Clinical pharmacokinetics of angiotensin II (AT₁) receptor blockers in hypertension

Abstract

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy.

The ARBs specifically block the interaction of angiotensin II at the AT₁ receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development.

The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect.

The variation in the molecular structure of the ARBs results in differences in the binding affinity to the receptor and pharmacokinetic profiles. The differences observed in lipid solubility, absorption/distribution, plasma protein binding, bioavailability, biotransformation, plasma half-life, and systemic elimination influence the time of onset, duration of action, and efficacy of the ARBs. On the basis of the daily mg dose, the antihypertensive potency of the ARBs follows the sequence: candesartan cilexetil > telmisartan losartan > irbesartan valsartan > eprosartan.

After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels = 0.5–4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60–80% for irbesartan); food does not influence the bioavailability, except for valsartan (a reduction of 40–50%) and eprosartan (increase). A limited dose-peak plasma levels/areas under the plasma level-time curve proportionality is observed for some of the ARBs. Most of these drugs have high plasma protein binding (95–100%); irbesartan has the lowest binding among the group (90%). The steady-state volumes of distribution vary from a low of 9 L (candesartan) to a high of 500 L (telmisartan). Plasma elimination half-life is short for candesartan cilexetil and losartan (1–4 h), intermediate for eprosartan and valsartan (5–10 h), and longer for candesartan, irbesartan and telmisartan (11–38 h); the active metabolite of losartan has a longer half-life than for the parent drug. The drugs and their active metabolites do not accumulate to a significant extent after repeated dosing, except for telmisartan (100%). Most of the orally administered dose of ARBs is excreted via bile into the faeces; from 2% (telmisartan) to 33% (candesartan) of the oral dose is excreted in the urine. In most cases, changes in pharmacokinetic parameters due to aging, mild to moderate renal disease and heart failure do not require dosage modification; dosage has to be individualised for eprosartan, losartan, telmisartan and valsartan in patients with hepatic disease. In general, pharmacokinetic drug–drug interactions are rare, with the exception of combination of digoxin and telmisartan.

The ARBs are an important treatment option for hypertension, being relatively safe and efficacious. The beneficial effects of the ARB therapy go beyond blood pressure control. They may prove to have beneficial haemodynamic and neurohormonal effects in heart failure and provide renoprotection in diabetic nephropathy. Journal of Human Hypertension