Coronary vascular dilators Tomáš Goněc 12.11.2012 Ischemic heart disease  when lumen of coronary artery is restricted (due to atherosclerotic changes, spasm or inflammatory reaction), supplying of myocard with oxygen and nutrients is insufficient  primary symptom is Angina pectoris – sudden, severe pain originating in the chest and radiating to the left shoulder and arm Ischemic heart disease therapy  vasodilators – direct (NO releasing agents, xanthine derivatives, nicotinic acid, chromone derivatives, prostaglandines, trimetazidin) indirect (Ca2+inhibitors, ACE inhibitors, angiotensin II receptor antagonists)  drugs preventing myocardial infarction (anicoagulants, antithrombotics) Organic nitrates  prodrugs releasing NO  NO is endotelial guanylatcyclase activator  increased intracelular cGMP decrease Ca2+ levels → vessel wall smooth muscle relaxation → vasodilatation Organic nitrates N O N N N O O O +- Molsidomine ONO2O2NO ONO2 ONO2 ONO2 ONO2 O2NO O2NO ONO2 ONO2 O2NO O O H H ONO2 O2NO glyceryl trinitrate erithrityl tetranitrate pentaerythritol tetranitrate isosorbide dinitrate ONO amyl nitrite Organic nitrates synthesis Molsidomine synthesis Xanthin derivatives  nature xanthines – theophylin, theobromin, coffein  all are central stimulants, vasodilators, bronchodilators, diuretics  theophylin has enhanced smooth muscle relaxing activity  synthetic analogues are vasodilators and bronchodilators Xanthin derivatives N N N N O O O N N N N O O OH N OH N NN N N Pentoxifylline Xanthinol Trapidil Pentoxifylline Xanthinol Nicotinic acid  low dosis – vasodilating effect on upper part of body  higher dosis – antihyperlipidemic effect Cromone derivatives  PDE inhibitor, enhances anaerobic glycolysis  2X increased coronary flow without affecting blood pressure O O N O O O Carbocromen Carbocromen Prostaglandines  various prostaglandines has vasodilating effect  Alprostadil is used in some heart insufficiencies Trimetazidine  decreases intracelular ATP N NH MeO MeO OMe Trimetazidine synthesis Papaverine β-adrenergic receptor antagonists  in lower dosis decrease myocardium need for oxygen  Propranolol, Metoprolol, Acebutolol, Atenolol, Nadolol – see adrenergic antagonists Calcium channel blockers  reduction of calcium ions decrease strength of heart contraction = decrease need for oxygen  Verapamil  Diltiazem  Dihydropyridines Verapamil Diltiazem Dihydropyridines NR3 CH3 R4 R5 R2OOC COOR1 H 2 4 6 2 1 DIHYDROPYRIDINES R1, R2 – aliphatic ester, branched aliphatic chain R4 or R5 nitro group or halogen R3 methyl or substituted alkyl Nifedipine Nicardipine Dipyridamole  potentiates adenosine activity  blocks phosphodiesterase, improves microcirculation  inhibits thrombocyte formation and aggregation – see antithrombotics