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Pharmocotherapy of Ischaemic Heart Disease Ischaemic Heart Disease Causes of IHD aren´t totally clear No satisfactory causal treatment, we eliminate only symptoms and treat complications 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 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 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 Deffects of blood perfusion can develop slowly and progressively (chronic) or can develop abruptly (acute form; even MI). Changes caused by ischaemia 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. Angina pectoris • Anginous pains is symptom of IHD • Not every ischaemia is accompanied with pain – silent ischaemia (only at ECG – depression of ST segment) Patologically-anatomical ground Coronary atherosclerosis Organ damage – embolia, vasculitis Function impairment – spasms, defects in relaxation of arteriolas Non-pharmacologic approach Changes of lifestyle (nicotine, food) → lowering lipids Psychosocial factors (excercise, taking care of oneself) → primary and secondary prevention Risk factors - Hyperlipoproteinaemia Hypertension Diabetes mellitus Smoking Obesity Family disposition Male gender Age CAN BE INFLUENCED CAN´T BE INFLUENCED 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) 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 significantly increases risk of coronary event occurrence 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 Stabilised IHD 1. We make better prognosis through prevention of occurrence of MI and cardiovascular death 2. We eliminate and decrease symptoms of patient – medications, catetrisation, aortocoronary bypass Therapy of stable AP • • • • • Antiaggregatory drugs Nitrates – EBM didn´t prove benefit Calcium channel blockers Betablockers Others (molsidomin, trimetasidin, ivabradin) Drugs Inhibiting Aggregation Platelet Antiaggregatory therapy decreases among patients with AP risk of complications (MI, sudden heart death) by 23 %. Drugs inhibiting platelet aggregation devided according to mechanism of action 1. Inhibition of TXA A2 formation through prostaglandin pathway – inhibition of COX-1 (ASA, indobufen) 2. 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) - inhibition of receptor for fibrinogen on thrombocyte membrane – glykoprotein IIb/IIIa (fibans, abciximab) Examples of Drugs Inhibiting Platelet Aggregation • • • • • Aspirin Ticlopidine Clopidogrel Indobufen Dipyridamole Aspirin • Antiaggregatory effect is given by irreversible blockade of COX-1 (thromboxane A2 is missing) • Optimal dose is between 1 mg/1kg daily • IND.- manifested IHD, AP, silent ischaemia • KI – allergy, ulcer, GIT bleeding Ticlopidine • Inhibition of platelet activation, mediated with adenosindiphosphate, starting after several days • 2 times per day 250 mg • Risk of leukopenia occurance Clopidogrel • • • • Tienopyridine 1 times per day 75 mg Good tollerance According to CAPRIE lowers atherotrombotic complication occurance regardless of its localisation by 9% more than ASA Indobufen • Dose 2 times per day 200 mg effective in already 2 hours • Effect is reversible, vanishes till 24 hours • 10 days before planned surgery we administer instead of ASA 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 Nitrates Lower intensity and also frequency of episodes, but according to EBM doesn´t influence morbidity and mortality 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 • In system 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 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) 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 Ca2+ Channel Blockers • Different chemical structures, with different haemodynamic and clinic effects • According to chemical structure divided to: - dihydropyridins (amlodipine, felodipine, lacidipine, nifedipine, isradipine) - phenylalkylamins (verapamil, gallopamil) - benzothiazepins (diltiazem) Ca2+CB – Mechanism of Action Block influx of calcium to cell through slow L-type channels, lower its intracellular concentration what causes relaxation of smooth muscle in vessel wall, decrease of contractility, decrease of electrical irritability and conductivity Antianginal effect of Ca2+CB 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 contractility and decrease of frequency Selectivity of Ca2+CB 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 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 Verapamil • Only phenylalkylamine in practice • Administered to patients, which can´t take BB • KI – combination with BB AV blocks II., III. degree Lowers renal excretion of digoxin Diltiazem • Suitable for monotherapy • KI combination with BB, AV block • Retard form 2 times per day Beta Blockers • • • • Decrease oxygen consumption Increase fibrilation base Antiarrhytmic effect Stopping of administration can´t be abrupt KI BB • Atrial bradycardia • Bradycardia below 50 per min • Ischaemic disease of lower extremities, worsening claudication BB • We try to chose cardioselective drugs • Importance of ISA is still questionable – not recommended after overcomed MI Representatives • • • • • Metipranol – nonselective Pindolol – nonselective with ISA Metoprolol – cardioselective Atenolol – cardioselective Carvedilol – hybrid (alfa1 also beta) Molsidomin • At its administration no tollerance • Not suitable for acute episode of AP • Effective in long-term prevention Trimetazidin • Metabolic modulator • Influence metabolism of cardiomyocytes • At ischaemia transfers ATP production from to oxygen more demanding boxidation of fatty acids to glykolysis, which demands less oxygen • Has no haemodynamic effects Ivabradin • Is blocker of sinus node, in which blocks flow If • Causes atrial bradycardia Hyperhomocysteinaemia Marker of increased cardiovaskular risk, no its reason Preventive taking of niacin has no proven benefit No pharmacologic proofs, that lowering of homocysteinaemia is connected with lower risk of CVD occurance Dyslipidemia Is disorder of plasmatic protein metabolism, can have different manifestation. Disorder can have genetic or dietetic reason, or connected disease. Classification of Lipids Pharmacotherapy of dyslipoprotinemias 1. Affecting mainly cholesterol - Statins – atorvastatin Bile acid-binding resins – cholestyramine Ezetimibe – selective inhibitor of CH resorbtion 2. Affecting cholesterol and TAG - fibrates – fenofibrate - derivates of nicotinic acid – lower synthesis of VLDL in liver and so also formation of LDL Statins Inhibit enzyme HMGCoA reductase, and so decreases intracellular synthesis of new cholesterol a decreases concentration of LDL Fibrates Bind as ligand for PPAR α – receptor activated with peroxisome proliferator Increase lipolysis of lipoprotein lipases State after MI 1. 2. 3. 4. 5. 6. 7. Modification of life-style Antiagreggatory therapy Anticoagulant therapy Betablockers iACE Ca2+CB Coronary angioplastic Unstable AP 1. 2. 3. 4. 5. Anticoagulant therapy Antiaggregatory therapy Nitrates BB Urgent angiography