Overview of Hypertension Pharmacologic Treatments
The general approach to pharmacologic treatment of hypertension is outlined in JNC-VI. Treatment is stratified as a function of blood pressure stage (high normal: 130-139/85-89; stage 1: 140-159/90-99; and stage 2 and 3: ≥160/≥100 mmHg) and three levels of risk. Because age greater than 60 years is considered as one component of cardiovascular risk, all older hypertensive patients fall into the middle risk group (risk group B) at a minimum.
For those with high-normal and stage 1 hypertension with no additional cardiovascular risk factors, 6-month trial of nonpharmacologic therapy is warranted. If a 6-month trial of nonpharmacologic treatment fails to produce the desired reduction in blood pressure, pharmacologic therapy should be initiated while nonpharmacologic treatments are continued. Older patients who initially present with more severe hypertension (stage 2 or 3), as well as those with diabetes or additional cardiovascular risk factors or evidence of target organ damage (risk group C), should receive pharmacologic therapy initiated concurrently with nonpharmacologic methods.
The choice of initial antihypertensive drug class should be based on an individualized patient assessment. One should consider whether the patient has simple hypertension or if their hypertension is complicated by the coexistence of other conditions (e.g., diabetes, coronary artery disease, heart failure, or prostatism) that may influence drug selection. Each of the antihypertensive drug classes have been shown to be effective in reducing blood pressure in the older patient population. For those with simple hypertension, the initial drug selection based on the evidence available to date is either a thiazide diuretic or a long-acting dihydropyridine calcium channel antagonist. Beyond this general recommendation, selection of a particular antihypertensive drug needs to be an individualized decision for each patient, taking into account the drug’s potential advantages and disadvantages (
see Table 40.2), together with the patient’s comorbidities. Irrespective of the initial agent that is selected, in general, the starting dose should be reduced and dose titration done more gradually in an older hypertensive patient. If the target blood pressure goal is not obtained at a maximal dose of the initial agent following several months of treatment, therapy may either be switched to an alternate class or a second drug from another class may be added. A brief overview of the major classes of antihypertensive drugs that are currently recommended for initial therapy follows, focusing on their potential benefits and side effect profiles.
Therapy with low-dose thiazide diuretics (e.g., hydrochlorthiazide dose <50 mg daily, or equivalent) has demonstrated significant benefits in mortality, stroke, and coronary events in randomized clinical trials in older hypertensive patient populations. These beneficial effects combined with their relative safety, favorable side effect profile (their adverse metabolic effects—hypokalemia, hyperuricemia, and glucose intolerance—are attenuated at lower doses), once-daily dosing, and low cost have led to the recommendation that thiazide diuretics are preferred for initial therapy. Another advantage is that diuretic therapy leads to a disproportionate reduction in systolic relative to diastolic blood pressure and is better at achieving a reduction in systolic blood pressure compared to other agents.
Thiazide diuretics are also well suited for use in combination therapies because of synergistic effects with other antihypertensive drug classes. It is worth nothing that, despite these recommendations, only 23% of the subjects who were on monotherapy at the time of their entry into the TONE study were treated with diuretics, suggesting that this class of therapy is being underutilized.
Each of the three chemical classes of calcium channel antagonists, that is, phenylalkylamines, dihydropyridines, and benzothiazepines, has been shown to be effective in treating hypertension in older patient populations. There are significant age-associated alterations in the pharmacokinetics of each of the three classes of calcium channel antagonists (a decrease in clearance and an increase in plasma levels) such that lower doses of these agents should be used in older patients. Based on their mechanism of action, which leads to a reduction in peripheral vascular resistance and their lack of significant CNS or metabolic effects, the calcium channel antagonist family of medications is well matched to the pathophysiology of the older hypertensive patient. The dihydropyridine class (e.g., nifedipine) has more potent direct vasodilator effects and may be more likely to produce peripheral edema and reflex tachycardia. Members of the phenylalkylamine (e.g., verapamil) and benzothiazepine (e.g., diltiazem) classes have more potent effects on suppressing atrioventricular (AV) conduction and may produce heart block, and also these appear to be more commonly associated with the development of constipation.
Several randomized controlled trials of the efficacy of long-acting dihydropyridine calcium channel antagonists (nicardipine or amlodipine) in the treatment of older hypertensive patient populations have been reported. The Systolic Hypertension in Europe (Syst-Eur) trial identified that active treatment was associated with a significant decrease in cardiovascular complications, including a 44% reduction in nonfatal stroke. No significant benefits were observed in all-cause mortality. The conclusions were similar in a subsequent per protocol analysis of these data. The benefits of treatment on total and cardiovascular mortality were less in those older than 80 years. From the per protocol analysis, it was estimated that treating 1000 patients for 5 years would prevent 24 deaths, 54 major cardiac events, and 29 strokes.
To address concerns that calcium antagonist therapy may be deleterious in those with diabetes, a subgroup analysis of the Syst-Eur population found similar beneficial effects in the diabetic population as had been noted in nondiabetics. Finally, a Japanese Intervention Cooperative Study followed older hypertensive patients randomized to the dihydropyridine calcium channel antagonist nicardipine or a thiazide diuretic and reported similar benefits in decreasing the risk of cardiovascular events between groups.
Beta-receptor antagonists are recommended in the JNC-VI report as another option for initial drug therapy for uncomplicated hypertension. The primary mechanism of action of β-adrenergic antagonists is a reduction in cardiac output without significant reduction in peripheral vascular resistance (and less reduction in systolic blood pressure compared to other agents). Based on the physiologic characteristics of the older hypertensive (
Table 40.3
), there are several reasons to question whether β-adrenergic antagonists would be the appropriate choice for the older hypertensive patient. Indeed, one report that analyzed evidence from recent randomized controlled trials has questioned whether β-adrenergic antagonists are effective therapy for older hypertensive individuals. This report analyzed results from 10 randomized controlled trials that evaluated morbidity and mortality outcomes in hypertensive patients above the age of 60 years following β-adrenergic antagonist therapy. These results suggested that β-receptor antagonist therapy is less effective as monotherapy with respect to blood pressure reduction and in the prevention of cardiovascular events and death in comparison with low-dose thiazide diuretics. In addition, there was a higher discontinuation rate due to adverse side effects. This report concluded with a recommendation that β-receptor antagonists not be considered as first-line monotherapy for simple hypertension in older patients.Because of their effectiveness in the management of symptomatic coronary artery disease, in secondary prevention following myocardial infarction, and in certain congestive heart failure settings, β-receptor antagonists should be considered in older patients whose hypertension is complicated by these comorbid conditions. Glucose and lipid profile monitoring should be done in patients who are treated with β-receptor antagonists. In addition, depression and lethargy may develop during β-receptor antagonist therapy, particularly with those who are more lipophilic.
Angiotensin-Converting Enzyme (ACE) Inhibitors
Because older hypertensive individuals are in general characterized as having low renin levels (
see Table 40.3
), one might predict that ACE inhibitors would not be effective therapeutic agents in this population. Nevertheless, this antihypertensive class has been shown to be effective in treating the older hypertensive. ACE inhibitors are generally well tolerated by older patients (with the exception of cough), and their lack of CNS and metabolic (glucose, electrolyte, and lipid) effects may be a particular advantage. Although postural hypotension is not common, an exaggerated hypotensive effect may develop in volume-depleted patients receiving concurrent therapy with diuretics; particular attention to this possibility is required with the initiation of ACE inhibitor therapy. There are compelling indications to use ACE inhibitor therapy in patients with coexisting left ventric-ular systolic dysfunction as well as in diabetic patients who have microalbuminuria.The major limitations to the use of ACE inhibitors in older hypertensive patients are the development of hyperkalemia (especially in those with renal insufficiency) and the potential for development of renal failure in the setting of bilateral renal artery stenosis. Fortunately, ACE inhibitor-mediated renal failure is not a common occurrence and is generally reversible. The use of ACE inhibitors with short duration of action and frequent monitoring of renal function will aid in the detection and prevention of this adverse outcome. Although it may seem paradoxical, despite these potential adverse effects on renal function, there appears to be a role for ACE inhibitors in treating hypertensive patients with chronic renal insufficiency. Close monitoring of potassium levels and renal function is necessary when ACE inhibitors are utilized in these patient groups. Other potential adverse effects of ACE inhibitors are the development of a nonproductive cough (occurring in up to 10% of patients), rash, or angioneurotic edema.
α1-Adrenergic Receptor Antagonists
Although the reduction in peripheral vascular resistance that occurs with α-receptor antagonist therapy is particularly appropriate for the pathophysiologic profile of geriatric hypertension, and although these agents are effective in blood pressure reduction, the development of postural hypotension has limited the widespread use of this class of antihypertensive in the geriatric population. Further, a preliminary report from the currently ongoing Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) identified that subjects randomized to therapy with the α-receptor antagonist doxazosin had similar outcomes to those receiving a diuretic but had a twofold greater likelihood to be hospitalized for CHF. Consequently, this arm of the ALLHAT study was closed. Until additional information is available from the ALLHAT and other ongoing trials, monotherapy with α-adrenergic receptor antagonists to treat simple hypertension is not advised. One clinical situation in which α-receptor antagonist therapy may be considered is in older hypertensive men with prostatism, because these drugs have been shown to be efficacious in improving obstructive urinary symptoms.