Angiotensin Antagonists or Angiotensin Receptor Blockers or ARBs

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Chapter: Essential pharmacology : Drugs Affecting Renin-Angiotensin System And Plasma Kinins

Over the past 2 decades, several nonpeptide orally active AT1 receptor antagonists have been developed as alternatives to ACE inhibitors. These include losartan, candesartan, valsartan, telmisartan and irbesartan. Selective antagonists of AT2 receptors as well as combined AT1 + AT2 antagonists have also been produced.


ANGIOTENSIN ANTAGONISTS

(Angiotensin Receptor Blockers or ARBs)

 

Over the past 2 decades, several nonpeptide orally active AT1 receptor antagonists have been developed as alternatives to ACE inhibitors. These include losartan, candesartan, valsartan, telmisartan and irbesartan. Selective antagonists of AT2 receptors as well as combined AT1 + AT2 antagonists have also been produced.

 

Losartan

 

It is a competitive antagonist and inverse agonist of AII, 10,000 times more selective for AT1 than AT2 receptor; does not block any other receptor or ion channel, except thromboxane A2 receptor (has some platelet antiaggregatory property). It blocks all overt actions of AII, viz. vasoconstriction, central and peripheral sympathetic stimulation, release of aldosterone and Adr from adrenals, renal actions promoting salt and water reabsorption, central actions like thirst, vasopressin release and growth promoting actions on heart and blood vessels. No inhibition of ACE has been noted.

 

Pharmacologically, AT1 receptor antagonists differ from ACE inhibitors in the following ways:

 

·    They do not interfere with degradation of bradykinin and other ACE substrates: no rise in level or potentiation of bradykinin occurs. Consequently, ACE inhibitor related cough is rare.

 

·    They result in more complete inhibition of AT1 receptor activation, because alternative pathway of AII generation and consequent AT1 receptor activation remain intact with ACE inhibitors.

 

·    They result in indirect AT2 receptor activation. Due to blockade of AT1 receptor mediated feedback inhibition—more AII is produced which acts on AT2 receptors that remain unblocked. ACE inhibitors result in depression of both AT1 and AT2 activation.

 

The impact of these differences on clinical efficacy and therapeutic value of the two classes of RAS inhibitors is not known.

 

Losartan causes fall in BP in hypertensive patients which lasts for 24 hours, while HR remains unchanged and cardiovascular reflexes are not interfered. No significant effect on plasma lipid profile, carbohydrate tolerance, insulin sensitivity has been noted. It is also a mild uricosuric.

 

Pharmacokinetics

 

Oral absorption of losartan is not affected by food, but bioavailability is only 33% due to first pass metabolism. It is partially carboxylated in liver to an active metabolite (E3174) which is a 10–30 times more potent noncompetitive AT1 receptor antagonist. After oral ingestion peak plasma levels are attained at 1 hr for losartan and at 3–4 hours for E3174. Both compounds are 98% plasma protein bound, do not enter brain and are excreted by the kidney. The plasma t½ of losartan is 2 hr, but that of E3174 is 6–9 hr. No dose adjustment is required in renal insufficiency, but dose should be reduced in presence of hepatic dysfunction.

 

Adverse Effects

 

Losartan is well tolerated; has side effect profile similar to placebo. Like ACE inhibitors it can cause hypotension and hyperkalemia, but first dose hypotension is uncommon. Though, a few reports of dry cough have appeared, losartan is considered to be free of cough and dysgeusia inducing potential. Patients with a history of ACE inhibitor related cough have taken losartan without recurrence. Angioedema is reported in fewer cases. Headache, dizziness, weakness and upper g.i. side effects are mild and occasional. However, losartan has fetopathic potential like ACE inhibitors—not to be administered during pregnancy.

 

Dose: 50 mg OD, rarely BD; in liver disease or volume depletion 25 mg OD; addition of hydrochlorothiazide 12.5–25 mg enhances its effectiveness.

 

LOSACAR, TOZAAR, ALSARTAN 25, 50 mg tabs.

 

Candesartan

 

It has the highest affinity for the AT1 receptor and produces largely unsurmountable antagonism, probably due to slow dissociation from the receptors or receptor desensitization. Elimination occurs by both

hepatic metabolism and renal excretion with a t½ of 812 hours: action lasts 24 hours.

 

Dose: 8 mg OD (max 8 mg BD), liver/kidney impairment 4 mg OD.

 

CANDESAR 4, 8, 10 mg tab., CANDILONG, CANDESTAN 4, 8 mg tabs.

 

Irbesartan

 

The oral bioavailability of this AT1 antagonist is relatively high. It is partly metabolized and excreted mainly in bile. The t½ is ~12 hours.

 

Dose: 150–300 mg OD.

 

IROVEL, IRBEST 150, 300 mg tabs.

 

Valsartan

 

The AT1 receptor affinity of valsartan is similar to that of losartan. Its oral bioavailability averages 23% and food interferes with its absorption. Elimination occurs mainly by the liver in unchanged form with a t½ of 6–9 hours; action lasts 24 hours.

 

Dose: 80–160 mg OD 1 hour before meal (initial dose in liver disease 40 mg).

 

DIOVAN, STARVAL, VALZAAR 40, 80, 160 mg tabs.

 

Telmisartan

 

The AT1 receptor blocking action of telmisartan is similar to losartan, but it does not produce any active metabolite. After an oral dose, peak action occurs in 3 hours and action lasts > 24 hours. It is largely excreted unchanged in bile; dose reduction is needed in liver disease.

 

Dose: 20–80 mg OD.

 

TELMA, TELSAR, TELVAS 20, 40, 80 mg tabs.

 

Uses Of AT1 Receptor Antagonists (ARBS)

 

The ARBs have the same overall range of clinical utility as ACE inhibitors, but the suitability/ efficacy of one over the other is not clearly defined; may depend on the condition being treated and/ or specific features of the patient. The value of their combination versus monotherapy is also still unsettled.

 

Hypertension

 

Losartan and other ARBs are now first line drugs, comparable in efficacy and desirable features to ACE inhibitors, with the advantage of not inducing cough and a lower incidence of angioedema, rashes and dysgeusia. As such, their popularity has increased. Like ACE inhibitors, the maximum antihypertensive effect is reached in 2–4 weeks and ventricular/vascular hypertrophy/remodeling is arrested/reversed.

 

The Losartan intervention for endpoint reduction in hypertension (LIFE, 2002) study has found losartan to be more effective than βblockers in reducing stroke among 9000 hypertensive patients with left ventricular hypertrophy.

 

CHF

 

The ARBs afford clear cut symptomatic relief as well as survival benefit in CHF. However, their relative value compared to ACE inhibitors, especially in long-term morbidity and mortality reduction, is still uncertain.

 

A number of large randomized endpoint trials like Evaluation of losartan in the elderly (ELITE, 1997), ELITE (2000), OPTIMAAL (2002), Valsartan in acute MI (VALIANT, 2003) have produced contradictory results. Some find ACE inhibitors more effective, others find ARBs more effective, while still others find them equi-effective. For CHF, the current consensus is to use ACE inhibitors as the first choice drugs and to reserve ARBs for those who fail to respond well or who develop cough/angioedema/ other intolerance to ACE inhibitors.

 

Myocardial Infarction

 

The evidence so far indicates that utility of ARBs in MI, including long-term survival, is comparable to ACE inhibitors. However, the latter are generally used first, since there is greater experience with them.

 

Diabetic Nephropathy

 

Several studies have confirmed that ARBs are renoprotective in type 2 diabetes mellitus, independent of BP lowering. The magnitude of benefit is comparable to ACE inhibitors, but because of better tolerability profile, many consider ARBs to be the first choice now.

 

Combination of ACE Inhibitors With ARBs

 

There are theoretical reasons to combine an ACE inhibitor with an ARB to obtain more complete suppression of RAS and achieve added cardio-protection in CHF or renoprotection in diabetic nephropathy. These are:

 

·       AII is generated in several tissues (especially heart and kidney) by non-ACE mechanisms, whose effect can be blocked by ARBs.

 

·            ACE inhibitors produce bradykinin related vasodilatation and other effects that are not produced by ARBs.

 

·      ARBs cause compensatory increase in AII production that is checked by ACE inhibitors.

 

·        ARBs enhance unblocked AT2 receptor mediated effects that can be prevented by concurrent ACE inhibition.

 

Additional haemodynamic and symptomatic improvement over short-term has been obtained in CHF with addition of an ARB to exhisting ACE inhibitor therapy. However, several large randomized trials including Randomized evaluation of strategies for left ventricular dysfunction (RESOLVD, 1999), Valsartan heart failure trial (VALHe FT, 2001), CHAR-Madded trial (2003) of combinations of ARBs and ACE inhibitors Vs their monotherapy in affording mortality and other end point benefits in CHF have yielded controversial results. The Ongoing Telmisartan alone and in combination with ramipril global endpoint trial (ON TARGET) may clarify whether long-term use of ARB + ACE inhibitor combination is advisable or not.

 

In nondiabetic renal disease, the Combination treatment of ARB and ACE inhibitor randomized trial (COOPERATE, 2003) has concluded that ARB + ACE inhibitor combination therapy retards progression of nondiabetic renal disease to a greater extent compared with their monotherapy.

 

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