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