The term ‘factors of risk’ was first introduced by the Framingham Heart Study almost five decades ago to identify demographically specific clinical characteristics that confer increased risk of cardiovascular morbidity and mortality. Initially encompassing only four risk factors, the factors of risk comprise hypertension, hyperlipidaemia, left ventricular hypertrophy, diabetes mellitus, smoking, exogenous obesity, several non-modifiable factors including age, black race and male gender, some less established factors that include hyperuricaemia and hyperfibrinogenaemia, and certain currently investigated ‘biomarkers’ that are end-points of cardiovascular diseases. Obesity is associated with increased intravascular (plasma) volume, which in turn is associated with increased venous return to the heart and cardiac output and increased blood flow and cardiac output to kidneys and other organs in both normal and hypertensive subjects. These haemodynamic derangements are associated with structural changes that include deposition of fat around the major organs such as the heart and kidney. Thus, and most importantly, obesity results in an increased intravascular volume and pressure overload on the heart, which increase the risk of hypertension.

Salt has played an important role in the social, economic and other aspects of human existence for millennia. However, over the past 100 years, medical practitioners have become increasingly interested in the role of salt excess in disease. More specifically, the adverse effect of salt or sodium excess has captured broad attention because of its direct role in cardiovascular and renal diseases and their outcomes. Stimulated by repeated epidemiological studies that have shown a strongly positive association between the magnitude of salt consumption and the prevalence of hypertensive diseases, many fundamental and clinical studies have focused on the potential mechanisms that might explain this association. However, only about one-third of patients with essential hypertension demonstrate increased ‘salt sensitivity’. Our imagination has been provoked by the possibility that salt excess might not only increase arterial pressure, but might even enhance the pathophysiological changes of hypertensive disease in addition to, and independent of, its effect on arterial pressure. Thus, we have demonstrated experimentally in our laboratory that salt excess produces diastolic dysfunction associated with deposition of collagen in the extracellular matrix and perivascularly in the ventricle; diminished aortic distensibility; and, in renal failure associated with diminished renal blood flow, afferent and efferent glomerular arteriolar constriction with increased glomerular hydrostatic pressure and severe arteriolar and glomerular injury. Most of these findings have been confirmed in humans.

The thiazide diuretics have been recommended for initial pharmacological monotherapy of hypertension ever since promulgation of the very first guidelines were published. The rationale for their use was not based solely on clinical empiricism, but on strong clinical evidence and, just as important, on sound physiological rationale. Were antihypertensive treatment to be initiated with either of the two oldest antihypertensive drug classes (i.e. adrenergic inhibitors, smooth muscle relaxants), following an initial reduction in the blood pressure, the pressure would most likely return to on or around pretreatment values. The mechanism for this is not ‘drug tolerance’ to these agents; intravascular (i.e. plasma) volume expands as a consequence of pressure reduction (‘pseudotolerance’). Diuretic monotherapy has its own intrinsic ability to reduce (if not control) arterial pressure in 15-50% of patients with essential hypertension (depending upon the initial pressures of the population group studied).

The various options for diuretic agents are:

Generally, the thiazide agents (e.g. chlorothiazide, hydrochlorothiazide) are recommended, and the thiazide congeners (e.g. chlorthalidone) have also been used for several decades and in several multicentre studies. Table 4.5 presents patients who might be selected for initial thiazide monotherapy.

The more common biochemical effects of the drugs are listed in Table 4.6; but, as discussed in Chapter 4, they are less likely to occur with a low initial dose (e.g. hydrochlorothiazide 12.5-25 mg daily), which can be increased to 25 or even 50 mg. These considerations and other details are discussed in Chapter 5, including the risk of hypoglycaemia and sudden cardiac death. With the addition or initial selection of agents from other antihypertensive drug classes, effective pressure control may be expected in upwards of 85% of patients with lower doses of diuretics. This therapeutic manoeuvre serves to reduce the development of side-effects from other agents or even higher doses of the added agent. It is noteworthy, however, that the addition of a diuretic to a calcium antagonist may not be very effective in reducing pressure further. Perhaps this explains why these two classes of drugs are not available as combination therapy.

This class of antihypertensive agents has been recommended for initial therapy because abundant experience has indicated that beta-blockers can be prescribed without the likelihood of intravascular volume expansion, loss of arterial pressure control, and with predictable effectiveness in a significant population (but not all) of hypertensive patients. Moreover, their antihypertensive effectiveness may be increased further with the addition of a diuretic. The various options of beta-blockers (Table 4.7) and the patients most likely to be selected for therapy (Table 4.8) are presented.

In recent years some authorities have expressed their opinion that these beta-blockers do not merit consideration for prescription as initial therapy. However, we do not accept this concept. The arguments advanced by the former thought-leaders are based upon experiences derived from groups of patients or by meta-analysis. In our experience there are individual patients who are more likely to respond to beta-blockers alone (see 4.8). In particular, they include patients with a hyperdynamic circulation; younger patients with a lesser degree of blood pressure elevation; and patients with certain cardiac dysrhythmias, mitral valvular prolapse (idiopathic), angina pectoris or prior myocardial infarction.

The clinical pharmacological characteristics of this class of agents are discussed in greater detail in Chapter 5; a summary of the mechanisms of action (Table 4.9) and side-effects (Table 4.10) are presented in Tables 4.9 and 4.10.

Although suggested in earlier JNC reports, the alpha-1-adrenergic and the alpha-beta adrenergic receptor inhibitors have been recommended for initial monotherapy. These agents are effective in controlling arterial pressure but may be associated with expanded intravascular (plasma) volume (i.e. pseudotolerance). Because of this, peripheral oedema may occur and could be associated with symptoms suggesting cardiac failure. For this reason, doxazosin was removed from the ALLHAT study, with the statement that cardiac failure occurred with increased frequency compared with the other agents in that study (i.e. chlorthalidone, lisinopril and amlodipine). Nevertheless, alpha-1-adrenergic receptor inhibitors have continued to be used by patients with prostatic hyperplasia; concerns regarding further blood pressure reduction or postural hypotension have been raised, and falls with possible bone fractures have occurred. An alpha-1-adrenergic inhibitor has been made available (relatively recently) for normotensive patients with benign prostatic hyperplasia, which does not seem to be as potent in reducing arterial pressure.