HYPERTENSION
Hypertension is the most common cardiovascular disease. The prevalence of hypertension increases with advancing age; for example, about 50% of people between the ages of 60 and 69 years old have hypertension, and the prevalence is further increased beyond age 70. Elevated arterial pressure causes pathological changes in the vasculature and hypertrophy of the left ventricle. As a consequence, hypertension is the principal cause of stroke, is a major risk factor for coronary artery disease and its attendant complications myocardial infarction and sudden cardiac death, and is a major contributor to cardiac failure, renal insufficiency, and dissecting aneurysm of the aorta.
Hypertension is defined conventionally as a sustained increase in blood pressure ³140/90 mm Hg, a criterion that characterizes a group of patients whose risk of hypertension-related cardiovascular disease is high enough to merit medical attention. Actually, the risk of both fatal and nonfatal cardiovascular disease in adults is lowest with systolic blood pressures of less than 120 mm Hg and diastolic BP less than 80 mm Hg; these risks increase progressively with higher systolic and diastolic blood pressures. Recognition of this continuously increasing risk provides a simple definition of hypertension. Although many of the clinical trials classify the severity of hypertension by diastolic pressure, progressive elevations of systolic pressure are similarly predictive of adverse cardiovascular events; at every level of diastolic pressure, risks are greater with higher levels of systolic blood pressure. Indeed, beyond age 50 years, systolic blood pressure predicts outcome better than diastolic blood pressure. Systolic blood pressure tends to rise disproportionately greater in the elderly due to decreased compliance in blood vessels associated with aging and atherosclerosis. Isolated systolic hypertension (sometimes defined as systolic BP >140 to 160 mm Hg with diastolic BP <90 mm Hg) is largely confined to people >60 years of age.
At very high blood pressures (systolic ³210 and/or diastolic ³120 mm Hg), a subset of patients develops fulminant arteriopathy characterized by endothelial injury and a marked proliferation of cells in the intima, leading to intimal thickening and ultimately to arteriolar occlusion. This is the pathological basis of the syndrome of immediately life-threatening hypertension, which is associated with rapidly progressive microvascular occlusive disease in the kidney (with renal failure), brain (hypertensive encephalopathy), congestive heart failure, and pulmonary edema. These patients typically require in-hospital management on an emergency basis for prompt lowering of blood pressure. Interestingly, isolated retinal changes with papilledema in an otherwise asymptomatic patient with very high blood pressure (formerly called “malignant hypertension”) may benefit from a more gradual lowering of blood pressure over days rather than hours.
The presence of pathologic changes in certain target organs heralds a worse prognosis than the same level of blood pressure in a patient lacking these findings. Thus, retinal hemorrhages, exudates, and papilledema indicate a far worse short-term prognosis for a given level of blood pressure. Left ventricular hypertrophy defined by electrocardiogram, or more sensitively by echocardiography, is associated with a substantially worse long-term outcome that includes a higher risk of sudden cardiac death. The risk of cardiovascular disease, disability, and death in hypertensive patients also is increased markedly by concomitant cigarette smoking, diabetes, or elevated low-density lipoprotein; the coexistence of hypertension with these risk factors increases cardiovascular morbidity and mortality to a degree that is compounded by each additional risk factor. Since the purpose of treating hypertension is to decrease cardiovascular risk, other dietary and pharmacological interventions may be required.
Pharmacological treatment of patients with hypertension associated with elevated diastolic pressures reduces morbidity and mortality from cardiovascular disease. Effective antihypertensive therapy markedly reduces the risk of strokes, cardiac failure, and renal insufficiency due to hypertension. However, reduction in risk of myocardial infarction may be less impressive.
Nonpharmacological therapy is an important component of treatment of all patients with hypertension. In some stage 1 hypertensives, blood pressure may be adequately controlled by a combination of weight loss (in overweight individuals), restricting sodium intake, increasing aerobic exercise, and moderating consumption of alcohol. These lifestyle changes, though difficult for many to implement, may facilitate pharmacological control of blood pressure in patients whose responses to lifestyle changes alone are insufficient.
Arterial pressure is the product of cardiac output and peripheral vascular resistance. Drugs lower blood pressure by actions on peripheral resistance, cardiac output, or both. Drugs may reduce the cardiac output by inhibiting myocardial contractility or by decreasing ventricular filling pressure. Reduction in ventricular filling pressure may be achieved by actions on the venous tone or on blood volume via renal effects. Drugs can reduce peripheral resistance by acting on smooth muscle to cause relaxation of resistance vessels or by interfering with the activity of systems that produce constriction of resistance vessels (e.g., the sympathetic nervous system). In patients with isolated systolic hypertension, complex hemodynamics in a rigid arterial system contribute to increased blood pressure; drug effects may be mediated by changes in peripheral resistance but also via effects on large artery stiffness. Antihypertensive drugs can be classified according to their sites or mechanisms of action
The hemodynamic consequences of long-term treatment with antihypertensive agents such as Ace inhibitors, Calcium channel blockers, Diuretics and Angiotensin receptor blockers provide a rationale for potential complementary effects of concurrent therapy with two or more drugs. The simultaneous use of drugs with similar mechanisms of action and hemodynamic effects often produces little additional benefit. However, concurrent use of drugs from different classes is a strategy for achieving effective control of blood pressure while minimizing dose-related adverse effects.
It is generally not possible to predict the responses of individuals with hypertension to any specific drug. For example, for some antihypertensive drugs, on average about two-thirds of patients will have a meaningful clinical response, whereas about one-third of patients will not respond to the same drug. There is considerable interest in identifying genetic variation in order to improve selection of antihypertensive drugs in individual patients. Polymorphisms in a number of genes involved in the metabolism of antihypertensive drugs have been identified, for example in the CYP family (phase I metabolism) and in phase II metabolism, such as catechol-O-methyltransferase. While these polymorphisms change the pharmacokinetics of specific drugs, it is not clear that there will be substantial differences in efficacy given the dose range available clinically for these drugs. Consequently, identification of polymorphisms that influence pharmacodynamic responses to antihypertensive drugs are of considerable interest. Polymorphisms influencing the actions of a number of classes of antihypertensive drugs, including angiotensin-converting enzyme inhibitors and diuretics, have been identified; so far, individual genes have not been found to have a major impact on pharmacodynamic responses. Genome-wide scanning may lead to identification of novel genes that are more clinically significant. Likewise, treatment may profit from an understanding of the molecular and genetic bases of hypertension.
By: Ammarah Khan
