Adrenocorticosteroid Pharmacology · Module 3 of 4

Adverse Effects, Drug Interactions, and Glucocorticoid-Induced Osteoporosis

Metabolic toxicity, GIO prevention, cardiovascular and infectious complications, and steroid-sparing strategies

Glucocorticoid hyperglycemia is predominantly postprandial, not fasting — hepatic PEPCK and G6Pase upregulation increases gluconeogenesis; peripheral GLUT4 translocation is impaired (insulin resistance); fasting glucose underestimates dysglycemia and HbA1c is unreliable if therapy began within 8–12 weeks; monitor with 2-hour postprandial glucose after the largest meal; in pre-existing diabetes, antidiabetic medications typically require acute escalation; steroid myopathy (proximal weakness, normal CK) requires dose reduction, while inflammatory myositis (elevated CK) requires more steroids — distinguishing them avoids treatment in the wrong direction.
GIOP is the most common cause of secondary osteoporosis, and fracture risk exceeds what DXA alone predicts — glucocorticoids simultaneously suppress osteoblast differentiation (Wnt/β-catenin inhibition) and promote osteoclast activation (RANKL upregulation + osteoprotegerin suppression); impaired intestinal calcium absorption and increased renal calcium excretion cause secondary hyperparathyroidism that further drives resorption; FRAX must be adjusted upward ~15% (major fracture) and ~20% (hip) for prednisone >7.5 mg/day for >3 months; denosumab rebound bone loss if doses missed or therapy stopped — always transition to bisphosphonate before stopping.
Posterior subcapsular cataracts are cumulative lifetime dose-dependent, not reversible, and can occur with inhaled and intranasal corticosteroids in addition to systemic therapy — baseline slit-lamp exam before therapy >6 months, then annually; ~30–40% of long-term systemic glucocorticoid patients develop elevated IOP, with 5–10% reaching glaucomatous levels; IOP monitoring every 3 months; fluorinated glucocorticoids (dexamethasone, triamcinolone) carry higher myopathy risk than non-fluorinated agents at equivalent anti-inflammatory doses.
Ritonavir + fluticasone raises fluticasone levels ~350-fold — causes iatrogenic Cushing syndrome even at standard inhaled doses; always use beclomethasone (not a CYP3A4 substrate) in ritonavir-boosted antiretroviral regimen patients; rifampin reduces prednisolone exposure 45–75% and can precipitate acute transplant rejection; when rifampin is stopped, the compensatory glucocorticoid dose can become toxic as normal enzyme activity returns over 2–4 weeks; warfarin: check INR within 1–2 weeks of any significant glucocorticoid dose change.
Steroid-sparing agents are indicated for prednisone equivalent >7.5 mg/day for >3 months — methotrexate: onset 6–12 weeks, permits 30–50% prednisone dose reduction, requires folate supplementation and LFT/CBC monitoring; azathioprine: check TPMT genotype before initiation (poor metabolizers at risk for myelosuppression), onset 3–6 months; mycophenolate mofetil: preferred for lupus nephritis, teratogenic (requires pregnancy prevention); tocilizumab: IL-6 receptor antagonist, proven steroid-sparing in GCA (GiACTA trial), screen for TB and HBV before initiating.

Abbreviations: GR = glucocorticoid receptor · GIOP = glucocorticoid-induced osteoporosis · DXA = dual-energy X-ray absorptiometry · RANKL = receptor activator of nuclear factor kappa-B ligand · OPG = osteoprotegerin · FRAX = Fracture Risk Assessment Tool · PEPCK = phosphoenolpyruvate carboxykinase · G6Pase = glucose-6-phosphatase · GLUT4 = glucose transporter type 4 · CK = creatine kinase · IOP = intraocular pressure · PJP = Pneumocystis jirovecii pneumonia · IGRA = interferon-gamma release assay · TPMT = thiopurine methyltransferase · GCA = giant cell arteritis

Metabolic and Structural Adverse Effects

Hyperglycemia — Postprandial Pattern

Two Mechanisms

Hepatic: GR transactivation upregulates PEPCK and G6Pase → increased gluconeogenesis from amino acid and glycerol substrates
Peripheral: GLUT4 translocation impaired → insulin resistance in muscle and adipose
Pattern: predominantly postprandial; fasting glucose underestimates; HbA1c unreliable if therapy <8–12 weeks old
Monitor: glucose 2 h after largest meal; escalate antidiabetic therapy proactively in pre-existing diabetes

Dyslipidemia and Cardiovascular

Lipids, BP, Atherosclerosis

↑ LDL, VLDL/triglycerides, total cholesterol; mechanism: hepatic lipogenic enzymes + increased FFA from lipolysis
Hypertension: mineralocorticoid overflow (overwhelms 11β-HSD2 in distal nephron → Na/water retention) + suppressed endothelial NOS + ↑ vascular sensitivity to ATII and catecholamines
Atrial fibrillation risk ~2× at high doses (hypokalemia + direct cardiomyocyte electrical remodeling)
Lipid monitoring every 3 months if >7.5 mg/day; statin at standard CV risk thresholds

Muscle, Eye, and CNS

Steroid Myopathy, Cataracts, Neuropsychiatric

Steroid myopathy: proximal limb weakness; MuRF1/MAFbx ubiquitin ligases degrade myofibrillar protein; CK normal (vs. inflammatory myositis: CK markedly elevated and needs more steroids); fluorinated agents (dexamethasone, triamcinolone) highest risk
Posterior subcapsular cataracts: cumulative lifetime dose; includes inhaled and intranasal; irreversible; baseline slit-lamp before >6 months, then annually
Neuropsychiatric spectrum: euphoria/insomnia (low dose) → irritability/anxiety (moderate) → mania/psychosis ~5–10% at >60 mg/day; depression more common during taper
IOP elevation in ~30–40% (5–10% reach glaucomatous levels); monitor q3 months; refer if >21 mmHg

Glucocorticoid-Induced Osteoporosis — Prevention Framework

Agent	Risk Threshold	Key Points
Calcium + Vitamin D	Universal — all patients ≥3 months	Calcium 1000–1200 mg/day + vitamin D 600–800 IU/day; check 25-OH vitamin D at baseline; foundation for all other bone protection
Bisphosphonates (alendronate, risedronate, zoledronic acid)	Medium/high risk FRAX-adjusted >10–20%	First-line; 50–70% vertebral fracture risk reduction; inhibit farnesyl pyrophosphate synthase in osteoclasts; oral contraindicated if GFR <30–35; IV zoledronic acid annual = alternative for GI intolerance or poor adherence
Denosumab (anti-RANKL monoclonal Ab)	Bisphosphonate intolerance or GFR <30	Directly neutralizes RANKL → osteoclast activation blocked; rebound bone loss if doses missed or therapy stopped — always transition to bisphosphonate before stopping; subcutaneous every 6 months
Teriparatide (recombinant PTH 1–34)	Very high risk: FRAX >20% or multiple vertebral fractures	Bone anabolic; stimulates osteoblast differentiation via PTH receptor 1; superior to alendronate for vertebral fractures in GIOP (Saag 2007 trial); 24-month limit; transition to antiresorptive agent after

Drug Interactions, Infection Prophylaxis, and Steroid-Sparing Agents

CYP3A4 inducers reduce glucocorticoid levels: rifampin (45–75% prednisolone reduction → acute transplant rejection), phenytoin, carbamazepine, phenobarbital, efavirenz. Increase glucocorticoid dose; when inducer stopped, previously compensatory dose becomes toxic as enzyme activity normalizes over 2–4 weeks. CYP3A4 inhibitors raise levels: ritonavir + fluticasone ICS → ~350-fold fluticasone increase → iatrogenic Cushing syndrome at standard inhaled doses; always substitute beclomethasone (not a CYP3A4 substrate); azole antifungals, clarithromycin. NSAIDs + glucocorticoids: ~15-fold increased peptic ulcer risk (vs. ~3-fold each alone) → mandatory PPI. Warfarin: check INR within 1–2 weeks of any significant glucocorticoid dose change (variable INR effects from factor synthesis changes and protein binding competition).

Infection prophylaxis thresholds: PJP (TMP-SMX 1 DS tablet 3×/week): prednisone >20 mg/day for >4 weeks monotherapy, OR >10 mg/day for >4 weeks + additional immunosuppressant; alternatives for sulfonamide intolerance: dapsone 100 mg/day or atovaquone 1500 mg/day. Live vaccines contraindicated if ≥20 mg/day for ≥2 weeks; recombinant zoster vaccine (Shingrix) recommended age ≥50 before therapy or between cycles; TB screening (IGRA preferred) before long-term therapy in high-risk patients → isoniazid preventive therapy before starting when possible; pneumococcal vaccination for all adults on pharmacological glucocorticoid therapy.

Steroid-sparing agents (indicated for prednisone >7.5 mg/day for >3 months): Methotrexate — dihydrofolate reductase inhibition + adenosine-mediated anti-inflammation; onset 6–12 weeks; permits 30–50% prednisone dose reduction; folate supplementation required; monitor LFTs and CBC. Azathioprine — 6-MP prodrug; inhibits de novo purine synthesis in lymphocytes; onset 3–6 months; check TPMT genotype first (poor metabolizers → myelosuppression). Mycophenolate mofetil — IMPDH type II inhibition in activated lymphocytes; onset 4–8 weeks; preferred for lupus nephritis; teratogenic (pregnancy prevention required). Tocilizumab — IL-6 receptor antagonist; onset 4–8 weeks; proven steroid-sparing in GCA (GiACTA trial); screen for TB and HBV before initiating; monitor for serious infections and lipid elevation.

Suggested References

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