Clinical Pharmacology of Antihypertensive Agents
Introduction
In this chapter the available classes of antihypertensive agents will be discussed. The potential for individualized therapeutic approaches for specifically identified groups of patients is also considered, as well as for those with specific complications from hypertension or with associated cardiovascular risk factors. The evolution of the remarkable development of this large number of therapeutic options presents an exciting history and is a testimony to the major efforts of basic and clinical scientists from academia, industry and governments for over six decades (Table 3.1).
Table 3.1 Major events in the development of antihypertensive therapy | ||||||||||
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Lifestyle (non-pharmacological) interventions
The 3rd Joint National Committee report (and thereafter) included various non-pharmacological interventions for the treatment of hypertension for the first time. In these reports, several non-pharmacological modalities were included in considerable detail and, in subsequent reports, other interventions were added (Table 3.2). The more recent reports provide the evidence basis for inclusion of the non-pharmacological interventions; clearly, weight control and sodium restriction have the support of a large body of literature. The inclusion of alcohol moderation, a regular aerobic exercise programme, potassium supplementation and tobacco cessation is more recent. Smoking cessation has generally been emphasized in national and international guidelines for overall cardiovascular health value. However, it is of note that in the earlier Medical Research Council and Australian Mild Hypertension trials, one important finding was confirmed. Thus, if blood pressure was reduced by the same magnitude with diuretic or beta-adrenergic receptor blocker therapy in patients who smoked or did not, beta-blocker therapy failed to demonstrate protection against deaths from coronary heart disease and strokes in smokers.
Table 3.2 Lifestyle modifications in the management of hypertension | ||||||||||||||||
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Diuretics
Antihypertensive drugs have been available for over 50 years, and they continue to remain the mainstay of therapy. Inherent in their use is the rationale for low-sodium dietotherapy for reversing hypertensive disease and for enhancing the effectiveness of other antihypertensive agents. To be effective as the sole therapy (i.e. the Kempner rice-fruit diet), however, dietary sodium restriction must usually be <200 mg/day. It must be remembered that approximately one-half of dietary sodium intake is provided by sodium chloride; the other half is found in food additives and preservatives. Since this form of diet therapy is highly impractical, oral natriuretic agents which promote natriuresis and diuresis at all levels of the nephron (3.1) are used instead. There are three major classes of oral diuretic agents: thiazides and their congeners, ‘loop’ diuretics, and potassium-retaining agents.
Thiazides and congeners
These agents, including chlorothiazide, hydrochlorothiazide and a long list of their chemical congeners, are all similar in action, side-effects, and dosages (Table 3.3). To date, however, there have been no prospective, large-scale, double-blinded, controlled studies that have determined dose equivalencies, side-effects and end-points comparing any two agents. This statement is all the more pertinent since prospective studies comparing potency between chlorthalidone and a thiazide have not been reported.
However, one tablet of any one agent is considered to be equivalent to another compound in antihypertensive and natriuretic potency, as well as potential for hypokalaemic side-effects. According to the most recent joint national and international guidelines (i.e. JNC-V through JNC-VII and WHO/ISH), the thiazide diuretics (and their congeners) should be considered for initial therapy of patients with uncomplicated, essential hypertension, in contrast to the ‘loop’ diuretics. Thiazides are preferred unless the patient has previously demonstrated intolerance or idiosyncracy to these agents or unless renal excretory function is impaired. Increasing diuretic dosages (up to 1000 mg of chlorothiazide or 100 mg of hydrochlorothiazide) demonstrate increasing diuretic and associated metabolic effects. Larger doses offer little more natriuretic and diuretic efficacy but are more likely to enhance development of metabolic sideeffects (e.g. hypokalaemia, hyperuricaemia) (Table 3.4). If, however, the patient has impaired renal excretory function, a loop diuretic may be prescribed in doses that may be progressively increased until, eventually, adequate diuresis is achieved (3.2).
 3.1 Sites of action on the nephron of the different classes of diuretic agents. |
Table 3.3 Diuretic agents | ||||||||||||||||||||||||||||||||||||
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It is important to recognize that the thiazides were originally prescribed in doses equivalent to ≥100 mg hydrochlorothiazide. This explains the greater likelihood for development of metabolic side-effects (Table 3.4) and the associated effects of higher doses. However, the more recent national and international guidelines have recommended an initial dose of 12.5-25 mg hydrochlorothiazide and 50 mg full dose, to provide therapeutic levels of thiazides at which the adverse side-effects are less pronounced.
Haemodynamics
The thiazides reduce arterial pressure initially as a consequence of contracted extracellular (plasma and interstitial) fluid volume but, later (after 6-10 weeks), as a consequence of reduced total peripheral resistance. Thus, following initial administration there is a decreased plasma volume and cardiac output that is associated with reduced total body sodium and water. Within a few days, arterial pressure falls (by 10-15%) associated with continued natriuresis and diuresis. After about 6 weeks, the plasma volume and cardiac output return towards pretreatment levels, and the reduced arterial pressure becomes associated with a decreased total peripheral resistance. The precise mechanism for the diminished vascular resistance remains incompletely understood (Table 3.5). It is likely that no one mechanism is responsible and all (or possibly still other unknown) mechanisms may participate in the overall antihypertensive action.
 3.2 Dose-response curves of high ceiling (‘loop’) and thiazide diuretics. |
In addition to the hypotensive effect, there is an additional important consequence of attenuation of pressor agents and enhanced responsiveness to depressor substances. This latter effect provides the explanation for the antihypertensive synergism of diuretics with all other antihypertensive drugs except, possibly, calcium antagonists.
Table 3.4 Metabolic effects of diuretic agents | |
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Table 3.5 Postulated mechanisms for diureticinduced reduced vascular resistance | |
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Mechanisms of action
The thiazide diuretics promote natriuresis through inhibition of carbonic anhydrase as well as active sodium reabsorption at the proximal and distal tubules. With natriuresis and volume contraction, the kidney releases renin from the juxtaglomerular apparatus, leading to the secondary generation of angiotensin II and consequent adrenal cortical release of aldosterone, thereby providing a feedback to the natriuretic stimulus. Additionally, potassium, magnesium and chloride ions are also lost in the urine, thereby inducing hypokalaemic alkalosis (i.e. secondary hyperaldosteronism) that may be confused with other causes of hypokalaemic alkalosis from hyperaldosteronism (e.g. primary aldosteronism, renal arterial disease, cardiac failure). Most notable with excessive dietary sodium intake, this secondary hyperaldosteronism can exacerbate diureticinduced hypokalaemia by favouring sodium-for-potassium exchange at the distal tubule. Hence, one important means of reducing the hypokalaemia produced by thiazides is restriction of dietary sodium intake.
Metabolic effects
Hyperuricaemia
The thiazides increase tubular reabsorption of urate and plasma uric acid concentration. If this is severe enough, symptomatic gout may result. Therefore, if the uric acid concentration is borderline or elevated at the outset of therapy, or if there is a personal or family history of gout, uric acid should be rechecked intermittently during treatment anticipating potential gout. If uric acid concentrations exceed levels which can produce symptomatic gout, specific drug therapy may be prescribed to reduce serum uric acid concentration, e.g. the uricosuric agent probenecid or allopurinol, an inhibitor of the enzyme xanthine oxidase that reduces uric acid synthesis.
Hyperglycaemia
The thiazides may also induce carbohydrate intolerance or hyperglycaemia of varying degrees. When using the lower dose recommendations, the risk of development of diabetes requiring therapy may not be any greater than that with other antihypertensive drug classes (3.3). A number of underlying mechanisms of carbohydrate intolerance have been suggested (Table 3.6).
In the author’s experience, overt insulin-dependent diabetes mellitus will not result from thiazide therapy de novo in hypertensive patients who do not already have abnormal carbohydrate intolerance prior to initiation of the diuretic. Should clinical diabetes mellitus exist or develop, this does not necessarily require discontinuance of the thiazide; it may be possible to prevent expression of diabetes with a lower dose (i.e. 12.5-50 mg hydrochlorothiazide) or by controlling the underlying problem with either dietotherapy and weight reduction alone, an oral hypoglycaemic agent or, if necessary, insulin. Alternatively, should this problem be of sufficient concern, another agent from a different antihypertensive drug class may be substituted for the initial diuretic.
Table 3.6 Potential diabetogenic mechanisms of thiazides | ||||||||||
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 3.3 Risk of requiring hypoglycaemia therapy associated with the use of antihypertensive drugs, relative to the use of thiazides. |
Hypokalaemia
The problem of hypokalaemia had been minimized clinically in earlier years of thiazide therapy. However, it is now recognized that lower doses of thiazides provide similar control of pressure with less severe hypokalaemia and other metabolic side-effects. Furthermore, reduced dietary sodium intake (against a background of diuretic-induced secondary hyperaldosteronism) minimizes the hypokalaemic effect of the sodium-for-potassium distal tubular exchange mechanism. Addition of spironolactone, eplerenone or amiloride will augment the thiazide hypotensive effect although triamterene does not. However, each of these potassium-sparing agents protects against hypokalaemia (Table 3.7). The problem of sudden cardiac arrest has been clearly shown to be minimized by reducing the dose of thiazide or using potassium-sparing agents (3.4).
 3.4 Risk of cardiac arrest with thiazides with and without potassium-sparing agents (compared with beta-blockers). |
If primary hyperaldosteronism is considered to be the cause of this problem, the diuretic should be discontinued pending further clinical evaluation. Moreover, if the patient is receiving digitalis or there are other explanations for hypokalaemia (e.g. laxative abuse, chronic diarrhoea, vomiting, intestinal villous adenoma), the hypokalaemia should be corrected or an alternative antihypertensive agent should be considered. An angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin II type 1 receptor antagonist) should be used with extreme caution in patients receiving potassium supplementation or any of the potassium-retaining agents, and in patients with impaired renal excretory function. In these patients, therapeutic alternatives to diuretics should be considered. Although not diuretic agents, the calcium antagonists exert a natriureticlike action (Table 3.8). Their ‘natriuretic’ action is mediated by a renal calcium-for-sodium exchange mechanism. This explains the symptom of increased nocturia associated with calcium antagonist therapy.
Table 3.7 Symptoms or complications of hypokalaemia | |
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Loop diuretics
Bumetanide, ethacrynic acid and furosemide are the most potent loop-acting diuretic agents in clinical use. Unlike the thiazides, they promote natriuresis by inhibiting sodium transport at the ascending limb of the loop of Henle (3.1). Since more of the filtered sodium is delivered to the distal tubule for exchange, a greater degree of potassium wastage results. Their onset of action is more immediate, frequently within 20 minutes. Consequently, the diuresis is more rapid than the thiazides and their congeners produce, the rebound sodium and water retention may be more pronounced, and there may be greater potassium wastage. For these reasons, these compounds should be reserved for patients who cannot take the thiazides or when more prompt diuresis is desired, in patients with renal functional impairment or when an intravenous diuretic is necessary. In those patients with renal functional impairment, the dose-response curve of the loop agents is linear, unlike that of the thiazides (3.2). Thus, the ‘loop diuretics’ are not recommended for patients with uncomplicated, essential hypertension. In patients with secondary hyperaldosteronism (e.g. congestive heart failure), particular care should be exercised to prevent hypokalaemia and cardiac dysrhythmias. These patients present a very real potential for sudden cardiac death (3.4). One final important, but occasionally overlooked, indication for these agents is in the hypertensive patient who is already receiving antihypertensive drugs, including maximal thiazide doses. These patients may have developed pseudotolerance as a consequence of intravascular volume expansion, and this may be overcome by switching to the more potent loop-acting agent.
Table 3.8 Indications for use of a calcium antagonist in lieu of a diuretic | |
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Potassium-sparing agents
Spironolactone or eplerenone
These agents are discussed separately because they promote diuresis through a very specific mechanism: inhibition of the distal tubular action of aldosterone. Thus, by antagonizing the aldosterone-mediated sodium-for-potassium ion exchange mechanism, natriuresis and diuresis are effected without potassium wastage. Since much of the obligate sodium ion transport occurs at the level of the proximal tubule, the potency of these agents is not as great as that of thiazides. Nevertheless, they are particularly useful, either alone or in combination with a thiazide, for patients with primary and secondary hyperaldosteronism. Hence, in patients with hyperaldosteronism, the major value of these agents is that they achieve significant sodium and water excretion without depleting potassium (even when used with a thiazide).
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