The Roll of ARBs in

Hypertension
Introduction of RAAS…
 There are many important factors that together keep the blood pressure at 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 chain is 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 the angiotensin- 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 also causes the secretion of an additional blood pressure
elevating hormone in the adrenal glands, called aldosterone.
 This chain of blood pressure regulating hormones is referred to as the renin-
angiotensin-aldosterone (RAA) hormonal system.
Blocking of RAAS through medicine..

 Several classes of blood pressure lowering (anti-

hypertensive) medications may have some effects
on 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). Both
of these classes of drugs lower blood pressure by
blocking certain specific steps in the RAA chain.
The mode of action of ARB…
 AT1 Receptor:
Vasoconstriction,
Sympathetic activation,
Cellular growth,
Fibrosis, Thrombosis
 AT2 Receptor:
Vasodilation, Apoptosis,
Inhibition of cellular
growth
For What
Conditions ARBs are Used?

 ARBs are used for controlling high blood pressure,

treating heart failure, and preventing kidney failure in
people with diabetes or high blood pressure. They
may also prevent diabetes and reduce the risk of
stroke in patients with high blood pressure and an
enlarged heart. ARBs may also prevent the
recurrence of atrial fibrillation. Since these
medications have effects that are similar to those of
ACE inhibitors, they often are used when ACE
inhibitors are not tolerated by patients (for example,
due to excessive coughing)
ARBs available in Market !

 Losartan
 Valsartan
 Irbesartan
 Candesartan
 Telmisartan
 Eprosartan
 Olmesartan
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.
MORE Study …
 European researchers claim to have identified an
antiatherosclerotic effect of an ARB, olmesartan medoxomil
(olmesartan), that is independent of its blood-pressure lowering
effect. The principal results of the Multicenter Olmesartan
Atherosclerosis Regression Evaluation (MORE) trial, presented
at the 17th European Meeting on Hypertension by Prof. Klaus
O. 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
presence of blood pressure reductions similar to those
produced by atenolol.
Presenter: Prof. Klaus O. Stumpe, MD (University Clinic Bonn, Bonn, Germany)
Olmesartan versus Captopril
The Williams Study..
 In a multicenter, double-blind study,27291 patients with mild to moderate
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 doses of eitherdrug could be
doubled after fourweeks of therapy if the diastolic BP was ator above 90 mm
Hg or had decreased less than 10 mm Hg from baseline values. The dosage
of either drug could be doubled 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 mm
Hg) than in the captopril group (–6.8 + 0.6 mm Hg; mean difference –3.1 mm
Hg, 95% confidence interval [CI] of –4.8, –1.5). In addition, reductions in
mean systolic BP were greater in the olmesartan medoxomil 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).
Olmesartan versus other Angiotensin II
receptor Blockers (The Ball Study)
 In a multicenter, double-blind study,28 patients with mild to moderate
hypertension (mean sitting diastolic BP of 95 to 114 mm Hg) were
randomly assigned to receive either olmesartan medoxomil 10 mg
once daily (n = 158) or losartan 50 mg once daily (n = 152) for 12
weeks. After four weeks of treatment, if the diastolic BP was greater
than 90 mm Hg or had decreased less than 10 mm Hg from the
baseline, the dose of either drug could be doubled. If the diastolic BP
remained uncontrolled, HCTZ (12.5 mg) once daily could be added to
the treatment regimen after 12 weeks and could be doubled after 16
weeks. After 12 weeks, the mean reduction in seated trough diastolic
BP in the olmesartan medoxomil group (–10.6 + 0.5 mm Hg) was
significantly 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, the
reduction in mean the seated systolic BP was greater in the
olmesartan 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).
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 to
receive 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 mean
reduction in the seated cuff diastolic BP from the baseline value was
significantly greater in the patients receiving olmesartan medoxomil (–11 mm
Hg) 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 the
reduction 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 more
with 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 mm Hg).
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. Following the
conversion of olmesartan medoxomil to olmesartan, virtually no further
metabolism occurs. The bioavailability of olmesartan is approximately
26%, similar to that of losartan and valsartan. Following oral
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 approximately 13 hours. It is highly
bound to plasma proteins (99%) and does not penetrate red blood
cells. Olmesartan takes approximately three to five days to reach a
steady state, and there is no accumulation in plasma with once-daily
dosing.
Pressor Inhibition…

 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 fold
Thanks !