Chapter 28: Adrenocorticosteroid Pharmacology — Module 3: Adverse Effects, GIO Management, and Drug Interactions
1. [CASE 1 — QUESTION 1]
A 63-year-old man with well-controlled type 2 diabetes (baseline HbA1c [hemoglobin A1c] 6.6 percent) is started on once-daily morning prednisone 40 mg for biopsy-proven giant cell arteritis. Two weeks later his fasting glucose is near 125 mg per dL, but he describes malaise and blurred vision in the late afternoon. His clinician suspects glucocorticoid-induced hyperglycemia that his usual fasting checks are missing. Which monitoring strategy will most sensitively detect his glucocorticoid-induced glucose abnormality?
A) Fasting morning glucose drawn before the prednisone dose
B) HbA1c (hemoglobin A1c) repeated at 2-week intervals
C) Point-of-care glucose measured about 2 hours after the largest meal of the day
D) A single random glucose at the morning clinic visit
E) Bedtime glucose only, after the evening meal
ANSWER: C
Rationale:
Once-daily morning glucocorticoid dosing produces a postprandial-dominant pattern with an afternoon and early-evening glucose peak that fasting values and HbA1c (hemoglobin A1c) underestimate; point-of-care glucose roughly 2 hours after the largest meal is the most sensitive way to detect it.
Option A: Option A is incorrect because fasting glucose captures the least affected part of the pattern and misses the postprandial peak.
Option B: Option B is incorrect because HbA1c underestimates postprandial excursions, particularly in the first 8 to 12 weeks, and lags recent change.
Option D: Option D is incorrect because a morning random glucose is drawn before the characteristic afternoon peak.
Option E: Option E is incorrect because a bedtime-only reading can miss the afternoon and early-evening peak produced by morning dosing.
2. [CASE 1 — QUESTION 2]
Continuing with the same patient. His endocrinologist explains the dual mechanism by which glucocorticoids raise blood glucose. Which combination best describes how glucocorticoids produce hyperglycemia?
A) Increased hepatic glucose output through upregulation of the gluconeogenic enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase), together with reduced insulin-stimulated GLUT4 (glucose transporter type 4) translocation in peripheral tissues
B) Suppression of pancreatic beta-cell insulin gene transcription as the sole mechanism
C) Increased renal tubular glucose reabsorption with no change in hepatic output
E) Direct activation of the insulin receptor enhancing downstream signaling
ANSWER: A
Rationale:
Glucocorticoids raise glucose by two converging actions: in the liver, GR-alpha upregulates the gluconeogenic enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase), increasing hepatic glucose output; in skeletal muscle and adipose tissue, they reduce insulin-stimulated GLUT4 (glucose transporter type 4) translocation, impairing peripheral uptake.
Option B: Option B is incorrect because hyperglycemia arises from insulin resistance and increased hepatic output, not from suppression of beta-cell insulin gene transcription.
Option C: Option C is incorrect because the dominant contributions are hepatic output and peripheral resistance, not renal reabsorption.
Option D: Option D is incorrect because glucocorticoids reduce, not enhance, GLUT4 translocation.
Option E: Option E is incorrect because glucocorticoids impair rather than enhance insulin-receptor signaling.
3. [CASE 1 — QUESTION 3]
Continuing with the same patient. After 3 months on prednisone, his lipid panel shows elevated total and LDL (low-density lipoprotein) cholesterol and elevated triglycerides. Which statement best characterizes his glucocorticoid-induced dyslipidemia and its management?
A) The pattern is isolated low HDL (high-density lipoprotein) with normal LDL and triglycerides, requiring no treatment
B) Glucocorticoids lower LDL (low-density lipoprotein) cholesterol, so the elevation must be unrelated to the drug
C) The dyslipidemia resolves spontaneously regardless of dose and never needs treatment
D) The pattern of elevated total and LDL (low-density lipoprotein) cholesterol with elevated VLDL (very low-density lipoprotein) triglycerides is dose- and duration-related, contributes to accelerated atherosclerosis, and warrants lipid monitoring with statin therapy at standard cardiovascular risk thresholds
E) Glucocorticoid dyslipidemia is treated only with dietary change and statins are contraindicated
ANSWER: D
Rationale:
Glucocorticoid-induced dyslipidemia is characterized by elevated total and LDL (low-density lipoprotein) cholesterol and elevated VLDL (very low-density lipoprotein) triglycerides, is generally dose- and duration-related, contributes to accelerated atherosclerosis, and warrants lipid monitoring with statin therapy started at standard cardiovascular risk thresholds in patients on long-term therapy.
Option A: Option A is incorrect because the abnormality is elevated LDL and triglycerides, not an isolated low HDL.
Option B: Option B is incorrect because glucocorticoids raise, not lower, LDL cholesterol.
Option C: Option C is incorrect because the dyslipidemia is dose-related and may require treatment rather than resolving spontaneously.
Option E: Option E is incorrect because statins are appropriate, not contraindicated, at standard risk thresholds.
4. [CASE 1 — QUESTION 4]
Continuing with the same patient. His afternoon glucose excursions are confirmed on post-meal monitoring, and the team must adjust his diabetes regimen. Which management approach best matches the glucose pattern produced by his morning prednisone?
A) Add only basal long-acting insulin, since the defect is predominantly fasting
B) Time a short-acting glucose-lowering agent (such as prandial insulin or an agent matched to the steroid peak) to the afternoon and early-evening rise produced by the morning dose
C) Move the prednisone to bedtime to shift the peak overnight
D) Discontinue all glucose-lowering therapy because the fasting glucose is acceptable
E) Rely on HbA1c (hemoglobin A1c) trends alone to titrate therapy
ANSWER: B
Rationale:
Because morning prednisone produces an afternoon and early-evening glucose peak, the most effective strategy is to time a short-acting agent (prandial insulin or an agent matched to the steroid peak) to that window, rather than relying on basal insulin alone.
Option A: Option A is incorrect because basal insulin alone misses the postprandial peak that dominates the pattern.
Option C: Option C is incorrect because bedtime dosing would shift hyperglycemia into the overnight and fasting window.
Option D: Option D is incorrect because acceptable fasting glucose does not exclude significant postprandial dysglycemia that warrants treatment.
Option E: Option E is incorrect because HbA1c underestimates the postprandial excursions and should not be the sole titration guide.
5. [CASE 2 — QUESTION 1]
A 46-year-old woman with no psychiatric history is admitted for a severe autoimmune flare and started on prednisone 80 mg per day. On day 5 she develops paranoid delusions, agitation, and disorganized thinking; she is medically stable and her underlying disease is improving. Which management approach is most appropriate for her acute presentation?
A) Continue the current dose unchanged and provide reassurance only, as the symptoms will not respond to dose change
B) Diagnose a primary psychotic disorder unrelated to the steroid and commit to indefinite antipsychotic therapy alone
C) Escalate the prednisone dose to treat presumed central nervous system disease involvement
D) Abruptly discontinue all glucocorticoids regardless of disease control or adrenal status
E) Recognize steroid psychosis, reduce the glucocorticoid dose as the disease allows, and use a temporary antipsychotic during the acute phase
ANSWER: E
Rationale:
New psychosis within days of high-dose glucocorticoid initiation in a patient without psychiatric history is characteristic of steroid psychosis, which is dose-related and typically resolves within days to weeks of dose reduction; a temporary antipsychotic is appropriate during the acute phase.
Option A: Option A is incorrect because steroid psychosis generally responds to dose reduction rather than remaining fixed at the current dose.
Option B: Option B is incorrect because the temporal link to high-dose initiation points to steroid psychosis rather than a primary psychotic disorder.
Option C: Option C is incorrect because increasing the dose would worsen the steroid-induced psychosis.
Option D: Option D is incorrect because abrupt complete discontinuation risks adrenal insufficiency and loss of disease control; the dose is reduced as the disease allows.
6. [CASE 2 — QUESTION 2]
Continuing with the same patient. Her family asks why she felt energetic and slightly euphoric in the first day or two but then became severely disturbed. Which statement best describes the dose-dependent spectrum of glucocorticoid neuropsychiatric effects?
A) High doses cause only mild euphoria, while low doses cause psychosis
B) Low to moderate doses tend to produce euphoria, increased energy, and insomnia, whereas high doses can produce serious effects including mania and frank psychosis
C) Neuropsychiatric effects are uniform across all doses, with psychosis equally likely at any dose
D) Neuropsychiatric effects occur only after the drug is discontinued
E) Only patients with a prior psychiatric history experience any neuropsychiatric effect
ANSWER: B
Rationale:
Glucocorticoid neuropsychiatric effects follow a dose-dependent spectrum: low to moderate doses commonly cause mild euphoria, increased energy, and insomnia, while high doses can produce serious effects including major mood disturbance, mania, and frank psychosis, with an estimated 5 to 10 percent incidence of any psychiatric complication above about 40 mg per day prednisone equivalent.
Option A: Option A is incorrect because it inverts the dose relationship; euphoria is the lower-dose effect and psychosis the higher-dose effect.
Option C: Option C is incorrect because the effects are dose-dependent, not uniform.
Option D: Option D is incorrect because these effects occur during therapy, especially at high doses, not only after discontinuation.
Option E: Option E is incorrect because individual vulnerability varies but a prior psychiatric history is not required for these effects to occur.
7. [CASE 2 — QUESTION 3]
Continuing with the same patient. After her flare is controlled she remains on maintenance glucocorticoids for many months and later reports glare and difficulty driving at night, with preserved central vision. Which statement about the most likely ophthalmic complication is correct?
A) This is a posterior subcapsular cataract (PSC); it develops slowly over months to years, presents with glare and night-driving difficulty while central vision is preserved until later, and cumulative lifetime dose is a stronger predictor than current dose
B) This is acute angle-closure glaucoma requiring no change in glucocorticoid therapy
C) The glare indicates an oxidative nuclear cataract that will respond to antioxidant supplements
D) Posterior subcapsular cataract occurs only with systemic, never inhaled or topical, glucocorticoids
E) The symptom reflects early and complete central vision loss with preserved peripheral vision
ANSWER: A
Rationale:
Glare and night-driving difficulty with preserved central vision after months of glucocorticoid therapy is characteristic of posterior subcapsular cataract (PSC), which develops slowly over months to years; cumulative lifetime dose is a stronger predictor than current dose.
Option B: Option B is incorrect because PSC develops gradually and is not acute angle closure.
Option C: Option C is incorrect because PSC is not primarily oxidative-stress driven and does not respond to antioxidants.
Option D: Option D is incorrect because PSC can occur with topical, inhaled, and intranasal glucocorticoids, not only systemic.
Option E: Option E is incorrect because central vision is preserved until later stages rather than lost early.
8. [CASE 2 — QUESTION 4]
Continuing with the same patient. Screening reveals an intraocular pressure (IOP) of 26 mmHg, and her mother has primary open-angle glaucoma. Which statement best explains this finding and the appropriate response?
A) The elevated IOP is caused by increased aqueous humor production and is harmless
B) Steroid-induced IOP elevation never causes optic nerve damage, so no referral is warranted
C) The IOP response is unrelated to family history and has no heritable component
D) She is likely a steroid responder; glucocorticoids raise IOP by GR-dependent increases in trabecular meshwork outflow resistance, the response is heritable and associated with a family history of open-angle glaucoma, and referral to ophthalmology is appropriate for an IOP above 21 mmHg
E) The finding indicates a posterior subcapsular cataract rather than any pressure abnormality
ANSWER: D
Rationale:
Glucocorticoid-induced IOP elevation results from GR-dependent increases in trabecular meshwork outflow resistance (via upregulation of myocilin and extracellular matrix proteins); the response is heritable and more common in those with a family history of primary open-angle glaucoma, defining the steroid responder, and ophthalmology referral is appropriate for IOP above 21 mmHg.
Option A: Option A is incorrect because the mechanism is reduced trabecular outflow, not increased production, and the elevation is not harmless.
Option B: Option B is incorrect because a subset of steroid responders develop glaucomatous optic nerve damage.
Option C: Option C is incorrect because the IOP response is heritable and linked to family history.
Option E: Option E is incorrect because an IOP of 26 mmHg is a pressure abnormality, distinct from a cataract.
9. [CASE 3 — QUESTION 1]
A 65-year-old postmenopausal woman is beginning prednisone 15 mg per day for an inflammatory condition expected to last at least 9 months. Her FRAX (Fracture Risk Assessment Tool) score, after the glucocorticoid adjustment, places her at high fracture risk; renal function is normal. According to the ACR (American College of Rheumatology) framework, which bone-protection plan is most appropriate at initiation?
A) Begin teriparatide first-line because she is postmenopausal
B) Provide no intervention until a fragility fracture occurs
C) Start calcium and vitamin D universally and add an oral bisphosphonate, since her FRAX-adjusted high risk with a course of 3 months or longer meets the threshold for pharmacological protection
D) Give calcium and vitamin D only, withholding antiresorptive therapy despite high risk
E) Withhold all therapy because courses under 1 year do not affect bone
ANSWER: C
Rationale:
The ACR (American College of Rheumatology) framework recommends universal calcium and vitamin D for any course of 3 months or longer and adds an oral bisphosphonate for medium-to-high fracture risk; her FRAX (Fracture Risk Assessment Tool)-adjusted high risk meets that threshold.
Option A: Option A is incorrect because teriparatide is reserved for very high risk, not used first-line based on menopausal status.
Option B: Option B is incorrect because high risk warrants proactive protection rather than waiting for a fracture.
Option D: Option D is incorrect because calcium and vitamin D alone are insufficient for a high-risk patient, who also needs an antiresorptive.
Option E: Option E is incorrect because a course of 3 months or longer at this dose causes meaningful bone loss, so protection is warranted.
10. [CASE 3 — QUESTION 2]
Continuing with the same patient. She asks why glucocorticoids weaken bone. Which description best captures the dual cellular mechanism of glucocorticoid-induced osteoporosis?
A) Glucocorticoids only increase resorption, with no effect on bone formation
B) Glucocorticoids increase OPG (osteoprotegerin) and decrease RANKL (receptor activator of nuclear factor kappa-B ligand), strengthening bone
C) Glucocorticoids only suppress bone formation, with no effect on resorption
D) Glucocorticoids increase intestinal calcium absorption, suppressing parathyroid hormone and bone turnover
E) Glucocorticoids 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 osteoclastic resorption
ANSWER: E
Rationale:
Glucocorticoid-induced osteoporosis arises from simultaneous actions on both sides of the remodeling unit: suppression of osteoblast differentiation through Wnt/beta-catenin inhibition with increased osteoblast and osteocyte apoptosis, plus increased RANKL (receptor activator of nuclear factor kappa-B ligand) and suppressed OPG (osteoprotegerin) driving osteoclastic resorption.
Option A: Option A is incorrect because formation is also suppressed, not just resorption increased.
Option B: Option B is incorrect because the RANKL-to-OPG shift is toward resorption (RANKL up, OPG down), weakening bone.
Option C: Option C is incorrect because resorption is also increased, not solely formation suppressed.
Option D: Option D is incorrect because glucocorticoids impair intestinal calcium absorption and tend to drive secondary hyperparathyroidism rather than suppress it.
11. [CASE 3 — QUESTION 3]
Continuing with the same patient. She is started on oral alendronate. By what mechanism does this nitrogen-containing bisphosphonate reduce her fracture risk?
A) Monoclonal antibody neutralization of RANKL (receptor activator of nuclear factor kappa-B ligand)
B) Uptake into bone mineral and ingestion by osteoclasts, where it inhibits farnesyl pyrophosphate synthase in the mevalonate pathway, impairing osteoclast function and promoting osteoclast apoptosis
C) Direct stimulation of osteoblast differentiation through PTH1R (parathyroid hormone receptor 1)
D) Selective inhibition of IMPDH (inosine monophosphate dehydrogenase) type II in osteoclasts
E) Enhanced intestinal calcium absorption through increased enterocyte transport
ANSWER: B
Rationale:
Nitrogen-containing bisphosphonates such as alendronate are taken up into bone mineral and ingested by osteoclasts during resorption, where they inhibit farnesyl pyrophosphate synthase in the mevalonate pathway, impairing osteoclast cytoskeletal function and promoting osteoclast apoptosis, reducing fracture risk.
Option A: Option A is incorrect because RANKL neutralization describes denosumab.
Option C: Option C is incorrect because PTH1R-mediated osteoblast stimulation describes teriparatide.
Option D: Option D is incorrect because IMPDH (inosine monophosphate dehydrogenase) type II inhibition describes mycophenolate, not a bisphosphonate.
Option E: Option E is incorrect because bisphosphonates act on osteoclasts in bone, not by enhancing intestinal calcium absorption.
12. [CASE 3 — QUESTION 4]
Continuing with the same patient. Her clinician notes that her fracture probability is higher than her DXA (dual-energy X-ray absorptiometry) T-score alone would suggest. Why does the FRAX (Fracture Risk Assessment Tool) algorithm apply an upward glucocorticoid adjustment?
A) Glucocorticoids lower fracture risk at any given bone density, so FRAX is adjusted downward
B) DXA systematically overestimates bone density in steroid users, requiring correction
C) The adjustment exists only because glucocorticoid users are older on average
D) Glucocorticoids degrade bone quality faster than bone density declines, so fracture risk exceeds what BMD predicts; FRAX is therefore increased for patients on prednisone greater than 7.5 mg per day for more than 3 months
E) FRAX cannot be used in glucocorticoid-treated patients and must be replaced by BMD alone
ANSWER: D
Rationale:
In glucocorticoid-induced osteoporosis, bone-quality deterioration outpaces BMD (bone mineral density) decline, so fracture risk at a given T-score exceeds that of untreated patients; FRAX (Fracture Risk Assessment Tool) therefore applies an upward adjustment (roughly 15 percent for major fracture and 20 percent for hip fracture) for patients on prednisone greater than 7.5 mg per day for more than 3 months.
Option A: Option A is incorrect because the adjustment is upward, reflecting increased risk.
Option B: Option B is incorrect because the issue is bone quality not captured by DXA, not systematic overestimation of density.
Option C: Option C is incorrect because the adjustment reflects a direct drug effect on bone quality, not merely user age.
Option E: Option E is incorrect because FRAX remains usable and is adjusted rather than abandoned.
13. [CASE 4 — QUESTION 1]
A 71-year-old woman on long-term prednisone for vasculitis has sustained two new vertebral compression fractures despite adherent oral bisphosphonate therapy with calcium and vitamin D; her FRAX-adjusted fracture risk is very high and her renal function is normal. Which therapeutic choice is most appropriate now?
A) Switch to teriparatide, the anabolic PTH (parathyroid hormone) 1-34 fragment preferred for very high fracture risk, recognizing its 24-month treatment limit
B) Continue the same oral bisphosphonate unchanged, since it remains optimal despite the new fractures
C) Stop all bone-directed therapy and rely on calcium and vitamin D alone
D) Add a second oral bisphosphonate for a dual antiresorptive effect
E) Begin long-term systemic glucocorticoid escalation to suppress the underlying disease further
ANSWER: A
Rationale:
With very high fracture risk and incident vertebral fractures despite an antiresorptive, teriparatide, the anabolic PTH (parathyroid hormone) 1-34 fragment shown to be superior to alendronate for vertebral fracture prevention in glucocorticoid-induced osteoporosis, is preferred; it carries a 24-month treatment limit.
Option B: Option B is incorrect because continuing a regimen that failed does not address the very high risk.
Option C: Option C is incorrect because stopping therapy in a very-high-risk patient is inappropriate.
Option D: Option D is incorrect because combining two bisphosphonates is not a standard or evidence-based strategy.
Option E: Option E is incorrect because escalating glucocorticoids would worsen bone loss rather than treat the osteoporosis.
14. [CASE 4 — QUESTION 2]
Continuing with the same patient. She completes the maximum 24-month course of teriparatide. Why is a subsequent antiresorptive agent recommended rather than simply stopping?
A) Teriparatide is itself an antiresorptive, so the follow-on agent merely continues the same mechanism
B) The anabolic gains are permanent, so the follow-on agent has no real effect
C) 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
D) Teriparatide depletes bone mineral, so an antiresorptive is needed to replace it
E) The 24-month limit is purely for cost reasons and stopping has no skeletal consequence
ANSWER: C
Rationale:
Teriparatide is anabolic, stimulating osteoblast activity through PTH1R (parathyroid hormone receptor 1); once stopped, the gains are not maintained without further treatment, so transition to an antiresorptive (typically a bisphosphonate) within about 3 months is recommended to preserve the benefit.
Option A: Option A is incorrect because teriparatide is anabolic, not antiresorptive, so the follow-on uses a different mechanism.
Option B: Option B is incorrect because the gains are lost without follow-on therapy.
Option D: Option D 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 limit is regulatory with real skeletal consequences if no follow-on therapy is given.
15. [CASE 4 — QUESTION 3]
Continuing with the same patient. Several years later she develops chronic kidney disease with an estimated GFR (glomerular filtration rate) of 26 mL per minute per 1.73 m2 and again needs an antiresorptive for ongoing glucocorticoid therapy. Why is denosumab often selected over a bisphosphonate in this setting?
A) Bisphosphonates are preferred at low GFR (glomerular filtration rate) because they are renally cleared without concern
B) Denosumab requires intact renal function and is contraindicated in chronic kidney disease
C) Denosumab and bisphosphonates are equivalent at any GFR (glomerular filtration rate), so the choice is arbitrary
D) Oral and intravenous bisphosphonates are relatively contraindicated at an estimated GFR (glomerular filtration rate) below roughly 30 to 35 mL per minute per 1.73 m2, whereas denosumab does not require dose adjustment for renal function, making it a suitable alternative
E) Denosumab works by inhibiting farnesyl pyrophosphate synthase, so it is filtered and accumulates in renal failure
ANSWER: D
Rationale:
Oral and intravenous bisphosphonates are relatively contraindicated at an estimated GFR (glomerular filtration rate) below roughly 30 to 35 mL per minute per 1.73 m2; denosumab, a monoclonal antibody against RANKL, is not renally cleared and does not require renal dose adjustment, making it a suitable alternative in chronic kidney disease.
Option A: Option A is incorrect because bisphosphonates are limited, not preferred, at low GFR.
Option B: Option B is incorrect because denosumab does not require intact renal function and is used precisely when bisphosphonates are contraindicated.
Option C: Option C is incorrect because the agents are not equivalent across renal function; GFR drives the choice.
Option E: Option E is incorrect because farnesyl pyrophosphate synthase inhibition is the bisphosphonate mechanism, not denosumab's, and denosumab is not renally filtered.
16. [CASE 4 — QUESTION 4]
Continuing with the same patient. After a period on denosumab the team considers stopping it. Which consideration is most important at discontinuation?
A) Denosumab can be stopped abruptly with no precautions because its effect persists for years
B) Its antiresorptive effect wanes rapidly after the dosing interval lapses, and rebound bone loss with increased fracture risk can occur, so transition to another antiresorptive should be planned before stopping
C) Discontinuation reliably increases bone density through a rebound anabolic effect
D) Rebound bone loss is avoided simply by stopping at any time of year
E) Denosumab incorporates permanently into bone mineral, eliminating any rebound concern
ANSWER: B
Rationale:
Denosumab's antiresorptive effect wanes rapidly once the dosing interval lapses, and discontinuation can cause rebound bone loss with increased fracture risk, so a transition to another antiresorptive should be planned before stopping (with the renal limitation on bisphosphonates considered).
Option A: Option A is incorrect because the effect does not persist for years and abrupt cessation risks rebound.
Option C: Option C is incorrect because discontinuation causes rebound bone loss, not an anabolic gain.
Option D: Option D is incorrect because simply stopping does not prevent rebound; an active transition is needed.
Option E: Option E is incorrect because denosumab is an antibody that does not incorporate into bone mineral.
17. [CASE 5 — QUESTION 1]
A 69-year-old man is started on high-dose hydrocortisone for an acute condition and within days develops new hypertension with a serum potassium of 3.2 mmol per L. Which mechanism best explains the renal sodium retention and potassium loss driving this presentation?
A) Glucocorticoids block the mineralocorticoid receptor in the distal nephron, paradoxically retaining sodium
B) Glucocorticoids increase 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2) activity, accelerating cortisol inactivation
C) Glucocorticoids inhibit ENaC (epithelial sodium channel), reducing sodium reabsorption
E) At high doses, cortisol-like glucocorticoids overwhelm 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2), the enzyme that normally inactivates cortisol before it reaches the mineralocorticoid receptor, so cortisol activates that receptor and upregulates ENaC (epithelial sodium channel), driving sodium retention and potassium excretion
ANSWER: E
Rationale:
At pharmacological doses, glucocorticoids overwhelm renal 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2), which normally inactivates cortisol before it reaches the mineralocorticoid receptor; cortisol then activates that receptor and upregulates ENaC (epithelial sodium channel) and Na/K-ATPase, promoting sodium and water retention with potassium excretion, an effect most pronounced with hydrocortisone and prednisolone.
Option A: Option A is incorrect because the mechanism is receptor activation, not blockade.
Option B: Option B is incorrect because the enzyme is overwhelmed, not upregulated.
Option C: Option C is incorrect because ENaC is upregulated, not inhibited.
Option D: Option D is incorrect because glucocorticoids activate the system to raise blood pressure rather than suppressing aldosterone to lower it.
18. [CASE 5 — QUESTION 2]
Continuing with the same patient. While on high-dose glucocorticoids he develops new-onset atrial fibrillation (AF). Which statement best links his glucocorticoid therapy to the arrhythmia?
A) Glucocorticoids reduce the risk of new-onset atrial fibrillation compared with non-users
B) The mineralocorticoid effect causes hyperkalemia, which directly triggers atrial fibrillation
C) Glucocorticoid use is associated with an approximately 2-fold, dose-dependent increase in new-onset atrial fibrillation risk; contributing factors include hypokalemia from mineralocorticoid overflow and direct GR-mediated atrial electrical remodeling, with risk greatest at high doses
D) Atrial fibrillation risk with glucocorticoids is independent of dose
E) The arrhythmia is explained solely by suppression of the renin-angiotensin-aldosterone system (RAAS)
ANSWER: C
Rationale:
Glucocorticoid use carries an approximately 2-fold, dose-dependent increase in new-onset atrial fibrillation risk, most elevated at high doses; contributing mechanisms include hypokalemia from mineralocorticoid overflow, direct GR-mediated atrial electrical remodeling, and the broader cardiovascular risk milieu.
Option A: Option A is incorrect because glucocorticoids increase, not reduce, AF risk.
Option B: Option B is incorrect because the mineralocorticoid effect produces hypokalemia, not hyperkalemia.
Option D: Option D is incorrect because the risk is dose-dependent and greatest at high doses.
Option E: Option E is incorrect because glucocorticoids activate rather than suppress the RAAS (renin-angiotensin-aldosterone system), and the link is multifactorial rather than solely RAAS suppression.
19. [CASE 5 — QUESTION 3]
Continuing with the same patient. His condition requires prednisone 30 mg per day as monotherapy (no other immunosuppressants) for an expected 8 weeks. He has no sulfonamide allergy. Which preventive measure against opportunistic infection is most appropriate?
A) No prophylaxis is indicated at any glucocorticoid dose in non-HIV patients
B) Start isoniazid as PCP (Pneumocystis jirovecii pneumonia) prophylaxis
C) Start prophylaxis only if respiratory symptoms develop
D) Start TMP-SMX (trimethoprim-sulfamethoxazole) for PCP (Pneumocystis jirovecii pneumonia) prophylaxis, since prednisone exceeds 20 mg per day for more than 4 weeks in monotherapy; dapsone or atovaquone is an alternative for sulfonamide intolerance
E) Start acyclovir as PCP (Pneumocystis jirovecii pneumonia) prophylaxis
ANSWER: D
Rationale:
In glucocorticoid monotherapy, PCP (Pneumocystis jirovecii pneumonia) prophylaxis is generally indicated when prednisone exceeds 20 mg per day for more than 4 weeks; first-line is TMP-SMX (trimethoprim-sulfamethoxazole), with dapsone or atovaquone as alternatives for sulfonamide intolerance.
Option A: Option A is incorrect because prophylaxis is indicated above this monotherapy threshold even in non-HIV patients.
Option B: Option B is incorrect because isoniazid is used for latent tuberculosis, not PCP.
Option C: Option C is incorrect because prophylaxis is meant to prevent a first episode, not started only after symptoms.
Option E: Option E is incorrect because acyclovir targets herpesviruses, not Pneumocystis.
20. [CASE 5 — QUESTION 4]
Continuing with the same patient. He is due for several vaccinations, including a live attenuated vaccine and inactivated vaccines, while on prednisone 30 mg per day. Which approach is most appropriate?
A) The live attenuated vaccine is contraindicated at prednisone greater than 20 mg per day for more than 2 weeks and should be deferred or given before therapy; needed inactivated vaccines may be given and are best administered before therapy or at the lowest maintenance dose when immunogenicity is best
B) Administer the live attenuated vaccine now, since immunosuppression improves its effect
C) Withhold inactivated vaccines because they are unsafe during glucocorticoid therapy
D) Defer all vaccines indefinitely because glucocorticoids permanently contraindicate vaccination
E) Give all vaccines, live and inactivated, only once high-dose therapy is well underway
ANSWER: A
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 they should be deferred or given before therapy; 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 B: Option B is incorrect because immunosuppression reduces immunogenicity and live vaccines are contraindicated at this dose.
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 govern the approach.
Option E: Option E is incorrect because the live vaccine should not be given once high-dose therapy is underway, and inactivated vaccines are best given before therapy.
21. [CASE 6 — QUESTION 1]
A 54-year-old kidney transplant recipient maintained on prednisolone develops a serious infection requiring rifampin (rifampicin), a drug that strongly increases the activity of the liver enzyme (CYP3A4, cytochrome P450 3A4) that metabolizes glucocorticoids. Which consequence should the team most anticipate, and how should they respond during co-administration?
A) Rifampin will raise glucocorticoid levels, so the prednisolone dose should be reduced
B) Rifampin induces CYP3A4 (cytochrome P450 3A4), accelerating glucocorticoid metabolism and lowering plasma levels, risking under-immunosuppression and transplant rejection; the glucocorticoid dose should be increased to maintain therapeutic effect during co-administration
C) Rifampin has no clinically important effect on glucocorticoid metabolism, so no change is needed
D) Rifampin inhibits CYP3A4 (cytochrome P450 3A4), so glucocorticoid toxicity should be anticipated
E) Prednisolone should be stopped entirely while on rifampin and resumed afterward
ANSWER: B
Rationale:
Rifampin (rifampicin) is a potent CYP3A4 (cytochrome P450 3A4) inducer that accelerates glucocorticoid metabolism and can substantially lower prednisolone exposure, risking loss of immunosuppressive effect and transplant rejection; the glucocorticoid dose should be increased to maintain therapeutic effect during co-administration.
Option A: Option A is incorrect because induction lowers, not raises, glucocorticoid levels.
Option C: Option C is incorrect because rifampin has a clinically significant inducing effect.
Option D: Option D is incorrect because rifampin induces rather than inhibits CYP3A4.
Option E: Option E is incorrect because stopping immunosuppression in a transplant recipient risks rejection.
22. [CASE 6 — QUESTION 2]
Continuing with the same patient. After the infection resolves, the rifampin is stopped while he remains on the increased prednisolone dose. What should the team anticipate as the rifampin effect resolves?
A) Glucocorticoid levels will fall further when rifampin is stopped, requiring another dose increase
B) Levels will not change, so the increased dose can be continued indefinitely without adjustment
C) Enzyme activity normalizes instantly on stopping rifampin, so the dose should be cut to zero immediately
D) Rifampin actually inhibits CYP3A4 (cytochrome P450 3A4), so stopping it will reduce glucocorticoid exposure
E) As CYP3A4 (cytochrome P450 3A4) activity returns toward baseline over about 2 to 4 weeks, the previously compensatory higher dose can produce toxic glucocorticoid concentrations, so the dose must be tapered with monitoring
ANSWER: E
Rationale:
When a potent inducer such as rifampin is stopped, CYP3A4 (cytochrome P450 3A4) activity returns toward baseline over roughly 2 to 4 weeks; the previously compensatory higher glucocorticoid dose can then yield toxic concentrations, so the dose must be tapered with monitoring during that window.
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 C: Option C is incorrect because enzyme activity normalizes gradually over weeks, not instantly, and an abrupt cut to zero is inappropriate.
Option D: Option D is incorrect because rifampin induces rather than inhibits CYP3A4.
23. [CASE 6 — QUESTION 3]
Continuing with the same patient. Some years later he is on a ritonavir-boosted regimen for HIV (human immunodeficiency virus) and is also prescribed inhaled fluticasone for asthma by a different provider. He develops cushingoid features with a suppressed morning cortisol. Which explanation is correct?
A) 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
B) Ritonavir induces CYP3A4 (cytochrome P450 3A4), lowering fluticasone levels and causing primary adrenal failure
C) The suppressed cortisol indicates the fluticasone dose is too low and should be increased
D) Inhaled fluticasone cannot produce systemic effects, so the findings are unrelated to these drugs
E) The interaction reflects displacement of fluticasone from plasma proteins without any change in metabolism
ANSWER: A
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 despite a high exogenous steroid burden.
Option B: Option B is incorrect because ritonavir inhibits rather than induces the enzyme, and the low cortisol reflects HPA suppression, not primary adrenal failure.
Option C: Option C is incorrect because the low cortisol reflects excess exogenous glucocorticoid, so the dose should be reduced, not increased.
Option D: Option D is incorrect because the interaction makes inhaled fluticasone systemically active.
Option E: Option E is incorrect because the dominant mechanism is CYP3A4 inhibition reducing fluticasone clearance, not protein displacement.
24. [CASE 6 — QUESTION 4]
Continuing with the same patient. He later takes chronic prednisone, a daily NSAID (non-steroidal anti-inflammatory drug) for joint pain, and warfarin for atrial fibrillation. Which plan best addresses his combined medication risks?
A) No additional measures are needed, since these drugs do not interact
B) Only the warfarin interaction matters; the NSAID adds no additional risk
C) The glucocorticoid-NSAID combination reduces gastrointestinal injury, and warfarin needs no monitoring after a steroid change
D) Start a proton pump inhibitor because the glucocorticoid-NSAID combination markedly increases peptic ulcer complication risk, and monitor the INR (international normalized ratio) around glucocorticoid initiation or dose changes because glucocorticoids can shift it
E) Increase the prednisone dose to offset NSAID-induced enzyme induction
ANSWER: D
Rationale:
Glucocorticoids and NSAIDs (non-steroidal anti-inflammatory drugs) each impair prostaglandin-mediated gastric mucosal defense and together greatly increase peptic ulcer complication risk, so proton pump inhibitor prophylaxis is indicated; glucocorticoids can also produce variable INR (international normalized ratio) changes, so warfarin should be monitored around glucocorticoid initiation or dose changes.
Option A: Option A is incorrect because both interactions are clinically significant.
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.
25. [CASE 7 — QUESTION 1]
A 33-year-old woman with lupus nephritis has required prednisone above 7.5 mg per day for more than 3 months to maintain disease control, and her rheumatologist is concerned about cumulative glucocorticoid toxicity. Why is a steroid-sparing strategy pharmacologically justified at this level of exposure?
A) Glucocorticoid monotherapy is always safer than adding a second immunosuppressant, so sparing agents should be avoided
B) Steroid-sparing therapy is justified only after irreversible organ damage has occurred
C) At prednisone above roughly 7.5 mg per day for more than 3 months, the cumulative chronic adverse-effect burden substantially exceeds the risk of most steroid-sparing agents, so adding a sparing agent to permit dose reduction or discontinuation is justified
D) Steroid-sparing agents work by increasing glucocorticoid plasma levels, allowing a lower oral dose
E) Steroid-sparing therapy is indicated only for doses below 5 mg per day
ANSWER: C
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 at that exposure the cumulative chronic adverse-effect burden substantially exceeds the risk of most steroid-sparing agents; adding a sparing agent permits dose reduction or discontinuation.
Option A: Option A is incorrect because at this exposure the chronic toxicity burden makes adding a sparing agent advantageous rather than inherently less safe.
Option B: Option B is incorrect because sparing therapy is used proactively to limit toxicity, not only after irreversible damage.
Option D: Option D is incorrect because steroid-sparing agents act through independent immunosuppressive mechanisms, not by raising glucocorticoid levels.
Option E: Option E is incorrect because the threshold is above 7.5 mg per day, not confined to doses below 5 mg per day.
26. [CASE 7 — QUESTION 2]
Continuing with the same patient. Her team selects mycophenolate as the steroid-sparing agent. Which statement best describes its mechanism and its role in her disease?
A) Mycophenolate inhibits dihydrofolate reductase, blocking folate-dependent purine synthesis broadly
B) Mycophenolate is hydrolyzed to mycophenolic acid, which selectively inhibits IMPDH (inosine monophosphate dehydrogenase) type II, the isoform preferentially expressed in activated lymphocytes, giving relatively targeted immunosuppression; it is a preferred steroid-sparing agent in lupus nephritis
C) Mycophenolate antagonizes the interleukin-6 (IL-6) receptor on lymphocytes
D) Mycophenolate is converted to 6-mercaptopurine and inhibits purine synthesis nonselectively
E) Mycophenolate inhibits farnesyl pyrophosphate synthase in lymphocyte precursors
ANSWER: B
Rationale:
Mycophenolate mofetil is hydrolyzed to mycophenolic acid, which selectively inhibits IMPDH (inosine monophosphate dehydrogenase) type II, the isoform preferentially expressed in activated lymphocytes; this limits purine synthesis in T and B cells while relatively sparing other dividing cells, and it is a preferred steroid-sparing agent in lupus nephritis.
Option A: Option A is incorrect because dihydrofolate reductase inhibition describes methotrexate.
Option C: Option C is incorrect because IL-6 (interleukin-6) receptor antagonism describes tocilizumab.
Option D: Option D is incorrect because conversion to 6-mercaptopurine describes azathioprine.
Option E: Option E is incorrect because farnesyl pyrophosphate synthase inhibition is the bisphosphonate mechanism, unrelated to mycophenolate.
27. [CASE 7 — QUESTION 3]
Continuing with the same patient. During counseling she asks how mycophenolate differs from other steroid-sparing agents. Which pairing of agent to mechanism is correct?
A) Methotrexate antagonizes the interleukin-6 (IL-6) receptor
B) Azathioprine selectively inhibits IMPDH (inosine monophosphate dehydrogenase) type II
C) Tocilizumab inhibits dihydrofolate reductase
D) Mycophenolate is converted to 6-mercaptopurine to inhibit purine synthesis
E) Methotrexate inhibits dihydrofolate reductase (with adenosine-mediated anti-inflammatory effects at low doses); azathioprine is converted to 6-mercaptopurine to inhibit purine synthesis; mycophenolate selectively inhibits IMPDH (inosine monophosphate dehydrogenase) type II; tocilizumab antagonizes the interleukin-6 (IL-6) receptor
ANSWER: E
Rationale:
The correct mapping is: methotrexate inhibits dihydrofolate reductase with adenosine-mediated anti-inflammatory effects at low doses; azathioprine is converted to 6-mercaptopurine to inhibit purine synthesis; mycophenolate selectively inhibits IMPDH (inosine monophosphate dehydrogenase) type II in activated lymphocytes; and tocilizumab antagonizes the interleukin-6 (IL-6) receptor.
Option A: Option A is incorrect because IL-6 receptor antagonism describes tocilizumab, not methotrexate.
Option B: Option B is incorrect because IMPDH type II inhibition describes mycophenolate, not azathioprine.
Option C: Option C is incorrect because dihydrofolate reductase inhibition describes methotrexate, not tocilizumab.
Option D: Option D is incorrect because conversion to 6-mercaptopurine describes azathioprine, not mycophenolate.
28. [CASE 7 — QUESTION 4]
Continuing with the same patient. She is 33 years old and may wish to conceive in the future. Which counseling point about mycophenolate is most important in this context?
A) Mycophenolate is safe in pregnancy, so no contraceptive counseling is needed
B) Mycophenolate enhances fertility and should be continued through any planned conception
C) Mycophenolate has no reproductive implications and can be stopped at any time without planning
D) Mycophenolate is teratogenic, so effective contraception is required during therapy, and any pregnancy planning should prompt review and likely transition to a pregnancy-compatible agent
E) Mycophenolate need only be stopped on the day a positive pregnancy test is obtained, with no advance planning
ANSWER: D
Rationale:
Mycophenolate is teratogenic and requires effective contraception in women of childbearing potential during therapy; pregnancy planning should prompt review and a likely transition to a pregnancy-compatible agent well in advance.
Option A: Option A is incorrect because mycophenolate is not safe in pregnancy.
Option B: Option B is incorrect because it does not enhance fertility and should not be continued through planned conception.
Option C: Option C is incorrect because mycophenolate has clear reproductive implications requiring planning.
Option E: Option E is incorrect because teratogenic exposure in early pregnancy makes advance planning and a pre-conception switch necessary rather than stopping only after a positive test.
This Web-based pharmacology and disease-based integrated teaching site is based on reference materials that are believed reliable and consistent with standards accepted at the time of development.
Possibility of error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete.
Users should confirm the information contained herein with other sources.
This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site.
Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals.
Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.
Medical or other information thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.