Which comment by the patient indicates understanding about the side effects of enalapril Quizlet

There are many classes of antihypertensive drugs of which six (ACE inhibitors, ARBs, renin inhibitors, calcium channel blockers, diuretics, and beta-blockers) are suitable for initial therapy based on efficacy and tolerability. A number of considerations enter into the selection of the initial regimen for a given patient. These include the weight of evidence for beneficial effects on clinical outcomes, the safety and tolerability of the drug, its cost, demographic differences in response, concomitant medical conditions, and lifestyle issues. The specific classes of antihypertensive medications are discussed below, and guidelines for the choice of initial medications are offered.

A. Angiotensin-Converting Enzyme Inhibitors

ACE inhibitors are commonly used as the initial medication in mild to moderate hypertension (Table 11–6). Their primary mode of action is inhibition of the RAAS, but they also inhibit bradykinin degradation, stimulate the synthesis of vasodilating prostaglandins, and can 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.

Table 11–6.Antihypertensive drugs: renin and ACE inhibitors and angiotensin II receptor blockers.

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Table 11–6. Antihypertensive drugs: renin and ACE inhibitors and angiotensin II receptor blockers.

ACE inhibitors are the agents of choice in persons with type 1 diabetes with frank proteinuria or evidence of kidney dysfunction because they delay the progression to end-stage renal disease. Many authorities have expanded this indication to include persons with type 1 and type 2 diabetes mellitus with microalbuminuria who do not meet the usual criteria for antihypertensive therapy. ACE inhibitors may also delay the progression of nondiabetic kidney disease. The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that the ACE inhibitor ramipril reduced the number of cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes and also reduced the incidence of new-onset heart failure, kidney 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 are a drug of choice (usually in conjunction with a diuretic and a beta-blocker) in patients with heart failure with reduced ejection fraction and are indicated also in asymptomatic patients with reduced ejection fraction.

How to initiate therapy

A baseline metabolic panel should be drawn prior to starting medications that interfere with the RAAS, repeated 1–2 weeks after initiation of therapy to evaluate changes in creatinine and potassium. Minor dose adjustments of these medications rarely trigger significant shifts in these values.

Side effects

An advantage of the ACE inhibitors is their relative freedom from troublesome side effects (Table 11–6). Severe hypotension can occur in patients with bilateral renal artery stenosis; significant increases in creatinine may ensue but are usually reversible with the discontinuation of the ACE inhibitor. Hyperkalemia may develop in patients with kidney disease and type IV renal tubular acidosis (commonly seen in patients with diabetes) and in older adults. A chronic dry cough is common, seen in 10% of patients or more, and may require stopping the drug. Skin rashes are observed with any ACE inhibitor. Angioedema is an uncommon but potentially dangerous side effect of all agents of this class because of their inhibition of kininase. Exposure of the fetus to ACE inhibitors during the second and third trimesters of pregnancy has been associated with a variety of defects due to hypotension and reduced renal blood flow.

B. Angiotensin II Receptor Blockers

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. By contrast, valsartan seems as effective as ACE inhibitors in these settings. Within group heterogeneity of antihypertensive potency and duration of action might explain such observations. The Losartan Intervention for Endpoints (LIFE) trial in nearly 9000 hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy—comparing losartan with the beta-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 a subgroup analysis from the LIFE trial, atenolol appeared to be superior to losartan in blacks, while the opposite was the case in non-blacks. A similar lack of efficacy of lisinopril compared to diuretics and calcium channel blockers was observed in blacks in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attach Trial (ALLHAT), suggesting that ACE inhibitors and ARBs may not be the preferred agents in black patients. In the treatment of hypertension, combination therapy with an ACE inhibitor and an ARB is not advised because it generally offers no advantage over monotherapy at maximum dose with addition of a complementary class where necessary.

Side effects

Unlike ACE inhibitors, the ARBs rarely cause cough and are less likely to be associated with skin rashes or angioedema (Table 11–6). However, as seen with ACE inhibitors, hyperkalemia can be a problem, and patients with bilateral renal artery stenosis may exhibit hypotension and worsened kidney function. Olmesartan has been linked to a sprue-like syndrome, presenting with abdominal pain, weight loss, and nausea, which subsides upon drug discontinuation. There is evidence from an observational study suggesting that ARBs and ACE inhibitors are less likely to be associated with depression than calcium channel blockers and beta-blockers.

C. Renin Inhibitors

Since renin cleavage of angiotensinogen is the rate-limiting step in the renin-angiotensin cascade, the most efficient inactivation of this system would be expected with renin inhibition. Conventional ACE inhibitors and ARBs probably offer incomplete blockade, even in combination. Aliskiren, a renin inhibitor, binds the proteolytic site of renin, thereby preventing cleavage of angiotensinogen. As a consequence, levels of angiotensins I and II are reduced and renin concentration is increased. Aliskiren effectively lowers blood pressure, reduces albuminuria, and limits left ventricular hypertrophy, but it has yet to be established as a first-line drug based on outcomes data. The combination of aliskiren with ACE inhibitors or ARBs in persons with type 2 diabetes mellitus offers no advantage and might even increase the risk of adverse cardiac or renal consequences.

D. 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 11–7). For these reasons, they may be preferable to beta-blockers and ACE inhibitors in blacks and older persons. Verapamil and diltiazem should be combined cautiously with beta-blockers because of their potential for depressing atrioventricular (AV) conduction and sinus node automaticity as well as contractility.

Table 11–7.Antihypertensive drugs: calcium channel blocking agents.

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Table 11–7. Antihypertensive drugs: calcium channel blocking agents.

Initial concerns about possible adverse cardiac effects of calcium channel blockers have been convincingly allayed by several subsequent large studies that have demonstrated that calcium channel blockers are equivalent to ACE inhibitors and thiazide diuretics in prevention of coronary heart disease, major cardiovascular events, cardiovascular death, and total mortality. A protective effect against stroke with calcium channel 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.

Side effects

The most common side effects of calcium channel blockers are headache, peripheral edema, bradycardia, and constipation (especially with verapamil in older adults) (Table 11–7). 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. Edema is minimized by coadministration of an ACE inhibitor or ARB. Calcium channel blockers have negative inotropic effects and should be used cautiously in patients with cardiac dysfunction. Amlodipine is the only calcium channel blocker with established safety in patients with severe heart failure. According to a case-control study based in the Pacific Northwest of the United States, calcium channel blockers as a class may increase the risk of breast cancer by 2.5-fold, but this relationship has not been consistently observed in other studies, and calcium channel blockers do not appear to increase the risk of breast cancer recurrence.

E. Diuretics

Thiazide diuretics (Table 11–8) are the antihypertensives that have been most extensively studied and most consistently effective in clinical trials. They lower blood pressure initially by decreasing plasma volume, but during long-term therapy, their major hemodynamic effect is reduction of peripheral vascular resistance. Most of the antihypertensive effect of these agents is achieved at lower dosages than used previously (typically, 12.5 mg of hydrochlorothiazide or equivalent), but their biochemical and metabolic effects are dose related. Chlorthalidone has the advantage of better 24-hour blood pressure control than hydrochlorothiazide in clinical trials. Thiazides may be used at higher doses if plasma potassium is above 4.5 mmol/L. The loop diuretics (such as furosemide) may lead to electrolyte and volume depletion more readily than the thiazides and have short durations of action. Because of these adverse effects, loop diuretics should be reserved for use in patients with kidney dysfunction (serum creatinine greater than 2.5 mg/dL [208.3 mcmol/L]; estimated glomerular filtration rate [eGFR] less than 30 mL/min) in which case they are more effective than thiazides. Relative to beta-blockers and ACE inhibitors, diuretics are more potent in blacks, older individuals, the obese, and other subgroups with increased plasma volume or low plasma renin activity (or both). They are relatively more effective in smokers than in nonsmokers. Long-term thiazide administration also mitigates the loss of bone mineral content in older women at risk for osteoporosis.

Table 11–8.Antihypertensive drugs: diuretics (in descending order of preference).

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Table 11–8. Antihypertensive drugs: diuretics (in descending order of preference).

Overall, diuretics administered alone control blood pressure in 50% of patients with mild to moderate hypertension and can be used effectively in combination with all other agents. They are also useful for lowering isolated or predominantly systolic hypertension.

Side effects

The adverse effects of diuretics relate primarily to the metabolic changes listed in Table 11–8. Erectile dysfunction, skin rashes, and photosensitivity are less frequent. Hypokalemia has been a concern but is uncommon at the recommended dosages. The risk can be minimized by limiting dietary salt or increasing dietary potassium; potassium replacement is not usually required to maintain serum K+ at greater than 3.5 mmol/L. Higher serum K+ levels are prudent in patients at special risk from intracellular potassium depletion, such as those taking digoxin or with a history of ventricular arrhythmias in which case a potassium-sparing agent could be used. Compared with ACE inhibitors and ARBs, diuretic therapy is associated with a slightly higher incidence of mild new-onset diabetes. Diuretics also increase serum uric acid and may precipitate gout. Increases in blood glucose, triglycerides, and LDL cholesterol may occur but are relatively minor during long-term low-dose therapy. The potential for worsening of diabetes is outweighed by the advantages of blood pressure control, and diuretics should not be withheld from diabetic patients.

F. Aldosterone Receptor Antagonists

Spironolactone and eplerenone are natriuretic in sodium-retaining states, such as heart failure and cirrhosis, but only very weakly so in hypertension. These drugs have reemerged in the treatment of hypertension, particularly in resistant patients and are helpful additions to most other antihypertensive medications. Consistent with the increasingly appreciated importance of aldosterone in essential hypertension, the aldosterone receptor blockers are effective at lowering blood pressure in all hypertensive patients regardless of renin level, and are also effective in blacks. Aldosterone plays a central role in target-organ damage, including the development of ventricular and vascular hypertrophy and renal fibrosis. Aldosterone receptor antagonists ameliorate these consequences of hypertension, to some extent independently of effects on blood pressure.

Side effects

Spironolactone can cause breast pain and gynecomastia in men through activity at the progesterone receptor, an effect not seen with the more specific eplerenone. Hyperkalemia is a problem with both drugs, chiefly in patients with chronic kidney disease. Hyperkalemia is more likely if the pretreatment plasma potassium exceeds 4.5 mmol/L.

G. Beta-Adrenergic Blocking Agents

These drugs are effective in hypertension because they decrease the heart rate and cardiac output. Even after continued use of beta-blockers, cardiac output remains lower and systemic vascular resistance higher with agents that do not have intrinsic sympathomimetic or alpha-blocking activity. The beta-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 heart failure as well as those with migraine headaches and somatic manifestations of anxiety.

Although all beta-blockers appear to be similar in antihypertensive potency, they differ in a number of pharmacologic properties (these differences are summarized in Table 11–9), including specificity to the cardiac beta-1-receptors (cardioselectivity) and whether they also block the beta-2-receptors in the bronchi and vasculature; at higher dosages, however, all agents are nonselective. The beta-blockers also differ in their pharmacokinetics, lipid solubility—which determines whether they cross the blood-brain barrier predisposing to central nervous system side effects—and route of metabolism. Metoprolol reduces mortality and morbidity in patients with chronic stable heart failure with reduced ejection fraction (see Chapter 10). Carvedilol and nebivolol maintain cardiac output and are beneficial in patients with left ventricular systolic dysfunction. Carvedilol and nebivolol may reduce peripheral vascular resistance by concomitant alpha-blockade (carvedilol) and increased nitric oxide release (nebivolol). Because of the lack of efficacy in primary prevention of myocardial infarction and inferiority compared with other drugs in prevention of stroke and left ventricular hypertrophy, traditional beta-blockers should not be used as first-line agents in the treatment of hypertension without specific compelling indications (such as active coronary artery disease). Vasodilating beta-blockers may emerge as alternative first-line antihypertensives, but this possibility has yet to be rigorously tested in outcome studies.

Table 11–9.Antihypertensive drugs: beta-adrenergic blocking agents.

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Table 11–9. Antihypertensive drugs: beta-adrenergic blocking agents.

Side effects

The side effects of beta-blockers include inducing or exacerbating bronchospasm in predisposed patients; sinus node dysfunction and AV conduction depression (resulting in bradycardia or AV block); nasal congestion; Raynaud phenomenon; and central nervous system symptoms with nightmares, excitement, depression, and confusion. Fatigue, lethargy, and erectile dysfunction may occur. The traditional beta-blockers (but not the vasodilator beta-blockers carvedilol and nebivolol) have an adverse effect on lipids and glucose metabolism. Beta-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. 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. Nebivolol can be safely used in patients with stage II claudication (claudication at 200 m).

In treatment of pheochromocytoma, beta-blockers should not be administered until alpha-blockade (eg, phentolamine) has been established. Otherwise, blockade of vasodilatory beta-2-adrenergic receptors will allow unopposed vasoconstrictor alpha-adrenergic receptor activation with worsening of hypertension. For the same reason, beta-blockers should not be used to treat hypertension arising from cocaine use.

In addition to adverse metabolic changes associated with their use, some experts have suggested that the therapeutic shortcomings of traditional beta-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 central systolic and pulse pressures. By contrast, traditional beta-blockers appear to potentiate reflection of pressure waves, possibly because peripheral resistance vessels are a reflection point and peripheral resistance is increased by these drugs. This might explain why the traditional beta-blockers are less effective at controlling systolic and pulse pressure.

Great care should be exercised if the decision is made, in the absence of compelling indications, to remove beta-blockers from the treatment regimen because abrupt withdrawal can precipitate acute coronary events and severe increases in blood pressure.

H. Alpha-Adrenoceptor Antagonists

Prazosin, terazosin, and doxazosin (Table 11–10) block postsynaptic alpha-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. Unlike beta-blockers and diuretics, alpha-blockers have no adverse effect on serum lipid levels. In fact, alpha-blockers increase HDL cholesterol while reducing total cholesterol; whether this is beneficial in the long term has not been established.

Table 11–10.Alpha-adrenoceptor blocking agents, sympatholytics, and vasodilators.

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Table 11–10. Alpha-adrenoceptor blocking agents, sympatholytics, and vasodilators.

Side effects

Side effects—Side effects are relatively common (Table 11–10). These include marked hypotension after the first dose which, therefore, should be small and given at bedtime. Post-dosing palpitations, headache, and nervousness may continue to occur during long-term therapy; these symptoms may be less frequent or severe with doxazosin because of its more gradual onset of action. In ALLHAT, persons receiving doxazosin as initial therapy had a significant increase in heart failure hospitalizations and a higher incidence of stroke relative to those receiving diuretics, prompting discontinuation of this arm of the study. Cataractectomy in patients exposed to alpha-blockers can be complicated by the floppy iris syndrome, even after discontinuation of the drug, so the ophthalmologist should be alerted that the patient has been taking the drug prior to surgery.

To summarize, alpha-blockers should generally not be used as initial agents to treat hypertension—except perhaps in men with symptomatic prostatism or nightmares linked to posttraumatic stress disorder.

I. Drugs With Central Sympatholytic Action

Methyldopa, clonidine, guanabenz, and guanfacine (Table 11–10) lower blood pressure by stimulating alpha-adrenergic receptors in the central nervous system, thus reducing efferent peripheral sympathetic outflow. There is considerable experience with methyldopa in pregnant women, and it is still used for this population. Clonidine is available in patches, which may have particular value in noncompliant patients. All of these central sympatholytic 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. Methyldopa has the potential to prevent type 1 diabetes through interaction with the antigen binding cleft of the major histocompatibility molecule DQ8.

Side effects

Side effects include sedation, fatigue, dry mouth, postural hypotension, and erectile dysfunction. An important concern is rebound hypertension following withdrawal. Methyldopa also causes hepatitis and hemolytic anemia and should be restricted to individuals who have already tolerated long-term therapy.

J. 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.

K. 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. To counteract these effects, the agents are usually given in combination with diuretics and beta-blockers in resistant patients. Hydralazine produces frequent gastrointestinal disturbances and may induce a lupus-like syndrome. Minoxidil causes hirsutism and marked fluid retention; this very potent agent is reserved for the most refractory of cases.

Which effect indicates that a patient is experiencing an adverse effect of enalapril?

What is the most common side effect of enalapril?

What should be monitored when taking enalapril?

Which of the following is a contraindication to enalapril?