Department of Clinical Pharmacology

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

2. www.zfk.ump.edu.pl www.ump.edu.pl/eng

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

7. Anginal conditions other than CAD causing chest discomfort

9. ANTIANGINAL DRUGS • ORGANIC NITRATES • ΒETA- ADRENORECEPTOR- BLOCKING DRUGS • CALCIUM CHANNEL- BLOCKING DRUGS • METABOLIC AGENTS • HEART – RATE LIMITING AGENTS

10. 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

11. ORGANIC NITRATES

12. ORGANIC NITRATES • NTG, ISDN, IS-5-MN • Donors of NO in vascular smooth muscle cells • Induce cross-tolerance when given in large doses • All are highly lipophylic • The lipophility (depending on the stereochemical configuration and the number of ONO2-groups) affects the degree of activation of guanylate cyclase, of the NO-release and of a rapid onset of efficacy (NTG > ISDN > IS-5-MN) • Due to a slow denitration IS-5-MN maintaines the effects for hours

13. ORGANIC NITRATES • The higher the lipophylity of a nitrate, the higher the velocity of its uptake in different tissues ( NTG > ISDN > IS-5-MN ), particularly in the smooth muscle cells of blood vessels • Nitrates are acting via the release of NO – they need intracellular SH-groups to form NO

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

15. MECHANISM OF ANTIANGINAL ACTION OF NITRATES • DECREASED MYOCARDIAL O2 CONSUMPTION - decreased LV dimension - decreased LV filling pressure - decreased LV systolic pressure - decreased vascular impedence • INCREASED CORONARY BLOOD SUPPLAY - epicardial coronary artery dilation - coronary stenosis enlargement - dilation of coronary collaterals • ANTIPLATELET ANTITHROMBOTIC ACTION

16. UNDESIRABLE EFFECTS OF NITRATES • INCREASED MYOCARDIAL O2 DEMAND - reflex tachycardia - reflex increase in contractility • DECREASED MYOCARDIAL PERFUSION - decreased diastolic perfusion time due to tachycardia

18. MECHANISMS OF NITRATE TOLERANCE • BIOCHEMICAL TOLERANCE = CELLULAR - exhaustion of the cysteine (SH) store - decreased sensivity of guanylate cyclase • PSEUDO-TOLERANCE = ACTIVATION OF NEUROHUMORAL MECHANISMS - increased sympathetic activity - increased ACE activity

20. EXCRETION OF NITRATES • Primarily in the form of glucuronide derivatives of the denitrated metabolites • Largely by way of the kidney

21. BETA-ADRENORECEPTOR BLOCKING DRUGS

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

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

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

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

26. 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

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

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

33. CALCIUM CHANNEL-BLOCKING DRUGS

35. 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;

38. METABOLIC DRUGS METABOLIC INHIBITORS WITH CARDIO-CYTOPROTECTIVE EFFECT RANOLAZINE (RANEXA 375mg, 500mg, 750mg) TRIMETAZIDINE (PREDUCTAL MR 35mg)

39. TRIMETAZIDINE • 3 - ketoacylo – CoA thiolase inhibitor • In cells exposed to ischaemia, the drug: - prevents a decrease in intracellular ATP levels - reduces intracellular acidosis - alterations in transmembrane ion flow - decreases the migration and infiltration of PNN

40. TRIMETAZIDINE • In man the drug: - increases coronary flow reserve - limits rapid swings in blood pressure - decreases the frequency of angina attacks - decreases the use of NTG

41. PK OF TRIMETAZIDINE • Well absorbed with Cmax, on average, 5 hours after taking the tablet • Protein binding is low • Eliminated primarily in the urine, mainly in the unchanged form; T1/2 7 hours

42. TRIMETAZIDINE • Side effects: - gastrointestinal (dyspepsia, diarrhoea, nausea, vomiting, constipation) - nervous system (headaches, vertigo, sleep disorders) aggravation of Parkinsonian symptoms - cardiovascular (orthostatic hypotension) - skin disorders • Special warnings: pregnancy and breastfeedindg

43. RANOLAZINE ( R ) • Inhibitor of the late Na+ current (late INa) • Inhibitor of the fast rectifying K+ current (IKr) • Reduces Ca++overload in the ischemic myocyte • Does not affect Na+- H+ and Na+- Ca++exchangers • Antianginal effect related to decreased LV diastolic tension and improved myocardial perfusion

44. PHARMACOKINETICS OF R • Sustained – release form • Prolonged absorption with Cmax 4 – 6 h after oral administration • Bioavailability 30% - 55% • Plasma protein binding ~ 62% • T1/2~ 7h • Steady state within 3 days

45. RANOLAZINE METABOLISM • CYP 3A4 – the major pathway • Additional pathways include: - CYP 2D6 (10% - 15%) - glucuronidation (< 5%) • ~ 5% excreted unchanged • Weak inhibitor of CYP 3A4 and CYP 2D6 • Inhibitors of CYPs 3A4 and 2D6 increase plasma R concentration 2 – 4 fold • Clearance of R is reduced by renal insufficiency and moderate hepatic impairment

46. DRUG – DRUG INTERACTION • Inhibitors of CYP 3A4 (itraconazole, ketokonazole, voriconazole, HIV protease inhibitors, clarithromycin, verapamil, diltiazem, erythromycin, fluconazole grapefruit juice • Inhibitors of CYP 2D6 (paroxetine) • Inhibitors of P-gp (cyclosporin, verapamil) INCREASED EXPOSURE TO RANOZALINE

47. DRUG-DRUG INTERACTION • CYP 2D6 inducers (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s Wort) DECREASED EXPOSURE TO RANOZALINE

48. ADVERSE DRUG REACTIONS • Mild to moderate in severity • Common ADRs: dizziness, headache, constipatin, vomiting, nausea, • ECG effects: ↑QTc, ↓T wave amplitude, T wave notching

49. CONTRAINDICATIONS • Hypersensitivity to the drug • Severe renal impairment (CrC < 30ml/min) • Moderate or severe hepatic impairment • Co-administration of potent CYP 3A4 inhibitors • LQTS • Co-administration QT-prolonging drugs (quinidine, dofetilide, sotalol)

50. HEART-RATE LOWERING DRUGS • Ivabradin (Procoralan 5 mg, 7,5 mg tablets) • Selective and specific inhibitor of If current that controls the spontaneous diastolic depolarisation in the sinus node • Dose-dependent reduction in heart rate and MO2