UPDATE ARTICLE

Different Uses Of AngiotensinConverting Enzyme Inhibitors

B M Y Cheung*, MA, MB BChir, MRCP PhDDivision of Clinical Pharmacology & Therapeutics

C P Lau, MD, FHKCP, FHKAM (Medicine), FRCP (London), FRCP (Edin)Division of Cardiology

Department of MedicineThe University of Hong Kong

Summary

The renin-angiotensin-a/dosterone system plays a keyrole in the regulation of fluid and electrolyte balance. Angiotensin-converting enzyme inhibitors (ACE/s) inhibit angiotensin-converting enzyme and have been shown to be effective in manycardiovascular diseases, including hypertension, heart failure, myocardial infarction and diabetic nephropathy. ACE/s arethe most effective class of drugs in reversing left ventricular hypertrophy due to hypertension. ACE/s improve cardiacfunction and reduce mortality in congestive heart failure and after myocardial infarction. ACE/s should be considered indiabetics with microalbuminuria or albuminuria, especially in the presence of hypertension. There are many differentACE/s available now; they are largely similar in their effects, but differ particularly in pharmacokinetics. Choice willdepend on previous experience, availability and price. There are a number of side-effects associated with ACEIs;periodic monitoring of renal function and electrolytes is required. (HK Pract 1996; 18: 398-406)

Keywords: angiotensin converting enzyme inhibitor, hypertension, myocardial infarction, heart failure, diabetic nephropathy

3BM (ACEIs) Stg^/CMtoggHSMfcact,— Jffil

eg B mi S • /ka?ACEIsgi

— mmm^&i^m-mmi&& • rrami^^ilffiSKffiJS^ttS^tsiW^ii^ffl

HbBJU

Introduction

Angiotensin-converting enzymeinhibitors (ACEI) are a class of drugswhich inhibit angiotensin-convertingenzyme (ACE). In the last decade,they have been shown to be effectivein many cardiovascular diseases,including hypertension, heart failure,myocardial infarction and diabeticnephropathy.

Pharmacology

The renin-angiotensin-aldosteronesystem (RAAS) plays a key role in theregulation of fluid and electrolytebalance (Table 1). Decreased renalperfusion pressure, as a result ofhypotension for example, triggers therelease of renin. Renin is a plasmaenzyme which cleaves angio-tensinogen to angiotensin I.

Angiotensin I is relatively inactive; itspotency is increased 100-fold whenit is converted to angiotensin II byACE. Angiotensin II is a potentconstrictor of vascular smooth muscleand also stimulates the synthesis andrelease of aldosterone from theadrenal cortex. Aldosterone acts onthe distal tubules and collectingducts of nephrons in the kidney toincrease the absorption of sodiumand excretion of potassium. By

'' Address for correspondence: Dr Bernard M Y Cheung, AMedicine, The University of

Assistant Professor, Division of Clinical Pharmacology & Therapeutics, University Deparof Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.

•tment of

Hong Kong Practitioner 18 (8) August 1996

UPDATE ARTICLE

inhibiting the formation of angiotensinII, ACEIs indirectly reducealdosterone secretion and therebysuppress the reabsorption of sodiumand excretion of potassium in thedistal tubule.

In addition to the effect on theRAAS, ACEIs have other effects. ACEhas been described as a promiscuousenzyme because, beside convertingangiotensin I to angiotensin II, it alsocatalyses other substrates includingthe kinins.1'2 Whilst angiotensin I isconverted to the more activeangiotensin II by ACE, bradykinin isinactivated by ACE. Hence, blocking

ACE increases bradykinin. Whetherthis accounts for part of the effectsof ACEI and whether the potentiationof bradykinin is beneficial or not isunclear, and more studies areneeded to clarify this.

There are now more than half adozen ACEIs available (Table 2). Theyare largely similar in terms of theireffects, but differ in several respects,particularly in pharmacokinetics.Captopril, which was the first ACEIdeveloped, has a relatively short half-life, necessitating two or three timesa day dosages. The newer ACEIstend to have longer half- l ives

allowing once-daily dosage. Some ofthe new ACEIs, such as fosinopril, aremetabolised by the liver as well asexcreted by the kidneys.J This dualroute of excretion may be anadvantage in patients who haveimpaired renal function including forexample, the elderly. ACEIs alsodiffer in the extent of tissue binding.It is now known that apart fromcirculating angiotensin II, angiotensinII is also generated in tissues by tissueACE. It is possible that theproliferative effects of angiotensin IIin tissues may be better blocked byACEIs which achieve higherconcentrations in the tissues.

Table 1: A simplified diagram illustrating the role of the renin-angiotensin-aldosterone system in sodium andvolume homeostasis

Na+ depletion

V

\> blood volume

blood pressure

angiotensinogen

renin release

angiotensin

catalyseACE

inhibitACE/

angiotensin

V

aldosterone release Na* retention

II* blood volume

T* blood pressure

3QP

Different Uses of ACE Inhibitors

UPDATE ARTICLE

Table 2: ACE inhibitors currently available in Hong Kong

Drug TradeName Name

DosageHypertension Heart Failure

Comments

captopril Capoten 12.5mgbd-50mg td 6.25 mg td-50 mg td short-acting

cilazapril Inhibace 1 mg od-5 mg od

Major Trials

SAVE,19 ISIS-422

enalapril Renitec 5-20 mg od

fosinopril Monopril 10-40mgod

5-20 ms od-bd not a true once-daily drug CONSENSUS,15

V-HeFT II,16 SOLVD17

hepatic and renal routeof elimination

lisinopril Zestril

perindopril Acertil

2.5-20 mgod

2-8 mg od

quinapril Accupril 2.5-20 mg od-bd

ramipril Tritace 1.25-10 mgod

2.5-20 mgod

2-8 mg od

2.5-20 mg od-bd

1.25-5mgbd

GISSI-3P

1 st dose hypotensionless likely

Some ACEIs are claimed to causeless side-effects. For example, first-dose hypotension is rare withperindopril while fosinopril is thoughtto cause less cough/-5 Whilst theseclaims are interesting, the scientificbasis of these differences have notbeen elucidated.

Adverse effects of ACEI

Since ACEIs inhibit the release ofaldosterone, they decrease thesodium/potassium exchange in thedistal renal tubules and potassiumretention tends to occur. Hyper-kalaemia is therefore a common side-effect of ACEIs (Table 3). It isespecially likely in patients with poorbaseline renal function. Since it is awell recognised side-effect, mostphysicians will take the precaution ofnot prescribing potassiumsupplement, nor potassium-sparingdiuretics such as amiloride orspironolactone concurrently.

As the RAAS is activated when aperson is volume or salt depleted,ACEIs may induce in such individualspostural hypotension, especially afterthe first dose. This phenomenon hasbeen termed "first-dose hypotension"and is also a well recognised side-effect. Therefore, in patients who maybe affected by first-dose hypotension,such as those patients with severeheart failure already receiving high-dose diuretics, those whose bloodpressure is already low, and elderlypatients, ACEI should be initiatedvery carefully, usually under closemedical supervision in hospital. In suchpatients, diuretics would be reducedin dosage or stopped, and anyhypovolaemia corrected. Then, thelowest dose of an ACEI, such ascaptopril 6.25 mg, would be startedwith the patient recumbent, withfrequent blood pressuremeasurements for the first few hours.

In patients who are less likely tosuffer from first-dose hypotension,precautions should still be taken. It iscustomary to request the patient to

take the first dose at night as they areabout to retire. One of the newACEIs, perindopril, is thought to havea much lower incidence of first-dosehypotension. The reason for this isunclear.

ACEIs should be used cautiouslyin patients with renal impairment fortwo reasons. Firstly, most ACEIs areexcreted by the kidneys andtherefore the plasma drug levels willbe higher in patients with pre-existingrenal disease. Secondly, ACEIs cansometimes worsen renal function,particularly in patients with bilateralrenal artery stenosis or stenosis in therenal artery of a single functioningkidney. Some young hypertensivepatients have bilateral renal arteriesstenosis due to fibromuscularhyperplasia, while in the elderly, therenal arteries may be narrowed byatherosclerosis. Hence, it iscustomary to be cautious whenprescribing ACEIs in patients withperipheral vascular disease as they

(Continued on page 402)

400

Different Uses of ACE Inhibitors

UPDATE ARTICLE

may have silent renovascular disease.Any sudden change in renal functionafter the initiation of an ACEI in suchpatients should alert the clinician tothis possibility.

The renal toxicity of ACEI isexacerbated as expected whenother nephrotoxic drugs areprescribed concurrently. For example,NSAIDs should be used with cautionin a patient who is already takingACEI. ACEIs tend to reduce renalexcretion of lithium and may causetoxic plasma levels of lithium.Although ACEIs may worsen renalfunction or cause dangeroushyperkalaemia in patients with renalfailure, nephrologists do use ACEIs inearly renal failure to retard diseaseprogression.6 In particular, they havebeen shown to slow thedeterioration in renal function indiabetic nephropathy.7 ACEI shouldbe used with specialist advice inthese patients.

None of the ACEIs have beentested in human pregnancy andtherefore this class of drugs shouldnot be used in pregnancy.Methyldopa (Aldomet) remains thedrug of choice for hypertension inpregnancy.

Captopril used at high doses hasbeen associated with rare cases ofthrombocytopenia, neutropenia andagranulocytosis. This is thought to berelated to the sulphhydryl group, soother ACEIs may not share thisproblem. ACEIs may depresserythropoiesis, which is especially aproblem in patients with chronicrenal failure. ACEIs sometimes causehypersensitivity reactions, rash,urticaria and angioneurotic oedema.In such patients, ACEIs arecontraindicated.

i

A common and importantproblem is that a proportion ofpatients suffer from ACEI-inducedtroublesome dry cough. This side-effect may be caused bypotentiation of kinins. The coughtends to occur in women and atnight. It does not respond to coughmixtures and anti-histamines, and

frequently necessitates a reductionin dosage or withdrawal of the drug.It has been suggested that theincidence of dry cough is particularlyhigh in Hong Kong Chinese. Theauthors' approach is to ascertainthat the cough is related to ACEI inthe first place. Sometimes, a carefulhistory would reveal that the coughis due to some other reasons such ascommon cold, chest infection orworsening heart failure. There is littleevidence that cough mixtures thatare commonly prescribed work, butthere is no harm in trying them. Then,the indications for ACEI would bereviewed. If the patient has heartfailure (e.g. ejection fraction 35% orless) or diabetic nephropathy, thecase for continuing the ACEI is strong.Otherwise, the ACEI should bechanged to another class of drugs.In those patients who require ACEIdespite cough, it is worth tryinginhaled sodium cromoglycate, whichis normally used for asthma. Thistreatment is not harmful and there issome evidence from small trials thatit works.8 In future, losartan, anangiotensin II receptor antagonist,may be used instead of ACEI as itdoes not cause cough, but itseffectiveness in reducingcardiovascular mortality or retardingnephropathy needs to beestablished first.

Hypertension

ACEIs are effective drugs in thetreatment of hypertension.9 They

may also have additional beneficialeffects such as regression of leftventricular hypertrophy (LVH) andremodelling of blood vessels. Inmeta-analyses of trials investigatingagents which regress LVH, ACEIs haveconsistently been shown to besuperior to other classes of anti-hypertension drugs.10 LVH is nowrecognised to be the single mostpotent risk factor for cardiovascularevents and mortality. Patients whohave concomitant conditions such asdiabetes, heart failure or history ofMl should receive an ACEI as the firstchoice. Otherwise, ACEIs arecurrently not recommended as first-line drugs in hypertension, becauseunlike diuretics and beta-blockers,there are no clinical trials which haveshown that an ACEI reducescardiovascular mortal i ty inhypertensive patients.11

If one chooses an ACEI forhypertension, one should use a once-daily agent to minimise the peaks andtroughs in blood pressure and toimprove compliance. However,ACEIs are not uniformly effective inall individuals. The response to ACEImay have a genetic component andmay also be dependent on thedegree of activation of the RAAS.12'13

If the blood pressure response to anACEI is unsatisfactory despiteadequate dosage and compliance,another class of anti-hypertensivedrugs should be considered.

Table 3: Adverse effects of ACE inhibitors

hypotension (especially following the 1st dose)persistent dry coughtaste alterationrenal impairmenthyperkalaemiaurticariarashesangioedemahypersensitivity reactionsblood disorders (anaemia, thrombocytopcnia, neutropenia, agranulocytosis)jaundice

402.

Hong Kong Practitioner 18 (8) August 1996

UPDATE ARTICLE

Heart failure

In heart failure, there is activationof the RAAS, resulting in sodium andfluid retention. This may initially be aresponse to low cardiac output butcan be deleterious in the long run.Currently, it is believed that suchneurohormonal activation in heartfailure is harmful and therapy shouldbe directed at reducins this.14 ACEIsare effective in suppressing theRAAS. Successive clinical trials suchas Cooperative North ScandinavianEnalapril Survival Study(CONSENSUS),15 Vasodilator HeartFailure Trial (V-HeFT II)16 and Studiesof Left Ventricular Dysfunction(SOLVD)17 have shown that ACEIsreduce mortality in heart failure(Table 4). The data are now socompelling that it is no longerthought to be ethical to withholdsuitable heart failure patients fromACEI therapy. Furthermore, SOLVDshowed that patients with leftventricular ejection fraction of 35%or less benefited from treatment withACEI even if they were asymptomatic.Hence, in patients suspected to haveany significant degree of leftventricular dysfunction, measurementof ejection fraction by echocardio-graphy is necessary and is now partof the modern management of heartfailure.18 As mentioned above, ACEIsshould be started cautiously in heartfailure patients, usually in hospital withclose monitoring. The starting doseshould be low and increasedgradually. Diuretics should bereduced or stopped for a few daysbefore introducing an ACEI. Theoptimal dose of ACEI in heart failureremains unresolved. In SOLVD, thetarget dose of enalapril was quitehigh, 20 mg daily. In practice, mostphysicians tend to use lower doses.It remains to be established thatlower doses are as effective as highdoses in reducing mortality. ACEIs,when used in conjunction withdiuretics in heart failure, may causedisturbances in renal function andelectrolytes, and so carefulmonitoring of these are essential.

Summary or the major clinical trials investigating the effect onmortality after ACEI therapy

Trial

CONSENSUS15

SOLVD"

SAVE1*

AIRE20

GISSI-381

ISIS-488

Subjects

CHF (NVHA Class IV)

CHF(EF<S35%)

MI(EF<;40%)

Ml with HF

Ml

Ml

Myocardial infarction

ACEI and thrombolysis representmajor advances in the treatment ofmyocardial infarction (Ml) in recentyears. Large-scale studies such asSurvival and Ventricular EnlargementStudy (SAVE),19 Acute InfarctionRamipril Efficacy Study (AIRE),20

Gruppo Italiano per lo Studio dellaSopravvivenza nel l ' infarctoMiocardico (GISSI-3)21 andInternational Study of Infarct Survival(ISIS-4)SS all testified to theeffectiveness of ACEIs in reducinglong-term mortality of patients afterMl and improving their cardiacfunction (Table 4). By influencingcardiac remodelling following Ml,ACEIs help to prevent deteriorationin ventricular function anddevelopment of heart failure. It is stillan unresolved question as to whoshould receive ACEIs after Mis.Hypotension and poor renal functionare relative contraindications. Itseems that patients with overt heartfailure20 or poor ejection fractions19

would benefit most from thesedrugs, but all Ml patients mightbenefit to some extent.21-28 However,CONSENSUS II showed thataggressive non-selective use of anACEI (involving an intravenous firstdose) immediately after acute Ml maynot be beneficial.23 Although GISSI-3 and ISIS-4 both showed that oralACEIs can be given within the first 24hours, the magnitude of benefit wasnot very large, around 10% reduction

Drug ,

enalapril

enalapril

captopril

ramipril

lisinopril

captdpril

Relative risk reduction,.-;;(% deaths .prevented)>:

;;• , 40 % 'H?-' .' '•

? 13 % ^

11 %, 9 %

in mortality. In contrast, thereduction in mortality in the SAVEand AIRE studies were 19% and 27%respectively, largely because ofselective inclusion of patients withlow ejection fraction19 or overt heartfailure.20 Nevertheless, these twostudies which randomised patientsfrom day 3 onwards after Mlindicated that the ACEI does notneed to be started within the first 24hours. The authors' view is that it isnot worth subjecting a haemo-dynamically unstable patient afteracute Ml to ACEI within the first 24hours when the benefits are somodest and when the probability ofhypotension is high (20% in ISIS-4)22.The decision to start ACEI can bemade when a patient is stabilised.

Diabetes

A pioneering study by Lewis andcolleagues showed that captoprilprevented the progression ofdiabetic nephropathy.7 The outcomemeasures were doubling of serumcreatinine or progression to dialysisor transplantation. Other studiesshowed that ACEIs prevent theprogression from microalbuminuria toalbuminuria.24 Microalbuminuria(albumin excretion 30-300 mg/24hr)is an early maker for deterioration inrenal function, and is often present10 years after the onset of diabetes.

(Continued on page 405)

Hong Kong Practitioner 18 (8) August 1996

UPDATE ARTICLE

Currently, it is thousht that diabeticswith microalbuminuria or albuminuriashould receive an ACEI, especially inthe presence of hypertension. Toidentify diabetic patients withmicroalbuminuria, either a spot urinespecimen, 12-hour overnisht urinecollection or 24-hour urine collectionshould be sent to the laboratory asurine dipsticks are not sensitiveenoush. We favour 24-hour urinecollection as creatinine clearance canbe determined at the same time.

Other beneficial effects

ACEIs may have other beneficialeffects, such as improvins endothelialdysfunction. The on-going Trial onReversing ENdothelial Dysfunction(TREND) study is investigating ifquinapril restores the reactivity ofvascular muscle to vasodilatingagents in coronary arteries. ACEIsmay also reduce the thickness ofarterial walls and restore arterialcompliance.85-26

Choice of ACEIs

There are now numerous ACEIson the market. Choice will depend onprior experience of a particular drug,availability and price. Captopril isoften used as the test dose whenACEI therapy is started because it isshort-acting and so adverse effectswould be comparatively short-lived.For long term use, a long-acting drughas the theoretical advantage ofonce-daily dosage to improvecompliance and smoother plasmalevels. If first dose hypotension orrenal impairment is a concern, thenperindopril or fosinopril respectivelymay be preferred. In using some ofthe latest ACEIs, one is of courseextrapolating from clinical trials inwhich a different ACEI might havebeen used, but the evidence so farsuggests that the benefits in heartfailure and Ml are class effects.

Losartan

Losartan, an angiotensin IIantagonist, is a new class of drugwhich has recently been launchedworld-wide.87 It acts in a differentmanner to ACEIs in that it blocks thebinding of angiotensin II to one ofits receptors. This may result in amore complete blockade of thecardiovascular effects of angiotensinII. Moreover, losartan does not causecough and first dose hypotension.58

Nevertheless, there are two reasonswhy losartan should be used withreservation at this stage. Firstly, it is anew drug and there are no long termstudies showing any benefit in termsof reduction of mortality inhypertension, heart failure or Ml.Secondly, ACEIs block not only theRAAS but also enhance the formationof kinins. There are animal data tosuggest that some of the beneficialeffects of ACEI are brought about bychanges in the kinin system.2 Losartanwill have no direct effect on the kininsystem and therefore may notreproduce all the benefits of ACEIs.

Conclusion

ACEIs have established anenviable reputation, especially in thetreatment of heart failure and Ml.There are many potential problemsand side-effects associated withACEIs, and patients taking ACEIs mayrequire periodic monitoring of renalfunction and electrolytes. However,large clinical trials have establishedclearly the usefulness of ACEIs in heartfailure, Ml and diabetic nephropathy,so they have an important place inthe formulary.

References

1. Gavros H. Angiotensin-converting enzymeinhibition and the heart. Hypertension 1994;23: 813-818.

2. Linz W, Wiemer G, Gohlke P, Unger T,Schoelkens BA. Contribution of kinins to thecardiovascular actions of angiotensin-convertins enzyme inhibitors. Pharmacol Rev1995; 41: 25-49.

3. Hui KK, Duchin KL, Kripalani KJ et a/.Pharmacokinetics of fosinopril in patients withvarious degrees of renal function. ClinPharmacol Ther 1991; 49: 457-467.

4. McFadyen RJ, Lees KR, Reid JL. Differences infirst dose response to angiotensin convertingenzyme inhibition in congestive heart failure.Br Heart J 1991; 66: 206-211.

5. Punzi HA. Safety update: Focus on cough.Am J Cardiol 1993; 72: 4SH-48H.

6. Kamper AL, Strandgaard S, Leyssac PP. Effectof enalapril on the progression of chronicrenal failure. A randomised controlled trial.Am J Hypertens 1992; 5: 423-430.

7. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD.The effect of angiotensin-convertins enzymeinhibition on diabetic nephropathy. N Engl JMed 1993; 329: 1456.

8. Hargreaves MR, Benson MK. Inhaled sodiumcromoglycate in angiotensin-convertingenzyme inhibitor cough. Lancet 1995; 345:13-16.

9. Tse HF, Lau CP. Current issues on themanagement of hypertension. HK Pract1996; 18(4): 147-157,

10. Dahlof B, Pennert K, Hansson L. Reversal ofleft ventricular hypertrophy in hypertensivepatients. Am J Hypertens 1992; 5: 95-110.

11. Collins R, Peto R, MacMahon S, eta/. Bloodpressure, stroke, and coronary heart disease.Lancet 1990; 335: 827-838.

12. Ajayi AA, Oyewo EA, Ladipo GO, AkinsolaA. Enalapril and hydrochlorothiazide inhypertensive Africans. Eur J O/n Pharmacol1989; 36: 229-234.

13. Moser M. Relative efficacy of, and someadverse reactions to, dif ferentantihypertensive regimens. Am J Csrdiol1989; 63: 2B-7B.

14. Packer M. Evolution of the neurohormonalhypothesis to explain the progression ofchronic heart failure. Eur Heart J 1995; 16suppl F: 4-6.

15. The CONSENSUS Trial Study Group. Effects ofenalapril on mortality in severe congestiveheart failure: results of the Cooperative NorthScandinavian Enalapril Survival Study(CONSENSUS). N Engl J Med 1987; 316:1429-1435.

16. Cohn JN, Johnson G, Ziesche S et a/. Acomparison of enalapril with hydralazine-isosorbide dinitrate in the treatment ofchronic congestive heart failure. N Engl JMed 1991; 325: 303-310.

17. The SOLVD investigators. Effect of enalaprilon survival in patients with reduced leftventricular dysfunction after myocardialinfarction. N £ng/ J Med 1991: 325: 293-302.

18. Ng W, Lau CP. Management of heart failurewith current perspectives. HK Pract 1995;17 (11): 520-537.

19. Pfeffer MA, Braunwald E, Moyet LA, BastaL, Brown EJ, Cuddy TE et al. Effect ofcaptopril on mortality and morbidity inpatients with left ventricular dysfunction aftermyocardial infarction. N Engl J Med 1992;327: 669-677.

20. The Acute Infarction Ramipril Efficacy (AIRE)Study Investigators. Effect of ramipril onmortality and morbidity of survivors of acutemyocardial infarction with clinical evidenceof heart failure. Lancet 1993; 342: 1418-1419.

405

Different Uses of ACE Inhibitors

UPDATE ARTICLE

21. Gruppo Italiano per lo Studio della

Sopravvivenza nell'infarcto Miocardico.

GISSI-3: effects of lisinopril and transdermal

Slyceryl trinitrate singly and together on 6-

week mortality and ventricular function after

acute myocardial infarction. Lancet 1994;

343: 1632.

22. ISIS-4 (Fourth International Study of Infarct

Survival) Collaborative Group. ISIS-4 : a

randomised factorial trial assessins early oral

captopril, oral mononitrate, and intravenous

masnesium sulphate in 58,050 patients with

suspected acute myocardial infarction. Lancet

1995; 345: 669-685.

23. SwedbersK, Held P, KjekshusJ, Rasmussen K,

Ryden L, Wedel H. Effects of the early

administration of enalapril on mortality in

patients with acute myocardial infarction.

Results of the Cooperative New Scandinavian

Enalapril Survival Study II (CONSENSUS II). N

Engl J Med 1992; 327: 725-727.

24. Viberti G, Mogensen CE, Groop LC, Pauls JF.

Effect of captopril on progression to clinical

proteinuria in patients with insulin-dependent

diabetes mellitus and microalbuminuria. JAMA

1994; 271: 275.

25. Schiffrin EL, Deng LY, Larochelle P. Effects

of a beta-blocker or a converting enzyme

inhibitor on resistance arteries in essential

hypertension. Hypertension 1994; 1: 83-91.

26. Thybo NK, Stephens N, Cooper A, AalkjaerC,

Heagerty AM, Mulvany MJ. Effect of

antihypertensive treatment on small arteries

of patients with previously untreated

essential hypertension. Hypertension 1995:

25: 474-481.

27. Timmermans PBMWM, Wong PC, Chiu A et al.

Angiotensin II receptors and ansiotensin II

receptor antagonists. Pharmacol Rev 1993;

205-251.

28. Goldberg Al, DunlayMC, Sweet CS. Safety

and tolerability of losartan compared with

atenolol, felodipine, and angiotensin

converting enzyme inhibitors. J Hypertens

1995; 13 (suppl 1): S77-S80.

SUPPOSITORIESFOR CHILDREN

QUICK RELIEVE FOR CHILDRENEach suppository contains:100 mg PARACETAMOL + 100mg PROPYPHENAZONE(No Phenacetin, no Aspirin)

RELIEVE PAIN RAPIDLYACT AGAINST INFLAMMATION

DOSAGEfrom 1 to 4 years of age: 1/2 to 1 suppository 2 times daily,after 4 years of age up to 3 suppositories daily, dependingupon weight.

Samples upon request. 20% Bonus for Trial order.

• CALMING AND SOOTHING• DECREASE FEVER FAST

MERCK Gesellschaft mbH, Wien Austria,division arcanaSole Agents: __>«« *z^Lin# Pharmaceutical Co_<r, Ltd)

Room 1012, Block. 3, Nan Fung Industrial City,18 Tin Hau Road, Tuen Mun, N.T., Hong KongTel: 2455 8138 Fax: 2455 80O8

4f)fi