PH4.1-11 | Cardiovascular and Blood Pharmacology — Graded Quiz

Alpha-1 blockers (prazosin, doxazosin) are NOT first-line antihypertensives. They are reserved as add-on therapy or for patients with benign prostatic hyperplasia. The three recognised first-line classes for uncomplicated hypertension are: thiazide diuretics, ACEi/ARBs, and dihydropyridine CCBs.

Three first-line drug classes for uncomplicated HTN: (1) Thiazide diuretics, (2) ACEi or ARB, (3) Dihydropyridine CCBs. Beta-blockers and alpha-blockers are no longer first-line monotherapy for uncomplicated HTN due to inferior outcomes in trials.

Thiazides, ACEi/ARBs, and dihydropyridine CCBs are all evidence-based first-line antihypertensives.

HFrEF is defined as LVEF < 40%. This is the threshold at which neurohormonal blockade (the four pillars — ACEi/ARNI, beta-blocker, MRA, SGLT2i) provides proven mortality benefit. HFmrEF (mildly reduced) = 40-49%; HFpEF (preserved) ≥ 50%.

EF thresholds: HFrEF < 40% (four-pillar GDMT), HFmrEF 40-49% (some GDMT benefit emerging), HFpEF ≥ 50% (limited pharmacological options beyond SGLT2i). ICD is considered when EF ≤ 35% despite optimal GDMT.

LVEF < 50% is abnormal but not the threshold for HFrEF; <35% is a threshold for ICD implantation (separate from pharmacological GDMT).

Adenosine is not classified in the Vaughan-Williams system. It acts by stimulating A1 receptors in the AV node, increasing K+ conductance and decreasing Ca2+ conductance — resulting in transient AV block that terminates PSVT. Its ultra-short half-life (10-15 seconds) makes it safe and diagnostic.

Drugs outside Vaughan-Williams: Adenosine (A1 receptor), Digoxin (Na/K-ATPase + vagal enhancement). Both slow AV nodal conduction by different mechanisms. Adenosine is the drug of first choice for terminating stable narrow-complex SVT (AVNRT, AVRT). Give as rapid IV push followed immediately by saline flush.

Adenosine does not act via sodium channels, beta-receptors, or potassium channel blockade. It works through its own receptor system distinct from the four Vaughan-Williams classes.

Statins (HMG-CoA reductase inhibitors) competitively block the rate-limiting step of hepatic cholesterol synthesis: conversion of HMG-CoA to mevalonate. Reduced intrahepatic cholesterol upregulates LDL receptor expression, increasing LDL clearance from plasma.

Mechanism memory: Statins → HMG-CoA reductase → ↓liver cholesterol synthesis → ↑LDL receptors → ↓plasma LDL. Downstream consequences: reduced mevalonate also decreases isoprenoids (pleiotropic anti-inflammatory effects). This explains why statins reduce CV events beyond their LDL-lowering effect.

Cholesterol absorption inhibition = ezetimibe. PPAR-alpha activation = fibrates (↑triglyceride clearance, ↑HDL). Bile acid sequestration = cholestyramine, colestipol.

Thiazide diuretics block the NCC (Na-Cl cotransporter) in the DCT. This increases distal delivery of Na+ to the collecting duct, enhancing aldosterone-mediated Na+ reabsorption in exchange for K+ and H+ secretion — resulting in hypokalaemia and metabolic alkalosis. Muscle weakness, fatigue, and cramps are classical symptoms of hypokalaemia.

Thiazide electrolyte profile: ↓K+, ↓Na+, ↓Mg2+, ↑Ca2+, ↑urate, ↑glucose. Contrast with loop diuretics: ↓K+, ↓Na+, ↓Mg2+, ↓Ca2+, ↑urate. Mnemonic: Thiazides — HyperGLUC (↑Glucose, ↑Lipids, ↑Urate, ↑Ca2+); HypoK, HypoMg, HypoNa.

Thiazides cause hyponatraemia (not hypernatraemia), hypokalaemia (not hyperkalaemia), and hypomagnesaemia (not hypermagnesaemia). They cause hypercalcaemia (unlike loop diuretics which cause hypocalcaemia).

GTN is bioactivated to nitric oxide (NO), which activates soluble guanylate cyclase → ↑cGMP → smooth muscle relaxation. The primary anti-anginal effect at low doses is venodilation: pooling of blood in peripheral veins reduces venous return (preload) → reduced left ventricular end-diastolic pressure (LVEDP) → reduced wall tension → ↓myocardial O2 demand. At higher doses, arterial dilation also occurs.

GTN anti-anginal mechanism: (1) Primary: venodilation → ↓preload → ↓LVEDP → ↓O2 demand; (2) Secondary: arterial dilation (coronary + peripheral) at higher doses. Key ADRs: headache (cerebral vasodilation), postural hypotension, reflex tachycardia. Tolerance develops with continuous exposure — nitrate-free intervals of 8-12 hours required.

GTN does not block beta receptors (beta-blockers do) or calcium channels (CCBs do). GTN can cause reflex tachycardia (not bradycardia) due to vasodilation. GTN does relieve coronary spasm but through NO-mediated smooth muscle relaxation, not calcium channel blockade.

UFH therapy is monitored by aPTT. Heparin enhances antithrombin III activity (inhibiting thrombin/factor IIa and factor Xa). This effect prolongs the intrinsic pathway — measured by aPTT. Therapeutic aPTT = 1.5-2.5 times normal (60-100 seconds). Monitor every 6 hours until stable.

Monitoring quick-reference: UFH → aPTT (1.5-2.5× normal); Warfarin → INR (2-3 for VTE/AF, 2.5-3.5 for mechanical valves); LMWH → anti-Xa (usually not needed, but peak anti-Xa 0.6-1.0 IU/mL for therapeutic dosing); DOACs → no routine monitoring. Also monitor UFH platelet count at days 4-14 for HIT.

PT/INR monitors the extrinsic pathway — used for warfarin, not heparin. Anti-Xa levels are used for LMWH (enoxaparin) and are the preferred monitoring method for special populations (renal impairment, obesity, pregnancy) where weight-based LMWH dosing may be unreliable. Platelet count is monitored separately for HIT (heparin-induced thrombocytopenia) but not for UFH anticoagulant effect.

ACEi (and ARBs) are contraindicated in bilateral renal artery stenosis. Both kidneys depend on Ang II-mediated efferent arteriolar vasoconstriction to maintain GFR when afferent arteriolar pressure is low (due to stenosis). Blocking Ang II removes this compensatory mechanism → acute kidney injury. Unilateral renal artery stenosis is a relative contraindication.

ACEi/ARB absolute contraindications: bilateral renal artery stenosis, pregnancy (any trimester), history of ACEi-induced angio-oedema, hereditary angio-oedema. Use with caution in: severe aortic stenosis, CKD with high K+, single functioning kidney. The mechanism: ACEi → ↓Ang II → efferent dilation → ↓GFR in a kidney already dependent on efferent vasoconstriction.

Amlodipine, thiazides, and methyldopa are safe alternatives. Methyldopa is centrally acting (alpha-2 agonist) and is also preferred in pregnancy.

Aspirin irreversibly acetylates the serine residue at the active site of COX-1 (and COX-2). In platelets — which are anucleate — this permanent inhibition of COX-1 prevents thromboxane A2 (TXA2) synthesis throughout the platelet's 7-10 day lifespan. TXA2 is a potent platelet activator and vasoconstrictor. Low-dose aspirin selectively inhibits platelet COX-1 with minimal gastric COX-1 effect.

Aspirin selectivity: at low doses (≤150 mg), preferentially inhibits platelet COX-1 (irreversible, permanent for platelet lifespan); vascular endothelial cells can regenerate COX-2 → prostacyclin (PGI2, anti-aggregatory) production is preserved. Higher doses inhibit both COX-1 and COX-2 — at very high doses, actually opposing effects on platelet aggregation.

COX-2 inhibition is the basis for aspirin's anti-inflammatory/analgesic effect at higher doses. P2Y12 blockade is the mechanism of clopidogrel/ticagrelor. Thrombin receptor blockade is vorapaxar.

Streptokinase is an indirect plasminogen activator derived from beta-haemolytic streptococci. It forms a 1:1 complex with plasminogen, causing a conformational change that exposes the active site. This streptokinase-plasminogen complex then converts free plasminogen to plasmin, which degrades fibrin. Streptokinase is not fibrin-specific — it activates both clot-bound and circulating plasminogen, causing systemic fibrinolysis.

Fibrinolytics comparison: Streptokinase — indirect (via complex formation), not fibrin-specific, antigenic, cheaper. Alteplase (tPA)/Tenecteplase — bind fibrin-bound plasminogen → fibrin-specific, not antigenic, preferred. Contraindications to fibrinolytics: prior haemorrhagic stroke, active bleeding, BP >180/110 after treatment, recent major surgery/trauma, aortic dissection.

Streptokinase does not directly degrade fibrin — it converts plasminogen to plasmin first. It does not affect factor Xa directly. It does not interact with tPA.

This patient has digoxin toxicity (level 2.8 ng/mL — 3× the upper therapeutic limit + GI symptoms + visual symptoms). Stop digoxin immediately. Check K+ (hypokalaemia potentiates toxicity). Monitor ECG for arrhythmias (heart block, VT). If severe toxicity with haemodynamic compromise, administer digoxin-specific antibody fragments (Digibind/DigiFab).

Digoxin toxicity: GI (nausea, vomiting) and neurological (visual halos, xanthopsia — yellow-green vision) symptoms are hallmarks. ECG: PR prolongation → heart block; ST scooping ('reversed tick'); arrhythmias. Risk factors: hypokalaemia (K+ competes with digoxin for Na/K-ATPase), hypomagnesaemia, renal impairment, drug interactions (amiodarone, verapamil, quinidine raise levels). Therapeutic level: 0.5-0.9 ng/mL for HF.

Simply reducing the dose is inappropriate when toxicity symptoms are present. Amiodarone interacts with digoxin, increasing levels. Verapamil also increases digoxin levels and slows AV conduction — dangerous in toxicity.

Hypertensive emergency with end-organ damage requires IV antihypertensive with titratable action. Sodium nitroprusside (SNP) is a direct vasodilator (releases NO; dilates arteries and veins) with immediate onset and cessation — ideal for precise BP titration. Intra-arterial monitoring ensures safe, controlled reduction: aim for 20-25% reduction in MAP in the first hour, then to 160/100 mmHg over next 2-6 hours.

Hypertensive emergency (end-organ damage present) vs urgency (no end-organ damage): Emergency → IV therapy, controlled reduction over hours; Urgency → oral agents, reduction over 24-48 hours. IV agents: nitroprusside, labetalol, nicardipine, hydralazine, phentolamine (phaeochromocytoma). Sublingual nifedipine is banned — causes uncontrolled drops.

Oral agents are too slow for hypertensive emergency. Sublingual nifedipine capsule is contraindicated — causes unpredictable precipitous BP drop leading to ischaemic stroke, MI. Furosemide alone does not adequately lower BP in encephalopathy.