Pharmocotherapy of Ischaemic Heart Disease

1. Pharmocotherapy of Ischaemic Heart Disease

2. Ischaemic Heart Disease Causes of IHD aren´t totally clear No satisfactory causal treatment, we eliminate only symptoms and treat complications

3. IHD Is condition/disease, at which requirements of myocardium exceed possibilities of its supply with oxydized blood. The cause of this imbalance is wide spectrum of patophysiologic mechanisms and reasons. • cardiac: coronary, extracoronary • extracardiac

4. Clinical Forms of IHD Acute – unstable angina pectoris acute myocardial infarction sudden heart death Chronic – asymptomatic IHD angina pectoris - after excercise - combined - variant - Prinzmetal´s state after MI dysrythmic IHD chronic heart failure

5. Types of AP • Stable – occurence of problems at standard situations and their frequency, intensity and duration not changed • Unstable – sudden beginning, longer duration of pain • Prinzmetal´s – caused by spasmus, elevation of ST segment on ECG

6. Disturbances of blood perfusion can develop slowly and progressively (chronic) or can develop abruptly (acute form; even MI). Changes caused by ischemia can be temporary or permanent (irreparable damage of myocard). Conditions are usually interconnected, without sharp limits and IHD needs to be understood dynamically and individually. AP was the first time described in the second half of 18th century by Wiliam Heberden and treated with nitroglycerin in the year 1879.

7. Angina pectoris • Anginous pain is symptom of IHD • Not every ischemia is accompanied with pain – silent ischemia (only at ECG – depression of ST segment)

10. Patologically-anatomical ground Coronary atherosclerosis Organ damage – embolia, vasculitis Function impairment – spasms, defects in relaxation of arteriolas

11. Non-pharmacologic approach Changes of lifestyle (nicotine, food) → lowering lipids Psychosocial factors (excercise, taking care of oneself) → primary and secondary prevention

12. Risk factors • Hyperlipoproteinemia • Hypertension • Diabetes mellitus • Smoking • Obesity • Family disposition • Male gender • Age CAN BE INFLUENCED CAN´T BE INFLUENCED

13. Primary prevention Active monitoring and searching for persons having risk factors with the goal to prevent formation of atherosclerosis !! Low doses of acetylsalicylic acid!! Males – accorcing to clinical studies taking aspirin din´t decrease mortlity, decreased occurrence of MI, increased cerebral bleeding (US Physician´s Health Study)

14. females even more unclear – prospective study 1991 showed that occurrence of the first MI decreased, but overall or cardiovascular mortality didn´t decrease HST – postmenopausal women Women´s Health Initiative Study proved, that among women in the first year of using HST, it significantly increases risk of coronary event occurrence

15. Secondary prevention Consistent pharmacologic intervention to influence all risk factors among persons with clinically manifested IHD, among persons after MI, with the goal to prevent or at least slower disease progression

16. Stable IHD • We improve prognosis through prevention of occurrence of MI and cardiovascular death • We eliminate and decrease symptoms of patient – medications, catetrisation, aortocoronary bypass

17. Therapy of stable AP • Antiplatelet drugs • Nitrates – EBM didn´t prove benefit • Calcium channel blockers • Betablockers • Others (molsidomin, trimetasidin, ivabradin)

19. Antiplatelet drugs (Antiaggregatory drugs) Antiplatelet therapy decreases among patients with AP risk of complications (MI, sudden heart death) by 23 %.

20. Antiplatelet drugs devided according to mechanism of action • Inhibition of TXA A2 formation through prostaglandin pathway - inhibition of COX-1 (ASA, indobufen) • Inhibition of TXA A2 formation through increasing level of cAMP in thorbocyte - inhibition of fosfodiesterase (dipyridamole) - stimulation of adenylatcyclase (prostacyclin) • Inhibition of fibrinogen bridges formation between thrombocytes - inhibition of receptor for ADP on thrombocyte membrane (thienopyridines – ticlopidine, clopidogrel, prasugrel) (ticagrelor) - inhibition of receptor for fibrinogen on thrombocyte membrane - glykoprotein IIb/IIIa (fibans, abciximab)

21. Examples of Antiplatelet Drugs • Aspirin • Ticlopidine • Clopidogrel • Indobufen • Dipyridamole

22. Aspirin • Antiaggregatory effect is given by irreversible blockade of COX-1 (thromboxane A2 is missing) • Optimal dose is about 100 mg/day • IND.- manifested IHD, AP, silent ischemia • KI - allergy, ulcer, GIT bleeding

24. Ticlopidine • Inhibition of platelet activation, mediated by adenosindiphosphate, starting after several days • 2 times per day 250 mg • Risk of leukopenia

25. Clopidogrel • Tienopyridine • 1 times per day 75 mg • Good tollerance • According to CAPRIE lowers atherotrombotic complications regardless of their localisation by 9% more than ASA

26. Dipyridamole • Alone not recommended because of low antiaggregatory effect and making worse IHD „steal phenomenon“ • Combination of dipyridamole with retarded release 200 mg and 30 mg ASA (Aggrenox) is used in neurology in prevention of stroke

27. Nitrates Lower intensity and also frequency of episodes, but according to EBM doesn´t influence morbidity and mortality

29. Nitrates Mechanism of Action • Nitrates are changed by sulfhydrylic groups of gluthation to nitrosotiol, from which in endothelium is released NO (equivalent of EDRF) • Vasodilation of epicardial coronary arteries • Systemic venodilation, lower blood return and lower metabolic requirements of myocardium • In higher doses occurs vasodilation also in arterial portion with subsequent BP reduction, which is compensated by reflex tachycardia

30. Tollerance • Maintaining of high plasmatic levels of nitrates leads to their antianginal effect decrease • Reason is depletion of free sulfhydrylic groups in vessel wall • We avoid tollerance by skipping one dose (10-12 hours without nitrates)

31. Nitroglycerin • Different application forms • At sublingual administration pain subsides in 1-5 minutes • At peroral administration effect starts in 20-40 minutes and lasts 2-6 hours • Used mainly at acute episodes

32. Ca2+ Channel Blockers (CCB) • Different chemical structures, with different hemodynamic and clinical effects • According to chemical structure divided to: - dihydropyridins (amlodipine, felodipine, lacidipine, nifedipine, isradipine) - phenylalkylamins (verapamil, gallopamil) - benzothiazepins (diltiazem)

33. CCB – Mechanism of Action Block influx of calcium to cell through slow L-type channels and lower its intracellular concentration, what causes relaxation of smooth muscles in vessel wall, decrease in contractility, electrical irritability and conductivity of conducting system of the heart

35. Antianginal effect of CCB Direct dilation of coronary arteries and so increased oxygen supply Decreased demand of myocardium to oxygen with systemic arterial dilation, with subsequent decrease of peripheral vascular resistance, decrease of heart contractility and frequency

36. Selectivity of CCB

37. Nifedipine • The oldest Ca2+CB • If nowadays administered, only as retarded form! • Otherwise occurs fast vasodilation with subsequent reflex activation of sympathicus - tachycardia • 2nd and 3rd generation of DHP are much more convenient

38. More Convenient DHP • Amlodipine – 1 times per day 5-10 mg, possible combination with BB • Felodipine – 1 times per day 5-10 mg • Isradipine – 2 times per day 2.5 mg • Lacidipine – 4-8 mg daily • Nitrendipine – 1 times per day 10-40 mg

39. Verapamil • Only phenylalkylamine in practice • Administered to patients, who can´t take BB • KI – combination with BB AV blocks II., III. degree Lowers renal excretion of digoxin

40. Diltiazem • Suitable for monotherapy • KI combination with BB, AV block • Retard form 2 times per day

41. Beta Blockers • Decrease oxygen consumption • Increase fibrilation treshold • Antiarrhytmic effect • Stopping of administration can´t be abrupt

43. KI BB • Atrial bradycardia • Bradycardia below 50 per min • Ischemic disease of lower extremities, worsening claudication

44. BB • We try to chose cardioselective drugs • Importance of ISA is still questionable – not recommended after overcomed MI

45. Representatives • Metipranol – nonselective • Pindolol – nonselective with ISA • Metoprolol – cardioselective • Atenolol – cardioselective • Carvedilol – hybrid (alfa1 also beta)

46. Molsidomin • At its administration no tollerance • Not suitable for acute episode of AP • Effective in long-term prevention

47. Trimetazidin • Metabolic modulator • Influences metabolism of cardiomyocytes • At ischemia transfers ATP production from to oxygen more demanding beta-oxidation of fatty acids to glykolysis, which demands less oxygen • Has no hemodynamic effects

48. Ivabradin • Is blocker of sinus node, in which it blocks If flow • Causes atrial bradycardia

49. Hyperhomocysteinemia Marker of increased cardiovaskular risk, no its reason Preventive taking of niacin has no proven benefit No pharmacologic proofs, that lowering of homocysteinemia is connected with lower risk of CVD occurance

50. Dyslipidemia Is disorder of plasmatic protein metabolism Can have different manifestation. Disorder can have genetic or dietetic reason, or other disease.