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The Roll of ARBs in

Hypertension

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Introduction of RAAS«

There are many important factors that together keep the blood pressureat a certain level. A central role in maintaining the blood pressure is

 played by a chain of key hormonal reactions. The first step in the chainis the production of renin in the kidneys when the kidneys detect lower blood pressure. The renin stimulates the formation of a protein called angiotensin I, which is then converted to angiotensin II by theangiotensin- converting enzyme in the lungs. Angiotensin II is the most  powerful constrictor of blood vessels known. This effect of constricting

blood vessels tends to elevate the blood pressure. Angiotensin II alsocauses the secretion of an additional blood pressure elevating hormonein the adrenal glands, called aldosterone.

This chain of blood pressure regulating hormones is referred to as therenin-angiotensin-aldosterone (RAA) hormonal system.

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Blocking of RAAS through medicine..

Several classes of blood pressure lowering (anti-

hypertensive) medications may have some effectson this hormonal system. However, two classes of 

drugs have the most substantial effects on the RAA

system. These two classes are the angiotensin

receptor blockers (ARB drugs) and the angiotensin

converting enzyme inhibitors (ACE inhibitors). Bothof these classes of drugs lower blood pressure by

blocking certain specific steps in the RAA chain.

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The mode of action of ARB«

 AT1 Receptor:

Vasoconstriction,Sympathetic activation,

Cellular growth,

Fibrosis, Thrombosis

 AT2 Receptor:

Vasodilation, Apoptosis, Inhibition of 

cellular growth

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For WhatConditions ARBs are Used?

 ARBs are used for controlling high blood pressure,treating heart failure, and preventing kidney failure inpeople with diabetes or high blood pressure. Theymay also prevent diabetes and reduce the risk of stroke in patients with high blood pressure and anenlarged heart. ARBs may also prevent therecurrence of atrial fibrillation. Since these

medications have effects that are similar to those of  ACE inhibitors, they often are used when ACEinhibitors are not tolerated by patients (for example,due to excessive coughing)

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ARBs available in Market !

Losartan

Valsartan Irbesartan

Candesartan

Telmisartan Eprosartan

Olmesartan

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Latest FDA approved ARB !

Olmesartan Medoxomil is the latest FDA

approved ARB. SEARLE has launched it first time in

Pakistan with the brand name of OLESTA.

Which is available in two strengths 20 mg

and 40 mg.

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MORE Study «

European researchers claim to have identified anantiatherosclerotic effect of an ARB, olmesartan medoxomil

(olmesartan), that is independent of its blood-pressure loweringeffect. The principal results of the Multicenter Olmesartan Atherosclerosis Regression Evaluation (MORE) trial, presentedat the 17th European Meeting on Hypertension by Prof. KlausO. Stumpe, MD (University Clinic Bonn, Bonn, Germany),showed that compared with the beta-blocker atenolol,olmesartan produced similar reductions in carotid intima media

thickness (IMT), but that olmesartan also reduced the volume of the larger plaques.[1] These changes occurred in the presenceof blood pressure reductions similar to those produced byatenolol.Presenter: Prof. Klaus O. Stumpe, MD (University Clinic Bonn, Bonn, Germany)

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Olmesartan versus CaptoprilThe Williams Study..

In a multicenter, double-blind study,27291 patients with mild tomoderate hypertension(mean sitting diastolic BP of 95 to114 mm Hg)

were randomly assigned toreceive either olmesartan medoxomil (5mg)once daily or captopril (25 mg) twicedaily for up to 12 weeks. The dosesof eitherdrug could be doubled after fourweeks of therapy if thediastolic BP was ator above 90 mm Hg or had decreased less than 10 mm Hg from baseline values. The dosage of either drug could bedoubled again after eight weeks if the diastolic BP remained uncontrolled.The reduction in the seated trough diastolic BP from the

baseline was greater in the olmesartan medoxomil group (±9.9 +0.6 mmHg) than in the captopril group (±6.8 + 0.6 mm Hg; mean difference ±3.1mm Hg, 95% confidence interval [CI] of ±4.8, ±1.5). In addition,reductions in mean systolic BP were greater in the olmesartanmedoxomil group (±14.7 + 1.1 mm Hg) than in the captopril group (±7.1 +1.1 mm Hg; mean difference ±7.6 mm Hg, 95% CI of ±10.4, ±4.7).

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Olmesartan versus other Angiotensin IIreceptor Blockers (The Ball Study)

In a multicenter, double-blind study,28 patients with mild to moderatehypertension (mean sitting diastolic BP of 95 to 114 mm Hg) wererandomly assigned to receive either olmesartan medoxomil 10 mgonce daily (n = 158) or losartan 50 mg once daily (n = 152) for 12weeks. After four weeks of treatment, if the diastolic BP was greater than 90 mm Hg or had decreased less than 10 mm Hg from thebaseline, the dose of either drug could be doubled. If the diastolic BPremained uncontrolled, HCTZ (12.5 mg) once daily could be added tothe treatment regimen after 12 weeks and could be doubled after 16weeks. After 12 weeks, the mean reduction in seated trough diastolic

BP in the olmesartan medoxomil group (±10.6 + 0.5 mm Hg) wassignificantly greater than in the losartan group (±8.5 + 0.6 mm Hg;mean difference ±2.1 mm Hg, 95% CI of ±3.6, ±0.5). Further, thereduction in mean the seated systolic BP was greater in theolmesartan group than in the losartan group (±14.9 + 1.0 vs. ±11.6 +1.0 mm Hg; mean difference ±3.3 mm Hg, 95% CI of ±6.0, ±0.6).

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The Oparil Study

In another multicenter, double-blind study,29 588 patients with hypertension(mean sitting diastolic BP of 100 to 115 mm Hg) were randomly assigned toreceive one of four AII-receptor antagonists (olmesartan medoxomil 20 mg

once daily, losartan 50 mg once daily, valsartan 80 mg once daily, or irbesartan 150 mg once daily) for eight weeks. After eight weeks, the meanreduction in the seated cuff diastolic BP from the baseline value wassignificantly greater in the patients receiving olmesartan medoxomil (±11 mmHg) than in patients receiving losartan (±8.2 mm Hg, P = < .0002), valsartan (±7.9 mm Hg; P < .0001), or irbesartan (±9.9 mm Hg, P = .0412). Although thereduction in the mean seated systolic BP was not significant, it was also greater in patients receiving olmesartan medoxomil than in those receiving losartan (±9.5 mm Hg), valsartan (±8.4 mm Hg), and irbesartan (±11.0 mm Hg). At week

eight, the mean 24-hour ambulatory systolic BP was reduced significantly morewith olmesartan medoxomil (±12.5 mm Hg) than with losartan and valsartan (±9.0 and ±8.1 mm Hg; P < .05) but not more than with irbesartan (±11.3 mmHg).

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PHARMACOKINETICS

Olmesartan medoxomil, which is administered as a prodrug, is rapidly

and completely de-esterified to the active metabolite olmesartan(RNH-6270) during absorption from the gastrointestinal tract. Followingthe conversion of olmesartan medoxomil to olmesartan, virtually nofurther metabolism occurs. The bioavailability of olmesartan isapproximately 26%, similar to that of losartan and valsartan. Followingoral administration, the peak plasma concentration (Cmax) of olmesartan is reached after one to two hours. The bioavailability of olmesartan is not affected by food. Olmesartan is eliminated in a

biphasic manner, with a terminal elimination half-life of approximately13 hours. It is highly bound to plasma proteins (99%) and does notpenetrate red blood cells. Olmesartan takes approximately three to fivedays to reach a steady state, and there is no accumulation in plasmawith once-daily dosing.

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Pressor Inhibition«

Pressor inhibition at trough level - this clinically important 

measurement relates to the amount of blockade or inhibition of the BPraising effect of angiotensin II. Pressor inhibition is not a measure of blood pressure efficacy, though. The rates as listed in the US FDAPackage 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 2540% Irbesartan 150 mg 40% Irbesartan 300 mg 60% Olmesartan 20 mg 61% Olmesartan 40 mg 74%

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AT1 Affinity«

 AT1 affinity vs AT2 is not a meaningful efficacymeasurement of blood pressure response. The

specific AT1 affinity relates to how specificallyattracted the medicine is for the correct receptor, theUS FDA Package Insert rates for AT1 affinity are asfollows:

Losartan 1000 fold

Telmisartan 3000 fold Irbesartan 8500 fold

Olmesartan 12500 fold

Valsartan 20000 fold

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Thanks !