Cardiovascular Pharmacology - USMLE Step 1

1. This adverse effect is most characteristic of a drug with which of the following mechanisms?
   Answer: Peripheral α1-adrenergic blockade The patient is experiencing first-dose orthostatic hypotension, a classic side effect of α1-adrenergic blockers such as prazosin, terazosin, and doxazosin. These drugs are used for both hypertension and BPH. By blocking α1 receptors on vascular smooth muscle, they cause both arteriolar and venous dilation. The venodilation leads to peripheral pooling of blood, reducing venous return and causing a sharp drop in blood pressure upon standing. This effect is most pronounced with the first dose.
2. Which of the following drugs was most likely administered?
   Answer: Lidocaine Lidocaine is a Class IB antiarrhythmic agent. Class IB drugs exhibit 'use-dependence,' meaning they have a high affinity for sodium channels in the open or inactivated states, but low affinity for channels in the resting state. Ischemic myocardium is partially depolarized, which means more sodium channels are in the inactivated state. This makes lidocaine particularly effective for arrhythmias arising from ischemic tissue, such as post-MI ventricular tachycardia. Its rapid dissociation kinetics mean it has little effect on the QRS complex at normal heart rates. Flecainide (Class IC) and Procainamide (Class IA) have slower kinetics and widen the QRS.
3. The patient's digoxin toxicity is most likely exacerbated by which of the following factors?
   Answer: Hypokalemia induced by furosemide The patient is presenting with classic signs of digoxin toxicity (gastrointestinal upset, visual changes, arrhythmias). Digoxin works by inhibiting the Na+/K+-ATPase pump. Potassium and digoxin compete for the same binding site on this pump. Hypokalemia, a common side effect of loop diuretics like furosemide, reduces the competition for binding sites, allowing for increased digoxin binding and leading to enhanced therapeutic and toxic effects. While renal impairment (which can be worsened by ACE inhibitors) also increases the risk of digoxin toxicity by reducing its clearance, the presence of severe hypokalemia is a direct and potent precipitating factor.
4. The medication responsible for these findings primarily exerts its effects by blocking which of the following?
   Answer: L-type calcium channels in the heart and smooth muscle The combination of rate control in atrial fibrillation, first-degree AV block, and constipation points to a non-dihydropyridine calcium channel blocker, such as verapamil or diltiazem (with verapamil being more known for causing constipation). These drugs block L-type calcium channels in cardiac tissue (slowing AV conduction) and in smooth muscle (causing vasodilation and decreased gut motility). Beta-blockers (A) can cause AV block but do not typically cause constipation. Anticholinergics (C) cause constipation but would cause tachycardia. Digoxin (D) can cause AV block but is more associated with nausea/vomiting than constipation.
5. The medication responsible for this ECG finding most likely acts by blocking which of the following ion channels?
   Answer: Potassium channels Significant QT prolongation is a hallmark effect of Class III antiarrhythmic drugs (e.g., amiodarone, sotalol, dofetilide, ibutilide). These drugs primarily block the delayed rectifier potassium channels responsible for phase 3 repolarization of the cardiac action potential. This prolongs the action potential duration and, consequently, the QT interval on the ECG, increasing the risk for early afterdepolarizations and torsades de pointes. Sodium channel blockers (Class I) primarily affect the QRS duration. Calcium channel blockers (Class IV) primarily affect the PR interval. Funny current blockers (ivabradine) slow the heart rate without affecting the QT interval.
6. Which of the following is the primary mechanism of action of this medication for treating her hypertension?
   Answer: Blockade of voltage-gated L-type calcium channels The patient's side effects, gingival hyperplasia and peripheral edema, are characteristic of dihydropyridine calcium channel blockers (e.g., amlodipine, nifedipine). These drugs act by blocking L-type calcium channels on vascular smooth muscle, leading to arteriolar vasodilation. This reduces systemic vascular resistance and blood pressure. Non-dihydropyridine calcium channel blockers (e.g., verapamil, diltiazem) have a greater effect on the heart, decreasing the SA node firing rate, but are less associated with these specific side effects. Nitrates increase cGMP. Thiazide diuretics inhibit sodium reabsorption in the distal convoluted tubule.
7. The primary survival benefit of adding spironolactone in this patient is attributed to preventing which of the following long-term pathologic changes?
   Answer: Myocardial fibrosis and remodeling Spironolactone is a mineralocorticoid receptor antagonist (MRA). In heart failure, aldosterone levels are elevated and contribute to disease progression. While spironolactone is a potassium-sparing diuretic and helps with fluid and electrolyte balance, its major survival benefit in HFrEF comes from blocking the non-epithelial effects of aldosterone on the heart and blood vessels. Aldosterone promotes myocardial fibrosis, inflammation, and adverse ventricular remodeling. By blocking these effects, MRAs improve long-term outcomes in HFrEF.
8. The medication most likely belongs to which class of antiarrhythmics?
   Answer: Class IC Class IC antiarrhythmics, such as flecainide and propafenone, are potent sodium channel blockers with slow dissociation kinetics. They are very effective at suppressing ventricular ectopy. However, the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that these drugs increase mortality in patients with underlying structural heart disease, such as a prior myocardial infarction, due to a significant proarrhythmic risk. Therefore, their use is contraindicated in this patient population. Class IB agents (e.g., lidocaine) are safer in the post-MI setting.
9. The administered drug exerts its therapeutic effect by activating which of the following?
   Answer: Gi-coupled purinergic receptors leading to K+ channel opening This clinical scenario describes the administration of adenosine for acute termination of paroxysmal supraventricular tachycardia (PSVT). Adenosine has a very short half-life (<10 seconds) and causes transient side effects like flushing and chest pain. It acts on A1 purinergic receptors in the AV node, which are coupled to an inhibitory G protein (Gi). Activation of this pathway opens potassium channels, causing hyperpolarization of the cell membrane and slowing conduction through the AV node, which terminates the reentrant circuit. Acetylcholine acts on M2 receptors (C), but this is not adenosine's mechanism.
10. Which of the following drugs is most likely responsible for this patient's syndrome?
    Answer: Hydralazine The patient's presentation of arthralgias, myalgias, malar rash, and positive anti-histone antibodies is characteristic of drug-induced lupus erythematosus (DILE). Hydralazine, a direct-acting arterial vasodilator, is one of the most common causes of DILE, along with procainamide. The risk is higher in patients who are slow acetylators. Prazosin is an alpha-1 blocker, clonidine is a central alpha-2 agonist, and minoxidil is another direct vasodilator, but they are not strongly associated with DILE.
11. Which of the following medications is most likely responsible for these laboratory findings?
    Answer: Hydrochlorothiazide The constellation of hypokalemia, hypercalcemia, hyperglycemia, and hyperuricemia is characteristic of thiazide diuretics like hydrochlorothiazide. They inhibit the Na-Cl cotransporter in the distal convoluted tubule. In contrast, loop diuretics like furosemide cause hypocalcemia because they inhibit calcium reabsorption in the thick ascending limb. Spironolactone is a potassium-sparing diuretic and would cause hyperkalemia. Lisinopril, an ACE inhibitor, can cause hyperkalemia, particularly in patients with renal insufficiency.
12. The therapeutic effect of this medication is primarily mediated by which of the following intracellular changes?
    Answer: Increased intracellular cyclic GMP The patient was treated with sublingual nitroglycerin for an anginal attack. Nitrates are metabolized to nitric oxide (NO), which stimulates soluble guanylate cyclase to produce cyclic GMP (cGMP). Increased cGMP activates protein kinase G, which leads to the dephosphorylation of myosin light chains in vascular smooth muscle, causing relaxation. This effect is more pronounced on veins than arteries, leading to venodilation, decreased preload, and reduced myocardial oxygen demand. The drop in blood pressure can cause a reflex tachycardia. Increased cAMP is the mechanism of beta-agonists. Decreased calcium is a downstream effect, not the primary mediator.
13. The patient's symptom is most likely a side effect of a drug that acts by which of the following mechanisms?
    Answer: Inhibition of angiotensin-converting enzyme The patient's persistent dry cough is a classic adverse effect of angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril, enalapril). ACE is responsible for the breakdown of bradykinin. Inhibition of ACE leads to an accumulation of bradykinin, which is thought to cause bronchial irritation and cough. Angiotensin II receptor blockers (ARBs) do not affect bradykinin levels and are a suitable alternative for patients who develop an ACE inhibitor-induced cough. Calcium channel blockers can cause peripheral edema and gingival hyperplasia. Loop diuretics inhibit the Na-K-2Cl cotransporter and can cause electrolyte abnormalities.
14. Dobutamine exerts these effects primarily through which of the following mechanisms?
    Answer: Predominant β1-adrenergic agonism Dobutamine is a synthetic catecholamine used as an inotropic agent in acute heart failure and cardiogenic shock. Its primary mechanism is agonism at β1-adrenergic receptors, which increases myocardial contractility and heart rate via the Gs-adenylyl cyclase-cAMP pathway. This leads to an increase in cardiac output. Dobutamine also has weak β2-agonist activity, which results in mild vasodilation and a decrease in systemic vascular resistance (afterload reduction). It has negligible α1-agonist effects. Milrinone inhibits phosphodiesterase.
15. The new medication most likely works by which of the following mechanisms?
    Answer: Selectively blocking the angiotensin II type 1 (AT1) receptor The patient was switched from an ACE inhibitor (lisinopril) to an angiotensin II receptor blocker (ARB) like losartan or valsartan. ACE inhibitors (mechanism A) block the enzyme that converts angiotensin I to angiotensin II but also block the breakdown of bradykinin, leading to cough. ARBs directly and selectively block the AT1 receptor, preventing the actions of angiotensin II without affecting bradykinin metabolism. Therefore, they do not cause cough. Beta-blockers can inhibit renin release (B). Spironolactone antagonizes the aldosterone receptor (D).
16. Which of the following best describes the primary renal mechanism of action of this drug?
    Answer: Inhibition of the sodium-glucose cotransporter 2 The medication described is a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., empagliflozin, dapagliflozin). These drugs have emerged as a key therapy for HFrEF, regardless of diabetes status. They work by blocking the SGLT2 transporter in the proximal convoluted tubule, which prevents the reabsorption of filtered glucose and sodium. This leads to glucosuria and an osmotic diuresis, which reduces intravascular volume and preload, contributing to their cardiovascular benefits.
17. The added medication most likely has which of the following mechanisms of action?
    Answer: Blockade of β1-adrenergic receptors Beta-blockers (e.g., carvedilol, metoprolol succinate, bisoprolol) are a cornerstone of HFrEF therapy and improve long-term survival. However, due to their negative inotropic and chronotropic effects, they can cause a transient worsening of heart failure symptoms upon initiation. This is why they are started at a very low dose and titrated slowly. The other agents listed do not typically cause an initial worsening of symptoms. Direct vasodilators (hydralazine/isosorbide dinitrate) reduce preload and afterload. Digoxin is a positive inotrope. Aldosterone antagonists like spironolactone primarily prevent myocardial fibrosis.
18. The drug prescribed has properties of which two Vaughan Williams antiarrhythmic classes?
    Answer: Class II and Class III The drug described is sotalol. Sotalol is a unique antiarrhythmic agent that has properties of both Class II (beta-blockade) and Class III (potassium channel blockade). The beta-blocking (Class II) activity is responsible for the bradycardia. The potassium channel blocking (Class III) activity prolongs repolarization and the action potential duration, which manifests as QT prolongation on the ECG. This dual action makes it useful for treating both supraventricular and ventricular arrhythmias. No other option correctly combines these two specific effects.
19. The sacubitril component of this medication improves cardiac function primarily by increasing the levels of which of the following substances?
    Answer: Atrial natriuretic peptide Sacubitril is a neprilysin inhibitor. Neprilysin is an endopeptidase that degrades several endogenous vasoactive peptides, including natriuretic peptides (ANP, BNP), bradykinin, and angiotensin II. By inhibiting neprilysin, sacubitril increases the levels of natriuretic peptides. ANP and BNP promote vasodilation, natriuresis, and diuresis, which counteracts the maladaptive neurohormonal activation in heart failure. Because neprilysin inhibition also increases angiotensin II, it must be co-administered with an angiotensin receptor blocker (ARB) like valsartan.
20. Which of the following is the mechanism of action of the administered drug?
    Answer: Inhibition of phosphodiesterase-3 The drug described is a phosphodiesterase-3 (PDE3) inhibitor, such as milrinone. These drugs are inodilators. By inhibiting the breakdown of cAMP, they increase intracellular cAMP levels in both cardiac myocytes (increasing contractility, or inotropy) and vascular smooth muscle (causing vasodilation, which reduces afterload). This combination is useful in cardiogenic shock. Dobutamine (B) is a β1-agonist. Levosimendan (C) is a calcium sensitizer. Digoxin (D) inhibits the Na+/K+-ATPase pump and is not used as an infusion for acute shock.

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