NONPEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS

Pharmacological Effects: The angiotensin II receptor blockers (ARBs) available for clinical use bind to the AT1 receptor with high affinity and generally are more than 10,000-fold selective for the AT1 receptor versus the AT2 receptor. The rank-order affinity of the AT1 receptor for ARBs is candesartan = omesartan irbesartan = eprosartan telmisartan = valsartan = EXP 3174 (the active metabolite of losartan) losartan. Although binding of ARBs to the AT1 receptor is competitive, the inhibition by ARBs of biological responses to angiotensin II often is insurmountable; i.e., the maximal response to angiotensin II cannot be restored in the presence of the ARB regardless of the concentration of angiotensin II added to the experimental preparation. Of the currently available ARBs, candesartan suppresses the maximal response to angiotensin II the most, whereas insurmountable blockade by irbesartan, eprosartan, telmisartan, and valsartan is less. Although losartan antagonism is surmountable, its active metabolite, EXP 3174, causes some degree of insurmountable blockade. The mechanism of insurmountable antagonism by ARBs may be due to slow dissociation kinetics of the compounds from the AT1 receptor; however, a number of other factors may contribute, such as ARB-induced receptor internalization and alternative binding sites for ARBs on the AT1 receptor. Regardless of the mechanism, insurmountable antagonism has the theoretical advantage of sustained receptor blockade even with increased levels of endogenous ligand and with missed doses of drug. Whether this theoretical advantage translates into an enhanced clinical performance remains to be determined.

The pharmacology of ARBs is well described. ARBs potently and selectively inhibit, both in vitro and in vivo, most of the biological effects of angiotensin II, including angiotensin II-induced:(1) Contraction of vascular smooth muscle(2) Rapid pressor responses(3) slow pressor responses (4) Thirst(5) Vasopressin release (6) aldosterone secretion (7) Release of adrenal catecholamine (8) Enhancement of noradrenergic neurotransmission (9) Increases in sympathetic tone(10) Changes in renal function(11) Cellular hypertrophy and hyperplasia.

A critical issue is whether or not ARBs are equivalent to ACE inhibitors with regard to therapeutic efficacy. Although both classes of drugs block the renin-angiotensin system, ARBs differ from ACE inhibitors in several important aspects: (1) ARBs reduce activation of AT1 receptors more effectively than do ACE inhibitors. ACE inhibitors reduce the biosynthesis of angiotensin II produced by the action of ACE on angiotensin I but do not inhibit alternative non-ACE angiotensin II-generating pathways. Because ARBs block the AT1 receptor, the actions of angiotensin II via the AT1 receptor are inhibited regardless of the biochemical pathway leading to angiotensin II formation.

(2) In contrast to ACE inhibitors, ARBs permit activation of AT2 receptors. ACE inhibitors increase renin release; however, because ACE inhibitors block the conversion of angiotensin I to angiotensin II, ACE inhibition is not associated with increased levels of angiotensin II. ARBs also stimulate renin release; however, with ARBs, this translates into a several-fold increase in circulating levels of angiotensin II. Because AT2 receptors are not blocked by clinically available ARBs, this increased level of angiotensin II is available to activate AT2 receptors. (3) ACE inhibitors may increase angiotensin(1-7) levels more than do ARBs. ACE is involved in the clearance of angiotensin(1-7), so inhibition of ACE may increase angiotensin(1-7) levels more so than do ARBs. (4) ACE inhibitors increase the levels of a number of ACE substrates, including bradykinin and Ac-SDKP. ACE is a nondiscriminating enzyme that processes an array of substrates; inhibiting ACE therefore increases the levels of ACE substrates and decreases the levels of their corresponding products. Whether the pharmacological differences between ARBs and ACE inhibitors result in significant differences in therapeutic outcomes is an open question.

The specific efficacy of each ARB within this class is made of up of a combination three pharmacodynamic and pharmacokinetic parameters. For these three key PD/ PK areas that indicate efficacy, it is important to see that one needs a combination of all three at an effective level; the parameters of the three characteristics will need to be compiled into a table similar to one below, eliminating duplications and arriving at consensus values; the latter are at variance now.

Pressor inhibitio:Pressor inhibition at trough level - this clinically important measurement relates to the amount of blockade or inhibition of the BP raising effect of angiotensin II. Pressor inhibition is not a measure of blood pressure efficacy, though. The rates as listed in the US FDA Package Inserts for inhibition of this effect at the 24th hour for the ARBs are as follows: (all doses listed in PI are included)

Valsartan 80 mg 30%

Telmisartan 80 mg 40%

Losartan 100 mg 25–40%

Irbesartan 150 mg 40%

Irbesartan 300 mg 60%

Olmesartan 20 mg 61%

Olmesartan 40 mg 74%AT1 affinity:AT1 affinity vs AT2 is not a meaningful efficacy measurement of blood pressure response. The specific AT1 affinity relates to how specifically attracted the medicine is for the correct receptor, the US FDA Package Insert rates for AT1 affinity are as follows:

Losartan 1000 fold

Telmisartan 3000 fold

Irbesartan 8500 fold

Olmesartan 12500 fold

Valsartan 20000 foldBiological half life:The third area that completes the overall efficacy picture of an ARB is its biological half life. The half-lives from the US FDA Package Inserts are as follows:

Valsartan 6 hours

Losartan 6–9 hours

Irbesartan 11–15 hours

Olmesartan 13 hours

Telmisartan 24 hours

Clinical Pharmacology. Oral bioavailability of ARBs generally is low (50%, except for irbesartan, with 70% available), and protein binding is high (90%).

Candesartan Cilexetil (ATACAND). Candesartan cilexetil is an inactive ester prodrug that is completely hydrolyzed to the active form, candesartan, during absorption from the gastrointestinal tract. Peak plasma levels are obtained 3 to 4 hours after oral administration, and the plasma half-life is about 9 hours. Plasma clearance of candesartan is due to renal elimination (33%) and biliary excretion (67%). The plasma clearance of candesartan is affected by renal insufficiency but not by mild to moderate hepatic insufficiency. Candesartan cilexetil should be administered orally once or twice daily for a total daily dosage of 4 to 32 mg.

Eprosartan (TEVETEN). Peak plasma levels are obtained approximately 1 to 2 hours after oral administration, and the plasma half-life ranges from 5 to 9 hours. Eprosartan is metabolized in part to the glucuronide conjugate, and the parent compound and its glucuronide conjugate are cleared by renal elimination and biliary excretion. The plasma clearance of eprosartan is affected by both renal insufficiency and hepatic insufficiency. The recommended dosage of eprosartan is 400 to 800 mg/day in one or two doses.

Irbesartan (AVAPRO). Peak plasma levels are obtained approximately 1.5 to 2 hours after oral administration, and the plasma half-life ranges from 11 to 15 hours. Irbesartan is metabolized in part to the glucuronide conjugate, and the parent compound and its glucuronide conjugate are cleared by renal elimination (20%) and biliary excretion (80%). The plasma clearance of irbesartan is unaffected by either renal or mild to moderate hepatic insufficiency. The oral dosage of irbesartan is 150 to 300 mg once daily.

Losartan (COZAAR). Approximately 14% of an oral dose of losartan is converted to the 5-carboxylic acid metabolite EXP 3174, which is more potent than losartan as an AT1-receptor antagonist. The metabolism of losartan to EXP 3174 and to inactive metabolites is mediated by

CYP2C9 and CYP3A4. Peak plasma levels of losartan and EXP 3174 occur approximately 1 to 3 hours after oral administration, respectively, and the plasma half-lives are 2.5 and 6 to 9 hours, respectively. The plasma clearances of losartan and EXP 3174 (600 and 50 ml/min, respectively) are due to renal clearance (75 and 25 ml/min, respectively) and hepatic clearance (metabolism and biliary excretion). The plasma clearance of losartan and EXP 3174 is affected by hepatic but not renal insufficiency. Losartan should be administered orally once or twice daily for a total daily dose of 25 to 100 mg. In addition to being an ARB, losartan is a competitive antagonist of the thromboxane A2 receptor and attenuates platelet aggregation. Also, EXP3179, an active metabolite of losartan, reduces COX-2 mRNA up-regulation and COX-dependent prostaglandin generation.

Olmesartan Medoxomil (BENICAR). Olmesartan medoxomil is an inactive ester prodrug that is completely hydrolyzed to the active form, olmesartan, during absorption from the gastrointestinal tract. Peak plasma levels are obtained 1.4 to 2.8 hours after oral administration, and the plasma half-life is between 10 and 15 hours. Plasma clearance of olmesartan is due to both renal elimination and biliary excretion. Although renal impairment and hepatic disease decrease the plasma clearance of olmesartan, no dose adjustment is required in patients with mild to moderate renal or hepatic impairment. The oral dosage of olmesartan medoxomil is 20 to 40 mg once daily.

Telmisartan (MICARDIS). Peak plasma levels are obtained approximately 0.5 to 1 hour after oral administration, and the plasma half-life is about 24 hours. Telmisartan is cleared from the circulation mainly by biliary secretion of intact drug. The plasma clearance of telmisartan is affected by hepatic but not renal insufficiency. The recommended oral dosage of telmisartan is 40 to 80 mg once daily.

Valsartan (DIOVAN). Peak plasma levels occur approximately 2 to 4 hours after oral administration, and the plasma half-life is about 9 hours. Food markedly decreases absorption. Valsartan is cleared from the circulation by the liver (about 70% of total clearance). The plasma clearance of valsartan is affected by hepatic but not renal insufficiency. The oral dosage of valsartan is 80 to 320 mg once daily.

Therapeutic Uses of Angiotensin II-Receptor Antagonists: All ARBs are approved for the treatment of hypertension. In addition, irbesartan and losartan are approved for diabetic nephropathy, losartan is approved for stroke prophylaxis, and valsartan is approved for heart failure patients who are intolerant of ACE inhibitors. The efficacy of ARBs in lowering blood pressure is comparable with that of other established antihypertensive drugs, with an adverse-effect profile similar to that of placebo. ARBs also are available as fixed-dose combinations with hydrochlorothiazide.

Losartan is well tolerated in patients with heart failure and is comparable to enalapril with regard to improving exercise tolerance. The Evaluation of Losartan in the Elderly (ELITE) study reported that in elderly patients with heart failure, losartan was as effective as captopril in improving symptoms and reduced mortality more than did captopril. However, the greater reduction in mortality by losartan was not confirmed in the larger Losartan Heart Failure Survival Study (ELITE II) trial; in fact, captopril tended to have a more favorable effect on

several outcome measures. The results of the OPTIMAAL trial support the conclusions of the ELITE II study favoring captopril over losartan. However, the Valsartan in Acute Myocardial Infarction (VALIANT) trial demonstrated that valsartan is as effective as captopril in patients with myocardial infarction complicated by left ventricular systolic dysfunction with regard to all-cause-mortality. Both valsartan and candesartan reduce mortality and morbidity in heart failure patients. Current recommendations are to use ACE inhibitors as first-line agents for the treatment of heart failure and to reserve ARBs for treatment of heart failure in patients who cannot tolerate or have an unsatisfactory response to ACE inhibitors. At present, there is conflicting evidence regarding the advisability of combining an ARB and an ACE inhibitor in heart failure patients.

In part via blood pressure-independent mechanisms, ARBs are renoprotective in type 2 diabetes mellitus. Based on these results, many experts now consider them the drugs of choice for renoprotection in diabetic patients. The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study demonstrated the superiority of an ARB compared with a 1 adrenergic receptor antagonist with regard to reducing stroke in hypertensive patients with left ventricular hypertrophy. Also, irebesartan appears to maintain sinus rhythm in patients with persistent, long-standing atrial fibrillation. Losartan is reported to be safe and highly effective in the treatment of portal hypertension in patients with cirrhosis and portal hypertension without compromising renal function.

Adverse Effects: The incidence of discontinuation of ARBs owing to adverse reactions is comparable with that of placebo. Unlike ACE inhibitors, ARBs do not cause cough, and the incidence of angioedema with ARBs is much less than with ACE inhibitors. As with ACE inhibitors, ARBs have teratogenic potential and should be discontinued before the second trimester of pregnancy. ARBs should be used cautiously in patients whose arterial blood pressure or renal function is highly dependent on the renin-angiotensin system (e.g., renal artery stenosis). In such patients, ARBs can cause hypotension, oliguria, progressive azotemia, or acute renal failure. ARBs may cause hyperkalemia in patients with renal disease or in patients taking K+ supplements or K+-sparing diuretics. ARBs enhance the blood pressure-lowering effect of other antihypertensive drugs, a desirable effect but one that may necessitate dosage adjustment.

ARBs in Bangladesh:

Drug Company name Brand name DoseLosartan potassium

Square

Eskayef

Renata

Beximco

Angilock

Cardon

Ostan

Prosan

25mg, 50mg increasing upto 100mg once daily

Ref: Goodman & Gilman, Wikipedia, Tripathi.