|Year : 2006 | Volume
| Issue : 4 | Page : 296
KK Sharma, K Sahaya, PK Mediratta
Department of Pharmacology, University College of Medical Sciences & GTB Hospital, Delhi - 110095, India
K K Sharma
Department of Pharmacology, University College of Medical Sciences & GTB Hospital, Delhi - 110095
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sharma K K, Sahaya K, Mediratta P K. Reply. Indian J Pharmacol 2006;38:296
This is in reference to the editorial 'Irrational drug combinations: need to sensitise the undergraduates' (Indian J Pharmacol 2006; 38:169-70), wherein the authors have rightly emphasised the need to sensitise undergraduate students, in the health care profession, to the use of irrational fixed-dose combinations available in the Indian market.
In [Table 1], entry no. 8 lists the combination of enalapril and losartan as irrational because both drugs have been suggested to affect the same pathway and, in combination, do not add to each other's efficacy. However, it is a question of whether we are talking about "addition" or "synergism". A strong case can be made in favour of both as the following would suggest.
It is true that both drugs act on the same pathway, i.e., the renin-angiotensin-aldosterone system (RAAS) where, besides renin, the angiotensin converting enzyme (ACE) is a key player in the formation of angiotensin II (AT II). This is a potent regulator of blood pressure (BP) and cardiovascular structure and functioning by virtue of its number of actions.
Enalapril (through its metabolite enalaprilat) competitively inhibits ACE to produce a decrease in the conversion of AT I to AT II. It also leads to accumulation of certain other peptides such as bradykinin, substance P and neurokinins, which depend for their degradation on ACE (kininase II). The BP lowering effect of ACE inhibitors such as enalapril is not only contributed 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 angioedema.
In the RAAS pathway, the AT II- AT 1 receptor blocker (ARB), losartan, like other ARBs, can also increase bradykinin concentration due to unhindered AT 2 receptor activity. This, as in the case of ACE inhibitors, contributes to their BP lowering activity. In view of the above effect, ARB being a competitive antagonist, if combined with an ACE inhibitor would be ineffective or less effective as the agonist. AT II concentration is already reduced by ACE inhibitor due to inhibition of its synthesis. However, it may have an added effect by virtue of AT 2 receptor mediated accumulation of bradykinin. This is because whatever little AT II is there would act on AT 2 receptors in the face of AT receptor blockade by the ARB. This makes a case for their additive effect if both classes of agents are combined.
In some tissues, which include the heart and the kidneys, there is a functioning non-ACE enzymatic pathway for processing angiotensinogen, i.e., chymase, which form AT II in such organs. In certain situations such as long-term hypertension, congestive heart failure and primary or secondary (due to diabetes mellitus) renal failure, an upregulation of this non-ACE pathway of AT II formation leads to both cardiac and vascular remodeling and restructuring. Thus, in both the heart and the kidneys, the ACE inhibitor would fail to influence non-ACE mediated AT II effects. But AT 1 ARB would be able to counteract this influence. This makes a case for the synergistic effect if both classes of agents are combined.
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 1 receptors in areas where AT II is synthesised by non-ACE pathway. Based on this assumption of rationality, clinical trials are being conducted to find out the effect of the ACE inhibitor plus ARB combination in patients with cardiovascular diseases.,
In both studies, results suggested a favourable effect of two drugs in combination [candesartan + enalapril/ lisinopril/ captopril/ ramipril, etc. valsartan + captopril in patients with heart failure. However, in patients with myocardial infarction, combining valsartan + captopril did not improve survival over and above what was obtained by full doses of each agent used individually, although the combination therapy resulted in an apparent reduction in the cumulative rate of admission for recurrent myocardial infarction or heart failure.
Hence, there is a robust evidence to combine these two classes of drugs in patients with hypertension and heart failure. However, it is advisable that each agent be titrated for optimum effective doses before switching to their fixed dose combination as the use of the latter would improve patient compliance.
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