutaneous absorption by up to tenfold. For inhaled corticosteroids, systemic bioavailability is the sum of the fraction absorbed from the lung (which enters the systemic circulation directly) and the fraction swallowed and absorbed from the gut (which is often subject to high first-pass metabolism).

Distribution

Corticosteroids are widely distributed throughout body tissues. Their volume of distribution is relatively large, approximately 0.5–1.0 L/kg, reflecting extensive tissue binding. In plasma, they are bound to proteins, primarily corticosteroid-binding globulin (transcortin) and, to a lesser extent, albumin. The percentage of unbound, pharmacologically active drug varies: cortisol is approximately 90% protein-bound, while synthetic steroids like dexamethasone are less bound (approximately 70%). Conditions that decrease plasma protein concentrations, such as liver cirrhosis or nephrotic syndrome, can increase the free fraction and potential for toxicity. Corticosteroids readily cross the placenta and are excreted in breast milk.

Metabolism

Hepatic metabolism is the primary route of biotransformation. The key metabolic pathways include:

• Reduction: The 4,5 double bond and the 3-keto group are reduced by hepatic enzymes (5α- and 5β-reductases, 3α-hydroxysteroid dehydrogenase).
• Hydroxylation: At the C-6, C-16, and other positions, catalyzed by cytochrome P450 enzymes, particularly CYP3A4.
• Conjugation: The resulting metabolites are conjugated with glucuronic acid or sulfate to form water-soluble, inactive compounds ready for renal excretion.

Prednisone is a prodrug that requires hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) conversion to its active form, prednisolone. This conversion may be impaired in patients with severe liver disease. Drugs that induce (e.g., phenytoin, rifampin) or inhibit (e.g., ketoconazole, itraconazole) CYP3A4 can significantly alter corticosteroid metabolism and clinical effect.

Excretion

The conjugated metabolites are primarily excreted by the kidneys, with approximately 60-70% of a dose appearing in the urine and the remainder in the bile and feces. Less than 1% of an administered dose is excreted unchanged in urine. Renal impairment does not typically necessitate dose adjustment for most corticosteroids, as the active parent compounds are not renally eliminated. However, the accumulation of fluid and electrolytes due to mineralocorticoid effects may be problematic in renal failure.

Half-Life and Dosing Considerations

The relationship between plasma half-life (t_1/2) and biological effect is complex. The biological half-life, which correlates with the duration of HPA axis suppression, is more clinically relevant than the plasma elimination half-life. For example, dexamethasone has a plasma t_1/2 of 3–4 hours but a biological t_1/2 of 36–54 hours. Dosing schedules are designed around these principles. Alternate-day morning dosing with intermediate-acting agents (e.g., prednisone) aims to minimize HPA axis suppression by allowing recovery between doses, while still providing therapeutic anti-inflammatory effects. Single morning doses align with the body’s natural circadian rhythm of cortisol secretion, further reducing HPA disruption.

Therapeutic Uses/Clinical Applications

Corticosteroids are employed in a vast array of clinical conditions, primarily for their anti-inflammatory, immunosuppressive, and metabolic effects.

Endocrine Disorders

The primary use is as replacement therapy in adrenal insufficiency (Addison’s disease, secondary adrenal failure). Physiological replacement typically uses hydrocortisone (15–25 mg daily in divided doses) or cortisone acetate due to their mixed glucocorticoid and mineralocorticoid activity. In congenital adrenal hyperplasia, glucocorticoids suppress excessive adrenal androgen production via negative feedback on the HPA axis.

Rheumatologic and Autoimmune Diseases

These agents serve as first-line therapy for many systemic inflammatory conditions. Low to moderate doses are used for disease-modifying control in rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, and giant cell arteritis, often in combination with other immunosuppressants. High-dose “pulse” intravenous methylprednisolone (e.g., 1 g daily for 3 days) is used for severe disease flares or life-threatening manifestations like lupus nephritis or systemic vasculitis.

Respiratory Diseases

Inhaled corticosteroids are the mainstay of controller therapy for persistent asthma, reducing airway inflammation and hyperresponsiveness. Systemic corticosteroids (oral or intravenous) are crucial for managing acute exacerbations. In chronic obstructive pulmonary disease (COPD), systemic steroids are used for exacerbations, while inhaled steroids are reserved for patients with frequent exacerbations and an eosinophilic phenotype. Corticosteroids are also used in interstitial lung diseases like sarcoidosis and idiopathic pulmonary fibrosis.

Dermatological Conditions

Topical corticosteroids, classified by potency from Class I (super potent) to Class VII (least potent), are first-line therapy for many inflammatory skin disorders such as eczema, psoriasis, and contact dermatitis. Systemic corticosteroids may be required for severe conditions like pemphigus vulgaris, toxic epidermal necrolysis, or severe erythema multiforme.

Hematologic and Oncologic Disorders

High-dose dexamethasone is a key component of regimens for multiple myeloma and diffuse large B-cell lymphoma. Corticosteroids are used to manage complications of malignancy and its treatment, including chemotherapy-induced nausea and vomiting (where dexamethasone is highly effective), brain tumor-associated cerebral edema, spinal cord compression, and autoimmune hemolytic anemia.

Gastrointestinal Diseases

They induce and maintain remission in inflammatory bowel disease, particularly Crohn’s disease and ulcerative colitis. Budesonide, a corticosteroid with high first-pass hepatic metabolism, is used for ileal and right-sided colonic Crohn’s due to its targeted topical action and reduced systemic effects.

Organ Transplantation

Corticosteroids remain a fundamental component of most immunosuppressive regimens to prevent and treat acute allograft rejection, though modern protocols often aim for early withdrawal or use of low doses to minimize long-term toxicity.

Neurological Conditions

High-dose corticosteroids are standard therapy for acute exacerbations of multiple sclerosis and are used in the management of cerebral edema associated with brain tumors or neurosurgery.

Ophthalmic Diseases

Topical ophthalmic preparations are used to treat inflammatory conditions of the eye such as uveitis, allergic conjunctivitis, and postoperative inflammation.

Adverse Effects

The adverse effects of corticosteroids are extensive, predictable, and often related to the dose and duration of therapy. They largely represent an exaggeration of their physiological actions.

Common Side Effects

• Metabolic Effects: Iatrogenic Cushing’s syndrome (moon facies, central obesity, buffalo hump), hyperglycemia and steroid-induced diabetes mellitus, dyslipidemia.
• Fluid and Electrolyte Disturbances: Sodium and water retention, hypertension, hypokalemia, and metabolic alkalosis, particularly with agents possessing mineralocorticoid activity.
• Musculoskeletal Effects: Proximal myopathy, osteoporosis (due to inhibited osteoblast function, increased osteoclast activity, and reduced intestinal calcium absorption), osteonecrosis (especially of the femoral head), and growth suppression in children.
• Dermatological Effects: Skin thinning, striae, purpura, impaired wound healing, and acneiform eruptions.
• Neuropsychiatric Effects: Insomnia, mood swings, euphoria, depression, psychosis, and cognitive impairment.
• Gastrointestinal Effects: Dyspepsia, peptic ulcer disease (risk increased when co-administered with NSAIDs), and pancreatitis.
• Ophthalmic Effects: Posterior subcapsular cataracts and increased intraocular pressure (glaucoma).

Serious and Rare Adverse Reactions

• Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression: Chronic administration suppresses endogenous cortisol production. Abrupt withdrawal can lead to adrenal insufficiency, characterized by hypotension, hyponatremia, hyperkalemia, fever, and even death. Tapering schedules are mandatory after more than 2-3 weeks of systemic therapy.
• Increased Susceptibility to Infections: Corticosteroids impair both innate and adaptive immunity, increasing the risk of bacterial, viral (especially herpes viruses), fungal, and opportunistic infections (e.g., Pneumocystis jirovecii pneumonia). They may also mask the classic signs of infection, such as fever and inflammation.
• Cardiovascular Events: Accelerated atherosclerosis, increased risk of myocardial infarction and stroke, partly mediated by metabolic effects.

While corticosteroids do not carry a formal FDA Black Box Warning, the serious nature of these potential effects, particularly HPA axis suppression and increased infection risk, demands careful patient education and monitoring.

Drug Interactions

Corticosteroids participate in numerous pharmacokinetic and pharmacodynamic drug interactions that can significantly alter their efficacy or toxicity profile.

Major Pharmacokinetic Interactions

• Enzyme Inducers: Drugs such as phenytoin, phenobarbital, carbamazepine, and rifampin induce hepatic CYP3A4, accelerating corticosteroid metabolism and potentially reducing their therapeutic effect. Dose increases of the corticosteroid may be required.
• Enzyme Inhibitors: Drugs such as ketoconazole, itraconazole, clarithromycin, and ritonavir inhibit CYP3A4, decreasing corticosteroid metabolism and increasing the risk of toxicity, including Cushing’s syndrome and adrenal suppression. Dose reduction may be necessary.
• Antacids and Bile Acid Sequestrants: May reduce the absorption of orally administered corticosteroids when taken concomitantly.

Major Pharmacodynamic Interactions

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Anticoagulants: Corticosteroids increase the risk of gastrointestinal ulceration and bleeding when combined with NSAIDs. Their effects on coagulation factors and vascular integrity may also potentiate the action of warfarin, requiring more frequent INR monitoring.
• Diuretics (especially potassium-wasting): Concurrent use with corticosteroids that have mineralocorticoid activity can lead to severe hypokalemia.
• Antidiabetic Agents and Insulin: Corticosteroid-induced hyperglycemia can antagonize the effects of oral hypoglycemics and insulin, necessitating dose adjustments and frequent blood glucose monitoring.
• Vaccines: The immunosuppressive effects of corticosteroids, particularly at high doses (e.g., prednisone ≥20 mg/day for ≥2 weeks), can diminish the immune response to live attenuated vaccines (e.g., MMR, varicella) and increase the risk of vaccine-strain infection. Administration of live vaccines is generally contraindicated in such patients.
• Neuromuscular Blocking Agents: Corticosteroid-induced myopathy may potentiate the effects of these agents.

Contraindications

Absolute contraindications to systemic corticosteroid therapy are few but include:

• Systemic fungal infection (unless used for management of associated adrenal insufficiency or as part of antifungal therapy in specific contexts like Pneumocystis pneumonia).
• Known hypersensitivity to the specific corticosteroid or formulation excipients.
• Administration of live virus vaccines in immunocompromised individuals.

Relative contraindications, requiring careful risk-benefit assessment, include: active peptic ulcer disease, uncontrolled hypertension, congestive heart failure, diabetes mellitus, osteoporosis, psychiatric disorders, and active tuberculosis or other untreated latent infections.

Special Considerations

Use in Pregnancy and Lactation

Corticosteroids are classified as FDA Pregnancy Category C (D for dexamethasone in the first trimester when used for certain indications). They cross the placenta, but the degree varies; betamethasone and dexamethasone cross more readily than prednisone or prednisolone. This property is utilized to promote fetal lung maturation when administered to mothers at risk of preterm delivery. Chronic maternal use has been associated with a small increased risk of oral clefts when used in the first trimester and may contribute to intrauterine growth restriction. In lactation, corticosteroids are excreted in breast milk in small amounts, but doses equivalent to prednisone ≤20 mg daily are generally considered compatible with breastfeeding. Dosing immediately after nursing can minimize infant exposure.

Pediatric Considerations

Children are particularly susceptible to certain adverse effects. Growth suppression is a major concern with chronic systemic therapy, mediated by inhibition of growth hormone secretion and direct effects on epiphyseal cartilage. Monitoring growth velocity is essential. Alternate-day dosing may mitigate this effect. Behavioral changes and increased intracranial pressure (pseudotumor cerebri) are also more common in children. The risk of infection from live vaccines is a critical consideration.

Geriatric Considerations

Older adults are at increased risk for several corticosteroid toxicities, including hypertension, hyperglycemia, osteoporosis, cataracts, and psychosis. Age-related reductions in lean body mass and renal/hepatic function may alter pharmacokinetics. The lowest effective dose for the shortest possible duration should be employed, with proactive monitoring for and prophylaxis against osteoporosis and other complications.

Renal and Hepatic Impairment

Dosage adjustment is not typically required for renal impairment, as active drug is not renally eliminated. However, caution is warranted regarding fluid retention, hypertension, and electrolyte disturbances, especially with mineralocorticoid-active steroids. In hepatic impairment, the metabolism of corticosteroids may be reduced, potentially leading to prolonged effect and increased toxicity. This is particularly relevant for prednisone, which requires hepatic conversion to prednisolone. In severe liver disease, prednisolone may be preferred over prednisone. Albumin synthesis may be reduced, increasing the free fraction of highly protein-bound steroids.

Summary/Key Points

• Corticosteroids are synthetic analogues of adrenal cortex hormones, primarily used for their potent anti-inflammatory and immunosuppressive effects mediated through genomic (transactivation and transrepression) and non-genomic mechanisms.
• They are classified by duration of action (short, intermediate, long) and biological activity (glucocorticoid vs. mineralocorticoid potency), which guides clinical selection.
• Pharmacokinetics are characterized by good oral absorption, wide distribution, extensive hepatic metabolism via CYP450 enzymes (notably CYP3A4), and renal excretion of inactive metabolites. The biological half-life dictates dosing schedules.
• Therapeutic applications span nearly all medical specialties, including endocrine replacement, rheumatologic, respiratory, dermatologic, hematologic, gastrointestinal, and neurological diseases.
• Adverse effects are extensive, dose-related, and mimic Cushing’s syndrome. Key concerns include metabolic disturbances, osteoporosis, increased infection risk, HPA axis suppression, and neuropsychiatric effects.
• Significant drug interactions occur with CYP450 inducers/inhibitors, NSAIDs, diuretics, and antidiabetic agents. Live vaccines are generally contraindicated during immunosuppressive dosing.
• Special populations require tailored management: caution regarding growth in children, cumulative toxicities in the elderly, fetal risk/benefit in pregnancy, and potential altered metabolism in hepatic disease.

Clinical Pearls:

1. Always use the lowest effective dose for the shortest possible duration to minimize adverse effects.
2. For chronic systemic therapy exceeding 2-3 weeks, a gradual taper is mandatory to avoid adrenal insufficiency.
3. Administer systemic doses in the morning to align with the circadian rhythm and reduce HPA axis suppression.
4. Consider prophylactic measures for common toxicities: bisphosphonates for osteoporosis, proton pump inhibitors for GI protection, and monitoring for hyperglycemia and hypertension.
5. The therapeutic index of corticosteroids is narrow; their immense benefit is inextricably linked to significant risk, necessitating vigilant monitoring and patient education.

References

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