Chapter 28: Adrenocorticosteroid Pharmacology — Module 3: Adverse Effects, GIO Management, and Drug Interactions
1. A 58-year-old man on high-dose prednisone for giant cell arteritis develops new fasting hyperglycemia. His clinician explains that glucocorticoids raise blood glucose in part by increasing hepatic glucose output. Which transcriptional action of the activated glucocorticoid receptor (GR) most directly accounts for the increased hepatic glucose production?
A) Increased translocation of GLUT4 (glucose transporter type 4) to the hepatocyte plasma membrane
B) Suppression of pancreatic beta-cell insulin gene transcription
C) Upregulation of the gluconeogenic enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase)
D) Inhibition of hepatic glycogen synthase kinase 3 with increased glycogen storage
E) Direct phosphorylation of the insulin receptor to enhance downstream signaling
ANSWER: C
Rationale:
In the liver, GR-alpha transactivation upregulates the rate-limiting gluconeogenic enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase), increasing hepatic glucose output from amino acid and glycerol substrates; GR also induces the coactivator PGC-1alpha, which amplifies gluconeogenic gene transcription. This hepatic mechanism, combined with impaired peripheral glucose uptake, produces glucocorticoid-induced hyperglycemia.
Option A: Option A is incorrect because glucocorticoids reduce, not increase, insulin-stimulated GLUT4 translocation, and GLUT4 mediates peripheral (muscle and adipose) uptake rather than hepatic output.
Option B: Option B is incorrect because glucocorticoid hyperglycemia arises from insulin resistance and increased hepatic output, not from suppression of beta-cell insulin gene transcription.
Option D: Option D is incorrect because glucocorticoids upregulate glycogen synthase kinase 3 and promote glycogen breakdown rather than inhibiting the kinase to store glycogen.
Option E: Option E is incorrect because glucocorticoids impair rather than enhance insulin signaling, and the GR does not phosphorylate the insulin receptor.
2. A 64-year-old woman started on once-daily morning prednisone has an HbA1c (hemoglobin A1c) of 6.4 percent, but her clinician suspects significant glucocorticoid-induced dysglycemia that the HbA1c is underestimating. Which monitoring approach is most sensitive for detecting the characteristic glucose abnormality produced by once-daily morning glucocorticoid dosing?
A) Point-of-care glucose measured 2 hours after the largest meal of the day
B) Fasting morning plasma glucose drawn before the prednisone dose
C) A single HbA1c repeated every 3 months
D) Bedtime plasma glucose after the evening meal only
E) Random glucose drawn at the morning clinic visit
ANSWER: A
Rationale:
Glucocorticoid-induced hyperglycemia is characterized by relatively modest fasting elevation but pronounced postprandial excursions, with once-daily morning dosing producing a predictable afternoon and early-evening glucose peak. Point-of-care glucose measured roughly 2 hours after the largest meal of the day is therefore the most sensitive way to detect these excursions, which HbA1c underestimates, particularly within the first 8 to 12 weeks of therapy.
Option B: Option B is incorrect because fasting glucose captures the least affected part of the pattern and will miss the postprandial peak.
Option C: Option C is incorrect because HbA1c specifically underestimates postprandial dysglycemia in this setting and lags recent changes, so repeating it does not add sensitivity.
Option D: Option D is incorrect because the morning-dose glucose peak occurs in the afternoon and early evening, so a bedtime-only reading can miss the peak depending on meal timing.
Option E: Option E is incorrect because a random morning glucose is drawn near the dose administration time, before the characteristic afternoon peak develops.
3. A 55-year-old woman on prednisone for several months for polymyalgia rheumatica develops gradual symmetrical proximal weakness of the shoulder and pelvic girdles. Her creatine kinase (CK) is normal, deep tendon reflexes are preserved, and there are no inflammatory changes on imaging. Which statement about her most likely diagnosis is correct?
A) The CK is expected to be markedly elevated, confirming an inflammatory process
B) Increasing the glucocorticoid dose is the appropriate first management step
C) Non-fluorinated agents such as hydrocortisone carry the highest risk for this complication
D) This is steroid myopathy, and reducing the glucocorticoid dose is the appropriate management
E) The weakness characteristically begins distally before progressing proximally
ANSWER: D
Rationale:
The gradual onset of symmetrical proximal weakness with a normal or only mildly elevated CK, preserved reflexes, and no inflammatory changes is the classic picture of steroid myopathy, a GR-mediated catabolic effect driven by upregulation of the ubiquitin ligases MuRF1 and MAFbx and suppression of mTOR-dependent protein synthesis. Because it is caused by the drug rather than active disease, the correct management is glucocorticoid dose reduction.
Option A: Option A is incorrect because steroid myopathy characteristically shows a normal or only mildly elevated CK, in contrast to inflammatory myositis where CK is markedly elevated.
Option B: Option B is incorrect because increasing the dose is the treatment for an inflammatory flare, not for steroid myopathy, and would worsen the drug-induced catabolic state.
Option C: Option C is incorrect because fluorinated agents (dexamethasone, triamcinolone), not non-fluorinated ones, carry the higher steroid myopathy risk at equivalent anti-inflammatory doses.
Option E: Option E is incorrect because steroid myopathy preferentially affects proximal girdle muscles rather than beginning distally.
4. A clinician selecting a systemic glucocorticoid for a patient judged to be at high risk for steroid myopathy wants to minimize that specific risk. Based on the pharmacological distinction between glucocorticoid agents, which choice best reflects this consideration?
A) All glucocorticoids carry identical myopathy risk at equipotent anti-inflammatory doses
B) Fluorinated agents such as dexamethasone and triamcinolone carry higher myopathy risk than non-fluorinated agents
C) Non-fluorinated agents such as prednisone carry the highest myopathy risk
D) Inhaled glucocorticoids cause more steroid myopathy than systemic agents
E) Myopathy risk is determined solely by cumulative dose and is independent of the specific agent
ANSWER: B
Rationale:
Fluorinated glucocorticoids, including dexamethasone and triamcinolone, carry a higher risk of steroid myopathy than non-fluorinated agents at equivalent anti-inflammatory doses, a pharmacological distinction relevant to agent selection in patients at high myopathy risk.
Option A: Option A is incorrect because risk is not identical across agents; the fluorinated agents are specifically higher-risk.
Option C: Option C is incorrect because it inverts the relationship, attributing the highest risk to non-fluorinated prednisone rather than to the fluorinated agents.
Option D: Option D is incorrect because steroid myopathy is principally a systemic-exposure phenomenon and inhaled agents are not the leading cause.
Option E: Option E is incorrect because, although cumulative exposure matters, the specific agent (fluorinated versus non-fluorinated) independently modifies myopathy risk.
5. A patient who completed a prolonged high-dose glucocorticoid course 8 weeks ago now has a normal basal morning cortisol. Before clearing him for an elective surgery, his endocrinologist cautions that he may still be at risk for adrenal crisis under physiological stress. Which statement best explains this concern about HPA (hypothalamic-pituitary-adrenal) axis recovery?
A) A normal basal morning cortisol confirms full restoration of the stress-response capacity
B) HPA axis suppression from exogenous glucocorticoids resolves within days regardless of duration
C) Basal cortisol secretion recovers more slowly than the stress-induced cortisol surge capacity
D) Adrenal crisis risk is eliminated as soon as the exogenous glucocorticoid is discontinued
E) The reserve capacity for stress-induced ACTH and cortisol surges recovers more slowly than basal secretion
ANSWER: E
Rationale:
After prolonged high-dose therapy, basal cortisol secretion typically recovers within weeks to months, but full restoration of the cortisol stress response can take 6 to 12 months; during this window the reserve capacity for stress-induced ACTH (adrenocorticotropic hormone) and cortisol surges lags behind basal secretion, leaving the patient at risk for adrenal crisis during physiological stress even when basal morning cortisol has normalized.
Option A: Option A is incorrect because a normal basal cortisol does not confirm an intact stress response, which recovers later.
Option B: Option B is incorrect because the degree and duration of suppression depend on dose and duration, and recovery after prolonged high-dose therapy takes months, not days.
Option C: Option C is incorrect because it inverts the actual sequence; basal secretion recovers faster than the stress-surge capacity, not more slowly.
Option D: Option D is incorrect because crisis risk persists during the recovery phase after discontinuation rather than being eliminated at the moment the drug is stopped.
6. A 47-year-old man started on prednisone 80 mg per day for a severe inflammatory flare develops paranoid delusions and disorganized thinking within the first week. Which statement about glucocorticoid-induced neuropsychiatric effects best applies to this presentation?
A) Serious psychiatric complications are essentially never seen even at doses above 60 mg per day prednisone equivalent
B) The most common effect at low to moderate doses is frank psychosis
C) Frank psychosis (steroid psychosis) can occur at high doses and typically resolves within days to weeks of dose reduction
D) Steroid psychosis, once present, is permanent and unresponsive to dose changes
E) Neuropsychiatric effects are dose-independent and unrelated to glucocorticoid receptor distribution in limbic structures
ANSWER: C
Rationale:
Glucocorticoid neuropsychiatric effects follow a dose-dependent spectrum; at high doses (prednisone equivalent greater than 60 mg per day) serious complications including mania and frank psychosis (steroid psychosis) can occur, and steroid psychosis typically resolves within days to weeks of dose reduction, sometimes requiring temporary antipsychotic treatment during the acute phase.
Option A: Option A is incorrect because serious psychiatric complications do occur at high doses, with an estimated 5 to 10 percent incidence of any psychiatric complication above 40 mg per day prednisone equivalent.
Option B: Option B is incorrect because at low to moderate doses the common effects are mild euphoria, increased energy, and insomnia, not frank psychosis.
Option D: Option D is incorrect because steroid psychosis is generally reversible with dose reduction rather than permanent.
Option E: Option E is incorrect because these effects are dose-dependent and reflect GR (glucocorticoid receptor) density in limbic structures such as the hippocampus, amygdala, and prefrontal cortex.
7. A patient on long-term inhaled and intermittent systemic glucocorticoids reports glare and difficulty driving at night, while central vision remains preserved. Which statement about the most likely ophthalmic complication, PSC (posterior subcapsular cataract), is correct?
A) PSC occurs with both systemic and topical, inhaled, or intranasal glucocorticoids, and cumulative lifetime dose is a stronger predictor than current dose
B) PSC is caused by oxidative stress and responds well to antioxidant supplementation
C) PSC presents with early loss of central vision and preserved peripheral vision
D) PSC develops only with systemic glucocorticoids and never with inhaled administration
E) PSC develops acutely within days of starting glucocorticoid therapy
ANSWER: A
Rationale:
Posterior subcapsular cataract is a GR-dependent effect on lens epithelial cells that occurs with both systemic and topical routes including inhaled and intranasal glucocorticoids; it develops slowly over months to years and cumulative lifetime dose is a stronger predictor than current dose. The classic early symptom is glare with bright light or night driving, with central vision preserved until later stages.
Option B: Option B is incorrect because, unlike age-related nuclear cataract, PSC is not primarily oxidative-stress driven and does not respond to antioxidant supplements.
Option C: Option C is incorrect because it inverts the visual pattern; central vision is preserved until late while glare is the early complaint.
Option D: Option D is incorrect because inhaled and intranasal routes can also cause PSC, not systemic exposure alone.
Option E: Option E is incorrect because PSC develops gradually over months to years rather than acutely.
8. A patient on long-term systemic glucocorticoids is found to have an intraocular pressure (IOP) of 26 mmHg. His mother has primary open-angle glaucoma. Which statement about glucocorticoid-induced IOP elevation is correct?
A) It results from increased aqueous humor production by the ciliary body
B) It affects fewer than 1 percent of patients on long-term systemic glucocorticoids
C) The response is unrelated to family history and shows no heritable component
D) It results from GR-dependent changes in trabecular meshwork cells that increase outflow resistance, and the response is heritable, defining steroid responders
E) IOP elevation from glucocorticoids cannot progress to glaucomatous optic nerve damage
ANSWER: D
Rationale:
Glucocorticoid-induced IOP elevation, or steroid-induced glaucoma, results from GR-dependent effects on trabecular meshwork cells, which upregulate myocilin and extracellular matrix proteins such as fibronectin and laminin, increasing outflow resistance and reducing aqueous drainage; the response is heritable and partially predicted by a family history of primary open-angle glaucoma, defining the steroid responder phenotype.
Option A: Option A is incorrect because the mechanism is reduced trabecular outflow, not increased aqueous production.
Option B: Option B is incorrect because elevated IOP develops in roughly 30 to 40 percent of patients on long-term systemic glucocorticoids, far more than 1 percent.
Option C: Option C is incorrect because the IOP response is heritable and associated with a positive family history of open-angle glaucoma.
Option E: Option E is incorrect because a subset of patients (about 5 to 10 percent) develop IOP elevation sufficient to cause glaucomatous optic nerve damage.
9. A 50-year-old woman is starting prednisone 15 mg per day, anticipated to continue for at least 6 months. According to the ACR (American College of Rheumatology) framework for glucocorticoid-induced osteoporosis prevention, which intervention is recommended universally for all such patients at the outset of therapy?
A) Annual intravenous zoledronic acid as the first-line foundation for every patient
B) Calcium 1000 to 1200 mg per day and vitamin D 600 to 800 IU (international units) per day
C) Teriparatide as the universal first-line agent regardless of fracture risk
D) Denosumab for all patients regardless of renal function
E) No intervention unless a fragility fracture has already occurred
ANSWER: B
Rationale:
For patients initiating glucocorticoid therapy anticipated to last 3 months or longer at any dose, calcium 1000 to 1200 mg per day and vitamin D 600 to 800 IU (international units) per day are recommended universally as the foundation of bone protection, with higher vitamin D if 25-hydroxyvitamin D is below 20 ng per mL.
Option A: Option A is incorrect because oral bisphosphonates are the standard pharmacological step for medium-to-high fracture risk; zoledronic acid is an alternative for those intolerant of oral agents, not a universal foundation.
Option C: Option C is incorrect because teriparatide is reserved for very high fracture risk, not used universally.
Option D: Option D is incorrect because denosumab is an alternative for selected patients, not a universal recommendation, and renal function influences agent choice.
Option E: Option E is incorrect because prevention should be proactive; calcium and vitamin D are started universally rather than waiting for a fracture.
10. In glucocorticoid-induced osteoporosis (GIO), glucocorticoids act on both sides of the bone remodeling unit. With respect to the bone-resorbing side, which molecular change best explains the increased osteoclast activity?
A) Increased OPG (osteoprotegerin) with decreased RANKL (receptor activator of nuclear factor kappa-B ligand)
B) Enhanced Wnt/beta-catenin signaling driving osteoblast commitment
C) Increased intestinal calcium absorption suppressing parathyroid hormone
D) Direct stimulation of osteoblast survival prolonging bone formation
E) Increased RANKL (receptor activator of nuclear factor kappa-B ligand) with suppressed OPG (osteoprotegerin), shifting the ratio toward osteoclast activation
ANSWER: E
Rationale:
On the bone-resorbing side, glucocorticoids increase osteoblast and stromal-cell expression of RANKL (receptor activator of nuclear factor kappa-B ligand) while suppressing OPG (osteoprotegerin), the decoy receptor that neutralizes RANKL; the resulting shift toward RANKL dominance drives osteoclast differentiation, activation, and prolonged survival, increasing bone resorption.
Option A: Option A is incorrect because it inverts the actual change; OPG falls and RANKL rises in GIO.
Option B: Option B is incorrect because glucocorticoids suppress, not enhance, Wnt/beta-catenin signaling, and this concerns the bone-forming side rather than resorption.
Option C: Option C is incorrect because glucocorticoids impair intestinal calcium absorption and tend to drive secondary hyperparathyroidism rather than suppressing parathyroid hormone.
Option D: Option D is incorrect because glucocorticoids promote apoptosis of osteoblasts and osteocytes rather than prolonging their survival.
11. A clinician notes that two patients with identical DXA (dual-energy X-ray absorptiometry) T-scores have different fracture probabilities because one is taking long-term prednisone. Which statement best explains why the FRAX (Fracture Risk Assessment Tool) algorithm includes a glucocorticoid adjustment?
A) Glucocorticoids lower fracture risk at any given BMD (bone mineral density), so FRAX is adjusted downward
B) FRAX requires adjustment because DXA systematically overestimates bone density in steroid users
C) Fracture risk exceeds what BMD alone predicts because glucocorticoids degrade bone quality, so FRAX is increased for patients on prednisone greater than 7.5 mg per day for more than 3 months
D) The adjustment exists only because glucocorticoid users are older on average
E) FRAX cannot be used at all in glucocorticoid-treated patients and must be replaced by BMD alone
ANSWER: C
Rationale:
In GIO, fracture risk does not track linearly with BMD (bone mineral density); at any given T-score, glucocorticoid-treated patients have higher fracture probability because bone-quality deterioration outpaces BMD decline. FRAX therefore applies an upward adjustment (roughly 15 percent for major fracture and 20 percent for hip fracture probability) for patients on prednisone greater than 7.5 mg per day for more than 3 months to capture the quality effect not reflected by DXA.
Option A: Option A is incorrect because the adjustment is upward, reflecting increased risk, not decreased.
Option B: Option B is incorrect because the issue is bone quality not captured by DXA, not systematic overestimation of density by the scan.
Option D: Option D is incorrect because the adjustment reflects a direct bone-quality effect of the drug rather than merely the age of users.
Option E: Option E is incorrect because FRAX remains usable and is adjusted, not abandoned in favor of BMD alone.
12. A patient at high fracture risk on long-term prednisone is started on oral alendronate for bone protection. Which mechanism best describes how nitrogen-containing bisphosphonates reduce fracture risk in GIO?
A) Monoclonal antibody binding and neutralization of RANKL (receptor activator of nuclear factor kappa-B ligand)
B) Inhibition of 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) signaling
D) Inhibition of dihydrofolate reductase in osteoclast precursors
E) Increased intestinal calcium absorption through enhanced enterocyte transport
ANSWER: B
Rationale:
Bisphosphonates are taken up into bone mineral and ingested by osteoclasts during resorption, where nitrogen-containing agents inhibit farnesyl pyrophosphate synthase in the mevalonate pathway; this impairs osteoclast cytoskeletal function and promotes osteoclast apoptosis, producing a 50 to 70 percent relative risk reduction in vertebral fractures in glucocorticoid-treated patients.
Option A: Option A is incorrect because RANKL neutralization by a monoclonal antibody describes denosumab, not bisphosphonates.
Option C: Option C is incorrect because PTH1R-mediated osteoblast stimulation describes teriparatide, an anabolic agent, not an antiresorptive bisphosphonate.
Option D: Option D is incorrect because dihydrofolate reductase inhibition is the mechanism of methotrexate and is unrelated to bisphosphonate action.
Option E: Option E is incorrect because bisphosphonates act on osteoclasts in bone rather than by enhancing intestinal calcium absorption.
13. A patient with chronic kidney disease who cannot take bisphosphonates has been receiving denosumab for GIO. The team plans to eventually stop it. Which consideration is most important when discontinuing denosumab?
A) Denosumab can be stopped abruptly with no special precautions because its effect persists indefinitely
B) Denosumab is contraindicated in chronic kidney disease, unlike bisphosphonates which are preferred at low GFR (glomerular filtration rate)
C) Denosumab works by inhibiting farnesyl pyrophosphate synthase, so its effect accumulates in bone
D) Its antiresorptive effect wanes rapidly after the dosing interval lapses, and rebound bone loss with increased fracture risk can occur, so transition to a bisphosphonate before stopping is recommended
E) Rebound bone loss after denosumab is prevented by simply extending the dosing interval rather than transitioning therapy
ANSWER: D
Rationale:
Denosumab is a monoclonal antibody against RANKL used when bisphosphonates cannot be tolerated or are contraindicated, as with low GFR (glomerular filtration rate). Its antiresorptive effect wanes rapidly once the injection interval is extended or a dose is missed, and rebound bone loss with increased fracture risk has been observed after discontinuation; transitioning to a bisphosphonate before stopping denosumab is therefore recommended.
Option A: Option A is incorrect because the effect does not persist indefinitely and abrupt cessation risks rebound bone loss.
Option B: Option B is incorrect because it inverts the renal relationship; bisphosphonates are relatively contraindicated at low GFR, which is precisely when denosumab is considered.
Option C: Option C is incorrect because farnesyl pyrophosphate synthase inhibition is the bisphosphonate mechanism, not denosumab's RANKL-directed action.
Option E: Option E is incorrect because extending the interval does not prevent rebound; an active transition to another antiresorptive is needed.
14. A patient on chronic glucocorticoids has two prevalent vertebral fractures and a very high FRAX-adjusted fracture probability. The team considers teriparatide. Which statement about teriparatide in GIO is correct?
A) It is a recombinant PTH (parathyroid hormone) 1-34 fragment that stimulates osteoblast activity through PTH1R (parathyroid hormone receptor 1), is preferred for very high fracture risk, and is limited to 24 months with subsequent transition to an antiresorptive
B) It reduces fracture risk primarily by inhibiting osteoclast-mediated resorption like a bisphosphonate
C) It can be continued indefinitely with no regulatory time limit
D) It is first-line for all glucocorticoid-treated patients regardless of fracture risk
E) After completion, no further therapy is needed because the anabolic gains are permanent
ANSWER: A
Rationale:
Teriparatide is the recombinant 1-34 amino acid fragment of PTH (parathyroid hormone) and the only approved bone anabolic agent specifically studied in GIO; it stimulates osteoblast differentiation and activity directly through PTH1R (parathyroid hormone receptor 1) signaling, is preferred for patients at very high fracture risk (such as those with two or more prevalent vertebral fractures), and carries a 24-month treatment limit after which transition to an antiresorptive is required to preserve the gains.
Option B: Option B is incorrect because teriparatide is anabolic, increasing bone formation, rather than acting as an antiresorptive like bisphosphonates.
Option C: Option C is incorrect because there is a 24-month regulatory limit.
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 transition to an antiresorptive within about 3 months of completion is needed, since anabolic gains are lost without follow-on therapy.
15. A patient on high-dose hydrocortisone develops new hypertension with mild hypokalemia. Which mechanism best explains the renal contribution to glucocorticoid-induced hypertension at high doses?
A) Selective blockade of the mineralocorticoid receptor (MR) in the distal nephron
B) Enhanced renal potassium retention through inhibition of ENaC (epithelial sodium channel)
C) Increased nitric oxide-mediated vasodilation reducing vascular resistance
E) Saturation of 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2) allowing cortisol to activate the mineralocorticoid receptor, promoting sodium retention and potassium excretion
ANSWER: E
Rationale:
At pharmacological concentrations, glucocorticoids overwhelm the capacity of renal 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2) to inactivate cortisol before it reaches the mineralocorticoid receptor (MR) in the distal nephron; the resulting MR activation upregulates ENaC (epithelial sodium channel) and Na/K-ATPase, promoting sodium and water retention and potassium excretion. This mineralocorticoid overflow is most pronounced with hydrocortisone and prednisolone.
Option A: Option A is incorrect because the mechanism is MR activation, not blockade.
Option B: Option B is incorrect because ENaC is upregulated, driving potassium excretion (hypokalemia), not retention.
Option C: Option C is incorrect because glucocorticoids suppress eNOS (endothelial nitric oxide synthase) and reduce nitric oxide-mediated vasodilation, raising vascular resistance.
Option D: Option D is incorrect because glucocorticoids stimulate renin gene expression and RAAS (renin-angiotensin-aldosterone system) activity rather than suppressing it.
16. A 70-year-old man requires high-dose prednisone (greater than 40 mg per day) for a severe flare. His clinician arranges electrocardiographic monitoring. Which statement about atrial fibrillation (AF) risk with glucocorticoids is correct?
A) Glucocorticoids reduce the risk of new-onset AF compared with non-users
B) Glucocorticoid use is associated with an approximately 2-fold increase in new-onset AF risk, and the risk appears dose-dependent and most elevated at high doses
C) AF risk with glucocorticoids is unrelated to dose
D) AF risk is mediated solely by hyperkalemia from mineralocorticoid effects
E) AF risk is identical at low and very high prednisone equivalent doses
ANSWER: B
Rationale:
Meta-analyses estimate an approximately 2-fold increase in new-onset AF risk with glucocorticoid use compared with non-users; the risk appears dose-dependent and is most elevated at high prednisone equivalent doses (greater than 30 to 40 mg per day), supporting electrocardiographic monitoring and risk-factor optimization in high-risk patients on high-dose therapy. Proposed mechanisms include electrolyte disturbance such as 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 rather than reduce AF risk.
Option C: Option C is incorrect because the risk is dose-dependent.
Option D: Option D is incorrect because the mineralocorticoid effect produces hypokalemia, not hyperkalemia, and is only one of several contributing mechanisms.
Option E: Option E is incorrect because risk rises with dose and is greatest at high doses, not identical across the dose range.
17. A patient on glucocorticoid monotherapy (no other immunosuppressants) is being assessed for PCP (Pneumocystis jirovecii pneumonia) prophylaxis. At what glucocorticoid exposure is TMP-SMX (trimethoprim-sulfamethoxazole) prophylaxis generally indicated in this monotherapy setting?
A) Any glucocorticoid dose for any duration
B) Prednisone equivalent greater than 5 mg per day for any duration
C) Only after a first episode of PCP has occurred
D) Prednisone equivalent greater than 20 mg per day for more than 4 weeks
E) Prophylaxis is never indicated with glucocorticoids in non-HIV patients
ANSWER: D
Rationale:
In patients on glucocorticoid monotherapy who are not receiving other immunosuppressants, PCP (Pneumocystis jirovecii pneumonia) prophylaxis with TMP-SMX (trimethoprim-sulfamethoxazole) is generally indicated at prednisone equivalent greater than 20 mg per day for more than 4 weeks; the threshold is lower (greater than 10 mg per day for more than 4 weeks) when glucocorticoids are combined with additional immunosuppressants.
Option A: Option A is incorrect because prophylaxis is not indicated at any dose for any duration; it is reserved for sustained higher-dose exposure.
Option B: Option B is incorrect because the monotherapy threshold is greater than 20 mg per day for more than 4 weeks, not greater than 5 mg per day.
Option C: Option C is incorrect because prophylaxis is given to prevent a first episode in at-risk patients, not only after one has occurred.
Option E: Option E is incorrect because PCP is the most consistently preventable opportunistic infection in glucocorticoid-treated non-HIV patients, so prophylaxis is indicated above the threshold.
18. A 60-year-old patient on prednisone 30 mg per day for the past month is due for vaccinations. Which statement about vaccination in significantly immunosuppressed glucocorticoid-treated patients is correct?
A) Live attenuated vaccines are preferred because immunosuppression boosts their immunogenicity
B) Inactivated vaccines are contraindicated at high glucocorticoid doses due to disseminated infection risk
C) Live attenuated vaccines are contraindicated at prednisone equivalent greater than 20 mg per day for more than 2 weeks, while inactivated vaccines are safe at any degree of immunosuppression
D) All vaccines, live and inactivated, are equally contraindicated during glucocorticoid therapy
E) Inactivated vaccines must never be given to glucocorticoid-treated patients
ANSWER: C
Rationale:
Live attenuated vaccines (for example MMR, varicella, yellow fever, intranasal influenza) are contraindicated in patients on prednisone equivalent greater than 20 mg per day for more than 2 weeks because of the risk of disseminated infection from the vaccine strain, whereas inactivated vaccines (injectable influenza, pneumococcal, hepatitis A and B, recombinant zoster) are safe at any degree of immunosuppression, though immunogenicity may be reduced.
Option A: Option A is incorrect because immunosuppression reduces, not boosts, immunogenicity, and live vaccines are contraindicated, not preferred.
Option B: Option B is incorrect because the disseminated-infection risk applies to live, not inactivated, vaccines.
Option D: Option D is incorrect because live and inactivated vaccines differ; only live vaccines are contraindicated at significant immunosuppression.
Option E: Option E is incorrect because inactivated vaccines are recommended, ideally before therapy or at the lowest maintenance dose.
19. A transplant patient stabilized on prednisolone is started on rifampin (rifampicin) for an infection. Which consequence should the clinician most anticipate from this drug interaction?
A) Rifampin induces CYP3A4 (cytochrome P450 3A4), accelerating glucocorticoid metabolism and lowering plasma levels, risking loss of therapeutic effect or precipitating an event such as transplant rejection
B) Rifampin inhibits CYP3A4 (cytochrome P450 3A4), raising glucocorticoid levels and causing toxicity at standard doses
C) Rifampin has no effect on glucocorticoid metabolism
D) Rifampin increases glucocorticoid levels and should prompt an immediate dose reduction
E) The interaction requires no monitoring when rifampin is later discontinued
ANSWER: A
Rationale:
Rifampin (rifampicin) is a potent CYP3A4 (cytochrome P450 3A4) inducer that accelerates glucocorticoid metabolism and can reduce prednisolone exposure by 45 to 75 percent, risking loss of therapeutic effect and, in dependent patients, events such as adrenal crisis or acute transplant rejection; patients often need higher glucocorticoid doses while on the inducer.
Option B: Option B is incorrect because rifampin induces rather than inhibits CYP3A4, so it lowers rather than raises glucocorticoid levels.
Option C: Option C is incorrect because rifampin has a clinically significant effect on glucocorticoid metabolism.
Option D: Option D is incorrect because the level falls, so a dose increase, not reduction, is typically needed during co-administration.
Option E: Option E is incorrect because careful monitoring is required when the inducer is stopped, since normal enzyme activity returns over 2 to 4 weeks and the compensatory dose may then become toxic.
20. A patient with HIV (human immunodeficiency virus) on a ritonavir-boosted regimen is also using inhaled fluticasone for asthma, managed by a different provider. He develops features of Cushing syndrome. Which mechanism best explains this iatrogenic Cushing syndrome?
A) Ritonavir induces CYP3A4 (cytochrome P450 3A4), lowering fluticasone levels and causing adrenal insufficiency
B) Inhaled fluticasone undergoes negligible systemic absorption regardless of co-medications
C) The features are unrelated to any pharmacokinetic interaction between the drugs
D) Ritonavir displaces fluticasone from albumin, with no change in metabolism
E) Ritonavir potently inhibits CYP3A4 (cytochrome P450 3A4), markedly raising systemic fluticasone exposure and producing iatrogenic Cushing syndrome even with standard inhaled doses
ANSWER: E
Rationale:
Ritonavir is a potent CYP3A4 (cytochrome P450 3A4) inhibitor; when combined with inhaled fluticasone it can raise systemic corticosteroid exposure dramatically (reported on the order of several hundred-fold), producing iatrogenic Cushing syndrome even at standard inhaled doses. The interaction is easily missed when HIV (human immunodeficiency virus) care and respiratory care are managed separately.
Option A: Option A is incorrect because ritonavir inhibits rather than induces CYP3A4, raising rather than lowering fluticasone levels.
Option B: Option B is incorrect because the interaction specifically increases systemic absorption and exposure of inhaled fluticasone, contradicting the idea of negligible absorption.
Option C: Option C is incorrect because the syndrome is directly caused by the pharmacokinetic interaction.
Option D: Option D is incorrect because the dominant mechanism is CYP3A4 inhibition reducing fluticasone clearance, not albumin displacement.
21. A patient on chronic prednisone also takes a daily NSAID (non-steroidal anti-inflammatory drug) for joint pain. Which statement best characterizes this combination and its management?
A) The interaction is pharmacokinetic, with the NSAID inducing glucocorticoid metabolism
B) Both agents independently suppress prostaglandin-mediated gastric mucosal defense, and their combination markedly increases peptic ulcer complication risk, warranting proton pump inhibitor prophylaxis
C) The combination reduces gastrointestinal mucosal injury risk compared with either agent alone
D) The combination has no greater ulcer risk than either drug used alone
E) The interaction is corrected by spacing the two drugs several hours apart without acid suppression
ANSWER: B
Rationale:
The glucocorticoid-NSAID (non-steroidal anti-inflammatory drug) interaction is pharmacodynamic: both agents independently suppress the prostaglandin-mediated gastric mucosal defense mechanisms, so their combination produces substantially greater gastrointestinal mucosal injury risk, with peptic ulcer complication relative risk estimated around 15-fold versus neither drug (compared with roughly 3-fold for each agent alone), and proton pump inhibitor prophylaxis is indicated when both are used together.
Option A: Option A is incorrect because the interaction is pharmacodynamic, not a pharmacokinetic induction of glucocorticoid metabolism by the NSAID.
Option C: Option C is incorrect because the combination increases rather than reduces mucosal injury risk.
Option D: Option D is incorrect because combined use carries clearly higher ulcer-complication risk than either drug alone.
Option E: Option E is incorrect because the additive mucosal injury is not solved by dose spacing; acid suppression with a proton pump inhibitor is the appropriate measure.
22. A patient with lupus nephritis is treated with MMF (mycophenolate mofetil) as a steroid-sparing agent alongside hydroxychloroquine and low-dose prednisone. Which mechanism explains the relatively targeted immunosuppression of mycophenolate?
A) Inhibition of dihydrofolate reductase, blocking folate-dependent purine synthesis broadly
B) Conversion to 6-mercaptopurine to inhibit de novo purine synthesis nonselectively
C) Antagonism of the interleukin-6 (IL-6) receptor on T cells
D) Selective inhibition of IMPDH (inosine monophosphate dehydrogenase) type II, the isoform preferentially expressed in activated lymphocytes, limiting purine synthesis in T and B cells
E) Inhibition of farnesyl pyrophosphate synthase in lymphocyte precursors
ANSWER: D
Rationale:
Mycophenolate mofetil (MMF) 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, giving a targeted immunosuppressive effect that supports steroid-sparing in lupus nephritis and other conditions.
Option A: Option A is incorrect because dihydrofolate reductase inhibition is the mechanism of methotrexate, not mycophenolate.
Option B: Option B is incorrect because conversion to 6-mercaptopurine describes azathioprine, a less selective purine-synthesis inhibitor.
Option C: Option C is incorrect because IL-6 (interleukin-6) receptor antagonism describes tocilizumab, not mycophenolate.
Option E: Option E is incorrect because farnesyl pyrophosphate synthase inhibition is the bisphosphonate mechanism and is unrelated to mycophenolate.
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