Chapter 28: Adrenocorticosteroid Pharmacology — Module 3: Adverse Effects, GIO Management, and Drug Interactions
1. A patient on once-daily morning prednisone has near-normal fasting glucose but pronounced hyperglycemia in the afternoon and early evening. Integrating the pharmacokinetics of morning dosing with the characteristic glucose pattern, which management approach best matches the abnormality?
A) Add basal long-acting insulin alone, since the predominant defect is fasting hyperglycemia
B) Time a short-acting glucose-lowering agent to coincide with the afternoon glucose peak produced by the morning steroid dose
C) Switch the prednisone to an evening dose to move the glucose peak into the overnight fasting window
D) Rely on HbA1c (hemoglobin A1c) trends alone to guide therapy, since it captures the postprandial excursions accurately
E) Discontinue glucose monitoring because morning fasting values are near normal
ANSWER: B
Rationale:
Once-daily morning glucocorticoid dosing produces a predictable afternoon and early-evening glucose peak driven by the postprandial-dominant pattern of glucocorticoid hyperglycemia; matching a short-acting agent (such as prandial insulin or an agent timed to the steroid peak) to that window addresses the actual defect more effectively than basal insulin alone.
Option A: Option A is incorrect because the predominant abnormality is postprandial, not fasting, so basal insulin alone misses the peak.
Option C: Option C is incorrect because shifting to evening dosing would tend to move the peak into the night and worsen overnight and fasting glucose rather than solve the problem.
Option D: Option D is incorrect because HbA1c (hemoglobin A1c) underestimates the postprandial excursions in this setting, particularly within the first 8 to 12 weeks.
Option E: Option E is incorrect because near-normal fasting glucose does not exclude significant postprandial dysglycemia, which still requires monitoring.
2. A patient with an inflammatory condition controlled on dexamethasone (a fluorinated glucocorticoid) develops gradual proximal weakness with a normal creatine kinase (CK). Integrating agent-specific risk with the interpretation of the weakness, which course best fits the clinical picture?
A) The presentation fits steroid myopathy, which fluorinated agents make more likely; switching toward a non-fluorinated agent and reducing dose addresses both the cause and the agent-specific risk
B) The normal CK confirms an active inflammatory myositis, so the dexamethasone dose should be increased
C) Because all glucocorticoids carry identical myopathy risk, changing the agent cannot help and only the underlying disease should be treated
D) The weakness indicates hypokalemic periodic paralysis, so potassium repletion is the definitive treatment
E) The normal CK rules out any muscle process, so no change in therapy is warranted
ANSWER: A
Rationale:
Gradual proximal weakness with a normal or only mildly elevated CK is the picture of steroid myopathy, and fluorinated agents such as dexamethasone carry higher myopathy risk than non-fluorinated agents; integrating these facts, switching toward a non-fluorinated agent and reducing dose addresses both the drug-induced cause and the agent-specific risk.
Option B: Option B is incorrect because a normal CK argues against inflammatory myositis (where CK is markedly elevated), and raising the dose would worsen steroid myopathy.
Option C: Option C is incorrect because myopathy risk is not identical across agents; fluorinated agents are higher-risk, so agent choice matters.
Option D: Option D is incorrect because the picture is steroid myopathy, not hypokalemic periodic paralysis, and potassium repletion is not the treatment.
Option E: Option E is incorrect because a normal CK does not exclude steroid myopathy, in which CK is characteristically normal or only mildly elevated.
3. A patient who completed several months of high-dose glucocorticoids now has a normal basal morning cortisol and is scheduled for major surgery. Integrating the kinetics of HPA (hypothalamic-pituitary-adrenal) axis recovery with the physiology of surgical stress, which reasoning best supports perioperative stress-dose glucocorticoid coverage?
A) A normal basal cortisol guarantees an intact stress response, so no perioperative coverage is needed
B) Glucocorticoid coverage is unnecessary because HPA suppression fully resolves within days of stopping the drug
C) Coverage is needed only if the patient currently takes a daily glucocorticoid, regardless of recent history
D) Basal cortisol secretion recovers before the stress-surge reserve does, so a normal basal cortisol can coexist with an inadequate surge response, justifying perioperative coverage during the high-stress period
E) Stress-dose coverage is contraindicated because exogenous glucocorticoids would further suppress recovery of the axis
ANSWER: D
Rationale:
After prolonged high-dose therapy, basal cortisol secretion recovers within weeks to months, but the capacity for stress-induced ACTH (adrenocorticotropic hormone) and cortisol surges recovers more slowly; a normal basal morning cortisol can therefore coexist with an inadequate surge response, so perioperative stress-dose coverage is justified during the high-stress surgical period.
Option A: Option A is incorrect because a normal basal cortisol does not guarantee an intact stress response, which recovers later.
Option B: Option B is incorrect because suppression after prolonged high-dose therapy resolves over months, not days.
Option C: Option C is incorrect because recent prolonged high-dose use leaves residual risk even after the drug is stopped, so current daily use is not the only trigger for coverage.
Option E: Option E is incorrect because short perioperative coverage addresses an acute deficiency and is appropriate, not contraindicated.
4. A patient on high-dose hydrocortisone develops new atrial fibrillation (AF). Integrating the renal mineralocorticoid effects of glucocorticoids with arrhythmia risk, which mechanistic link best connects the drug to the arrhythmia?
A) Mineralocorticoid overflow causes hyperkalemia, which directly triggers atrial fibrillation
B) Glucocorticoids lower vascular resistance, reducing cardiac workload and provoking atrial fibrillation
C) Mineralocorticoid overflow at high glucocorticoid doses promotes potassium excretion and hypokalemia, which together with direct atrial electrical remodeling contributes to the increased atrial fibrillation risk
D) Suppression of the renin-angiotensin-aldosterone system (RAAS) lowers blood pressure and causes atrial fibrillation
E) Glucocorticoids have no plausible mechanistic link to atrial fibrillation
ANSWER: C
Rationale:
At high doses, glucocorticoids overwhelm 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2), activating the mineralocorticoid receptor to drive sodium retention and potassium excretion; the resulting hypokalemia, together with direct GR-mediated atrial electrical remodeling and the broader cardiovascular risk milieu, contributes to the roughly 2-fold increased atrial fibrillation risk.
Option A: Option A is incorrect because the mineralocorticoid effect produces hypokalemia, not hyperkalemia.
Option B: Option B is incorrect because glucocorticoids tend to raise vascular resistance and the AF link is not via reduced workload.
Option D: Option D is incorrect because glucocorticoids activate rather than suppress the RAAS (renin-angiotensin-aldosterone system), and the link is not RAAS suppression.
Option E: Option E is incorrect because there is a recognized, approximately 2-fold dose-dependent increase in AF risk with glucocorticoids.
5. In glucocorticoid-induced osteoporosis, fracture risk at a given DXA (dual-energy X-ray absorptiometry) T-score exceeds that of glucocorticoid-naive patients. Integrating the actions of glucocorticoids on both sides of the bone remodeling unit, which explanation best accounts for this excess risk beyond bone density?
A) Glucocorticoids only increase bone resorption, so fracture risk is fully explained by BMD (bone mineral density) loss alone
B) Glucocorticoids only suppress bone formation, and BMD captures this completely
C) Glucocorticoids increase OPG (osteoprotegerin) and reduce RANKL (receptor activator of nuclear factor kappa-B ligand), improving bone quality
D) Fracture risk is unrelated to bone quality and depends solely on the T-score
E) Glucocorticoids simultaneously suppress osteoblast differentiation and promote osteoblast and osteocyte apoptosis while shifting the RANKL-to-OPG ratio toward resorption, degrading bone quality faster than BMD declines
ANSWER: E
Rationale:
Glucocorticoids act on both sides of the remodeling unit: they suppress osteoblast differentiation (via Wnt/beta-catenin inhibition) and promote osteoblast and osteocyte apoptosis, while increasing RANKL (receptor activator of nuclear factor kappa-B ligand) and suppressing OPG (osteoprotegerin) to enhance resorption; together these degrade bone quality faster than BMD (bone mineral density) declines, so fracture risk exceeds what the T-score predicts.
Option A: Option A is incorrect because resorption is only one side; formation is also suppressed, and BMD alone does not capture the risk.
Option B: Option B is incorrect because resorption is also increased and BMD does not fully capture the quality deficit.
Option C: Option C is incorrect because the RANKL-to-OPG shift is toward resorption (RANKL up, OPG down), worsening rather than improving bone.
Option D: Option D is incorrect because the excess risk is precisely due to bone-quality deterioration not reflected by the T-score.
6. A 62-year-old woman is starting prednisone 10 mg per day for at least 6 months. Her FRAX (Fracture Risk Assessment Tool) score, after the glucocorticoid adjustment, places her in a high fracture-risk category. Integrating risk stratification with the ACR (American College of Rheumatology) intervention framework, which plan is most appropriate?
A) Calcium and vitamin D only, deferring any antiresorptive until a fracture occurs
B) Universal calcium and vitamin D plus an oral bisphosphonate, because her FRAX-adjusted high risk meets the threshold for pharmacological bone protection
C) No intervention, since FRAX should not be adjusted for glucocorticoid use
D) Teriparatide as first-line for every patient starting glucocorticoids regardless of risk category
E) Withhold all therapy because a 6-month course is too short to affect bone
ANSWER: B
Rationale:
The ACR (American College of Rheumatology) framework recommends universal calcium and vitamin D for any anticipated course of 3 months or longer, and adds pharmacological protection (an oral bisphosphonate) for patients at medium-to-high fracture risk; her FRAX (Fracture Risk Assessment Tool)-adjusted high-risk status meets that threshold, so calcium, vitamin D, and a bisphosphonate are appropriate.
Option A: Option A is incorrect because high risk warrants proactive pharmacological protection rather than waiting for a fracture.
Option C: Option C is incorrect because FRAX is specifically adjusted upward for glucocorticoid exposure to capture bone-quality risk.
Option D: Option D is incorrect because teriparatide is reserved for very high risk, not used first-line for all patients.
Option E: Option E is incorrect because a 3-month-or-longer course at this dose is sufficient to drive clinically meaningful bone loss, justifying intervention.
7. A patient with advanced chronic kidney disease (estimated GFR [glomerular filtration rate] of 25 mL per minute per 1.73 m2) on chronic glucocorticoids was placed on denosumab because bisphosphonates were contraindicated. The team now wishes to stop denosumab. Integrating the renal contraindication with the rebound phenomenon, which dilemma best describes the situation?
A) Bisphosphonates are the standard follow-on to prevent denosumab rebound, yet the low GFR (glomerular filtration rate) that prompted denosumab also makes bisphosphonate transition problematic, so the discontinuation strategy must be planned carefully rather than simply stopping the drug
B) Denosumab can be stopped abruptly with no rebound risk, so renal function is irrelevant to the decision
C) The low GFR (glomerular filtration rate) eliminates rebound risk, so no transition is needed
D) Restarting a bisphosphonate is always safe at any GFR (glomerular filtration rate), so transition is straightforward
E) Rebound bone loss only occurs in patients with normal renal function, so this patient is not at risk
ANSWER: A
Rationale:
Denosumab is chosen when bisphosphonates are contraindicated, as at low GFR (glomerular filtration rate), but its antiresorptive effect wanes rapidly on discontinuation with a risk of rebound bone loss and fractures; the standard mitigation is transition to a bisphosphonate, which is precisely the agent class limited by the patient's renal impairment, creating a genuine sequencing dilemma that requires careful planning rather than abrupt cessation.
Option B: Option B is incorrect because abrupt cessation carries real rebound risk.
Option C: Option C is incorrect because low GFR does not eliminate rebound risk.
Option D: Option D is incorrect because bisphosphonates are relatively contraindicated at low GFR, so transition is not straightforward.
Option E: Option E is incorrect because rebound bone loss is not confined to patients with normal renal function.
8. A patient at very high fracture risk completes the maximum 24-month course of teriparatide for glucocorticoid-induced osteoporosis. Integrating teriparatide's anabolic mechanism with what follows discontinuation, why is a subsequent antiresorptive agent recommended?
A) Teriparatide is itself an antiresorptive, so the follow-on agent simply continues the same mechanism
B) The anabolic gains are permanent, so the follow-on agent is purely precautionary with no real effect
C) Teriparatide depletes bone mineral, so an antiresorptive is needed to replace lost mineral content
D) Teriparatide is anabolic, stimulating bone formation through PTH1R (parathyroid hormone receptor 1); after it is stopped the newly formed bone is not maintained, so an antiresorptive is used to preserve the gains
E) The 24-month limit exists only for cost reasons, and stopping teriparatide has no skeletal consequence
ANSWER: D
Rationale:
Teriparatide is an anabolic agent that stimulates osteoblast activity through PTH1R (parathyroid hormone receptor 1) signaling, increasing bone formation; once it is stopped, the gains are not maintained without further treatment, so transition to an antiresorptive (typically a bisphosphonate) within about 3 months of completing the 24-month course is recommended to preserve the benefit.
Option A: Option A is incorrect because teriparatide is anabolic, not antiresorptive, so the follow-on agent uses a different mechanism.
Option B: Option B is incorrect because the gains are not permanent and are lost without follow-on therapy.
Option C: Option C is incorrect because teriparatide builds rather than depletes bone, so the rationale is preservation, not mineral replacement.
Option E: Option E is incorrect because the time limit is a regulatory restriction with real skeletal consequences if no follow-on therapy is given.
9. A transplant patient on prednisolone had the dose increased while taking rifampin, a drug that markedly increases the activity of the liver enzyme (CYP3A4, cytochrome P450 3A4) that breaks down glucocorticoids. The rifampin is now being stopped. Integrating enzyme induction with its time course, what should the team anticipate?
A) Stopping rifampin will further lower glucocorticoid levels, requiring an additional dose increase
B) Glucocorticoid levels will not change when rifampin is stopped, so the elevated dose can be continued indefinitely
C) As CYP3A4 (cytochrome P450 3A4) activity returns to baseline over about 2 to 4 weeks, the previously compensatory higher glucocorticoid dose can produce toxic concentrations, so the dose must be tapered with monitoring
D) Enzyme activity normalizes instantly when rifampin is stopped, so the dose should be cut to zero immediately
E) Rifampin inhibits CYP3A4 (cytochrome P450 3A4), so stopping it will reduce glucocorticoid exposure
ANSWER: C
Rationale:
Rifampin is a potent CYP3A4 (cytochrome P450 3A4) inducer, so a higher glucocorticoid dose was needed during co-administration; when the inducer is stopped, enzyme activity returns toward baseline over roughly 2 to 4 weeks, and the previously compensatory dose can then yield toxic glucocorticoid concentrations, so the dose must be tapered with monitoring.
Option A: Option A is incorrect because stopping the inducer raises, not lowers, glucocorticoid levels.
Option B: Option B is incorrect because levels do change as induction resolves, so the elevated dose cannot be continued unchanged.
Option D: Option D is incorrect because enzyme activity normalizes gradually over weeks, not instantly, and an abrupt cut to zero is inappropriate.
Option E: Option E is incorrect because rifampin induces rather than inhibits CYP3A4.
10. A patient with HIV (human immunodeficiency virus) on a ritonavir-boosted regimen using inhaled fluticasone develops cushingoid features and, on testing, a suppressed morning cortisol. Integrating the pharmacokinetic interaction with its effect on the HPA (hypothalamic-pituitary-adrenal) axis, which explanation is correct?
A) Ritonavir induces the metabolizing enzyme, lowering fluticasone levels and causing primary adrenal failure
B) Ritonavir potently inhibits CYP3A4 (cytochrome P450 3A4), markedly raising systemic fluticasone exposure; the resulting glucocorticoid excess produces iatrogenic Cushing syndrome and suppresses the HPA (hypothalamic-pituitary-adrenal) axis, lowering endogenous cortisol
C) The suppressed cortisol proves the fluticasone level is too low and the dose should be increased
D) Inhaled fluticasone cannot cause systemic effects, so the findings must be unrelated to the drugs
E) The interaction reflects displacement of fluticasone from plasma proteins without any change in metabolism
ANSWER: B
Rationale:
Ritonavir is a potent CYP3A4 (cytochrome P450 3A4) inhibitor that dramatically raises systemic exposure to inhaled fluticasone; the resulting glucocorticoid excess produces iatrogenic Cushing syndrome and, through negative feedback, suppresses the HPA (hypothalamic-pituitary-adrenal) axis, lowering endogenous cortisol even though the exogenous steroid burden is high.
Option A: Option A is incorrect because ritonavir inhibits rather than induces the enzyme, raising fluticasone levels, and the low cortisol reflects HPA suppression, not primary adrenal failure.
Option C: Option C is incorrect because the suppressed cortisol reflects excess exogenous glucocorticoid, so the dose should be reduced, not increased.
Option D: Option D is incorrect because the interaction specifically makes inhaled fluticasone systemically active.
Option E: Option E is incorrect because the dominant mechanism is CYP3A4 inhibition reducing fluticasone clearance, not protein displacement.
11. A patient on chronic prednisone takes a daily NSAID (non-steroidal anti-inflammatory drug) for arthritis and is also on warfarin. Integrating the interactions of glucocorticoids with both drugs, which assessment is most accurate?
A) The combinations are pharmacologically inert, requiring no monitoring or prophylaxis
B) Only the warfarin interaction matters; the NSAID adds no additional risk
C) The glucocorticoid-NSAID combination reduces gastrointestinal injury, while warfarin requires no monitoring after a steroid change
D) The glucocorticoid and NSAID independently impair gastric mucosal defense and together greatly increase peptic ulcer complication risk, warranting proton pump inhibitor prophylaxis, while the glucocorticoid can shift the INR (international normalized ratio), so warfarin needs monitoring after dose changes
E) The NSAID induces glucocorticoid metabolism, so the prednisone dose must be doubled
ANSWER: D
Rationale:
Glucocorticoids and NSAIDs (non-steroidal anti-inflammatory drugs) each suppress prostaglandin-mediated gastric mucosal defense, and in combination they markedly raise the risk of peptic ulcer complications (relative risk on the order of 15-fold), warranting proton pump inhibitor prophylaxis; separately, glucocorticoids can produce variable INR (international normalized ratio) changes, so warfarin requires monitoring around glucocorticoid initiation or dose changes.
Option A: Option A is incorrect because both interactions are clinically significant and require action.
Option B: Option B is incorrect because the NSAID adds substantial gastrointestinal risk on top of the glucocorticoid.
Option C: Option C is incorrect because the combination increases rather than reduces gastrointestinal injury, and warfarin does require monitoring after a steroid change.
Option E: Option E is incorrect because the glucocorticoid-NSAID interaction is pharmacodynamic, not an NSAID induction of glucocorticoid metabolism.
12. A patient with lupus nephritis requires prednisone above 7.5 mg per day for longer than 3 months to maintain disease control. Integrating the rationale for steroid-sparing therapy with disease-appropriate agent selection, which approach is best supported?
A) Because chronic exposure above this dose-and-duration threshold carries a high cumulative toxicity burden, a steroid-sparing agent is justified, and mycophenolate, which selectively inhibits IMPDH (inosine monophosphate dehydrogenase) type II in lymphocytes, is a preferred choice in lupus nephritis
B) Steroid-sparing agents should be avoided because the glucocorticoid alone is always safer than adding a second immunosuppressant
C) Methotrexate is the preferred steroid-sparing agent specifically for lupus nephritis because it inhibits IMPDH (inosine monophosphate dehydrogenase) type II
D) Steroid-sparing therapy is indicated only after irreversible organ damage has occurred
E) Tocilizumab, an interleukin-6 (IL-6) receptor antagonist, is the established first-line steroid-sparing agent for lupus nephritis
ANSWER: A
Rationale:
Steroid-sparing therapy is pharmacologically justified when glucocorticoid requirements exceed roughly 7.5 mg prednisone equivalent per day for more than 3 months, because the cumulative adverse-effect burden then outweighs the risk of most sparing agents; in lupus nephritis, mycophenolate, which selectively inhibits IMPDH (inosine monophosphate dehydrogenase) type II in activated lymphocytes, is a preferred agent.
Option B: Option B is incorrect because at this exposure the chronic glucocorticoid toxicity burden makes adding a sparing agent advantageous rather than inherently less safe.
Option C: Option C is incorrect because methotrexate inhibits dihydrofolate reductase, not IMPDH type II, and is not the preferred agent for lupus nephritis.
Option D: Option D is incorrect because steroid-sparing is used proactively to limit toxicity, not only after irreversible damage.
Option E: Option E is incorrect because tocilizumab's established steroid-sparing role is in giant cell arteritis, not as first-line for lupus nephritis.
13. A patient is about to begin prednisone 40 mg per day for several weeks and needs vaccinations updated, including a live attenuated vaccine and several inactivated vaccines. Integrating the immunosuppression threshold with vaccine type and timing, which plan is most appropriate?
A) Administer the live attenuated vaccine during high-dose therapy, since immunosuppression improves its effect
B) Give all vaccines, live and inactivated, only after the high-dose course is well underway
C) Withhold inactivated vaccines entirely because they are unsafe during glucocorticoid therapy
D) Delay all vaccines indefinitely because glucocorticoids permanently contraindicate vaccination
E) Give the live attenuated vaccine before starting therapy (or defer it), since it is contraindicated above prednisone 20 mg per day for more than 2 weeks, while administering needed inactivated vaccines, ideally before therapy when immunogenicity is best
ANSWER: E
Rationale:
Live attenuated vaccines are contraindicated at prednisone equivalent greater than 20 mg per day for more than 2 weeks because of disseminated-infection risk, so the live vaccine should be given before initiating therapy or deferred; inactivated vaccines are safe at any degree of immunosuppression and are ideally given before therapy or at the lowest maintenance dose, when immunogenicity is best.
Option A: Option A is incorrect because immunosuppression reduces immunogenicity and live vaccines are contraindicated at this dose, not improved.
Option B: Option B is incorrect because the live vaccine should not be given once high-dose therapy is underway, and inactivated vaccines are best given before therapy.
Option C: Option C is incorrect because inactivated vaccines are safe during glucocorticoid therapy.
Option D: Option D is incorrect because vaccination is not permanently contraindicated; timing and vaccine type determine the approach.
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