Cardiovascular Physiology and Pharmacology Flashcards

A 58-year-old patient on chronic amiodarone therapy undergoes elective surgery. Intraoperatively, refractory vasodilatory hypotension develops despite adequate fluid resuscitation and norepinephrine at 0.3 mcg/kg/min. Which mechanism best explains amiodarone's contribution to this vasopressor resistance?

Answer: Competitive antagonism at α1-adrenergic receptors reducing norepinephrine efficacy

Amiodarone and its active metabolite desethylamiodarone exert non-competitive and competitive α1-adrenergic receptor antagonism in vascular smooth muscle. This direct α-blockade reduces the vasoconstrictive response to exogenous catecholamines such as norepinephrine, resulting in vasopressor resistance. While amiodarone does have calcium channel blocking properties and can affect thyroid function, the acute intraoperative vasopressor resistance is primarily mediated through α1-receptor antagonism. Vasopressin, which acts via V1 receptors independently of adrenergic pathways, is the preferred rescue agent in this scenario.

During cardiac surgery requiring deep hypothermic circulatory arrest at 18°C, which of the following best describes the relationship between myocardial oxygen consumption (MVO₂) and temperature according to the Q10 effect?

Answer: MVO₂ decreases by approximately 50% for every 10°C reduction, so cooling from 37°C to 18°C reduces MVO₂ to roughly 12.5% of normothermic baseline

The Q10 effect describes that metabolic rate (including MVO₂) approximately halves for every 10°C reduction in temperature. Cooling from 37°C to 27°C reduces MVO₂ to ~50%; from 27°C to 17°C reduces it to ~50% again, i.e., 25% of baseline. At 18°C (approximately 19°C drop), MVO₂ is reduced to roughly 12-13% of normothermic baseline. This is why deep hypothermia provides substantial myocardial protection during prolonged circulatory arrest. Mitochondrial activity is not zero below 20°C—it is greatly diminished but still present—and the reduction is exponential, not linear.

A patient with severe aortic stenosis (valve area 0.6 cm², mean gradient 55 mmHg) is undergoing non-cardiac surgery under general anesthesia. Heart rate acutely increases to 130 bpm. Which hemodynamic consequence is MOST immediately life-threatening in this specific valvular pathology?

Answer: Reduced coronary perfusion pressure due to shortened diastole with simultaneous increased subendocardial oxygen demand from tachycardia

In severe aortic stenosis, the hypertrophied left ventricle has markedly increased oxygen demand at baseline and critically depends on diastolic coronary perfusion. Tachycardia shortens diastole disproportionately, reducing coronary filling time while simultaneously increasing MVO₂. The pressure-overloaded, non-compliant LV has elevated systolic wall stress and requires higher perfusion pressure to maintain subendocardial flow. This creates a lethal mismatch—increased demand and decreased supply—that can precipitate subendocardial ischemia, ventricular fibrillation, and cardiovascular collapse within minutes. While loss of atrial kick and elevated LVEDP are important chronic features of AS, the acute tachycardia-induced ischemic imbalance is the most immediately lethal consequence.

Which of the following most accurately explains why milrinone produces a greater increase in heart rate than dobutamine at equi-inotropic doses in patients with decompensated heart failure?

Answer: Milrinone lacks β1-receptor agonism and therefore does not activate baroreceptor-mediated reflex bradycardia to counteract its tachycardic effect from peripheral vasodilation

Both milrinone and dobutamine increase heart rate through elevated intracellular cAMP. However, dobutamine directly stimulates β1-receptors in the SA node for its chronotropic effect but simultaneously activates β1-receptors in the myocardium improving contractility and cardiac output, which partially restores arterial pressure—thus triggering baroreceptor-mediated reflex parasympathetic activity (vagal tone increase) that opposes tachycardia. Milrinone, acting downstream of receptors via PDE-3 inhibition, bypasses receptor-level regulation and causes peripheral vasodilation that reduces afterload and mean arterial pressure, eliciting reflex sympathetic activation (increased HR) without the receptor-level counterbalancing. The net effect is greater tachycardia with milrinone relative to equivalent inotropic doses of dobutamine, particularly in patients with impaired baroreflex sensitivity.

A 72-year-old patient with chronic kidney disease (eGFR 18 mL/min) and chronic heart failure (EF 30%) is started on sacubitril/valsartan (Entresto). Four weeks later, she develops marked angioedema. Which pharmacological mechanism specifically makes this combination uniquely dangerous regarding bradykinin metabolism?

Answer: Neprilysin inhibition by sacubitril prevents bradykinin degradation while valsartan's AT1 blockade increases bradykinin synthesis by removing angiotensin II-mediated suppression of kallikrein, creating a dual augmentation of bradykinin levels

Sacubitril/valsartan (ARNI) has a unique dual mechanism affecting bradykinin: (1) Sacubitril inhibits neprilysin, which is one of the enzymes responsible for degrading bradykinin (along with ACE and aminopeptidase P). Neprilysin inhibition alone increases bradykinin levels. (2) Valsartan blocks AT1 receptors; normally, angiotensin II acting on AT1 receptors suppresses kallikrein activity and thus bradykinin synthesis. AT1 blockade removes this inhibition, increasing kallikrein activity and thus bradykinin production. The combination therefore simultaneously increases bradykinin synthesis AND decreases its degradation. This is why ARNIs carry a substantially higher risk of angioedema than either ARBs or neprilysin inhibitors alone, and why prior ACE inhibitor use is a contraindication (ACE is another major bradykinin-degrading enzyme).

During a Valsalva maneuver performed for diagnostic purposes, a patient with hypertrophic obstructive cardiomyopathy (HOCM) exhibits paradoxical worsening of symptoms during Phase II (straining phase) and dramatic improvement during Phase IV (overshoot). Which hemodynamic sequence best explains this pattern?

Answer: Phase II reduces venous return and LV cavity size, increasing dynamic LVOT obstruction; Phase IV overshoot increases LV preload via the reflex tachycardia and increased venous return, enlarging the LV cavity and reducing the dynamic gradient

In HOCM, the severity of dynamic LVOT obstruction is exquisitely sensitive to LV cavity size—smaller cavities worsen obstruction. During Valsalva Phase II (sustained straining), elevated intrathoracic pressure impedes venous return, reducing LV preload and end-diastolic volume. The smaller LV cavity causes the hypertrophied septum and anterior mitral leaflet (systolic anterior motion—SAM) to approximate more closely, dramatically worsening the dynamic gradient and murmur. During Phase IV overshoot, the release of straining triggers a surge in venous return augmented by reflex sympathetic tachycardia and increased cardiac output, rapidly filling the LV. This increased LV preload enlarges the cavity, physically separating the obstruction elements and reducing the gradient—explaining the dramatic symptom improvement. This is the physiological basis of the 'Valsalva test' being pathognomonic for HOCM.