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Correspondence

Is enalapril and combination irrational?irrational?

I read with great interest the editorial by C.S. Gautam and of exogenous I pressor effects.[4] Therefore, the S. Aditya, which appeared in the Indian Journal of enalapril-losartan combinations are more potent at Pharmacology in June 2006 (vol, 38(3):167-70). A very achieving these goals than any of their constituents important topic was addressed in the editorial, and I individually. compliment the authors on this. On the other hand, I felt � Similarly synergistic efficacy of enalapril and losartan in confused when I found Enalapril + Losartan in the list of combination on exercise performance and oxygen irrational fixed dose combinations. I agree with the authors consumption at peak exercise in congestive that combining the two drugs affecting the same pathway is has been sugested.[5] irrational as it does not add to its efficacy, but I am not sure � The combination of an angiotensin-converting enzyme whether this combination should be categorised as irrational inhibitor and an angiotensin II receptor antagonist (AT1 or as rational. The results of ongoing research may answer receptor antagonist) in patients can significantly enhance this question in future. reduction in left ventricular hypertrophy. This can provide Apparently this combination may appear irrational, but greater protection to the heart against the overload caused actually rationality does exist for combining these two drugs. by persistent . Furthermore, the combination

� From a physiological point of view, the general mechanism of these drugs did not increase the incidence of adverse of action of both angiotensin-converting enzyme inhibitor effects. On the contrary, the possibility of using a lower

and AT 1 receptor antagonist is the same, i.e., inhibition of dose of angiotensin converting enzyme inhibitor, combined the rennin-angiotensin system. Their sites of action are, with an AT1 receptor antagonist, might in fact reduce the however, different and, therefore, differences exist in their chance of persistent cough, the main factor limiting the intrinsic mechanisms of action. Angiotensin converting use of angiotensin-converting enzyme inhibitor in enzyme inhibitor acts by blocking conversion of angiotensin hypertension.[6]

I to angiotensin II, while angiotensin receptor blockers act � Similarly, the beneficial effect of combination therapy with at terminal receptor level. an angiotensin II receptor antagonist and angiotensin-

� It has been shown that even maximum doses of angiotensin converting enzyme inhibitor on overt proteinuria in a patient converting enzyme inhibitors do not completely suppress with type 1 is very encouraging.[7] [1,2] angiotensin II generation because it is known that there � A combination of a full-dose ACE-inhibitor and an ARB may are several alternative pathways to generate this peptide be a rational choice in selected patients. Further trials are, from angiotensin I.[3] The conversion of angiotensin I into however, needed to evaluate long-term safety, efficacy, angiotensin II is catalysed not only by angiotensin- quality of life, and survival before the combination can be converting enzyme, but also by other peptidases, such as, recommended for routine use. chymase, tonin, and cathepsin G. This fact might explain Therefore, I would like the authors to address this issue the loss of antihypertensive and antihypertrophic effects and contemplate whether it is right to categorise this during long-term use of angiotensin-converting enzyme combination as irrational just because it is not in the approved inhibitors in hypertensive patients.[2] The addition of an list of WHO. I especially recommend this because the answer angiotensin II type 1 receptor blocking agent to an ACE about its rationality is awaited from the ongoing research in inhibitor would theoretically block ACE as well as non-ACE­ this field. dependent angiotensin II formation and will achieve a more V.R. Tandon complete inhibition of the -angiotensin. Post-graduate Department of Pharmacology & Therapeutics, � ARBs also simulate rennin release. With ARBs, however, Govt. Medical College, Jammu (J&K) India - 180001. India this translates into a several fold increase in circulating E-mail: [email protected] levels of angitensinogen II. As AT2 receptors are not blocked

by clinically available ARBs, ARBs indirectly stimulate AT2 References receptors by increasing angitensin II levels. Therefore, in 1. Juillerat L, Nussberger J, Menard J, Mooser V, Christen Y, Waeber B, et al. the presence of ACE inhibitors, it will block conversion of Determinants of angiotensin II generationduring converting enzyme inhibition. angitensin I to angitensin II and will prevent this indirect Hypertension 1990;16:564-72.

stimulation of AT 2 receptors. The clinical significance of 2. Van Den Meiracker AH, Man in’t Veld AJ, Admiraal PJJ, Ritsema van Eck HJ, this action, however, remains to be defined. Boomsma F, Derkx FH, et al. Partial escape of angiotensinconverting enzyme inhibition during prolongued ACE inhibitor treatment: does it exist and does it � Ealapril and losartan do exert dose-dependent and, when affect the antihypertensive response? J Hypertension 1992;10:803-12. combined, additive effects in terms of blood pressure fall 3. Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II-forming and cardiac hypertrophy limitation and synergistic effects pathways in normal and failing human hearts. Circulation Res 1990;66: in terms of plasma active renin stimulation and blockade 883-90.

Indian J Pharmacol | August 2006 | Vol 38 | Issue 4 | 295-298 295 Correspondence

4. Richer C, Bruneval P, Menard J, Giudicelli JF. Additive effects of enalapril and in such organs.[1] In certain situations such as long-term losartan in (mREN-2)27 transgenic rats. Hypertension 1998;31:692-8. hypertension, congestive heart failure and primary or 5. Guazzi M, Palermo P, Pontone G, Susini F, Agostoni P. Synergistic efficacy of secondary (due to diabetes mellitus) renal failure, an enalapril and losartan on exercise performance and oxygen consumption at peak exercise in congestive heart failure. Am J Cardiol 1999;84:1038-43. upregulation of this non-ACE pathway of AT II formation leads 6. Avanza AC Jr, El Aouar LM, Mill JG. Reduction in left ventricular hypertrophy to both cardiac and vascular remodeling and restructuring. in hypertensive patients treated with enalapril, losartan or the combination of Thus, in both the heart and the kidneys, the ACE inhibitor would enalapril and losartan. Arq Bras Cardiol 2000;74:103-17. fail to influence non-ACE mediated AT II effects. But AT1 ARB 7. Kuriyama S, Tomonari H, Abe A, Imasawa T, Hosoya T. Beneficial effect of would be able to counteract this influence. This makes a case combination therapy with an angiotensin II receptor antagonist and angiotensin- converting enzyme inhibitor on overt proteinuria in a patient with type 1 dia­ for the synergistic effect if both classes of agents are combined. betic nephropathy. Nephron 2000;86:529-30. On the basis of this knowledge, the combination of an ACE inhibitor and ARB cannot be labelled as irrational as the two classes of drugs appear to act on the RAAS pathway,but one of them, i.e., ARB can block AT receptors in areas where AT II This is in reference to the editorial ‘Irrational drug 1 is synthesised by non-ACE pathway. Based on this assumption combinations: need to sensitise the undergraduates’ (Indian J of rationality, clinical trials are being conducted to find out the Pharmacol 2006; 38:169-70), wherein the authors have rightly effect of the ACE inhibitor plus ARB combination in patients emphasised the need to sensitise undergraduate students, in with cardiovascular diseases.[2,3] the health care profession, to the use of irrational fixed-dose In both studies, results suggested a favourable effect of combinations available in the Indian market. two drugs in combination [ + enalapril/ / In Table 1, entry no. 8 lists the combination of enalapril / , etc.[2] + captopril[3] in patients and losartan as irrational because both drugs have been with heart failure. However, in patients with myocardial suggested to affect the same pathway and, in combination, do infarction, combining valsartan + captopril did not improve not add to each other’s efficacy. However, it is a question of survival over and above what was obtained by full doses of whether we are talking about “addition” or “synergism”. A each agent used individually, although the combination therapy strong case can be made in favour of both as the following resulted in an apparent reduction in the cumulative rate of would suggest. admission for recurrent myocardial infarction or heart failure.[3] It is true that both drugs act on the same pathway, i.e., Hence, there is a robust evidence to combine these two the renin-angiotensin-aldosterone system (RAAS) where, classes of drugs in patients with hypertension and heart failure. besides renin, the angiotensin converting enzyme (ACE) is a However, it is advisable that each agent be titrated for optimum key player in the formation of angiotensin II (AT II). This is a effective doses before switching to their fixed dose combination potent regulator of blood pressure (BP) and cardiovascular as the use of the latter would improve patient compliance. structure and functioning by virtue of its number of actions. Enalapril (through its metabolite ) competitively inhibits ACE to produce a decrease in the conversion of AT I to K.K. Sharma, K. Sahaya, P.K. Mediratta AT II. It also leads to accumulation of certain other peptides Department of Pharmacology, such as bradykinin, substance P and neurokinins, which depend University College of Medical Sciences & GTB Hospital, for their degradation on ACE (kininase II). The BP lowering Delhi – 110095, India effect of ACE inhibitors such as enalapril is not only contributed E-mail: [email protected] by the decrease in AT II, but also by an accumulation of the powerful vasodilator, bradykinin. This, albeit along with other accumulated peptides, is responsible for adverse reactions such as dry cough and . References

In the RAAS pathway, the AT II- AT1 receptor blocker (ARB), 1. Jackson EK. Renin and angiotensin. In: Brunton LL, Lazo JS, Parker KL, losartan, like other ARBs, can also increase bradykinin editors. Goodman & Gilman’s. The pharmacological basis of therapeutics. 11th ed. New York, USA: McGraw-Hill Medical Publications division; 2006. p794-5. concentration due to unhindered AT2 receptor activity. This, as in the case of ACE inhibitors, contributes to their BP lowering 2. McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, et al. Effects of candesartan in patients with chronic heart failure and reduced activity. In view of the above effect, ARB being a competitive left-ventricular systolic function taking angiotensin-converting-enzyme inhibi- antagonist, if combined with an ACE inhibitor would be tors: the CHARM-added trial. Lancet 2003; 362:767-71. ineffective or less effective as the agonist. AT II concentration 3. Pfeffer MA, McMurray JJ, Valazquez EJ, Rouleau JL, Kober L, Maggioni AP, et is already reduced by ACE inhibitor due to inhibition of its al. Valsartan, captopril or both in myocardial infarction complicated by heart synthesis. However, it may have an added effect by virtue of failure, left ventricular dysfunction or both. New Engl J Med 2003;349:1893- 906. AT2 receptor mediated accumulation of bradykinin. This is because whatever little AT II is there would act on AT2 receptors in the face of AT receptor blockade by the ARB. This makes a 1 Reply: case for their additive effect if both classes of agents are combined. In response to the queries raised about the topic, authors In some tissues, which include the heart and the kidneys, would like to highlight the following facts which may explain there is a functioning non-ACE enzymatic pathway for to some extent the irrationality behind the fixed dose processing angiotensinogen, i.e., chymase, which form AT II combination of ACE inhibitors and ARBs.

296 Indian J Pharmacol | August 2006 | Vol 38 | Issue 4 | 295-298