Two Current Views on Antihypertensive Therapy

Taking the right steps to combat severe hypertension - one, two, three or four? Severely hypertensive patients represent only a small proportion of the total hypertensive population. Their

importance lies not in their absolute numbers, but in the marked increase in morbidity and mortality associated with severe disease, and in the problem of adequate control of BP. The potential benefits of therapy are much greater, although the aggressive treatments often required carry their own risks.

Dietary control of hypertension has the advantage of avoiding toxic effects. However, its effect on BP is usually inadequate in severe disease. Of greater value is the elimination of identifiable causes of hypertension, where appropriate. Iatrogenic effects should be considered as should phaeochromocytoma, primary aldosteronism, and renal or renovascular disease. However, in the vast majority of patients non-pharmacological management will prove inappropriate or ineffective.

Stepped care regimens: up to 3 drugs at a time . .. The standard approach to pharmacological intervention involves the first-line administration of a thiazide or

potassium-sparing diuretic or a !J-blocker, either alone or, more usually, in combination. If control is still inadequate a 'third-line' agent, commonly hydralazine or prazosin, is added. A combination of diuretic, !J­blocker and vasodilator (triple therapy) will control most severely hypertensive patients. Two newer groups of antihypertensives, the calcium antagonists and angiotensin converting enzyme (ACE) inhibitors, are rapidly gaining acceptance as alternatives to the vasodilator component of triple therapy, particularly where the vasodilator is poorly tolerated.

Hypertension resistant to triple therapy generally requires hospitalisation as many of these patients develop malignant hypertension. This risk, along with those of myocardial infarction, cerebrovascular accident and renal failure, provides life-threatening reasons for more aggressive treatment with appropriate inpatient supervision .

. . . or a fourth, alone or as quadruple therapy The potent arteriolar vasodilators, diazoxide and minoxidil, should be reserved for use only when

conventional triple therapy has failed. Ideally a !J-blocker should be co-administered to reduce any reflex increase in sympathetic activity. Adverse effects are much more common and include hirsutism, sodium retention, oedema, nausea, vomiting, rashes, dysrhythmias and extrapyramidal effects. In addition, diazoxide is associated with a high induction of diabetes. Despite the high incidence of side effects, both agents have proven very effective in controlling previously resistant hypertension. In the absence of intrinsic disease a significant improvement in renal function is observable,and is dependent on two mechanisms. The immediate hypotensive response will improve cardiac function, thus increasing renal blood flow, and directly reduce hypertensive renovascular damage. In the absence of heart failure, however, the immediate response to the hypotensive effect may be reduced renal perfusion and, in the case of over-zealous treatment, compromise of the cerebral circulation. Careful monitoring during early therapy is therefore essential. Captopril was initially tried as a fourth-line agent but its lower efficacy and high incidence of renal side effects make it a less attractive choice.

In an attempt to avoid 'fourth-line' agents, therapies involving conventional triple therapy with prazosin added (quadruple therapy) have been used successfully. These may produce fewer adverse effects than 'fourth-line' agents but have the disadvantage of being complex to administer. They are perhaps best suited to those in which conventional triple therapy is just unable to achieve the desired level of control. Captopril and vasodilator combinations are also very effective, but they carry the risk of profound hypotensive response and should also be limited to inpatient use.

The 5 classes of drugs available to the clinician, prudently used, provide the opportunity to treat severe hypertension successfully in almost every patient. Swales. JO.· Journal of the Royal College of PhysiCians of London 18.' 46 (1 Jan 1984) [20 references]

Prazosin and the importance of serum lipid levels during antihypertensive therapy It has been suggested that the failure of blood pressure (BP) lowering to reduce the incidence of

myocardial infarction might be due to adverse effects of antihypertensive medications on serum lipids, thereby offsetting the potentially beneficial effects of BP reduction. Chlorthalidone and selective and non-selective !J-blockers have both been found to increase serum triglyceride concentrations, and either to increase the low­density lipoprotein (LDL) or to decrease the high-density lipoprotein (HDL) cholesterol concentrations, all of which are risk factors for coronary artery disease. However, prazosin has been found to cause a significant reduction in serum triglyceride and LDL and to increase the ratio of HDL to total cholesterol.

Monotherapy with prazosin Studies have shown that decreases in BP due to prazosin monotherapy have also been associated with a

reduction in total serum cholesterol, attributable to a decrease in the LDL fraction and a variable decrease in serum triglycerides. An increase in HDL cholesterol levels and cholesterol ratio has been seen with prazosin use. It was also found that the HDL2 subfraction, which exhibits the strongest (negative) correlation with the incidence of coronary artery disease, was increased in prazosin-treated patients.

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Combination therapy with prazosin The addition of prazosin to regimens consisting of ,B-blockers and chlorthalidone or thiazides has resulted

in further significant BP decreases. The effect of prazosin on serum lipids has been variable in that some studies observed small insignificant changes in serum triglyceride, total serum cholesterol, HDL and LDL cholesterol, and cholesterol ratio, while others have seen a significant reduction in total serum cholesterol and triglyceride, a small but significant increase in HDL cholesterol , and an increase in cholesterol ratio . These discrepancies are unexplained; however, in no instance was an 'unfavourable' response of serum lipid fractions recorded.

Non-selective ,B-blockers (such as propranolol and oxprenolol) and selective ,B-blockers (atenolol and metoprolol) have been found to increase total triglyceride and VLDL (very low density lipoprotein) triglyceride, while reducing the concentration of free fatty acids and HDL cholesterol. These reciprocal changes in serum triglycerides with prazosin and ,B-blockers indicate that the adrenergic nervous system plays an important role in the control of plasma lipid concentration. Results from these and other studies may indicate that adrenergic control of triglyceride turnover might affect the steady-state concentration of HDL, whose production may be partially related to the removal of triglyceride from circulating lipoprotein complexes.

The results of several studies indicate consistent differences in the effects of different types of antihypertensives on serum lipids. Although additional data concerning the long term metabolic effects of these drugs are needed, ' ... the metabolic response to antihypertensive therapy may prove to be an important determinant of the overall effectiveness of treatment in reducing the risk of coronary heart disease, which has emerged as the major cardiovascular consequence of essential hypertension.' Lowenstein. J : American Journal of Cardiology 53.' 21A (27 Jan 1984) [25 references]

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