Angiotensin receptor blockers in essential hypertension

of a low-cost food plan, and the sum has been adjusted annually to reflect the consumer price index. This income level does not include the value of food stamps, Medicare or Medicaid, or employer health insurance; it does include social security and welfare payments. Should factors such as alcohol intake, diet, drug use, unemployment, or housing status also be taken into account? However fiercely the debate rages it cannot obscure one incontestable fact: that income directly affects one’s ability to make choices about the quality of one’s lifestyle, healthy or otherwise. Galbraith9 lately pointed out the resistance of American culture to the entire notion of class: "we have a classless society; to this we point with considerable pride. The social mythology of the Republic is built on the concept of classlessness". Yet the existence of an urban and rural underclassGalbraith’s group who "do not share the comfortable well being of the prototypical American"-is undeniable, as the latest poverty statistics indicate. Meanwhile the rest of society is gradually becoming richer. In 1967, the incomes of the most affluent 20% in society were 6 times the poverty level; in 1992, they amounted to 8-4 times.6This widening gap has created a culture of contentment. Most people have little incentive to confront the issues-health being but one-created by the presence of an underclass. The implications for the health of this group are deeply troubling. In the Bronx, New York, for example, the social context of drug use-drug preference, prostitution, poor education, lack of health-care facilities, and overcrowded housing-has been an important part of understanding not only addiction behaviour but also patterns of disease such as HIV seroprevalence and spread of tuberculosis.1O Poverty is inextricably tied to class, and both of these factors influence patterns of behaviour that determine health. How can US public health services even begin to answer the complex and increasingly urgent questions posed by the association of poverty with disease? First, politicians must be persuaded that to deny the existence of class in urban and rural societies is to deny the very real health issues that arise from those inequalities. Second, health professionals, in partnership with politicians and the public, must reform the institutions that serve these communities. Doctors should be encouraged to work in poorer areas. At present, there is’an average of 3-3 doctors per 1000 people in Manhattan; in the Bronx it is 0-2. President Clinton has proposed a 20% bonus payment for doctors who choose to work in "health professional shortage areas". Medical school curricula need to emphasise primary and generalist care, which these communities desperately lack. And universal health coverage should help to lift the 1374

financial impediment to entering the health-care system. In the face of such profound social decay, none of us can afford to feel contented.

Coulter A. Socio-economic influences on health. In: Fowler G, Gray M, Anderson P, eds. Prevention in general practice. Oxford: Oxford University Press, 1993: 19-36. 2 American Heart Association. Report of the task force on the availability of cardiovascular drugs to the medically indigent. Dallas: AHA, 1992. 3 Pappas G, Queen S, Hadden W, Fisher G. The increasing disparity in mortality between socioecnomic groups in the United States, 1960 and 1986. N Engl J Med 1993; 329: 103-09. 4 Navarro V. Race or class versus race and class: mortality differentials in the United States. Lancet 1990; 336: 1238-40. 5 Karp RJ, ed. Malnourished children in the United States. New York: 1

Springer, 1993. US Department of Commerce (Bureau of the Census). Poverty in the United States: 1992. Current Population Reports, series P60-185. Washington DC: US Government Printing Office, 1993. 7 Rosenberg TJ. Poverty in New York City, 1991: a research bulletin. New York: Community Service of New York, 1992. 8 Fuchs VR. The future of health policy. Cambridge: Harvard University Press, 1993. 9 Galbraith JK. The culture of contentment. Boston: Houghton Mifflin, 1992. 10 Grund J-PC, Stern LS, Kaplan CD, Adriaans NFP, Drucker E. Drug use contexts of HIV consequences: the effect of drug policy on patterns of everyday drug use in Rotterdam and the Bronx. Br J Addiction 1992;

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87: 41-52.

COMMENTARY

Angiotensin receptor blockers in essential hypertension Antihypertensive drugs have been one of the success stories of the past four decades and can take some of the credit for the steep decline in incidence of myocardial infarction. The recent TOMHS study, in which all five main groups of antihypertensive drugs were compared in 900 patients, has shown that the average response to, and tolerance of, the various drug groups are similar. Consequently, in terms of initial therapy, one might expect most patients to receive a thiazide which costs a few pence per month rather than one of the other agents which cost a few pounds.l This expectation is heightened by the realisation that most of the reduction in incidence of hypertensive proven can be attributed to thiazides. Yet in many complications areas the proportion of patients who receive these drugs as initial therapy is similar to that for the other agents. Against this background, can the introduction of another class of antihypertensives be justified? The angiotensin receptor blockers prevent access of angiotensin II to its principal receptor, much as ACE inhibitors prevent formation of angiotensin II.2,3 Losartan is the furthest forward in development, being well into phase 3 clinical trials. To pharmacologists, these drugs are interesting because they show the possibility of developing nonpeptide (and therefore orally bioavailable) antagonists to the growing number of peptide receptors. The angiotensin receptor is especially interesting as a therapeutic target for two reasons. First, it should now be possible to determine how much the effects of ACE inhibitors are due to a reduction in angiotensin production and how much to potentiation of bradykinin. The importance here is not only in the mechanism of blood pressure reduction but also in the reversal of longer term effects of angiotensin IIsuch as

its role in cardiac hypertrophy and vascular remodelling. Second, the angiotensin receptor has distinct subtypes, the relative roles of which await studies with specific antagonists. Losartan blocks selectively the AT receptor, which seems to be responsible for almost all known actions of angiotensin. However, there have been some reports of AT mediated effects in the kidney and a clinical issue is whether the selectivity of losartan will translate into freedom from the occasional renal function impairment seen with ACE inhibitors.4 Studies of losartan in healthy volunteers have shown that even a normal blood pressure can be lowered provided that the subjects are salt depleted, just as with ACE inhibitors,S but the relative efficacy of angiotensin II blockade vs ACE inhibitors in the treatment of hypertension or heart failure is unclear.6 What might angiotensin receptor antagonists have to offer that is new? There are two possibilities. The main one is improved tolerance, especially in the 10% or so of patients who get a dry cough with an ACE inhibitor. This cough is probably due to potentiation of a peptide substrate of ACE, such as bradykinin or a neurokinin, and therefore should not be a side-effect of angiotensin receptor blockade.7 The second and more speculative possibility is to combine the new drugs with ACE inhibitors, whose efficacy may, in theory, be partly attenuated by either

breakthrough production of, or "denervation-type" hypersensitivity to, angiotensin II. Until the new drugs have completed clinical trials it is premature to predict either their likely or their rightful place in the treatment of hypertension; resistant hypertensives who are controlled by, but do not tolerate, ACE inhibitors are obvious candidates. Their eventual role may be more important in heart failure, where there is no real alternative to ACE inhibitors when these are not tolerated. A sceptic might remark that neither the treatment nor the understanding of essential hypertension has advanced as much since the introduction of thiazide diuretics as the weight or contents of the hypertension literature might suggest. Perhaps a more positive way of expressing the sceptic’s concern would be to point to the responsibilities that come with choice-for both clinician and investigator. For instance, the next few years should see progress in unravelling the genetic basis of hypertension, and this work will confirm that essential hypertension is a heterogeneous condition.8 We do not know whether recognition of the

heterogeneity

will

precede

and therefore

help

the

genetic

studies or whether success with the latter is a prerequisite to recognition of different types of essential hypertension. Either way an increased choice among types of antihypertensive is desirable to help in the identification of genes and to profit from their discovery. However, against a background of trial data showing efficacy and tolerance rates of around 80% for all five main groups of in current use, and a healthy placebo in of the other 20%, our sceptic might take response many some convincing that clinical practice has considered how to face the challenge and responsibility of identifying the small minority of patients who require drugs costing up to 100-fold more than thiazides. Paradoxically, the economics and therefore size of most clinical trials causes clinicians to overlook the heterogeneity of essential hypertension and thus to fail both the individual patient and the investigator wishing to learn what underlies the diversity. We should wish good luck to those designing new drugs, but hope also

antihypertensives

that the future of these agents owes something to the design of the patients who use them. M J Brown Clinical

1

2

3

4 5

6

7 8

Pharmacology Unit, Addenbrooke’s Hospital, Cambridge, UK

Neaton JD, Grimm RH, Prineas RJ, et al. Treatment of Mild Hypertension Study: final results. TOMHS Research Group. JAMA 1993; 270: 713-24. Burnier M, Centeno G, Grouzmann E, et al. In vitro effects of DuP 753, a nonpeptide angiotensin II receptor antagonist, on human platelets and rat vascular smooth muscle cells. Am J Hypertens 1991; 4: 438-43. Christen Y, Waeber B, Nussberger J, et al. Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers: inhibition of pressor response to exogenous angiotensin I and II. Circulation 1991; 83: 133-42. Smith RD, Chiu AT, Wong PC, et al. Annu Rev Pharmacol Toxicol 1992; 32: 135-65. Doig JK, MacFadyen RJ, Sweet CS, et al. Dose-ranging study of the angiotensin type 1 receptor antagonist losartan (DuP753/MK954) in salt-deplete normal man. J Cardiovasc Pharmacol 1993; 21: 7323-28. Weber MA. Clinical experience with the angiotensin II receptor antagonist losartan: a preliminary report. Am J Hypertens 1992; 5: 2475-251S. Morice AH, Lowry R, Brown MJ, Higenbottam T. Angiotensin converting enzyme and the cough reflex. Lancet 1987; ii: 1116-18. Jeunemaitre X, Soubrier F, Kotelevtsev YV, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 1992; 71: 169-80.

Menarche when and

why?

The menarche is the milestone that indicates the capacity to reproduce. There has been a secular trend to earlier menarche over the past century, with a decrease of about 3-4 months per decade. Thus the average age of menarche in 1840 was 16-5 and is presently 12-8. One interpretation of this fall is that it reflects improvement in health and environmental conditions. However, the curve is now levelling off in many industrialised countries, for reasons that are not entirely clear. Dann and Roberts1 lately reported data collated from the final 16 years of a 28-year ongoing survey of menarcheal age, in which the recalled age of menarche of 5206 caucasian women entering Warwick University, UK, between 1971 and 1986 was studied. The researchers conclude that the downward trend has now been replaced by one in the opposite direction. What determines the age of menarche? Numerous factors act in combination, including genetic influences, socioeconomic conditions, general health and wellbeing, nutritional status, and some types of exercise. The importance of genetic factors is illustrated by the similar age of menarche in members of an ethnic population and in mother/daughter pairs. Social class differences are disappearing. Delayed menarche is well recognised in chronic diseases-for example, it is about a year late in girls with diabetes.2 The role of body weight and body fat has received considerable attention,3and anorexia and malnutrition are associated with delayed menarche. Mean weight at menarche is 47-8 kg at the mean height of 158-5 cm in the USA. This observation led to the hypothesis of a threshold weight for height and a critical proportion of body fat before menarche can occur. There is a change in body composition during adolescent growth spurt: the ratio of lean body weight to fat is 5:at the initiation of the spurt and 3:at the menarche, when about 22% of body weight is fat. Adipose tissue is an important source of oestrogen, and its amount influences the direction of oestrogen metabolism to more potent or less potent forms. Very thin women have an

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