Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from

Postgrad Med J (1990) 66, 166 - 185 © The Fellowship of Postgraduate Medicine, 1990 Reviews in Medicine Clinical pharmacology and therapeutics M.J. Kendall and R.C. Horton Department ofMedicine, Queen Elizabeth Hospital, Birmingham B15 2TH, UK.

Introduction The combined subject Clinical Pharmacology and ofthrombolytic agents on the acute infarct patient, Therapeutics is concerned with all aspects of the the role of aspirin as a prophylactic agent in drug treatment ofdisease. It therefore overlaps to a relation to ischaemic heart disease' and the con- greater or lesser extent the areas of interest of all tinuing interest in newer antihypertensive agents clinicians whose patients require drug treatment. It have been the subject of reviews published is also concerned with drug actions, drug develop- elsewhere. We have chosen in this section to ment, drug assessment and drug administration. In consider three quite different aspects of addition, adverse effects, drug interactions and therapeutics which appear to be having a major drug overdosage are within the province of the impact on the development and consequences of clinical pharmacologist. ischaemic heart disease. These are the recent In this review we have chosen to consider some of advances in the management of heart failure, the the main systems ofthe body and to highlight those increasing use oflipid lowering drugs and hormone aspects of therapy in which treatment has im- replacement therapy. where the of for or bad proved, impact drugs good copyright. is becoming better understood or where advances in our understanding ofdrug actions are leading to Heart failure hopes of better methods of treatment in the relatively near future. Two of the major areas of interest in the In some instances we have attempted to draw therapeutics of chronic heart failure have been a attention to the recent advances, in others we have reappraisal of the use of inotropic agents and the attempted to define the present position based on precise indications for and benefits of angiotensin the progress made over the last few years. We have converting enzyme (ACE) inhibitors. For each not tried to be comprehensive: rather we have drug the clinically relevant end points should be http://pmj.bmj.com/ chosen some areas of therapeutics where we feel seen as more important than the improvements in that the advances in knowledge made by the abstract haemodynamic variables alone. Thus we specialist should be presented to the non-specialist should focus particularly upon improvement of with the suggestion that his or her therapeutic clinical symptoms with prolonged exercise approach may need to undergo a little reconsidera- tolerance and reduction in NYHA class, resolution tion. of the clinical signs of heart failure and finally a We also include a the reduction in a sudden death. piece highlighting impact mortality including on September 26, 2021 by guest. Protected ofclinical trial methodology on various treatments under the broad heading of alternative medicine. Positive inotropes Areas such as adverse reactions, interactions, phar- macokinetics and toxicology will not be dealt with The traditional use ofdigoxin as an inotropic agent specifically in this review. in heart failure patients who are in sinus rhythm was questioned in the 1970s by studies showing that on digoxin withdrawal there were few adverse long Cardiovascular pharmacology term clinical effects.2 Moreover, digoxin appeared to have poor haemodynamic value acutely3 and its There have been a large number of advances in the proarrhythmic effects4 were raised as a potential management of cardiovascular disease in general cause of further morbidity and mortality. and in the prevention and treatment of myocardial However, there has been a tendency to ignore infarction in particular. Assessments of the impact some ofthe known facts about digoxin. It has much broader physiological effects than merely acting as a positive inotrope or slowing atrioventricular Correspondence: M.J. Kendall. M.D., F.R.C.P. conduction. Extensive in vivo animal studies have Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from CLINICAL PHARMACOLOGY AND THERAPEUTICS 167

shown that it has potent neurally mediated effects and arterial vasodilatation thereby reducing after- on the cardiovascular system. It has excitatory load. Again the clinical benefits are apparent in effects on baro- and chemoreceptors leading to small studies: NYHA class and symptoms are vasodilatation and a fall in arterial pressure. It improved and exercise capacity is increased." stimulates cardiac mechanoreceptors, facilitates However, mortality appears to remain high, a vagal effects and is able to antagonize sympathetic proarrhythmic effect has been demonstrated and input to the heart. All of these influences lead to a symptomatic tolerance develops after three months reduction in afterload and so are beneficial in heart of therapy. Despite these drawbacks it may well failure.5 These effects have been neglected and now prove useful as a bridge for short term cardiac that other agents are being investigated in patients, support in patients awaiting transplantation.'2 digoxin has undergone a signficant reassessment. The difficulties ofinotropic agents centre around For example, controlled studies do show a their proarrhythmic actions and tendency to inc- beneficial haemodynamic effect of digoxin rease myocardial oxygen consumption. These therapy.6 problems may be overcome by partial Pi agonists Furthermore, the clinical benefit of digoxin such as xamoterol. These drugs act as agonists to appears to be more firmly established. The the PI receptor when sympathetic tone is low but Captopril-Digoxin Multicentre Research Group7 antagonists when tone is high and therefore pre- showed a significant increase in left ventricular vent the adverse effects of excessive sympathetic ejection fraction and the German and Austrian activation in heart failure such as tachycardia, and Xamoterol Study Group8 found that digoxin pro- renin-angiotensin activation. In patients at rest duced significant improvement in the symptoms they can improve contractility, reduce diastolic and signs of heart failure together with a reduction wall stress and left ventricular filling pressure.'3 In in the cardiothoracic ratio. These are not simply exercise they reduce myocardial ischaemia and short term effects. The captopril and xamoterol maintain cardiac output.'4 In clinical terms this studies ran over 6 and 3 months respectively. means an improvement of exercise capacity by Guyatt et al., in a randomized study, examined 33% and reduction in the symptoms and signs digoxin versus placebo in 20 patients with heart of failure.8 Their specific indication is in copyright. failure of variable severity.9 A clear benefit was mild-moderate failure (NYHA II, III) principally demonstrated in terms of improving dyspnoea, due to ischaemic heart disease and in situations of exercise capacity and reducing deterioration in echocardiographically or angiographically proven heart failure. They attempted to analyse the predic- diastolic dysfunction. They should not be used in tors of this response and found that a third heart severe heart failure where haemodynamic stability sound, cardiothoracic ratio of greater than 0.55, is strongly dependent upon activation of the sym- together with jugular venous pressure of 6 cm or pathetic system. more and poor exercise capacity were all associated The place of other inotropic agents, such as the http://pmj.bmj.com/ with a beneficial response to digoxin. It was noted dopamine (receptor subclass 1) agonists, L-dopa, that the drug level at which digoxin proved dopexamine and fenoldopam, remains to be fully therapeutic was higher than conventionally recog- evaluated but appears to offer encouraging signs nized with a mean of 1.75 ± 0.45 nmol/l (range that alternatives to digitalis may be available in the 1.54- 2.56 nmol/l). future. Alternatives to cardiac glycosides have been sought but few have been clinically successful. ACE inhibitors Milrinone combines a positive inotropic effect with on September 26, 2021 by guest. Protected a vasodilatory action. Though found to have The early use of ACE inhibitors in severe heart definite beneficial effects in heart failure - inc- failure is now clearly recognized as a means of reasing exercise tolerance and reducing the fre- reducing mortality in this progressive condition. In quency ofdecompensation - up to 20% ofpatients the patients studied in the CONSENSUS trial the on milrinone deteriorate, an adverse trend in mean dose of frusemide was 200 mg and one third mortality is found (though non-significant) and the were using other forms of vasodilators, e.g. ni- frequency ofventricular arrhythmias is increased.'° trates. One year follow-up confirmed a highly Moreover, in this study (involving 230 patients in a significant mortality benefit.'5 This effect may not double-blind 12 week protocol) digoxin caused be a property of ACE inhibition per se but reflects deterioration in only 3% of patients, increased left the value of vasodilatation as shown in a similar ventricular ejection fraction (unchanged with mil- mortality reduction using nitrates and hydra- rinone) and had no effect on the frequency of lazine.16 arrhythmias. Moreover, captopril is of confirmed value in Enoximone is a type III phosphodiesterase mild heart failure. In a study of 300 patients with inhibitor and acts by increasing intracellular predominantly NYHA class II symptoms captopril cAMP. This promotes myocardial contractility added to diuretic therapy significantly increased Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from 168 M.J. KENDALL & R.C. HORTON exercise time, reduced NYHA class and reduced Overall therefore in the practical management of incidence of ventricular ectopic activity as com- heart failure, patients should be broadly divided pared to placebo.7 into two groups. Those with class II symptoms Cardioprotection remains the elusive goal of (symptomatic during ordinary activity) should therapeutics for myocardial infarction (MI). While initially be treated with diuretics. The choice of a thrombolytic agents improve mortality within a second agent depends on further assessment. If the 24-hour period after onset of chest pain (which patient has a third sound with cardiomegaly, persists for up to one year), reversing disease digoxin may be indicated; if the patient has progression in the longer term remains prob- predominantly diastolic dysfunction proven lematic. Calcium antagonists are of no benefit echocardiographically then a drug like xamoterol while beta-blockers are contraindicated in a large may be appropriate. For the majority of patients group of patients. ACE inhibitors may bridge this with such mild symptoms, however, an ACE gap. inhibitor would be the second agent chosen. Pfeffer et al. were able to show in a randomized In class III and IV failure (symptomatic with double-blind placebo controlled study with a one minimal activity or at rest) the treatment schedule year follow-up in 59 patients that captopril therapy is clearer. Diuretics should be followed by an ACE significantly reduced left ventricular end diastolic inhibitor (reduced mortality) and patients may volume and left ventricular filling pressure.'7 These benefit from digoxin.25 patients had sustained their first anterior MI and captopril was initiated at a mean of 20 days post-infarct. The target dose was 25 mg three times The management of hyperlipidaemia a day for in-patients and 50 mg three times a day for outpatients. In addition, a subgroup with an Over the last few years there appears to have been occluded left anterior descending coronary artery an exponential increase in the interest in and papers were at high risk of ventricular dilatation and this on plasma lipids. Although the importance of was prevented by captopril. Exercise capacity was hyperlipidaemia as a risk factor in coronary artery also in increased the captopril group. Hence, disease has been appreciated for many years, the copyright. ventricular dilatation which indicates systolic dys- development of a range of more effective lipid function and is a major adverse prognostic loweringdrugs26'27 and in particular the HMG CoA indicator for acute MI appeared to be preventable reductase inhibitors28-30 has made the subject of with captopril treatment in this small study. A large serum lipid reduction a matter of considerable scale investigation of the role of captopril in this commercial importance. The result has been a situation is currently in progress. rapid growth in sponsored research, publications, Captopril also has a proven anti-arrhythmic meetings and journal supplements. effect reducing the incidence of ventricular ectopics, couplets and salvoes in chronic therapy18 Lipidmeasurements and classifications http://pmj.bmj.com/ as well as inhibiting the generation of reperfusion arrhythmias in isolated rat hearts.'9 Two questions High concentrations of low density lipoprotein arise. Firstly, why?, and secondly, can this be (LDL) are associated with increased risk of cor- translated into any mortality benefit? The latter onary heart disease.32'33 Unfortunately precise question awaits confirmation but some interesting measurements of this fraction are difficult and clues exist as to its possible mechanism of action. therefore since LDL represents 70% of the total

Captopril is unique to the ACE inhibitors as a free cholesterol the latter is a useful guide to the patients on September 26, 2021 by guest. Protected radical scavenger in vitro due to its sulphydryl lipid status and hence prognosis. A better assess- group.20'2' A preliminary report confirms this in 25 ment follows from measuring high density lipo- patients with congestive cardiac failure who had protein (HDL) and subtracting this from the total documented increased free radical activity.22 cholesterol. This becomes more precise if the triglyceride concentration (all measurement in The dynamics of sodium and water retention in mmol/l) is included by use of the following for- heart failure are now more clearly understood and mula,34 drugs promoting natriuresis may have a benefit in triglyceride offloading the heart.23 Atrial natriuretic peptide is a (LDL = total cholesterol - (HDL + trglycede novel route through which a beneficial effect may be seen. Promoting its activity by inhibiting an In the future, apolipoprotein ratios may be useful endopeptidase (its principal degradative enzyme) (B/A representing the principle apolipoproteins of increases natriuresis and diuresis.24 Further clinical LDL and HDL respectively) together with apo E trials are awaited with interest since this may phenotyping.3 represent a direct route for influencing deleterious It is recommended that blood for cholesterol be neuroendocrine reflex activation in heart failure. taken in the non-fasting state preferably with the Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from CLINICAL PHARMACOLOGY AND THERAPEUTICS 169 patient resting quietly and with no venous com- (2) cholesterol concentration 5.3-6.5 mmol/l: pression at the time the blood sample is withdrawn. dietary advice with reinforcement, encouragement On the basis of the results of the above and follow-up; (3) cholesterol concentration measurements it is possible to categorize patients > 6.5 mmol/l: dietary advice with recourse to drug into groups within defined classifications or treat- therapy if no improvement after 3 months; (4) ment strategies. However, for the non-expert cholesterol concentration > 8 mmol/l: immediate wishing to improve the patients prognosis in rela- drug therapy with dietary advice and careful tion to ischaemic heart disease it is probably follow-up. enough to note simply that (a) a high total cholesterol is bad, (b) the prognosis is adversely Drug treatment influenced by increasing LDL and decreasing HDL and (c) the triglyceride concentration not In considering the drug treatment of hyper- associated with a raised cholesterol merits atten- lipidaemia it seems reasonable to predict that the tion as a cause of pancreatitis and as a possible data available will increase markedly and the associate of obesity, alcohol excess and diabetes patterns of drug use will change over the next year but does not merit treatment as a coronary risk or two. Accordingly we propose to consider what factor. the doctor might expect of the drug in relation to a particular compound and then to review very Plasma concentrations and risk briefly the extent to which some of the currently available compounds match our requirements. The concept of a normal range is not really These compounds may be given to large applicable to the serum cholesterol. Most individ- numbers of patients who are currently well and uals fall within the range of 2-9 mmol/l and there treatment may be required for long periods. The is an approximately Gaussian distribution. The patient population will include patients who are mortality rate in individuals with low cholesterol, overtly at risk of developing the manifestations of below 5 mmol/l, is increased because they include coronary artery disease and because of this may be some patients with carcinomas or other disorders. taking certain classes of drugs. copyright. Above 5.2 mmol/l (200 mg/dl) the coronary heart Facing the drug company representative who disease (CHD) mortality rate starts to increase and wants to recommend a lipid lowering drug we increases markedly above 6.5 mmol/l (or 250 mg/ might reasonably ask (1) Mode of action: How dl).34 does it work? (2) Efficacy: Is it effective? (a) Does it Countries with a low incidene of CHD such as decrease LDL and triglycerides and increase HDL? Japan have populations with serum cholesterol (b) Has it been shown to reduce the clinical levels at the lower end of the range. In the United manifestations ofcoronary artery disease in proper which has a incidence of CHD well double blind clinical trials? Because Kingdom high (c) it does http://pmj.bmj.com/ over half the population have cholesterol levels reduce CHD and because it has no other adverse over 5.2 mmol/l, 25% over 6.5 mmol/l and 3-5% effects does it reduce total mortality? (3) have grossly elevated values in the 8-9 mmol/l Tolerability: (a) Specific - will it adversely affect range. the coronary-prone? It should have no pro- arrhythmic effects, or give hypokalaemia. It should Managementplan not be a vasoconstrictor, negative inotrope or have adverse effects on diabetes. (b) Non-specific - will The first important differentiation one must make it upset the patient? (4) Safety: Are there any long on September 26, 2021 by guest. Protected is that of primary and secondary prevention. It is term effects of blocking the delivery of an essential unfortunate that no evidence exists to support the component ofcells and a source ofenergy? What is reduction ofserum cholesterol following a myocar- the evidence of long term safety? (5) Simple dial infarction.35 All treatment that we shall discuss regimen. (6) Acceptable cost. (7) Pharmaceutical focusses on primary prevention only. Whatever is and pharmacological - Reasonable half life; long done about the serum lipids should be carried out shelf life; no interactions with other drugs taken by as part of a total strategy of multiple coronary risk the coronary-prone patient. factor intervention. Those factors which can be The drugs which are available have to be corrected, such as smoking habit and hypertension, measured against the above criteria and the should be corrected. Those which cannot, such as decision about which drug to use will depend on family history and being male, should be seen as how well they meet the criteria and the problem factors which provoke the doctor and patient to posed by the particular patient. The drugs fall into correct the raised lipids more rigorously. one of six main groups: (1) ion exchange resins; The management strategy for the patient with a (2) fibric acid derivatives; (3) HMG CoA reductase raised serum cholesterol can be summarized as: inhibitors; (4) fish oils; (5) probucol; (6) nicotinic (1) correct correctable coronary risk factors; acid analogues. Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from 170 M.J. KENDALL & R.C. HORTON

Several reviewers have commented on the impor- improvement in serum lipids is not absolutely clear tant features of the drugs in each of the above and it is likely that the different members of this groups.27 34 Fish oils have been used predominantly group act in slightly different ways. They are fairly to reduce serum triglycerides.34 Probucol is well tolerated making compliance less likely to be a effective but unpredictable and reduces both HDL problem than with the resins.35 In addition they are and LDL.34 As with all the lipid lowering agents less expensive than the resins but they are not work on its mode of action is continuing.36 cheap. Nicotinic acid is a potent lipid lowering agent 3. HMG CoA reductase inhibitors are inhibitors which lowers LDL and triglycerides and may of 3 hydroxy-3 methyl glutaryl-coenzyme A, the increase HDL.37 However, side effects, particularly rate limiting enzyme in the synthesis of cho- flushing and itching, are common,37 although lesterol.28-30 They are very effective cholesterol- newer precursor agents such as acipimox reduce lowering agents and are much more powerful in these. this regard than any of the other hypolipidaemic The three other classes of drug merit more drugs. The assumption is that they will drama- attention. tically reduce the risk of coronary artery disease 1. Bile acid sequestrant resins - this group of and the hope is that they will not have other drugs have been in use for several years.27'37 They unwanted effects. The enthusiasts are moving for- are not absorbed and reduce cholesterol by binding ward rapidly clinging to the assumption and the to and preventing the reabsorption of bile acids. hope, the more cynical (perhaps the more scientific) The result is increased production of bile acids are awaiting the evidence. which is achieved by increasing the hepatic uptake There can be little doubt that the commercial of LDL, thereby reducing plasma LDL. HDL and pressures to encourage doctors to prescribe the triglycerides may increase a little. The adverse HMG CoA reductase inhibitors will be great. effects are constipation, gastrointestinal discom- Many doctors will be confused about their role in fort and impaired absorption of other food subs- the management of hyperlipidaemia but over the tances and drugs which bind to the resin. Up to 4 next year or so the rival merits of these agents and sachets need to be taken daily and these drugs are the other groups mentioned above will have to be copyright. relatively expensive. sorted out. At the moment it would be difficult to Cholestyramine was the drug used in the lipid produce a strategy for the drug treatment of lipid research clinics study which was reported in 1984.38 disorders which would gain universal acceptance. It showed that over 7 years, in middle aged hyperlipidaemic males who are prescribed 6 sachets No data exist to show that treatment of hyper- daily, there was a 9% fall in serum cholesterol and lipidaemia for a few years produces a reduction in a 19% decrease in CHD risk. overall mortality. However, the 15 year mortality 2. The fibrates include bezafibrate, clofibrate and of the now shows a Coronary Drug Project clearly http://pmj.bmj.com/ gemfibrozil. Clofibrate and gemfibrozil have been significant fall in total mortality, the first to have subjected to large scale clinical trials. The clofibrate been shown with any lipid lowering agent.4' Reduc- WHO trial showed a 9% reduction in cholesterol tion in coronary events is demonstrated with both and a reduction in coronary events.39 However, cholestyramine and gemfibrozil but not HMG there was also an increase in gall stones and all CoA reductase inhibitors as yet. The assumption cause mortality which left clofibrate under a cloud. that it is the reduction in cholesterol concentration Gemfibrozil was studied in the Helsinki Heart alone which produces benefit requires caution as

Study in which 4081 symptomatic middle aged men shown with the WHO clofibrate study. Thus no on September 26, 2021 by guest. Protected with a 'primary dyslipidaemia' were randomized to data are available to support treatment with HMG receive the active drug 600 mg twice daily or CoA reductase inhibitors as a definite means of placebo using a randomized double blind techni- reducing either cardiovascular or overall mortality. que.33'4 Whilst there were no major changes in Currently, because of their proven long term lipids in those on placebo, gemfibrozil increased beneficial effects, nicotinic acid, perhaps as HDL and reduced LDL, non-HDL cholesterol and acipimox to reduce side effects, or gemfibrozil triglycerides. The beneficial impact on serum lipids which is better tolerated than other agents, might was associated with an improved cumulative rate be considered the agents of choice in primary of cardiac end points of 27.3 as against 41.4 per prevention. Clearly the newer agents are to be 1000 in the placebo group - a significant effect. welcomed but they will need to show that they are There was no difference in overall mortality superior to the older drugs in terms of their clinical because the numbers studied were too small but efficacy. there was no evidence that gemfibrozil increased This cautionary note does not imply any doubts the risk of developing other disorders particularly about the lipid hypothesis. We accept that the cancer. correction of hyperlipidaemia by the most effective The mechanism by which the fibrates achieve the agents may prove to be the optimum therapy but Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from CLINICAL PHARMACOLOGY AND THERAPEUTICS 171 only if long term follow-up demonstrates a low HRT and compared them to a group in the same incidence of unacceptable adverse effects. geographical area. The study found no increased risk of breast cancer in the population as a whole but sub-group analysis revealed major differences. Hormone replacement therapy (HRT) and the car- Firstly, in those treated with oestradiol for 9 years diovascular system there was an increased risk of 1.8 times in develop- ing breast cancer. Secondly, this risk rose to A leading article in the British Medical Journal in fourfold in those on treatment with oestradiol and June 1989 was entitled: "Hormone replacement a progestagen for 4 years. This study conflicts with therapy - deserves wider use".42 In it Belchetz others55 and there are methodological problems in reviewed briefly the value of HRT in relation to its analysis. The finding with combined oestrogen control of menopausal symptoms, its impact on and progestagen treatment was in 10 patients only cardiovascular disease and bone density, and refer- with wide confidence intervals. Moreover, the red to the potential risks of malignancy and how oestrogen preparation used is one uncommonly these may be reduced. Each aspect has provoked an prescribed in the United Kingdom. enormous literature and it is therefore relatively The potential impact of HRT on osteoporosis easy for the non-specialist to become overwhelmed. and on female malignancies would be relatively As a result the medical profession may be over- small compared with either a beneficial or detri- cautious and uncertain about the use of this mental effect on cardiovascular disease, particular- potentially very effective form of therapy. Oes- ly coronary artery disease (CAD). Initially because trogen replacement therapy may save between of the potential adverse effects of the oral cont- 250-280 lives per 100,000 per year.43 raceptives on cardiovascular mortality and mor- The beneficial effects of HRT on vasomotor bidity56 (even though the risks are extremely small), symptoms, insomnia and postmenopausal prob- it seemed possible that HRT might increase the risk lems ofthe lower genital tract are well documented of CAD in post-menopausal females. However, and widely accepted.42 A recent study on peripheral although a study from Framingham57 did suggest blood flow confirmed the peripheral circulatory an adverse effect of HRT, other studies have copyright. abnormalities in flushing women and demon- yielded results58-62 which taken together strongly strated the benefit of oestrogen replacement suggested a positive prophylactic role for oestrogen therapy.44 Studies on psychological symptoms have therapy in relation to CAD. More recent results been more difficult to perform but seem to show have confirmed this conclusion and have added to that HRT is useful. our understanding of the possible mechanisms. The longer term benefits in relation to post- The lipid research clinics follow-up study63 fol- menopausal osteoporosis and the tendency to lowed a cohort of 2270 white women over a period develop fractures seems to be well established. of 8.5 years. There were 44 deaths due to cardio- http://pmj.bmj.com/ Notelovitz45 has written a useful review of this vascular disease in the 1677 non-users ofoestrogen subject explaining its complexity and the many (2.62%) and six in the 593 users (1.01%). These aetiological variables involved. In addition Ham- were carefully examined for selection bias, and mond and Maxson include a section on other risk factors, but finally the authors concluded osteoporosis in their review of oestrogen replace- that oestrogen therapy conferred a relative risk of ment therapy46 and underline the magnitude of the 0.42 (95% confidence limits 0.13 to 1.10). They also problem in terms of the frequency of fractures demonstrated that the most likely explanation for particularly vertebral crush fractures (25% of the beneficial effect was an increase in HDL. on September 26, 2021 by guest. Protected Caucasian women over 60), the risks from hip The so-called Walnut Creek Study64 involved a fractures occurring in the elderly and the overall 10-13 year follow-up of 3437 women. This study hospital costs. Hormone replacement therapy pro- was different from others in that some of the tects against fractures of the wrist,47 spine48 and women were relatively young adults 'at the time of hips.42 47-49 entry' and those on oestrogen showed a lower all The concern over the possibility ofincreasing the cause mortality. However, the beneficial effects of incidence of carcinoma is readily understood. oestrogen therapy on cardiovascular disease shown Unopposed oestrogen therapy given to women in previous studies were confirmed in this study. with a uterus does increase the risk of endometrial A rather novel approach to assessing the impact carcinoma.50-52 Cyclical progestogen therapy given of HRT on coronary arteries was to examine the in addition produces withdrawal bleeds but results of angiography on women on the Mil- appears to abolish the cancer risk.42 The impact of waukee cardiovascular data registry.65 This study HRT on breast cancer risk is still debated.42'50'53 involved 933 post-menopausal women who Serious concern has now been raised over the risk required coronary angiography for accepted ofbreast cancer from a recent Swedish study.54 This clinical reasons. However, by definition this was a prospective study examined over 23,000 women on selected population. It contained 154 oestrogen Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from 172 M.J. KENDALL & R.C. HORTON users and 779 non-users who were comparable in partly lost on recommencing treatment.75 This terms of risk factors except that the users had a rebound in smooth muscle reactivity will clearly significantly higher proportion of smokers (20.9 vs lead to clinical exacerbations and may contribute 13.4%). The angiograms were rated by experienced to the worsening clinical problem.74 cardiologists who were unaware of the patients' Moreover, a major study has now been pub- coronary risk factors or oestrogen consumption. lished directly implicating fenoterol as the agent They found a signficantly lower occlusion score in responsible for the New Zealand mortality peak in the oestrogen users. Of further interest was the the late 1970s.76 The wider implications of this tendency for occlusion scores to increase with study, ifaccepted, are serious. It was a case control advancing age in the non-users and to decrease in study to determine whether fenoterol by metered the users. The users also had signficantly more dose inhaler (MDI) led to an increase in risk of favourable HDL and total cholesterol/HDL death in patients and asthma. It was based on two cholesterol ratio scores. observations. First, that this drug was introduced Although some studies have not shown any in 1976, the same year mortality began to rise and benefit,66 the consensus appears to be that HRT that by 1983 it represented 30% of the total MDI significantly reduces the incidence of coronary P2-agonist market in New Zealand compared to heart disease. Further, the potential impact on 5% elsewhere in the world. Second, that in the New mortality and morbidity which could result from Zealand mortality survey, 50% of deaths were this cardioprotective effect could be considerable. associated with fenoterol use although fenoterol The mechanisms involved are probably complex represented only 25% of total sales. and certainly not fully understood. A positive effect From reports on 271 asthma deaths, a case group on serum lipids is likely to be an important of 125 aged 5-45 years was selected because the factor.63'65'67'68 HRT does not seem to increase (and diagnosis of asthma is made more reliably in may slightly lower) blood pressure,69 does not children and young adults. The control group were adversely affect clotting factors70'7' nor does it asthma patients who recovered and left hospital produce carbohydrate intolerance.72 In conclusion, during the period in which the above asthma deaths the benefits from HRT appear convincing and occurred. The diagnosis of asthma was made from copyright. despite recent evidence, there is no statistically hospital coding, 4 controls were selected per case convincing data linking HRT to breast cancer. and were matched for age and ethnic group. Information on drug treatment was obtained in two ways. In cases, prescribed treatment (not drug Asthma use in the preceding 24 hours) was documented from a GP questionnaire on regular medication. In Mortality controls, hospital notes were used. Though data collection was different in the two the

groups http://pmj.bmj.com/ The impetus for development of further anti- authors attempted to demonstrate that there was asthma medications derives mainly from no bias by two validation exercises. epidemiological data showing that there was a The results of this study demonstrated that the gradual rise in mortality in asthmatic patients from relative risk ofdeath using MDI fenoterol was 1.55, 1970-72 up to 1982-84.73 The most publicised the risk being greater for those aged less than 20. reports are from New Zealand where there was a This was estimated to represent 40% of the excess superimposed mortality peak in the late 1970s. mortality. This is the first major study of drug

Thus, the mortality per 100,000 of the New Zea- treatment in asthma mortality and has been on September 26, 2021 by guest. Protected land population was 1.3, 4.2 and 1.85 for 1974, strongly criticized77 78 and equally vigorously 1979 and 1985 respectively.73 No such dramatic defended.79 change has been reported elsewhere and the Firstly, the study examines the prescribed, long- reasons for this peak in particular and the gradual term treatment of patients while in the discussion rise in general are uncertain. they invoke acute toxic effects of P2-agonists as a In considering why mortality continued to rise potential explanation. Thus, in order to provide despite apparent improvement in available drugs data to fit with their conclusion they should have much concern has focussed on P2-agonists.74 There examined treatment taken immediately prior to the is now evidence that they may actually lead to final attack. This could have been obtained from adverse effects on the primary underlying problem friends or relatives of the asthmatic victim. in asthma - that is, bronchial hyper- Although this would certainly have been the ideal, responsiveness. Thus, after regular long term P2 it is practically impossible to obtain this data and agonist treatment there is, during the 24 hours after families are unreliable in this respect. Furthermore, stopping treatment, a hyperreactivity or hyperres- the investigators argue that it is reasonable to ponsiveness of bronchial smooth muscle and hence assume that the patient uses acutely what has been the protection conferred via bronchodilatation is prescribed chronically. Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from CLINICAL PHARMACOLOGY AND THERAPEUTICS 173

Secondly, there were problems over control older asthmatics as shown in a study in 77 patients subjects. There is concern that those derived from over 50 years ofage. Mean peak flow rate increased hospital records may have been less severe and that and inhaled P2 agonist use decreased considerably in any case severity was based on markers of in one quarter of the patients studied.82 chronicity, for example, taking oral steroids or Management ofchronic asthma remains a major admission in previous 12 months, as opposed to clinical problem. Inhaled steroids are now the markers of severity of the final attack. However, treatment of choice for asthma prophylaxis as the first criticism is purely subjective and the second opposed to using long term 2-agonists.83 may be missing the point, which is, that long term Moreover, high dose inhaled steroids decrease the treatment may be contributory to mortality in requirement for oral steroids. terms of, for example, increased bronchial hyper- The systemic effects of inhaled steroids may responsiveness or cardiotoxicity. produce adverse effects which are potentially Finally, mortality has now fallen while fenoterol serious. The hypothalamic-pituitary axis is signifi- sales have remained static. Although sales figures cantly suppressed, growth may be affected and may have been a useful pointer initially, prior to bone mass reduced but the exact clinical extent and undertaking the study, reliance on these alone is relevance of such changes in the long term remains unsound and definitive conclusions cannot be to be assessed.84 Dysphonia and oral candidiasis made on these alone. remain treatment complications at a rate of 5% or Thus, critics would argue that the real conclusion more. of the study is that fenoterol was used to treat In some patients, inhaled steroids are insufficient patients with severe, unstable asthma who were and the clinician may have to resort to systemic likely to be at greater risk of death anyway. administration. Minimizing side effects may be Although the methodological inconsistencies des- achieved by alternate day dosage, repeated cribed certainly weaken the overall conclusion this attempts to taper dosages and co-prescription of study nevertheless runs in parallel with clinical inhaled steroids.5 However, despite these work showing that long term treatment with P2- manoeuvres the search for steroid sparing agents agonists may be harmful in some situations. continues. Agents tried with variable success in- copyright. clude gold salts and troleanomycin (a macrolide Drug treatment antibiotic). More recent work has focussed on low dose methotrexate (15mg/week) which in a Advances in the drug treatment of asthma may be double-blind study caused a 37% reduction in broadly divided into three groups. First, im- requirement for prednisolone in 14 patients as provements in treating the acute attack; second, compared to placebo over 24 weeks.86 Larger, improvements in long term treatment and pro- longer term studies are required to confirm its and areas of future phlyaxis finally, drug develop- benefit and demonstrate its longterm efficacy and http://pmj.bmj.com/ ment. safety. It is generally considered that ipratropium and In conclusion, the concern over P2 -agonists has cromoglycate are not 'first-line' treatments for led to a shift in treatment prophylaxis towards adult acute asthmatics. Standard teaching has routine use of inhaled steroids. The cost implica- suggested that the former may have a role in those tions of this trend will require further considera- with chronic airflow limitation and the latter has a tion. Moreover, we may be soon approaching a proven place in childhood asthma. However, point where steroid sparing agents may be rou- recent studies do point to positive roles for these tinely used.87 For severe attacks, P2-agonists on September 26, 2021 by guest. Protected drugs in adult asthmatics. should probably be supplemented with ipratrop- In 56 patients with asthma and 47 with chronic ium. The value of assessing each patient's respon- obstructive pulmonary disease (COPD) in a siveness to inhaled medication by monitoring double-blind protocol, 10mg nebulised salbuta- changes in PFR at the bedside is always worth mol was compared to 10 mg nebulised salbutamol emphasizing. plus 0.5 mg nebulised ipratropium bromide.80 In In the future, the major areas of drug develop- asthmatics there was a 31% increase in peak ment will probably focus on manipulation of two expiratory flow rate (PEFR) with salbutamol but a relatively recently described physiological systems 77% increase with salbutamol plus ipratropium. In controlling airways diameter and flow - those of patients with COPD there were small identical platelet activating factor (PAF) and vasoactive increases with both treatments. Although the 95% intestinal polypeptide (VIP). confidence intervals were wide (8-84%) this does PAF is a phospholipid which acts as a potent imply a useful benefit acutely and ipratropium has inflammatory mediator, eliciting a long lasting the additional advantage of a prolonged duration increase in bronchial reactivity in both animals and of action.8' man and increasing the microvascular permeability Sodium cromoglycate may prove beneficial in of guinea-pig airways. Furthermore, it is able to Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from 174 M.J. KENDALL & R.C. HORTON cause an eosinophilic infiltrate into alveoli.88 In oesophagus with an 18 month course of treat- animal studies, the increased bronchial reactivity ment.98 and eosinophilic infiltration can be inhibited by a Non-steroidal anti-inflammatory drugs (NSAID)- PAF antagonist.89 The precise relevance of PAF is induced gastroduodenal damage may also be uncertain however. Although PAF can cause a treated successfully. Ninety five per cent of healing bronchoconstrictor response in asthmatics it does of gastric ulcers occurs with an 8 week treatment not increase bronchial hyper-responsiveness.90 regimen of omeprazole (40mg/day) which is Moreover, it is questionable whether targetting significantly better than ranitidine (53% with drugs specifically against one of many mediators 300 mg/day).96 will prove of significant benefit in the long term. Relapse following treatment with omeprazole VIP is a 28 amino acid peptide which is normally remains a problem. Continued daily long term present in those pulmonary neurones responsible administration is contraindicated since animal for bronchial smooth muscle relaxation.9' In a studies show that chronic dosing may cause gastric recent pathological study of 5 patients with ECL (enterochromaffin like) cell hyperplasia and asthma, none of 468 sections stained positive for carcinoids. An alternative would be to use pulses of intraneuronal, immunoreactive VIP as against treatment for 3 days a week. This has been 92% positivity in 9 controls with other forms of evaluated in 8 patients in remission following chronic lung disease.9 Furthermore, it has been treatment of a duodenal ulcer.99 Omeprazole demonstrated previously that VIP given by aerosol 20 mg/day for 3 days per week was used for 2 does reduce the severity ofbronchial hyper-respon- months at the end ofwhich there was a reduction in siveness by protecting against histamine-induced acid secretion by over 50%. This is encouraging bronchoconstriction.93 Further clinico-patholog- and a trial examining relapse rates with this ical studies are awaited but if this is a primary 'weekend' therapy is needed. Compliance may be phenomenon in asthma as opposed to a secondary expected to be a major problem outside of a effect, treatment based on VIP replacement may structured clinical trial protocol. offer a significant therapeutic advance. Misoprostil, a new prostaglandin analogue, is

now available specifically for protecting against copyright. NSAID-induced gastroduodenal damage.'0° This Gastroenterology consists predominantly of gastric erosions and ulceration. Misoprostil prevents gastric damage Gastroenterological therapeutics has witnessed the but not duodenal lesions. Superficially this appears development ofa number ofnew drugs whose place to be a major advance in protecting against in treatment remains to be assessed. Of particular NSAID-induced mucosal damage. There are a significance is the development of peptide number of concerns however. to both and new First, the of analogues investigate provide important complications gastric http://pmj.bmj.com/ potential treatments for gastrointestinal disease. ulceration are haemorrhage and perforation and no evidence exists showing misoprostil reduces Peptic ulcer disease these. Second, misoprostil has no effect on duodenal lesions and this is important since in at The production of further H2-receptor antagonists least one study the 2 month prevalence with (nizatidine and famotidine) has not added greatly NSAID ofduodenal ulcer was 8% and gastric ulcer to the existing members of this group.94 Further- 6%.'0° At least half of the lesions would therefore more, with the recent launch of omeprazole be unaltered by misoprostil. Thirdly, misoprostil is on September 26, 2021 by guest. Protected (specifically indicated for duodenal and gastric no better than placebo at preventing pain. Finally, ulceration unresponsive to adequate doses of con- up to one halfofpatients are symptomless but these ventional treatment and the Zollinger-Ellison syn- also need to be treated to prevent complications drome) refractory peptic ulcers may now be treated developing. The question of how one identifies this with far greater ease. population is at present unknown. Clearly the Though recommended as a treatment for refrac- precise indications for the drug are far from certain. tory peptic ulceration it is clear that omeprazole In those requiring an NSAID who develop a gastric accelerates healing when compared to H2- ulcer, misoprostil may be appropriate for healing. antagonists in both duodenal and gastric ulcers.95'96 However, whether this will actually prevent serious Moreover, it is of proven efficacy in ulcerative morbidity is as yet unanswered. reflux oesophagitis. In a study of 196 patients, There is currently a renewed interest in antacid omeprazole (40 mg) healed 81% of lesions com- therapy in peptic ulcer disease. Aluminium- pared to 6% in the placebo group.97 However, the containing antacids are not simply acid neutraliz- rate ofrelapse was high: 82% by 6 months, and this ing agents but also have a mucosal protective role was not influenced by smoking status. In addition, via stimulation of prostaglandin synthesis.'02 This omeprazole is able to cause regression of Barrett's enables them to prevent, for example, alcohol Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from CLINICAL PHARMACOLOGY AND THERAPEUTICS 175 induced gastric mucosal damage.103 Moreover, provide an alternative since in 10 patients with they may be useful as a low cost maintenance colitis 4-ASA has proved useful for symptomatic therapy to prevent duodenal ulcer relapse. Maalox control using an open protocol.'08 contains aluminium hydroxide and magnesium Olsalazine consists of two molecules of 5-ASA hydroxide and in 251 patients with healed joined by an azo bond. Double-blind studies have duodenal ulcers was found to reduce relapse to confirmed its efficacy in ulcerative colitis in remis- 23% at one year compared to 37% on placebo."04 sion as compared to sulphasalazine, with relapse This compared favourably to cimetidine 400 mg rates of 19.5% on olsalazine and 12.2% on sul- nocte (25%). This benefit was independent of phasalazine (not significant) over a 6 month smoking status. period.'09 Moreover, as a treatment for the first Figure 1 demonstrates current treatment options attack of distal colitis it is as effective as sul- for peptic ulcer disease. H2-antagonists remain the phasalazine, as shown in 37 patients who tolerated first line therapy, ranitidine being favoured in men olsalazine better than sulphasalazine."0 (gynaecomastia with cimetidine) or in those on Finally, methotrexate may have value as a drugs metabolized by cytochrome P450 oxidase steroid sparing agent in both ulcerative colitis and systems (inhibited by cimetidine). Crohn's disease."' This study was completed in 21 In future, treatment strategies may need to be patients using an open protocol. Their chronic based on a better understanding of the role of inflammatory bowel disease had been refractory to Helicobacter pylori. This organism has aroused other forms of therapy. In addition, cyclosporin A considerable interest and probably plays an impor- is emerging as a potentially safe form of tant part in the tendency for healed ulcers to immunomodulatory treatment though, again, use relapse. In future, the use of bismuth compounds, outside of properly designed trials cannot yet be antibiotics or other drugs capable of eliminating recommended. Continued studies are required. this organism may become part of the regimen for treating peptic ulcers. Motility disturbance Inflammatory bowel disease is a novel which Cisapride prokinetic agent appears copyright. to promote upper gastrointestinal motility. Two The major advances in management of inflamma- recent studies confirm its value in different clinical tory bowel disease have been in new ways of areas. In a study on morphine-induced delay on delivering the active moiety of sulphasalazine - 5 gastric emptying prior to surgery in 40 patients, amino salicyclic acid (5.ASA) - to the colon cisapride 10mg intramuscularly reversed the thereby removing the side effects of the sul- effects of morphine more effectively than metoclo- phonamide component. pramide.'2 It may therefore prove useful in preven- Mesalazine (delayed release 5.ASA) is proven to ting aspiration during general anaesthesia. be superior to sulphasalazine in maintenance treat- In a further study of 26 patients, treatment for 6 http://pmj.bmj.com/ ment of colitis (at doses of 2-4 g/day) when weeks with 10 mg three times a day produced a assessed by sigmoidoscopic appearance of rectal significant increase in gastric emptying and antral mucosa and rectal bleeding.°05 This preparation motility together with normalization of manome- releases 5.ASA into the colon where the pH rises trically measured oesophageal pressures (11 above 7.7. Other studies confirm its equal efficacy patients with diabetic gastroparesis and 15 with in maintenance therapy in ulcerative colitis with chronic idiopathic pseudo-obstruction)."3 fewer side effects."'6"'7 4-ASA is and The of this remains to be clarified in cheaper may place drug on September 26, 2021 by guest. Protected

Nocte dose H2 antagonist Success: Maintenance Antacid Peptic(ulcerPepticulcer: H2H antagonist?antagonist ?'weekend' omeprazole (DU/GU) 8/52 Success: Maintenace Failure: Omeprazole ? Antacid Failure: Try other agents eg: sucralfate pirenzepine Nocte dose H2 antagonist Success: Maintenance ? Antacid NSAID induced H2 antagonist gastroduodenal 8/52 ulceration~~~~~ulceration NFailure: Misoprostil (gastric lesions) Omeprazole Figure 1 Strategy for ulcer disease Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from 176 M.J. KENDALL & R.C. HORTON patients with symptomatic reflux oesophagitis. therapeutic value of these peptides. Furthermore, However, cisapride is proven to increase lower peptides have potent in vivo effects which may be oesophageal sphincter pressure in patients with independently of value in treatment. reflux' 4 and there was a significant improvement in Somatostatin (or rather, its long acting healing versus placebo when combined with analogue, octreotide administered subcutaneously) cimetidine as opposed to cimetidine alone."6 is the only peptide currently available for general use. Its specific indications are for relief of symp- Hepatic encephalopathy toms of carcinoid tumours, VIPomas and glucagonomas. However, its value in secretory'20 Hepatic encephalopathy is thought to represent a and ileostomy diarrhoea'2' is proven and its roles in state where there is an increase in an endogenous acute variceal haemorrhage'22 (reducing portal benzodiazepine. This is demonstrated by both tributary blood flow in animal models of portal increased serum and cerebrospinal fluid (CSF) hypertension) and acute pancreatitis'23 (the first benzodiazepine activity."7 It is postulated that this clinical trial showed promising benefits on limiting endogenous benzodiazepine binds to a specific pancreatic inflammation and abscess formation) allosteric binding site on the GABAA receptor remain to be clarified. Furthermore, animal studies thereby facilitating GABAergic synaptic transmis- show that somatostatin can reduce growth of sion and provoking an encephalopathic state. implanted human colon adenocarcinoma cell Standard treatment of a low protein diet, lactulose lines. 124 and neomycin often fails to alleviate encepha- Cholecystokinin (CCK) antagonists have pro- lopathy and a direct approach via inhibition of the ven benefit in acute pancreatitis'25 and limit the endogenous benzodiazepine ligand has been pro- trophic effects of CCK on pancreatic adenocar- posed. cinoma cells'26 in animal models. Clinical studies In an open, uncontrolled study of the benzo- are available, however, only on motility regulation. diazepine antagonist, flumazenil, in 17 patients The specific CCK antagonist, loxiglumide, signi- with encephalopathy secondary to both acute and ficantly increased gastric emptying and shortened chronic liver failure, a 60% benefit in clinical state colonic transit time.127 It may therefore represent a was observed (12 out of 20 episodes of encepha- useful prokinetic agent. Moreover, it is reported to copyright. lopathy remitting)."8 Moreover, this clinical prevent biliary colic.128 In 6 patients who developed resolution was correlated to improvement in more colic following extracorporeal shock wave litho- objective measures of cerebral functioning, e.g. tripsy for gallstones, all 6 reported pain relief visual evoked potentials. within 20 minutes of taking a single oral dose. Flumazenil may therefore represent the first Metabolic correction of the sodium retaining direct treatment of hepatic encephalopathy. Its state in ascites may be reversible with the vasopres- problems are twofold. First, it has a short duration sin analogue, ornipressin, which in 9 patients with of action. However, a study of an oral preparation decompensated alcoholic cirrhosis and impaired http://pmj.bmj.com/ of flumazenil, 25 mg twice daily for 14 months renal function, improved creatinine clearance and successfully prevented recurrence of the ence- promoted sodium excretion.'29 The hyperdynamic phalopathic state though termination of treatment state was also normalized and therefore in patients during this period saw a rapid return."9 This with decompensated cirrhosis with sympathetic clinical improvement was also parallelled with activation, vasoconstrictor agents may be of use. normalization of evoked potentials. Secondly, Finally, peptides have demonstrated new although it may reverse the encephalopathic state it insights into pathophysiological processes which does not alter the underlying disease process may or may not have therapeutic potential. For on September 26, 2021 by guest. Protected leading to this state. example, VIP appears to be an essential neuro- transmitter at the internal anal sphincter and in Peptides studies in patients with idiopathic chronic con- stipation significant reductions in smooth muscle Peptides are found extensively within the gastro- VIP content are found.'30 Clearly this area will intestinal tract and although they have been shown grow in future years as another route for pharma- to have multiple effects on secretion, cell growth, cological manipulation. blood flow and motility, an integrated understan- ding of their function is lacking. This poor under- standing of their precise physiological importance Non-steroidal anti-inflammatory drugs makes evaluation of their contribution to pathophysiology even more difficult to assess. It has always been appreciated that NSAIDs cause However, information is becoming available on indigestion and sometimes ulceration and bleeding their role in disease processes and this allows for from the upper gastrointestinal (GI) tract. More rational design of trials to investigate the recently reappraisal of their adverse effects'3' par- Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from CLINICAL PHARMACOLOGY AND THERAPEUTICS 177

ticularly on the gastrointestinal tract, on the arteriole. This leads to reduced salt and water kidney, on fluid and electrolyte balance and even reabsorption from the proximal tubule.'32 Other on articular cartilage suggests that prolonged PG-mediated effects include alterations in relative administration to patients with relatively mild blood flow to cortex and medulla, and effects on the disorders which lack a major inflammatory com- actions of ADH.'32 A drug which impairs PG ponent may do more harm than good. This may be formation may therefore be expected to cause salt particularly true of the elderly. and water retention. It follows that NSAIDs will tend to counteract the actions of diuretics and NSAID and the kidney antihypertensive drugs. Considerable interest has been focussed on the NSAIDs may be responsible for a number of question of whether renal PG inhibiting potency different renal disorders but at least four have been will predict renal effects. In particular, does sulin- relatively clearly defined'32 though they are pro- dac, a NSAID with minimal PG inhibiting effects, bably interrelated. have less unwanted effects on the kidney?'33 There is evidence that it is safer and that it is not different. 1. Haemodynamically induced renal dysfunction Certainly care is required to ensure that com- parable doses of sulindac and a comparative drug Prostaglandins probably play a relatively minor are given, that the patients studied are in a state in role in the functioning of the kidneys of normal which they require intra-renal PG production and individuals who are fully hydrated. However, that measurements of PGs truly reflect intra-renal under certain circumstances such as volume deple- PG status. On balance when all factors are con- tion, heart failure and some forms of renal disease, sidered it does seem that sulindac may have less in which renal perfusion may be expected to be effect on renal PGs and therefore on renal function reduced, hormonal mechanisms are stimulated to but the evidence is not overwhelming. provoke vasoconstriction and fluid retention.'32'33 In these situations angiotensin II and nor- 3. Interstitial nephritis adrenaline constrict the renal arteries and aldosterone and antidiuretic hormone work to This is believed to be a relatively infrequent copyright. 'restore' blood volume. Since vasoconstriction may complication of NSAID therapy which is charac- impair renal function these hormones also provoke terized histologically by marked interstitial prostaglandin (PG) production. These, specifically inflammatory changes and minimal change PGE2 and PGI2, dilate some intrarenal arteries and glomerulopathy. It has been suggested that help to maintain renal function. NSAIDs which NSAIDs in some way act as an allergen, interact impair PG production may therefore leave with T lymphocytes and that there is a release of uncompensated intra-renal vasoconstriction lymphokines. The clinical and pathological leading to renal dysfunction. features ofthe disease are explained by the produc- http://pmj.bmj.com/ Based on the above explanation it is possible to tion of pro-inflammatory leukotrienes and by an predict that when renal perfusion is normal or near increase in vascular permeability.'34 normal, NSAIDs will not adversely affect renal Interstitial nephritis has been associated with function. On the other hand elderly patients, those fenoprofen and other propionic acid derivatives in on diuretics, or those with renal vascular disease, particular and seems more likely to occur in older diabetes, coronary artery disease or heart failure patients and those with underlying renal disease.'32 be at risk if are on an NSAID at a time of may they on September 26, 2021 by guest. Protected reduced renal artery perfusion for whatever cause. 4. Analgesic nephropathy If this happens urine output falls, serum urea and creatinine rise. This may be reversed if the NSAID This disorder has been known for many years. is stopped otherwise persisting renal damage may Initially it was recognized that it tended to occur in result. certain parts of the world more than others, it was more common in females, and the cause seemed to 2. Drug interactions andfluid retention be an excessive intake of analgesic mixtures. Fur- ther study suggested than phenacetin was the main The numerous effects of PGs on fluid and electro- cause and therefore this drug was withdrawn in lyte balance are not fully understood. The net result most countries. The role ofphenacetin as a cause of of their actions is to produce sodium, potassium renal failure has been confirmed quite recently in a and fluid loss. The mechanisms involve efferent study from North Carolina.'35 Interestingly, they arterial vasodilatation which reduces intra- also showed that a regular intake of glomerular pressure leading to a reduction in the acetaminophen (paracetamol), which is the major amount of fluid filtered and an increase in volume metabolite of phenacetin may be a cause of renal and decrease in osmotic pressure in the efferent damage.'35 An earlier study did not confirm a Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from 178 M.J. KENDALL & R.C. HORTON relationship between paracetamol intake and For the clinical pharmacologist the problems analgesic nephropathy but did raise the possibility caused by NSAIDs on the GI tract pose a number that it might cause ureteric cancer.'36 Clearly the of interesting questions. These include firstly how effects of paracetamol need to be monitored should this problem be evaluated, secondly what is carefully as the tendency to use simple analgesics the cause of the adverse effects and thirdly having more frequently gains momentum. It is of interest considered the methods available and the results that phenacetin alone has not been shown to obtained can a simple message for the prescriber be produce analgesic nephropathy whilst large doses provided. of aspirin (though not low doses daily aspirin'37) In a review of this subject, Carson and Strom'40 have been shown to be nephrotoxic and other suggest that there are four main methods of NSAIDs are associated with this syndrome. The assessing the adverse effects of NSAIDs on the association with analgesic mixtures perhaps partic- upper gastrointestinal tract. These are animal ularly those containing caffeine is intriguing,'37 in studies, microbleeding studies, gastroscopic assess- part the adverse effects of mixtures may relate to ment and epidemiological studies. Data from drugs the capacity of aspirin to deplete renal glutathione applied topically on to the gastric mucosa need to levels.138 Analgesic nephropathy remains an impor- be interpreted with caution if inferences about tant cause of chronic renal failure.'37 human patient problems are to be drawn. This From the above it is apparent that NSAIDs may method will not be considered further. produce a number of different renal disorders and Microbleeding studies assess bleeding in the gut should be considered as a possible cause in any before and during NSAID therapy by measuring patient on these drugs who shows deteriorating 51Cr labelled red cells in the stools. This has certain renal function or who presents with unexplained aesthetic disadvantages and suffers from the fact renal failure. The problem is to see the relationship that 5'Cr is excreted in the bile and bile flow may be of NSAID intake in perspective. For the nephro- stimulated by aspirin and perhaps by related logist NSAID may appear to be an important cause compounds. Further there is not a clear relation- of kidney disease, the rheumatologist occasionally ship between microbleeding detected in this way sees patients with renal dysfunction and is aware of and clinically relevant gastrointestinal In bleeding. copyright. the problem whereas the general practitioner addition the difficulty of performing these studies knows that there are vast numbers of patients on tends to mean that the number ofpatients involved NSAIDs who benefit from their actions and he or is relatively small and the duration of therapy she has never seen a patient who has developed relatively short. Information on NSAID gastro- renal failure or nephrotic syndrome. The conc- pathy derived from microbleeding studies is lusion must be that all prescribers ofNSAIDs must therefore limited. be aware of the risk of renal complications, know Endoscopic studies may require the patients to which types ofpatient are likely to be at greater risk undergo upper GI endoscopy before starting and be ready to withdraw NSAIDs at the first sign NSAIDs and during treatment. This prospect http://pmj.bmj.com/ of renal involvement. In addition, the known renal makes these investigations seem uninviting to the effects must be seen as sufficiently important as to patient and poses the question how long after argue against the widespread and chronic use of starting therapy and how often need the endoscopy NSAID when they are not really indicated and be repeated. An alternative approach is to compare when simple analgesics may be equally effective. the NSAID intake of those found at endoscopy to have an ulcer with controls who are shown not to Lesions ofthe upper gastrointestinal (GI) tract have an ulcer. This method of assessment will

only on September 26, 2021 by guest. Protected yield relevant information if peptic ulcer disease It is widely accepted that NSAIDs are potentially and NSAID gastropathy are essentially the same damaging to the upper GI tract. This observation disorder (which they are possibly not)4"' and if the has provoked a large number of questions and a control and disease group were comparable except rather smaller number of answers. Hazleman'39 for NSAID intake. summarizes the problem as far as the United Epidemiological methods include post-market- Kingdom is concerned. There are 23 million pre- ing surveillance, case reports or small series, case scriptions for NSAIDs each year which is about control studies, cohort studies and randomized 5% of the total NHS prescriptions. Of these, 12 clinical trials. Studies without adequate controls million are for patients over 60 years of age. They may highlight the occurrence of possible adverse account for 25% of all adverse reaction reports to effects but these observations need to be confirmed the Committee on Safety ofMedicines and many of and quantitated. However, even relatively well them are for gastrointestinal haemorrhage. About controlled studies may give misleading results if 60% report dyspepsia. In England it has been follow-up is incomplete, ifrecall about drug intake estimated that NSAIDs may cause 400 deaths per is defective or if other possible causes of gastro- year. pathy are not carefully documented and included in Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from

CLINICAL PHARMACOLOGY AND THERAPEUTICS 179 the assessment. do in relation to an increasing knowledge on the In 1986 Somerville and colleagues'42 organized a gastrotoxic effects ofNSAIDs. Clearly the risk is so case control study to investigate the possible rela- small that no single doctor will be aware of any tionship between NSAID intake and bleeding from benefits to be derived from reducing the number of peptic ulcers in London, England. The cases were NSAIDs prescribed and his or her patients may patients over the age of 60 with a proven bleeding suffer a great deal more pain. However, the com- gastric or duodenal ulcer. The hospital controls munity will benefit and lives will be saved if (a) were age and sex matched patients without peptic doctors are well aware ofthe problem, (b) NSAIDs ulcers admitted to hospital on the same medical are used to treat patients in whom a definite intake. In addition there was a community based anti-inflammatory action is required, i.e. not if a control group consisting of age and sex matched simple analgesic could be used, and (c) care is taken patients who were next on an alphabetical list ofthe in relation to prescribing for those who may be same general practitioner. This study showed that susceptible which means the ulcer or indigestion those with a bleeding ulcer were 2.7-3.8 times prone and perhaps the older female patient. Unfor- more likely to be taking NSAID than the controls. tunately, good data on the impact of smoking, A subsequent study by Carson and colleagues'43 other drugs, a history of indigestion and on the used a computerized data base on patients in nature of the disease which is being treated, is Michigan and Minnesota to compare the risk ofGI lacking. It also seems difficult to produce evidence bleeding in 47,136 patients exposed to NSAID and on the potential benefits of taking the drug after 44, 634 unexposed patients. Those exposed had a food or with alkali, ofusing enteric coated prepara- 1.5 (95% confidence limit 1.1-1.9) times risk of tions or suppositories. All these manoeuvres might having an upper GI bleed. Ulcer perforations be considered prudent if a NSAID is required by which have been increasing particularly in older someone who is prone to get upper GI symptoms. women have also been linked with NSAID intake. 144145 Lower gastrointestinal tract Recent reviews of these and other studiesl39'146

have considered the data presented and the poten- The effects of NSAIDs on the small intestine have copyright. tially confounding factors. The conclusions which also created some interest recently.'49 These drugs may be drawn are as follows: (1) NSAIDs probably may modify gut permeability allowing the mucosa do cause an increased rate ofupper GI bleeding and to become exposed to bacterial degradation pro- perforation, though not all studies support this ducts and other toxins.'5° This may explain the belief. (2) Serious complications are relatively increased risk ofperforations and strictures and the infrequent and figures such as one bleed from tendency to provoke quiescent inflammatory bowel about 6,500 prescriptions and one perforation for disease into activity.151 every 30- 50,000 prescriptions are quoted. NSAID-induced enteropathy poses a number of http://pmj.bmj.com/ (3) Because such large numbers of NSAIDs are problems. These include firstly trying to define the prescribed their impact on the total problem of GI mechanisms more precisely other than to confirm bleeds and perforations is considerable, particular- the role of reduced prostaglandin formation. ly in elderly females, who are a group more likely to Secondly the incidence of this disorder needs to be be taking these drugs. determined and to make this possible better ways of The second question about NSAID gastropathy making a positive diagnosis need to be found. In is - what is the mechanism and how may this the meantime the prescriber and the gastro- influence treatment? It then becomes important to enterologist must be aware of the possible role of on September 26, 2021 by guest. Protected decide on the rival merits of increasing prostaglan- NSAID in provoking small bowel dysfunction and din activity and/or reducing gastric acidity - a disease. discussion which has considerable commercial implications which have an impact on the funding NSAIDs and articular cartilage of studies and the publication of results in supp- lements. This subject has been reviewed by Rains- The possibility that NSAIDs might have a ford.147 What emerges is that the inhibition of significant impact on cartilage structure and func- prostaglandin cyclo-oxygenase is an important tion has provoked considerable interest in the last consideration, that a large number of biochemical few years.152-154 In view ofthe large volume ofsales, consequences, including an effect on gastric acid the commercial impact of being able to show that secretion, follow from this but that other perhaps some members of this group were chondro- less well known factors such as an inhibitory effect protective whilst others were chondro-destructive on high energy phosphates may play a part. In would be enormous. At the moment this seems a addition a recent report suggests a possible role for possibility rather than a proven fact. Helicobacter pylori.'48 A full understanding of the possible effects of The third question is what should the prescriber drugs on cartilage requires a knowledge of its Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. Downloaded from 180 M.J. KENDALL & R.C. HORTON molecular structure, how it maintains its water increased weight loss and protein-calorie malnutri- content and the role of a variety of enzymes in its tion, clearly adverse effects in cancer patients. For maintenance and destruction. Descriptions ofthese those who may combine a macrobiotic diet with have been writtenl53'M54 and drug companies who more conventional treatment of potential think they have a chondro-protective drug usually significance was the finding that drugs dependent have relatively easy-to-understand literature with on mixed function oxidase systems have a reduced helpful coloured pictures. clearance on such a diet. This may cause potential The non-expert needs to approach the subject toxicity in the patient on drugs dependent on such with a clear head and a little scepticism. It is easy to degradative metabolic pathways. accept that protein degrading enzymes and a Hypnotherapy has recently been evaluated in corresponding group of inhibitors may be preventing duodenal ulcer relapse. Treatment of influenced directly and indirectly by prostaglan- duodenal ulcers is not a therapeutic problem in dins, inflammatory cells and other mediators of most cases but up to 85% of patients may relapse inflammation. However, designing and performing following a course of H2-antagonists. Colgan et al. studies to assess the impact ofdrugs and any active in an open, controlled trial followed 30 patients metabolites at appropriate concentrations in living with endoscopically proven duodenal ulcer.'63 human cartilage is difficult. In spite of the Fifteen were allocated to hypnotherapy (initially 7 difficulties a number of studies have shown that sessions with a home tape and subsquently at 3 some drugs modify the activity of various pro- monthly intervals) and 15 to placebo. Re-endo- teinases,'55-157 cathepsin B, or elastase'58'159 whereas scopy at 12 months found recurrence in all 15 in the others do not. Relating the results ofsuch studies to control group but only 8 (53%) in the hypno- the aetiology of osteoarthritis or coming to con- therapy group. In addition, hypnotherapy has long clusions about the possible helpful effects ofpartic- been regarded as a useful treatment in irritable ular drugs requires caution. Nevertheless, in one bowel syndrome. Recently an 85% success rate has recent study the potentially damaging effect of been reported in 200 patients.64 potent PG inhibition was demonstrated in relation Acupuncture theory depends upon lines of to osteoarthritis of the hip.'60 energy (meridians) which flow through the body. If copyright. The NSAID prescriber could not yet base his or these become 'out of step' they may be normalized her choice of drug on the known effects of the by needle stimulation into precise anatomical loca- compound on cartilage.'6' Nevertheless it is impor- tions which is maintained by manual rotation. An tant that there is an increasing awareness of this alternative is acupressure over the same points. The work and that we should take the result ofresearch evidence ofbenefit in the suppression ofnausea and in this area very seriously. vomiting following general anaesthesia, post- cytotoxic chemotherapy and in pregnancy is strik- ing and an American group have recently shown Alternative medicine benefit in severe alcoholism.'65 Eighty patients were http://pmj.bmj.com/ studied in a placebo-controlled protocol. Forty Over the past decade, as individuals have wished to received acupuncture at specific treatment points take a more active role in their choice of treatment while 40 received acupuncture in non-specific within the overall health care system, there has areas. In the control group there was a greater been a move away from orthodox medicine to desire for alcohol, more drinking episodes and complementary techniques. These therapies are more admissions for detoxification as compared to not largely validated by conventional standards the treated group. on September 26, 2021 by guest. Protected and there have been recent attempts - notably in Homeopathy spans herbal medicine and the France - to subject them to randomized controlled homeopathy based on the 'Simillimum' principle. trials to assess their true efficacy. This is a difficult The latter means using small quantities of drugs area to test scientifically however, since one cannot which in healthy people induce the symptoms simply exclude the psychotherapeutic benefit of an which they resolve in ill patients. Feverfew holistic approach to the patient and so interpre- represents a herbal preparation advocated for the tation has to be made with caution. The major treatment of migraine. The scientific justification areas of interest in alternaive medicine are diet, for this is that feverfew can inhibit serotonin release hypnotherapy, acupuncture and homeopathy. from plateletsl66 and serotonin is thought to be Dietary therapy as the primary means ofcontrol- important in the aetiology of migraine. Seventy ling disease, for example cancer, is advocated to the two patients were included in a randomized cross- exclusion of all other therapy in the macrobiotic over study offeverfew versus placebo in preventing diet. This is a high carbohydrate, low fat diet with attacks and reducing symptoms ofmigraine. There no animal food sources. One study'62 has found a was a significant reduction in the number ofattacks beneficial effect, as would be predicted, on reducing (424 vs 559) and vomiting (42 events vs 78 events). plasma lipids but there was also evidence of No side effects were documented.'67 Postgrad Med J: first published as 10.1136/pgmj.66.773.166 on 1 March 1990. 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The philosophical tenets ofmodern therapeutics of patients with improved pain and sleep (assessed have been seriously challenged by a study from a by visual analogue scores) when compared to French group showing that human basophil de- placebo. granulation occurred using an IgE antiserum at a Ofany treatment we may reasonably ask, does it dilution where there was calculated to be no work and is it safe? While it is true that apart from possibility of any IgE remaining in the solution.'68 the macrobiotic diet, no adverse effects have been They proposed that the water lattice itselfmay hold found from other treatments one must be aware of a 'memory' of the IgE which is chemically active. the possibility. Examples are comfrey tea as a cause Though contradicted by a supposed independent of hepatic veno-occlusive disease'72 and the group of reviewers the paper stands as a landmark Department of Health warning on dietary supp- linking orthodox medical research to complemen- lements containing germanium. tary medical techniques. The therapeutic potential, The benefits of most forms of alternative however, remains to be proven. Mayaux et al. medicine in the setting of a scientific trial seem found no significant effects of a specifically unconvincing apart possibly from acupuncture. indicated homeopathic preparation - opium and Other work remains to be confirmed. The benefit raphanus - in the time to recovery of bowel achieved may be as much from the attentive, function in post-operative ileus.'69 Furthermore, holistic approach ofthe physician as ofthe medica- although a statistically significant result was tion per se. Nevertheless, only an open, unpre- obtained in a study of a preparation for treatment judiced mind will allow the true place of these of influenza-like symptoms the result was hardly therapies to be accurately assessed. Therefore the clinically relevant. Of237 patients on treatment, 39 recent trend towards scientific assessment of what (17.1%) recovered within a 48 hour period as seems like less scientific methods of treatment is to against 24 of 241 (10.3%) in the placebo group.'70 be welcomed. It is of interest to note the relative Definition of influenza-like symptoms included lack of papers in this area. pyrexia, headache, stiffness, arthralgia and shivers. However, Rhus toxicodendron (leaves from poison at a oak) dilution of 10-12 was assessed in a Acknowledgement copyright. randomized double-blind protocol in 30 patients with fibrositis.'71 There was a significant improve- We thank Mrs J. Bourne for her skill and patience in ment in mean number oftender points and number typing the manuscript.

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