Cardiovascular Physiology and Pharmacology Flashcards

A patient with severe aortic stenosis undergoes induction of anaesthesia. Despite fluid loading, cardiac output remains critically low. Which haemodynamic mechanism best explains why vasopressor use with predominantly alpha-1 agonist activity may paradoxically worsen coronary perfusion in this context?

Answer: Increased afterload elevates LV end-diastolic pressure, reducing the coronary perfusion pressure gradient across the already critically thickened LV wall

In severe aortic stenosis, the hypertrophied LV operates near maximal wall stress. Increasing afterload with a pure alpha-1 agonist raises LV systolic and end-diastolic pressure (LVEDP). Since coronary perfusion pressure = aortic diastolic pressure − LVEDP, and transmural perfusion is compromised by high intramyocardial pressure in the thick wall, LVEDP elevation can critically reduce subendocardial perfusion even if aortic diastolic pressure rises modestly. The net coronary driving gradient worsens.

During cardiopulmonary bypass, a patient receives protamine to reverse heparin. Pulmonary artery pressure rises from 22/10 to 54/30 mmHg and systemic arterial pressure falls sharply. Complement activation is confirmed. Which receptor pathway is the PRIMARY mediator of the pulmonary vasoconstriction in this protamine reaction?

Answer: Thromboxane A2 receptors on pulmonary vascular smooth muscle, activated by TXA2 released from complement-triggered platelet and macrophage activation

Protamine-heparin complexes activate complement via the classical pathway, generating C3a and C5a. These anaphylatoxins trigger pulmonary intravascular macrophages and platelets to release thromboxane A2 (TXA2). TXA2 binds TP receptors on pulmonary vascular smooth muscle causing intense vasoconstriction — the dominant mechanism in complement-mediated protamine pulmonary hypertension. Histamine contributes to systemic vasodilation rather than pulmonary vasoconstriction. ET-1 elevation is slower and not the acute mediator. Catecholamine surge is secondary.

A 68-year-old patient on long-term amiodarone therapy requires urgent surgery. Intraoperatively, refractory hypotension occurs despite high-dose noradrenaline. Which pharmacokinetic and pharmacodynamic property of amiodarone MOST directly explains the catecholamine resistance?

Answer: Amiodarone's active metabolite desethylamiodarone causes non-competitive antagonism at beta-adrenoceptors and partial alpha-adrenoceptor blockade, persisting due to the drug's extremely long half-life of 40–55 days

Amiodarone and its primary active metabolite desethylamiodarone exhibit non-competitive (insurmountable) beta-blockade and partial alpha-blockade. Because amiodarone has an exceptionally long half-life (40–55 days) and large volume of distribution (60 L/kg), these adrenoceptor-blocking effects persist for weeks to months after discontinuation. This renders standard doses of catecholamines ineffective, requiring vasopressin (V1 receptor, bypassing adrenoceptors) or methylene blue (inhibits NO synthase/guanylate cyclase) as rescue vasopressors. CYP2D6 involvement, calcium channel blockade, and thyroid effects are real but not the dominant cause of acute catecholamine resistance.

In a patient with hypertrophic obstructive cardiomyopathy (HOCM) under general anaesthesia, acute systemic hypotension occurs. A registrar administers phenylephrine (200 mcg IV bolus). Five minutes later, the patient develops syncope with LVOT gradient increasing from 40 to 110 mmHg. What is the most likely explanation?

Answer: Phenylephrine's alpha-1-mediated increase in SVR reduced forward flow, but the simultaneous negative chronotropic effect increased time for systolic anterior motion (SAM) to develop

Phenylephrine, a pure alpha-1 agonist, raises SVR and arterial pressure — which is generally desirable in HOCM to increase afterload and reduce obstruction. However, via baroreceptor reflex, it causes significant reflex bradycardia. The prolonged diastolic filling time increases LV end-diastolic volume, and the slower heart rate increases time available per systole for SAM to develop. Paradoxically, in a setting of already elevated contractility, the combination of reflex bradycardia + increased preload may worsen the dynamic obstruction. While the increase in SVR helps, the net effect in this case was worsening. This subtle interaction is clinically important: phenylephrine is still preferred over vasodilators, but the reflex bradycardia component can worsen dynamic obstruction.

During management of a patient with acute right heart failure following massive pulmonary embolism, inhaled nitric oxide (iNO) is commenced. Despite iNO at 20 ppm, pulmonary vascular resistance remains elevated. An intensivist adds intravenous sildenafil. What is the pharmacological rationale for this combination's potential superiority over either agent alone?

Answer: Sildenafil inhibits PDE-5, preventing breakdown of cGMP generated by iNO-stimulated guanylate cyclase, amplifying and prolonging pulmonary vasodilation; selectivity is maintained because iNO is inactivated by haemoglobin before reaching systemic circulation

iNO activates soluble guanylate cyclase in pulmonary smooth muscle, increasing cGMP and causing vasodilation. PDE-5 (the dominant phosphodiesterase in pulmonary vasculature) rapidly hydrolyses cGMP, limiting the effect. Sildenafil selectively inhibits PDE-5, preserving cGMP — thus synergistically potentiating the effect of iNO. The pulmonary selectivity of the combination is maintained because iNO is rapidly scavenged by oxyhaemoglobin in the pulmonary capillaries before reaching the systemic circulation. Sildenafil is not a NO donor; PDE-5 inhibition does not acutely upregulate eNOS; and sildenafil does not act on adenylate cyclase.

A patient with end-stage heart failure (EF 15%) is on maximally tolerated carvedilol, sacubitril/valsartan, and eplerenone. Invasive haemodynamic monitoring shows: CI 1.4 L/min/m², PCWP 28 mmHg, SVR 2200 dyn·s·cm⁻⁵. Milrinone infusion is started. Despite an initial improvement, after 72 hours CI falls back to 1.5 L/min/m² and arrhythmias develop. Which molecular mechanism MOST accurately explains tachyphylaxis to milrinone in this clinical context?

Answer: Chronic cAMP elevation activates CaMKII, which phosphorylates RyR2 at Ser2814, increasing diastolic SR calcium leak and causing both reduced contractility and triggered arrhythmias

In the failing heart, sustained elevations in cAMP (whether from milrinone or catecholamines) chronically activate CaMKII (calmodulin-dependent protein kinase II). CaMKII phosphorylates the ryanodine receptor 2 (RyR2) at Ser2814, causing pathological spontaneous diastolic calcium release from the SR. This depletes SR calcium load (reducing contractility = tachyphylaxis) and produces delayed afterdepolarisations (DADs) that trigger ventricular arrhythmias — a well-recognised hazard of long-term milrinone use in ambulatory heart failure (as seen in the PROMISE trial). Beta-receptor downregulation is a real phenomenon but is driven by upstream PKA, not the primary cause of 72-hour tachyphylaxis. Option B is mechanistically inverted (milrinone increases phospholamban phosphorylation). Option D is not a recognised mechanism.