Cardiac Pharm

ECG shows sinus tachycardia with ST segment elevation in leads II, III, and aVF. Medical management for the patient's acute condition is initiated. After initial treatment, the chest pain decreases in intensity and a reperfusion complex ventricular arrhythmia emerges. The arrhythmia is asymptomatic and resolves spontaneously. Which of the following drugs is most likely responsible for rapid reperfusion in this patient?

*Alteplase* This patient had an ST-elevation myocardial infarction (STEMI) and, following medical treatment, experienced symptomatic improvement and reperfusion-related arrhythmia; this is most likely the result of fibrinolytic (thrombolytic) therapy. Fibrinolytic agents (eg, alteplase) are indicated in patients with acute STEMI who cannot receive percutaneous coronary intervention in a timely manner. Administration of these agents leads to breakdown of fibrin clot and often restoration of myocardial perfusion; some patients develop a self-limiting reperfusion-related arrhythmia (most commonly an accelerated idioventricular rhythm). In the fibrinolytic pathway, tissue plasminogen activator (tPA) is released by the endothelium and cleaves plasminogen to form plasmin. Plasmin then acts to both degrade individual fibrinogen molecules and break down fibrin clot that has already formed. The breakdown of fibrin clot leads to elevated levels of fibrin split products (eg, d-dimer) in the blood. Pharmacologic fibrinolytic agents that are used clinically include streptokinase and recombinant forms of tPA (eg, alteplase, tenecteplase). All of these agents inherently increase bleeding risk and are contraindicated in patients with increased risk of bleeding complications (eg, recent hemorrhagic stroke).

A 47yro man w/ muscle weakness and dark urine for the past several days. Two weeks ago, the patient was evaluated for dyspepsia and found to have Helicobacter pylori infection; he was started on treatment and has had partial symptom improvement. Medical history includes hypertension and hyperlipidemia, for which he takes amlodipine and simvastatin. Laboratory evaluation reveals elevated blood urea nitrogen and serum creatinine levels. Urine microscopy shows no red or white blood cells. Which of the following medications most likely precipitated this patient's current condition?

*Clarithromycin* This patient has muscle tenderness and weakness. The dark urine suggests myoglobinuria due to myocyte necrosis. In the context of ongoing statin therapy for hyperlipidemia, this presentation likely represents statin myopathy. Statin myopathy is due, likely at least in part, to decreased myocyte production of coenzyme Q10 (ubiquinone). Serum muscle breakdown markers (eg, creatine kinase) are often elevated, and severe cases may lead to rhabdomyolysis with subsequent acute kidney injury (eg, elevated BUN and creatinine). Statin myopathy is most common in the initial weeks or months of therapy. However, it can occasionally occur later, and can be acutely triggered by medications that increase circulating statin levels. This patient's myopathy is most likely related to the initiation of clarithromycin as part of a multidrug regimen for Helicobacter pylori. Statins, primarily simvastatin, lovastatin, and atorvastatin, are metabolized by CYP3A4. This enzyme can be inhibited by macrolide antibiotics (eg, erythromycin, clarithromycin), leading to increased statin drug levels and subsequent statin myopathy. (Azithromycin does not significantly inhibit CYP3A4.) Other significant CYP3A4 inhibitors that can induce statin myopathy include ketoconazole, non-dihydropyridine calcium channel blockers (eg, diltiazem), amiodarone, and protease inhibitors (eg, ritonavir). Because pravastatin is not primarily metabolized by CYP3A4, patients who must take a CYP3A4 inhibitor may benefit from switching to this drug.

The patient is prescribed metoprolol and is advised that the medication is expected to decrease the frequency of headaches and also lower blood pressure in the long term. Which of the following best explains this medication's effect on blood pressure?

*Dec level of circulating renin* Beta blockers are useful for treating hypertensive patients with comorbid conditions such as migraine, essential tremor, angina pectoris/prior myocardial infarction, and atrial fibrillation. Beta blockers lower blood pressure via 2 mechanisms: 1. Reducing myocardial contractility and heart rate 2. Decreasing renin release by the kidney Renin release is mediated in part through sympathetic stimulation of beta-1 receptors located on juxtaglomerular cells. Therefore, beta-adrenergic blocking drugs (eg, metoprolol) act to inhibit renin release, which in turn reduces the conversion of angiotensinogen to angiotensin I and reduces the levels of angiotensin II (a potent vasoconstrictor) and aldosterone (decreasing renal

Which of the following lipid-lowering agents would be most effective for preventing future cardiovascular events in this patient?

*Enzyme inhibitor* Patients with low high-density lipoprotein (HDL) levels (men <40 mg/dL, women <50 mg/dL) are at increased risk for cardiovascular disease. HDL is involved in reverse cholesterol transport; it helps to remove cholesterol from peripheral tissues and transports it to the liver for metabolism. This is accomplished through 2 different pathways. In the direct pathway, HDL delivers cholesterol esters directly to the liver via a scavenger receptor (SCARB1) on the hepatocyte cell membrane. In the indirect pathway, the cholesterol in HDL is transferred to low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) by the cholesteryl ester transfer protein. Nonpharmacologic measures such as exercise, weight loss, and smoking cessation help to raise HDL levels and have significant cardiovascular benefits. In contrast, use of medications to raise HDL levels does not improve cardiovascular outcomes. Pharmacologic treatment of patients with low HDL levels should focus on lowering LDL cholesterol with HMG-CoA reductase inhibitors (statins), as these are the most effective lipid-lowering drugs for preventing cardiovascular events. Statins are indicated for secondary prevention in all patients with known atherosclerotic cardiovascular disease, regardless of baseline lipid levels.

17 yro girl with syncope. The patient is taking an antimicrobial agent for a recent infection but has no other chronic medical conditions. A detailed evaluation reveals a decrease-in-function mutation in the KCNH2 gene, which codes for a voltage-gated potassium channel that is active during the repolarization phase of cardiomyocyte action potential. The patient's medication was causing further impairment of the ion channel function, leading to the incident of syncope. This patient was most likely taking which of the following medications?

*Erythromycin* A decrease-in-function mutation affecting the KCNH2 gene is one of the most common causes of congenital long QT syndrome (LQTS); it can be inherited in autosomal dominant (Romano-Ward syndrome) or autosomal recessive (Jervell and Lange-Nielsen syndrome) fashion. The mutation impairs the function of the voltage-gated potassium channels controlling the delayed rectifier potassium current that allows repolarization of the cardiomyocyte action potential. Delayed repolarization manifests as a prolonged QT interval on ECG and predisposes to the development of torsades de pointes (TdP) (a form of polymorphic ventricular tachycardia), which can cause syncope or sudden cardiac death. Most patients with underlying congenital LQTS do not develop TdP unless exposed to an external influence. Medications are the most common cause of acquired LQTS and the most important exacerbating factor in patients with congenital LQTS. Most medications that prolong the QT interval do so by delaying the repolarizing potassium current via blockade of the same voltage-gated potassium channels affected by the KCNH2 gene mutation. Macrolide antibiotics (eg, erythromycin, azithromycin) prolong the QT interval and increase the risk of TdP, especially in patients with underlying congenital LQTS. Other medications that prolong the QT interval include fluoroquinolone antibiotics (eg, ciprofloxacin, moxifloxacin) and many antipsychotics (eg, haloperidol, risperidone) and antiemetics (eg, ondansetron, metoclopramide). The coadministration of multiple QT-prolonging medications may precipitate TdP in patients without congenital LQTS.

A 56yro woman w/ heart failure with reduced ejection fraction. In the last 3 months, the patient has been hospitalized twice due to acute decompensation of heart failure that required treatment with intravenous furosemide. Since her most recent discharge, she has been taking high doses of oral furosemide, but she continues to have progressive lower extremity edema and weight gain. Serum creatinine is 1.2 mg/dL and serum potassium is 4.1 mEq/L. The addition of metolazone may assist in treating this patient because of which of the following effects of loop diuretics?

*Inc. Na+ delivery to the distal tubules* This patient has decompensated heart failure with ongoing volume retention despite high doses of oral furosemide (ie, loop diuretic) therapy. Thiazide diuretics, especially metolazone, potentiate the diuretic effect of loop diuretics and can be helpful in treating refractory volume overload. Sodium is the major determinant of volume status. Loop diuretics function by inhibiting the Na-K-2Cl cotransporter in the ascending limb of the loop of Henle to block sodium absorption and encourage the excretion of sodium and water in the urine. However, the sodium excretion caused by loop diuretics is limited by the reabsorption of sodium in the distal convoluted tubule; the Na-Cl cotransporter in the distal tubule counteracts some of the effect of loop diuretics by absorbing much of the sodium that is not absorbed in the loop of Henle. Inhibition of the Na-Cl cotransporter with metolazone prevents reabsorption of the increased sodium delivered to the distal tubule, significantly increasing total sodium excretion.

Patient with HTN, Type 2 DM, and degenerative joint disease taking all his medications as prescribed. He has no chest pain but does have diffuse muscle aches and cramps, especially after exercise. Laboratory testing reveals elevated serum creatine kinase. The medication most likely responsible for this patient's current findings also causes which of the following effects?

*Increased hepatocyte LDL receptor recycling* This patient's symptoms are most likely due to statin-induced myopathy. Statins are an effective treatment for hypercholesteremia and are now routinely prescribed for all patients with symptomatic coronary artery disease, regardless of baseline cholesterol levels. Myopathy is the most common complication of statin use, and symptoms can range from myalgia or myopathy, with or without myonecrosis (elevated serum creatine kinase), to frank rhabdomyolysis. Statins act through competitive inhibition of HMG-CoA reductase, preventing conversion of HMG-CoA to mevalonic acid (the rate-limiting step in cholesterol biosynthesis). Decreased liver cholesterol synthesis leads to increased hepatic clearance of LDL from the circulation by LDL receptors. After mediating endocytosis of LDL particles, the LDL receptors are returned to the cell surface for reuse (receptor recycling); LDL is digested and used for metabolic purposes. This increase in LDL receptor recycling allows intrahepatic cholesterol levels to remain at normal levels while blood levels are kept low.

Laboratory studies show a current LDL level of 190 mg/dL. Which of the following should be obtained before starting statin therapy in this patient?

*LFTs* This patient has a severe elevation in his LDL level. This degree of hyperlipidemia, especially with a family history of coronary artery disease, suggests familial hypercholesterolemia and confers a very high risk for cardiovascular events. HMG-CoA reductase inhibitors (statins) are the first-line therapy for most patients with hypercholesterolemia and have been proven to reduce the risk of cardiac events. The statins are structural analogs of HMG-CoA and competitively inhibit HMG-CoA reductase, the enzyme responsible for the rate-limiting step in cholesterol synthesis. Serious side effects of statins include myopathy and hepatitis. Although mild elevations of liver enzymes are common, significant liver injury (aspartate transaminase/alanine transaminase levels more than 3 times the upper limit of normal) is seen in less than 1% of patients and is usually reversible if the medication is discontinued. Liver function tests are recommended before starting statin therapy; otherwise, routine monitoring is not necessary unless symptoms of hepatic injury develop (eg, fatigue, malaise, anorexia).

Patient with chest tightness when he walks upstairs, but it subsides. The patient is prescribed a medication that is metabolized to S-nitrosothiols in the vascular smooth muscle cells, and he reports rapid and significant symptom relief. Which of the following components of the cardiovascular system is most susceptible to the medication prescribed to this patient?

*Large veins* This patient has stable angina pectoris and experienced rapid symptomatic relief following receipt of a nitrate. Pharmacologic nitrates (eg, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate) are metabolized to nitric oxide and S-nitrosothiols via mitochondrial aldehyde dehydrogenase within vascular smooth muscle cells. These compounds in turn activate guanylate cyclase and promote the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP), which leads to dephosphorylation of myosin light chains and causes vascular smooth muscle relaxation. Nitrates predominantly affect the large veins, where smooth muscle relaxation leads to venodilation and increased venous capacitance. Cardiac venous return (preload) is reduced, leading to a reduction in left ventricular end-diastolic volume and pressure and a consequent decrease in left ventricular wall stress. Decreased myocardial oxygen demand leads to relief of anginal symptoms.

Patient with hx of COPD comes to ED. This patient's clinical presentation—chest discomfort, ST elevation on ECG, elevated troponin I level—is consistent with acute myocardial infarction (AMI). What drug would you prescribe?

*Metoprolol* Beta blockers are used in AMI to reduce myocardial oxygen demand by lowering heart rate, cardiac contractility, and afterload. They have been shown to reduce short-term morbidity (eg, recurrent symptoms or reinfarction), minimize infarct size, and improve long-term survival. Contraindications to beta blockers include bradycardia or heart block, hypotension, and overt heart failure (eg, pulmonary edema). Also, non-cardioselective beta blockers (eg, propranolol, nadolol) can trigger bronchospasm in patients with underlying obstructive lung disease (asthma, chronic obstructive pulmonary disease [COPD]) due to beta-2 receptor blockade and should be avoided. Cardioselective beta blockers with predominant action on beta-1 receptors (eg, metoprolol, atenolol, bisoprolol, nebivolol) are safe in patients with stable obstructive lung disease and are the beta blocker of choice in these patients. Combined beta and alpha receptor blockers (eg, carvedilol, labetalol) are also well tolerated and have been used safely in patients with COPD.

In an experiment investigating vasoconstriction of the arterial wall, two samples of isolated porcine arterial vessels are studied. Vascular tone is measured in the control vessel during infusion of increasing doses of norepinephrine. The other vessel is pretreated with experimental drug A prior to infusion of norepinephrine. The results show that pretreatment with drug A results in decreased maximal effect (Vmax) of norepinephrine without a significant change in the affinity (Km) of norepinephrine for α1 receptors. Drug A is most similar to....

*Phenoxybenzamine* Alpha-1 adrenergic receptors mediate arterial vasoconstriction whereas β2 receptors mediate vasodilation. Norepinephrine is an agonist at α1 and β1 receptors but has significantly less action at β2 receptors; it is therefore a potent vasoconstrictor. This experiment is testing the efficacy of drug A at blocking the α1-mediated vasoconstriction caused by norepinephrine administration. The graph suggests that drug A is acting as either a noncompetitive antagonist or an irreversible antagonist of α1 adrenergic receptors. Phenoxybenzamine is an irreversible α1 and α2 receptor antagonist that would produce results similar to those observed. It is primarily used in the treatment of pheochromocytoma, in which a tumor of the adrenal medulla overproduces norepinephrine, causing systemic arterial vasoconstriction.

A 54-year-old man is evaluated for paroxysmal atrial fibrillation. During the episodes, the patient experiences palpitations, chest tightness, light-headedness, and shortness of breath. Medical history is significant for asthma, hypertension, and diet-controlled diabetes mellitus. Prior testing showed normal left ventricular ejection fraction, no evidence of valvular disease, and no obstructive coronary artery disease. It is decided to proceed with dofetilide therapy. Initiation of this therapy increases this patient's risk for which of the following?

*Polymorphic ventricular tachycardia** Relatively young patients with symptomatic paroxysmal atrial fibrillation are often treated with a rhythm-control strategy to restore and maintain normal sinus rhythm and to eliminate symptoms. Antiarrhythmic drugs commonly used for rhythm control of atrial fibrillation include class IC (eg, flecainide, propafenone) and class III (eg, ibutilide, dofetilide) agents. Dofetilide and ibutilide selectively block the rapid component of the delayed-rectifier potassium current. This slows repolarization and prolongs action potential duration and the effective refractory period in cardiomyocytes, suppressing the electrical foci that lead to atrial fibrillation. As a result, the QT interval is prolonged, leading to an increased risk of torsade de pointes, a form of polymorphic ventricular tachycardia that can cause syncope and sudden cardiac death. To minimize this risk, dofetilide or ibutilide therapy is started only in the hospital with temporary cardiac monitoring.

A 65-year-old immigrant from Eastern Europe comes to the physician because of a four-week history of low-grade fever, multiple joint pains, and a well-demarcated erythematous rash on his face and trunk. His serum test is positive for the presence of anti-nuclear antibody (ANA) in very high titers. PMH of coronary artery disease, congestive heart failure, and "cardiac rhythm abnormalities." This patient should be specifically questioned about the intake of which of the following medications?

*Procainamide* Drug-induced lupus erythematosus (DILE) should be considered in patients presenting with signs and symptoms of systemic lupus erythematosus (SLE). Both hydralazine and procainamide are categorized as high-risk drugs for the development of DILE. Procainamide is metabolized via hepatic acetylation. Individuals who are "slow acetylators" are at greatest risk for DILE, while individuals who metabolize the drug more rapidly are less likely to experience this adverse effect. Drug-induced lupus erythematosus occurs in up to 20% of patients taking procainamide. The presence of autoantibodies can be used to help differentiate DILE from SLE. Although anti-histone antibodies are very common in DILE, they are seen in only 50% of SLE patients. Likewise, anti-dsDNA antibodies are present in 80% of SLE patients, but are rarely seen in DILE. Anti-nuclear antibodies are frequently positive in both diseases.

What is the cause of the dry cough associated w/ ACE I

A dry, nonproductive, and persistent cough is one of the most well-known side effects of ACE inhibitor therapy. The mechanism of ACE inhibitor induced cough is believed to involve increased bradykinin, substance P, or prostaglandins. ACE is a very nonspecific enzyme responsible for the breakdown of many substrates. By blocking ACE, ACE inhibitors block degradation of bradykinin and substance P. Bradykinin and substance P accumulation can cause inflammation and stimulate lung irritation. Because angiotensin receptor blockers (ARBs) do not affect ACE activity, they theoretically should not cause cough.

He agrees to enroll in a trial of a new long-acting medication that causes selective direct relaxation of the smooth muscle of arterioles but does not affect the veins. Which of the following adverse effects is most likely to be caused by the drug during the clinical trial?

*Sodium and fluid retention* Selective arteriolar vasodilators (eg, hydralazine, minoxidil) lower blood pressure by reducing systemic vascular resistance. However, this effect is limited by subsequent stimulation of baroreceptors with resulting reflex sympathetic activation. This leads to increased heart rate, contractility, and cardiac output. In addition, sympathetic stimulation of the renin-angiotensin-aldosterone axis results in sodium and fluid retention with peripheral edema. These effects offset much of the blood pressure lowering effect of these drugs and limit their long-term efficacy. These agents are rarely used as monotherapy for chronic management of hypertension. However, they are useful acutely for patients with severely elevated blood pressure. They can also be given in combination with sympatholytics and diuretics to mitigate the side effects and provide synergistic blood pressure lowering in patients with resistant hypertension.

A 60-year-old Caucasian male is diagnosed with exertional angina. His treatment regimen includes metoprolol, isosorbide dinitrate and aspirin. He takes isosorbide dinitrate early in the morning and again in the afternoon, but he does not take an evening dose. Such a pattern of drug administration is intended to decrease which of the following?

*Tolerance development* Around-the-clock nitrate administration (in any form) rapidly results in development of tolerance to nitrates. This is why a nitrate-free interval must be provided every day in patients that are using daily long acting nitrates. The mechanism by which this occurs has not been fully demonstrated, but it is theorized that it is due to a decreased vascular sensitivity to nitrates and an increased sensitivity to endogenous vasoconstricting agents. Usually the nitrate-free period is timed to occur during the night when the patient is sleeping and cardiac work is the least.

A 54-year-old man comes to the office due to new-onset muscle cramps. The patient has a history of hypertension and was started on hydrochlorothiazide 4 weeks ago. Based on his most recent laboratory results, triamterene is added to the current therapy. Which of the following best describes the mechanism of action of this medication?

*block renal tubular ENAC channel* Thiazide diuretics lower blood pressure by inhibiting Na+/Cl− cotransporters in the distal convoluted tubules, thereby decreasing reabsorption of Na+ and Cl−. Both thiazides and loop diuretics induce volume loss with subsequent activation of the renin-angiotensin-aldosterone system. Aldosterone increases renal sodium resorption in exchange for potassium by upregulating the synthesis and activity of the following: Epithelial sodium channels: Found on the apical membrane of principal cells, it absorbs Na+ from the tubular lumen Na+/K+-ATPase pump: Located on the basal membrane of principal cells, it extrudes Na+ into the interstitial space in exchange for potassium Because of these effects, increased aldosterone levels commonly result in hypokalemia, which can lead to muscle cramps, weakness, and (when severe) cardiac arrhythmias. Potassium-sparing diuretics may be added to prevent hypokalemia. These weak diuretic medications act in the distal nephron, where they reduce potassium excretion via the following mechanisms: -Triamterene and amiloride directly inhibit the epithelial sodium channel, preventing sodium from entering principal cells. This reduces the electrochemical gradient (ie, negative luminal charge) that helps drive potassium secretion. -Aldosterone antagonists (ie, spironolactone, eplerenone) directly inhibit the mineralocorticoid receptor, resulting in decreased formation and activity of epithelial sodium channels and Na+/K+-ATPase pumps

A 55-year-old man comes to the emergency department with recurrent episodes of retrosternal chest pain. The episodes occur during physical activity, usually when he climbs stairs or walks uphill. He is given a sublingual tablet and reports rapid relief of the pain. This drug most likely improved this patient's symptoms by causing which of the following hemodynamic changes?

*dec in LVEDV* This patient has a classic presentation of chronic stable angina, which is characterized by chest pain that occurs with activity and is relieved with rest or sublingual nitroglycerin. Nitrates exert their effect by direct vascular smooth muscle relaxation that results in: 1. Vasodilation of the peripheral veins and arteries, predominantly venodilation 2. Decreased left ventricular wall stress due to reduced preload (decreased left ventricular end-diastolic volume and pressure) 3. Modest reduction in afterload due to systemic arterial vasodilation 4. Mild coronary artery dilation and reduction of coronary vasospasm This results in decreased myocardial oxygen demand, leading to improved exercise tolerance and relief of angina symptoms.

The physician discusses adding isosorbide dinitrate to his current therapy but the patient is concerned about adverse effects. Which of the following is most likely to occur in this patient with the add-on therapy?

*headaches* Nitrates are frequently used for symptomatic relief in patients with chronic stable angina. The anti-ischemic effect of nitrates is mediated by systemic vasodilation (predominantly venodilation) with a decrease in left ventricular end-diastolic volume and wall stress, resulting in decreased myocardial oxygen demand and relief of angina symptoms. The main adverse effects seen with nitrate therapy include headaches, cutaneous flushing, lightheadedness, hypotension, and reflex tachycardia. Nitrates must be avoided in patients with hypertrophic cardiomyopathy (due to increased outflow tract obstruction), right ventricular infarction (due to reduction in preload, impairing cardiac output), and those on phosphodiesterase inhibitors (synergism increases the risk of severe hypotension).

Blood pressure is 60/30 mm Hg and pulse is 120/min and regular. After receiving several intravenous fluid boluses, the patient is given an intravenous infusion of an agent that increases peripheral vascular resistance, increases blood pressure, and decreases heart rate. Which of the following agents is most likely being described?

Adrenergic agonists are often used to increase blood pressure in patients with shock. Phenylephrine is a selective alpha-1 agonist with no effect on alpha-2 receptors or beta receptors; it causes peripheral vasoconstriction, resulting in increased systemic vascular resistance (SVR) and increased blood pressure, but it has no direct effect on the heart. Drugs that increase blood pressure by increasing SVR are called pressors and are most useful in treating septic shock. Phenylephrine has indirect effects on the heart mediated via the baroreceptor reflex. Increased blood pressure stimulates firing of aortic and carotid baroreceptors. In response, the CNS increases parasympathetic output and decreases sympathetic output, which causes decreased heart rate and myocardial contractility. These reflexive changes slightly attenuate the initial increase in blood pressure and lead to overall reduced cardiac output.

The patient is treated with sildenafil, which gives significant improvement in his sexual performance. The intracellular signaling of this drug is most similar to that of which of the following substances?

Atrial and brain natriuretic peptides (ANP and BNP) are polypeptide hormones that exert their effect by binding ANP receptors. These transmembrane receptors are linked to a guanylyl cyclase that converts guanosine 5′-triphosphate to cyclic guanosine 3′,5′-monophosphate (cGMP). cGMP then activates a downstream cGMP-dependent protein kinase, leading to relaxation of vascular smooth muscle and subsequent vasodilation. Nitric oxide activates the same cGMP second messenger system by binding a cytosolic guanylyl cyclase. Penile erection is initiated by release of acetylcholine and nitric oxide (NO) from parasympathetic fibers, leading to a rise in intracellular cGMP and vasodilation of the arteries supplying the corpus cavernosum. Sildenafil is a phosphodiesterase-5 inhibitor that decreases degradation of cGMP, enhancing the effect of parasympathetic activation in erectile tissues. Because vasodilatory nitrates (eg, nitroglycerin, isosorbide mononitrate) work by releasing NO, coadministration of sildenafil with nitrates can lead to excessive cGMP-induced vasodilation and severe hypotension.

What drugs improve longterm survival in patients with systolic heart failure?

Beta blockade decreases myocardial work and oxygen demand by slowing the ventricular rate and reducing contractility. It also lowers peripheral resistance (afterload) by decreasing circulating levels of vasoconstricting hormones (eg, renin, endothelin). These effects are cardioprotective and help reduce cardiomyocyte death and limit deleterious cardiac remodeling. Beta blockers should not be initiated in patients with unstable (decompensated) HF, as they can further impair cardiac output; they should be introduced slowly after the patient has been stabilized. Other drugs that improve long-term survival in patients with systolic HF include ACE inhibitors, angiotensin II receptor blockers, and aldosterone antagonists (eg, spironolactone, eplerenone).

This patient with elevated blood pressure, tachycardia, palpitations, and anginal pain following recent discontinuation of metoprolol is most likely experiencing what phenomena

Beta blocker withdrawal syndrome. With changes in environmental stimulus, the feedback mechanisms in cells adjust the density of cell surface membrane receptors to regulate sensitivity to the stimulus. Prolonged beta-adrenergic blockade, for example, stimulates an increase in surface membrane expression of beta-adrenergic receptors, a process called upregulation. When beta-adrenergic blockade is abruptly withdrawn, the increased density of beta-adrenergic receptors creates an amplified response to circulating catecholamines (ie, increased sensitivity). Because metoprolol is cardioselective and primarily blocks beta-1 receptors, abrupt cessation stimulates beta-1 receptor-mediated increased heart rate and cardiac contractility. There is also increased blood pressure due to increased cardiac output. These changes create increased oxygen demand that may cause ischemia (evidenced by ST depression on ECG) and trigger angina in patients with underlying coronary artery disease.

B1 receptors exert their effects in what two locations?

Beta blockers are the preferred treatment for patients with chronic stable angina and hypertension. They relieve anginal symptoms by inhibiting sympathetic stimulation of the heart, reducing both heart rate and contractility. Because beta blockers reduce heart rate and blood pressure during rest and exercise, the onset of angina is avoided or delayed. At low doses, atenolol is a selective β1 adrenergic antagonist. β1 receptors are found in cardiac tissue and on renal juxtaglomerular cells, but not in vascular smooth muscle. The β1 receptor is a G protein-coupled receptor (GPCR) associated with Gs, which increases intracellular cAMP levels. Blockade of the β1 receptor leads to decreased cAMP levels in cardiac and renal tissue without significantly affecting cAMP levels in vascular smooth muscle

How is digoxin cleared?

Digoxin is renally cleared and has a narrow therapeutic window, so toxicity frequently results from alterations in kidney function. As patients age, renal function decreases progressively. This decrease in renal function is often not accompanied by a concomitant rise in serum creatinine, as creatinine is derived from muscle tissue and lean body mass also decreases with age. Therefore, elderly patients (even those with a normal serum creatinine) should receive reduced doses of renally cleared medications to prevent toxicity.

The patient is started on a medication to treat his hypertension. During his follow-up visit 3 weeks later, he reports bilateral leg swelling. Cardiopulmonary examination is normal, but there is bilateral, symmetrical, 2+ pitting lower extremity edema. Laboratory studies show serum creatinine of 0.8 mg/dL, and urinalysis is negative for proteinuria. Which of the following was most likely prescribed to treat this patient's hypertension?

Dihydropyridine calcium channel blockers (eg, amlodipine, nifedipine) are effective antihypertensive agents commonly used as monotherapy or in combination with other agents for treatment of hypertension. The major side effects associated with use of calcium channel blockers include headache, flushing, dizziness, and peripheral edema. Development of peripheral edema is related to preferential dilation of precapillary vessels (arteriolar dilation), which leads to increased capillary hydrostatic pressure and fluid extravasation into the interstitium. Renin-angiotensin system blockers (eg, ACE inhibitors or angiotensin II receptor blockers [ARBs]) cause postcapillary venodilation and can normalize the increased capillary hydrostatic pressure, reducing the risk of peripheral edema in patients taking calcium channel blockers.

The patient is diagnosed with an acute myocardial infarction complicated by acute severe heart failure. He is started on dobutamine infusion and prepared for coronary catheterization. Which of the following is most likely to be increased due to the medication used in this patient?

Dobutamine is a beta adrenergic agonist with predominant activity on beta-1 receptors, weaker activity on beta-2 receptors, and minimal activity on alpha-1 receptors. It is used for management of refractory heart failure associated with severe left ventricular systolic dysfunction and cardiogenic shock. Stimulation of beta adrenergic receptors results in increased production of cAMP in target cells and causes the following effects: 1. Positive inotropy and chronotropy: Increased cardiac contractility (potent effect) and heart rate (weaker effect), leading to increased cardiac output (improves end-organ perfusion) and decreased left ventricular filling pressures (improves pulmonary congestion/edema) 2. Mild vasodilation: Decreased systemic vascular resistance that often causes a slight reduction in blood pressure; this avoids the increase in afterload seen with other vasopressor/inotropic agents (eg, norepinephrine) but limits its usefulness in severely hypotensive patients The strong inotropic effect of dobutamine significantly increases myocardial oxygen consumption, which can trigger or exacerbate MI. As such, dobutamine should not be used routinely in patients with decompensated heart failure. However, in patients with cardiogenic shock, this drawback is often outweighed by improvement in cardiac output and end-organ perfusion.

When a patient is exposed to frequent agonist activity, what happens?

Downregulation of surface membrane receptors occurs when cells are exposed to frequent agonist activity. For example, prolonged use of an alpha-1 agonist nasal spray (eg, phenylephrine) causes downregulation of alpha-1 receptors and reduced sensitivity to endogenous catecholamines.

Vasodilation of the ?afferent or efferent? arteriole reduces GFR as part of the MOA of ACE-I

Enalapril is an angiotensin-converting-enzyme (ACE) inhibitor. All ACE inhibitors decrease circulating levels of angiotensin II, a substance that causes the following: 1. Systemic vasoconstriction 2. Preferential constriction of the glomerular efferent arteriole 3. Enhancement of adrenal aldosterone secretion As a result, reduced angiotensin II production in patients taking an ACE inhibitor would be expected to acutely decrease efferent arteriolar resistance and systemic vascular resistance. Selective efferent arteriolar dilation combined with the decreased renal perfusion pressure causes a reduction in glomerular filtration rate.

What is the MOA of fibrates

Fibrates activate peroxisomal proliferator-activated receptor alpha, a transcription factor that increases lipoprotein lipase activity. Fibrates decrease triglyceride levels and raise HDL levels. However, fibrates are inferior to statins for reducing cardiovascular events and are primarily used to prevent pancreatitis in patients with very high triglyceride levels.

Describe the two GPCRs associated with signaling

GPCRs comprise a large family of 7 transmembrane domain receptors that activate intracellular second messenger systems. There are 2 principal second messenger systems involving GPCRs: 1. cAMP signaling pathway: The activated Gs α subunit activates the enzyme adenylyl cyclase, which catalyzes the conversion of ATP into cAMP. Elevated cAMP leads to the activation of protein kinase A. Conversely, the Gi α subunit inhibits adenylyl cyclase, thereby reducing cAMP levels. 2. Phosphatidylinositol signaling pathway: The activated Gq α subunit activates phospholipase C, which degrades membrane lipids into diacylglycerol (DAG) and inositol triphosphate (IP3). Protein kinase C is activated by DAG, and calcium is released from the sarcoplasmic reticulum under the influence of IP3.

A 76-year-old man is brought to the emergency department with severe midsternal chest pain and diaphoresis.The patient receives aspirin immediately upon arrival followed by alteplase and a low-dose beta blocker. Several hours later, the patient is found to be comatose with asymmetric pupils and an irregular breathing pattern. What is the most likely cause of this patient's current condition?

Intracranial hemorrage This patient's presentation of chest pain and diaphoresis along with a history of systemic atherosclerosis and type 2 diabetes mellitus is suggestive of acute coronary syndrome. ECG findings are consistent with an inferior ST elevation myocardial infarction (STEMI). Percutaneous coronary intervention (PCI) or fibrinolysis to achieve myocardial reperfusion is recommended for acute MI patients who present within 12 hours of symptom onset. PCI is preferred over fibrinolytic therapy due to lower rates of intracerebral hemorrhage (ICH) and recurrent MI; however, it may not be available at all institutions. In such cases, treatment with fibrinolytics (tenecteplase, alteplase) improves clinical outcomes in the absence of contraindications (eg, gastrointestinal bleeding, recent surgery). Alteplase binds fibrin in the thrombus (clot) and converts entrapped plasminogen to plasmin. Plasmin hydrolyzes key bonds in the fibrin matrix causing clot lysis and restoration of coronary arterial blood flow. The most common adverse effect of fibrinolytic therapy is hemorrhage. This patient has signs of ICH, such as decreased level of consciousness, asymmetric pupils, and irregular breathing.

A cardiac electrophysiologic study is performed. During the study, intravenous infusion of a medication is administered and produces increased contractility and decreased vascular resistance. What drug is likely administered?

Isproterenol The effects seen in the graphs above are most similar to those elicited by isoproterenol, a nonselective β adrenergic agonist. Isoproterenol increases cardiac contractility (positive inotropic effect) by acting on myocardial β-1 adrenergic receptors. It also binds to β-2 adrenergic receptors and causes vasodilation by relaxation of vascular smooth muscle, leading to decreased vascular resistance and mean arterial blood pressure. Isoproterenol has negligible effects on α-1 adrenergic receptors.

Pt is started on a statin. Four weeks later, the patient's total cholesterol level is 140 mg/dL, down from 200 mg/dL before discharge. Which of the following has most likely increased as the result of the therapy?

LDL receptor density HMG-CoA reductase inhibitors (statins) inhibit the rate-limiting enzyme in hepatic cholesterol synthesis. In response to these changes, hepatocytes increase their surface expression of the LDL receptor to increase uptake of circulating LDL. Treatment generally produces a 20%-50% reduction in serum cholesterol and LDL concentration. High-intensity statin therapy reduces the risk of acute coronary events. This risk reduction is greater than that seen with other classes of lipid-lowering medications and is likely due to additional properties of statins. Besides effects on lipids, statins have anti-inflammatory properties, improve endothelial dysfunction, and appear to stabilize atherosclerotic plaques.

What medication used in hypertensive emergency would cause a dec in SVR and a dec in heart rate with no change to stroke volume?

Labetalol is a nonselective vasodilatory beta blocker that blocks beta-1, beta-2, and alpha-1 adrenergic receptors and reduces blood pressure. The alpha-1 receptor blockade outweighs beta-2 receptor blockade in vascular smooth muscle to cause peripheral vasodilation of both venules and arterioles. Venular vasodilation decreases venous return and arteriolar vasodilation decreases systemic vascular resistance (SVR); because the vasodilation is relatively balanced, blood pressure is reduced with stroke volume unchanged. Normally, reduced blood pressure stimulates a baroreceptor reflex-mediated increase in heart rate, but the strong beta-1 receptor blockade of labetalol overrides this response, causing overall decreased heart rate. Hydralazine is an arterial vasodilator that has little effect on veins. Nitroprusside is a nitric oxide donor that causes balanced arterial and venous vasodilation. Phentolamine is a nonselective alpha receptor blocker that also causes balanced vasodilation. All these drugs reduce blood pressure primarily via a reduction in SVR, but they have no negative chronotropic effects and are associated with a baroreceptor reflex-mediated increase in heart rate. Stroke volume is increased with hydralazine, and unchanged with the balanced vasodilation that occurs with nitroprusside and phentolamine.

This patient, with hypertension, hypercholesterolemia, and sudden-onset neurologic deficits (eg, right arm weakness, difficulty speaking) that fully resolved within minutes, most likely had a transient ischemic attack (TIA). In addition to optimal blood pressure control and statin therapy _____ should be prescribed.

Low-dose aspirin is commonly used to prevent ischemic stroke in patients with TIA. It works by irreversibly acetylating/inhibiting the cyclooxygenase (COX) enzymes. At low doses, aspirin predominantly inhibits COX-1, preventing platelet synthesis of thromboxane A2, which impairs platelet aggregation and reduces vasoconstriction. At least 2 distinct COX-1-dependent mechanisms contribute to the increased risk of upper gastrointestinal (GI) bleeding associated with aspirin therapy: Inhibition of platelet aggregation and impairment of prostaglandin-dependent GI mucosal protection. The risk of upper GI bleeding increases with higher doses but is increased 2- to 3-fold even with low-dose aspirin. Proton pump inhibitors can help reduce the risk of upper GI bleeding in patients taking aspirin.

Describe the MOA of milrinone

Milrinone is a selective phosphodiesterase (PDE)-3 enzyme inhibitor that can be used in patients with refractory heart failure due to left ventricular systolic dysfunction. The PDE-3 enzyme is normally responsible for degrading cyclic adenosine monophosphate (cAMP) to AMP; the inhibition of cAMP degradation via milrinone has 2 positive effects on heart failure: In cardiomyocytes, intracellular calcium influx is increased, which increases cardiac contractility (positive inotropy) to improve stroke volume and cardiac output. In vascular smooth muscle, uptake of calcium by the sarcoplasmic reticulum is increased, which reduces calcium-myosin light chain kinase interaction to stimulate relaxation and vasodilation. Venous vasodilation reduces preload and arterial vasodilation reduces afterload to provide a cumulative reduction in cardiac work. Although the vasodilatory action of milrinone can lead to hypotension, this effect is often compensated for by an increase in stroke volume that maintains blood pressure.

There is a third heart sound on heart auscultation and mild lower extremity pitting edema. A recent echocardiogram showed a left ventricular ejection fraction of 30%. Which of the following diuretics would most likely improve survival if added to this patient's current regimen?

Mineralocorticoid receptor antagonists (eg, spironolactone, eplerenone) prevent aldosterone from binding to its receptor in the distal renal tubules. This leads to increased sodium and water excretion while conserving potassium ions (potassium-sparing diuresis). These antagonists also block the deleterious effect of aldosterone on the heart, causing regression of myocardial fibrosis and improvement in ventricular remodeling. Mineralocorticoid receptor antagonists reduce morbidity and improve survival in patients with congestive heart failure and decreased ejection fraction. Therefore, they are recommended in addition to standard heart failure therapy (ACE inhibitors and beta blockers). They should not be used in patients with hyperkalemia or renal failure. The most common side effects are hyperkalemia and gynecomastia (spironolactone >> eplerenone).

Laboratory studies show normal hepatic and pancreatic enzyme levels, but the patient again has a severely elevated triglyceride level. The physician prescribes the appropriate medications and explains that the patient is likely to experience skin flushing and warmth after taking the pills. Which of the following is the primary agent mediating these side effects?

Nicotinic acid, or niacin, has been used in the treatment of hyperlipidemia for almost 4 decades. It is effective in raising HDL cholesterol levels, as well as lowering triglycerides and LDL levels. Niacin's main side effects are cutaneous flushing, warmth, and itching; these are primarily mediated by release of prostaglandins (particularly PGD2 and PGE2). Aspirin, which inhibits prostaglandin synthesis, can significantly reduce these side effects if given 30-60 minutes before niacin administration. The side effects are also reduced with slow-release preparations or if niacin is taken with meals. They are worst when niacin is first initiated and tend to fade over time due to tachyphylaxis.

Further evaluation confirms moderate peripheral arterial disease involving both lower extremities. Which of the following drugs would best provide symptomatic improvement due to direct dilation of arteries and inhibition of platelet aggregation?

Several molecules, including thrombin, adenosine diphosphate, and thromboxane A2, activate platelets by acting on cell surface receptors. However, interference with post-receptor signaling can alter platelet function. In particular, cyclic adenosine monophosphate (cAMP) activates a family of enzymes known as the cAMP-dependent protein kinases, or protein kinase A, and leads to inhibition of platelet aggregation. Agents that increase intra-platelet cAMP levels decrease platelet aggregation by preventing platelet shape change and granule release. Cilostazol reduces platelet activation by inhibiting platelet phosphodiesterase, the enzyme responsible for the breakdown of cAMP. It is also a direct arterial vasodilator. The net effect is a decrease in claudication symptoms and an increase in pain-free walking distances in patients with peripheral arterial disease (PAD). Patients with PAD should be initiated on a graded exercise program, which has also been shown to improve symptoms.

Which of the following cardiac electrophysiologic changes are most likely to occur in this patient on Amiodarone? Sinus rate: inc/dec? PR interval: Prolonged/no change QRS: Prolonged/no change QT interval: prolonged/no change?

Sinus: Decreased PR interval: Prolonged QRS: Prolonged QT interval: Prolonged Amiodarone is a commonly used antiarrhythmic drug with wide-ranging antiarrhythmic effects and corresponding ECG manifestations. It primarily functions as a class III antiarrhythmic by inhibiting the rapid component of the delayed rectifier potassium current, which is responsible for ventricular repolarization. This prolongs action potential duration and the effective refractory period, suppressing electrical foci that stimulate atrial and ventricular arrhythmias. It also prolongs the QT interval on ECG, which increases the risk of torsade de pointes; however, compared to other class III antiarrhythmics (eg, dofetilide, ibutilide), the risk of torsade de pointes with amiodarone is low. Amiodarone also has the following effects: Class I effect: Amiodarone somewhat inhibits the fast sodium channels responsible for cardiomyocyte depolarization (phase 0). This slows ventricular depolarization to suppress arrhythmogenic foci, and it prolongs QRS complex duration on ECG. Class II and IV effects: Amiodarone has beta-blocking properties that inhibit sympathetic stimulation of the conduction system. The drug also inhibits the slow L-type calcium channels responsible for depolarization of the sinus node and atrioventricular node. Both effects prolong the refractory period of the conduction system to suppress arrhythmogenic foci and in doing so contribute to a decreased sinus rate (ie, slowed heart rate) and a prolonged PR interval on ECG.

What drug in combo with statins will raise creatine kinase

Statins (eg, atorvastatin) are the first-line therapy for most patients with hypercholesterolemia and are useful in primary and secondary prevention of acute coronary events. Statins inhibit HMG-CoA reductase, the enzyme responsible for the rate-limiting step in synthesis of cholesterol. Statins lower total cholesterol, LDL, and triglyceride levels. The primary side effects of statins include myopathy and hepatitis. Statin-associated myopathy is usually characterized by mild muscular pain and resolves with discontinuation of the medication. However, some patients will develop severe myopathy with striking elevations in creatine kinase levels and occasional rhabdomyolysis. The risk of severe myopathy is increased when statins are given concurrently with fibrates (particularly gemfibrozil), which impair the hepatic clearance of statins and lead to excessive blood levels. An increased risk of statin myopathy is also likely with concurrent use of niacin or ezetimibe, but to a lesser extent

A 45-year-old man who was recently started on medication for paroxysmal atrial fibrillation undergoes stress ECG testing. His pre-test resting QRS complex duration is 95 msec (normal: 80-120 msec) and corrected QT (QTc) interval duration is 410 msec (normal <440 msec). ECG findings recorded at his maximally achieved heart rate show a QRS complex duration of 125 msec and QTc interval duration of 400 msec. Based on the patient's test results, which of the following medications is most likely being used to treat his atrial fibrillation?

The QRS complex duration is typically slightly reduced during exercise in response to the increase in cardiac conduction velocity that accompanies faster heart rates. However, this patient's QRS duration is normal at rest and prolonged at near-maximal heart rate. This suggests that the drug used to treat his atrial fibrillation lengthens the QRS duration in a rate-dependent manner, which is consistent with a drug exhibiting strong use-dependence such as flecainide. Flecainide is a class 1C antiarrhythmic that is typically used to treat supraventricular tachycardias such as those caused by atrial fibrillation. Class 1C antiarrhythmics bind to the fast sodium channels responsible for phase 0 depolarization of cardiac myocytes, blocking the inward sodium current. This prolongs the QRS duration with little effect on total action potential or QT interval duration. Class 1C drugs are the slowest of the class 1 agents to dissociate from the sodium channel, and do so primarily during diastole. This results in a phenomenon known as use-dependence, in which their sodium-blocking effects intensify as the heart rate increases due to less time for the medication to dissociate from the receptor.

What would happen to the graph of an action potential after administration of disopyramide?

The illustration shows predominant slowing of phase 0 depolarization and prolongation of phase 3 repolarization (red curve) of ventricular action potential after administration of the drug. This action is usually seen with the use of class IA antiarrhythmics drugs (quinidine, procainamide, and disopyramide). Class I antiarrhythmic drugs block sodium channels and inhibit initial phase 0 depolarization of action potential, thereby slowing conduction. Class IA agents also have moderate potassium channel-blocking activity, leading to a slow rate of repolarization and prolongation of action potential duration in the cardiac myocytes.

Patient is started on fenofibrate therapy. This medication is most likely to help the patient by which of the following mechanisms?

This patient has a moderately elevated (>500 mg/dL) triglyceride level, which is associated with an increased risk of cardiovascular disease. Lifestyle modifications (increased aerobic exercise, decreased alcohol and total caloric intake) can decrease triglycerides, but moderate (or worse) hypertriglyceridemia usually requires pharmacologic therapy. Lipoprotein lipase (LPL) hydrolyzes triglycerides in chylomicrons and VLDL to release free fatty acids, which can be used for energy or converted back to triglycerides for storage in adipose tissue. It also facilitates the transfer of triglycerides from these lipoproteins to HDL. Fibrates (eg, gemfibrozil, fenofibrate) activate peroxisome proliferator-activated receptor alpha (PPAR-α), which leads to decreased hepatic VLDL production and increased LPL activity. They are able to decrease triglyceride levels by 25%-50% and increase HDL by 5%-20%. Fish oil supplements containing high concentrations of omega-3 fatty acids also decrease VLDL production, and inhibit synthesis of apolipoprotein B as well. These supplements lower triglycerides and can be used as an alternate treatment for patients with moderate hypertriglyceridemia.

What drug tx beta blocker overdose

This patient has most likely overdosed on beta blocker medications. Beta blocker overdose causes diffuse non-selective blockade of peripheral beta adrenergic receptors, causing depression of myocardial contractility, bradycardia, and varying degrees of AV block. The result is a low cardiac output state. Glucagon is the drug of choice for beta blocker overdose. Glucagon acts on G protein-coupled receptors, increasing intracellular cAMP and thus increasing the release of intracellular calcium during muscle contraction. This increases heart rate and cardiac contractility. Improvements in heart rate and blood pressure may be observed within minutes.

A 43-year-old man comes to the emergency department due to a 3-day history of persistent headaches. The patient has a history of hypertension and has had poor medical follow-up. Blood pressure is 224/115 mm Hg and pulse is 67/min. He appears mildly confused during the physical examination, but no focal neurologic deficits are noted. Funduscopic examination shows bilateral papilledema. Serum creatinine is 1.4 mg/dL. An intravenous medication is initiated that causes arteriolar dilation while also improving renal perfusion and increasing natriuresis. Which of the following agents is most likely being used in this patient?

This patient has severe hypertension. In addition, he has clinical evidence of secondary end-organ damage, including encephalopathy (eg, confusion), papilledema, and acute kidney injury (eg, elevated creatinine). This presentation is consistent with hypertensive emergency and requires aggressive treatment with immediate but controlled blood pressure reduction to minimize organ damage. Intravenous agents are preferred in hypertensive emergency due to their rapid action and dose titration ability. Fenoldopam is a short-acting, selective, peripheral dopamine-1 receptor agonist with little to no effect on alpha- or beta-adrenergic receptors. Dopamine-1 receptor stimulation activates adenylyl cyclase and raises intracellular cyclic AMP, resulting in vasodilation of most arterial beds with a corresponding decrease in systemic blood pressure. Renal vasodilation is particularly prominent and leads to increased renal perfusion, increased urine output, and natriuresis (ie, sodium excretion). This makes fenoldopam especially beneficial in patients with hypertensive emergency and renal insufficiency.

Patient is given diuretics that help his HF. Laboratory evaluation reveals a serum potassium level of 2.2 mEq/L. The patient receives potassium supplements, which improve the weakness. Another diuretic is added to her medical regimen to help prevent this adverse effect in the future. This additional medication predominantly acts on which of the following nephron segments?

This patient has symptomatic hypokalemia, likely due to treatment with loop diuretics (eg, furosemide) used to reduce the symptoms of heart failure. The physician most likely added a potassium-sparing diuretic to this patient's treatment regimen to minimize potassium loss caused by loop diuretic use. All diuretics except for the potassium-sparing class cause potassium loss by increasing sodium delivery to the late distal tubule and cortical collecting duct, where aldosterone-induced sodium reabsorption occurs at the expense of potassium. Potassium-sparing diuretics act primarily by antagonizing this effect of aldosterone. Some potassium-sparing diuretics, such as amiloride and triamterene, function by directly blocking the epithelial sodium channels (ENaCs) in the apical membrane of principal cells. Others, including spironolactone and eplerenone, competitively inhibit the aldosterone receptor, causing downregulation of both the apical ENaCs and basolateral Na+/K+ pumps. Spironolactone and eplerenone (a more specific receptor antagonist than spironolactone with fewer side effects) are preferred in patients with heart failure because they can also prevent the deleterious effects of aldosterone-induced cardiac remodeling.

Patient in for syncope. Has a PMH of spinal surgery. Says he used to do heroin as a teen. No hx of heart disease. BP is 120/70 supine and 125.75 standing. What ECG finding is likely?

This patient most likely has QT interval prolongation, a common adverse effect of methadone. QT interval prolongation is the ECG manifestation of delayed ventricular repolarization, which occurs due to impairment of the voltage-gated potassium channels that control the delayed rectifier potassium current. Significant slowing of ventricular repolarization can trigger torsade de pointes (TdP), a form of polymorphic ventricular tachycardia named for a repetitive "twisting of the peaks" pattern. TdP is a serious arrhythmia that can cause palpitations, lightheadedness, syncope, and sudden cardiac death (SCD). Many medications, including methadone, are known to inhibit the delayed rectifier potassium current to prolong the QT interval and predispose to TdP. Methadone undergoes slow and variable hepatic clearance, making consistent avoidance of toxic blood levels challenging; therefore, the use of high doses of methadone increases the risk of QT interval prolongation and TdP.

Immediate ECG shows normal sinus rhythm with a 2-mm ST-segment elevation in leads II, III, and aVF. Aspirin and morphine are administered. As the patient is about to be transported to the cath lab for urgent PCI, he develops dizziness and the telemetry monitor shows sinus bradycardia at 40/min. The patient appears pale and diaphoretic and peripheral pulses are faint. Blood pressure is 70/40 mm Hg. Which of the following is the best immediate step for managing this patient's condition?

This patient with ST elevation in leads II, III, and aVF has an acute inferior wall myocardial infarction (MI), which most commonly occurs due to occlusion of the right coronary artery (RCA). The RCA usually supplies blood to the sinoatrial node, the atrioventricular node, and most of the bundle of His; therefore, conduction impairment (eg, sinus bradycardia, atrioventricular block) is common in patients with inferior wall MI. Sinus bradycardia is the most common arrhythmia in those with inferior wall MI (nearly 50% of patients); it occurs due to both nodal ischemia and enhanced vagal tone triggered by infarction of myocardial tissue. The bradycardia is usually transient and resolves with restoration of coronary blood flow; however, patients with hypotension or symptoms of bradycardia (eg, lightheadedness, syncope) should be managed with intravenous atropine. The anticholinergic effects of atropine counteract the enhanced vagal tone to increase heart rate and improve symptoms.

A 65-year-old woman with type 2 diabetes mellitus and hypertension comes to the office for routine follow-up. She has occasional numbness in her feet. The patient takes ibuprofen for chronic back pain along with hydrochlorothiazide, metformin, atorvastatin, and insulin detemir. Her blood pressure is 120/76 mm Hg supine and 122/80 mm Hg standing. Laboratory evaluation shows a serum potassium level of 4.2 mEq/L and a creatinine level of 0.8 mg/dL. Urinalysis shows albuminuria. Lisinopril therapy is initiated. The next day, the patient returns due to lightheadedness and near-syncope. Her blood pressure is 102/66 mm Hg supine and 80/45 mm Hg standing. Her pulse is 94/min. Cardiopulmonary examination is normal. Which of the following is most likely the major factor contributing to this patient's current symptoms?

This patient with albuminuria was started on an ACE inhibitor for treatment of early diabetic nephropathy. Although most patients remain asymptomatic with only a mild reduction in blood pressure, first-dose hypotension can be a potential limiting factor when initiating ACE inhibitors. Significant hypotension is most likely to occur in patients with high plasma renin activity, such as those with volume depletion (eg, from diuretic use [hydrochlorothiazide in this patient]) or heart failure. Initiation of ACE inhibitor therapy causes abrupt removal of the vasoconstrictive effects of angiotensin II, resulting in decreased peripheral vascular tone and a precipitous drop in blood pressure in susceptible patients. To prevent the development of first-dose hypotension, therapy should be started at low doses and slowly titrated upward as needed.

A 76-year-old woman w/ lethargy and confusion. The patient has persistent atrial fibrillation and congestive heart failure and is on multiple medications. Recently, she has had nausea and decreased appetite. Today, she had 3 episodes of vomiting. The patient also reports vision difficulties. Temperature is 36.7 C (98 F) and blood pressure is 133/80 mm Hg. Labs show elevated K+. ECG shows junctional escape rhythm at a rate of 48/min with occasional ventricular premature beats. Increased blood level of which of the following medications is most likely responsible for her symptoms?

This patient with atrial fibrillation and congestive heart failure has signs and symptoms of digoxin toxicity. Although calcium channel blockers and beta blockers are the preferred treatments for patients with atrial fibrillation with rapid ventricular response, digoxin is a common second-line treatment that is particularly useful in patients with underlying systolic cardiac dysfunction. Its major effects are: 1. Increased vagal tone, causing slowing of conduction through the atrioventricular (AV) node (rate-control effect) 2. Na-K-ATPase inhibition, causing increased intracellular sodium and calcium (increases cardiac contractility) Digoxin has a narrow therapeutic index, making toxicity relatively common. Symptoms of digoxin intoxication are fairly nonspecific and include nausea, abdominal pain, fatigue, dizziness, confusion, blurred vision, and abnormal color perception. Digoxin toxicity can cause a wide range of cardiac arrhythmias, including bradycardia and junctional escape beats due to increased AV nodal block. Hypokalemia can precipitate toxicity by increasing digoxin binding to Na-K-ATPase. However, elevated potassium is a sign of digoxin toxicity as inhibition of Na-K-ATPase pumps increases extracellular potassium.

Describe Prinzmetal angina

This patient with episodes of recurrent chest discomfort that spontaneously resolve within 10-15 minutes most likely has vasospastic angina (formerly called Prinzmetal angina). It results from coronary endothelial dysfunction and autonomic imbalance that lead to intermittent coronary vasospasm and myocardial ischemia. Affected patients are usually young (eg, age <50) and lack typical risk factors for coronary artery disease (CAD) (eg, hypertension, diabetes mellitus); however, smoking is a strong risk factor, likely because it contributes to endothelial dysfunction. Symptoms of vasospastic angina are thought to be triggered by excess vagal tone, and they occur most commonly at night when vagal tone is at a peak. The diagnosis is made by ambulatory ECG demonstrating ST-segment elevation during an episode of chest discomfort and coronary angiography revealing an absence of obstructive atherosclerotic CAD. Because of the pathophysiology of the disorder, both acetylcholine and ergot alkaloids (eg, dihydroergotamine) provoke symptoms and may also aid in diagnosis, as follows: Acetylcholine normally stimulates endothelial muscarinic receptors to cause vasodilation via increased release of nitric oxide. However, a deficiency of endothelial nitric oxide in affected patients causes increased vagal tone to instead trigger vasoconstriction and precipitate vasospastic symptoms. Ergot alkaloids activate 5-HT2 serotonergic receptors to cause vasoconstriction. Normally, the vasoconstriction is somewhat offset by endothelial release of vasodilatory prostaglandins, but this response is lacking in affected patients due to endothelial dysfunction.

Patient with stable angina. The patient is started on low-dose aspirin therapy for secondary prevention of cardiovascular disease but experiences shortness of breath and wheezing with the medication. Which of the following is the best alternate therapy for this patient?

This patient's clinical history is consistent with stable angina (angina pectoris) due to underlying coronary heart disease (CHD). Patients with stable angina should be started on aspirin to decrease the risk of adverse cardiovascular events. Aspirin impairs prostaglandin synthesis by irreversibly inhibiting cyclooxygenase (COX). Inhibition of COX-1 in platelets prevents synthesis of thromboxane A2, a potent stimulator of platelet aggregation and vasoconstriction. This helps reduce the risk of occlusive thrombus formation and subsequent myocardial infarction. Some patients are unable to tolerate aspirin due to exacerbation of preexisting respiratory symptoms (eg, rhinitis, asthma) or development of allergic reactions (eg, urticaria, angioedema, anaphylaxis). In these patients, alternate antiplatelet agents should be used for prevention of cardiovascular events. Clopidogrel irreversibly blocks the P2Y12 component of ADP receptors on the platelet surface and prevents platelet aggregation. Clopidogrel is as effective as aspirin for prevention of cardiovascular events and should be used in patients with aspirin allergy

What is the cellular MOA of nitrates?

This patient's clinical presentation is consistent with acute pulmonary edema due to severely elevated blood pressure (hypertensive emergency). In such cases, intravenous vasodilators (nitroglycerine, sodium nitroprusside) are often used to improve the acute heart failure by reducing preload and afterload. Nitrates are metabolized within vascular smooth muscle cells to nitric oxide, which activates guanylate cyclase and promotes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). Increased levels of cGMP lead to decreased intracellular calcium (reduces the activity of myosin light-chain kinase) and activation of myosin light chain phosphatase. This promotes myosin light-chain dephosphorylation and vascular smooth muscle relaxation.

Describe the benefits of nitrates (effect on LVEDP, SVR, and Venous capacitance)

This patient's clinical presentation is consistent with acute pulmonary edema due to severely elevated blood pressure (hypertensive emergency). Intravenous vasodilators (eg, nitroglycerine, sodium nitroprusside) are often used in management of acute heart failure due to severe hypertension. Nitrates are primarily venodilators that increase peripheral venous capacitance, thereby reducing cardiac preload and left ventricular end-diastolic pressure (LVEDP) and volume. This is the primary mechanism of action for symptom relief in patients with acute pulmonary edema. Lower LVEDP also leads to a reduction in LV systolic wall stress and a decrease in myocardial oxygen demand, resulting in relief of angina symptoms. Although the vasodilatory effects of nitrates act primarily on the venous system, they also have a modest effect on arteriolar dilation (dec SVR). Higher doses can lead to a significant drop in systemic blood pressure, thereby decreasing cardiac afterload, reducing left ventricle wall stress, and causing a further decrease in myocardial oxygen demand.

On examination, the patient has a faint systolic murmur at the left sternal border in the supine position that increases to 3/6 in intensity with Valsalva maneuver. Echocardiogram shows interventricular septal hypertrophy and increased left ventricular mass. The patient is started on high-dose beta blocker therapy.

This patient's echocardiogram shows increased left ventricular (LV) mass with predominant interventricular septal hypertrophy, which are classic findings for hypertrophic cardiomyopathy (HCM). Many patients with HCM have LV outflow tract obstruction that can lead to symptoms of poor cardiac output (eg, dyspnea, syncope). The outflow tract obstruction worsens with decreased LV blood volume (as can occur during exercise due to decreased LV filling time and increased LV contractility); on physical examination, this effect is evidenced by a systolic murmur that increases in intensity with maneuvers that decrease LV blood volume (eg, Valsalva strain phase, abrupt standing). In patients with HCM and symptomatic LV outflow tract obstruction, beta blockers (eg, metoprolol, nadolol) improve symptoms mostly via an increase in LV volume that reduces LV outflow tract obstruction and improves cardiac output. This occurs via the following 2 mechanisms: 1. Beta blockers reduce heart rate, which lengthens diastolic filling time and increases the amount of blood that can enter the heart during each beat (increasing end-diastolic volume) 2. Beta blockers also reduce LV contractility, which reduces the amount of blood ejected during systole (increasing end-systolic volume)

This patient's presentation, family history of premature sudden death, and systolic murmur that accentuates with standing from a supine position is consistent with ______. What medication should be avoided when treating his condition?

This patient's presentation, family history of premature sudden death, and systolic murmur that accentuates with standing from a supine position is consistent with hypertrophic cardiomyopathy(HCM). Patients with HCM have dynamic left ventricular outflow tract (LVOT) obstruction that worsens with decreased left ventricular (LV) volume (as can be caused by decreased preload and/or reduced systemic vascular resistance). As such, medications that generally should be avoided in patients with HCM include: Vasodilators (eg, dihydropyridine calcium channel blockers, nitroglycerin, and ACE inhibitors) decrease systemic vascular resistance, leading to decreased afterload and lower LV volumes. Diuretics decrease LV venous filling (preload) and also result in greater outflow obstruction. In contrast, negative inotropic agents such as beta blockers (metoprolol), nondihydropyridine calcium channel blockers (verapamil), and disopyramide reduce LVOT obstruction and are helpful in symptomatic patients with HCM (Choices B, D, and E). In addition, beta blockers may also help reduce anginal symptoms by decreasing myocardial oxygen demand.

A 65-year-old man w/ pain as "very severe" and "going back all the way to my spine." He has a 20-pack-year smoking history. Blood pressure is 195/101 mm Hg, and pulse is 93/min and regular. ECG shows sinus rhythm and voltage criteria for left ventricular hypertrophy. Portable chest x-ray reveals a widened mediastinum. The patient is immediately treated with intravenous esmolol. Which of the following is the most likely purpose of this patient's current therapy?

This patient's severe chest pain radiating to the back and a widened mediastinum on chest x-ray are consistent with acute aortic dissection. Uncontrolled hypertension, suggested by the patient's nonadherence with medical therapy and ECG evidence of left ventricular (LV) hypertrophy, is the strongest risk factor for aortic dissection. With each LV contraction, the ejected stroke volume rapidly increases aortic pressure and generates shear stress on the aortic wall. Medical therapy for aortic dissection is aimed at reducing aortic wall shear stress to limit extension of the dissection. This is accomplished via anti-impulse therapy to decrease the rate of change in aortic blood pressure per time (ie, reduce dP/dt). Esmolol is a selective beta-1 receptor blocker that is given by intravenous infusion. It is first-line therapy for acute aortic dissection as it has a short half-life (allowing for easy dose titration) and reduces shear stress in 2 ways: 1. Negative inotropy decreases LV contraction velocity. This decreases the rate of blood ejection and reduces stroke volume to decrease the rise in blood pressure with each contraction (ie, decreased rate and magnitude of blood pressure change). 2. Negative chronotropy decreases heart rate, subjecting the aortic wall to fewer LV contractions per minute (ie, decreased number of blood pressure changes). Once shear stress has been minimized with adequate reduction in LV contractility and heart rate, decreasing peripheral vascular resistance (PVR) to further reduce blood pressure is also beneficial. Because esmolol has little effect on PVR, vasodilators (eg, nitroprusside, nicardipine) may be added for this purpose. Vasodilators should never be given prior to a negative chronotropic agent because vasodilation causes reflex tachycardia that increases aortic wall shear stress.

Pt who was hospitalized two weeks ago for A fib and given medication. He has a PMH of HTN and COPD. HIs BP is now under control but ECG shows new onset second degree heart block and he has constipation. What medication likely caused this?

This patient's severe constipation and new-onset second-degree atrioventricular (AV) block (causing syncope) in the setting of new medication use for atrial fibrillation (AF) is likely due to calcium channel blocker (CCB) therapy. Diltiazem and verapamil are nondihydropyridine CCBs that are frequently used for hypertension, angina pectoris, and supraventricular arrhythmias (atrial flutter, AF, paroxysmal supraventricular tachycardia). These drugs exert their primary action by blocking the L-type calcium channels, thereby decreasing phase 0 depolarization and conduction velocity in the sinoatrial and AV nodes. This leads to slowing of the sinus rate and conduction through the AV node, which can then cause bradycardia and varying degrees of AV block. The drugs also have a negative inotropic effect and are relatively contraindicated in patients with congestive heart failure due to left ventricular systolic dysfunction. Constipation is a major side effect of nondihydropyridine CCBs (verapamil > diltiazem).

A 50-year-old man is brought to the ER with severe dizziness and confusion. He states that he had an episode of chest pain and took several tablets of nitroglycerin. His current medications include a daily aspirin for heart attack prevention, an occasional acetaminophen for headaches and occasionally tadalafil for erectile dysfunction. His blood pressure is 50/20 mmHg and his heart rate is 120 beats/min. Which of the following cellular changes is most likely responsible for this patient's symptoms?

cGMP accumulation The interaction between nitrates and phosphodiesterase inhibitors used in erectile dysfunction (tadalafil, sildenafil, vardenafil) is well known and very important to understand. Nitrates are converted to nitric oxide by vascular smooth muscle cells, and nitric oxide causes increased intracellular cGMP as a second-messenger. Increased cGMP concentration leads to vascular smooth muscle relaxation. Additionally, cGMP is metabolized within the cells by phosphodiesterase, and phosphodiesterase inhibitors will lead to increased intracellular cGMP. cGMP accumulation in vascular smooth muscle cells due to both enhanced synthesis (nitrates) and inhibited degradation (PDE inhibitors) is responsible for profound hypotension due to extreme vasodilatation when these drugs are used together.

Administration of the drug caused an increase in systolic and diastolic blood pressures and a reflexive (delayed) decrease in heart rate is indicative of what drug class?

these are the typical effects of a selective α1-adrenergic agonist (eg, phenylephrine, methoxamine). Activation of α1-adrenoreceptors (in blood vessels of skin and viscera) leads to vasoconstriction and increased systemic blood pressure. Stimulation of baroreceptors in the carotid sinus and aortic arch causes a reflexive increase in vagal influence on the heart. The increased vagal tone results in inhibition of pacemaker activity of the sinoatrial node, slowed conduction through the atrioventricular node, and decreased myocardial contractility.