Pharmocotherapy of Ischaemic Heart Disease

1. Pharmocotherapy of Ischaemic Heart Disease

2. IschaemicHeartDisease 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. 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.

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

8. Patologically-anatomicalground Coronary atherosclerosis Organ damage – embolia, vasculitis Function impairment – spasms, defects in relaxation of arteriolas

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

10. Radiationofpainat IHD

11. IHD Chronic forms: Stable angina pectoris (Chronic heart failure) Acute coronary syndromes (ACS): Unstable angina pectorisACS without ST elevation AMI without ST segment elevation (NSTEMI) AMI with ST segment elevation (STEMI) Sudden heart death

12. Typesof AP • Stable – occurence of problems at standard situations and their frequency, intensity and duration not changed • Unstable – sudden beginning, longer duration of pain. Reason is disruption of an atherosclerotic plaque. • Prinzmetal´s (variant, vasospastic) – caused by spasmus, elevation of ST segment on ECG • Cardial syndrome X –decreased blood flow to heart tissue but with normal coronary arteries. Findings of microvascular dysfunction.

13. Non-pharmacologicapproach Changes of lifestyle (nicotine, alcohol, diet – lowering lipid intake, excercise) Psychosocial factors (stress, relaxation)

14. Primaryprevention Active monitoring and searchingforpersonshaving risk factorswiththegoal to preventformationofatherosclerosis HST – postmenopausalwomen Women´sHealthInitiative Study proved, thatamongwomen in thefirstyearofusing HST, itsignificantlyincreases risk ofcoronaryeventoccurrence

15. Primary prevention – low doses of aspirin Males – accorcing to clinical studies taking aspirin din´t decrease mortlity, decreased occurrence of MI, increased cerebral bleeding (US Physician´s Health Study) Females–even more unclear – prospective study 1991 showed that occurrence of the first MI decreased, but overall or cardiovascular mortality didn´t decrease

16. Secondaryprevention 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

17. Antithrombotics AntiplateletdrugsAnticoagulantsFibrinolytics

18. Antithrombotics AntiplateletdrugsAnticoagulantsFibrinolytics (inh. thrombocyty) (inh. coagulation factors) (dissolveclots)

19. Antiplateletdrugs (Antiaggregatorydrugs) – secondaryprevention Antiplatelet therapy decreases among patients with AP risk of complications (MI, sudden heart death) by 23 %.

20. Antiplateletdrugsdevidedaccording to mechanismofaction • Inhibition of TXA A2 formation through prostaglandin pathway - inhibition of COX-1 (aspirin) • Inhibition of TXA A2 formation through increasing level of cAMP in thorbocyte - inhibition of fosfodiesterase (dipyridamole) - stimulation of adenylatcyclase(prostacyclin) 3. 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. 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 • Interactions – e.g. warfarin, ibuprofen

23. ADP receptor antagonists • Thienopyridines: inhibition of platelet activation through adenosine diphosphate by irreversible blockade of ADP receptor; administered as prodrug ticlopidine – risk of leukopenia clopidogrel – good tollerance, according to CAPRIE dicreases atherothrombotic complications by 9% more than ASA (acetylsalicylic acid, aspirin) prasugrel – more effective than clopidogrel • ticagrelor – not prodrug as thienopyridines and reversible blockade of ADP receptor; efficacy cca as prasugrel, maybe ↓ risk of bleeding

24. 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

26. NitratesMechanismofAction • 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

28. Tollerance to Nitrates • 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)

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

30. 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

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 • ADRs: headache, facial flushing, palpitations, orthostatic disorders

32. History of Nitroglycerin • AP was the first time described in the second half of 18th century by Wiliam Heberden and treated with nitroglycerin in the year 1879. • Alfred Bernhard Nobel - a Swedish chemist, engineer. • His established the most prestigious award in the field of physics, chemistry, literature, physiology, medicine and peace-making (the Nobel Prize). • He invented dynamite in 1867 (the original composition: 75% nitroglycerin, diatomaceous earth 24.5% and 0.5% soda). • When Nobel suffered from heart problems, his doctor prescribed him nitroglycerin. Nobel refused to take it. In a letter he wrote: It's irony that I was now prescribed by the physician to eat nitroglycerin.

33. Isosorbide Dinitrate, Isosorbide Mononitrate • For the prevention of angina pectoris • KI: acute circulatory failure, cardiogenic shock, systolic blood pressure below 90 mmHg, use of sildenafil, tadalafil, vardenafil

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

35. CCB – MechanismofAction 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 Verapamil and diltiazem influence alsoconduction system of the heart

37. Antianginaleffectof CCB Direct dilation of coronary arteries, can cause "steal phenomenon"Systemic arterial dilation with a consequent reduction in peripheral vascular resistanceVerapamil ˃ diltiazem impact on the conduction system of the heart

38. Selectivity of CCB

39. Nifedipine(dihydropyridine CCB) • The oldest CCB • If nowadays administered, only as sustained-release form! • Otherwise occurs fast vasodilation with subsequent reflex activation of sympathicus – tachycardia • 2nd and 3rd generation of DHP are much more convenient

40. More ConvenientDihydropyridine CCB • 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

41. Verapamil(non-dihydropyridine CCB) • 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

42. Diltiazem(non-dihydropyridine CCB) • Suitable for monotherapy • KI: combination with BB, AV block • Retard form 2 times per day

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

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

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

47. Representativesof BB • Metipranol – nonselective • Pindolol – nonselective with ISA • Metoprolol – cardioselective • Atenolol – cardioselective • Carvedilol – hybrid (alfa1 also beta)

48. Molsidomine • Atitsadministration no tollerance(its effect unlike organic nitratesdoes not require - SH groups) • Its metabolite activates guanylylcyclase and subsequently increases cGMP(like organic nitrates) + increases cAMP in platelets (antiplatelet effects) • Notsuitableforacuteepisodeof AP • Effective in long-termprevention

49. Trimetazidine • 3-KAT inhibitor (metabolicmodulator) • Influencesmetabolismofcardiomyocytes • Atischemiatransfers ATP productionfrom to oxygen more demandingbeta-oxidationoffattyacids to glykolysis, whichdemandslessoxygen • Has no hemodynamiceffects

50. Ivabradine • Isblockerofsinusnode, in whichitblocksIfflow • Causesatrialbradycardia