Elsevier

The Lancet

Volume 355, Issue 9204, 19 February 2000, Pages 637-645
The Lancet

New Drug Classes
Angiotensin II receptor antagonists

https://doi.org/10.1016/S0140-6736(99)10365-9Get rights and content

Summary

Blockade of the renin-angiotensin system began as a way of studying the pathogenesis of cardiovascular disease with specific pharmacological probes. Oral activity, achieved by shortening the original peptide structures, transformed the probes into therapeutic agents, the angiotensin-converting enzyme (ACE) inhibitors. However, ACE is a non-specific target for blocking the renin-angiotensin enzymatic cascade. The availability of orally active drugs turned ACE inhibition into a therapeutic breakthrough but more specific blockade always seemed desirable. This goal has now been achieved with the orally active angiotensin II receptor antagonists; six are on the market and more are under development. This new class of drugs is equal in efficacy to ACE inhibitors, at least in hypertensive patients. Trials now underway will demonstrate whether angiotensin II receptor antagonists can prevent target-organ damage and reduce cardiovascular morbidity and mortality. If they do, these compounds might one day replace ACE inhibitors.

Section snippets

Renin-angiotensin system

Via ACE inhibitors and angiotensin II receptor antagonists the renin-angiotensin system has been characterised in greater detail (figure 1). The cascade starts with cleavage of angiotensinogen by renin to form the inactive decapeptide angiotensin I. Angiotensin I can also be generated by non-renin enzymes such as tonin or cathepsin. Thereafter, angiotensin I is converted by ACE into angiotensin II. Although other angiotensin peptides have biological effects, angiotensin II is the major

Angiotensin receptors

The final step of the renin-angiotensin cascade is activation of angiotensin II receptors by angiotensin II. The development of specific angiotensin II receptor antagonists (figure 2) has been a crucial step in the recognition of angiotensin II receptor subtypes.11 The clinically important ones are types 1 and 2. AT1 receptors are selectively inhibited by losartan and are sensitive to dithiothreitol whereas AT2 receptors are inhibited by PD 123177 and related compounds but are insensitive to

Pharmacology of AT1 receptor antagonists

So far, six orally active AT1 receptor antagonists have been accepted by the US Food and Drug Administration and launched in the USA and various European countries for the treatment of hypertension (panel 2). Others are being developed. The pharmacodynamic and pharmacokinetic characteristics are summarised in panel 3. One feature of most, if not all, AT1 receptor antagonists is “insurmountable blockade”. This refers to the non-parallel displacement of the angiotensin II response curves seen in

Preclinical pharmacology

AT1 receptor antagonists dose-dependently attenuate the pressor response to intravenous angiotensin II24, 25, 26, 27, 28, 29 and reduce blood pressure in animal models of hypertension. They also reduce cardiac hypertrophy and improve haemodynamics in animal models of heart failure.24, 30, 31, 32 They increase sodium excretion and diuresis and lower blood pressure and proteinuria and reduce glomerulosclerosis in rats with chronic renal failure.33, 34 In Dahl salt-sensitive and in stroke-prone

Are there differences between angiotensin II receptor antagonists?

These drugs have the same mechanism of action but different pharmacokinetic profiles, which may account for potential differences in efficacy. Also the starting dose may have been chosen on different criteria. When the recommended starting doses of losartan (50 mg), valsartan (80 mg), and irbesartan (150 mg) were compared for their ability to block the blood pressure response to exogenous angiotensin II in healthy volunteers, irbesartan exhibited the greatest inhibition of the renin-angiotensin

Safety and tolerability

Several thousands of patients have taken part in double-blind controlled studies evaluating the antihypertensive efficacy of the various angiotensin II receptor antagonists. A characteristic of this class of drugs is an adverse-effect profile comparable with that seen in the placebo groups;63 none of the six drugs reviewed here has a specific, dose-dependent adverse effect that can be attributed to the drug itself.

Because cough is seen as a class effect of ACE inhibitors, studies with these new

Cardiac and renal effects

Renin-angiotensin system inhibition with an ACE inhibitor is currently a recommended approach for the management of heart failure and appears to be very effective for left-ventricular hypertrophy in hypertensive patients. A recent study with valsartan shows that this angiotensin II antagonist also produces a significant regression of left-ventricular hypertrophy in previously untreated patients with essential hypertension.82 In heart failure, short-term studies indicate that AT1 receptor

Combining AT1 receptor antagonist with ACE inhibitors

Because of the pharmacokinetic properties of ACE inhibitors and the possibility that angiotensin II is generated by non-ACE pathways, there is a frequent concern about incomplete blockade of the renin-angiotensin system with ACE inhibitors. Additional efficacy might be expected theoretically from a combination of an ACE inhibitor with an AT1 receptor antagonist but if the antagonist blocks all the effects of angiotensin II independently of circulating angiotensin II in the circulation, ACE

Ongoing clinical trials

Blood pressure, proteinuria, left-ventricular hypertrophy, and haemodynamics are surrogate endpoints and large clinical trials are underway to establish the morbidity and mortality benefits of specific AT1 receptor blockade in patients with hypertension, chronic renal failure, or heart failure (panel 4). These studies101, 102, 103 should also help to determine whether the mechanistic differences between ACE inhibitors and angiotensin II blockers lead to significant clinical differences, and

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