Adrenal Disorders: Corticosteroids PDF

Adrenal Disorders… And Clinical Use of Corticosteroids Dustin Wilson, PharmD, BCPS, FNCAP Associate Professor Campbell University CPHS Spring 2024 Objectives Discuss the judicious use of glucocorticoids Discuss the mechanism of action, indications, therapeutic course, contraindications, drug-drug an...

Adrenal Disorders… And Clinical Use of Corticosteroids Dustin Wilson, PharmD, BCPS, FNCAP Associate Professor Campbell University CPHS Spring 2024 Objectives Discuss the judicious use of glucocorticoids Discuss the mechanism of action, indications, therapeutic course, contraindications, drug-drug and drug-food interactions, side effects, and monitoring parameters of the pharmacologic agents commonly used in the treatment of adrenal insufficiency and Cushing’s syndrome Discuss the goals of treatment for adrenal insufficiency and Cushing’s syndrome Develop an evidence-based treatment plan for a patient with acute and chronic adrenal insufficiency based on patient specific factors Develop an evidence-based treatment plan for a patient with Cushing’s syndrome based on patient specific factors Objectives Develop an appropriate monitoring plan for a patient being treated for adrenal insufficiency and Cushing’s syndrome Discuss the nonpharmacologic treatment of Cushing’s disease Nuts and Bolts of Steroids Terminology Corticosteroid – Mineralcorticoid [MC]- “Na+-retaining” ↑ NA+ = ↑ H2O = ↑ volume ; ↓ K+ endogenous = aldosterone synthetic = fludrocortisone, oral [Florinef®] – Glucocorticoid [GC]- “glucose retaining” endogenous = cortisol Regulation of fat, carbohydrate and protein metabolism naturally occurring = hydrocortisone and cortisone synthetic [ex. prednisone] - differ by duration, MC and antiinflammatory potency Glucocorticoid Equivalencies, Potencies and Durations Short acting [Duration 8-12 hrs] – cortisone – hydrocortisone Intermediate acting [Duration 18-36 hrs] – prednisone:prednisolone [1:1 equivalency] – methylprednisolone Glucocorticoid Equivalencies, Potencies and Durations Long acting [Duration 36-60 hrs] – dexamethasone – no NA+ retaining properties – most potent anti-inflammatory steroids Prednisone equivalents – hydrocortisone 20mg = prednisone & prednisolone 5mg = methylpred 4mg = dexamethasone 0.75mg General Principles – Use lowest dose for shortest time – Taper usually not necessary if duration of use < 2 wks can be very disease specific Dose and Administration Physiological dose – approximately 5 mg of pred-equiv or 20 mg hydrocortisone Pharmacological dose – Low - slightly higher than physiological dose – Moderate - anti-inflammatory 0.5 mg/kg/day of pred-equiv [25-30 mg prednisone] – High - immunosuppressive 1-3 mg/kg/day of pred-equiv [60-180 mg prednisone] use < 5 days probably has minimal effect on immune system – Massive 15-30 mg/kg/day of pred-equiv [1-2 gm methylpred] Discontinuation of Therapy Patient specific – depends upon dose, duration and disease Methylprednisolone dosepak – 4 mg x 21 tabs tapered over 6 days Prednisone available in many strengths Adverse Effects In general – ↑ duration of use + ↑ dose = ↑ risk of adrenal suppression [> 5 mg prednisone for > 2-3 weeks] – suppression unlikely with short term use of high doses Measures to avoid suppression – low dose; short acting; short term – use route other than systemic – Use < 7.5 mg pred-equivalent/day Adverse Effects Immunosuppression – PJP prophylaxis???? Based on other immunosuppressive risk factors, dose of steroid, and duration of steroid GI – routine use of antacids, PPI’s and H2 antagonists not recommended for ulcer prevention Unless patient also on chronic NSAID/antiplatelet/ anticoagulant therapy  PPIs – N/V; diarrhea/constipation; take with food Electrolytes – Hypokalemia Adverse Effects Cardiovascular – BP, lipids, weight gain CNS - vertigo; insomnia; depression Dermatological – skin atrophy; ecchymosis Endocrine - hyperglycemia Musculoskeletal - aseptic necrosis; myalgias; weakness Adverse Effects Ophthalmic – ↑ IOP; cataracts [risk highest in peds and RA pts] Osteoporosis [OP] – 50% of pts on > 7.5mg pred-equiv for > 1 yr have 4x ↑ vertebral fractures and double risk of hip fractures – inhibits osteoblasts; ↓ intestinal absorption of Ca++ – Consider Ca and vit D supplementation if on doses > than physiologic for > 3 months Case 1 Which of the following adverse events are most associated with systemic corticosteroids? A. B. C. D. Hypoglycemia Insomnia Weight loss Nephrotoxicity Adrenal Disorders Physiology Adrenal gland – 90% cortex secretes cortisol, aldosterone, androgens – 10% medulla secretes catecholamines [norepi, epinephrine] Feedback control – ACTH regulates secretion of cortisol – RAAS regulates secretion of aldosterone Renin angiotensin aldosterone system Physiology Hypothalamus 3° failure overuse of GC Corticotrophin releasing hormone [CRH] Anterior Pituitary ACTH release Adrenal Cortex 2° failure Issues with pituitary 1° failure Addison’s disease Cortisol release Periphery Adrenal Insufficiency 1º = Addison’s disease 2º = deficiency of ACTH due to gland dysfunction 3º = usually caused by overuse of exogenous corticosteroids Addison’s Disease In general: – Usually asymptomatic until loss of > 90% of adrenal cortex – 50% usually involve clinical disorder of another hormonal system Common Symptoms – weakness, fatigue, anorexia, nausea, diarrhea, light headedness Common Signs – Weight loss, ↓ BP, hyperkalemia, hyponatremia, ↓ glucose, hyperpigmentation Addison’s Disease Treatment – physiologic doses of corticosteroids Range of 15-30 mg QD of hydrocortisone 2/3 AM and 1/3 PM [HC 15 mg qAM; 10 mg qPM] Alternatives: Prednisone 5 mg or dexamethasone 0.75 mg nightly MC: fludrocortisone [Florinef®] 0.05 - 0.2 mg oral QD – Adjust dose based on blood pressure and K – Higher doses more often needed with dexa and pred vs hydro Addison’s Disease Monitoring [goals of therapy] – Normalization of BP, K+, Na+ Emergency precautions – Prescription for injectable glucocorticoid Hydrocortisone 100 mg IM Addisonian Crisis “Endocrine emergency” – stress replacement doses range from 100 -300 mg HC IV – Hypovolemia may require use of vasopressors and fluids Symptoms – ↓ BP, Na+, glucose = “shock” Treatment – 100 mg IV bolus, followed by 50 mg HC IV q6h x 24h; dose can then be adjusted according to stability Secondary and Tertiary Adrenal Insufficiency Deficiency of ACTH and CRH release – Most commonly due to overuse of exogenous steroids – MC usually WNL Symptoms – weakness, arthralgias, hypoglycemia, ↓ BP, ↓ Na – Do not see hyperkalemia Does not affect mineralocorticoid activity Treatment  glucocorticoid replacement – Hydrocortisone or prednisone Sick days Patients with adrenal insufficiency who are steroid dependent Double the dose during febrile illness or use the 3 x 3 rule – e.g. take hydrocortisone 30 mg qam and 20 mg qpm instead of 15 and 10. Case 2 MR is admitted to the hospital for adrenal crisis. She has a previous diagnosis of Addison’s Disease, but stopped taking her meds. In addition to fluids, what corticosteroid regimen would you start on MR? A. B. C. D. Hydrocortisone PO 15 mg qam and 10 mg qpm Prednisone PO 7.5 mg daily Hydrocortisone 50 mg IV q6hrs Methylpredinsolone 500 mg IV q6 hrs Case 2 (continued) What should you monitor acutely regarding her corticosteroid regimen? A. Blood glucoses B. Liver function tests C. Serum creatinine Cushing’s Syndrome Cushing’s Disease Cushing’s Syndrome vs. Disease Syndrome: Result of supraphysiologic cortisol amounts ACTH-dependant Result of ACTH secreting adenomas ACTH-independant – Exogenous – pharmacologic doses of GCs [most common cause – Endogenous – excessive cortisol secretion by adrenal glands [15%] Cushing’s Syndrome vs. Disease Disease – Refers specifically to Cushing’s syndrome from an ACTHsecreting pituitary adenoma – Treatment of choice is surgical resection Alternative: pituitary radiation, bilateral adrenalectomy Glucocorticoid replacement after adrenal surgery – Yes for unilateral… physiologic doses of hydrocortisone  months to years – If bilateral adrenalectomy  add mineralocorticoid replacement therapy to glucocorticoid replacement Example: fludrocortisone 0.1mg daily + Hydrocortisone 15 mg in am and 10 mg in pm Lifelong Cushing’s Syndrome vs. Disease Goals of Treatment – Reversal of hypercortisolism and management of comorbidities Metabolic syndrome  hyperlipidemia Infections insulin resistance, HTN, obesity, and – Vaccines Osteoporosis Psychiatric disorders – Pharmacologic therapy indicated in: Patients who have failed pituitary surgery Bridge until radiation therapy Patients with contraindications to surgery Pharmacologic Treatment of Cushing’s Syndrome Adrenal steroidogenesis inhibitors – Ketoconazole First line agent – Effective in majority of cases Monitor LFTS – Warning from FDA regarding hepatotoxicity in 2013 – Contraindicated in patients with active or chronic liver disease – Weekly monitoring of ALT while on therapy Requires acidic environment for absorption  blockers if possible Decreased androgen production in men – Gynecomastia, decreased libido, and impotence – Consider testosterone replacement Drug Interactions! Avoid PPIs and H2 Pharmacologic Treatment of Cushing’s Syndrome Adrenal steroidogenesis inhibitors – Metyrapone Available through the manufacturer only – Can be used as add on therapy to ketoconazole Increased androgen production in females – Increased hirsutism and acne Gastrointestinal adverse effects  take with food – Etomidate Anesthesia induction IV route limits use Used in emergent situations or preoperatively Pharmacologic Treatment of Cushing’s Syndrome Neuromodulators of ACTH release – Pasireotide – somatostatin agonist SC administration – Cabergoline – dopamine agonist – Target pituitary – Often used in mild hypercortisolism and for tumor shrinkage – Cabergoline --> impulse-control disorders  avoid in patients with Bipolar Disorder or Impulse-Control Disorders – Pasireotide  hyperglycemia Pharmacologic Treatment of Cushing’s Syndrome Adrenolytic agent – Mitotane Used in adrenal cancers RARELY USED FOR CUSHING’S DISEASE Pharmacologic Treatment of Cushing’s Syndrome Glucocorticoid receptor blocker – Mifepristone (Korlym) Indication – Treatment of hyperglycemia associated with Cushing’s Syndrome – May also be reasonable for cortisol-induced psychosis Decrease glucose, decrease weight Adverse effects – Hypertension – Hypokalemia – Adrenal insufficiency Must rule out pregnancy in females  abortifacient Monitoring cortisol concentrations is not reliable Expensive!!!!!! Pharmacologic Treatment of Cushing’s Syndrome Cortisol synthesis inhibitor – Osilodrostat (Isturisa) Adrenal steroidogenesis inhibitor Indication – Treatment of Cushing’s disease in adults for whom pituitary surgery is not an option or has not been curative Dosing – 2 mg po bid  Adverse effects – – – – – Edema Nausea and vomiting Headache Adrenal insufficiency QTc prolongation Expensive!!!!!! up to 30 mg po bid Quiz Which agent used for Cushing’s Disease can lead to impulse-control disorders? A. Ketoconazole B. Osilodrostat C. Mitotane D. Cabergoline Take home points! Know physiologic doses of corticosteroids Know the adverse events of corticosteroid therapy Do not abruptly stop corticosteroid therapy – Characteristics of the drug that makes the patient more at risk for developing adrenal insufficiency Adrenal insufficiency – Supplement with physiologic doses of corticosteroids – May need to give “stress” dose steroids Cushing’s Syndrome – Preferred therapy is surgical resection – First line pharmacologic therapy is often ketoconazole, but is patient specific Adrenal Disorders… And Clinical Use of Corticosteroids Dustin Wilson, PharmD, BCPS, FNCAP Associate Professor Campbell University CPHS Spring 2024