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The clinical pharmacology of angiotensin converting enzyme inhibitors in chronic heart failure
Pharmac. Ther.Vol. 53, pp. 187-197, 1992 Printed in Great Britain.All rights reserved
0163-7258/92$15.00 © 1992PergamonPress Ltd
Associate Editor: D. G. McDEV1TT
THE CLINICAL PHARMACOLOGY OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN CHRONIC HEART FAILURE ALLAN D. STRUTHERS Department of Pharmacology and Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, DD1 9SY, Scotland, U.K. A~traet--ACE inhibitors (ACEIs) have now been shown to improve symptoms and survival in patients with mild, moderate and severe chronic heart failure. Their mechanism of action is thought to be a combination of RAAS suppression and augmentation of bradykinin and prostaglandins. Although ACE inhibitors improve hemodynamics post myocardial infarction, we do not yet have consistent data on their effects on symptoms or survival in these particular patients. One other potential benefit is their effects on reperfusion injury and free radicals. As yet only minor differences have been found to exist between different ACEIs but increasing attention is now being focussed in this direction.
CONTENTS 1. Introduction 2. Pharmacological Properties of Different ACEIs 3. Mechanism of Action 4. Hemodynamic and Symptomatic Effects in CHF 5. Effects on Mortality in CHF 6. Post Myocardial Infarction Studies 7. Reperfusion injury and free radicals 8. Myocardial ischemia 9. Comparisons between ACEIs in CHF 10. Adverse Effects of ACEIs References
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1. I N T R O D U C T I O N A C E inhibitors (ACEIs) have revolutionized the treatment of chronic heart failure (CHF). In particular, they improve the appallingly high mortality in C H F . We currently have eight A C E I s to choose from in the U.K. although a large number of new ACEIs will be marketed later in the 1990s. They all bind to a zinc ion in the ACE enzyme by way of either a sulphydryl, a carboxyl or a phosphoryl group in their structure. With each A C E I which is developed, the studies performed generally follow a logical sequence from in vitro studies to normal volunteer studies to studies of hypertensive patients and then to C H F patients. For this reason, ACEIs are licensed in the U.K. first for hypertension and only later for C H F . Even within the C H F patient group, initial studies focus on the effects of single doses on hemodynamics followed by chronic dosing studies of hemodynamics and then chronic dosing studies of exercise tolerance.
2. P H A R M A C O L O G I C A L
P R O P E R T I E S OF D I F F E R E N T A C E I s
A comparison of different A C E I s is shown in Table 1. Captopril was the first orally active ACEI. It contains a sulphydryl group and its affinity for plasma A C E is relatively low (IDs0 15 nmol/L). Bioavailability is 60-70% but this is decreased by 187
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Captopril
TABLE 1. Comparison of the Pharmacological Properties of Different ACEIs Affinity of Method of ACE enzyme active substances Duration of excretion of binding group Pro-drug for ACE action active substance Sulphydryl No Low Short Renal
Enalapril
Carboxyl
Yes
Moderate
Long
Renal
Lisinopril
Carboxyl
No
Moderate
Long
Renal
Perindopril
Carboxyl
Yes
High
Long
Renal
Ramipril
Carboxyl
Yes
High
Long
Renal
Quinapril
Carboxyl
Yes
High
Long
Renal and Gut
Cilazapril
Carboxyl
Yes
High
Long
Renal
Fosinopril
Phosphoryl
Yes
Long
Hepatic and Renal
--
25-50% when captopril is co-administered with food (Brogden et al., 1988; Muller et al., 1985). However, plasma drug concentrations do not correlate well with hemodynamic or neurohormonal responses so that food co-administration does not appear to alter the antihypertensive effect of captopril. The majority of the drug is excreted unchanged in the urine by tubular secretion (94% in urine by 6 hr). CHF does not affect the pharmacokinetics of captopril although interindividual variability is greater than in normal man. Enalapril was the next ACEI available. It is a carboxyi containing ACEI. About 60% of enalapril is absorbed reaching peak concentrations at l hr and this absorption is unaffected by food. Enalapril undergoes deesterification in the liver to form the active substance, enalaprilat which reaches peak concentration in 3-4 hr (Todd and Goa, 1989). Overall, the absolute bioavailability of enalapril as enalaprilat is 40%. The affinity of enalaprilat for human plasma ACE is greater than for captoprii (IDs0 1 nmol/L). Enalaprilat is 50% protein bound. Both enalapril and enalaprilat are eliminated purely by the kidney so that lower doses should be used in patients with renal impairment. Lisinopril is the lysine derivative of enalaprilat and it is also a carboxyl containing ACEI. Lisinopril has a low bioavailability at 25-50% and peak drug levels do not occur until 6hr, (Lancaster and Todd, 1988). Absorption is unaffected by food and the absorbed drug is excreted unchanged in urine. Lower doses are required in renal impairment and even in CHF patients there is a correlation between creatinine clearance and lisinopril clearance. Perindopril is a carboxyl group containing pro-drug ester of its active metabolite, perindoprilat. The bioavailability of perindopril varies (65-95%). Perindopril reaches its peak concentration at 1 hr and perindoprilat at 3-4 hr (Todd and Fitton, 1991). Only 17-20% of the oral dose becomes perindoprilat as extensive metabolism to other inactive metabolites occurs. Perindoprilat has high affinity for human plasma ACE (IDs0 0.40 nmol/L). Perindoprilat is excreted mainly by the kidneys so that dosage reduction is required in renal impairment. In CHF, absorption of perindopril, formation of perindoprilat, and clearance of perindoprilat are reduced. Ramipril is also a carboxyl containing pro-drug which is activated to ramiprilat (Todd and Benfield, 1990). Ramiprilat has high affinity for human plasma ACE (IDs0 0.08 nmol/L). Food has no influence on drug absorption. Ramipril reaches its peak concentration at 1 hr and ramiprilat at 3 hr. Ramiprilat is 56% protein bound and is excreted by the kidneys in the form of either ramiprilat, its glucuronide derivative or its diketo piperazine derivative. Clearance of ramiprilat is reduced in renal dysfunction but not in hepatic impairment although there is a delay in reaching peak level in hepatic impairment. Quinapril is also a carboxyl containing drug which is hydrolyzed to its more active form, quinaprilat. However, in contrast to other pro-drugs, both quinapril and quinaprilat are active
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ACEIs. Bioavailability is 60%, and peak concentrations of quinapril and quinaprilat occur at 1 and 2 hr post-dose respectively (Wadworth and Brogden, 1991). Both quinapril and quinaprilat are 97% protein bound. Quinaprilat has very high affinity for human plasma ACE (IDs0 0.07 nmol/L) with a much lower figure for quinapril itself (IDs0 55 nmol/L). Excretion is via urine (40%) and faeces (60%) the latter being a combination of unabsorbed drug and biliary excretion. Cilazapril is another carboxyl containing pro-drug which is hydrolyzed to cilazaprilat. Peak concentrations of cilazapril and cilazaprilat occur at 1 and 3 hr after administration. Bioavailability is estimated as 57-77% (Deget and Brogden, 1991). Cilazaprilat is excreted almost exclusively by the kidneys so that a dose reduction is required in patients with renal dysfunction. Fosinopril is a phosphoryl group containing pro-drug which is activated to fosinoprilat which has a long terminal half life. Fosinoprilat is unique among ACEIs in undergoing both renal and hepatic elimination so that dosage adjustment is unnecessary even in moderate renal dysfunction (e.g. creatinine clearance 40 mL/min). 3. MECHANISM OF ACTION The principal effect of ACEIs is to block the conversion of angiotensin I (AI) to angiotensin II (AII). Initially AI and All were thought to be circulating hormones and the effect of ACEIs was thought to be due entirely to suppression of circulating All. This is now recognized to be a gross oversimplification which overlooks 3 other major actions of ACEIs. Firstly, the whole renin-angiotensin system (RAS) is patently more than a system of circulating hormones and many components of the RAS are synthesized locally and exert effects locally within many different tissues, e.g. blood vessel walls, kidneys, adrenals, brain and even the gonads (Dzau, 1988; Samani, 1991). Thus plasma concentrations of AI and AII probably represent spillover from their tissue sites of production (Campbell, 1987). Indeed Schalekamp et al. (1989) have demonstrated that 40-90% of venous AI in many vascular beds is generated by regional production from angiotensin. It is also worth noting that AII is produced in the heart in abundance, especially the right atrium (Lindpainter et al., 1987) and that ACE activity is also present in the right atrium and on the surface of cardiac valves (Johnston et al., 1989). ACEIs are known from in vitro studies to inhibit tissue ACE activity as well as serum ACE. It is now thought that most of the pharmacodynamic and therapeutic effects of ACEIs are due to inhibition of tissue ACE rather than serum ACE. This may explain for example why the long-term antihypertensive effects of ACEIs are poorly related in magnitude to the pretreatment measurement of plasma renin activity (PRA) in the blood. Secondly, ACEI may act on hormonal systems other than the RAS such as bradykinin and prostaglandins. ACE is identical in structure to the enzyme, kininase II, which normally degrades endogenous bradykinin, a potent vasodilator. Thus ACEIs may increase endogenous levels of bradykinin. The data suggesting this is not entirely consistent but this may simply reflect difficulties in assaying bradykinin levels (Van Leeuwen et al., 1983). What is however fairly consistent is that most ACEIs potentiate the vasodepressor effect of exogenous bradykinin in animal models. The other endogenous hormone system which may be increased by ACEIs is the prostaglandins but here again the data are inconsistent which may be due to assay problems. Another mechanism of action which ought to be borne in mind relates to the now welldocumented interaction between All and the sympathetic nervous system (Zimmerman, 1978). AII increases the prejunctional release of noradrenaline in response to sympathetic nerve stimulation (Seidelin et al., 1991). As a result, ACEIs impair sympathetically mediated vasoconstriction (Clough et al., 1982) and even more importantly reduce mycocardial noradrenaline overflow during exercise in CHF (Mulligan et al., 1989). A clinically important byproduct of this is that reducing noradrenaline release prevents fl-receptor downregulation. This explains the mechanism behind experimental data that captopril increases the number and the responsiveness of postsynaptic cardiac fl-receptors (Maisel et al., 1989). Thus the beneficial clinical effects of ACEIs may be due not only to reducing preload and afterload but also to favourably modifying cardiac sympathetic tone.
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A.D. STRUTHERS 4. HEMODYNAMIC AND SYMPTOMATIC EFFECTS IN CHF
Captopril has been extensively investigated in CHF. Its acute hemodynamic effects are a reduction in right atrial pressure, pulmonary capillary wedge pressure and mean arterial pressure with accompanying increases in cardiac index (Romankiewicz et al., 1983). These acute hemodynamic effects are maintained during long-term administration. During chronic therapy, there are also symptomatic improvements in dyspnoea, fatigue and exercise capacity (Captopril Multicenter, Research Group, 1985; Cleland et al., 1984). In various comparisons, captopril was less effective than a diuretic as monotherapy in mild CHF (Richardson et al., 1987), was equally effective as enalapril in severe CHF (Packer et al., 1986) and was more effective than digoxin in moderate CHF (Captopril-Digoxin Multicenter Research Group, 1988). There are two comparisons between captopril and lisinopril with one study finding lisinopril better and the other finding no difference (Powers et al., 1987; Lie et al., 1991). Enalapril produces the same favourable hemodynamic response during long-term therapy in CHF i.e. reductions in right atrial pressure, pulmonary capillary wedge pressure and mean blood pressure with increased cardiac index. These effects are also translated into beneficial effects on dyspnoea, tiredness and exercise duration (Enalapril CHF Investigators, 1987). What is particularly noteworthy about enalapril is that there are three large conclusive and encouraging mortality studies with enalapril in CHF (see mortality studies section). No other ACEI has been examined in such detail with regard to mortality. Although it is likely, it cannot be assumed that other ACEIs will be as beneficial on mortality as enalapril. Lisinopril has also been shown in CHF to acutely reduce pulmonary capillary wedge pressure, mean arterial pressure and increase cardiac index (Dickstein et al., 1986). During chronic therapy, lisinopril improves dyspnoea, fatigue, exercise duration and LV ejection fraction (Chalmers et al., 1987). Cilazapril produces the same acute hemodynamic effects in CHF as all the other ACEIs described above (Fong et al., 1987). These effects are sustained during chronic therapy and are accompanied by improved symptomatology and improved exercise tolerance (Drexler et al., 1989). This last paper makes the important observation that exercise tolerance improves gradually over the first 6-8 weeks of ACEI therapy and that this improvement in exercise tolerance is closely related to a slowly developing increase in skeletal muscle blood flow. It may be that this slow effect on muscle blood flow is due to accumulating effects of the ACEI on the tissue RAS and/or to effects on bradykinin and EDRF. An acute reduction in right atrial pressure, pulmonary capillary pressure and mean arterial pressure along with an increase in cardiac index is also seen with perindopril (Thuillez et al., 1990). Perindopril also improves symptomatology and exercise duration after 3 months of therapy in CHF (Bounhoure et al., 1989). Ramipril produced the same acute hemodynamic response as all other ACEIs described above (de Graeff et al., 1989). These effects persist during chronic therapy and are accompanied by improved symptomatology and exercise duration. An acute dose of quinapril reduces pulmonary capillary wedge pressure and mean arterial pressure and increases cardiac index in CHF (Sedman and Posvar, 1989). Chronic therapy with quinapril also improves symptomatology and exercise duration in CHF (Riegger, 1990). In one trial, quinapril was superior to digoxin in terms of improving exercise duration (Kromer et al., 1990). 5. EFFECTS ON MORTALITY IN CHF Large trials are now being undertaken with ACE inhibitors. The first such study was conducted by the CONSENSUS Trial Study Group (1987) where patients with severe CHF (grade IV) were randomized to placebo or enalapril. This study was terminated prematurely because enalapril produced a 40% reduction in mortality at 6 months, a 31% reduction at 1 year and a 27% reduction at the end of the study. Interestingly, the benefit was entirely due to a reduction in the progression of heart failure and enalapril had no effect on the rate of sudden unexpected death. Around the same time, there was published the results of a similar trial using non-ACEI vasodilators (Cohn et al., 1986). In this study, prazosin was found to produce no mortality benefit
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whereas a combination of hydralazine and isosorbide dinitrate did produce a sizeable reduction in mortality. This appeared to suggest that reducing afterload and preload could produce a mortality benefit, irrespective of whether the vasodilator was an ACEI or hydralazine/isosorbide although this does not explain why prazosin was ineffective. A VHeFT-2 study was therefore launched to compare enalapril and hydralazine/isosorbide and this reported in 1991 (Cohn et al., 1991). Here enalapril was superior to hydralazine/isosorbide in terms of mortality. The one and two-year mortalities were 8% and 18% on enalapril as compared to 13% and 25% on hydralazine/isosorbide. Curiously enough, hydralazine/isosorbide improved symptoms and hemodynamics more than did enalapril in that oxygen consumption on exercise and LV ejection fraction was better on hydralazine/nitrate. These latter parameters are difficult however to interpret since the two treatment groups had different mortality rates. This VHeFT-2 study suggests that vasodilator treatment does indeed reduce mortality but that an additional mortality benefit is achieved from the neuroendocrine suppression which occurred with enalapril but not with hydralazine/isosorbide. The mechanism for this additional effect remains unknown but one possibility relates to recent data showing that AII inhibits and ACEIs encourage the uptake and disposal of noradrenaline in the myocardium (M. A. Arnott and A. D. Struthers, submitted for publication). This mechanism may be important since mortality in CHF is closely related to the plasma level of noradrenaline. Since ACEIs were shown by the CONSENSUS study to reduce mortality in severe CHF, the question naturally arose whether a similar benefit would be seen in patients with mild to moderate CHF. Such a large study has just been published (The SOLVD Investigators, 1991). Here symptomatic CHF patients with a cardiac ejection fraction of < 35% were randomized to enalapril or placebo. Overall death was significantly reduced by enalapril and again like the CONSENSUS I trial, the reduction was in the progression of the disease and not on the rate of sudden unexpected death. What was even more striking was that enalapril reduced the hospitalization rate. It was estimated from this study that if enalapril was given to 1000 CHF patients for 3 years, this would save 50 premature deaths and 350 hospitalizations. This striking ability of ACEIs to reduce the progression of CHF has led to the hope that ACEI could retard the onset of symptomatic CHF if ACEIs were commenced very early in the disease before symptoms had occurred. There is an ongoing study (SOLVD Prevention study, 1991) which is designed to answer that very question: its preliminary results were announced at the American Heart Association meeting on 11 November 1991". Enalapril produced a 37% reduction in the development of overt CHF, a 36% reduction in CHF hospitalizations, a 21% reduction in hospitalizations for myocardial infarction and a 17% reduction in hospitalizations for angina. Enalapril reduced total mortality only by 8% and cardiovascular mortality by 14% but these effects on mortality were not significant. It is also worth noting that the survival curves did not start to diverge until after 18 months of treatment i.e. at a time when CHF symptoms were developing anyway.
6. POST MYOCARDIAL INFARCTION STUDIES There is a great interest in the use of ACEIs in the post myocardial infarction (MI) situation. There are 3 major reasons for this being a crucial area. Firstly, the majority of CHF patients acquire their disease by way of previous myocardial infarctions so that in a sense, the post MI period is the earliest time when intervention with an ACEI could halt the initiation of the heart failure process. Secondly, there are convincing animal studies to show that captopril reduces ventricular remodelling after an established MI (Pfeffer et al., 1985). Ventricular remodelling refers to the process whereby there is stretching and thinning of the infarcted segment which is then followed by a global dilatation and hypertrophy of the non-infarcted left ventricle. This process occurs in only about half of transmural infarctions and is progressive in about half of this group (Ginzton *SOLVD PREVENTIONTRIALINVESTIGATORS(1991) Principal results, American Heart Association Meeting, Anaheim, November 10-14, 1991.
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et al., 1989). Great interest was therefore generated when Pfeffer et al. (1985) showed beneficial
effects with regard to remodelling in an experimental model of MI in rats and this has led to several clinical studies to address this point (see below). The third reason for interest in the post-MI situation relates to reperfusion injury. When a coronary thrombosis occurs there can be two outcomes. One is (thrombolytic induced) reperfusion which prevents myocardial necrosis but which carries the separate hazard of reperfusion injury. The other outcome is true myocardial necrosis with subsequent remodelling as described above. Interest in reperfusion injury was sparked by several animal studies suggesting that ACEI attenuated this process (Li and Chen, 1987; Westlin and Mullane, 1988). The mechanism of this beneficial effect is uncertain. One popular but unproven theory is that it is due to the scavenging of toxic oxygen free radicals (see below) which are released during reperfusion and that it is the sulphydryl group contained in captopril (and zofenopril) which is instrumental in this process (Przyklenk and Kloner, 1989). Others have suggested that it is due to the production of prostaglandins or bradykinin. Studies of ACEI in post-MI patients can therefore be divided into 3 groups according to the different endpoints chosen to study. Firstly, there are studies examining the effect of ACEIs on hemodynamics. All studies are consistent that captopril reduces ventricular remodelling in that it improves cardiac stroke volume and reduces end diastolic dimensions (Pfeffer et al., 1988; Sharpe et al., 1991). However, there is often in CHF a poor correlation between hemodynamic changes and symptoms so that studies of ACEIs post MI are now focussing on patient symptomatology and survival. Pfeffer et al. (1988) reported in their study that exercise tolerance was better in the captopril-treated group than in the placebo-treated group although pretreatment exercise tests are not available to ensure comparability of patient groups. In a separate study in Glasgow, captopril did not improve exercise tolerance post MI (Oldroyd et al., 1991). The third and most important parameter, however, is mortality. We are currently lacking consistent data in this regard. A recent study was halted prematurely as there appeared to be no beneficial effect on mortality in this study (Swedberg for the CONSENSUS II Trial Study Group, 1991). It is worth noting that in this study, intravenous enalaprilat was administered to patients on admission to the coronary care unit and this may represent premature intervention. On the other hand, in the recent SAVE study, captopril produced a 17% reduction in mortality. There are more trials underway which will help us to answer this crucial question, namely the GISSI 3 study using lisinopril and the ISIS-4 study using captopril.
7. REPERFUSION INJURY AND FREE RADICALS It is worth briefly discussing the issue of reperfusion injury and free radicals (McMurray and Chopra, 1991). There is evidence that reperfusion itself can cause cell injury or death which is distinct from the cellular damage induced by the preceding period of ischemia. The best understood type of reperfusion injury is 'stunning' or reversible contractile dysfunction which has been recognized in both animals and man (Bolli et al., 1989; Patel et al., 1988). The pathogenesis of this injury process clearly involves free radicals (FR). In vitro studies suggest that SH containing ACEIs such as captopril and zofenopril are able to scavenge certain FRs such as the hydroxyl radical (OH'), hypochlorous acid (HOC1) and hydrogen peroxide (H202), but original data to suggest an effect of captopril on the superoxide anion radical (O~-) now seems doubtful (McMurray and Chopra, 1991). In vivo animal experiments raise the possibility that the improved recovery of contractility after an ACEI is at least in part due to increased prostaglandins as well as to the sulphydryl group. A prostaglandin effect is likely to be shared, albeit to different extents, by most ACEIs and this may explain why Li and Chen (1987) found that enalapril ameliorated reperfusion induced myocardial dysfunction in isolated rat hearts. One other study raises the possibility that bradykinin is involved. Scholkens et al. (1988) found that ramipril (with no sulphydryl group) was beneficial in reperfusion injury but that this effect could be abolished by a bradykinin antagonist. We therefore await clinical studies to assess the importance of the sulphydryl group on FR injury in patients although the problems of designing and executing such a trial are formidable.
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8. MYOCARDIAL ISCHEMIA One other clinical situation worthy of brief comment is myocardial ischemia. ACEIs reduce coronary vascular tone and they also reduce coronary perfusion pressure. In subendocardial regions, an increase in myocardial perfusion is liable to occur as end diastolic pressure falls within the LV. Such improved perfusion will be most prominent when the coronary arteries are unobstructed as in dilated cardiomyopathy (Foult et al., 1988). However, the reduced coronary perfusion pressure can exacerbate myocardial ischemia where there is epicardial coronary artery disease (Cleland et al., 1991). Overall, most studies have found no effect of ACEIs in angina pectoris. In the occasional study, a benefit has been found and conversely, occasionally a deleterious effect was found (Cleland et al., 1991). 9. COMPARISONS BETWEEN ACEIs IN CHF There are few data comparing different ACEIs in CHF. In the first such comparison, Packer et al. (1986) compared high doses of captopril (150mg/day) and enalapril (40mg/day) in
severe CHF. There was no difference in the symptomatic response to therapy but enalapril-treated patients developed more prolonged hypotension and more renal dysfunction. Renal dysfunction was particularly prominent in diabetic patients. Giles et al. (1989) recently compared lisinopril and captopril in CHF and found that the LV ejection fraction improved more on lisinopril and that in a subgroup of patients with renal impairment initially, lisinopril improved exercise duration significantly more than captopril did. However, lisinopril also caused more renal dysfunction than did captopril. In contrast, a recent European comparison between captopril and lisinopril found them equally effective at improving exercise tolerance (Lie et al., 1991). Data from the CSM yellow card adverse event monitoring system agrees with the above studies that captopril produces less renal dysfunction than the longer acting ACEIs. However, the Giles study raises the possibility that the better renal effect of captopril may be balanced by less of a symptomatic improvement. Indeed, it could be hypothesized that a short acting ACEI allows restoration of some AII at the end of each dose interval and that this helps maintain the G F R but that it also increases cardiac afterload and hence decreases exercise tolerance, albeit temporarily. This highlights an as yet unresolved controversy in ACEIs over whether long-acting or short-acting ACEIs are of more benefit to CHF patients. Very recently, lisinopril has been compared in CHF with enalapril and with digoxin (Lie et al., 1991). The result of both studies are unfortunate in that the baseline exercise tolerances were unequal in both studies. In both studies, lisinopril produced a non-significant trend towards a better improvement in exercise tolerance than either enalapril or digoxin but this apparent effect is unconvincing because of the different starting baselines. In terms of a hypotensive response to ACEIs, a recent comparative study in CHF suggests that perindopril is unique in that it causes no greater first dose fall in BP than placebo (McFadyen et al., 1991). In terms of mortality, there are no good comparative studies between ACEIs. A recent report by Pouleur et al. (1991) is worthy of comment. This was a retrospective analysis of baseline therapy in the Xamoterol mortality trial which showed that patients receiving baseline therapy with captopril had a significantly higher mortality than those receiving enalapril. The authors claim that this was due to captopril being given only twice daily which allowed some RAAS recovery between doses. These results are of interest but should be viewed with caution until these results are confirmed by other data. 10. ADVERSE EFFECTS OF ACEIs For a detailed discussion of this topic, the reader is referred to Ferner (1990). Side effects fall into 2 broad categories, those due to the sulphydryl group and those which occur with all ACEIs (often called the class effect). Side effects due to the former are similar to those found with penicillamine and are skin rash, taste disturbance, agranulocytosis and rarely drug-
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induced proteinuria leading on very rarely to membranous glomerulonephritis and the nephrotic syndrome. Side effects common to all ACEIs are first-dose hypotension, renal dysfunction, cough, angioneurotic edema, headache, dizziness, nausea, diarrhoea and fatigue. First-dose hypotension is more common in hyponatremic, overdiuresed patients with elevated levels of plasma renin/AII and a contracted extracellular fluid volume (Hodsman et al. 1983; J. G. Motwani, M. Fenwick and A. D. Struthers, submitted for publication). Curiously enough, the blood pressure often collapses suddenly and there is accompanying bradycardia which suggests involvement of parasympathetic stimulation. As AII as generally vagolytic, this is plausible. In the majority of C H F cases, systemic BP falls by < 20 mmHg after an ACEI. This more moderate BP fall is not dose related in magnitude and does not produce dizziness or renal dysfunction because ACEIs cause a redistribution of blood flow favouring cerebral and renal blood flow (McLay et al., 1992; Paulson et al., 1984). Renal function after an ACEI is a complex topic as there can be very different renal responses in different patients. Firstly, captopril can very rarely induce proteinuria in patients who had normal renal function originally. Secondly, ACEIs can cause a measurable deterioration in renal function. This is particularly common in bilateral renal artery stenosis but can occur more rarely in unilateral renal artery stenosis and in CHF. In CHF, the predictors are excessive BP reduction, diabetes mellitus and a G F R of < 4 5 m l / m i n before therapy (Packer, 1989). If the original G F R lies in the range 45-80 ml/min, then captopril reduces G F R by an average of 7 ml/min in C H F (J. G. Motwani, M. Fenwick, A. D. Struthers, submitted for publication). Interestingly, Motwani et al. (1992) have shown that ultra low dose captopril (1 mR) doubles the natriuretic effect of frusemide in C H F while standard doses of captopril (25 mR) reduce natriuresis. Thirdly, renal function can improve with ACEIs in certain patients especially patients with early diabetic nephropathy where ACEIs can retard the progression of the microalbuminuria and the renal dysfunction. Cough is more troublesome in hypertensive than in C H F patients. Bradykinin and prostaglandins are believed to sensitise pulmonary sensory C fibres such that ACEI-induced cough can sometimes be suppressed by sulindac (Nicholas and Gilchrist, 1987). Angioedema is said to be induced by ACEIs in about 1 in 1000 patients (Slater et al., 1988). A plausible mechanism is that it is due to build up of tissue bradykinin. One report suggests that there may be particular problems with ACEIs when they are given to the very elderly C H F patient (O'Neill et al., 1988). Particular problems were renal dysfunction and mesenteric ischemia, presumably due to the redistribution of blood ftow in an already atheromatous arterial tree.
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CLELAND,J. G. F., FINDLAY,I. N., MCLENACHAN,J., HENDERSON,E. and DARGIE,H. J. (1991). The effect of captopril, an ACEI, in patients with angina pcctoris and heart failure. J. Am. Coll. Cardiol. 17: 733-739. CLOUGH,D. P., COLEIS,M. G., CONWAY,J., HATTON,R. and KEDDIE,J. R. 0982). Interaction of angiotensin converting enzyme inhibitors with the function of the sympathetic nervous system. Am. J. Cardiol. 49: 1410-1414. COHN, J. N., ARCHIBALD,D. G., ZIESCHE,S., FRANCIOSA,J. A., HARSTON,W. E., TRISTANI,F. E., DUNKMAN, W. B., JACOBS,W., FRANCIS,G. S., FLOUR, K. H., GOKLMAN,S., COBB, F. R., SHAH,P. M., SAUNDERS,R., FLETCHER,R. D., LOEB,H. S., HUGHES,V. C. and BAKER,B. (1986). Effect of vasodilator therapy on mortality in chronic congestive heart failure. New Engl. J. Med. 314: 1547-1552. COHN,J. N., JOHNSON,G., ZIESCHE,S., COBB,F., FRANCIS,G., TRISTAN1T,F., SMITH,R., DUNKMAN,W. B., LOEB, H. and WONG, M. (1991). A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. New Engl. J. Med. 325: 303-310. CONSENSUSTRIALSTUDYGROUP (1987). Effects of enalapril on mortality in severe congestive heart failure: results of CONSENSUS. New Engl. J. Med. 316: 1429-1435. DEGET, F. and BROGDEN, R. (1991). Cilazapril. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in cardiovascular disease. Drugs 41: 799-820. DE GRAEFE,P. A., KINGMA,J. H., VIERSMA,J. W., WESSLING,H. and LIE, K. I. (1989). Acute and chronic effects of ramipril and captopril in CHF. Int. J. Cardiol. 23: 59-67. DICKSTEIN,K., AARSEAND,T., WOIE, L., ABRAHAMSEN,A. M., FYHRQUIST,F., CUMMINGS,S., GOMEX, H. J., HAGAN, E. and KRISTIANSON,K. (1986). Acute haemodynamic and hormonal effects of lisinopril in CHF. Am. Heart J. 112: 121-129. DREXLER,H., BANHARDT,U., MEINERTZ,T., WOLLSCHLAGER,H., LEHMANN,M. and JUST, H. (1989). Contrasting peripheral short term and long term effects of converting enzyme inhibition in patients with CHF: a double blind, placebo controlled trial. Circulation 79: 491-502. DZAU, V. J. (1988). Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Circulation 77(6 Pt 2): I4-I13. ENALAPRIL,C. H. F. INVESTIGATORS(1987). Long term effects of enalapril in patients with congestive heart failure: a multicenter, placebo controlled trial. Heart Failure 3: 102-107. FERNER, R. E. (1990). Adverse effects of ACEIs. Adverse Drug React. Bull. 141: 528-531. FONG, A., DUNTON,A., LE JEMTEL,T., RIBNER, H., MASSIN, E., MASON, D. and LIMACHER,M. (1987). Acute haemodynamic response to oral cilazapril in CHF. Clin. Pharmac. Ther. 41: 197. FOULT, J. M., TAVALORA,O., ANTONY,I. and NITENBERG,A. (1988). Direct myocardial and coronary effects of enalaprilat in patients with direct cardiomyopathy: assessment by a bilateral coronary infusion technique. Circulation 77: 337-344. GLEES, T. D., KATZ, R., SULLIVAN,J. M., WOLFSON, P., HAUGEANDM., KIRLIN, P., POWERS, E., RICH, S., HACKSHAW,B., CHIARAMIDA,A., ROUEEAU,J. L., FISHER,M. B., PIGEON,J. and RUSH,J. E. (1989). Short and long acting angiotensin converting enzyme inhibitors: A randomised trial of lisinopril versus captopril in the treatment of congestive heart failure. J. Am. Coll. Cardiol. 13: 1240-1247. GINZTON, L. E., CONANT, R., RODRIGUEZ, D. M. and LAKS, M. M. (1989). Functional significance of hypertrophy of the non-infarcted myocardium after myocardial infarction in humans. Circulation 80: 816-822. HODSMAN,G. P., ISLES,C. G., MURRAY,G. D., USHERWOOD,T. P., WEBB, O. J. and ROBERTSON,J. I. S. (1983). Factors related to first dose hypotensive effect of captopril: prediction and treatment. Br. Med. J. 286: 832-834. JOHNSTON, C. I., FABRIS, B., YAMADA,n., MENDELSOHN,F. A. O., CUBELA,R., SIVELL,D. and JACKSON,B. (1989). Comparative studies of tissue inhibition by ACE inhibitors. J. Hypertension 7, (Suppl. 5): S1 l-S16. KROMER,E. P., ELSNER,D. and RIEGGER,G. A. J. (1990). Digoxin, ACEI (quinapril) and the combination in patients with CHF functional class II and sinus rhythm. J. Cardiovasc. Pharmac. 16: 9-14. LANCASTER,S. G. and TODD, P. A. (1988). Lisinopril. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertension and congestive heart failure. Drugs 35: 646-669. LI, K. and CrmN, X. (1987). Protective effects of captopril and enalaprilat on myocardial ischaemia and reperfusion damage of rats. J. Mol. Cell Cardiol. 19: 909-915. LIE, K. I., ZARDINI,P., ZANNAD,F. and HERLITZ,J. (1991). Comparative studies of lisinopril with captopril, enalapril or digoxin in the treatment of patients with mild to moderate congestive heart failure. In: Heart Failure Management in the 9ON. Symposium Proceedings, Montreux, 7-8 November 199 l, pp. 34-35, RYDEN, L. (eds), ICI Publications, Macclesfield, UK. LINDPAINTER,K., WILHELM,M. J., JIN, M., UNGER,Z., LANG,R. E., SCHOELKENS,B. A. and GANTEN,D. (1987). Tissue renin angiotensin systems: focus on the heart. J. Hypertension 5 (Suppl. 2) $33-$38. MAISEL, A. S., PHILLIPS, C., MICHEL, M. C., ZIEGLER, M. G. and CARTER, S. M. (1989) Regulation of fl-adrenergic receptors by captopril: implications for CHF. Circulation 80: 669-675. MCFADYEN, R. J., LEES,K. R. and REID, J. L. (1991). Tissue and plasma angiotensin converting enzyme and the response to ACE inhibitor drugs. Br. J. clin. Pharmac. 31: 1-14. McLAY, J., McMURRAY, J., BRIDGES,A. and STRUTHERS,A. D. (1992). Practical issues on starting captopril in chronic heart failure: what dose and how long to observe them. Eur. Heart J., in press. JPT 53/2--C
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MCMURRAY, J. and CHOPRA,M. (1991). Influence of ACE inhibitors on free radicals and reperfusion injury: pharmacological curiosity or therapeutic hope? Br. J. clin. Pharmac. 31: 373-379. MOTWANI,J. G., FENWICK, M., MORTON,J. J. and STRUTHERS,A. D. (1992). Frusemide induced natriuresis is augmented by ultra low dose but not by standard doses of captopril in chronic heart failure. Circulation, in press. MULLER, H.-M., OVERLACK,A., HECK, I., KOLLOCH,R. and STUMPE,K. O. (1985). The influence of food intake on pharmacodynamics and plasma concentration of captopril. J. Hypertension 3 (Suppl. 2): S135-S136. MULLIGAN,I. P., FRASER,A. G., LEWIS,M. J. and HENDERSON,A. H. (1989). Effects of enalapril on myocardial noradrenaline overflow during exercise in CHF. Br. Heart J. 61: 23-28. NICHOLAS,M. G. and GILCHRIST,N. L. (1987). Sulindac and cough induced by converting enzyme inhibitors. Lancet 1: 872. OLDROYD,K. G., RAY, S. G., PYE, M., HENDERSON,E., MCFARLANE,N., CHRISTIE,J., FORD, I., COBBE,S. M. and DARGIE, H. J. (1991). Chronic ACE inhibition does not improve aerobic capacity after myocardial infarction. Br. Heart J. 66:112-113. O'NEILL, C. J. A., BOWLS,S. G., SULLENS,C. M., ROYSTON,J. P., HUNT, W. B., DENHAM,M. J., DODDS, R. J. and DoBBs S. M. (1988). Evaluation of the safety of enalapril in the treatment of heart failure in the very old. Eur. J. clin. Pharmac. 35:143 150. PACKER, M. (1989) Identification of risk factors predisposing to the development of functional renal insufficiency during treatment with ACEIs in CHF. Cardiology 76 (Suppl. 2): 50 55. PACKER, M., LEE,W. H., YUSHAK,M. and MEDINA,N. (1986). Comparison of captopril and enalapril in patients with severe CHF. New Engl. J. Med. 315:847 853. PATEL, B., KLONER, R. A., PRZYKLENK,K. and BRAUNWALD,E. (1988). Post ischemic myocardial 'stunning'. A clinically relevant phenomenon. Ann. intern. Med. 108: 626-628. PAUESON,O. B., JARDEN,J. O., GODTFREDSEN,J. and VORSTRUP,S. (1984). Cerebral blood flow in patients with CHF treated with captopril. Am. J. Med. 76(5B): 91-98. PEEEFER, M. A., PEEFFER,J. A., STEINBERG,C. and FINN, P. (1985). Survival after an experimental myocardial infarction: beneficial effects of long term therapy with captopril. Circulation 72: 406~12. PEEEEER, M. A., LAMAS,G. A., VAUGHAN,D. E., PARISI,A. F. and BRAUNWALD,E. (1988). Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. New Engl. J. Med. 319: 80-86. POULEUR, H., ROUSSEAU,M. F., OAKLEY,C. and RYDEN, L., for the Xamoterol in Severe Heart Failure Study Group (1991). Differences in mortality between patients treated with captopril or enalapril in severe heart failure study. Am. J. Cardiol: 68:71-74. POWERS, E. R., CHIARAMIDA,A., DEMARIA, A. N., GILES, T. O., HACKSHAW,l., HART, W., HAUGLAND,M., JOHNSTON, R., KATZ, R., KIRLIN, P., MCCALL, M., MOHIUDDIN,S., RICH, S., SULLIVAN,J. M., WOLESON,P. and CO-INVESTIGATORS(1987). A double blind comparison of lisinopril with captopril in patients with symptomatic CHF. J. Cardiov'asc. Pharmac. 9 (Suppl. 3): $82-$88. PRZYKLENK,K. and KLONER,R. A. (1989). Relationships between structure and effects of ACE inhibitors: comparative effects of myocardial ischaemic/reperfusion injury. Br. J. clin. Pharmac. 28 (Suppl. 2): 167S-175S. RICHARDSON,A., BAYLISS,J., SCRIVEN,A. J., PARAMESHWAR,J., POOLEWILSON,P. A. and SUTTON,G. C. (1987). Double blind comparison of captopril alone against frusemide plus amiloride in mild heart failure. Lancet 2:709-711. RIEGGER,G. A. J. (1990). The effect of ACEI on exercise capacity in the treatment of CHF. J. Cardiovasc. Pharmac. 15 (Suppl. 2): $41-$46. ROMANKIEWICZ,J. A., BROGDEN,R. N., HEEL, R. C. and SPEIGHT,T. M. (1983). Captopril. An update review of its pharmacological properties and therapeutic efficacy in congestive heart failure. Drugs 25: 6-40. SAMANI,N. J. (1991). New developments in renin and hypertension. Tissue generation of angiotensin I and II change the picture. Br. Med. J. 302: 981-982. SCHALEKAMP,M. A. D. H., ADMIRAAL,P. J. J. and DERKX, F. H. M. (1989). Estimation of regional metabolism and production of angiotensin in hypertensive subjects. Br. J. clin. Pharmac. 28:105S-113S. SCHOLKENS,B. A., LING, W. and KONIG, W. (1988). Effects of the ACEI, ramipril in isolated ischemic rat heart are abolished by a bradykinin antagonist. J. Hypertension 6 (Suppl. 4): $525-$528. SEDMAN,A. J. and POSVAR,E. (1989). Clinical pharmacology of quinapril in healthy volunteers and patients with hypertension and CHF. Angiology 40: 360-369. SEIDELIN, P. n., BENJAMIN, N., COLLIER, J. G., STRUTHERS, A. O. and WEBB, D. J. (1991). Intra arterial angiotensin II augments sympathetically mediated vasoconstriction in forearm resistance vessels in man. Clin. Sci. 81: 261-266. SHARPE, N., SMITH, H., MURPHY, J., GREAVES,S., HART, H. and GRAMBLE,G. (1991). Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin converting enzyme inhibition. Lancet i: 872-875. SEATER,E. E., MERRILL,D. D. and GUESS,H. A. (1988) Clinical profile of angioeodema associated with ACEI. J A M A 260: 967-970. SWEDBERG,K. for the CONSENSUS II Trial Study Group (1991). Lack of beneficial effects of mortality by early intervention with enalapril in acute myocardial infarction. Circulation 84 (Suppl. II): II-366. THE SOLVD INVESTIGATORS(1991). Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New Eng. J. Med. 325: 293-302.
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THUILLEZ,C., RICHARD,C., LOUESLATI,H., AUZEPY, P. and GUIDICELLI,J. F. (1990). Systemic and regional haemodynamic effects of perindopril in CHF. J. Cardiovasc. Pharmac. 15: 527-535. TODD, P. A. and BENFIELD,P. (1990). Ramipril. A review of its pharmacological properties and therapeutic efficacy in cardiovascular disorders. Drugs 39:110-135. TODD, P. A. and FITTON,A. (1991). Perindopril. A review of its pharmacological properties and therapeutic efficacy in cardiovascular disorders. Drugs 42: 90-114. TODD, P. A. and GOA, K. L. (1989). Enalapril: An update of its pharmacological properties and therapeutic use in congestive heart failure. Drugs 37: 141-161. VAN LEEUWEN,B. H., MILLER,J. A. HAMMATT,M. I. and JOHNSTON,C. I. (1983). Radioimmuno-assay of blood bradykinin purification of blood extracts to prevent cross reaction with endogenous Kininogen. Clin. Chim. Acta 127: 343-351. WADWORTH, A. N. and BROGDEN,R. N (1991). Quinapril. A review of its pharmacological properties and therapeutic efficacy in cardiovascular disorders. Drugs 41: 378-399. WESTLIN,W. and MULLANE,K. (1988). Does captopril attenuate reperfusion induced myocardial dysfunction by scavenging free radicals. Circulation 77 (Suppl. I): 1-30 1-39. ZIMMERmAN,B. G. (1978). Actions of angiotensin on adrenergic nerve findings. Fed. Proc. 37: 199-202.
0163-7258/92$15.00 © 1992PergamonPress Ltd
Associate Editor: D. G. McDEV1TT
THE CLINICAL PHARMACOLOGY OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN CHRONIC HEART FAILURE ALLAN D. STRUTHERS Department of Pharmacology and Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, DD1 9SY, Scotland, U.K. A~traet--ACE inhibitors (ACEIs) have now been shown to improve symptoms and survival in patients with mild, moderate and severe chronic heart failure. Their mechanism of action is thought to be a combination of RAAS suppression and augmentation of bradykinin and prostaglandins. Although ACE inhibitors improve hemodynamics post myocardial infarction, we do not yet have consistent data on their effects on symptoms or survival in these particular patients. One other potential benefit is their effects on reperfusion injury and free radicals. As yet only minor differences have been found to exist between different ACEIs but increasing attention is now being focussed in this direction.
CONTENTS 1. Introduction 2. Pharmacological Properties of Different ACEIs 3. Mechanism of Action 4. Hemodynamic and Symptomatic Effects in CHF 5. Effects on Mortality in CHF 6. Post Myocardial Infarction Studies 7. Reperfusion injury and free radicals 8. Myocardial ischemia 9. Comparisons between ACEIs in CHF 10. Adverse Effects of ACEIs References
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1. I N T R O D U C T I O N A C E inhibitors (ACEIs) have revolutionized the treatment of chronic heart failure (CHF). In particular, they improve the appallingly high mortality in C H F . We currently have eight A C E I s to choose from in the U.K. although a large number of new ACEIs will be marketed later in the 1990s. They all bind to a zinc ion in the ACE enzyme by way of either a sulphydryl, a carboxyl or a phosphoryl group in their structure. With each A C E I which is developed, the studies performed generally follow a logical sequence from in vitro studies to normal volunteer studies to studies of hypertensive patients and then to C H F patients. For this reason, ACEIs are licensed in the U.K. first for hypertension and only later for C H F . Even within the C H F patient group, initial studies focus on the effects of single doses on hemodynamics followed by chronic dosing studies of hemodynamics and then chronic dosing studies of exercise tolerance.
2. P H A R M A C O L O G I C A L
P R O P E R T I E S OF D I F F E R E N T A C E I s
A comparison of different A C E I s is shown in Table 1. Captopril was the first orally active ACEI. It contains a sulphydryl group and its affinity for plasma A C E is relatively low (IDs0 15 nmol/L). Bioavailability is 60-70% but this is decreased by 187
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Captopril
TABLE 1. Comparison of the Pharmacological Properties of Different ACEIs Affinity of Method of ACE enzyme active substances Duration of excretion of binding group Pro-drug for ACE action active substance Sulphydryl No Low Short Renal
Enalapril
Carboxyl
Yes
Moderate
Long
Renal
Lisinopril
Carboxyl
No
Moderate
Long
Renal
Perindopril
Carboxyl
Yes
High
Long
Renal
Ramipril
Carboxyl
Yes
High
Long
Renal
Quinapril
Carboxyl
Yes
High
Long
Renal and Gut
Cilazapril
Carboxyl
Yes
High
Long
Renal
Fosinopril
Phosphoryl
Yes
Long
Hepatic and Renal
--
25-50% when captopril is co-administered with food (Brogden et al., 1988; Muller et al., 1985). However, plasma drug concentrations do not correlate well with hemodynamic or neurohormonal responses so that food co-administration does not appear to alter the antihypertensive effect of captopril. The majority of the drug is excreted unchanged in the urine by tubular secretion (94% in urine by 6 hr). CHF does not affect the pharmacokinetics of captopril although interindividual variability is greater than in normal man. Enalapril was the next ACEI available. It is a carboxyi containing ACEI. About 60% of enalapril is absorbed reaching peak concentrations at l hr and this absorption is unaffected by food. Enalapril undergoes deesterification in the liver to form the active substance, enalaprilat which reaches peak concentration in 3-4 hr (Todd and Goa, 1989). Overall, the absolute bioavailability of enalapril as enalaprilat is 40%. The affinity of enalaprilat for human plasma ACE is greater than for captoprii (IDs0 1 nmol/L). Enalaprilat is 50% protein bound. Both enalapril and enalaprilat are eliminated purely by the kidney so that lower doses should be used in patients with renal impairment. Lisinopril is the lysine derivative of enalaprilat and it is also a carboxyl containing ACEI. Lisinopril has a low bioavailability at 25-50% and peak drug levels do not occur until 6hr, (Lancaster and Todd, 1988). Absorption is unaffected by food and the absorbed drug is excreted unchanged in urine. Lower doses are required in renal impairment and even in CHF patients there is a correlation between creatinine clearance and lisinopril clearance. Perindopril is a carboxyl group containing pro-drug ester of its active metabolite, perindoprilat. The bioavailability of perindopril varies (65-95%). Perindopril reaches its peak concentration at 1 hr and perindoprilat at 3-4 hr (Todd and Fitton, 1991). Only 17-20% of the oral dose becomes perindoprilat as extensive metabolism to other inactive metabolites occurs. Perindoprilat has high affinity for human plasma ACE (IDs0 0.40 nmol/L). Perindoprilat is excreted mainly by the kidneys so that dosage reduction is required in renal impairment. In CHF, absorption of perindopril, formation of perindoprilat, and clearance of perindoprilat are reduced. Ramipril is also a carboxyl containing pro-drug which is activated to ramiprilat (Todd and Benfield, 1990). Ramiprilat has high affinity for human plasma ACE (IDs0 0.08 nmol/L). Food has no influence on drug absorption. Ramipril reaches its peak concentration at 1 hr and ramiprilat at 3 hr. Ramiprilat is 56% protein bound and is excreted by the kidneys in the form of either ramiprilat, its glucuronide derivative or its diketo piperazine derivative. Clearance of ramiprilat is reduced in renal dysfunction but not in hepatic impairment although there is a delay in reaching peak level in hepatic impairment. Quinapril is also a carboxyl containing drug which is hydrolyzed to its more active form, quinaprilat. However, in contrast to other pro-drugs, both quinapril and quinaprilat are active
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ACEIs. Bioavailability is 60%, and peak concentrations of quinapril and quinaprilat occur at 1 and 2 hr post-dose respectively (Wadworth and Brogden, 1991). Both quinapril and quinaprilat are 97% protein bound. Quinaprilat has very high affinity for human plasma ACE (IDs0 0.07 nmol/L) with a much lower figure for quinapril itself (IDs0 55 nmol/L). Excretion is via urine (40%) and faeces (60%) the latter being a combination of unabsorbed drug and biliary excretion. Cilazapril is another carboxyl containing pro-drug which is hydrolyzed to cilazaprilat. Peak concentrations of cilazapril and cilazaprilat occur at 1 and 3 hr after administration. Bioavailability is estimated as 57-77% (Deget and Brogden, 1991). Cilazaprilat is excreted almost exclusively by the kidneys so that a dose reduction is required in patients with renal dysfunction. Fosinopril is a phosphoryl group containing pro-drug which is activated to fosinoprilat which has a long terminal half life. Fosinoprilat is unique among ACEIs in undergoing both renal and hepatic elimination so that dosage adjustment is unnecessary even in moderate renal dysfunction (e.g. creatinine clearance 40 mL/min). 3. MECHANISM OF ACTION The principal effect of ACEIs is to block the conversion of angiotensin I (AI) to angiotensin II (AII). Initially AI and All were thought to be circulating hormones and the effect of ACEIs was thought to be due entirely to suppression of circulating All. This is now recognized to be a gross oversimplification which overlooks 3 other major actions of ACEIs. Firstly, the whole renin-angiotensin system (RAS) is patently more than a system of circulating hormones and many components of the RAS are synthesized locally and exert effects locally within many different tissues, e.g. blood vessel walls, kidneys, adrenals, brain and even the gonads (Dzau, 1988; Samani, 1991). Thus plasma concentrations of AI and AII probably represent spillover from their tissue sites of production (Campbell, 1987). Indeed Schalekamp et al. (1989) have demonstrated that 40-90% of venous AI in many vascular beds is generated by regional production from angiotensin. It is also worth noting that AII is produced in the heart in abundance, especially the right atrium (Lindpainter et al., 1987) and that ACE activity is also present in the right atrium and on the surface of cardiac valves (Johnston et al., 1989). ACEIs are known from in vitro studies to inhibit tissue ACE activity as well as serum ACE. It is now thought that most of the pharmacodynamic and therapeutic effects of ACEIs are due to inhibition of tissue ACE rather than serum ACE. This may explain for example why the long-term antihypertensive effects of ACEIs are poorly related in magnitude to the pretreatment measurement of plasma renin activity (PRA) in the blood. Secondly, ACEI may act on hormonal systems other than the RAS such as bradykinin and prostaglandins. ACE is identical in structure to the enzyme, kininase II, which normally degrades endogenous bradykinin, a potent vasodilator. Thus ACEIs may increase endogenous levels of bradykinin. The data suggesting this is not entirely consistent but this may simply reflect difficulties in assaying bradykinin levels (Van Leeuwen et al., 1983). What is however fairly consistent is that most ACEIs potentiate the vasodepressor effect of exogenous bradykinin in animal models. The other endogenous hormone system which may be increased by ACEIs is the prostaglandins but here again the data are inconsistent which may be due to assay problems. Another mechanism of action which ought to be borne in mind relates to the now welldocumented interaction between All and the sympathetic nervous system (Zimmerman, 1978). AII increases the prejunctional release of noradrenaline in response to sympathetic nerve stimulation (Seidelin et al., 1991). As a result, ACEIs impair sympathetically mediated vasoconstriction (Clough et al., 1982) and even more importantly reduce mycocardial noradrenaline overflow during exercise in CHF (Mulligan et al., 1989). A clinically important byproduct of this is that reducing noradrenaline release prevents fl-receptor downregulation. This explains the mechanism behind experimental data that captopril increases the number and the responsiveness of postsynaptic cardiac fl-receptors (Maisel et al., 1989). Thus the beneficial clinical effects of ACEIs may be due not only to reducing preload and afterload but also to favourably modifying cardiac sympathetic tone.
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A.D. STRUTHERS 4. HEMODYNAMIC AND SYMPTOMATIC EFFECTS IN CHF
Captopril has been extensively investigated in CHF. Its acute hemodynamic effects are a reduction in right atrial pressure, pulmonary capillary wedge pressure and mean arterial pressure with accompanying increases in cardiac index (Romankiewicz et al., 1983). These acute hemodynamic effects are maintained during long-term administration. During chronic therapy, there are also symptomatic improvements in dyspnoea, fatigue and exercise capacity (Captopril Multicenter, Research Group, 1985; Cleland et al., 1984). In various comparisons, captopril was less effective than a diuretic as monotherapy in mild CHF (Richardson et al., 1987), was equally effective as enalapril in severe CHF (Packer et al., 1986) and was more effective than digoxin in moderate CHF (Captopril-Digoxin Multicenter Research Group, 1988). There are two comparisons between captopril and lisinopril with one study finding lisinopril better and the other finding no difference (Powers et al., 1987; Lie et al., 1991). Enalapril produces the same favourable hemodynamic response during long-term therapy in CHF i.e. reductions in right atrial pressure, pulmonary capillary wedge pressure and mean blood pressure with increased cardiac index. These effects are also translated into beneficial effects on dyspnoea, tiredness and exercise duration (Enalapril CHF Investigators, 1987). What is particularly noteworthy about enalapril is that there are three large conclusive and encouraging mortality studies with enalapril in CHF (see mortality studies section). No other ACEI has been examined in such detail with regard to mortality. Although it is likely, it cannot be assumed that other ACEIs will be as beneficial on mortality as enalapril. Lisinopril has also been shown in CHF to acutely reduce pulmonary capillary wedge pressure, mean arterial pressure and increase cardiac index (Dickstein et al., 1986). During chronic therapy, lisinopril improves dyspnoea, fatigue, exercise duration and LV ejection fraction (Chalmers et al., 1987). Cilazapril produces the same acute hemodynamic effects in CHF as all the other ACEIs described above (Fong et al., 1987). These effects are sustained during chronic therapy and are accompanied by improved symptomatology and improved exercise tolerance (Drexler et al., 1989). This last paper makes the important observation that exercise tolerance improves gradually over the first 6-8 weeks of ACEI therapy and that this improvement in exercise tolerance is closely related to a slowly developing increase in skeletal muscle blood flow. It may be that this slow effect on muscle blood flow is due to accumulating effects of the ACEI on the tissue RAS and/or to effects on bradykinin and EDRF. An acute reduction in right atrial pressure, pulmonary capillary pressure and mean arterial pressure along with an increase in cardiac index is also seen with perindopril (Thuillez et al., 1990). Perindopril also improves symptomatology and exercise duration after 3 months of therapy in CHF (Bounhoure et al., 1989). Ramipril produced the same acute hemodynamic response as all other ACEIs described above (de Graeff et al., 1989). These effects persist during chronic therapy and are accompanied by improved symptomatology and exercise duration. An acute dose of quinapril reduces pulmonary capillary wedge pressure and mean arterial pressure and increases cardiac index in CHF (Sedman and Posvar, 1989). Chronic therapy with quinapril also improves symptomatology and exercise duration in CHF (Riegger, 1990). In one trial, quinapril was superior to digoxin in terms of improving exercise duration (Kromer et al., 1990). 5. EFFECTS ON MORTALITY IN CHF Large trials are now being undertaken with ACE inhibitors. The first such study was conducted by the CONSENSUS Trial Study Group (1987) where patients with severe CHF (grade IV) were randomized to placebo or enalapril. This study was terminated prematurely because enalapril produced a 40% reduction in mortality at 6 months, a 31% reduction at 1 year and a 27% reduction at the end of the study. Interestingly, the benefit was entirely due to a reduction in the progression of heart failure and enalapril had no effect on the rate of sudden unexpected death. Around the same time, there was published the results of a similar trial using non-ACEI vasodilators (Cohn et al., 1986). In this study, prazosin was found to produce no mortality benefit
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whereas a combination of hydralazine and isosorbide dinitrate did produce a sizeable reduction in mortality. This appeared to suggest that reducing afterload and preload could produce a mortality benefit, irrespective of whether the vasodilator was an ACEI or hydralazine/isosorbide although this does not explain why prazosin was ineffective. A VHeFT-2 study was therefore launched to compare enalapril and hydralazine/isosorbide and this reported in 1991 (Cohn et al., 1991). Here enalapril was superior to hydralazine/isosorbide in terms of mortality. The one and two-year mortalities were 8% and 18% on enalapril as compared to 13% and 25% on hydralazine/isosorbide. Curiously enough, hydralazine/isosorbide improved symptoms and hemodynamics more than did enalapril in that oxygen consumption on exercise and LV ejection fraction was better on hydralazine/nitrate. These latter parameters are difficult however to interpret since the two treatment groups had different mortality rates. This VHeFT-2 study suggests that vasodilator treatment does indeed reduce mortality but that an additional mortality benefit is achieved from the neuroendocrine suppression which occurred with enalapril but not with hydralazine/isosorbide. The mechanism for this additional effect remains unknown but one possibility relates to recent data showing that AII inhibits and ACEIs encourage the uptake and disposal of noradrenaline in the myocardium (M. A. Arnott and A. D. Struthers, submitted for publication). This mechanism may be important since mortality in CHF is closely related to the plasma level of noradrenaline. Since ACEIs were shown by the CONSENSUS study to reduce mortality in severe CHF, the question naturally arose whether a similar benefit would be seen in patients with mild to moderate CHF. Such a large study has just been published (The SOLVD Investigators, 1991). Here symptomatic CHF patients with a cardiac ejection fraction of < 35% were randomized to enalapril or placebo. Overall death was significantly reduced by enalapril and again like the CONSENSUS I trial, the reduction was in the progression of the disease and not on the rate of sudden unexpected death. What was even more striking was that enalapril reduced the hospitalization rate. It was estimated from this study that if enalapril was given to 1000 CHF patients for 3 years, this would save 50 premature deaths and 350 hospitalizations. This striking ability of ACEIs to reduce the progression of CHF has led to the hope that ACEI could retard the onset of symptomatic CHF if ACEIs were commenced very early in the disease before symptoms had occurred. There is an ongoing study (SOLVD Prevention study, 1991) which is designed to answer that very question: its preliminary results were announced at the American Heart Association meeting on 11 November 1991". Enalapril produced a 37% reduction in the development of overt CHF, a 36% reduction in CHF hospitalizations, a 21% reduction in hospitalizations for myocardial infarction and a 17% reduction in hospitalizations for angina. Enalapril reduced total mortality only by 8% and cardiovascular mortality by 14% but these effects on mortality were not significant. It is also worth noting that the survival curves did not start to diverge until after 18 months of treatment i.e. at a time when CHF symptoms were developing anyway.
6. POST MYOCARDIAL INFARCTION STUDIES There is a great interest in the use of ACEIs in the post myocardial infarction (MI) situation. There are 3 major reasons for this being a crucial area. Firstly, the majority of CHF patients acquire their disease by way of previous myocardial infarctions so that in a sense, the post MI period is the earliest time when intervention with an ACEI could halt the initiation of the heart failure process. Secondly, there are convincing animal studies to show that captopril reduces ventricular remodelling after an established MI (Pfeffer et al., 1985). Ventricular remodelling refers to the process whereby there is stretching and thinning of the infarcted segment which is then followed by a global dilatation and hypertrophy of the non-infarcted left ventricle. This process occurs in only about half of transmural infarctions and is progressive in about half of this group (Ginzton *SOLVD PREVENTIONTRIALINVESTIGATORS(1991) Principal results, American Heart Association Meeting, Anaheim, November 10-14, 1991.
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et al., 1989). Great interest was therefore generated when Pfeffer et al. (1985) showed beneficial
effects with regard to remodelling in an experimental model of MI in rats and this has led to several clinical studies to address this point (see below). The third reason for interest in the post-MI situation relates to reperfusion injury. When a coronary thrombosis occurs there can be two outcomes. One is (thrombolytic induced) reperfusion which prevents myocardial necrosis but which carries the separate hazard of reperfusion injury. The other outcome is true myocardial necrosis with subsequent remodelling as described above. Interest in reperfusion injury was sparked by several animal studies suggesting that ACEI attenuated this process (Li and Chen, 1987; Westlin and Mullane, 1988). The mechanism of this beneficial effect is uncertain. One popular but unproven theory is that it is due to the scavenging of toxic oxygen free radicals (see below) which are released during reperfusion and that it is the sulphydryl group contained in captopril (and zofenopril) which is instrumental in this process (Przyklenk and Kloner, 1989). Others have suggested that it is due to the production of prostaglandins or bradykinin. Studies of ACEI in post-MI patients can therefore be divided into 3 groups according to the different endpoints chosen to study. Firstly, there are studies examining the effect of ACEIs on hemodynamics. All studies are consistent that captopril reduces ventricular remodelling in that it improves cardiac stroke volume and reduces end diastolic dimensions (Pfeffer et al., 1988; Sharpe et al., 1991). However, there is often in CHF a poor correlation between hemodynamic changes and symptoms so that studies of ACEIs post MI are now focussing on patient symptomatology and survival. Pfeffer et al. (1988) reported in their study that exercise tolerance was better in the captopril-treated group than in the placebo-treated group although pretreatment exercise tests are not available to ensure comparability of patient groups. In a separate study in Glasgow, captopril did not improve exercise tolerance post MI (Oldroyd et al., 1991). The third and most important parameter, however, is mortality. We are currently lacking consistent data in this regard. A recent study was halted prematurely as there appeared to be no beneficial effect on mortality in this study (Swedberg for the CONSENSUS II Trial Study Group, 1991). It is worth noting that in this study, intravenous enalaprilat was administered to patients on admission to the coronary care unit and this may represent premature intervention. On the other hand, in the recent SAVE study, captopril produced a 17% reduction in mortality. There are more trials underway which will help us to answer this crucial question, namely the GISSI 3 study using lisinopril and the ISIS-4 study using captopril.
7. REPERFUSION INJURY AND FREE RADICALS It is worth briefly discussing the issue of reperfusion injury and free radicals (McMurray and Chopra, 1991). There is evidence that reperfusion itself can cause cell injury or death which is distinct from the cellular damage induced by the preceding period of ischemia. The best understood type of reperfusion injury is 'stunning' or reversible contractile dysfunction which has been recognized in both animals and man (Bolli et al., 1989; Patel et al., 1988). The pathogenesis of this injury process clearly involves free radicals (FR). In vitro studies suggest that SH containing ACEIs such as captopril and zofenopril are able to scavenge certain FRs such as the hydroxyl radical (OH'), hypochlorous acid (HOC1) and hydrogen peroxide (H202), but original data to suggest an effect of captopril on the superoxide anion radical (O~-) now seems doubtful (McMurray and Chopra, 1991). In vivo animal experiments raise the possibility that the improved recovery of contractility after an ACEI is at least in part due to increased prostaglandins as well as to the sulphydryl group. A prostaglandin effect is likely to be shared, albeit to different extents, by most ACEIs and this may explain why Li and Chen (1987) found that enalapril ameliorated reperfusion induced myocardial dysfunction in isolated rat hearts. One other study raises the possibility that bradykinin is involved. Scholkens et al. (1988) found that ramipril (with no sulphydryl group) was beneficial in reperfusion injury but that this effect could be abolished by a bradykinin antagonist. We therefore await clinical studies to assess the importance of the sulphydryl group on FR injury in patients although the problems of designing and executing such a trial are formidable.
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8. MYOCARDIAL ISCHEMIA One other clinical situation worthy of brief comment is myocardial ischemia. ACEIs reduce coronary vascular tone and they also reduce coronary perfusion pressure. In subendocardial regions, an increase in myocardial perfusion is liable to occur as end diastolic pressure falls within the LV. Such improved perfusion will be most prominent when the coronary arteries are unobstructed as in dilated cardiomyopathy (Foult et al., 1988). However, the reduced coronary perfusion pressure can exacerbate myocardial ischemia where there is epicardial coronary artery disease (Cleland et al., 1991). Overall, most studies have found no effect of ACEIs in angina pectoris. In the occasional study, a benefit has been found and conversely, occasionally a deleterious effect was found (Cleland et al., 1991). 9. COMPARISONS BETWEEN ACEIs IN CHF There are few data comparing different ACEIs in CHF. In the first such comparison, Packer et al. (1986) compared high doses of captopril (150mg/day) and enalapril (40mg/day) in
severe CHF. There was no difference in the symptomatic response to therapy but enalapril-treated patients developed more prolonged hypotension and more renal dysfunction. Renal dysfunction was particularly prominent in diabetic patients. Giles et al. (1989) recently compared lisinopril and captopril in CHF and found that the LV ejection fraction improved more on lisinopril and that in a subgroup of patients with renal impairment initially, lisinopril improved exercise duration significantly more than captopril did. However, lisinopril also caused more renal dysfunction than did captopril. In contrast, a recent European comparison between captopril and lisinopril found them equally effective at improving exercise tolerance (Lie et al., 1991). Data from the CSM yellow card adverse event monitoring system agrees with the above studies that captopril produces less renal dysfunction than the longer acting ACEIs. However, the Giles study raises the possibility that the better renal effect of captopril may be balanced by less of a symptomatic improvement. Indeed, it could be hypothesized that a short acting ACEI allows restoration of some AII at the end of each dose interval and that this helps maintain the G F R but that it also increases cardiac afterload and hence decreases exercise tolerance, albeit temporarily. This highlights an as yet unresolved controversy in ACEIs over whether long-acting or short-acting ACEIs are of more benefit to CHF patients. Very recently, lisinopril has been compared in CHF with enalapril and with digoxin (Lie et al., 1991). The result of both studies are unfortunate in that the baseline exercise tolerances were unequal in both studies. In both studies, lisinopril produced a non-significant trend towards a better improvement in exercise tolerance than either enalapril or digoxin but this apparent effect is unconvincing because of the different starting baselines. In terms of a hypotensive response to ACEIs, a recent comparative study in CHF suggests that perindopril is unique in that it causes no greater first dose fall in BP than placebo (McFadyen et al., 1991). In terms of mortality, there are no good comparative studies between ACEIs. A recent report by Pouleur et al. (1991) is worthy of comment. This was a retrospective analysis of baseline therapy in the Xamoterol mortality trial which showed that patients receiving baseline therapy with captopril had a significantly higher mortality than those receiving enalapril. The authors claim that this was due to captopril being given only twice daily which allowed some RAAS recovery between doses. These results are of interest but should be viewed with caution until these results are confirmed by other data. 10. ADVERSE EFFECTS OF ACEIs For a detailed discussion of this topic, the reader is referred to Ferner (1990). Side effects fall into 2 broad categories, those due to the sulphydryl group and those which occur with all ACEIs (often called the class effect). Side effects due to the former are similar to those found with penicillamine and are skin rash, taste disturbance, agranulocytosis and rarely drug-
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induced proteinuria leading on very rarely to membranous glomerulonephritis and the nephrotic syndrome. Side effects common to all ACEIs are first-dose hypotension, renal dysfunction, cough, angioneurotic edema, headache, dizziness, nausea, diarrhoea and fatigue. First-dose hypotension is more common in hyponatremic, overdiuresed patients with elevated levels of plasma renin/AII and a contracted extracellular fluid volume (Hodsman et al. 1983; J. G. Motwani, M. Fenwick and A. D. Struthers, submitted for publication). Curiously enough, the blood pressure often collapses suddenly and there is accompanying bradycardia which suggests involvement of parasympathetic stimulation. As AII as generally vagolytic, this is plausible. In the majority of C H F cases, systemic BP falls by < 20 mmHg after an ACEI. This more moderate BP fall is not dose related in magnitude and does not produce dizziness or renal dysfunction because ACEIs cause a redistribution of blood flow favouring cerebral and renal blood flow (McLay et al., 1992; Paulson et al., 1984). Renal function after an ACEI is a complex topic as there can be very different renal responses in different patients. Firstly, captopril can very rarely induce proteinuria in patients who had normal renal function originally. Secondly, ACEIs can cause a measurable deterioration in renal function. This is particularly common in bilateral renal artery stenosis but can occur more rarely in unilateral renal artery stenosis and in CHF. In CHF, the predictors are excessive BP reduction, diabetes mellitus and a G F R of < 4 5 m l / m i n before therapy (Packer, 1989). If the original G F R lies in the range 45-80 ml/min, then captopril reduces G F R by an average of 7 ml/min in C H F (J. G. Motwani, M. Fenwick, A. D. Struthers, submitted for publication). Interestingly, Motwani et al. (1992) have shown that ultra low dose captopril (1 mR) doubles the natriuretic effect of frusemide in C H F while standard doses of captopril (25 mR) reduce natriuresis. Thirdly, renal function can improve with ACEIs in certain patients especially patients with early diabetic nephropathy where ACEIs can retard the progression of the microalbuminuria and the renal dysfunction. Cough is more troublesome in hypertensive than in C H F patients. Bradykinin and prostaglandins are believed to sensitise pulmonary sensory C fibres such that ACEI-induced cough can sometimes be suppressed by sulindac (Nicholas and Gilchrist, 1987). Angioedema is said to be induced by ACEIs in about 1 in 1000 patients (Slater et al., 1988). A plausible mechanism is that it is due to build up of tissue bradykinin. One report suggests that there may be particular problems with ACEIs when they are given to the very elderly C H F patient (O'Neill et al., 1988). Particular problems were renal dysfunction and mesenteric ischemia, presumably due to the redistribution of blood ftow in an already atheromatous arterial tree.
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