Treatment Of Hypertension
Hypertension is defined pragmatically as the level of blood pressure (BP) above which therapeutic intervention can be shown to reduce the risk of developing cardiovascular disease (Table 38.1). Risk increases progressively with both systolic and diastolic BP levels. Epidemiological studies predict that a long-term 5–6-mmHg diminution of diastolic blood pressure (DBP) should reduce the incidence of stroke and CHD by about 40 and 25%, respectively. However, rises in systolic pressure are now given more emphasis and isolated systolic hypertension (ISH), which often develops in the elderly, is particularly deleterious.
Individual BP measurements can vary significantly, and current guidelinesstatethat, unlesssevere, hypertension(BP>140/90 mmHg) initially detected in the clinic should be confirmed using an ambulatory BP monitor which records multiple BP measurements over a 24-hour period. Tests for damage to target organs vulnerable to hypertension (e.g. eyes, kidneys) and assessment of other cardio- vascular risk factors should also be carried out. Those with stage 1 hypertension should then be treated if they have overt cardio- vascular disease, diabetes, target organ damage, renal disease or an overall cardiovascular risk of >20% per 10 years (as estimated using risk tables derived from the Framingham study; see Chapter 34). All those with stage 2 or 3 hypertension should be treated. The goal of antihypertensive therapy is to reduce the blood pressure to below 140/90 mmHg (or to below 130/80 mmHg in diabetics and those with renal disease).
Lifestyle modifications such as weight reduction, regular aerobic exercise and limitation of dietary sodium and alcohol intake can often normalize pressure in mild hypertensives. They are also useful adjuncts to pharmacological therapy of more severe disease, and have the important added bonus of reducing overall cardiovascular risk. However, adequate BP control usually requires the lifelong use of antihypertensive drugs. These act to reduce cardiac output and/or total peripheral resistance.
Thiazide diuretics cause an initial increased Na+ excretion by the kidneys, which is due to inhibition of Na+/Cl− symport in the distal nephron. This leads to a fall in blood volume and cardiac output. Subsequently, blood volume recovers, but total peripheral resistance falls due to an unknown mechanism. Thiazide diuretics (e.g. chlorthalidone, indapamide) can cause hypokalaemia by promoting Na+– K+ exchange in the collecting tubule. This can be prevented by giving K+ supplements, or also by combining thiazide diuretics with K+-sparing diuretics (e.g. amiloride) to reduce Na+ reabsorption and therefore K+ secretion by blocking Na+ channels (EnaC) in the collecting duct. Additional side effects include increases in plasma insulin, glucose or cholesterol, as well as hypersensitivity reactions and impotence.
Angiotensin-converting enzyme inhibitors (ACEI) such as captopril, enalopril and lisinopril block the conversion of angiotensin I into angiotensin II. This reduces total peripheral resistance because angiotensin II stimulates the sympathetic system centrally, promotes release of noradrenaline from sympathetic nerves, and vasoconstricts directly. The fall in plasma angiotensin II, and consequently in aldosterone, also promotes diuresis/natriuresis because both hormones cause renal Na+ and water retention (see Chapter 29). ACE also metabolizes the vasodilators bradykinin and substance P, and part of the beneficial action of ACEI may be due to elevated levels of bradykinin. However, increases in bradykinin and substance P may also sensitize sensory nerves in the airways, leading to the chronic cough that is the most common adverse effect of ACEI. This effect does not occur with angiotensin II receptor (AT1) blockers (ARB) such as losartan and valsartan, which selectively inhibit the effects of angiotensin II on its AT1 subtype without affecting bradykinin levels. Both ACEI and ARB have few side effects, leading to their increasing popularity. However, they are contraindicated in pregnancy, renovascular disease and aortic stenosis. Eplerenone, a selective aldosterone receptor antagonist (see also Chapter 47), is also used to treat hypertension, as is the newer drug aliskiren, an antagonist of renin which prevents it from producing angiotensin I.
Calcium-channel blockers (CCBs) such as nifedipine, verapamil and diltiazem are commonly used to treat hypertension due to their vasodilating properties, as described in Chapter 35. The dihydropyridine CCBs, which are selective for vascular smooth muscle over the heart, are used most widely, and also have a useful diuretic effect. The 2005 ASCOT trial showed that the long-acting dihydropyridine amlodipine (with the ACEI perindopril added in if required to meet blood pressure targets) reduced cardiovascular morbidity and mortality more effectively than the β-blocker atenolol (with the diuretic bendroflumethiazide if required). DHPs have been shown to be especially effective in the elderly, and are safe in pregnancy.
In view of the results of ASCOT and other recent clinical trials, β-receptor blockers (see Chapter 35), once a first line treatment for hypertension, are now recommended for use mainly in combination with other drugs in patients who do not respond well to treatment. β-Blockers antagonize sympathetic nervous system stimulation of cardiac β-receptors (mainly β1), thereby reducing cardiac output through negative inotropic and chronotropic effects. They also block β-receptors on juxtaglomerular granule cells in the kidney, thus inhibiting renin release and reducing plasma levels of angiotensin II and aldosterone. During treatment, total peripheral resistance rises initially and then returns to the predrug level via an unknown mechanism, while cardiac output remains depressed. Some β-blockers are selective for the β1 subtype (atenolol), while others block both β1 and β2 subtypes (pro-pranolol), and several (pindolol) are partial β-receptor agonists. In each case, the effects on blood pressure are similar, although the partial β-receptor agonists are probably acting more as vasodilators than by reducing cardiac output. All β-blockers are contraindicated in moderate/severe asthma due to their potential effects on bronchiolar β2-receptors. Adverse effects of these drugs include fatigue, negative inotropy, CNS disturbances in some (e.g. nightmares), and worsening and masking of the signs of hypoglycaemia.
α1-receptor-selective blockers cause vasodilatation by inhibiting the ongoing constriction of arteries by the sympathetic neurotransmitter noradrenaline. These drugs are used in preference to non- selective α-antagonists in order to prevent the increased norepinephrine release from sympathetic nerves that would occur if presynaptic α2-receptors were also blocked. Like β-blockers, these drugs are used at a late stage of stepped treatment if combinations of other drugs have failed to adequately control the blood pressure.
The drugs rilmenidine and moxonidine reduce sympathetic outflow by activating central imidazoline (I1) receptors in the rostral ventrolateral medulla (RVLM). This lowers blood pressure with few side effects, but the use of these drugs is limited due to the present lack of evidence from clinical trials that they have beneficial effects on survival.
Stepped treatment: treatment of hypertension is typically initiated with a single drug, but combinations of several drugs are usually needed to achieve adequate blood pressure control. The renin–angiotensin–aldosterone axis is more likely to be a contributing factor in causing hypertension in younger white patients, and so step 1 is to try an ACEI or ARB in white patients <55 of age and a CCB or a diuretic in black and older white hypertensives. If this fails to control BP, step 2 in all patients is to try a combination of a CCB or diuretic with an ACE-I or ARB. If BP is still not lowered enough, step 3 is to use an (ACE-I or ARB)/ CCB/diuretic combination. Antagonists to aldosterone and α- or β-receptors, or other drugs, can then be tried in step 4. Drug selection is also influenced by whether a patient has a coexisting condition which renders a certain type of antihypertensive more or less appropriate in that individual (e.g. ACEI are also useful for treating heart failure and diabetic nephropathy but should not be used in pregnant women; Ca2+ channel blockers are used to control angina).
In cases in which hypertension is secondary to a known condition or factor (e.g. renal stenosis, oral contraceptives), removal of this cause is often sufficient to normalize the blood pressure.