PH7.1-9 | Endocrine Pharmacology — Graded Quiz

Correct. Metformin activates AMP-activated protein kinase (AMPK) in hepatocytes, which suppresses gluconeogenesis (the major source of fasting hyperglycaemia in T2DM). It also improves peripheral insulin sensitivity.

Metformin mechanism mnemonic: AMPK → blocks AMPle gluconeogenesis. It is insulin-independent (no hypoglycaemia), weight-neutral, and first-line for T2DM.

Incorrect. Metformin does not stimulate insulin secretion (hence no hypoglycaemia), does not block renal glucose reabsorption (that is SGLT2 inhibitors), and does not inhibit intestinal alpha-glucosidase (that is acarbose). Its primary action is AMPK-mediated suppression of hepatic gluconeogenesis.

Correct. Insulin degludec (Tresiba) has the longest duration of action among available insulins — up to 42 hours — with an ultra-flat, peakless profile. It provides more stable basal coverage and lower nocturnal hypoglycaemia risk than glargine U100.

Insulin duration hierarchy: rapid (3–5 hr) → short/regular (6–8 hr) → intermediate/NPH (12–20 hr) → long/glargine/detemir (20–24 hr) → ultra-long/degludec (up to 42 hr).

Incorrect. Aspart is rapid-acting (3–5 hr duration); regular insulin is short-acting (6–8 hr); NPH is intermediate (12–20 hr with a peak). Degludec is the ultra-long-acting analogue.

Correct. DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin — collectively 'gliptins') block the enzyme that rapidly degrades GLP-1 and GIP, thereby prolonging incretin action. They are weight-neutral and have a low hypoglycaemia risk.

Incretin drugs: DPP-4 inhibitors (gliptins) block DPP-4 enzyme → prolong endogenous GLP-1 → modest HbA1c lowering (~0.5-1%). GLP-1 RAs act directly on GLP-1R → stronger HbA1c lowering + weight loss + CV benefit.

Incorrect. Sulfonylureas close K-ATP channels on β-cells (insulin-independent of GLP-1). GLP-1 receptor agonists are injectable drugs that directly activate the GLP-1 receptor — they do not inhibit DPP-4. SGLT2 inhibitors act on the renal proximal tubule.

Correct. Nitrogen-containing bisphosphonates (alendronate, risedronate, zoledronate) inhibit farnesyl pyrophosphate synthase (FPPS) — an enzyme in the mevalonate pathway within osteoclasts. This prevents prenylation of small GTPases (Rac, Rho, Ras), disrupting the osteoclast cytoskeleton and inducing apoptosis, thereby reducing bone resorption.

Bisphosphonate mechanism: bind hydroxyapatite at bone resorption sites → osteoclast internalises the drug → FPPS inhibition → osteoclast apoptosis. Anti-resorptive, not anabolic. Denosumab (anti-RANK-L) is the alternative anti-resorptive.

Incorrect. Bisphosphonates are anti-resorptive — they reduce osteoclast activity, they do not stimulate osteoblasts (that is teriparatide/PTH analogues). RANK-L blockade is the mechanism of denosumab (a monoclonal antibody), not bisphosphonates.

Correct. Carbimazole is the preferred thionamide outside pregnancy. It is a prodrug converted to methimazole, has a longer duration allowing once-daily dosing, and has a better safety profile than PTU in the long-term. PTU is preferred only in the first trimester of pregnancy (due to carbimazole's teratogenicity) and in thyroid storm (due to its additional T4→T3 peripheral conversion block).

Thionamide selection: carbimazole = standard (non-pregnant adults, children from T2 of pregnancy). PTU = first trimester of pregnancy + thyroid storm. Both can cause agranulocytosis — counsel patients to seek urgent review for any fever/sore throat.

Incorrect. Both carbimazole and PTU can cause agranulocytosis (rare, ~0.3%). PTU's apparent advantage of blocking peripheral T4→T3 conversion is modest in clinical practice and outweighed by its higher hepatotoxicity risk with long-term use. PTU requires thrice-daily dosing due to its short half-life.

Correct. Dexamethasone has the highest glucocorticoid potency of commonly used systemic corticosteroids (25–30× hydrocortisone). Crucially, it has negligible mineralocorticoid activity — it does NOT cause sodium retention. This makes it ideal for conditions where high anti-inflammatory potency without fluid retention is needed (cerebral oedema, ARDS, COVID-19 severe, antenatal lung maturation).

Potency table must-know: HC(1) → Pred(4) → MePred(5) → Dexa(25-30). Dexamethasone = zero mineralocorticoid. Fludrocortisone = high mineralocorticoid, NOT anti-inflammatory use.

Incorrect. Potency order (approximate, GC relative to hydrocortisone=1): hydrocortisone (1) → prednisolone (4) → methylprednisolone (5) → dexamethasone/betamethasone (25–30). Fludrocortisone has GC potency ~10 but is used almost exclusively for its mineralocorticoid activity (MC potency = 150–200).

Correct. After failure of anti-resorptive therapy (bisphosphonates or denosumab) in severe osteoporosis, teriparatide (PTH 1-34 analogue) provides anabolic stimulation — increasing osteoblast activity to build new bone. It is the agent of choice when anti-resorptive drugs are insufficient. Duration is 24 months (lifetime maximum), after which an anti-resorptive must be prescribed to prevent rebound bone loss.

Osteoporosis escalation: after bisphosphonate/anti-resorptive failure → teriparatide (anabolic, 24 months max) → must follow with anti-resorptive to prevent rebound bone loss. Sequence rule: anti-resorptive → anabolic (ok) vs anabolic → anti-resorptive (mandatory after teriparatide).

Incorrect. Denosumab is anti-resorptive (different mechanism — RANK-L antibody vs bisphosphonate FPPS inhibition) but still only reduces further bone loss; it does not rebuild lost bone. Increasing alendronate dose is not standard and does not improve outcome. Calcitonin is a weak anti-resorptive used for acute pain — not for treating refractory osteoporosis.

Correct. Sildenafil inhibits PDE5 (the enzyme that degrades cGMP) → increased cGMP → smooth muscle relaxation in corpora cavernosa. Nitrates act by donating NO → activating guanylyl cyclase → increasing cGMP. The combination causes synergistic and potentially fatal hypotension — sildenafil is absolutely contraindicated with all nitrates (GTN, isosorbide mononitrate/dinitrate).

Sildenafil-nitrate interaction: PDE5 inhibition + NO donation → cGMP accumulation → severe hypotension. Time rule: avoid nitrates within 24 hours of sildenafil; within 48 hours of tadalafil. Inform all patients — including those who get GTN spray for angina.

Incorrect. Sildenafil does NOT synthesise cGMP — it prevents its breakdown by inhibiting PDE5. There is no safe combination with nitrates regardless of clinical stability — the interaction is absolute and life-threatening. The contraindication in retinitis pigmentosa is due to PDE6 inhibition in the retina (not dopamine).

Correct. The PRIMARY mechanism of COCs is suppression of the LH surge, thereby preventing ovulation. Oestrogen suppresses FSH (inhibiting follicular development) and progestogen suppresses the LH surge. Secondary mechanisms — cervical mucus thickening and endometrial thinning — provide backup contraceptive efficacy but are not the primary mode of action.

COC mechanisms: (1) Primary — ovulation suppression (oestrogen ↓FSH + progestogen ↓LH surge); (2) Secondary — cervical mucus thickening (progestogen); (3) Tertiary — endometrial thinning. All three together give >99% effectiveness with perfect use.

Incorrect. While cervical mucus thickening and endometrial changes contribute to efficacy, the dominant contraceptive mechanism is ovulation suppression via HPO axis negative feedback. COCs have no cytotoxic effect on sperm.

Correct. The WHO PPH uterotonic escalation is: (1) Oxytocin first → (2) Ergometrine (or combined syntometrine) → (3) Carboprost (15-methyl PGF2α, Hemabate) IM → (4) Misoprostol rectal. Carboprost, a prostaglandin F2α analogue, produces powerful sustained uterine contraction and is the next agent when oxytocin + ergometrine have failed. Atosiban and nifedipine are tocolytics (uterine relaxants) — they would worsen PPH.

PPH uterotonic sequence: Oxytocin → Ergometrine → Carboprost (PGF2α) → Misoprostol rectal. Logic: Oxytocin = fast/titratable → Ergometrine = tetanic sustained → Carboprost = powerful PG → Misoprostol = heat-stable PG for resource-limited settings. Each step provides a different receptor mechanism.

Incorrect. Misoprostol (sublingual or rectal) is a prostaglandin E1 analogue used in resource-limited settings or as a later alternative. In full hospital settings with failed oxytocin + ergometrine, carboprost (prostaglandin F2α analogue) is the next escalation. Atosiban and nifedipine are tocolytics — absolutely contraindicated in PPH.

Correct. Nifedipine (oral calcium channel blocker) is currently the preferred first-line tocolytic in most guidelines (WHO, RCOG). It blocks L-type calcium channels in myometrial smooth muscle → reduces intracellular calcium → reduced myosin light chain kinase activity → uterine relaxation. It is effective, well-tolerated, oral, and safe for both mother and fetus.

First-line tocolytic: nifedipine (oral, Ca-channel blocker). Remember contraindications for alternatives: ritodrine → pulmonary oedema; indomethacin → avoid after 32 weeks (ductus arteriosus); magnesium → fetal neuroprotection, not tocolysis per se.

Incorrect. Ritodrine (β2-agonist) causes significant maternal tachycardia, hypokalemia, and pulmonary oedema — now largely replaced by nifedipine. Magnesium sulphate is used for fetal neuroprotection in preterm (<32 weeks) but is not first-line for tocolysis. Indomethacin is used before 32 weeks but risks premature closure of the ductus arteriosus.

Correct. Clomiphene citrate is a selective oestrogen receptor modulator (SERM). It acts at the hypothalamus/pituitary to block oestrogen negative feedback — the hypothalamus perceives a 'low-oestrogen' state → increases GnRH pulsatility → pituitary increases FSH secretion → stimulates follicular development and ovulation. This is a central (not ovarian) mechanism.

Clomiphene = SERM at hypothalamus → blocks oestrogen feedback → ↑GnRH/FSH → follicular stimulation. Anti-oestrogenic effect on endometrium (thin lining) and cervical mucus (thick) explains why letrozole (no anti-oestrogenic peripheral effects) is now preferred in PCOS.

Incorrect. Clomiphene does not act on FSH receptors on the ovary (that is gonadotropins acting directly). Aromatase inhibition is the mechanism of letrozole (not clomiphene). Clomiphene does not mimic LH — the LH surge is triggered endogenously once follicular maturation is sufficient.