Department of Clinical Pharmacology

1. Department of Clinical Pharmacology Pharmacotherapy of chronic ischemic heart disease Jerzy Jankowski, MD

3. FORMS OF ANGINA PECTORIS (AP) • ATHEROSCLEROTIC (CLASSIC) ANGINA • VARIANT (VASOSPASTIC ANGINA)

6. Anginal conditions other than CAD causing chest discomfort

8. ANTIANGINAL DRUGS • ORGANIC NITRATES • ΒETA- ADRENORECEPTOR- BLOCKING DRUGS • CALCIUM CHANNEL- BLOCKING DRUGS • METABOLIC AGENTS

9. DRUG ACTION IN ANGINA DECREASE MYOCARDIAL O2 REQUIREMENT BY: decreasing peripheral vascular resitance decreasing cardiac output both ways INCREASE MYOCARDIAL O2 DELIVERY nitrates calcium channel antagonists

10. ORGANIC NITRATES

11. PHARMACOKINETICS CHARACTERISTICS • EXTENSIVE FIRST-PASS EFFECT (90%) • LOW BIOAVAILABILITY (10%) • RAPID ONSET OF ACTION (1-3 min) • BRIEF DURATION OF ACTION (up to 30 min)

14. BETA-ADRENORECEPTOR BLOCKING DRUGS

15. MAJOR DIFFERENCES AMONG BBs • ISA • Beta-receptor selectivity Cardioselective Nonselective • Local anesthetic action • Pharmacokinetic characteristics

16. Beta-blockers with ISA • Acebutolol • Cartreolol • Celiprolol • Oxprenolol • Penbutolol • pindolol

17. Cardioselective beta-blokckers • Acebutolol • Atenolol • Betaxolol • Bisoprolol • Celiprolol • Metoprolol

18. Non-selective beta-blockers • Labetalol • Nadolol • Penbutolol • Pindolol • Propranolol • Sotalol • Timolol

19. Generations of beta-blockers • I generation: non-selective BBs • II generation: cardioselective BBs • III generation: beta-blockers (non-selective or cardioselectve BBs) with vasodilator activity: carvedilol, celiprolol, nebivolol

20. Local anesthetic action • Acebutolol • Betaxolol (slight) • Labetalol • Metoprolol • Pindolol • Propranolol

21. Pharmacokinetic differences • Lipid solubility: penbutolol, propranolol labetalol, metoprolol, pindolol, timolol • low lipid solubility: acebutolol, atenolol, betaxolol, bisoprolol, esmolol, nadolol, sotalol

26. CALCIUM CHANNEL-BLOCKING DRUGS

28. PHARMACOLOGIC EFFECTS OF CALCIUM CHANNEL BLOCKERS VER DIL DHPS HR ↓ ↓ ↑↔ A-V CONDUCTION ↓↓↓ ↓ ↔ CONTRACTILITY ↓↓ ↓ ↓ ↔ PERIPHERAL VASODILATION ↑ ↑ ↑↑ CO v v v CBF ↑ ↑ ↑ MO2 DEMAND ↓ ↓ ↓ ↑INCREASE; ↓ DECREASE; v VARIABLE;

31. METABOLIC DRUGS • METABOLIC INHIBITORS WITH CARDIO-CYTOPROTECTIVE EFFECT • RANOLAZINE • TRIMETAZIDINE (PREDUCTAL MR 35mg) • 3-KETOACYLO-CoA THIOLASE INHIBITOR

35. Thienopyridines • Ticlopidine (2 x 250 mg) • Clopidogrel (1 x 75 mg) • P2Y12 adenosine diphosphate receptor blocker • For 1 year after NSTEMI, PCI + DES

36. EUROPA TRIALEUropean trial on Reduction Of cardiac evens with Perindopril in stable coronary Artery disease • Randomized, placebo controled, duble blind study • 4 years follow-up • 12218 patients at low risk; perindopril 8 mg vs placebo

37. EUROPA TRIAL - RESULTS • The primary end-point ( cardiovascular death + nonfatal MI + non fatal cardiac arrest ) ↓ 20% • Risk of MI( fatal + nonfatal ) ↓ 24% • Hospitalisation for HF ↓ 39%

38. PERTINENT TRIALPERindopril, Thrombosis, INflammation,Endothelial dysfunction and NeurohormonalactivaTion • Rate of apoptosis of EC • Activity and expression of NOS • Proapoptotic protein Bax • Antiapoptotic protein Bcl-2 • Von Willebrand factor • Levels of AT II, bradykinin, TNF • Assesment at baseline and after 1 year of treatment

39. PERTINENT TRIAL - RESULTS One year of treatment with perindopril was able significantly reduce the rate of apoptosis and increase the activity and expression of NOS

40. Major purposes of the treatment • To improve short and long term prognosis by preventing MI and death and thereby increase the length of life • To improve quality of life by reducing symptoms of angina and occurrence of ischemia

44. Recommendations for Pharmacotherapy To Prevent MI and Death and To Reduce Symptoms The following agents should be used in patients with symptomatic chronic stable angina to prevent MI or death and to reduce symptoms: • Aspirin (level of evidence: A) or clopidogrel when aspirin is absolutely contraindicated (level of evidence: B) • ß-Blockers in patients with previous MI (level of evidence: A) or without previous MI (level of evidence: B) • Low-density lipoprotein cholesterol–lowering therapy with a statin (level of evidence: A) • ACE inhibitor (level of evidence: A)

45. Recommendations for Pharmacotherapy To Prevent MI and Death and To Reduce Symptoms The following agents should be used in patients with symptomatic chronic stable angina to reduce symptoms only: • Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina (level of evidence: B) • Calcium antagonists (long-acting) or long-acting nitrates when ß-blockers are clearly contraindicated (level of evidence: B) • Calcium antagonists (long-acting) or long-acting nitrates in combination with ß-blockers when ß-blockers alone are unsuccessful (level of evidence: B).

47. TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION CLASS I correction of risk factors, nitroglycerin sl aspirin 75-150mg CLASS II as above+ chronic therapy with LA nitrates or ß1-blockers or LA Calcium antagonists or Trimetazidine or combination of these drugs

48. TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION CLASS III and IV As above and establish indications for invasive treatment