Epidemiology and etiology

More than 1 billion people worldwide and 1 in every 4 Americans has high blood pressure (≥140/90 mm Hg). Hypertension adversely affects numerous body organs, including the heart, brain, kidney, and eye. Damage to these organ systems resulting from hypertension is termed cardiovascular disease (CVD). Uncontrolled hypertension increases CVD morbidity and mortality by increasing the risk of developing left ventricular hypertrophy, angina, myocardial infarction (MI), heart failure, stroke, peripheral arterial disease, retinopathy, and kidney disease. One of eight deaths can be attributed to hypertension, and the World Health Organization reports that suboptimal blood pressure (systolic blood pressure above 115 mm Hg) is responsible for 62% of cerebrovascular disease and 49% of ischemic heart disease. Blood pressure increases with age, and hypertension is more prevalent in adults older than 65 years. This fact is of great concern because it is estimated that by 2040, 25% of the American population will be older than 65. Hypertension occurs more frequently in men than in women and occurs in more blacks than whites. Evidence suggests that individuals who are normotensive have a greater than 90% lifetime risk for developing hypertension by age 55 (Table 22-1).¹

Hypertension is diagnosed by the mean of two or more separate seated blood pressure determinations on different days. The Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VII), published in 2003, is the most up-to-date guideline compared with other hypertension treatment recommendations.² The American Heart Association (AHA) released a statement regarding the treatment of hypertension as it relates to the prevention and management of ischemic heart disease, which differed from the JNC-VII recommendations.³ Significant differences between JNC-VII and the AHA statement include expanding the category of the high-risk hypertensive to include patients with known coronary artery disease (CAD) or CAD risk equivalents (e.g., carotid artery disease, peripheral arterial disease, or abdominal aortic aneurysm or a 10-year Framingham risk score of more than 10%).

For high-risk patients, the blood pressure goal remains less than 130/80 mm Hg and less than 140/90 mm Hg for primary prevention. More aggressive target blood pressure of less than 120/80 mm Hg is recommended in patients with left ventricular dysfunction (LVD). First-line treatments for patients with high blood pressure without CAD include four drug classes: thiazide diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs). β blockers were removed as first-line agents in patients with high blood pressure who do not have CAD. In addition, the AHA does not promote any single agent as preferred first-line therapy if no compelling indications exist.

Individuals with prehypertension, defined by JNC-VII as having a blood pressure reading between 120/80 mm Hg and 139/89 mm Hg, have a 50% greater risk of developing hypertension than individuals with lower blood pressure values. Overall, each increase in systolic blood pressure of 20 mm Hg (or 10 mm Hg in diastolic blood pressure) doubles the risk of a fatal coronary event. Early recognition, lifestyle modifications, and management of prehypertension are essential to decrease the rate of progression to hypertension or prevent hypertension entirely. Most patients require two or more drugs to reach target blood pressure, and when blood pressure is more than 20/10 mm Hg above goal, two drugs should be initiated from the time of diagnosis.

The discussion of hypertension in this chapter is based on the JNC-VII guidelines and 2007 AHA statement. The release of JNC-VIII is not anticipated until Spring 2012, and these guidelines are not reflected in this chapter.

In almost all cases, the etiology of hypertension is unknown, and it is termed either primary hypertension or essential hypertension. The prevalence of secondary hypertension is less than 10%; secondary hypertension includes many disease-induced and drug-induced etiologies. Disease-induced causes of hypertension include Cushing syndrome, hyperparathyroidism, hyperthyroidism, pheochromocytoma, primary aldosteronism, and kidney disease. Drug-induced causes of hypertension include amphetamines, corticosteroids, cyclosporine, erythropoietin, estrogens, nonsteroidal antiinflammatory drugs (NSAIDs) including cyclooxygenase-1 inhibitors (e.g., ibuprofen and naproxen) and cyclooxygenase-2 inhibitors (e.g., celecoxib), pseudoephedrine, sibutramine, tacrolimus, venlafaxine, high sodium–containing over-the-counter (OTC) products (e.g., Alka-Seltzer effervescent antacid tablets), OTC weight loss products (e.g., ephedrine-containing diet pills), and chronic alcohol ingestion.^4,5

Pathophysiology

Arterial blood pressure, termed blood pressure, is generated by the interplay between blood flow and the resistance to blood flow. Arterial blood pressure reaches a peak during cardiac systole and a nadir at the end of diastole. Arterial blood pressure is defined hemodynamically as the product of cardiac output (heart rate × stroke volume) and total peripheral resistance. Venous capacitance, which affects the volume of blood (preload), is a major determinant of cardiac output and systolic blood pressure. Arteriolar capacitance (afterload) is a major determinant of total peripheral resistance and diastolic blood pressure. Antihypertensives elicit actions on some or all of the hemodynamic parameters that define arterial blood pressure.

Hypertensive crisis

A patient with blood pressure greater than 180/120 mm Hg is considered to be in a hypertensive crisis. A hypertensive crisis represents either a hypertensive urgency or a hypertensive emergency. Hypertensive urgencies usually signify high blood pressures without signs or symptoms of acute target organ complications; however, patients may present with severe headaches, shortness of breath, nosebleeds, or severe anxiety. In these situations, improvement in blood pressure control can be accomplished over a period of 24 to 48 hours.² Overaggressive use of intravenous drugs and oral medications can cause too rapid a decrease in blood pressure. Rapid decrease in blood pressure can result in hypoperfusion of organs such as the brain, kidneys, and heart. Oral antihypertensive agents such as captopril, clonidine, and labetalol are routinely used to manage hypertensive urgencies, followed by close observation for several hours. Patients can benefit from antihypertensive medication adjustments if they are found to be noncompliant with taking their medications.

A hypertensive emergency exists when the elevation of blood pressure is accompanied by acute progressing target organ injury. Examples of acute target organ injury include encephalopathy, intracranial hemorrhage, severe retinopathy, renal failure, unstable angina, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, and eclampsia. Hypertensive emergencies require admission to an intensive care unit and invasive arterial blood pressure monitoring and immediate, but gradual blood pressure reduction over minutes to several hours with intravenous antihypertensives. The initial goal as outlined in JNC-VII is to reduce the mean arterial pressure (MAP) by no more than 25% within minutes to 1 hour after starting therapy. MAP can be calculated by adding one-third of the systolic blood pressure to two-thirds of diastolic blood pressure:

< ?xml:namespace prefix = "mml" />([⅓ systolic BP] + [⅔ diastolic BP])

In the next 2 to 6 hours, the blood pressure must be gradually decreased to 160/100 to 160/110 mm Hg. If the decreased blood pressure is well tolerated by the patient, further reduction of blood pressure toward normal can be attempted over the next 24 to 48 hours. Recommendations differ for patients with ischemic stroke, patients with aortic dissection, and patients awaiting antithrombolytic therapies. Intravenous labetalol and nitroprusside can be used to manage most types of hypertensive emergencies. Depending on other comorbid conditions, alternative intravenous medications can be employed (e.g., nicardipine, esmolol, nitroglycerin, ACEI, and hydralazine). Nitroprusside at high doses or when used for long durations can cause methemoglobinemia. Classic methemoglobin blood is chocolate brown and is without color change despite exposure to air.

Angiotensin-converting enzyme inhibitors

ACEIs act primarily through suppression of the renin-angiotensin-aldosterone system (RAAS). Because of a lack of renal blood flow, renin is released into the circulation, where it acts on angiotensinogen to produce angiotensin I. In the pulmonary vasculature, angiotensin I is converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II is a highly potent endogenous vasoconstrictor that also stimulates aldosterone secretion from the zona glomerulosa cells of the adrenal cortex, contributing to sodium and water retention.⁸ Angiotensin II also stimulates the release of catecholamines from the adrenergic nerve endings and mediates the release of central sympathetic outflow. ACE is abundant in the endothelial cells of blood vessels and to a lesser extent in the kidneys.

ACEIs block the conversion of angiotensin I to angiotensin II by competing with the physiologic substrate angiotensin I for the active site of ACE (Figure 22-2). The affinity of ACEIs for ACE is approximately 30,000 times greater than for angiotensin I. ACEIs also inhibit kininase which is responsible for the degradation of bradykinin and other vasodilating substances, including prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂), which enhances the antihypertensive effects of these drugs. Because ACEIs are potent antihypertensives in patients with low-renin hypertension, the effects on bradykinin may have an integral role in the mechanism of action of these agents. The hemodynamic effects of ACEIs are a reduction of peripheral arterial resistance, an increase in cardiac output, little or no change in heart rate, an increase in renal blood flow, and unchanged glomerular filtration rate (GFR). ACEIs have mild antihyperlipidemic effects.

Ten ACEIs are available in the United States. ACEIs are the preferred antihypertensives in the setting of systolic dysfunction heart failure, proteinuric kidney disease (diabetic and nondiabetic), and post-MI. ACEIs generally decrease systolic and diastolic blood pressure by 15% to 25%. ACEIs are most effective in normal-renin or high-renin hypertension; however, they are also effective in low-renin hypertension, especially when used at maximal doses. ACEIs are effective alone and in combination with other antihypertensive agents, especially thiazide-type diuretics. The combination of ACEIs and β blockers is less effective in inducing additive blood pressure–lowering effects than other combinations; this is due to the ability of β blockers to reduce renin secretion, which decreases angiotensin II formation.

ACEIs rival diuretics as the most effective first-line antihypertensives to decrease CVD morbidity and mortality in various settings. In contrast to β blockers and thiazide diuretics, ACEIs do not induce glucose intolerance, hyperlipidemia, or hyperuricemia. ACEIs are homogeneous, which means there is very little variability among ACEIs in terms of efficacy and toxicity. With the exception of captopril, all ACEIs are generally administered once or twice daily. Enalaprilat is the only available parenteral ACEI. Table 22-2 presents the pharmacokinetics and dosing guidelines for ACEIs.^4,5

The most common adverse effect associated with ACEIs is a persistent nonproductive dry cough (20% to 30%). The cough may be due to ACEI-induced accumulation of kinins, prostaglandins, or substance P in the respiratory tract. The cough may develop within days to 1 year after the start of therapy. Antitussives are ineffective in relieving ACEI-induced cough. Cross-reactivity among the ACEIs is absolute; however, ARBs rarely cause cough and may be considered an alternative. ACEI-induced rash is also common; the incidence is 10%, and the reaction is usually transient. The rash often occurs in the upper extremities and is often accompanied by pruritus and erythema. A higher incidence of rash with captopril relative to other ACEIs may be due to the sulfhydryl-containing structure of captopril. All other ACEIs, with the exception of fosinopril (phosphorus-containing), possess a dicarbocyl group. ACEIs are known to cause dysgeusia (6%), manifesting as a metallic or salty taste or loss of taste perception.

ACEIs may cause a slight increase in potassium that is generally inconsequential. The risk of hyperkalemia may be increased, with concomitant use of β blockers, heparin, low-molecular-weight heparin (LMWH), trimethoprim, amiloride, spironolactone, and salt substitutes and in patients with diabetes or renal failure. Orthostatic hypotension is common when initiating ACEI therapy, especially in patients who are in a high-renin state, such as patients who are salt or volume depleted (e.g., patients with heart failure, cirrhosis, or diabetes or receiving diuretics). Patients with bilateral renal artery stenosis, with unilateral stenosis of a solitary functioning kidney, or in a high-renin state (especially patients with heart failure) are susceptible to developing ACEI-induced acute renal failure. Proteinuria, defined as total urinary protein exceeding 1 g/day and, rarely, accompanied by increases in blood urea nitrogen and serum creatinine, may develop in patients receiving high-dose ACEIs or with average ACEI doses and preexisting renal dysfunction. ACEI-induced blood dyscrasias such as neutropenia and agranulocytopenia occur with an incidence of less than 1% and are more common in patients with connective tissue diseases (e.g., systemic lupus erythematosus). ACEIs should be avoided in women of childbearing age because of the potential for fetal and neonatal morbidity and mortality in the second and third trimesters of pregnancy manifesting as skull hypoplasia, hypotension, anuria, and death (pregnancy category D).

Angioedema is rare, occurring in about 1 to 5 of 1000 patients, but it can be life-threatening when accompanied by dyspnea. Angioedema can occur at any time during ACEI therapy, especially when starting and stopping regimens. Angioedema generally manifests in the upper extremities, primarily the face, lips, tongue, glottis, and larynx. ACEI-induced angioedema is an absolute contraindication for the administration of alternative ACEIs and a relative contraindication for ARBs, especially in patients with a history of angioedema with dyspnea or with documented aminopeptidase P deficiency. Angioedema symptoms may be associated with high concentrations of bradykinin. Bradykinin exerts its pharmacologic effects (vasodilation and proinflammation) on bradykinin-2 receptors and is metabolized primarily by ACE, to a lesser extent by aminopeptidase P, and to a minor extent by carboxypeptidase N. Delineating which patients have an aminopeptidase P plasma level deficiency may help predict which patients are predisposed to angioedema.

A significant drug interaction occurs when combining ACEIs with NSAIDs. NSAIDs increase renin release by inhibiting renal vasodilating prostaglandins (PGE₂ and PGI₂), blunting or negating the antihypertensive effects of ACEIs. NSAIDs less likely to reduce renal prostaglandins and to minimize or circumvent the interaction with ACEIs are sulindac (Clinoril), nabumetone (Relafen), etodolac (Lodine), salsalate (Disalcid), and choline magnesium trisalicylate (Trilisate). ACEIs may increase lithium concentrations and have been associated with life-threatening lithium toxicity. ACEI-induced renal sodium depletion may increase lithium renal tubule reabsorption. Patients receiving this combination should be monitored for symptoms of lithium toxicity such as nausea, vomiting, diarrhea, tremor, and mental status changes. Lithium levels should be monitored before and after initiating the ACEI. A quinapril tablet, in contrast to other ACEIs, contains magnesium carbonate at sufficient concentration to reduce tetracycline absorption 40%. The mechanism of this interaction may be chelation and plausibly may occur with quinolones. To circumvent this interaction, quinapril should be spaced 2 to 6 hours apart from tetracycline and quinolone antimicrobials.

Angiotensin II receptor blockers

Several nonrenin and non-ACE pathways are used for the production of angiotensin II (see Figure 22-2). Nonrenin pathways generate angiotensin II from angiotensinogen via tissue plasminogen activator, cathepsin G, and tonin. Non-ACE enzymes that generate angiotensin II from angiotensin I are cathepsin G, chymostatin-sensitive angiotensin II–generating enzyme, and chymase. ACEIs incompletely block the synthesis of angiotensin II. ARBs are angiotensin II type 1 (AT₁) receptor antagonists. AT₁ receptors are found in many tissues, such as vascular smooth muscle, myocardial tissue, brain, kidney, liver, uterus, and adrenal glands (cortex and medulla). Many tissues also have an AT₂ receptor; however, it is not known to have effects on myocardial hemostasis. ARBs have 1000-fold greater affinity for AT₁ receptors than AT₂ receptors and generally do not block the AT₂ receptor. Because ARBs do not inhibit ACE, they do not interfere with the concentrations of bradykinins and substance P. This kinin-sparing effect may explain why ARBs have a low incidence of inducing cough or angioedema. However, the beneficial effects of kinins, including blood pressure–lowering potency, may be sacrificed.

Seven ARBs are available in the United States. ARBs are indicated for hypertension and can be used to treat heart failure. ARBs have been shown to reduce morbidity, such as target organ damage (e.g., nephropathy) in patients with hypertension, cardiovascular events in patients with systolic heart failure, and progression of nephropathy in patients with type 2 diabetes. In black patients, ARBs and ACEIs may be less potent antihypertensives; however, this can be circumvented by administering maximal doses.

Compared with ACEIs, ARBs are considered as potent or slightly weaker antihypertensive agents. The inhibition of bradykinin by ACEIs may account for its augmented antihypertensive effect. Angiotensin II receptor blockers arguably are considered second-line agents to ACEIs for hypertension and heart failure and are indicated when ACEI-induced cough or other adverse effects are intolerable. However, ARBs may be considered superior to ACEIs in patients with type 2 diabetic nephropathy. ARBs are administered once or twice daily. Using the combination of an ACEI and an ARB has not been well studied; however, its beneficial effects have been observed in patients with heart failure and nephrotic syndrome. Table 22-3 presents the pharmacokinetics and dosing guidelines for ARBs.^4,5,8

The side-effect profile of ARBs seems to be similar to that of ACEIs. ARBs may cause orthostatic hypotension, hyperkalemia, neutropenia, nephrotoxicity, and fetotoxicity. Similar warnings and precautions exhibited with ACEIs should be undertaken for ARBs. ARBs can cause cough; however, the incidence is significantly less than with ACEIs. ARBs cause significantly less angioedema than ACEIs; cross-reactivity has been reported. ARBs are not absolutely contraindicated in ACEI-induced angioedema; however, their use in this setting can be dangerous and should be avoided. Rash and dysgeusia are rarely reported with ARBs.

Losartan is extensively metabolized by the hepatic cytochrome P450 3A4 (CYP3A4) and CYP2C9 isoenzymes to an active carboxylic acid metabolite that is predominantly responsible for the AT₁ blockade and antihypertensive effects of losartan. Drugs that induce these enzyme systems (e.g., phenytoin, phenobarbital, carbamazepine, oxcarbazepine, rifampin, and rifabutin) may increase the antihypertensive effects of losartan by increasing the concentration of the active metabolite. Phenobarbital has been shown to decrease the levels of losartan and its metabolite by 20%. Conversely, drugs that inhibit CYP3A4 (e.g., ketoconazole, fluconazole, erythromycin, clarithromycin, fluoxetine, and amiodarone) or CYP2C9 (e.g., amiodarone, cimetidine, and fluoxetine) or CYP3A4 and CYP2C9 simultaneously (e.g., fluoxetine, amiodarone) may decrease the antihypertensive effects of losartan by decreasing the concentration of the active metabolite. However, a study evaluating the effects of cimetidine (CYP3A4 and CYP2C9 inhibitor) on losartan did not yield any changes in the disposition of losartan’s carboxylic acid metabolite.

Telmisartan has been shown to increase digoxin peak plasma concentrations by 50%. Digoxin serum concentrations should be monitored before and after the addition of telmisartan. Several mechanistically similar drug-drug interactions that occur with ACEIs are likely to occur with ARBs, such as with NSAIDs and lithium.

Direct renin inhibitors

DRIs act by inhibiting renin, the enzyme that is the first step of the RAAS (see Figure 22-2). Renin is responsible for the conversion of angiotensinogen to angiotensin I, which is the rate-limiting step in RAAS. Renin inhibition also leads to decreased formation of angiotensin II and aldosterone. However, all agents that inhibit the RAAS, such as ACEIs, have the potential to inhibit feedback inhibition of renin leading to increases in renin and its activity. This effect can be blocked with the use of a renin inhibitor. DRIs can be used alone or in combination with other antihypertensive agents.

Aliskiren (Tekturna) is currently the only DRI available on the market. It is indicated only for the treatment of hypertension. Similar to ACEIs and ARBs, aliskiren is considered a poor antihypertensive agent for black patients. In addition, no studies show that aliskiren is effective in reducing cardiovascular risk. It can be used in combination with any other antihypertensive agents, but it has been studied most comprehensively in combination with ARBs and diuretics.

The most common side effects observed with aliskiren include diarrhea, headache, dizziness, fatigue, upper respiratory tract infection, nasopharyngitis, and back pain. Aliskiren can also cause dry cough, but its incidence is much less than that reported with ACEIs. Similar to other agents that affect the RAAS, aliskiren has been associated with angioedema, and has occurred in patients with and without a history of angioedema with ACEI or ARB therapy. Aliskiren possibly may be fetotoxic and is not recommended for use in pregnant patients (pregnancy category C for the first trimester and pregnancy category D for the second and third trimesters). Rare side effects include increased uric acid levels, renal stones, anemia, rash, renal impairment, myositis, and rhabdomyolysis. Aliskiren monotherapy has a low incidence of hyperkalemia; however, hyperkalemia occurs more frequently when aliskiren is used in combination with ACEIs. It should be used cautiously in combination with other agents that cause hyperkalemia, such as potassium-sparing diuretics and sulfamethoxazole-trimethoprim (Bactrim). Currently, there are no contraindications to use of aliskiren.

Aliskiren is administered once daily at a dose of 150 to 300 mg. It has very poor oral bioavailability; only about 2.5% is absorbed. Absorption of aliskiren is substantially decreased by high fatty meals; patients should always take it the same way: either with or without food. It undergoes minimal hepatic metabolism by CYP3A4. Cyclosporine and itraconazole, which are potent inhibitors of CYP3A4, were shown to increase aliskiren levels significantly and should not be used concomitantly. Other CYP3A4 inhibitors were also shown to increase aliskiren levels, but the clinical significance of their interaction is unknown. Aliskiren has also been shown to reduce the effectiveness of furosemide by 30% to 50%. The effectiveness of furosemide should be monitored when these two agents are used concomitantly. Approximately 25% of the absorbed dose is excreted unchanged in the urine. Most of the unabsorbed drug is excreted in the feces. No dosage adjustments are recommended at this time in patients with renal or hepatic impairment.^9,10

Calcium channel blockers

Vascular smooth muscle and cardiac cell contraction depends on free intracellular calcium ion concentration. Calcium enters vascular smooth muscle cells, myocardial cells, and pacemaker cells through voltage-gated L-type and T-type calcium channels. L-channel blockade mediates coronary and peripheral vasodilation and may cause reflex sympathetic activation or a negative inotropic effect. T-channel blockade also mediates coronary and peripheral vasodilation but is devoid of a reflex sympathetic activation. The influx of calcium from extracellular fluid into cells triggers a second messenger, inositol triphosphate, to release stored intracellular calcium from the sarcoplasmic reticulum. This increase in cytosolic calcium results in enhanced binding to the protein calmodulin. A calcium-calmodulin complex activates myosin kinase, promoting the interaction between actin and myosin, culminating in cellular contraction. Conventional calcium channel blockers inhibit only L-channels. The pharmacodynamic effects of the calcium antagonists on smooth muscle, myocardium, or specialized conduction and pacemaker tissues differ among the agents because of different receptor distribution and densities and the drug’s inherent receptor selectivity and affinity.

Nondihydropyridine CCBs include verapamil and diltiazem. Verapamil and, to a lesser extent, diltiazem possess negative chronotropic effects by lowering sinoatrial (SA) node automaticity and decreasing atrioventricular (AV) node conduction; these agents are indicated for the treatment of angina and arrhythmias in addition to hypertension. Verapamil and, to a lesser extent, diltiazem are also potent negative inotropes and may exacerbate heart failure and should be avoided in patients with severe left ventricular dysfunction.

Dihydropyridine CCBs are potent vasodilators; these agents include amlodipine, felodipine, isradipine, nicardipine, nifedipine, and nisoldipine. With the exception of nifedipine, dihydropyridines have negligible chronotropic effects. Immediate-release nifedipine, especially when administered as a liquid (pseudosublingual), causes a potent reflex tachycardia that increases coronary oxygen demand and has been implicated with an increased risk of MI and stroke. Only sustained-release dosage forms of nifedipine are indicated for hypertension.¹¹ Amlodipine and plausibly felodipine may be used in patients with heart failure because these agents do not decrease cardiac contractility. CCBs are very effective antihypertensive agents in both elderly and black patients. Table 22-4 presents the pharmacokinetics and dosing guidelines for calcium antagonists.^2–5

Verapamil (e.g., Covera-HS, Verelan PM) and diltiazem (Cardizem LA) have long-acting formulations that are specifically designed to target the circadian rhythm of blood pressure throughout the day. Many hypertensive patients have a catecholamine surge with a blood pressure peak in the morning between 6 a.m. and 12 p.m., followed by sustained high (but lower than the peak) blood pressures throughout the day and a nadir at night. Most MIs, strokes, dysrhythmias, and venous thromboembolic events occur in the morning hours, in concert with the circadian blood pressure peaks. CCB formulations are generally designed to be dosed at bedtime and begin to release medication in the early morning to achieve a peak effect in the morning hours and a sustained effect during the day.

These novel circadian dosage forms may have limited utility in hypertensive patients who do not have a nadir in blood pressure in the nighttime, or “nondippers.” These formulations leave patients unprotected with a high risk of a coronary event and have not been shown to have better effects on morbidity compared with thiazides and β blockers. Typical hypertensive nondippers (no nighttime nadir) are elderly patients, patients with renal insufficiency, and patients with secondary hypertension. Both verapamil and diltiazem are available in several immediate, extended, and sustained release products. The different dosage formulations of the same drug, with or without circadian effects, are usually not interchangeable and should not be switched on a milligram-to-milligram basis.

The incidence of verapamil-induced, and to a lesser extent diltiazem-induced, constipation is high and often necessitates the use of a stimulant laxative such as bisacodyl or sennosides. Dihydropyridines have potent peripheral vasodilating effects, and they have a high incidence of palpitations, orthostatic hypotension, flushing, headaches, lightheadedness, and syncope. These adverse effects are minimized with long-acting agents. All CCBs may cause peripheral edema, gingival hyperplasia, and gastroesophageal reflux (except diltiazem). CCB-induced peripheral edema does not respond to diuretic therapy and requires discontinuation of the offending agent.

Diltiazem and verapamil inhibit CYP3A4 metabolism and plausibly the P-glycoprotein transport of alfentanil, buspirone, carbamazepine, cyclosporine, digoxin, lovastatin, methylprednisolone, quinidine, simvastatin, and tacrolimus, resulting in higher serum levels and potential toxicity. Verapamil and diltiazem inhibit the hepatic metabolism of theophylline. Although dihydropyridine CCBs are not inhibitors of CYP3A4, they are major substrates of CYP3A4 and may result in significant drug and food interactions through competitive inhibition. Grapefruit juice inhibits the CYP3A4 in the gut and may increase significantly the levels of felodipine, nifedipine, and nisoldipine. Because many CCBs are significantly metabolized by the CYP450 system, CYP450 enzyme inducers, such as carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and rifampin, may lower the serum concentrations of CCBs and compromise efficacy.

β blockers

The antihypertensive effects of β blockers have multiple mechanisms of action and are as follows:

β blockers cannot be used interchangeably with each other. Instead, disease state guidelines dictate which β blockers to use for each comorbidity. β blockers with intrinsic sympathomimetic activity (ISA), including acebutolol, carteolol, penbutolol, and pindolol, cause less reduction of resting heart rate, cardiac output, and peripheral blood flow. ISA may be beneficial in patients with stable angina, bradyarrhythmias, compromised pulmonary function, and peripheral vascular (arterial) disease. Labetalol is an α and β blocker with weak β₂ ISA; nevertheless, it is relatively contraindicated in patients with asthma and chronic obstructive pulmonary disease. Labetalol is indicated for hypertension and is often used to manage hypertensive urgencies (oral formulation) and hypertensive emergencies (parenteral formulation). The α and β blocker carvedilol is indicated for patients with hypertension and for patients with mild to moderate heart failure.

The newest agent, nebivolol (Bystolic), is a highly cardioselective third-generation β₁ blocker, which also exhibits vasodilatory properties mediated through nitric oxide, resulting in decreased peripheral vascular resistance, increased stroke volume, and preserved cardiac output. It is approximately three times more β₁-selective than bisoprolol. It is indicated for the treatment of hypertension and has similar blood pressure reduction effects as atenolol, bisoprolol, ACEIs, ARBs, and CCBs.

β blockers are indicated for hypertension, angina pectoris, cardiac dysrhythmias, secondary prevention of MI, chronic heart failure, and pheochromocytoma. β blockers are no longer considered first-line agents in treatment of essential hypertension but should be reserved as add-on therapy to other antihypertensive agents. β blockers are also used for migraine prophylaxis, hypertrophic subaortic stenosis, tremors, alcohol withdrawal syndrome, prophylaxis of esophageal variceal rebleeding, anxiety, symptoms of thyrotoxicosis, and in combination with α blockers for pheochromocytoma. Table 22-5 presents the pharmacokinetics and dosing guidelines for β blockers.^2,3,5,9

β blockers increase triglycerides and decrease high-density lipoproteins; however, this deleterious effect may diminish after prolonged therapy (1 year). β blockers may cause hyperglycemia and glucose intolerance. These agents can be especially dangerous in diabetics because they mask some of the common symptoms of hypoglycemia, such as palpitations, tremors, and hunger. The use of β blockers in patients with hyperlipidemia or diabetes is acceptable if the lipid and glucose profiles are closely monitored. α and β blockers and agents with ISA are less likely to affect the lipid and glucose profiles adversely.

β blocker–induced pulmonary dysfunction may manifest as bronchospasm, bronchial obstruction, wheezing, dyspnea, cough, and exacerbation of previously stable asthma or chronic airway obstruction. Agents with β₁ selectivity, such as atenolol and metoprolol, are less likely to cause pulmonary dysfunction; however, they lose their selectivity with increasing doses. β-blocking agents may exacerbate intermittent claudication and Raynaud phenomenon, and they may cause CNS disturbances, such as vertigo, tiredness, fatigue, somnolence, mental depression, and nightmares. A correlation between the individual lipid solubility of a β blocker and its ability to penetrate the blood-brain barrier and cause CNS adverse effects may exist. Consequently, agents with high lipophilicity, such as propranolol and penbutolol, have a high incidence of CNS adverse effects. β blockers should not be discontinued abruptly because this causes a rebound (pretreatment blood pressure) or overshoot (blood pressure higher than pretreatment) hypertension; the drug should be tapered slowly over 1 to 2 weeks before discontinuing entirely.

Several β blockers, including carvedilol, metoprolol, nebivolol, propranolol, and timolol, are CYP2D6 substrates. Fluoxetine, paroxetine, and sertraline are potent CYP2D6 inhibitors and may significantly increase the effect of the substrate β blocker. Because almost all β blockers are significantly metabolized by the CYP450 system, CYP450 enzyme inducers, such as cigarettes and marijuana, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and rifampin, may lower serum concentrations of β blockers and compromise efficacy. Atenolol is almost entirely renally eliminated and may be used as an alternative to β blockers that interact via hepatic mechanisms or in patients with liver disease.

Diuretics

Diuretics are divided into the following five classes:

Thiazides and potassium-sparing agents are the only two classes that are used primarily for the management of hypertension. Thiazides, loop diuretics (except ethacrynic acid), and CAIs are sulfonamide-containing agents and may cross-react in patients who have a history of sulfonamide allergy. Sulfonamide-containing agents include sulfonylurea antidiabetics, silver sulfadiazine, tamsulosin, celecoxib, and probenecid. A significant drug-drug interaction occurs when combining diuretics with NSAIDs and combining sodium-depleting diuretics with lithium. The mechanisms of these interactions are similar to the mechanisms of ACEIs and have been discussed previously in this chapter.

Aldosterone antagonists

Spironolactone (Aldactone) and eplerenone (Inspra) are aldosterone antagonists that exert their effect on the late distal tubule and collecting duct. Spironolactone, a weak diuretic, is used primarily for its aldosterone antagonist effects. Spironolactone is indicated for hypertension, management of hepatic cirrhosis (diuretic of choice), primary hyperaldosteronism, hypokalemia, and heart failure. For hypertension, spironolactone is used in combination with other antihypertensives or to spare potassium when administered with diuretics. The chemical structure of spironolactone resembles the structure of the corticosteroids and may explain its sexual adverse effects, such as impotence, decreased libido, gynecomastia, deepening of the voice, menstrual irregularities, and hirsutism. Other spironolactone-induced adverse effects include diarrhea, gastritis, skin rashes, drowsiness, lethargy, ataxia, headaches, and confusion. Similar to the other potassium-sparing diuretics, spironolactone may cause hyperkalemia. Table 22-8 presents the pharmacokinetics and dosing guidelines for the aldosterone antagonists.^2,4,5

Eplerenone is indicated for heart failure after MI and hypertension. Similar to spironolactone, eplerenone blocks the mineralocorticoid receptor, but, in contrast to spironolactone, it does not block the progesterone or androgen receptor, minimizing the sexual adverse effects such as gynecomastia, breast pain, impotence, and menstrual irregularities. Eplerenone has a higher incidence of severe hyperkalemia, especially in patients with reduced renal function. Because of the risk of severe hyperkalemia, eplerenone is contraindicated in all patients with potassium values greater than 5.5 mEq/L or creatinine clearance less than 30 mL/min and in hypertensive patients with type 2 diabetes and microalbuminemia, concomitant use of potassium supplements or potassium-sparing diuretics, or serum creatinine greater than 2 mg/dL in men and greater than 1.8 mg/dL in women or a creatinine clearance less than 50 mL/min. Vigilant monitoring of serum potassium levels is necessary when eplerenone is administered with ACEIs, ARBs, or β blockers. Eplerenone is a CYP3A4 substrate; CYP3A4 inhibitors such as verapamil, diltiazem, erythromycin, fluconazole, and saquinavir may increase eplerenone levels by 50%. Grapefruit juice may also increase levels of eplerenone but to a lesser extent (approximately 25%). It is recommended to initiate eplerenone at a lower dose of 25 mg/day in patients who are taking CYP3A4 inhibitors.

Centrally acting adrenergic agents

The centrally acting adrenergic agents, or α₂ agonists, decrease blood pressure by affecting cardiac output and peripheral resistance; they are negative inotropes and chronotropes. α₂ agonists stimulate brainstem α₂ receptors, resulting in a decrease in sympathetic outflow from the CNS. α₂ agonists are very effective antihypertensives; however, they are not considered first-line therapy because of their side-effect profile. They have a high incidence of anticholinergic-like side effects, such as sedation, blurred vision, dry mouth, constipation, and urinary retention, and CNS side effects, such as drowsiness, fatigue, headaches, depression, psychosis, and nightmares. Long-term use of these agents results in sodium and fluid retention and almost always necessitates the use of concomitant diuretics; this is especially seen with methyldopa. α₂ agonists are not recommended for noncompliant patients and should never be withdrawn abruptly because of the risk of either rebound hypertension or overshoot hypertension.

The most effective and least toxic α₂ agonist is the clonidine transdermal therapeutic system (Catapres-TTS), which achieves sustained levels of clonidine for 7 days. The sustained clonidine levels avoid the peaks and troughs associated with the prompt release dosage form, and treatment is relatively devoid of the troublesome anticholinergic and CNS side effects. The clonidine patch is applied to a hairless area of intact skin on the upper torso. On the initial application, the clonidine patch takes 2 to 3 days to achieve target blood levels and a therapeutic effect. It is recommended to coadminister clonidine oral tablets along with the patch for the first 2 to 3 days of therapy. The most common adverse effects of the patch are local skin rashes and irritation. Table 22-9 presents the pharmacokinetics and dosing guidelines for α₂ agonists.^2,4,5

α₁-adrenergic antagonists

α₁-adrenergic receptor antagonists selectively block postsynaptic α₁ receptors. Total peripheral resistance is reduced through arterial and venous dilation; these agents decrease both preload and afterload and cause a potent first-dose sympathetic reflex increase in heart rate and renin activity.¹² α₁-adrenergic antagonists cause a first-dose phenomenon that manifests with orthostatic hypotension, tachycardia, palpitations, dizziness, headaches, and syncope. After several doses, despite persistent vasodilation, tolerance to the first-dose phenomenon develops, and heart rate, renin, and cardiac output return to normal. To minimize the first-dose phenomenon, initial doses of α₁-adrenergic antagonists should be low and administered at bedtime.

α₁-adrenergic antagonists are indicated for hypertension, benign prostatic hyperplasia (BPH), heart failure, and Raynaud vasospasm except for uroselective α₁-adrenergic antagonists (tamsulosin and alfuzosin), which are indicated only for BPH. In contrast to other antihypertensives, α₁-adrenergic antagonists have favorable effects on the lipoprotein profile and may decrease triglycerides and low-density lipoproteins and increase high-density lipoproteins by 5% to 10%, making them an ideal drug of choice. However, the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) study compared doxazosin with other antihypertensives (chlorthalidone) and revealed a 25% higher incidence of combined cardiovascular morbidity in patients receiving doxazosin.¹³ A higher incidence of doxazosin-induced stroke, heart failure, angina, and coronary revascularization was reported. On the basis of the results of this study, α₁-adrenergic antagonists are considered second-line antihypertensive therapy. Table 22-10 presents the pharmacokinetics and dosing guidelines for α₁-adrenergic antagonists.^2,4,5

Antiadrenergic agents

Reserpine, guanethidine (Ismelin), and guanadrel (Hylorel) are antiadrenergic antihypertensive agents. All three of these agents are second-line antihypertensives. Reserpine works by binding to storage vesicles of peripheral and central postganglionic adrenergic neurons and depleting norepinephrine. Subsequently, reserpine renders the neuronal storage vesicles dysfunctional. Reserpine may cause sedation, depression, suicidal ideation, psychosis, peptic ulcer disease, and nasal stuffiness. The side effects of reserpine can be minimized with low yet effective antihypertensive doses (0.25 mg or less). Guanethidine and guanadrel are postganglionic sympathetic inhibitors that produce a selective block of efferent peripheral sympathetic pathways. Guanethidine and guanadrel act as substitute neurotransmitters by replacing norepinephrine in the neuronal storage vesicle. Guanethidine and guanadrel cause similar adverse effects, such as orthostatic hypotension, sexual dysfunction, and diarrhea that can be occasionally explosive. The antihypertensive effects of these agents may be diminished when combined with tricyclic antidepressants, amphetamines, and ephedrine.

Vasodilators

The two common vasodilators used in the management of hypertension are hydralazine (Apresoline) and minoxidil (Loniten). Because of their side-effect profile, the vasodilators are second-line antihypertensive agents. Hydralazine is also indicated for heart failure and has been used for angina. These agents reduce total peripheral resistance by a direct action on vascular smooth muscle, increasing intracellular concentrations of cyclic guanosine 3′,5′-monophosphate (cGMP). These vasodilators are so potent that they cause a profound activation of baroreceptors, leading to reflex tachycardia, renin release, and an increase in cardiac output. To minimize tachycardia and fluid retention, these agents are often administered concomitantly with a β blocker and a loop diuretic, respectively. Hydralazine has been associated with peripheral neuropathy and drug-induced systemic lupus erythematosus–like syndrome. When hydralazine is administered with food, its bioavailability may double and may cause cardiac toxicity. Hydralazine should be administered consistently with or without food. Minoxidil-induced adverse effects include hirsutism, nausea and vomiting, and pericardial effusions.

Pharmacotherapy

Pharmacotherapy for angina pectoris includes nitrates, β blockers, CCBs, and ranolazine (Ranexa). Ranolazine was approved by the U.S. Food and Drug Administration (FDA) in 2006 for the treatment of chronic stable angina in combination with amlodipine, β blockers, or nitrates.¹⁵ For the management of vasospastic and chronic stable angina, diltiazem, verapamil, amlodipine, and nifedipine are indicated. For the management of angina, β blockers are usually dosed to achieve a resting heart rate of 50 to 60 beats/min and a maximal exercise heart rate of 100 beats/min. Goal blood pressure for patients with documented CAD (i.e., chronic stable angina, unstable angina, non–ST segment elevation MI, ST segment elevation MI) is less than 130/80 mm Hg because of increased risk for mortality. All patients with angina should receive daily aspirin (75 to 100 mg/day) to prevent MI.^16–19

Formation and elimination of acute coronary thrombus

Under normal conditions, the body maintains an equilibrium state between clot formation (thrombosis) and clot breakdown (fibrinolysis).²² Thromboses are initiated by an injury to the endothelial wall of a coronary vessel. When injury occurs, the anticoagulated endothelial surface is disrupted, and the highly procoagulant subendothelial surface is exposed. Instantaneously, platelets aggregate in response to the release of chemotactic substances, such as thromboxane A₂, followed by platelet adhesion to the subendothelial vessel surface, representing the initial step in clot formation. Platelet adhesion is mediated mainly by von Willebrand factor. von Willebrand factor is present in the subendothelium and is actively recruited when the subendothelium is injured. Adhered platelets are exposed to many subendothelial proteins, such as collagen and thrombin. Collagen and thrombin also promote platelet activation. Activated platelets release platelet agonists such as adenosine diphosphate (ADP), norepinephrine, serotonin, and arachidonic metabolites, mitigating and amplifying platelet aggregation and forming an unstable thrombus or platelet plug.

The most important consequence of platelet activation is the expression of platelet receptor glycoprotein (GP) IIb/IIIa on the platelet’s surface, allowing binding to fibrinogen. Fibrinogen binds to the two GP IIb/IIIa molecules, causing a cross-linking of receptors on adjacent platelets and initiating platelet aggregation. Triggers affecting platelet aggregation and their antagonists are depicted in Figure 22-4. Fibrinogen is converted into fibrin monomers by the action of thrombin; this is the final step in clot formation. Homeostasis is complete when the fibrin clot becomes insoluble within the vessel. This stable fibrin clot is the end result of the coagulation cascade. Under normal conditions, multiple inhibitors and control mechanisms keep these reactions localized to the site of the injury.

The fibrin clot ultimately must be removed for hemostasis to be maintained. Activation of the fibrinolytic system by tissue plasminogen activators (t-PAs), which are present in most body fluids and tissues, results in the conversion of plasminogen to plasmin, initiating the dissolution of fibrin and fibrinogen. The breakdown of fibrinogen and fibrin results in polypeptides termed fibrin split or fibrinogen degradation products (FDPs). FDPs are anticoagulant substances that can cause bleeding if fibrinolysis becomes uncontrolled and excessive. D-dimers are fragments of plasmin-digested, cross-linked fibrin that increase in concentration after the onset of fibrinolysis. Blood testing for D-dimer fragments may assist in the diagnosis of pathogenic venous thromboembolism. The extrinsic and intrinsic pathways of the coagulation system are depicted and described in Figure 22-5.^2,3,18

Heparin is a nonionic sulfated glycosaminoglycan anticoagulant naturally present in the secretory granules of human mast cells. When heparin is released from mast cells, it is ingested and destroyed by macrophages. Heparin is not detectable in plasma except in pathologic circumstances (e.g., mastocytosis). Commercially available unfractionated heparin (UFH), or simply heparin, is indicated for prevention and treatment of venous thromboembolism, prevention and treatment of pulmonary embolism, treatment of atrial fibrillation with embolization, diagnosis and treatment of disseminated intravascular coagulation, and prophylaxis and treatment of peripheral arterial embolism.

Heparin is extracted from porcine intestinal mucosa or bovine lungs; however, because of the high propensity of thrombocytopenia with the bovine lung derivative, only the porcine derivative is routinely employed in practice. Heparin serves as a catalyst that accelerates the rate of the thrombin-to-antithrombin III reaction by at least 1000-fold by serving as a catalytic template to which both bind, resulting in a ternary complex (heparin, thrombin, and antithrombin). Antithrombin III is a large protein (58,000 Da) that is synthesized in the liver and is known as a suicide substrate. Heparin is a high-molecular-weight complex mucopolysaccharide containing specific pentasaccharide units and approximately 45 monosaccharide side chains with a mean molecular mass of 12,000 Da (range 5000 to 30,000 Da).²³

Most of the monosaccharide side chains of UFH are more than 18 monosaccharides long and are necessary to form the ternary complex. Heparin molecules that possess less than 18 monosaccharide units (less than 5400 Da) do not catalyze the thrombin-to-antithrombin III reaction. However, the heparin molecules that include less than 18 monosaccharides catalyze a conformational change on antithrombin III that inhibits the effects of factor Xa (Stuart factor) and does not require a ternary complex. LMWHs are generally about 4500 Da (range 1000 to 10,000 Da) and contain 15 monosaccharide units and do not form a ternary complex. Their anticoagulant activity is exhibited via factor Xa inhibition. Because factor Xa occurs earlier in the coagulation cascade, the inhibition of a single molecule of factor Xa prevents thousands of thrombin molecules from forming. The anti–factor Xa/anti–factor IIa ratio of UFH is 1:1; the anti–factor Xa/anti–factor IIa ratio of LMWH ranges from 2:1 (dalteparin) to 3.8:1 (enoxaparin). Heparin also inhibits the conversion of fibrinogen to fibrin and inhibits the activation of factor XIII, preventing the formation of a stable fibrin clot. LMWH is postulated to suppress von Willebrand factor, which increases platelet aggregation, and to stimulate the release of tissue factor pathway inhibitor, which inhibits factor Xa.

LMWHs include dalteparin (Fragmin), enoxaparin (Lovenox), and tinzaparin (Innohep). In contrast to LMWHs, UFH binds extensively to plasma proteins such as glycoproteins, vitronectin, lipoproteins, fibrinogen, platelet proteins such as platelet factor-4, acute-phase reactant proteins, and endothelial cells, yielding poor UFH bioavailability and an unpredictable effect. The predictable bioavailability of LMWHs allows for subcutaneous administration for all indications. UFH is administered subcutaneously for venous thromboembolism prophylaxis but must be administered as a continuous infusion for serious indications such as MI and to minimize the risk of hemorrhage.

High-molecular-weight heparin (UFH) is cleared faster and requires more frequent dosing or an intravenous continuous infusion. The half-life of UFH is approximately 30 to 60 minutes, whereas the half-life of LMWH is 4 to 5 hours, allowing for once-daily or twice-daily LMWH administration. The onset of action of heparin is within 6 hours of initiation of a continuous infusion. LMWH time to peak anti–factor Xa activity is 2 to 5 hours. Each commercially available LMWH is synthesized by different mechanisms, possesses moderately different pharmacokinetic and pharmacodynamic characteristics, and has different FDA-approved indications and dosing regimens; these agents are not interchangeable. Table 22-12 presents the pharmacokinetic properties and dosing parameters for all heparins.

Dipyridamole

Dipyridamole is a vasodilator and platelet adhesion inhibitor. It has been postulated that patients with prosthetic heart valves have abnormally shortened platelet survival time. Dipyridamole lengthens the abnormally shortened platelet survival time in a dose-dependent manner. The primary effect of dipyridamole is to inhibit cGMP-specific phosphodiesterase, increasing cGMP levels and augmenting the effects of nitric oxide. Dipyridamole weakly inhibits red blood cell, endothelial cell, and platelet uptake of the platelet activity inhibitor adenosine and inhibits the formation of thromboxane A₂; this effect occurs in a dose-dependent manner (0.5 to 1.9 μg/mL). This uptake inhibition results in dipyridamole inhibiting platelet function by inhibiting cyclic adenosine 3′,5′-monophosphate (cAMP)–specific phosphodiesterase, which leads to increased cellular concentrations of cAMP within platelets, preventing platelet aggregation by stimuli such as collagen and ADP. Dipyridamole does not alter PT levels but can increase the platelet bleeding time.

Dipyridamole (Persantine) is indicated only as an adjunct to warfarin in the prevention of postoperative thromboembolic complications of cardiac valve replacement. Intravenous dipyridamole, occasionally used for cardiac exercise stress testing, may decrease blood pressure and increase heart rate and cardiac output; this effect is generally not seen with the oral dosage form. Dipyridamole is eliminated via hepatic conjugation and glucuronidation; it does not undergo hepatic cytochrome P450 elimination. Dipyridamole has a weak metabolite and undergoes negligible renal elimination. The half-life of dipyridamole is 13 hours. Adverse reactions are transient and include headache, dizziness, hypotension, and abdominal distress. Rarely, dipyridamole has aggravated angina symptoms; the intravenous form has precipitated acute myocardial ischemia. Dipyridamole can potentiate the effects of intravenous adenosine, causing fatal asystole or sustained ventricular tachycardia; a decreased dose of adenosine should be used when treating paroxysmal supraventricular tachycardias.

Aggrenox is a combination gelatin capsule containing 200 mg of extended-release dipyridamole with 25 mg of aspirin and is indicated to reduce the risk of stroke for patients who have had TIAs or complete ischemic strokes. Steady-state dipyridamole peak and trough plasma levels are 2 μg/mL and 0.5 μg/mL, allowing for dipyridamole to achieve its effects on cAMP and cGMP throughout the dosing interval; this is not likely to occur with prompt-release dipyridamole. Dipyridamole requires an acidic environment for gut absorption; Aggrenox contains tartaric acid, allowing for maximal bioavailability in patients who have gut hypochlorhydria or achlorhydria (e.g., elderly patients).

The second European Stroke Prevention Study (ESPS-2) showed that dipyridamole modified-release formulation, 200 mg given twice daily, is effective in the secondary prevention of stroke and TIA compared with placebo and that coadministration with aspirin, 25 mg twice daily, provides additional benefit.²⁸ ESPS-2 showed that the relative risk reduction for stroke with aspirin administration compared with placebo was 18.1% (P = .013); for modified-release dipyridamole, the relative risk reduction was 16.3% (P = .039); and with the combination, it was 37% (P < .001). Aggrenox must not be substituted by prompt-release dipyridamole and aspirin. The recommended dosage of Aggrenox is one capsule twice daily, swallowed whole. Because of increased risk of headache, it may be advisable to start with one capsule daily at bedtime up to 1 week until tolerated before increasing the dose to twice daily.

Clopidogrel (plavix)

Clopidogrel (Plavix) is a prodrug thienopyridine derivative platelet aggregation inhibitor that interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions. Indications for clopidogrel include the reduction of atherosclerotic events in patients with a history of MI, stroke, or peripheral arteriolar disease and acute coronary syndrome (ACS) regardless of whether a patient is managed medically, by percutaneous coronary intervention (PCI), or by coronary artery bypass grafting. Clopidogrel is slightly more effective than aspirin in reducing the combined risk of ischemic stroke, MI, or vascular death in patients with atherosclerotic vascular disease.²⁹ For patients with ACS, clopidogrel plus aspirin was found to be superior to aspirin alone in reducing composite endpoints of MI, stroke, and cardiovascular death. Clopidogrel has not shown superiority to aspirin for stroke prophylaxis except in patients with peripheral vascular disease.

Clopidogrel is extensively metabolized by the liver; its metabolites are eliminated equally via the kidneys and the feces. The half-life of clopidogrel metabolites is 8 hours; steady state is reached in 3 to 7 days. The onset of action of clopidogrel can be seen in 2 hours. The average platelet inhibition seen with clopidogrel is between 40% and 60%. Platelet aggregation and bleeding time return to normal within 5 days after clopidogrel discontinuation. The dose of clopidogrel in ACS is a 300-mg loading dose followed by 75 mg once daily (plus aspirin). A higher loading dose of 600 mg is recommended for patients undergoing PCI. For the prevention of cardiovascular events such as ACS, stroke, and peripheral arterial disease, the dose is 75 mg of clopidogrel once daily.

Because clopidogrel is a prodrug, it must undergo a two-step hepatic conversion to be activated. Only about 15% of the drug is converted to its active form, mainly through CYP2C19 and CYP3A4. Several trials have evaluated the possible interactions between clopidogrel and other drugs that can inhibit or competitively bind to these same isoenzymes, potentially inhibiting the conversion of clopidogrel to its active form and rendering the drug ineffective. Proton pump inhibitors (PPIs), which are commonly prescribed for prophylaxis of stress ulcer, gastrointestinal reflux disease, and prophylaxis of gastrointestinal bleeding, are metabolized by CYP2C19 at varying degrees. Studies have reported that there is a significant increase in clinical event rates (e.g., MI, death) or greater platelet reactivity with concurrent use of clopidogrel and a PPI. Pantoprazole (Protonix) is the only PPI that does not undergo CYP2C19 metabolism and may potentially be devoid of this interaction, but more studies need to be conducted to confirm this. Other medications such as cimetidine, etravirine, felbamate, fluconazole, fluvoxamine, fluoxetine, ketoconazole, voriconazole, and ticlopidine should also be avoided because they can reduce antiplatelet activity of clopidogrel.

Statins or 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors have also been an area of interest with regard to clopidogrel drug interactions. Similar to clopidogrel, statins are CYP3A4 substrates. In vivo studies that examined the degree of platelet inhibition by clopidogrel in patients taking a statin have shown that there is a significant decline in platelet inhibition with the use of statins. However, no large clinical trials have shown that this interaction can lead to negative clinical outcomes. Despite the lack of clinical trials evaluating the interaction between statins and clopidogrel, caution is advised when combining these two medications. If statin therapy is required, pravastatin (Pravachol) or rosuvastatin (Crestor) should be considered because these drugs do not undergo CYP3A4 metabolism and potentially are devoid of any significant drug interactions.³⁰

Testing for genetic polymorphism has also received considerable emphasis in the FDA boxed warning for clopidogrel. Although genetic polymorphism for CYP2C19 has been shown in several studies to reduce antiplatelet activity and increase major adverse cardiac events (MACEs), prospective studies show clinical efficacy of personalizing antiplatelet therapy based on genotype analysis. The recommendation issued by the FDA to clinicians is to consider alternative treatment strategies, such as combining clopidogrel with cilostazol or using high-dose clopidogrel (600 mg loading dose followed by 150 mg daily for ACS) in patients identified as poor CYP2C19 metabolizers. The efficacy and safety of these approaches remain uncertain.³¹ Alternatively, one may consider switching to another antiplatelet agent, such as prasugrel, which does not undergo CYP2C19 metabolism.

The most common adverse effect of clopidogrel is hemorrhage, manifesting with purpura and epistaxis; other adverse effects include headaches and dizziness, abdominal pain and diarrhea, and rash and pruritus. In contrast to ticlopidine, clopidogrel has a lower incidence of rash, gastrointestinal disturbances, neutropenia, and thrombotic thrombocytopenic purpura (TTP), and cholestatic jaundice has not been reported with clopidogrel.

Ticlopidine (ticlid)

Ticlopidine (Ticlid), a thienopyridine, is a platelet aggregation inhibitor that interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions. The effect of ticlopidine on platelet function is irreversible and lasts for the life of the platelet. Ticlopidine is indicated for stroke. In the Ticlopidine Aspirin Stroke Study (TASS), the ticlopidine group had a 21% greater relative risk reduction for stroke compared with the aspirin group and a 9% greater reduction in stroke, MI, or vascular death at 3 years.³¹ The Canadian-American Ticlopidine Study (CATS) showed that ticlopidine reduced the relative risk of stroke, MI, or vascular death by 30% compared with placebo (10.8%; P = .006).³² The half-life of ticlopidine is 14 hours; however, with repeat dosing it approaches 4 to 5 days. Steady state is achieved within 14 to 21 days. Platelet aggregation is inhibited 50% within 4 days and 60% to 70% within 10 days. Platelet aggregation and bleeding time return to normal within 14 days after ticlopidine discontinuation. Ticlopidine is extensively metabolized by the liver; active metabolites have not been elucidated.

Because of the risk of life-threatening blood dyscrasias such as TTP and neutropenia and agranulocytosis, ticlopidine is a refractory agent reserved for patients who are intolerant or allergic to aspirin or clopidogrel or failed therapy with these agents. The onset of TTP occurs after 3 to 4 weeks of therapy, and the onset of neutropenia occurs after 4 to 6 weeks of therapy. TTP rarely occurs after 3 months of therapy. The incidence of TTP may be 1 case in every 1600 to 4000 patients. Signs and symptoms of TTP include microangiopathic hemolytic anemia (schistocytes on peripheral smear), purpura, petechiae, pallor, renal dysfunction, fever, weakness, difficulty speaking, seizures, jaundice, and dark or bloody urine. With proper detection, ticlopidine discontinuation, and management by plasmapheresis, 80% of patients survive. Because of the risk of ticlopidine-induced TTP and neutropenia, patients should have a complete blood count monitoring neutrophils, platelets, and hemoglobin and hematocrit biweekly for the first 3 months.

Rarely, ticlopidine can cause thrombocytopenia not induced by TTP. Ticlopidine may cause gastrointestinal disturbances such as diarrhea, nausea, and vomiting in one-third of patients. Similar to clopidogrel, it does not directly cause peptic ulcer disease. Rare cases of rash that may progress to Stevens-Johnson syndrome and cholestatic jaundice have occurred with ticlopidine use. Ticlopidine may persistently increase total cholesterol levels by 10%.

Prasugrel (effient)

Prasugrel (Effient) is a prodrug thienopyridine derivative platelet aggregation inhibitor that interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions. When prasugrel is compared with other agents in the same class, it has a very limited scope; it is indicated only for the prevention of thrombosis in patients with ACS undergoing PCI. Prasugrel in combination with aspirin decreases nonfatal MI slightly more than clopidogrel in combination with aspirin but with an increased risk of bleeding. Prasugrel is contraindicated in patients who have had history of a TIA or stroke. In patients older than 75 years or in patients who weigh less than 60 kg, prasugrel was shown to have a greater risk of bleeding, which outweighs its benefit.³³ Prasugrel is extensively metabolized by hydrolysis in the liver followed by CYP3A4 and CYP2D6; its metabolites are eliminated via the kidneys and feces. The half-life of the active metabolite of prasugrel is 7 to 8 hours. The onset of action of prasugrel can be seen in 30 minutes. The average platelet inhibition observed with prasugrel is 50% to 80%. Platelet aggregation and bleeding time return to normal approximately 5 to 9 days after prasugrel discontinuation. The dose of prasugrel in ACS is a 60-mg loading dose followed by 10 mg once daily (plus aspirin). In patients who weigh less than 60 kg, a decreased dose of 5 mg is recommended, although there have not been any clinical trials to support this practice.

The most common adverse effect of prasugrel is hemorrhage, which is greater than that observed with clopidogrel. Other adverse effects are similar to clopidogrel. A higher incidence of colonic neoplasm was seen during the trial for its approval.^34,35

Cilostazol (pletal) and pentoxifylline (trental)

Cilostazol (Pletal) is a quinolinone derivative that selectively and reversibly inhibits cellular phosphodiesterase III by increasing the levels of cAMP, resulting in vasodilation and inhibition of platelet aggregation. Cilostazol is indicated for intermittent claudication in patients with peripheral arterial disease. Cilostazol allows for increased walking distances and improves symptoms and quality of life in patients with intermittent claudication. The clinical benefits may not be noticed for at least 2 to 4 weeks, and may take 12 weeks. The only alternative to cilostazol for intermittent claudication is pentoxifylline (Trental); however, it has been proven inefficacious. Pentoxifylline is a xanthine agent with rheologic properties that decrease blood viscosity and improve erythrocyte flexibility.

Cilostazol is associated with a high incidence of transient adverse effects, such as headache, diarrhea, dizziness, and palpitations. In patients with heart failure, oral phosphodiesterase inhibitors such as milrinone have been associated with increased mortality resulting from arrhythmias; cilostazol and several of its metabolites are contraindicated in patients with heart failure and should be used prudently in patients with CAD. Cilostazol has been associated with increases in heart rate and reductions in P–R, QRS, and Q–T intervals on ECG. In the dog model, cilostazol has been associated with cardiac lesions and endocardial hemorrhage, similar to toxicities noted with milrinone; the risk of developing cardiac lesions with long-term cilostazol use is unknown. Cilostazol is a CYP3A4 and CYP2C19 substrate and has been associated with significantly elevated levels when combined with the CYP3A4 inhibitors ketoconazole, diltiazem, and erythromycin. Smokers exhibited 20% lower levels of cilostazol. Cilostazol is dosed at 100 mg twice daily; the dose should be reduced in the presence of CYP3A4 inhibitors to 50 mg twice daily. Food increases the bioavailability of cilostazol by 90%; cilostazol should be administered on an empty stomach to circumvent this interaction. Grapefruit juice inhibits gut CYP3A4 and may increase plasma cilostazol levels and should be avoided during cilostazol use.

Glycoprotein iib/iiia inhibitors

GP IIb/IIIa inhibitors are indicated for the treatment of patients with ACS—unstable angina or non–ST segment elevation acute MI—and patients who are medically managed and patients undergoing PCI. Abciximab (ReoPro) is the GP IIb/IIIa inhibitor of choice for PCI. The management of unstable angina or non–ST segment elevation acute MI includes the use of aspirin, heparin, and a GP IIb/IIIa inhibitor. This combination has led to a decrease in the composite endpoints of new MI or death.³⁶ In patients who are being managed medically for a non–ST segment elevation ACS, the use of GP IIb/IIIa inhibitors has been marginalized to patients with moderate to high risk based on a risk assessment score and continued ischemia or patients with diabetes. GP IIb/IIIa inhibitors are administered via continuous intravenous infusions. Oral formulations of GP IIb/IIIa inhibitors failed to display efficacy in clinical trials and are unavailable.

The most common adverse effect reported during therapy was bleeding. The incidence of major bleeding manifesting as gastrointestinal, genitourinary, or intracranial hemorrhage with the three-drug combination was only slightly greater than with aspirin and heparin alone, illustrating the safety of the GP IIb/IIIa inhibitors. Although minor bleeding with GP IIb/IIIa inhibitors is common (10%), it is generally inconsequential. Because these agents may cause thrombocytopenia, daily platelet, hemoglobin, and hematocrit monitoring is required. Abciximab has been implicated as a cause of immune-mediated thrombocytopenia in 5% of patients. Table 22-14 presents the pharmacologic characteristics of GP IIb/IIIa inhibitors.