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If higher doses of diuretic are required, the drug should be used in combination with a potassium-sparing agent or with an ACE inhibitor or ARB. Diuretics reduce insulin sensitivity and cause modest increases in blood glucose. Compared with ACE inhibitors and ARBs, diuretic therapy is associated with a slightly higher incidence of new-onset diabetes. Diuretics also increase serum uric acid and may precipitate gout. Increases in blood glucose, triglycerides, LDL cholesterol, and plasma insulin may occur but are relatively minor during long-term low-dose therapy.

B. β-ADRENERGIC BLOCKING AGENTS

These drugs are effective in hypertension because they decrease the heart rate and cardiac output. Even after continued use of β-blockers, cardiac output remains lower and systemic vascular resistance higher with agents that do not have intrinsic sympathomimetic or α-blocking activity. The β-blockers also decrease renin release and are more efficacious in populations with elevated plasma renin activity, such as younger white patients. They neutralize the reflex tachycardia caused by vasodilators and are especially useful in patients with associated conditions that benefit from the cardioprotective effects of these agents. These include individuals with angina pectoris, previous myocardial infarction, and stable congestive heart failure as well as those with migraine headaches and somatic manifestations of anxiety. In some clinical trials, β-blockers have not been as effective as diuretics in preventing first myocardial infarctions.

Although all β-blockers appear to be similar in antihypertensive potency, controlling approximately 50% of patients, they differ in a number of pharmacologic properties (these differences are summarized in Table 11-7), including those relatively specific to the cardiac β₁-receptors (cardioselectivity) and whether they also block the β₂-receptors in the bronchi and vasculature; at higher dosages, however, all agents are nonselective. The β-blockers also differ in their pharmacokinetics and lipid solubility - which determines whether they cross the blood-brain barrier and affect the incidence of central nervous system side effects - and route of metabolism. Labetalol and carvedilol are combined α- and β-blockers and, unlike most β-blockers, decrease peripheral vascular resistance.

The side effects of all β-blockers include inducing or exacerbating bronchospasm in predisposed patients (eg, those with asthma and some patients with chronic obstructive pulmonary disease [COPD]); sinus node dysfunction and atrioventricular (AV) conduction depression (resulting in bradycardia or AV block); precipitating or worsening clinically important left ventricular failure; nasal congestion; Raynaud's phenomenon; and central nervous system symptoms with nightmares, excitement, depression, and confusion. Fatigue, lethargy, and impotence may occur. All β-blockers tend to increase plasma triglycerides. The nonselective and, to a lesser extent, the cardioselective (β1-selective) β-blockers tend to depress the protective HDL fraction of plasma cholesterol. As with diuretics, the changes are blunted with time and dietary changes.

β-Blockers have traditionally been considered contraindicated in patients with congestive heart failure. Evolving experience suggests that they have a propitious effect on the natural history of patients with chronic stable heart failure and reduced ejection fraction. β-Blockers are used cautiously in patients with type 1 diabetes, since they can mask the symptoms of hypoglycemia and prolong these episodes by inhibiting gluconeogenesis. Although they may increase blood glucose levels in type 2 diabetics, the prognosis of these patients on balance is improved. These drugs should also be used with caution in patients with advanced peripheral vascular disease associated with rest pain or nonhealing ulcers, but they are generally well tolerated in patients with mild claudication. In treatment of pheochromocytoma, β-blockers should not be administered until α-blockade has been established. Otherwise, blockade of vasodilatory β₂-adrenergic receptors will allow unopposed vasoconstrictor α-adrenergic receptor activation with worsening of hypertension.

Because of the lack of efficacy in prevention of myocardial infarction and inferiority compared with other drugs in prevention of stroke and left ventricular hypertrophy, there is now increasing doubt whether β-blockers should still be regarded as ideal first-line agents in the treatment of hypertension without specific compelling indications (such as active coronary artery disease). In addition to the adverse metabolic changes associated with their use, some experts have suggested that the therapeutic shortcomings of β-blockers are the consequence of the particular hemodynamic profile associated with these drugs. Pressure peaks in the aorta are augmented by reflection of pressure waves from the peripheral circulation. These reflected waves are delayed in patients taking ACE inhibitors and thiazide diuretics, resulting in decreased systolic and pulse pressures. By contrast, β-blockers have no effect on reflection of pressure waves, possibly because peripheral resistance vessels are a reflection point and peripheral resistance is not decreased by β-blockers. This might explain why β-blockers are less effective at control of systolic and pulse pressure.

The ASCOT trial showed that the atenolol/bendroflumethiazide combination was inferior to the amlodipine/perindopril combination in predominantly white patients with modestly elevated cardiovascular risk. Subsequent analyses indicated that differences in blood pressure and HDL cholesterol accounted for the excess risk of stroke and coronary events respectively in the β-blocker group. Despite these concerns, the compelling indications for β-blockers remain, such as active coronary artery disease and impaired left ventricular function. Great care should be exercised if the decision is made, in the absence of compelling indications, to remove β-blockers from the treatment regimen since abrupt withdrawal can precipitate acute coronary events and severe increases in blood pressure.

C. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

ACE inhibitors are being increasingly used as the initial medication in mild to moderate hypertension (Table 11-8). Their primary mode of action is inhibition of the renin-angiotensin-aldosterone system, but they also inhibit bradykinin degradation, stimulate the synthesis of vasodilating prostaglandins and, sometimes, reduce sympathetic nervous system activity. These latter actions may explain why they exhibit some effect even in patients with low plasma renin activity. ACE inhibitors appear to be more effective in younger white patients. They are relatively less effective in blacks and older persons and in predominantly systolic hypertension. Although as single therapy they achieve adequate antihypertensive control in only about 40-50% of patients, the combination of an ACE inhibitor and a diuretic or calcium channel blocker is potent.

ACE inhibitors are the agents of choice in persons with type 1 diabetes with frank proteinuria or evidence of renal dysfunction because they delay the progression to end-stage renal disease. Many authorities have expanded this indication to include persons with type 2 diabetes and those who have type 1 diabetes with microalbuminuria, even when they do not meet the usual criteria for antihypertensive therapy. The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that the ACE inhibitor ramipril reduces the number of cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes and also reduces the incidence of new-onset heart failure, renal dysfunction, and new-onset diabetes in a population of patients at high risk for vascular events. Although this was not specifically a hypertensive population, the benefits were associated with a modest reduction in blood pressure, and the results inferentially support the use of ACE inhibitors in similar hypertensive patients. ACE inhibitors may also delay the progression of other forms of renal disease. They are a drug of choice (usually in conjunction with a diuretic and a β-blocker) in patients with congestive heart failure and are indicated also in asymptomatic patients with reduced ejection fractions whether due to myocardial infarction or to other causes.

ACE inhibitors have effects on mortality and most cardiovascular outcomes similar to those achieved with diuretics and β-blockers. However, compared with calcium channel blockers, ACE inhibitors are associated with lower incidences of coronary events and heart failure.

An advantage of the ACE inhibitors is their relative freedom from troublesome side effects. Severe hypotension can occur in patients with bilateral renal artery stenosis; acute renal failure may ensue but is usually reversible with discontinuation of ACE inhibition. Hyperkalemia may develop in patients with intrinsic renal disease and type IV renal tubular acidosis (commonly seen in diabetics) and in the elderly. A chronic dry cough is common, seen in 10% of patients or more, and may require stopping the drug. Dizziness occurs but may not be related to the degree of blood pressure lowering. Skin rashes are observed with any ACE inhibitor. Taste alterations are seen more often with captopril than with the non-sulfhydryl-containing agents (enalapril and lisinopril) but often disappear with continued therapy. Angioedema is an uncommon but potentially dangerous side effect of all agents of this class because of their inhibition of kininase.

D. ANGIOTENSIN II RECEPTOR BLOCKERS

Although losartan, the first member of this group, was less potent than high doses of ACE inhibitors in reducing blood pressure, the newer ARBs (valsartan, irbesartan, candesartan, telmisartan, and eprosartan) appear to be equipotent to ACE inhibitors (Table 11-8). A growing body of data indicates that ARBs can improve cardiovascular outcomes in patients with hypertension as well as in patients with related conditions such as heart failure and type 2 diabetes with nephropathy. ARBs have not been compared with ACE inhibitors in randomized controlled trials in patients with hypertension, but two trials comparing losartan with captopril in heart failure and post-myocardial infarction left ventricular dysfunction showed trends toward worse outcomes in the losartan group. Whether this suggestion of reduced efficacy is specific to losartan or may also be true for other ARBs is as yet unknown. However, the Losartan Intervention for Endpoints (LIFE) trial in nearly 9000 hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy - comparing losartan with the β-blocker atenolol as initial therapy - demonstrated a significant reduction in stroke with losartan. Of note is that in diabetic patients, death and myocardial infarction were also reduced, and there was a lower occurrence of new-onset diabetes. In this trial, as in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with an ACE inhibitor, blacks exhibited less blood pressure reduction and less benefit with regard to clinical end points.

Unlike ACE inhibitors, the ARBs do not cause cough and are only infrequently associated with skin rashes, the most common side effects of the ACE inhibitors. However, they still present a risk of hypotension and renal failure in patients with bilateral renal artery stenosis and hyperkalemia, and, rarely - but much less frequently than with ACE inhibitors - angioedema.

E. CALCIUM CHANNEL BLOCKING AGENTS

These agents act by causing peripheral vasodilation but with less reflex tachycardia and fluid retention than other vasodilators. They are effective as single-drug therapy in approximately 60% of patients in all demographic groups and all grades of hypertension (Table 11-9). As a result, they may be preferable to β-blockers and ACE inhibitors in blacks and older subjects. Calcium channel blockers and diuretics are less additive when given together than when either is combined with β-blockers or ACE inhibitors. However, verapamil and diltiazem should be combined cautiously with β-blockers because of their potential for depressing AV conduction and sinus node automaticity as well as contractility.

Initial concerns about possible adverse cardiac effects of calcium channel blockers have been convincingly allayed by several subsequent large studies which have demonstrated that calcium channel blockers are equivalent to ACE inhibitors, thiazide diuretics, and β-blockers in prevention of coronary heart disease, major cardiovascular events, cardiovascular death, and total mortality. Diabetic patients receiving calcium channel blockers may have higher rates of heart failure and myocardial infarction than those receiving ACE inhibitors, and in other studies, heart failure has been more common than in patients treated with diuretics or ACE inhibitors. Whether these outcomes reflect beneficial effects of the comparators or specific risks of calcium channel blockers is uncertain. A protective effect against stroke with calcium blockers is well established, and in two trials (ALLHAT and the Systolic Hypertension in Europe trial), these agents appeared to be more effective than diuretic-based therapy.

The most common side effects of calcium channel blockers are headache, peripheral edema, bradycardia, and constipation (especially with verapamil in the elderly). The dihydropyridine agents - nifedipine, nicardipine, isradipine, felodipine, nisoldipine, and amlodipine - are more likely to produce symptoms of vasodilation, such as headache, flushing, palpitations, and peripheral edema. Calcium channel blockers have negative inotropic effects and may cause or exacerbate heart failure in patients with cardiac dysfunction. Amlodipine is the only calcium channel blocker with established safety in patients with severe heart failure. Most calcium channel blockers are now available in preparations that can be administered once daily.

F. α-ADRENOCEPTOR ANTAGONISTS

Prazosin, terazosin, and doxazosin (Table 11-10) block postsynaptic α-receptors, relax smooth muscle, and reduce blood pressure by lowering peripheral vascular resistance. These agents are effective as single-drug therapy in some individuals, but tachyphylaxis may appear during long-term therapy and side effects are relatively common. These include marked hypotension and syncope after the first dose which, therefore, should be small and be given at bedtime. Postdosing palpitations, headache, and nervousness may continue to occur during long-term therapy; they may be less frequent or severe with doxazosin because of its more gradual onset of action.

Unlike the β-blockers and diuretics, the α-blockers have no adverse effect on serum lipid levels - in fact, they increase HDL cholesterol while reducing total cholesterol. Whether this is beneficial in the long term has not been established. In ALLHAT, persons receiving doxazosin as initial therapy had a significant increase in heart failure hospitalizations and a higher incidence of stroke relative to the persons receiving diuretics and were removed from the study. To summarize, α-blockers should generally not be used as initial agents to treat hypertension - except perhaps in men with symptomatic prostatism.

G. DRUGS WITH CENTRAL SYMPATHOLYTIC ACTION

Methyldopa, clonidine, guanabenz, and guanfacine (Table 11-10) lower blood pressure by stimulating α-adrenergic receptors in the central nervous system, thus reducing efferent peripheral sympathetic outflow. These agents are effective as single therapy in some patients, but they are usually used as second- or third-line agents because of the high frequency of drug intolerance, including sedation, fatigue, dry mouth, postural hypotension, and impotence. An important concern is rebound hypertension following withdrawal. Methyldopa also causes hepatitis and hemolytic anemia and is avoided except in individuals who have already tolerated long-term therapy. There is considerable experience with methyldopa in pregnant women, and it is still used for this population. Clonidine is available in patches and may have particular value in patients in whom compliance is a troublesome issue.

H. ARTERIOLAR DILATORS

Hydralazine and minoxidil (Table 11-10) relax vascular smooth muscle and produce peripheral vasodilation. When given alone, they stimulate reflex tachycardia, increase myocardial contractility, and cause headache, palpitations, and fluid retention. They are usually given in combination with diuretics and β-blockers in resistant patients. Hydralazine produces frequent gastrointestinal disturbances and may induce a lupus-like syndrome. Minoxidil causes hirsutism and marked fluid retention; this agent is reserved for the most refractory of cases.

I. PERIPHERAL SYMPATHETIC INHIBITORS

These agents are now used infrequently and usually in refractory hypertension. Reserpine remains a cost-effective antihypertensive agent (Table 11-10). Its reputation for inducing mental depression and its other side effects - sedation, nasal stuffiness, sleep disturbances, and peptic ulcers - has made it unpopular, though these problems are uncommon at low dosages. Guanethidine and guanadrel inhibit catecholamine release from peripheral neurons but frequently cause orthostatic hypotension (especially in the morning or after exercise), diarrhea, and fluid retention.