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Clinical Pharmacokinetics of Angiotensin II (AT1) Receptor Blockers in Hypertension

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Clinical Pharmacokinetics of Angiotensin II (AT1) Receptor Blockers in Hypertension Journal of Human Hypertension (2000) 14, Suppl 1, S73–S86 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension ZH Israili Emory University School of Medicine, Atlanta, GA, USA Angiotensin II receptor blockers (ARBs) represent a new The variation in the molecular structure of the ARBs class of effective and well tolerated orally active antihy- results in differences in the binding affinity to the recep- pertensive agents. Recent clinical trials have shown the tor and pharmacokinetic profiles. The differences added benefits of ARBs in hypertensive patients observed in lipid solubility, absorption/distribution, (reduction in left ventricular hypertrophy, improvement plasma protein binding, bioavailability, biotransform- in diastolic function, decrease in ventricular arrhyth- ation, plasma half-life, and systemic elimination influ- mias, reduction in microalbuminuria, and improvement ence the time of onset, duration of action, and efficacy in renal function), and cardioprotective effect in patients of the ARBs. On the basis of the daily mg dose, the anti- with heart failure. Several large long-term studies are in hypertensive potency of the ARBs follows the progress to assess the beneficial effects of ARBs on sequence: candesartan cilexetil Ͼ telmisartan Ӎ losar- cardiac hypertrophy, renal function, and cardiovascular tan Ͼ irbesartan Ӎ valsartan Ͼ eprosartan. and cerebrovascular morbidity and mortality in hyper- After oral administration, the ARBs are rapidly h) but 4–0.5 ؍ tensive patients with or without diabetes mellitus, and absorbed (time for peak plasma levels the value of these drugs in patients with heart disease they have a wide range of bioavailability (from a low of and diabetic nephropathy. 13% for eprosartan to a high of 60–80% for irbesartan); The ARBs specifically block the interaction of angiot- food does not influence the bioavailability, except for ensin II at the AT1 receptor, thereby relaxing smooth valsartan (a reduction of 40–50%) and eprosartan muscle, increasing salt and water excretion, reducing (increase). A limited dose-peak plasma levels/areas plasma volume, and decreasing cellular hypertrophy. under the plasma level-time curve proportionality is These agents exert their blood pressure-lowering effect observed for some of the ARBs. Most of these drugs mainly by reducing peripheral vascular resistance usu- have high plasma protein binding (95–100%); irbesartan ally without a rise in heart rate. Most of the commercially has the lowest binding among the group (90%). The ste- available ARBs control blood pressure for 24 h after ady-state volumes of distribution vary from a low of 9 L once daily dosing. Sustained efficacy of blood pressure (candesartan) to a high of 500 L (telmisartan). Plasma control, without any evidence of tachyphylaxis, has elimination half-life is short for candesartan cilexetil and been demonstrated after long-term administration (3 losartan (1–4 h), intermediate for eprosartan and valsar- years) of some of the ARBs. The efficacy of ARBs is tan (5–10 h), and longer for candesartan, irbesartan and similar to that of thiazide diuretics, beta-blockers, angi- telmisartan (11–38 h); the active metabolite of losartan otensin-converting enzyme inhibitors or calcium chan- has a longer half-life than for the parent drug. The drugs nel blockers in patients with similar degree of hyperten- and their active metabolites do not accumulate to a sig- sion. Higher daily doses, dietary salt restriction, and nificant extent after repeated dosing, except for telmis- concomitant diuretic or ACE inhibitor administration artan (100%). Most of the orally administered dose of amplify the antihypertensive effect of ARBs. The ARBs ARBs is excreted via bile into the faeces; from 2% have a low incidence of adverse effects (headache, (telmisartan) to 33% (candesartan) of the oral dose is upper respiratory infection, back pain, muscle cramps, excreted in the urine. In most cases, changes in pharma- fatigue and dizziness), even in the elderly patients. After cokinetic parameters due to aging, mild to moderate the approval of losartan, five other ARBs (candesartan renal disease and heart failure do not require dosage cilexetil, eprosartan, irbesartan, telmisartan, and modification; dosage has to be individualised for epros- valsartan) and three combinations with hydrochlorothia- artan, losartan, telmisartan and valsartan in patients zide (irbesartan, losartan and valsartan) have been with hepatic disease. In general, pharmacokinetic drug– approved as antihypertensive agents, and some 28 com- drug interactions are rare, with the exception of combi- pounds are in various stages of development. nation of digoxin and telmisartan. The ARBs are non-peptide compounds with varied The ARBs are an important treatment option for structures; some (candesartan, losartan, irbesartan, and hypertension, being relatively safe and efficacious. The valsartan) have a common tetrazolo-biphenyl structure. beneficial effects of the ARB therapy go beyond blood Except for irbesartan, all active ARBs have a carboxylic pressure control. They may prove to have beneficial acid group. Candesartan cilexetil is a prodrug, while los- haemodynamic and neurohormonal effects in heart fail- artan has a metabolite (EXP3174) which is more active ure and provide renoprotection in diabetic nephropathy. than the parent drug. No other metabolites of ARBs con- Journal of Human Hypertension (2000) 14, Suppl 1, S73– tribute significantly to the antihypertensive effect. S86. Keywords: angiotensin receptor blockers; candesartan; eprosartan; irbesartan; losartan; telmisartan; valsartan; pharmacoki- netics Introduction Correspondence: Dr Zafar H Israili, Department of Medicine, Emory University School of Medicine, GMB, 69 Butler Street, Angiotensin II receptor blockers (ARBs) represent a Atlanta, GA 30303, USA new class of effective and well tolerated orally Clinical pharmacokinetics of ARBs in hypertension ZH Israili S74 active antihypertensive drugs1–15 that inhibit the effect on blood pressure response to ARBs.2–15,42,52,63 renin-angiotensin system by selectively blocking the The ARBs do not alter the circadian rhythm of blood 1,16,17 24,31,34,40,53,62 AT1 subtype of angiotensin II receptor. A num- pressure. Therapy with the ARBs does ber of studies have demonstrated the efficacy of not cause first dose (excessive) hypotension or sig- ARBs (used as monotherapeutic agents or in combi- nificant orthostatic hypotension.2–15,27,49,50,59,60 Cess- nation with other antihypertensive drugs) in the ation of treatment with ARBs causes no rebound treatment of hypertension.1–15,18–63 Initial studies hypertension.2–15,59 indicate that ARBs, either alone or in combination ARB therapy does not have any effect on heart rate with angiotensin-converting enzyme (ACE) inhibi- and cardiac output or electrocardiographic data.2– tors, are also useful in the management of heart fail- 15,19,24,34,38,39,49,50,52,58,59 The ARBs do not impair cere- ure.64–75 Several large, long-term studies are in pro- brovascular regulation, and may even improve cog- gress (Table 1) to assess the beneficial effects of nitive function. Treatment with the ARBs does not ARBs on cardiac hypertrophy, renal function, and result in clinically significant alterations in labora- cardiovascular and cerebrovascular morbidity and tory measurements of serum chemistry, haema- mortality in hypertensive patients with or without tology and urinalysis.2–15,19,23,39,44,50,59,62,81 The ARBs diabetes mellitus, and the value of these drugs in do not impair glucose or lipid metabolism.2–15,19,81– patients with heart failure, acute myocardial infarc- 83 These drugs have no adverse effect on renal func- tion, and diabetic nephropathy. tion.2–15,36,39,45,84–89 As a result of favourable safety profile, discontinuation rate with ARBs is low. In a study, it was shown that ARBs had the highest 1- Angiotensin receptor blockers as antihypertensive year compliance rate among five major classes of drugs antihypertensive drugs.90 As antihypertensive agents, the ARBs are as effec- The benefits of ARB therapy of hypertension go tive as ACE inhibitors, thiazide diuretics, beta- beyond the reduction in blood pressure. The blockers or calcium channel blockers, often with a additional advantages of ARB therapy include: (1) better tolerability profile.2–15,21,25,29,35,43,60 The ARBs reduction in left ventricular hypertrophy;5,22,48,91–95 are effective and relatively safe in the elderly hyper- (2) improvement in diastolic function;96 (3) decrease tensives,2–15,42,52,63 and in patients with isolated sys- in ventricular arrhythmias;97 (4) reduction in the tolic hypertension.76 The antihypertensive efficacy abnormal QT dispersion;98 (5) improvement in of ARBs is enhanced when combined with diuretics, endothelial dysfunction;99 (6) improvement in large ACE inhibitors, calcium channel blockers, beta- artery compliance;95 (7) reduction in microalbumin- blockers, or alpha-blockers.2–15,37,52,54,55,57 In combi- uria;29,35,45,89,100,101 (8) preservation of or improve- nation with other classes of antihypertensive drugs, ment in renal function;36,39,45,84–89 except in patients the ARBs are also efficacious in the treatment of with severe congestive heart failure or renal artery JNC-VI Stage III (severe) hypertension.77–80 In gen- stenosis; (9) increase in insulin sensitivity;102,103 and eral, the blood pressure lowering efficacy of ARB (10) decrease in serum
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