Adrenal Cortex Drugs: Glucocorticoids, Fludrocortisone, Spironolactone & Emergencies

Learning objectives

• Map adrenal hormones to the zona glomerulosa, fasciculata and reticularis and explain HPA-axis feedback.
• Compare hydrocortisone, prednisolone, prednisone, dexamethasone, methylprednisolone, betamethasone and fludrocortisone.
• Use glucocorticoids for replacement, inflammation, allergy, fetal lung maturation and adrenal crisis while preventing withdrawal.
• Recognise mineralocorticoid excess/deficiency, spironolactone and eplerenone use, and potassium/renal safety.
• Explain ketoconazole and other steroidogenesis inhibitors in Cushing syndrome and manage acute steroid toxicity.

1. Adrenal cortex physiology and receptor pharmacology

Glucocorticoid and mineralocorticoid receptors are intracellular. Steroid binding changes receptor conformation; dimers enter the nucleus, recruit co-activators or co-repressors and alter gene transcription. Genomic effects take hours, while non-genomic effects on vascular tone, membranes and catecholamine signalling can occur rapidly.

Physiological cortisol actions

• Promotes hepatic gluconeogenesis, protein catabolism in peripheral tissues and lipolysis, supplying fuel during stress.
• Maintains vascular responsiveness to catecholamines and supports glomerular filtration.
• Redistributes leucocytes: lowers circulating lymphocytes, eosinophils, basophils and monocytes while increasing neutrophils, erythrocytes and platelets.
• Suppresses phospholipase A2, COX-2, cytokines, leukocyte migration, mast-cell mediator release and capillary permeability.
• Excess causes insulin resistance, muscle wasting, psychiatric effects, hypertension, osteoporosis and infection; deficiency causes fatigue, hypotension, hypoglycaemia and shock.

2. Glucocorticoid potency and equivalence

Equivalence is approximate and product-specific. Do not exchange steroids by milligrams without accounting for potency, mineralocorticoid effect, route, duration and disease severity.

3. Hydrocortisone and adrenal replacement

3.1 Chronic primary adrenal insufficiency

• Typical oral hydrocortisone replacement is 15–25 mg/day in two or three doses, with the largest dose on waking (for example, two-thirds in the morning and one-third in the early afternoon). Avoid late-evening dosing that disrupts sleep.
• Primary Addison disease also needs mineralocorticoid replacement with fludrocortisone; secondary/tertiary adrenal insufficiency usually preserves aldosterone and does not require it.
• Teach a steroid emergency card/medical alert, sick-day rules, extra tablets and injection training where available.

3.2 Congenital adrenal hyperplasia

Hydrocortisone suppresses ACTH-driven adrenal androgen excess; doses are age- and growth-specific. Mineralocorticoid and salt replacement are needed in salt-wasting forms. Paediatric endocrine follow-up is essential to avoid growth suppression and iatrogenic Cushing syndrome.

3.3 Stress dosing

4. Fludrocortisone

Fludrocortisone is a potent mineralocorticoid with some glucocorticoid action. It increases sodium reabsorption and water retention in the distal nephron while promoting potassium and hydrogen-ion excretion.

• Indication: mineralocorticoid replacement in primary adrenal insufficiency and salt-wasting congenital adrenal hyperplasia.
• Dose: usual 0.1 mg orally daily; a product range of 0.1 mg three times weekly to 0.2 mg daily may be used. Reduce toward 0.05 mg/day if hypertension or oedema develops.
• Monitoring: sitting/standing BP, weight, oedema, sodium, potassium, plasma renin activity, salt craving and postural symptoms.
• Excess: hypertension, oedema, hypokalaemia, metabolic alkalosis, headache and heart failure.
• Interactions: diuretics, digoxin, amphotericin and laxative abuse increase potassium loss; NSAIDs may increase fluid retention; ACE inhibitors/ARBs and potassium supplements increase hyperkalaemia risk if fludrocortisone is reduced or stopped.

5. Systemic glucocorticoids for inflammation and allergy

Selected practical doses

• Asthma/COPD exacerbation: commonly prednisolone 40–50 mg orally daily for a short course, or IV methylprednisolone/hydrocortisone when oral therapy is impossible—follow the local emergency protocol.
• Anaphylaxis: adrenaline is first-line. Steroids are adjuncts only and must never delay IM adrenaline.
• Fetal lung maturation: betamethasone 12 mg IM, repeat once after 24 hours, or dexamethasone 6 mg IM every 12 hours for four doses, according to obstetric protocol and gestational age.
• Adrenal replacement: use hydrocortisone, not dexamethasone alone, when mineralocorticoid activity and physiologic replacement are needed.

6. Glucocorticoid adverse effects

7. Tapering and withdrawal

After more than about 2–3 weeks of systemic therapy, especially at supraphysiologic doses, the HPA axis may be suppressed. Abrupt withdrawal can cause adrenal insufficiency: fatigue, nausea, hypotension, hypoglycaemia, fever, myalgia and shock. Tapering depends on dose, duration, disease activity and symptoms. Do not taper a patient in adrenal crisis; give stress-dose replacement first. During major stress after recent steroid therapy, provide steroid cover until recovery of adrenal function is documented.

8. Inhaled, topical and intra-articular corticosteroids

• Local routes reduce systemic exposure but do not eliminate it. High-dose inhaled therapy can cause oral candidiasis, dysphonia and adrenal suppression; use a spacer and rinse the mouth.
• Topical steroids vary from mild to very potent. Excessive use causes skin atrophy, striae, telangiectasia and systemic absorption, especially under occlusion, in children or over large areas.
• Intra-articular injection can cause infection, cartilage injury, transient hyperglycaemia and systemic steroid exposure. Exclude septic arthritis before injection.

9. Mineralocorticoid antagonists

9.1 Spironolactone

Spironolactone competitively antagonises the mineralocorticoid receptor in the collecting duct, reducing sodium reabsorption and potassium/hydrogen loss. It also antagonises androgen receptors and inhibits testosterone synthesis.

• Uses: primary hyperaldosteronism, resistant hypertension, heart failure, cirrhotic ascites and selected hirsutism/acne.
• Dose: primary hyperaldosteronism often 100 mg/day, titrated between 25 and 200 mg/day; heart failure commonly starts at 25 mg once daily; hypertension 25–100 mg/day, according to indication and renal function.
• Adverse effects: hyperkalaemia, renal deterioration, gynaecomastia, menstrual irregularity, impotence, breast tenderness and rash.
• Monitoring: potassium and creatinine before treatment, within 3–7 days after initiation or dose change, again at about one month and periodically thereafter.

9.2 Eplerenone

Eplerenone is a more selective mineralocorticoid-receptor antagonist with less androgen receptor activity and therefore less gynaecomastia. It is used in hypertension and heart failure, but hyperkalaemia and renal monitoring remain essential. Avoid in significant renal impairment or with strong CYP3A4 inhibitors according to the label.

10. Drugs that reduce adrenal steroid synthesis

Ketoconazole

At higher systemic doses, ketoconazole inhibits CYP450 enzymes involved in adrenal and gonadal steroid synthesis and can reduce cortisol in Cushing syndrome. It is not the usual topical antifungal dose concept; oral use has serious liver and interaction risks.

• Dose: specialist protocols usually start 200 mg once or twice daily and titrate; the product warning states 200–400 mg/day should not be exceeded for ketoconazole tablets.
• Adverse effects: hepatotoxicity, adrenal insufficiency, QT prolongation and drug interactions.
• Interactions: potent CYP3A4 inhibition raises concentrations of many medicines; review statins, anticoagulants, sedatives, antiarrhythmics and immunosuppressants.
• Monitoring: baseline and serial liver tests, cortisol/clinical response, ECG when QT risk exists and symptoms of adrenal insufficiency.

Other specialist agents for Cushing syndrome include metyrapone, osilodrostat, mifepristone and pasireotide. Availability and approved indications vary; refer to endocrinology.

11. Adrenal crisis: emergency treatment

1. ABC assessment, oxygen, cardiac monitoring and two IV lines.
2. Hydrocortisone 100 mg IV or IM immediately, followed by 200 mg over 24 hours by continuous infusion or 50 mg IV every 6 hours according to protocol.
3. Rapid isotonic saline; add dextrose for hypoglycaemia or when glucose is low/at risk.
4. Check and correct sodium, potassium, glucose, renal function, blood gas and infection markers. Treat sepsis, trauma or other triggers.
5. Once stable and able to take oral medication, convert to physiologic hydrocortisone and add fludrocortisone in primary adrenal insufficiency.

12. Interactions and special precautions

• CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort) may lower steroid exposure; inhibitors such as azoles, macrolides and ritonavir may increase it.
• NSAIDs plus glucocorticoids increase gastrointestinal ulcer/bleeding risk; assess gastroprotection when indicated.
• Glucocorticoids antagonise diabetes medicines and can cause marked hyperglycaemia; monitor capillary glucose.
• Live vaccines may cause disseminated infection during high-dose immunosuppression; inactivated vaccines may be less effective.
• Potassium supplements, ACE inhibitors, ARBs, trimethoprim and NSAIDs can worsen hyperkalaemia with spironolactone/eplerenone.
• Digoxin toxicity is more likely when hypokalaemia from mineralocorticoid excess or loop diuresis is present.

13. Clinical cases

14. High-yield points

• Zona glomerulosa produces aldosterone; fasciculata cortisol; reticularis adrenal androgens.
• Hydrocortisone is the physiologic replacement steroid; fludrocortisone replaces mineralocorticoid in primary adrenal failure.
• Glucocorticoids suppress phospholipase A2/COX-2 pathways and immune-cell trafficking, but increase glucose and infection risk.
• Never stop prolonged systemic steroids abruptly; HPA suppression can cause fatal adrenal crisis.
• Spironolactone blocks aldosterone and androgen receptors; eplerenone is more selective but still causes hyperkalaemia.
• Ketoconazole can inhibit adrenal steroidogenesis but has severe hepatotoxicity and CYP3A4 interactions.
• Adrenal crisis: hydrocortisone plus saline and glucose; treat first, confirm second.

15. Sources and further reading

• Supplied SlideShare: Adrenal hormones—pharmacology.
• DailyMed: hydrocortisone tablets.
• DailyMed: fludrocortisone acetate.
• DailyMed: hydrocortisone sodium succinate injection.
• DailyMed: spironolactone.
• DailyMed: ketoconazole tablets.