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Newer anti anginals

Newer anti anginals. Dr Julian Johny Thottian. INTRODUCTION . Chronic angina is a condition that impairs quality of life and is associated with decreased life expectancy Cardiac metabolism- LCFAs are the major source of energy (80%) and Glucose (20%) in aerobic conditions.

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Newer anti anginals

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  1. Newer anti anginals Dr Julian JohnyThottian

  2. INTRODUCTION Chronic angina is a condition that impairs quality of life and is associated with decreased life expectancy Cardiac metabolism- LCFAs are the major source of energy (80%) and Glucose (20%) in aerobic conditions. In fetus , the main source of energy is glucose and shift to FFA is in the early post natal period.

  3. Cardiac metabolism

  4. Current therapies that reduce angina frequency and increase the threshold at which demand-induced myocardial ischemic symptoms become evident include : Drugs :Nitrates, β-blockers, Calcium antagonist Exercise conditioning Enhanced External Counterpulsation Coronary revascularization

  5. TMR EECP Chelation therapy Exercise training SCS Fasudil Nicorandil Trimetazidine Ivabradine Ranolazine Current antianginal strategies Non pharmacologic Current anti-anginal strategies Pharmacologic

  6. Oxygen supply and demand Mechanicaldysfunction Electricalinstability • Abnormal contraction and relaxation • ↑ diastolic tension(↑LV wall stiffness) • Increase ATP • consumption • Decrease ATP formation • Early after potentials • Beat-to-beat ΔAPD • Arrhythmias (VT) Consequences associated with dysfunction of late sodium current • Diseases(eg, ischemia, heart failure) • Pathological milieu(reactive O2 species,ischemic metabolites) • Toxins and drugs(eg, ATX-II, etc.) Na+ channel (Gating mechanism malfunction)

  7. Diastolic relaxation failure increases oxygen consumption and reduces oxygen supply Increased myocardial tension during diastole: • Increases myocardial O2 consumption • Compresses intramural small vessels • Reduces myocardial blood flow • Worsens ischemia and angina

  8. Advances • Ischemic heart disease is a prevalent clinical condition • Improved understanding of ischemia has prompted new therapeutic approaches • Rho kinase inhibition • Metabolic modulation • Preconditioning • Inhibition of If and late INa currents

  9. Ranolazine (N-(2,6-dimethyphenyl)-4-[2-hydroxy-3- (2-methoxyphenoxy)-propyl]-1-piperazineacetamide) is a substituted piperazine compound. • pFOX inhibitor -that ranolazine only inhibits fatty-acid oxidation during the periods of elevated plasma FFA levels associated with myocardial ischaemia • Late sodium current blocker

  10. Ranolazine Understanding Angina at the Cellular Level • Ischemia impairs cardiomyocyte sodium channel function • Impaired sodium channel function leads to: • Pathologic increased late sodium current • Sodium overload • Sodium-induced calcium overload • Calcium overload causes diastolic relaxation failure, which: • Increases myocardial oxygen consumption • Reduces myocardial blood flow and oxygen supply • Worsens ischemia and angina Ischemia ↑ Late INa Na+ Overload Ca++ Overload Diastolic relaxation failure Extravascular compression Chaitman BR. Circulation. 2006;113:2462-2472

  11. Na+/Ca2+ overload and ischemia Myocardial ischemia Intramural small vessel compression( O2 supply) O2 demand Late Na+ current Na+ overload Diastolic wall tension (stiffness) Ca2+ overload Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.

  12. 0 0 SodiumCurrent Late SodiumCurrent Late Peak Peak Myocardial ischemia causes enhanced late INa Ischemia Na+ Impaired Inactivation Na+ Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A10-13. Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.

  13. Ranolazine – hemodynamic affects • No affect of Blood Pressure or Heart Rate • Can be added to Conventional Medical therapy, especially when BP and HR do not allow further increase in dose of BetaBlockers, Ca Channel blockers, and Long Acting Nitrates. • Ranolazine has twin pronged action. • pFOX • Late Na inward entry blockade

  14. Metabolic modulation (pFOX) and ranolazine • Clinical trials showed ranolazine SR 500–1000 mg bid (~2–6 µmol/L) reduced angina • Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition • Ranolazine does not inhibit pFOX substantially at clinically relevant doses • Fatty acid oxidation Inhibition is not a major antianginal mechanism for ranolazine MacInnes A et al. Circ Res. 2003;93:e26-32. Antzelevitch C et al. J CardiovascPharmacolTherapeut. 2004;9(suppl 1):S65-83.Antzelevitch C et al. Circulation. 2004;110:904-10. pFOX = partial fatty acid oxidation

  15. Pharmacologic Classes for Treatment of Angina

  16. Development of ischemia Consequences of ischemia Ischemia Ranolazine Myocardial ischemia: Sites of action of anti-ischemic medication ↑ O2 Demand Heart rate Blood pressure Preload Contractility ↓ O2 Supply Ca2+ overload Electrical instability Myocardial dysfunction(↓systolic function/ ↑diastolic stiffness) Traditional anti-ischemic medications: β-blockers Nitrates Ca2+ blockers Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.

  17. 3 ranolazine trials

  18. Baseline characterstics

  19. NO MUCH BENEFIT IN ACS

  20. Contraindications • Ranolazine is known to increase the QT interval on the electrocardiogram. Mean increase in the corrected QT interval (QTc) is approximately 6 msec, about 5% of individuals may have QTc prolongations of 15 msec or longer. (MARISA) • It blocks Ikr and hence prolongs the QT interval. • Clinical experience in coronary syndrome population did not show an increased risk of proarrhythmia or sudden death • Strong CYP3A4 inhibitors and drug that interact with P glycoprotein

  21. Contd… • Used with caution with other CYP3A4 inhibitors and also drugs that prolong QT. • INTERACTS with Digoxin , simvastatin ,cyclosporine, diltiazem, verapamil, ketoconazole, macrolides , grape fruit juice

  22. Other beneficial effects •   US FDA  has granted permission for- HbA1c reduction in coronary artery disease patients with diabetes and antiarrhythmic benefits according to the results of MERLIN TIMI 36 trial. • Uses in heart failure and neuropathic pain are being studied extensively.

  23. Side effects • The most common adverse events that led to discontinuation placebo were Dizziness (1.3% versus 0.1%) Nausea (1% versus 0%) Asthenia, Constipation Headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated. Conclusions from CARISA MARISA & ERICA

  24. Sinus node inhibition: Ivabradine SA node AV node Common bundle Bundle branches Purkinje fibers IVABRADINE DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.

  25. Sinus node inhibition: Ivabradine • If current is an inward Na+/K+ current that activates pacemaker cells of the SA node • Ivabradine • Selectively blocks If in a current-dependent fashion • Reduces slope of depolarization, slowing HR Control Ivabradine 0.3 µM 40 20 Time (seconds) 0 0.5 –20 –40 –60 Potential (mV) DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.

  26. Trials associated • It produces similar effects to those of atenolol, as measured in the randomized double-blind INITIATIVE trial, which compared ivabradine (5, 7.5 and 10 mg bid) with atenolol at doses of 50 and 100 mg per day and found to be non inferior. • It is safe agent and no changes in QT interval. • ASSOCIATE Trial is double blind RCT done on 889 patients which found that ivabradine was better than placebo in anti anginal and anti ischaemic efficacy. Combination of this drug and betablockers was definitely effective without untoward effects.

  27. BEAUTifUL TRIAL-post hoc analysis • The BEAUTIFUL investigators sought to analyze, post hoc, the effect of ivabradine on patients with limiting angina at baseline within the BEAUTIFUL trial. Patients with limiting angina -13.8% of the trial population. 24% reduction in the primary endpoint [cardiovascular mortality or hospitalization for fatal and non-fatal myocardial infarction (MI) or heart failure HR, 0.76; 95% CI, 0.58–1.00] and a 42% reduction in hospitalization for MI (HR, 0.58; 95% CI, 0.37–0.92). In patients with heart rate ≥70 bpm, there was a 73% reduction in hospitalization for MI (HR, 0.27; 95% CI, 0.11–0.66) and a 59% reduction in coronary revascularization (HR, 0.41; 95% CI, 0.17–0.99). These results indicate that ivabradine is most helpful to reduce adverse cardiac events in patients with limiting angina and that in this population, its benefit may extend well beyond symptom control.

  28. Side effect /effects • Blurring of vision • No QT prolongation • No negative inotropic properties • Improvements in exercise tolerance and prevention of exercise-induced ischaemia

  29. Trimetazidine Metabolic modulation (pFOX): Trimetazidine Myocytes • O2 requirement of glucose pathway is lower than FFA pathway • During ischemia, oxidized FFA levels rise, blunting the glucose pathway Glucose FFA Acyl-CoA Pyruvate β-oxidation Acetyl-CoA Energy for contraction pFOX = partial fatty acid oxidation FFA = free fatty acid MacInnes A et al. Circ Res. 2003;93:e26-32. Lopaschuk GD et al. Circ Res. 2003;93:e33-7. Stanley WC. J CardiovascPharmacolTher. 2004;9(suppl 1):S31-45.

  30. It is piperazine derivative (1-[2,3,4-trimethoxibenzyl)]-piperazine). Launched as a cytoprotective agent. • No significant negative inotropic or vasodilator properties either at rest or during dynamic exercise • TRIMPOL II –RCT of 426 patients with CSA who were randomised to either trimetazidine 20 mg three times a day or placebo in addition to metoprolol 50mg. This study demonstrated an improvement in time to STsegment depression on exercise tolerance testing (ETT), total exercise workload, mean nitrate consumption, and angina frequency in patients randomised to receive trimetazidine

  31. Large multicentric trial of 19000 patients post MI by EMIP-FR group showed no benefit of iv infusion of trimetazidine immediately post MI over 48hrs • MOA – CPT -1 inhibitor and also acts in inhibition of the enzyme long-chain 3-ketoacyl coenzyme A thiolase (LC 3- KAT)[Kantor et al] • VASCO ,largest RCT , showed no benefit as an add on in angina • Safety issues and adverse effects ?????

  32. Side effects • Extrapyramidal and parkinsonian symptoms recently published by EMA 2012 • Restless leg syndrome. • Use is limited in severe renal impairment.

  33. Perhexilene • Earlier designed as a CCB but doesnot act like a CCB • It doesnot affect the heart rate or SVR • Multiple randomised trials show that it has anti anginal effect as monotherapy or as combination. • Inhibition of CPT-1 and, to a lesser extent, CPT-2, resulting in increased glucose and lactate utilisation • S/E hepatotoxicity and peripheral neuropathy due to phospholipid accumulation as a result of CPT ½ inhibition.

  34. Cole et al confirmed the safety of perhexiline in a randomised, double-blind, crossover study following initiation of 100 mg of perhexiline BD with subsequent plasma-guided dose titration; none of the developed the dreaded side effects. Other s/e nausea ,dizziness and hypoglycaemia Other uses – symptomatic aortic stenosis Circulation 1990;81(4):1260–70

  35. Etomoxir/ Oxfenicine • Potential anti anginal agent • Launched as an anti diabetic agent due to hypoglycaemic effects • CPT 1 INHIBITOR • Improvement in LV function in rats- Turcani & Rupp • Single study available on humans (15 patients) with NYHA II – III Etomoxir 80mg was administered.\ • Only animal studies on oxfenicine.

  36. Preconditioning: Nicorandil • Activation of ATP-sensitive K+ channels • Ischemic preconditioning • Dilation of coronary resistance arterioles O N HN NO2 O • Nitrate-associated effects • Vasodilation of coronary epicardial arteries IONA Study Group. Lancet. 2002;359:1269-75. Rahman N et al. AAPS J. 2004;6:e34.

  37. DOSAGE- 20mg bid • Tolerance is seen with chronic dosage • No cross tolerance with nitrates • The Impact Of Nicorandil in Angina (IONA) trial showed a significant reduction of major coronary events in stable angina patients treated with nicorandil compared with placebo as add-on to conventional therapy • Also used in unstable angina. It also reduces the number of further attacks • Additive effects with nitrates

  38. Rho Fasudil Rho kinase Rho kinase inhibition: Fasudil • Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin Agonist Ca2+ Ca2+ Receptor PLC PIP2 VOC ROC IP3 SR Ca2+ Myosin Myosin phosphatase MLCK Ca2+ Myosin-P Calmodulin Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.

  39. Fasudil up to 80 mg three times daily significantly increased the ischemic threshold of angina patients during exercise with a trend toward increased exercise duration. Double-Blind, Placebo-Controlled, Phase 2 Trial on 84 patients J Am CollCardiol. 2005;46(10):1803-1811

  40. Molsodomine & linsodomine • Anti anginal and anti ischaemic • Acts like nitrates • Metabolises in liver to form linsodomine • Orally active • Metabolised in liver

  41. TMLR • Surgical • surgeons use the laser to make holes between 20 and 40 tiny (one-millimeter-wide) • Surgical incision made • Done along with CABG sometimes

  42. Percutaneous TMR

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