Treatment Of Hypertension

Hypertension Exercise Program

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The goals of treatment are to reduce BP and the risk of cardiovascular events, but to minimize adverse effects and facilitate patient compliance. Treatment can be divided into nonpharmacological and pharmacological [11]. Both forms of therapy rely heavily on patient education and good communication between doctor and patient. Nonpharmacological measures have the advantages of minimal cost and lack of side-effects, although compliance is not necessarily better. Current generally agreed-upon recommendations are [ 11 ] : (i) appropriate weight loss; (ii) no tobacco and limited alcohol consumption; (iii) regular moderate exercise; (iv) modest sodium restriction ("no added salt"); (v) diet low in animal fat and high in vegetable fiber. More controversial advice includes dietary potassium, calcium and fish oil supplementation, and reduced stress and caffeine intake. If these recommendations are followed, a significant number of patients with mild hypertension can avoid drug therapy. Even if drug treatment proves necessary, these nonpharmacological measures are an important adjunct to therapy.

The aim of drug therapy in hypertension is to control BP with a drug that best suits the individual patient, taking into account causal factors and the presence of other cardiovascular risk factors. Since hypertension has a high prevalence and treatment is essentially life-long, the economic impact is high. With the ever rising cost of medical care, whatever the national system, drug expenditure is a major consideration and this must be taken into account when prescribing for hypertension. The main classes of antihypertensive drug, excluding diuretics, are listed in Table 4. It is important to recognize that no single class of antihypertensive drug has been established to be superior to another in all respects.

TABLE 4 The Main Classes of Antihypertensive Drug: Their Indications and Side-Effects

Class of drug

Mechanism of action

Advantageous in

Disadvantageous in

Main side-effect(s)


Reduced cardiac output

Angina, postmyocardial

Asthma, peripheral vascular disease

Fatigue, depression, dis

and heart rate, renin

infarction (MI),

(PVD), diabetes mellitus (DM, es

turbed sleep, impotence



pecially insulin-dependent), heart

failure, bradydysrhythmias


Vasorelaxant and

Black and elderly, angina,

Heart failure, bradydysrhythmias

Postural hypotension, flush



asthma, PVD, DM

(depending on type)

ing, ankle swelling


ACE inhibitor

Inhibit All production

All-dependent hypertension,

Renal artery stenosis, hyperkalaemia

First dose hypotension,

and kinin (vasodilatory)

DM (especially if protei

cough, angioedema

breakdown and aldoste

nuric) and other proteinuric

rone secretion

renal disease (and evidence of hyperfiltration), heart failure, post-MI, LVH

a rBlocker


Hyperlipidemia, prostate hypertrophy, DM, heart failure, phaeochromocytoma

First dose hypotension, fluid retention


Vaso- and venodilation

Heart failure, pregnancy

Postural hypotension, tachy

cardia, fluid retention


Reduced CO and HR


Phaeochromocytoma, MAOI use

Postural hypotension, fluid


retention, depression

Note. LVH, left ventricular hypertrophy; MAOI, monoamine oxidase inhibitor.

Note. LVH, left ventricular hypertrophy; MAOI, monoamine oxidase inhibitor.


Mainly three types of diuretic are used in treating hypertension: (i) thiazide; (ii) loop diuretics; (iii) potassium-sparing (antialdosterone and sodium channel blockers). All, except the aldosterone antagonist spironolactone, have a luminal site of action and are secreted into the tubule by an active transport mechanism common to organic anions and cations located along the late proximal tubule. They are highly protein bound in plasma and concentrated several-fold at their site of action in the tubule lumen. Figure 6 illustrates their respective sites of action, which is discussed in greater detail in Section III of this book.


Thiazide diuretics are the most widely used type in hypertension. Their mechanism of sustained action is incompletely understood, but still seems to be related to their natriuretic effect [14]. The initial hypotensive response to a thiazide diuretic is associated with increased urinary loss of sodium, negative sodium balance, ECV contraction, decreased cardiac output, and reflex increases in peripheral vascular resistance and renin release. Over the next several weeks, sodium balance is restored and ECV and cardiac output return toward normal, but hypotension is sustained by a decrease in peripheral vascular resistance. The mechanism of the decline in vascular resistance is unclear. One possibility is that a small (unmeasurable) and persistent decrease in ECV sets in motion a series of responses to maintain local tissue perfusion, resulting in decreased peripheral vascular resistance (see Fig. 7). A similar process may explain the rare occurrence of hypertension in patients with renal failure receiving slow and prolonged periods of dialysis and strict maintenance of their dry weight. Another possible effect of thiazide diuretics is to reduce the secretion of and endogenous digitalis-like substance. The presence of a circulating digitalislike substance is of continuing interest and has been reported in the plasma of hypertensive patients [2], It is thought to be produced as a result of a persistent positive sodium balance, especially in salt-sensitive hypertension, and to increase intracellular sodium and calcium concentrations, which in vascular smooth muscle would cause vasoconstriction and a rise in peripheral vascular resistance (see Fig. 5). Other speculative effects of thiazide diuretics include reduced vascular smooth muscle and endothelial cell swelling and direct vasodilatation mediated by potassium channel opening, prostacyclin, or nitric oxide release.

Apical Basolateral

FIGURE 6. Sites and mechanism of action of the three main classes of diuretic (thiazide, loop, and potassium-sparing) on a composite thick ascending limb (TAL) and distal convoluted tubule principal (DT) cell.
FIGURE 7. Possible mechanism of the long-term anti-hypertensive effect of diuretics.


Thiazide Diuretics

Thiazide diuretics are the most commonly used diuretics in the treatment of hypertension and most hypertensive patients respond to them. That the response to thiazides depends on sodium intake is emphasized by: (i) their failure to lower BP in advanced chronic renal failure and anephric patients; (ii) persistence of their antihypertensive effect after stopping therapy if sodium intake is restricted; (iii) reduction of their antihypertensive effect by a high sodium intake. Good responders to thiazide diuretics are those patients in whom the compensatory responses to sodium restriction are blunted, i.e., black and elderly, low-renin hypertensives. Unfortunately, in the individual patient, plasma renin measurement is not a reliable predictor of thiazide responsiveness. Non-responders can be converted to responders by sodium restriction or inhibition of the compensatory renin response by combination with a /^-blocker or an angiotensin converting enzyme (ACE) inhibitor. One danger of relying on sodium restriction alone as an adjunct to diuretic therapy in controlling hypertension is that it stimulates further the compensatory increases in renin and aldosterone levels and the risk of significant potassium loss and hypokalemia. This is where a potassium-sparing diuretic, or ACE inhibitor, may be a better option if a thiazide diuretic alone is insufficient to control blood pressure.

It is important to remember that the antihypertensive effect of thiazide di-

Fall in BP

FIGURE 8. Dose—response relationship for the anti-hypertensive versus metabolic effects of thiazide diuretics.

Fall in BP

Metabolic effects, e.g. fall in plasma [K]

Increasing dose of thiazide

FIGURE 8. Dose—response relationship for the anti-hypertensive versus metabolic effects of thiazide diuretics.

uretics has a relatively flat dose-response relationship (Fig. 8), and doses should be kept low and coupled with a "no added salt" diet (80-120 mmol day"1)- For example, there is little further lowering of BP with hydrochlorothiazide beyond 50 mg once a day and the optimal dose range is probably 12.525 mg daily (Fig. 8). Most patients will respond within 2-4 weeks of starting treatment, but some may take up to 12 weeks. Doses should not be adjusted more frequently than every 2-4 weeks. Higher doses are associated with an increase in adverse metabolic effects (see later). The next step in treatment should be to add another class of antihypertensive, or change the class if monotherapy is still the aim.

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