Drugtherapy

Blood pressure may be reduced by any one or more

32 DASH-Sodium Collaborative Research Group 2001 Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet. N Engl J Med 344: 3-10.

of the actions listed at the beginning of this chapter (p. 46). The large number of different drug classes for hypertension reduces, paradoxically, the likelihood of a randomly selected drug being the best for an individual patient. Patients and drugs can broadly be divided into two groups depending on their renin status and drug effect on this (Fig. 23.1). Type 1, or high-renin patients, are the younger Caucasians (aged < 55), and they respond better to a (3-blocker or ACE inhibitor. Other patients are type 2, or low-renin, in whom diuretics or calcium blockers are more likely to be effective as single agents.

Since each drug acts on only one or two of the blood pressure control mechanisms, the factors that are uninfluenced by monotherapy are liable to adapt (homeostatic mechanism), to oppose the useful effect and to restore the previous state. There are two principal mechanisms of such adaptation or tolerance:

1. Increase in blood volume: this occurs with any drug that reduces peripheral resistance (increases intravascular volume) or cardiac output (reduces glomerular flow) due to activation of the renin-angiotensin system. The result is that cardiac output and blood pressure rise. Adding a diuretic in combination with the other drug can prevent this compensatory effect.

Arteries

ACE inhibitors

Angiotenslnogen --Al

Renin

Arteries

Adrenal glands

Aldosterone / \

Renin

Adrenal glands

Aldosterone / \

Kidneys

Fig. 23.1 Effects of drugs on the renin-angiotensin system (AIIRA: angiotensin II receptor antagonists)

Kidneys

Fig. 23.1 Effects of drugs on the renin-angiotensin system (AIIRA: angiotensin II receptor antagonists)

2. Baroreceptor reflexes: a fall in blood pressure evokes reflex activity of the sympathetic system, causing increased peripheral resistance and cardiac activity (rate and contractility). Therefore, whenever high blood pressure is proving difficult to control and whenever a number of antihypertensives are used in combination, the drugs chosen should between them act on all three main determinants of blood pressure, namely:

• peripheral resistance

Such combinations will:

• maximise antihypertensive efficacy by exerting actions at three different points in the cardiovascular system;

• minimise the opposing homeostatic effects by blocking the compensatory changes in blood volume, vascular tone and cardiac function;

• minimise adverse effects by permitting smaller doses of each drug each acting at a different site and having different unwanted effects.

First-dose hypotension is now uncommon and occurs mainly with drugs having an action on veins (a-adrenoceptor blockers, ACE inhibitors) when baroreflex activation is impaired, e.g. old age or with contracted intravascular volume following diuretics.

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