4. IntroductionIntroduction
(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
5. Physicochemical differences of ARBsPhysicochemical 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.
6. Physicochemical differences of ARBsPhysicochemical differences of ARBs
Physicochemical differences affect pharmaco-
kinetic 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-γ.
Differences in pharmacokinetic propertiesDifferences in pharmacokinetic properties betweenbetween
ARBs translate intoARBs translate into marked differences inmarked differences in duration ofduration of
action,action, antihypertensive potency &antihypertensive potency & addedadded ↓↓ CV risksCV risks..
Clinical evidence suggests thatClinical evidence suggests that this is indeed the casethis is indeed the case..
9. Plasma half-lifePlasma half-life
24
11
10
3
9
6
5
4
5
8
3
2
0 6 12 18 24
Telmisartan
Irbesartan
Olmesartan
Candesartan
Valsartan
Losartan
Eprosartan
Plasma half life (h)
Burnier, Brunner. Lancet 2000;355:637–645, Brunner. J Hum Hypertens 2002;16 (Suppl 2):S13–S16, U.S. Pharm. 2004;10:HS19-HS25.,
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.
10. Smoothness index (SI)Smoothness index (SI)
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.
Effect of Telmisartan and Losartan on the
smoothness index at endpoint.
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
Superior, powerful BP reduction from
morning to morning
SI - a potential indicator for the
prevention of organ damage,
shows telmisartan was the most
effective therapy when compared
to other leading ARBs.
11. Volume of distributionVolume of distribution
Telmisartan has the largest volume of
distribution of clinically available ARBs
Song, White. Formulary 2001;36:487–499
Maximum tissue penetration
13. Trough/peak ratiosTrough/peak ratios
Trough-to-peak ratio is a widely used measure
of the duration of antihypertensive efficacy.
JNC VI recommendation >50% >50%
Losartan 50 mg 35% 51%
Telmisartan 40 mg 66% ~100%
Telmisartan 80 mg 92% ~100%
SBP DBP
JNC VI. Arch Intern Med 1997;157:2413–2446, Stergiou et al. J Hypertens 2003;21:913–920, Neutel. Blood Press 2001;10(suppl 4):27–32
Telmisartan produces smoother blood pressure control
over 24 h than losartan, reflecting its longer duration of
action.
16. Surmountable vs InsurmountableSurmountable vs Insurmountable
U.S. Pharm. 2004;10:HS19-HS25
Losartan Telmisartan
The blockade by the
ARB can be overcome
by increasing
concentrations of
angiotensin II.
The decrease in the
maximum response
cannot be overcome by
increasing concentrations
of angiotensin II
17. InsurmountableInsurmountable BindingBinding
Angiotensin II log (M)
-10 -9 -8 -7 -6 -5 -4
Controlofcontra
100
75
50
25
0
Telmisartan 10 nM
Telmisartan 100 nM
Telmisartan 1000 nM
Control
Telmisartan binds insurmountably to the AT1 receptor
Wienen et al. Br J Pharmacol 1993;110:245–252
18. ARBs Dissociation
half-life
Telmisartan 87 min
Candesartan 66 min
Losartan 2.5 min
Angiotensin II 12 min
Telmisartan has 35 times higher
dissociation half-life than Losartan
Hence, tighter binding+ slower dissociation
of olmesartan & candesartan may account
for higher magnitude of antihypertensive
efficacy and long duration of action
InsurmountableInsurmountable Binding -Binding - comparisoncomparison
Comparative ARB pharmacology, May 2010 Volume 17, Supplement 2 Br J Cardiol 2010;17:s3
19. Telmisartan activates PPARTelmisartan activates PPARγγ
Benson et al. Hypertension 2004;43:993–1002
PPARγ activation in a cell-based transfection assay
20. Drug interactionsDrug 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;16:123–126
21. Optimal dosing – difference in ARBsOptimal dosing – difference in ARBs
Some ARBs lose efficacy at the end of the
dosing interval
Smith et al. Blood Press Monit 2003;8:111–117
22. 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
Optimal dosing – difference in ARBsOptimal dosing – difference in ARBs
23. Decrease in BP – difference in ARBsDecrease in BP – difference in ARBs
Data on file, Boehringer Ingelheim GmbH
Greater reductions in trough blood pressure
24. Urate concentration – difference in ARBsUrate 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.
JPET 320:211-217, 2007
Beneficial cardiovascular effect of inhibiting the uptake of
uric acid ???
25. Which ARB for whom?Which ARB for whom?
A case study approachA case study approach
26. Case 1: Elderly patient withCase 1: Elderly patient with
renal impairmentrenal 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;36:487–499 ,Sharma et al. Clin Nephrol 2005;63:250–257, BUMC PROCEEDINGS 2003;16:123–126
27. Case 2: Hypertensive patient withCase 2: Hypertensive patient with
chronic renal failurechronic renal failure
-35
-30
-25
-20
-15
-10
-5
0
DBP SBP
Reductionfrombaseline(mmHg)
Losartan 100 mg/day
Telmisartan 80 mg/day
*P<0.05 vs Losartan
Telmisartan is superior to Losartan & other
ARBs in patients with chronic renal failure
Cice et al. XLI ERA. 2004
28. Case 3: Hypertensive patient onCase 3: Hypertensive patient on
hemodialysishemodialysis
• Telmisartan is 99.5% bound
to serum protein, so no post-
dialysis adjustment is
needed
U.S. Pharm. 2004;10:HS19-HS25. , Song, White. Formulary 2001;36:487–499 ,Sharma et al. Clin Nephrol 2005;63:250–257
-25
-20
-15
-10
-5
0
Mild-to-
moderate Severe Haemodialysis
Combined
groups
ChangeinSBP(mmHg)
• 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
29. Case 4: Hypertensive patient withCase 4: Hypertensive patient with
hepatic impairmenthepatic 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.
30. Case 5: Hypertensive patient withCase 5: Hypertensive patient with
metabolic syndromemetabolic syndrome
Greater reductions in markers of insulin sensitivity
than Losartan and other ARBs
2.86
-1.6
0.6 0.1
-8.3
-10.23
-26.1
-9.3
-30
-25
-20
-15
-10
-5
0
5
FPG FPI HOMA-IR HbA1c
Changefrombaseline(%)
Losartan
Telmisartan
* P<0.05 vs Losartan
* *
*
Cardiovascular Diabetology 2005, 4:6
Compared to
other AT(1)
receptor blockers
Telmisartan may
have further
additional
beneficial effects
in patients with
metabolic
syndrome
31. Case 6: Hypertensive patient withCase 6: Hypertensive patient with
heart failureheart failure
• Losartan, Valsartan and
Candesartan are the ARBs for
which studies have been
completed that involved long-
term follow-up 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;16:123–126
32. Case 7: Hypertensive patient withCase 7: Hypertensive patient with
goutgout
• 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.
33. Case 8: Hypertensive patient onCase 8: Hypertensive patient on
ARB – Possible to switch?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, The American Journal of Pharmacy Benefits e81-e87, July/August 2012
34. ConclusionConclusion
• 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, S9–S16
35. SummarySummary
• 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-
36. Take home messageTake home message
Beevers et al. BMJ 2001;322:912–916
Morning surge
effectively
blunted
Longer half life
Better distribution
Activates
PPAR-gamma
Trough-Peak ratio effective
for 24 hour control
Low renal excretion
No modification
of dosage
Free from drug
interactions
Telmisartan is indicated for cardiovascular prevention beyond that of blood pressure-lowering alone.
