Angiotensin receptor antagonists for the treatment of hypertension

Introduction
Angiotensin (AT₁) receptor antagonists are a new class of drugs for the treatment of hypertension.¹ Like ACE inhibitors, they block the renin angiotensin system, but at a different step.

Physiology
The renin angiotensin system (RAS) is a bioenzymatic cascade which results in the formation of the vasoactive peptide angiotensin II (Fig. 1). Angiotensin II acts on specific cell membrane receptors to produce its physiological effects. In humans, there are two specific angiotensin receptors. The AT₁ receptor is responsible for all the known physiological actions. This new class of drugs selectively blocks the effect of angiotensin II on AT₁ receptors only. Confusing though this may seem, the class is referred to as AT₁ receptor antagonists. The function of the AT₂ receptor is unknown.

Angiotensin II is important in blood pressure control and sodium and water homeostasis, as well as cardiovascular function and structure. It has been implicated in the pathophysiology of hypertension, congestive heart failure, diabetic nephropathy and in vascular disease including atherosclerosis. Non-selective inhibition of the RAS by ACE inhibitors has proved to be very effective in treating hypertension and reducing the morbidity and mortality of congestive heart failure. The ACE inhibitors also slow the progression of diabetic nephropathy and prevent ventricular remodelling, thereby reducing mortality after acute myocardial infarction.

The AT₁ receptor antagonists offer several possible advantages over the ACE inhibitors. As the ACE inhibitors are competitive inhibitors, their blockade can be overcome if the concentration of angiotensin I rises. This probably explains why concentrations of plasma angiotensin II return to normal with chronic ACE inhibitor administration. ACE is not a very fastidious enzyme. It has other substrates beside angiotensin II including bradykinin, substance P and the tachykinins. The adverse effects of cough and angioedema probably result from the accumulation of bradykinin or other tachykinins. Alternatively, there are some experimental data suggesting that bradykinin may also contribute to some of the beneficial effects of ACE inhibitors, although the evidence is very conflicting. Lastly, alternative non-ACE pathways, in particular human cardiac chymase for the formation of angiotensin II, have been proposed and these pathways are not blocked by ACE inhibitors.

All the known effects of angiotensin II are mediated by its interaction with its specific receptor. The AT₁ receptor antagonists therefore offer the possibility of a more precise mode of action and a more complete blockade of the RAS.²

Fig. 1 Renin angiotensin enzymatic pathway for the production of angiotensin II, its receptor, and physiological actions. The angiotensin receptor antagonist (AT1RA) acts at one of 3 steps where the pathway may be blocked.

AT₁ receptor antagonists
Several orally active AT₁ receptor antagonists are in various stages of clinical development. Losartan is the prototype of the angiotensin II receptor antagonist class.³ It has been followed by irbesartan, eprosartan and candesartan and others are coming, such as valsartan, telmisartan and tasosartan. By binding to the AT₁ receptor, all these drugs prevent the vasoconstrictor and other actions of angiotensin II. The majority of them produce non-competitive or insurmountable antagonism; even with increasing levels of angiotensin II, the blockade cannot be overcome.

The absorption of losartan, candesartan and irbesartan is not affected by food, whereas valsartan's bioavailability is decreased by food. The drugs vary in their potency, but most of them are very long acting. Some are prodrugs (losartan, candesartan) that have to be converted to an active compound. Losartan, although itself an antagonist, is converted to EXP3174 which is more potent and much longer acting than the parent compound. AT₁ receptor antagonists also vary in their metabolism, some being excreted exclusively by the kidney, whereas others are excreted both by hepatic metabolism and renal excretion.

The drugs have little or no effect on the AT₂ receptor. Similarly, they have no significant affinity for other hormone receptors or ion channels.

Observations from clinical studies
AT₁ receptor antagonists lower the blood pressure of hypertensive patients. Their action is slow in onset avoiding first-dose hypotension, although this may still occur, particularly if patients are salt depleted. Ambulatory blood pressure monitoring confirms that their hypotensive effect lasts for 24 hours, without changing the normal circadian rhythm of the blood pressure. Most published data refer to losartan. Extensive comparative multi centre trials⁴ show that losartan (50-100 mg) is as efficacious as atenolol (100 mg), felodipine ER (10 mg), amlodipine (5 mg) and enalapril (20 mg). In clinical trials, the other AT₁ receptor antagonists appear to be equally efficacious in young as well as adult patients, in men and women and also in mild, moderate or severe hypertension.

The class tends not to affect lipids, blood glucose and, in people with normal renal function, potassium. Their effect is potentiated by diuretics, but they blunt the adverse metabolic effects of diuretics.³ Losartan itself has an interesting uricosuric action which is not shared by its active metabolite. This leads to small falls in uric acid concentrations.

Tolerability and adverse effects
One of the outstanding features of the AT₁ receptor antagonists has been their tolerability. In numerous double-blind placebo-controlled clinical trials or in direct comparative studies with other groups of antihypertensive drugs, the numbers of drug-related adverse events were considerably lower with losartan and were not significantly different from placebo.⁴ The withdrawal rates due to adverse events were also very low being comparable to placebo and lower than with diuretics, beta blockers and calcium antagonists.

Cough, which is a frequent adverse effect of ACE inhibitors, has been studied in double-blind clinical trials. The rates of cough for losartan have been shown to be comparable to placebo or hydrochlorothiazide. A specific study of patients known to cough on ACE inhibitors randomly assigned them to either be rechallenged with an ACE inhibitor or to receive a diuretic or losartan. The frequency of coughing on losartan was the same as with the diuretic and comparable to the placebo range, and this was statistically significantly less than in the group rechallenged with an ACE inhibitor.⁵ The AT₁ receptor antagonists therefore offer the opportunity of achieving an increase in the response rate with increasing dosage without an increase in the adverse effect rate.

Like the ACE inhibitors, AT₁ receptor antagonists should be avoided in patients with renal artery stenosis and are contraindicated in pregnancy.

Role in cardiovascular therapy
Whether or not the AT₁ receptor antagonists have the other beneficial actions of ACE inhibitors is now being investigated in clinical trials. In experimental animals, the AT₁ receptor antagonists reverse left ventricular hypertrophy, prevent stroke, ventricular remodelling and cardiac failure and slow the progression of renal diabetic nephropathy.² Ongoing studies are addressing each of these issues.

The LIFE study is a large morbidity/mortality trial in 8300 hypertensive patients which is also evaluating the link between regression of left ventricular hypertrophy and reduced cardiovascular events. There are two ongoing studies evaluating the possible renal protective effects of losartan or irbesartan in patients with non-insulin dependent diabetes mellitus and micro albuminuria. Lastly, a pilot study of losartan in elderly patients with moderately severe heart failure (ELITE) was recently published.⁶ This showed an increased survival in those patients treated with losartan over those treated with captopril. That result, however, must be interpreted with caution as this was only a small pilot study and mortality was not the primary endpoint. The ELITE 2 study, a large outcome study in heart failure, is now being undertaken.

Currently, in Australia, it is likely that most practitioners will prescribe the AT₁ receptor antagonists in hypertensive patients who have proved to be intolerant of ACE inhibitors. Their use in the other clinical situations in which ACE inhibitors have proved to be so successful will have to await the outcome of the controlled clinical trials. However, it must be borne in mind that the long-term outcome data, both with respect to benefits and safety, are as yet unknown.

Professor Johnston has acted as a consultant to Merck Sharp & Dohme (Aust) Pty Ltd and is also on the International Cardiovascular Advisory Boards of Bristol-Myers Squibb Pharmaceuticals and Astra Pharmaceuticals Pty Ltd.