Chapter 28: Adrenocorticosteroid Pharmacology — Module 3: Adverse Effects, GIO Management, and Drug Interactions
1. Glucocorticoids raise blood glucose through actions in both the liver and the peripheral tissues. Which effect specifically accounts for the impaired peripheral (skeletal muscle and adipose) glucose uptake in glucocorticoid-induced insulin resistance?
A) Upregulation of the gluconeogenic enzyme PEPCK (phosphoenolpyruvate carboxykinase) in the liver
B) Increased hepatic glycogen breakdown driven by the coactivator PGC-1alpha
C) Suppression of pancreatic beta-cell insulin secretion
D) Reduced insulin-stimulated translocation of GLUT4 (glucose transporter type 4) to the plasma membrane
E) Increased renal tubular reabsorption of filtered glucose
ANSWER: D
Rationale:
In skeletal muscle and adipose tissue, glucocorticoids reduce insulin-stimulated translocation of GLUT4 (glucose transporter type 4) to the plasma membrane, impairing peripheral glucose uptake independently of circulating insulin levels; this is the peripheral component of glucocorticoid-induced insulin resistance.
Option A: Option A is incorrect because PEPCK (phosphoenolpyruvate carboxykinase) upregulation drives hepatic glucose output, which is the liver component, not peripheral uptake.
Option B: Option B is incorrect because PGC-1alpha-driven glycogen breakdown is also a hepatic effect contributing to glucose output rather than to peripheral uptake.
Option C: Option C is incorrect because glucocorticoid hyperglycemia results from insulin resistance and increased hepatic output, not suppression of beta-cell insulin secretion.
Option E: Option E is incorrect because glucocorticoid hyperglycemia is not driven by renal glucose reabsorption.
2. Which lipid profile best characterizes glucocorticoid-induced dyslipidemia?
A) Decreased total cholesterol and decreased triglycerides
B) Elevated total and LDL (low-density lipoprotein) cholesterol and elevated VLDL (very low-density lipoprotein) triglycerides, with variable effects on HDL (high-density lipoprotein)
C) Isolated low HDL (high-density lipoprotein) with normal LDL and triglycerides
D) Elevated HDL (high-density lipoprotein) with reduced LDL cholesterol
E) Normal lipid profile with no clinically relevant changes
ANSWER: B
Rationale:
Glucocorticoid-induced dyslipidemia is characterized by elevation of total and LDL (low-density lipoprotein) cholesterol and elevated VLDL (very low-density lipoprotein) triglycerides, with variable effects on HDL (high-density lipoprotein); it results from increased hepatic lipogenesis, increased free fatty acid flux to the liver, and reduced LDL receptor expression, and is generally dose- and duration-dependent.
Option A: Option A is incorrect because cholesterol and triglycerides rise rather than fall.
Option C: Option C is incorrect because the abnormality is not an isolated low HDL with otherwise normal lipids; LDL and triglycerides are elevated.
Option D: Option D is incorrect because LDL rises rather than falls and HDL change is variable, not consistently elevated.
Option E: Option E is incorrect because clinically relevant lipid changes do occur and contribute to accelerated atherosclerosis.
3. A patient on chronic glucocorticoids develops proximal weakness, and the clinician must distinguish steroid myopathy from an inflammatory myositis flare. Which laboratory finding best discriminates steroid myopathy from inflammatory myositis?
A) Creatine kinase (CK) is normal or only mildly elevated in steroid myopathy, whereas it is markedly elevated in inflammatory myositis
B) Creatine kinase (CK) is markedly elevated in steroid myopathy and normal in inflammatory myositis
C) Both conditions produce identical, markedly elevated creatine kinase (CK) values
D) Steroid myopathy is distinguished by a markedly elevated serum potassium
E) Inflammatory myositis is distinguished by an absent creatine kinase (CK) elevation
ANSWER: A
Rationale:
Steroid myopathy characteristically shows a normal or only mildly elevated creatine kinase (CK), while inflammatory myositis (an inadequately treated disease flare) shows a markedly elevated CK with active inflammatory changes; the CK level is therefore a key discriminator, and the distinction matters because steroid myopathy is treated by dose reduction whereas myositis is treated with increased immunosuppression.
Option B: Option B is incorrect because it inverts the relationship, attributing the marked elevation to steroid myopathy.
Option C: Option C is incorrect because the two conditions differ in CK, which is the basis for using it as a discriminator.
Option D: Option D is incorrect because steroid myopathy is not defined by a potassium abnormality.
Option E: Option E is incorrect because inflammatory myositis is characterized by elevated, not absent, CK.
4. Which molecular mechanism best explains the muscle protein catabolism that underlies steroid myopathy?
A) Increased mTOR (mechanistic target of rapamycin) signaling stimulating muscle protein synthesis
C) Increased GLUT4 (glucose transporter type 4) expression in myocytes
D) Suppression of RANKL (receptor activator of nuclear factor kappa-B ligand) in muscle tissue
E) GR-dependent upregulation of the E3 ubiquitin ligases MuRF1 (muscle RING finger protein 1) and MAFbx (muscle atrophy F-box protein), targeting myofibrillar proteins for proteasomal degradation
ANSWER: E
Rationale:
Steroid myopathy is driven by GR-dependent transcriptional upregulation of the E3 ubiquitin ligases MuRF1 (muscle RING finger protein 1) and MAFbx (muscle atrophy F-box protein), which tag myofibrillar proteins such as myosin heavy chain for proteasomal degradation; glucocorticoids also suppress mTOR-dependent protein synthesis, creating a net catabolic state.
Option A: Option A is incorrect because glucocorticoids inhibit rather than increase mTOR (mechanistic target of rapamycin) signaling, reducing protein synthesis.
Option B: Option B is incorrect because glucocorticoids impair, not enhance, IGF-1 (insulin-like growth factor 1)-driven anabolism.
Option C: Option C is incorrect because glucocorticoids reduce GLUT4 (glucose transporter type 4) function and this concerns glucose handling rather than the catabolic mechanism.
Option D: Option D is incorrect because RANKL (receptor activator of nuclear factor kappa-B ligand) relates to bone resorption, not skeletal muscle catabolism.
5. Exogenous glucocorticoids suppress the HPA (hypothalamic-pituitary-adrenal) axis through negative feedback. At the molecular level, where does this feedback suppression act?
A) Activation of positive glucocorticoid response elements that increase ACTH (adrenocorticotropic hormone) output
B) Stimulation of CRH (corticotropin-releasing hormone) gene transcription in the hypothalamus
C) GR-alpha binding to negative glucocorticoid response elements in the POMC (pro-opiomelanocortin) and CRH (corticotropin-releasing hormone) gene promoters, suppressing ACTH and CRH production
D) Direct destruction of the adrenal cortex by a cytotoxic mechanism
E) Blockade of the mineralocorticoid receptor in the distal nephron
ANSWER: C
Rationale:
HPA (hypothalamic-pituitary-adrenal) axis suppression operates through GR-alpha binding to negative glucocorticoid response elements in the POMC (pro-opiomelanocortin) gene promoter, the precursor of ACTH (adrenocorticotropic hormone), and in the CRH (corticotropin-releasing hormone) gene promoter, suppressing endogenous ACTH and CRH and thereby cortisol production.
Option A: Option A is incorrect because the feedback acts through negative, not positive, response elements and reduces ACTH output.
Option B: Option B is incorrect because CRH transcription is suppressed, not stimulated.
Option D: Option D is incorrect because suppression is a reversible transcriptional feedback effect, not cytotoxic destruction of the adrenal cortex.
Option E: Option E is incorrect because mineralocorticoid receptor blockade is unrelated to HPA negative feedback.
6. Which statement best describes the dose-dependent spectrum of glucocorticoid neuropsychiatric effects?
A) High doses cause mild euphoria while low doses cause frank psychosis
B) Effects are uniform across all doses, with psychosis equally likely at any dose
C) Only low doses produce any neuropsychiatric effect; high doses are neuropsychiatrically silent
D) Low to moderate doses tend to produce euphoria, increased energy, and insomnia, while high doses can produce serious effects including mania and frank psychosis
E) Neuropsychiatric effects occur only after the drug is discontinued, not during therapy
ANSWER: D
Rationale:
Glucocorticoid neuropsychiatric effects follow a dose-dependent spectrum: at low to moderate doses the common effects are mild euphoria, increased energy, and insomnia, whereas at high doses serious effects including major mood disturbance, mania, and frank psychosis can occur, 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 B: Option B is incorrect because the effects are dose-dependent, not uniform across doses.
Option C: Option C is incorrect because high doses are not neuropsychiatrically silent; they carry the greatest risk of serious effects.
Option E: Option E is incorrect because these effects occur during therapy, particularly at higher doses, not only after discontinuation.
7. Which clinical feature is most characteristic of the early presentation of glucocorticoid-induced PSC (posterior subcapsular cataract)?
A) Sudden painful loss of vision over hours
B) Glare and difficulty with night driving, with central vision preserved until later stages
C) Early and complete loss of central vision with preserved peripheral vision
D) Acute red, painful eye with photophobia
E) Sudden onset of double vision from extraocular muscle weakness
ANSWER: B
Rationale:
Posterior subcapsular cataract characteristically presents with early visual disturbance from glare in bright light or while driving at night, while central vision is preserved until later stages; it develops slowly over months to years and is related to cumulative dose.
Option A: Option A is incorrect because PSC develops gradually rather than as sudden painful vision loss.
Option C: Option C is incorrect because central vision is preserved until later, not lost early.
Option D: Option D is incorrect because PSC is a painless lens opacity, not an acute painful red eye.
Option E: Option E is incorrect because PSC is a lens problem, not extraocular muscle dysfunction causing diplopia.
8. By what mechanism do glucocorticoids raise intraocular pressure (IOP) in steroid-induced glaucoma?
A) GR-dependent upregulation of myocilin and extracellular matrix proteins in the trabecular meshwork, increasing aqueous outflow resistance
B) Increased aqueous humor production by the ciliary epithelium
C) Mechanical obstruction of the pupil by lens swelling
D) Destruction of retinal ganglion cells by a direct cytotoxic effect
Glucocorticoid-induced IOP elevation results from GR-dependent effects on trabecular meshwork cells, which upregulate myocilin (MYOC) and extracellular matrix proteins such as fibronectin and laminin, increasing resistance to aqueous outflow and reducing drainage.
Option B: Option B is incorrect because the mechanism is reduced trabecular outflow, not increased aqueous production.
Option C: Option C is incorrect because the pressure rise is due to outflow resistance at the trabecular meshwork, not mechanical pupillary obstruction by the lens.
Option D: Option D is incorrect because optic nerve damage in steroid glaucoma is a downstream consequence of elevated IOP, not a direct cytotoxic destruction of ganglion cells.
Option E: Option E is incorrect because outflow resistance increases rather than decreases.
9. In glucocorticoid-induced osteoporosis, which mechanism acts on the bone-forming (osteoblast) side of the remodeling unit?
A) Increased RANKL (receptor activator of nuclear factor kappa-B ligand) expression activating osteoclasts
B) Suppression of OPG (osteoprotegerin) permitting osteoclast survival
C) Inhibition of farnesyl pyrophosphate synthase in osteoclasts
E) Suppression of Wnt/beta-catenin signaling, impairing osteoblast differentiation, with increased osteoblast and osteocyte apoptosis
ANSWER: E
Rationale:
On the bone-forming side, glucocorticoids suppress Wnt/beta-catenin signaling, the principal pathway driving osteoblast lineage commitment, and promote apoptosis of mature osteoblasts and osteocytes, reducing osteoid synthesis and mineralization.
Option A: Option A is incorrect because increased RANKL (receptor activator of nuclear factor kappa-B ligand) acts on the bone-resorbing side by activating osteoclasts.
Option B: Option B is incorrect because OPG (osteoprotegerin) suppression also concerns the resorbing side, enhancing osteoclast activity.
Option C: Option C is incorrect because farnesyl pyrophosphate synthase inhibition is the bisphosphonate drug mechanism, not an endogenous glucocorticoid effect on osteoblasts.
Option D: Option D is incorrect because increased renal calcium excretion is a systemic calcium-handling effect, not a direct action on the osteoblast side.
10. The FRAX (Fracture Risk Assessment Tool) glucocorticoid adjustment increases the calculated fracture probability for patients above a defined glucocorticoid exposure. At what exposure does this upward adjustment apply?
A) Any glucocorticoid dose for any duration
B) Inhaled glucocorticoids at any dose
C) Prednisone greater than 7.5 mg per day for more than 3 months
D) A single dose of intravenous glucocorticoid
E) Only prednisone doses below 5 mg per day
ANSWER: C
Rationale:
FRAX (Fracture Risk Assessment Tool) scores are adjusted upward (approximately 15 percent for major osteoporotic fracture and 20 percent for hip fracture probability) for patients receiving prednisone greater than 7.5 mg per day for more than 3 months, to capture the bone-quality effect that DXA-measured BMD does not reflect.
Option A: Option A is incorrect because the adjustment is tied to a specific dose-and-duration threshold, not to any dose for any duration.
Option B: Option B is incorrect because the threshold is defined for systemic prednisone-equivalent dosing, not inhaled glucocorticoids at any dose.
Option D: Option D is incorrect because the adjustment reflects sustained exposure over more than 3 months, not a single intravenous dose.
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.
11. Among agents used in glucocorticoid-induced osteoporosis, which pairing of agent to mechanism is correct?
A) Denosumab — direct stimulation of osteoblast differentiation through PTH1R (parathyroid hormone receptor 1)
B) Teriparatide — monoclonal antibody neutralization of RANKL (receptor activator of nuclear factor kappa-B ligand)
C) Alendronate — selective inhibition of IMPDH (inosine monophosphate dehydrogenase) type II
D) Alendronate inhibits farnesyl pyrophosphate synthase in osteoclasts; denosumab neutralizes RANKL (receptor activator of nuclear factor kappa-B ligand); teriparatide is an anabolic PTH (parathyroid hormone) fragment acting through PTH1R (parathyroid hormone receptor 1)
E) Teriparatide — inhibition of farnesyl pyrophosphate synthase in osteoclasts
ANSWER: D
Rationale:
The correct mechanism-to-agent mapping is: alendronate (a bisphosphonate) inhibits farnesyl pyrophosphate synthase in osteoclasts; denosumab is a monoclonal antibody that neutralizes RANKL (receptor activator of nuclear factor kappa-B ligand); and teriparatide is an anabolic PTH (parathyroid hormone) 1-34 fragment acting through PTH1R (parathyroid hormone receptor 1).
Option A: Option A is incorrect because PTH1R-mediated osteoblast stimulation describes teriparatide, not denosumab.
Option B: Option B is incorrect because RANKL neutralization describes denosumab, not teriparatide.
Option C: Option C is incorrect because IMPDH (inosine monophosphate dehydrogenase) type II inhibition is the mechanism of mycophenolate, not alendronate.
Option E: Option E is incorrect because farnesyl pyrophosphate synthase inhibition is the bisphosphonate mechanism, not that of teriparatide.
12. Which statement about discontinuing denosumab in a patient treated for glucocorticoid-induced osteoporosis is correct?
A) Its antiresorptive effect persists for years after the last dose, so no follow-on therapy is needed
B) 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
C) Discontinuation reliably increases bone density through a rebound anabolic effect
D) Rebound bone loss is prevented simply by stopping the drug at any time of year
E) Denosumab permanently incorporates into bone mineral, eliminating any rebound concern
ANSWER: B
Rationale:
Denosumab's antiresorptive effect wanes rapidly once the dosing 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 for years; it wanes rapidly, which is precisely why follow-on therapy is needed.
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 to another antiresorptive is required.
Option E: Option E is incorrect because denosumab is an antibody that does not incorporate into bone mineral, unlike bisphosphonates.
13. Glucocorticoid-induced hypertension has a renal mineralocorticoid component. Which mechanism explains why high-dose cortisol-like glucocorticoids cause sodium retention through the mineralocorticoid receptor?
A) Glucocorticoids directly block the mineralocorticoid receptor, paradoxically retaining sodium
B) Glucocorticoids increase 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2) activity, accelerating cortisol inactivation
C) At high doses, glucocorticoids overwhelm 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2), the enzyme that normally inactivates cortisol before it reaches the mineralocorticoid receptor, allowing cortisol to activate that receptor and drive sodium retention
D) Glucocorticoids inhibit ENaC (epithelial sodium channel) in the distal nephron
Normally the renal enzyme 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2) inactivates cortisol before it can reach the mineralocorticoid receptor in the distal nephron; at pharmacological glucocorticoid concentrations this capacity is overwhelmed, so cortisol activates the mineralocorticoid receptor, upregulating ENaC (epithelial sodium channel) and Na/K-ATPase to promote sodium and water retention with potassium excretion.
Option A: Option A is incorrect because the mechanism is receptor activation, not blockade.
Option B: Option B is incorrect because the enzyme is saturated and effectively overwhelmed, not upregulated to accelerate inactivation.
Option D: Option D is incorrect because ENaC (epithelial sodium channel) is upregulated, not inhibited.
Option E: Option E is incorrect because the effect promotes sodium retention and hypertension rather than suppressing aldosterone to lower pressure.
14. How does the threshold for PCP (Pneumocystis jirovecii pneumonia) prophylaxis differ between glucocorticoid monotherapy and glucocorticoids combined with other immunosuppressants?
A) The threshold is identical in both settings: any glucocorticoid dose for any duration
B) Prophylaxis is recommended only in combination therapy and never in monotherapy
C) The monotherapy threshold is lower than the combination threshold
D) In monotherapy, prophylaxis is generally indicated above prednisone equivalent of 20 mg per day for more than 4 weeks, whereas with additional immunosuppressants the threshold is lower, around 10 mg per day for more than 4 weeks
E) Prophylaxis is recommended only after a first PCP (Pneumocystis jirovecii pneumonia) episode in either setting
ANSWER: D
Rationale:
For glucocorticoid monotherapy, PCP (Pneumocystis jirovecii pneumonia) prophylaxis is generally indicated above prednisone equivalent of 20 mg per day for more than 4 weeks; when glucocorticoids are combined with other immunosuppressants, the threshold falls to roughly 10 mg per day for more than 4 weeks because of the greater cumulative immunosuppression.
Option A: Option A is incorrect because the thresholds are dose-and-duration based and differ between the two settings.
Option B: Option B is incorrect because prophylaxis is indicated in monotherapy above the threshold, not only in combination therapy.
Option C: Option C is incorrect because it inverts the relationship; the combination threshold is the lower one.
Option E: Option E is incorrect because prophylaxis is given to prevent a first episode in at-risk patients, not only after one occurs.
15. Glucocorticoids are metabolized largely by CYP3A4 (cytochrome P450 3A4), the principal liver enzyme that breaks them down. Which statement correctly describes the directional effect of CYP3A4 inducers versus inhibitors on glucocorticoid exposure?
A) An inducer such as rifampin accelerates glucocorticoid metabolism and lowers plasma levels, whereas an inhibitor such as ritonavir slows metabolism and raises plasma levels
B) An inducer such as rifampin raises glucocorticoid levels, whereas an inhibitor such as ritonavir lowers them
C) Both inducers and inhibitors lower glucocorticoid plasma levels
D) Both inducers and inhibitors raise glucocorticoid plasma levels
E) Neither inducers nor inhibitors meaningfully change glucocorticoid exposure
ANSWER: A
Rationale:
CYP3A4 (cytochrome P450 3A4) inducers such as rifampin increase enzyme activity, accelerating glucocorticoid metabolism and lowering plasma concentrations, which can cause loss of effect; CYP3A4 inhibitors such as ritonavir slow metabolism and raise plasma concentrations, producing toxicity at standard doses.
Option B: Option B is incorrect because it reverses the directions; induction lowers and inhibition raises levels.
Option C: Option C is incorrect because inhibitors raise rather than lower levels.
Option D: Option D is incorrect because inducers lower rather than raise levels.
Option E: Option E is incorrect because both classes of interaction meaningfully alter glucocorticoid exposure.
16. Among steroid-sparing agents, which pairing of agent to mechanism is correct?
A) Methotrexate — antagonism of the interleukin-6 (IL-6) receptor
B) Azathioprine — selective inhibition of IMPDH (inosine monophosphate dehydrogenase) type II
C) Tocilizumab — inhibition of dihydrofolate reductase
D) Mycophenolate mofetil — conversion to 6-mercaptopurine with nonselective purine synthesis inhibition
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 mechanism-to-agent mapping is: methotrexate inhibits dihydrofolate reductase and has adenosine-mediated anti-inflammatory effects at low doses; azathioprine is a prodrug converted to 6-mercaptopurine that inhibits de novo purine synthesis; mycophenolate mofetil 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 (interleukin-6) receptor antagonism describes tocilizumab, not methotrexate.
Option B: Option B is incorrect because IMPDH (inosine monophosphate dehydrogenase) 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.
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