Adrenocorticosteroid Pharmacology

Correct Answer

D — Trimethoprim-sulfamethoxazole

Rationale

Trimethoprim-sulfamethoxazole (one double-strength tablet three times weekly) is the first-line prophylactic agent for Pneumocystis jirovecii pneumonia in patients on prolonged pharmacological glucocorticoid therapy. It is indicated when prednisone equivalent exceeds 20 mg per day for more than 4 weeks in glucocorticoid monotherapy, or 10 mg per day for more than 4 weeks when combined with additional immunosuppressants. Dapsone 100 mg daily and atovaquone 1500 mg daily are alternative agents for patients with sulfonamide intolerance. Pentamidine (inhaled monthly) is a less preferred alternative.

Correct Answer

B — Teriparatide

Rationale

Teriparatide is classified as a bone anabolic agent — it is recombinant parathyroid hormone (1-34) that stimulates osteoblast differentiation via PTH receptor 1, increasing bone formation. It is preferred at very high fracture risk (FRAX-adjusted 10-year major fracture probability greater than 20% or multiple vertebral fractures) and is superior to alendronate for vertebral fracture prevention specifically in glucocorticoid-induced osteoporosis. Alendronate, zoledronic acid, and denosumab are all antiresorptive agents — they reduce bone loss by inhibiting osteoclast activity rather than stimulating new bone formation.

Correct Answer

A — Denosumab

Rationale

Denosumab is a monoclonal antibody that directly targets and neutralizes RANKL (receptor activator of nuclear factor kappa-B ligand), the key cytokine driving osteoclast differentiation and activation. In glucocorticoid-induced osteoporosis, where the RANKL-to-osteoprotegerin ratio is shifted toward osteoclast activation, denosumab addresses this mechanism directly. It is used as an alternative when bisphosphonates are contraindicated. Teriparatide is a bone anabolic peptide. Risedronate and zoledronic acid are bisphosphonates that inhibit farnesyl pyrophosphate synthase in osteoclasts.

Correct Answer

C — Methotrexate

Rationale

Methotrexate is classified as a steroid-sparing agent that combines two anti-inflammatory mechanisms: inhibition of dihydrofolate reductase (reducing purine and thymidine synthesis needed for rapidly dividing immune cells) and adenosine-mediated anti-inflammation (accumulation of adenosine at inflammatory sites suppresses immune activation). It permits 30 to 50% prednisone dose reduction across multiple indications. Azathioprine inhibits de novo purine synthesis as a 6-mercaptopurine prodrug. Mycophenolate mofetil selectively inhibits inosine monophosphate dehydrogenase type II. Tocilizumab is an interleukin-6 receptor antagonist.

Correct Answer

D — Mycophenolate mofetil

Rationale

Mycophenolate mofetil is classified as a selective inosine monophosphate dehydrogenase type II inhibitor. This enzyme is required for de novo guanosine synthesis in activated lymphocytes, which — unlike most cells — rely on this pathway rather than the salvage pathway. The selectivity for lymphocytes is the pharmacological basis for its immunosuppressive profile with relatively limited effects on other rapidly dividing cells. Methotrexate inhibits dihydrofolate reductase. Azathioprine is a prodrug converted to 6-mercaptopurine that inhibits purine synthesis through a different enzymatic pathway. Tocilizumab is an interleukin-6 receptor antagonist.

Correct Answer

B — Azathioprine

Rationale

Azathioprine is classified as a prodrug: it is converted to 6-mercaptopurine, which is then incorporated into nucleotide biosynthesis pathways and inhibits de novo purine synthesis preferentially in lymphocytes. An important pharmacogenomic consideration is thiopurine methyltransferase (TPMT) genotype: poor metabolizers accumulate cytotoxic thiopurine metabolites and are at risk for severe myelosuppression, so TPMT genotype or enzyme activity should be checked before initiation. Mycophenolate mofetil is also converted to an active metabolite but acts through inosine monophosphate dehydrogenase type II inhibition. Methotrexate and tocilizumab act through entirely different mechanisms.

Correct Answer

A — Pharmacological glucocorticoid concentrations overwhelm the 11-beta-hydroxysteroid dehydrogenase type 2 enzyme in the distal nephron, allowing cortisol to activate mineralocorticoid receptors and upregulate epithelial sodium channels

Rationale

At pharmacological concentrations, glucocorticoids saturate the 11-beta-hydroxysteroid dehydrogenase type 2 enzyme that normally converts cortisol to inactive cortisone in aldosterone-sensitive distal nephron cells. Once the enzyme is overwhelmed, cortisol activates mineralocorticoid receptors directly, driving transcription of epithelial sodium channel subunits and sodium-potassium ATPase — producing sodium and water retention, volume expansion, and hypertension. This mineralocorticoid overflow effect is most prominent with hydrocortisone and prednisolone, which have intrinsic mineralocorticoid activity. Aldosterone synthesis from the zona glomerulosa is not directly stimulated, and the renin-angiotensin-aldosterone system is typically suppressed by the resulting volume expansion.

Correct Answer

C — Both agents independently suppress prostaglandin-mediated gastric mucosal defense through different mechanisms, producing approximately 15-fold greater peptic ulcer risk than either alone

Rationale

The glucocorticoid and nonsteroidal anti-inflammatory drug interaction is pharmacodynamic rather than pharmacokinetic: both drugs independently suppress prostaglandin-mediated gastric mucosal protection, but through different upstream mechanisms. Ibuprofen blocks cyclooxygenase (primarily cyclooxygenase-1), reducing prostaglandin E2 synthesis directly. Glucocorticoids suppress phospholipase A2 via annexin-A1 induction and repress cyclooxygenase-2 expression via nuclear factor kappa-B inhibition, reducing arachidonic acid availability and inducible prostaglandin synthesis. Their combined use produces approximately 15-fold increased risk of peptic ulcer complications compared with neither drug, versus approximately 3-fold for each alone. Proton pump inhibitor prophylaxis is standard when both agents are used simultaneously.

Correct Answer

B — Teriparatide stimulates osteoblast differentiation via PTH receptor 1, restoring bone formation that glucocorticoids have suppressed — an effect antiresorptive agents cannot provide

Rationale

Glucocorticoids suppress bone formation by inhibiting Wnt/beta-catenin signaling, reducing osteoblast differentiation, and inducing osteoblast apoptosis. Bisphosphonates and denosumab are antiresorptive agents — they reduce bone loss by impairing osteoclast function but do not restore the suppressed bone formation. Teriparatide, as recombinant parathyroid hormone (1-34), stimulates osteoblast differentiation via PTH receptor 1, actively promoting new bone formation. This anabolic mechanism directly counteracts the formation-suppressing effect of glucocorticoids, explaining its superiority for vertebral fracture prevention in high-risk patients. Treatment is limited to 24 months, after which transition to an antiresorptive agent is required.

Correct Answer

D — Glucocorticoid receptor activation in trabecular meshwork cells upregulates myocilin and extracellular matrix proteins, increasing resistance to aqueous humor outflow

Rationale

Glucocorticoid-induced intraocular pressure elevation results from glucocorticoid receptor activation in trabecular meshwork cells. This transcriptionally upregulates myocilin (a glycoprotein that accumulates in the trabecular meshwork) and promotes deposition of extracellular matrix proteins, increasing mechanical resistance to aqueous humor outflow through the conventional drainage pathway. The result is elevated intraocular pressure without increased aqueous production. The response is heritable — primary open-angle glaucoma patients and their first-degree relatives are at substantially higher risk, reflecting genetic variation in trabecular meshwork sensitivity. Intraocular pressure monitoring every 3 months during long-term therapy is standard.

Correct Answer

A — Fluorination of the glucocorticoid molecule, as seen with dexamethasone and triamcinolone, is associated with higher myopathy risk than non-fluorinated agents

Rationale

Fluorinated glucocorticoids — dexamethasone and triamcinolone — carry higher risk of steroid myopathy than non-fluorinated agents such as prednisone and prednisolone at equivalent anti-inflammatory doses. The fluorine substitution enhances binding to glucocorticoid receptors in muscle tissue and increases activation of ubiquitin ligases (MuRF1 and MAFbx) that target myofibrillar proteins for proteasomal degradation. This structural distinction is clinically relevant when choosing a glucocorticoid for patients at high risk of myopathy or when proximal weakness develops during therapy. Mineralocorticoid potency and prodrug status are not the determinants of myopathy risk.

Correct Answer

C — Glucocorticoids suppress endothelial nitric oxide synthase, reducing nitric oxide-mediated vasodilation and increasing vascular tone

Rationale

Glucocorticoid-induced hypertension arises through multiple parallel vascular and renal mechanisms. Beyond the mineralocorticoid overflow producing sodium retention in the distal nephron, glucocorticoids suppress endothelial nitric oxide synthase expression, reducing the production of nitric oxide — the primary endothelial vasodilator. Lower nitric oxide bioavailability increases resting vascular tone and reduces the vasodilatory response to physiological stimuli. Glucocorticoids also increase vascular sensitivity to vasopressors (angiotensin II and catecholamines) by upregulating their receptors on vascular smooth muscle, further raising blood pressure through distinct mechanisms. The combined effect of volume expansion, reduced vasodilation, and enhanced vasopressor sensitivity produces clinically significant hypertension.

Correct Answer

B — Glucocorticoid receptor activation in lens epithelial cells promotes protein aggregate accumulation in the posterior subcapsular region, with risk correlating with cumulative lifetime dose

Rationale

Posterior subcapsular cataract develops through glucocorticoid receptor-dependent effects on lens epithelial cells that promote protein aggregate accumulation specifically in the posterior subcapsular region. The mechanism is distinct from nuclear cataracts and does not require hyperglycemia — it occurs with topical, inhaled, and intranasal glucocorticoids as well as systemic agents. Risk correlates with cumulative lifetime dose more than current dose, meaning even periods of low-dose therapy contribute. Early presentation is glare and difficulty with night driving (posterior opacities scatter incoming light); central vision is preserved until late stages. Baseline slit-lamp examination before therapy anticipated to exceed 6 months is recommended.

Correct Answer

D — Stopping denosumab causes rapid rebound bone loss because RANKL suppression ends and osteoclast activity surges; transition to a bisphosphonate before stopping is required

Rationale

Denosumab suppresses osteoclast activity by neutralizing RANKL with each injection. Unlike bisphosphonates, which are incorporated into bone and provide residual antiresorptive activity after discontinuation, denosumab's effect fully wanes when antibody levels fall between doses (approximately 6-month half-effect). Stopping denosumab abruptly allows RANKL levels to rebound, producing a surge in osteoclast activity and rapid bone loss — including multiple vertebral fractures in some patients. To prevent this rebound, transition to a bisphosphonate (typically oral alendronate or intravenous zoledronic acid) is initiated before stopping denosumab. Adrenal insufficiency is not a risk of denosumab discontinuation.

Correct Answer

A — Alendronate 70 mg weekly, because bisphosphonates are first-line for medium fracture risk in patients initiating prolonged glucocorticoid therapy

Rationale

For patients initiating glucocorticoid therapy anticipated to last 3 or more months, bisphosphonates are first-line bone-protective agents when fracture risk is medium or high — defined as a FRAX-adjusted 10-year major fracture probability above 10 to 20%. This patient's adjusted probability of 14% falls in the medium-risk range, warranting alendronate 70 mg weekly (or risedronate 35 mg weekly as an alternative). Teriparatide is reserved for very high fracture risk (probability greater than 20% or multiple vertebral fractures already present). Denosumab is an alternative when bisphosphonates are contraindicated, not first-line. Bone mineral density alone does not determine the treatment threshold — fracture risk assessment is required because glucocorticoids impair bone quality beyond what density measurements capture.

Correct Answer

C — Glucocorticoids upregulate hepatic lipogenic enzymes, increase free fatty acid flux from glucocorticoid-stimulated lipolysis in adipose tissue, and reduce low-density lipoprotein receptor expression, raising cholesterol and triglycerides

Rationale

Glucocorticoid-induced dyslipidemia results from convergent mechanisms driven by glucocorticoid receptor transactivation. In the liver, upregulation of lipogenic enzymes increases very low-density lipoprotein assembly and triglyceride production. In adipose tissue, glucocorticoid-stimulated lipolysis releases free fatty acids that flow to the liver as substrate for further lipogenesis. Reduced low-density lipoprotein receptor expression impairs hepatic clearance of circulating low-density lipoprotein. Together these raise total cholesterol, low-density lipoprotein, and triglycerides — the characteristic triad. Lipid monitoring at baseline and every 3 months is recommended for patients on long-term therapy above a prednisone equivalent of 7.5 mg per day.

Correct Answer

B — Both prednisone and ibuprofen independently suppress prostaglandin-mediated gastric mucosal defense, and their combination produces a multiplicative increase in peptic ulcer risk requiring proton pump inhibitor prophylaxis

Rationale

This is a pharmacodynamic drug interaction, not a pharmacokinetic one. Ibuprofen suppresses cyclooxygenase-1, reducing prostaglandin E2 synthesis and impairing mucus and bicarbonate secretion that protect the gastric epithelium. Glucocorticoids suppress phospholipase A2 via annexin-A1 induction and repress cyclooxygenase-2 via nuclear factor kappa-B inhibition, further limiting prostaglandin availability for mucosal defense. Each drug alone increases ulcer risk approximately 3-fold; together the risk rises approximately 15-fold. Proton pump inhibitor prophylaxis should have been prescribed when this combination was initiated. Prednisone does not inhibit CYP2C9 or stimulate parietal cell H2 receptors, and plasma protein displacement is not clinically significant for this interaction.

Correct Answer

D — Trimethoprim-sulfamethoxazole, because prednisone 25 mg daily for more than 4 weeks exceeds the dose-duration threshold at which Pneumocystis jirovecii pneumonia prophylaxis is indicated

Rationale

Pneumocystis jirovecii pneumonia prophylaxis with trimethoprim-sulfamethoxazole (one double-strength tablet three times weekly) is indicated when prednisone equivalent exceeds 20 mg per day for more than 4 weeks in glucocorticoid monotherapy. At this dose-duration threshold, cell-mediated immunity impairment is sufficient to allow Pneumocystis jirovecii opportunistic infection. This patient has been on prednisone 25 mg daily for 8 weeks, clearly exceeding both parameters. Alendronate for bone protection is appropriate but requires 3 months of anticipated therapy as the threshold, and fracture risk assessment first. Isoniazid is required only for patients with risk factors for latent tuberculosis — not universally. Omeprazole is indicated for patients concurrently taking both glucocorticoids and nonsteroidal anti-inflammatory drugs, not for glucocorticoids alone.