Are all ARBS created

same?
The cardiologist perspective

Introduction
(RAS)

Introduction
(ARBs)

Introduction
(ARBs)
ARBs are an important drug class in hypertension & heart failure
therapy + protection from diabetic nephropathy.
8 are clinically available [azilsartan, eprosartan, candesartan,
irbesartan, losartan, olmesartan, telmisartan, valsartan].
As a class, ARBs are chemically similar but vital pharmacokinetic
and pharmacodynamic differences exist between them.
ARBs differ in the magnitude and duration of the antihypertensive
response as well as in added protection of reducing
cardiovascular risks: this has important implications in clinical
practice

Physicochemical differences of ARBs

Azilsartan, candesartan and olmesartan are
orally administered as prodrugs.
The physicochemical differences between ARBs manifest in
differences in binding mode and tissue penetration.
ARBs use different binding pockets in the receptor on the basis
of their chemical structures.
The receptor blocking action of some ARBs are mediated
through active metabolites.
This leads to differences in dissociation times & in most cases,
apparently insurmountable antagonism.
Tissue penetration including passage through the blood-brain
barrier are also impacted.

Physicochemical differences of ARBs

Physicochemical differences affect pharmacokinetic profile including duration of action
Although a consistent, continuous receptor blockade over a
24-hour period is desirable, the clinical relevance of
pharmacological differences affect individual ARB efficacy.
Although generally highly specific for angiotensin II type 1
receptors, some ARBs particularly telmisartan, are partial
agonists at peroxisome proliferator-activated receptor-.

Differences in pharmacokinetic properties

between ARBs translate into marked differences
in duration of action, antihypertensive potency &
added CV risks. Clinical evidence suggests that
this is indeed the case.

Differences in the
Pharmacokinetic parameters

Pharmacokinetic differences
Telmisartan has the longest half-life of
clinically available ARBs

Angiotensin Receptor Blockers - Advantages of the new Sartans, July 2013, VOL. 61

Plasma half-life
Telmisartan has the longest half-life of
clinically available ARBs

Telmisartan, with a
terminal 24-hour half-life,
may be the most effective
ARB in controlling early
morning surge in BP.

Burnier, Brunner. Lancet 2000;355:637645, Brunner. J Hum Hypertens 2002;16 (Suppl 2):S13S16, U.S. Pharm. 2004;10:HS19-HS25.,

Smoothness index (SI)

Superior, powerful BP reduction from
morning to morning
Effect of Telmisartan and Losartan on the
smoothness index at endpoint.

SI - a potential indicator for the

prevention of organ damage,
shows telmisartan was the most
effective therapy when compared
to other leading ARBs.

SI is defined as the average of the 24 hourly BP changes

induced by treatment divided by the corresponding standard
deviation. Thus, it takes into account the consistency of BP
reduction over the complete 24 hour dosing interval. A high SI
score represents a BP reduction that is meaningful and smooth.
Cardiovascular Diabetology 2005, 4:6, Evaluating 24-hour antihypertensive efficacy by the smoothness index: a meta-analysis of an ambulatory BP
monitoring database. Presented at the Annual Meeting of the European Society of Hypertension. June 2006, Madrid, Spain

Volume of distribution
Telmisartan has the largest volume of
distribution of clinically available ARBs

Maximum tissue penetration

Song, White. Formulary 2001;36:487499

Lipophilicity
Telmisartan is 5 times more lipophilic
than Losartan

ARBs

Partition
coefficient

Telmisartan

3.20

Irbesartan

1.48

Candesartan

-0.96

Valsartan

-0.95

Losartan
(active metabolite)

-2.45

Highest partition coefficient

Highest lipophilicity
Maximum tissue
penetration

Drugs 2001, 61(10), 1501-1529

Trough/peak ratios
Trough-to-peak ratio is a widely used measure
of the duration of antihypertensive efficacy.

SBP
JNC VI recommendation

DBP

>50%

>50%

35%

51%

Telmisartan 40 mg

66%

~100%

Telmisartan 80 mg

92%

~100%

Losartan 50 mg

Telmisartan produces smoother blood pressure control

over 24 h than losartan, reflecting its longer duration
of action.
JNC VI. Arch Intern Med 1997;157:24132446, Stergiou et al. J Hypertens 2003;21:913920, Neutel. Blood Press 2001;10(suppl 4):2732

Renal excretion
Lowest renal excretion of clinically available ARBs*

Song, White. Formulary 2001;36:487499

Differences in the
Pharmacodynamic
parameters

Surmountable vs
Insurmountable
Losartan

The blockade by the

ARB can be
overcome by
increasing
concentrations of
angiotensin II.

Telmisartan

The decrease in the

maximum response
cannot be overcome
by increasing
concentrations of
angiotensin II

U.S. Pharm. 2004;10:HS19-HS25

Insurmountable Binding
Telmisartan binds insurmountably to the AT1 receptor

Control of contractile force (%)

Control
100

Telmisartan 10 nM
Telmisartan 100 nM
Telmisartan 1000 nM

75

50

25

-10

-9

-8

-7

-6

-5

-4

Angiotensin II log (M)

Wienen et al. Br J Pharmacol 1993;110:245252

Insurmountable Binding comparison

Telmisartan has 35 times higher

dissociation half-life than Losartan

ARBs

Dissociation
half-life

Telmisartan

87 min

Candesartan

66 min

Losartan

2.5 min

Angiotensin II

12 min

Hence, tighter binding+ slower

dissociation of olmesartan &
candesartan may account for higher
magnitude of antihypertensive
efficacy andComparative
long duration
of action
ARB pharmacology,
May 2010

Volume 17, Supplement 2

Br J Cardiol 2010;17:s3-s5

Telmisartan activates PPAR

PPAR activation in a cell-based transfection assay

Benson et al. Hypertension 2004;43:9931002

Drug interactions
Comparison of the class as a whole reveals that
losartan has the highest potential for drug
interactions due to its involvement with the
hepatic cytochrome P450 enzyme system.

BUMC PROCEEDINGS 2003;16:123126

Optimal dosing difference in ARBs

Some ARBs lose efficacy at the end of the
dosing interval

Smith et al. Blood Press Monit 2003;8:111117

Optimal dosing difference in ARBs

Mean change from baseline in systolic BP for
candesartan vs. losartan

Comparative ARB pharmacology, May 2010

Volume 17, Supplement 2

Br J Cardiol 2010;17:s3-s5

Decrease in BP difference in
ARBs
Greater reductions in trough blood pressure

Data on file, Boehringer Ingelheim GmbH

Urate concentration difference in

ARBs
Losartan and telmisartan exhibited cis-inhibitory effects on
the uptake of uric acid by URAT1 whereas at higher
concentrations, only telmisartan did, and these ARBs
reduced the uptake in competitive inhibition kinetics.
On the other hand, candesartan, EXP3174 (a major
metabolite of losartan), olmesartan, and valsartan were not
inhibitory.
Beneficial cardiovascular effect of inhibiting the uptake of
uric acid ???

JPET 320:211-217, 2007

Which ARB for whom?

A case study approach

Case 1: Elderly patient with

renal impairment
Because
Telmisartan
is
excreted almost exclusively
via the bile, no dosage
adjustment is required in renal
disease
Telmisartan
effectively
reduces SBP and DBP in
patients with mild-moderate
or severe renal disease, or
with end-stage renal disease

Song, White. Formulary 2001;36:487499 ,Sharma et al. Clin Nephrol 2005;63:250257, BUMC PROCEEDINGS 2003;16:123126

Case 2: Hypertensive patient

with chronic renal failure
Telmisartan is superior to Losartan & other
ARBs in patients with chronic renal failure

*P<0.05 vs Losartan
Cice et al. XLI ERA. 2004

Case 3: Hypertensive patient

on hemodialysis
None of the ARBs are significantly cleared by hemodialysis (possibly
due to ARB-associated high protein binding), and no data were found
on the effects of peritoneal dialysis on ARBs
Telmisartan is 99.5% bound
to serum protein, so no postdialysis
adjustment
is
needed

U.S. Pharm. 2004;10:HS19-HS25. , Song, White. Formulary 2001;36:487499 ,Sharma et al. Clin Nephrol 2005;63:250257

Case 4: Hypertensive patient

with hepatic impairment
Losartan is a weaker antagonist and completely surmountable
compared to its active metabolite.
Losartan's potency may be affected, since the less potent
parent drug competes for the same receptor as the active
metabolite.
The other ARBs are active on their own and do not require
metabolism.
Losartan requires a 50% initial dose reduction in patients with
impaired hepatic function.

U.S. Pharm. 2004;10:HS19-HS25.

Case 5: Hypertensive patient

with metabolic syndrome
Greater reductions in markers of insulin sensitivity
than Losartan and other ARBs

Compared to
other AT(1)
receptor blockers
Telmisartan may
have further
additional
beneficial effects
in patients with
metabolic
syndrome

*
* P<0.05 vs Losartan

Cardiovascular Diabetology 2005, 4:6

Case 6: Hypertensive patient

with heart failure
Losartan, Valsartan and
Candesartan are the ARBs
for which studies have
been
completed
that
involved long-term followup with morbidity and
mortality as endpoints.
Trials with other ARB like
Telmisartan have also been
encouraging.

ELITE
VALHeFT
CHARM

TELMAR
ONTARGET
TRANSCEND

BUMC PROCEEDINGS 2003;16:123126

Case 7: Hypertensive patient

with gout
Losartan is a potent inhibitor of the urate/anion
transport in the renal proximal tubule and
increases uric acid excretion and decreases
plasma levels of uric acid in hypertensive
patients.
Losartan, although slightly less effective in
lowering blood pressure, may be the best ARB for
patients with gout.

Case 8: Hypertensive patient

on ARB Possible to switch?
One study examined the clinical and economic
implications of switching angiotensin receptor
blocker [ARB] therapy in patients with controlled
blood pressure (BP).
The results demonstrate that these switches may
result in higher post-switch BP, possibly leading
to loss of BP control and use of additional medical
resources.

Vol.4,No.4, TheAmericanJournalofPharmacyBenefits e81-e87, July/August2012

Conclusion

Differences in receptor binding kinetics between ARBs are

reflected in marked differences in antihypertensive efficacy.

Agents such as Telmisartan, Olmesartan and Candesartan

are insurmountable antagonists - produce a greater
maximum reduction in BP, higher response rates, and a
longer duration of action.

Amongst all ARBs, Telmisartan has the longest half-life and

highest voulme of distribution suggesting a 24 hr BP control
and maximum tissue penetration.

Telmisartan is the only ARB with effect on markers of insulin

resistance.
Journal of Human Hypertension (2002) 16, S9S16

Summary

Amongst all ARBs, advantages that will make all the

difference include:
1.

Once daily dosing,

2.

Absence of significant adverse reactions,

3.

Well tolerated side effect profile

4.

Negligible drug interactions

5.

Beneficial pleotropic effects.

One ARB that is getting greater acceptance due to fulfilling

such criteria is-

Take home message

Longer half life
Morning surge
effectively
blunted

Better distribution

Free from drug

interactions

Activates
PPAR-gamma

No modification
of dosage

Trough-Peak ratio effective

for 24 hour control
Low renal excretion

Telmisartan is indicated for cardiovascular prevention beyond that of blood pressure-lowering alone.
Beevers et al. BMJ 2001;322:912916

Thankyou