Are all arbs the same?


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ARBs - are they all the same?

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Are all arbs the same?

  1. 1. Are all ARBS created same?Are all ARBS created same? The cardiologist perspective
  2. 2. IntroductionIntroduction (RAS)
  3. 3. IntroductionIntroduction (ARBs)
  4. 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. 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. 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..
  7. 7. Differences in theDifferences in the Pharmacokinetic parametersPharmacokinetic parameters
  8. 8. Pharmacokinetic differencesPharmacokinetic differences Telmisartan has the longest half-life of clinically available ARBs Angiotensin Receptor Blockers - Advantages of the new Sartans, July 2013, VOL. 61
  9. 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. 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. 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
  12. 12. LipophilicityLipophilicity 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 Telmisartan is 5 times more lipophilic than Losartan
  13. 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.
  14. 14. Renal excretionRenal excretion Lowest renal excretion of clinically available ARBs* Song, White. Formulary 2001;36:487–499
  15. 15. Differences in theDifferences in the Pharmacodynamic parametersPharmacodynamic parameters
  16. 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. 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. 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. 19. Telmisartan activates PPARTelmisartan activates PPARγγ Benson et al. Hypertension 2004;43:993–1002 PPARγ activation in a cell-based transfection assay
  20. 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. 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. 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. 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. 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. 25. Which ARB for whom?Which ARB for whom? A case study approachA case study approach
  26. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.
  37. 37. ThankyouThankyou