Angiotensin receptor blockers in essential hypertension

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<ul><li><p>1374</p><p>of a low-cost food plan, and the sum has been adjustedannually to reflect the consumer price index. Thisincome level does not include the value of foodstamps, Medicare or Medicaid, or employer healthinsurance; it does include social security and welfarepayments. Should factors such as alcohol intake, diet,drug use, unemployment, or housing status also betaken into account? However fiercely the debate ragesit cannot obscure one incontestable fact: that incomedirectly affects ones ability to make choices about thequality of ones lifestyle, healthy or otherwise.</p><p>Galbraith9 lately pointed out the resistance ofAmerican culture to the entire notion of class: "wehave a classless society; to this we point withconsiderable pride. The social mythology of theRepublic is built on the concept of classlessness". Yetthe existence of an urban and rural underclass-Galbraiths group who "do not share the comfortablewell being of the prototypical American"-isundeniable, as the latest poverty statistics indicate.Meanwhile the rest of society is gradually</p><p>becoming richer. In 1967, the incomes of the mostaffluent 20% in society were 6 times the poverty level;in 1992, they amounted to 8-4 times.6 This wideninggap has created a culture of contentment. Most peoplehave little incentive to confront the issues-healthbeing but one-created by the presence of anunderclass.The implications for the health of this group are</p><p>deeply troubling. In the Bronx, New York, forexample, the social context of drug use-drugpreference, prostitution, poor education, lack ofhealth-care facilities, and overcrowded housing-hasbeen an important part of understanding not onlyaddiction behaviour but also patterns of disease suchas HIV seroprevalence and spread of tuberculosis.1OPoverty is inextricably tied to class, and both of thesefactors influence patterns of behaviour thatdetermine health.How can US public health services even begin to</p><p>answer the complex and increasingly urgentquestions posed by the association of poverty withdisease? First, politicians must be persuaded that todeny the existence of class in urban and rural societiesis to deny the very real health issues that arise fromthose inequalities. Second, health professionals, inpartnership with politicians and the public, mustreform the institutions that serve these communities.Doctors should be encouraged to work in poorerareas. At present, there isan average of 3-3 doctors per1000 people in Manhattan; in the Bronx it is 0-2.President Clinton has proposed a 20% bonuspayment for doctors who choose to work in "healthprofessional shortage areas". Medical schoolcurricula need to emphasise primary and generalistcare, which these communities desperately lack. Anduniversal health coverage should help to lift the</p><p>financial impediment to entering the health-caresystem. In the face of such profound social decay,none of us can afford to feel contented.</p><p>1 Coulter A. Socio-economic influences on health. In: Fowler G, GrayM, Anderson P, eds. Prevention in general practice. Oxford: OxfordUniversity Press, 1993: 19-36.</p><p>2 American Heart Association. Report of the task force on the availabilityof cardiovascular drugs to the medically indigent. Dallas: AHA, 1992.</p><p>3 Pappas G, Queen S, Hadden W, Fisher G. The increasing disparity inmortality between socioecnomic groups in the United States, 1960 and1986. N Engl J Med 1993; 329: 103-09.</p><p>4 Navarro V. Race or class versus race and class: mortality differentialsin the United States. Lancet 1990; 336: 1238-40.</p><p>5 Karp RJ, ed. Malnourished children in the United States. New York:Springer, 1993.</p><p>6 US Department of Commerce (Bureau of the Census). Poverty in theUnited States: 1992. Current Population Reports, series P60-185.Washington DC: US Government Printing Office, 1993.</p><p>7 Rosenberg TJ. Poverty in New York City, 1991: a research bulletin.New York: Community Service of New York, 1992.</p><p>8 Fuchs VR. The future of health policy. Cambridge: HarvardUniversity Press, 1993.</p><p>9 Galbraith JK. The culture of contentment. Boston: Houghton Mifflin,1992.</p><p>10 Grund J-PC, Stern LS, Kaplan CD, Adriaans NFP, Drucker E. Druguse contexts of HIV consequences: the effect of drug policy on patternsof everyday drug use in Rotterdam and the Bronx. Br J Addiction 1992;87: 41-52.</p><p>COMMENTARY</p><p>Angiotensin receptor blockers in essentialhypertensionAntihypertensive drugs have been one of the success storiesof the past four decades and can take some of the credit forthe steep decline in incidence of myocardial infarction. Therecent TOMHS study, in which all five main groups ofantihypertensive drugs were compared in 900 patients, hasshown that the average response to, and tolerance of, thevarious drug groups are similar. Consequently, in terms ofinitial therapy, one might expect most patients to receive athiazide which costs a few pence per month rather than oneof the other agents which cost a few pounds.l Thisexpectation is heightened by the realisation that most of theproven reduction in incidence of hypertensivecomplications can be attributed to thiazides. Yet in manyareas the proportion of patients who receive these drugs asinitial therapy is similar to that for the other agents.</p><p>Against this background, can the introduction of anotherclass of antihypertensives be justified? The angiotensinreceptor blockers prevent access of angiotensin II to itsprincipal receptor, much as ACE inhibitors preventformation of angiotensin II.2,3 Losartan is the furthestforward in development, being well into phase 3 clinicaltrials. To pharmacologists, these drugs are interestingbecause they show the possibility of developing non-peptide (and therefore orally bioavailable) antagonists tothe growing number of peptide receptors. The angiotensinreceptor is especially interesting as a therapeutic target fortwo reasons. First, it should now be possible to determinehow much the effects of ACE inhibitors are due to areduction in angiotensin production and how much topotentiation of bradykinin. The importance here is not onlyin the mechanism of blood pressure reduction but also inthe reversal of longer term effects of angiotensin II such as</p></li><li><p>1375</p><p>its role in cardiac hypertrophy and vascular remodelling.Second, the angiotensin receptor has distinct subtypes, therelative roles of which await studies with specificantagonists. Losartan blocks selectively the AT receptor,which seems to be responsible for almost all known actionsof angiotensin. However, there have been some reports ofAT mediated effects in the kidney and a clinical issue iswhether the selectivity of losartan will translate intofreedom from the occasional renal function impairmentseen with ACE inhibitors.4</p><p>Studies of losartan in healthy volunteers have shown thateven a normal blood pressure can be lowered provided thatthe subjects are salt depleted, just as with ACE inhibitors,Sbut the relative efficacy of angiotensin II blockade vs ACEinhibitors in the treatment of hypertension or heart failureis unclear.6 What might angiotensin receptor antagonistshave to offer that is new? There are two possibilities. Themain one is improved tolerance, especially in the 10% or soof patients who get a dry cough with an ACE inhibitor. Thiscough is probably due to potentiation of a peptide substrateof ACE, such as bradykinin or a neurokinin, and thereforeshould not be a side-effect of angiotensin receptorblockade.7 The second and more speculative possibility is tocombine the new drugs with ACE inhibitors, whoseefficacy may, in theory, be partly attenuated by eitherbreakthrough production of, or "denervation-type"hypersensitivity to, angiotensin II.</p><p>Until the new drugs have completed clinical trials it ispremature to predict either their likely or their rightfulplace in the treatment of hypertension; resistanthypertensives who are controlled by, but do not tolerate,ACE inhibitors are obvious candidates. Their eventual rolemay be more important in heart failure, where there is noreal alternative to ACE inhibitors when these are nottolerated.A sceptic might remark that neither the treatment nor the</p><p>understanding of essential hypertension has advanced asmuch since the introduction of thiazide diuretics as theweight or contents of the hypertension literature mightsuggest. Perhaps a more positive way of expressing thesceptics concern would be to point to the responsibilitiesthat come with choice-for both clinician and investigator.For instance, the next few years should see progress inunravelling the genetic basis of hypertension, and this workwill confirm that essential hypertension is a heterogeneouscondition.8 We do not know whether recognition of theheterogeneity will precede and therefore help the geneticstudies or whether success with the latter is a prerequisite torecognition of different types of essential hypertension.Either way an increased choice among types ofantihypertensive is desirable to help in the identification ofgenes and to profit from their discovery. However, against abackground of trial data showing efficacy and tolerancerates of around 80% for all five main groups ofantihypertensives in current use, and a healthy placeboresponse in many of the other 20%, our sceptic might takesome convincing that clinical practice has considered howto face the challenge and responsibility of identifying thesmall minority of patients who require drugs costing up to100-fold more than thiazides. Paradoxically, the economicsand therefore size of most clinical trials causes clinicians tooverlook the heterogeneity of essential hypertension andthus to fail both the individual patient and the investigatorwishing to learn what underlies the diversity. We shouldwish good luck to those designing new drugs, but hope also</p><p>that the future of these agents owes something to the designof the patients who use them.M J BrownClinical Pharmacology Unit, Addenbrookes Hospital, Cambridge, UK</p><p>1 Neaton JD, Grimm RH, Prineas RJ, et al. Treatment of MildHypertension Study: final results. TOMHS Research Group. JAMA1993; 270: 713-24.</p><p>2 Burnier M, Centeno G, Grouzmann E, et al. In vitro effects of DuP753, a nonpeptide angiotensin II receptor antagonist, on humanplatelets and rat vascular smooth muscle cells. Am J Hypertens 1991; 4:438-43.</p><p>3 Christen Y, Waeber B, Nussberger J, et al. Oral administration of DuP753, a specific angiotensin II receptor antagonist, to normal malevolunteers: inhibition of pressor response to exogenous angiotensin Iand II. Circulation 1991; 83: 133-42.</p><p>4 Smith RD, Chiu AT, Wong PC, et al. Annu Rev Pharmacol Toxicol1992; 32: 135-65.</p><p>5 Doig JK, MacFadyen RJ, Sweet CS, et al. Dose-ranging study of theangiotensin type 1 receptor antagonist losartan (DuP753/MK954) insalt-deplete normal man. J Cardiovasc Pharmacol 1993; 21: 7323-28.</p><p>6 Weber MA. Clinical experience with the angiotensin II receptorantagonist losartan: a preliminary report. Am J Hypertens 1992; 5:2475-251S.</p><p>7 Morice AH, Lowry R, Brown MJ, Higenbottam T. Angiotensinconverting enzyme and the cough reflex. Lancet 1987; ii: 1116-18.</p><p>8 Jeunemaitre X, Soubrier F, Kotelevtsev YV, et al. Molecular basis ofhuman hypertension: role of angiotensinogen. Cell 1992; 71: 169-80.</p><p>Menarche when and why?The menarche is the milestone that indicates the capacity toreproduce. There has been a secular trend to earliermenarche over the past century, with a decrease of about3-4 months per decade. Thus the average age of menarchein 1840 was 16-5 and is presently 12-8. One interpretation ofthis fall is that it reflects improvement in health andenvironmental conditions. However, the curve is nowlevelling off in many industrialised countries, for reasonsthat are not entirely clear. Dann and Roberts1 latelyreported data collated from the final 16 years of a 28-yearongoing survey of menarcheal age, in which the recalled ageof menarche of 5206 caucasian women entering WarwickUniversity, UK, between 1971 and 1986 was studied. Theresearchers conclude that the downward trend has nowbeen replaced by one in the opposite direction.What determines the age of menarche? Numerous factors</p><p>act in combination, including genetic influences,socioeconomic conditions, general health and wellbeing,nutritional status, and some types of exercise. Theimportance of genetic factors is illustrated by the similar ageof menarche in members of an ethnic population and inmother/daughter pairs. Social class differences aredisappearing. Delayed menarche is well recognised inchronic diseases-for example, it is about a year late in girlswith diabetes.2The role of body weight and body fat has received</p><p>considerable attention,3 and anorexia and malnutrition areassociated with delayed menarche. Mean weight atmenarche is 47-8 kg at the mean height of 158-5 cm in theUSA. This observation led to the hypothesis of a thresholdweight for height and a critical proportion of body fat beforemenarche can occur. There is a change in body compositionduring adolescent growth spurt: the ratio of lean bodyweight to fat is 5: at the initiation of the spurt and 3: at themenarche, when about 22% of body weight is fat. Adiposetissue is an important source of oestrogen, and its amountinfluences the direction of oestrogen metabolism to morepotent or less potent forms. Very thin women have an</p></li></ul>