Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Prescription costs wikipedia , lookup
Psychedelic therapy wikipedia , lookup
Discovery and development of beta-blockers wikipedia , lookup
Drug-eluting stent wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Neuropharmacology wikipedia , lookup
Psychopharmacology wikipedia , lookup
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 IHD Chronic forms: Stable angina pectoris (Chronic heart failure) Acute coronary syndromes (ACS): Unstable angina pectoris AMI without ST segment elevation AMI with ST segment elevation Sudden cardiac death ACS without ST elevation (NSTEMI) (STEMI) 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 • Cardiac Syndrome X 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. Angina pectoris • Anginous pain is symptom of IHD • Not every ischemia is accompanied with pain – silent ischemia (only at ECG – depression of ST segment) Radiation of Pain at IHD 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 - Hyperlipoproteinemia 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, it 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 Stable IHD 1. We improve prognosis through prevention of occurrence of MI and cardiovascular death 2. We eliminate and decrease symptoms of patient – medications, catetrisation, aortocoronary bypass Antithrombotics Antiaggregatory drugs Anticoagulants Thrombolytics (inh. platelets) (inh. coagulatory factors) (dissolve thrombus) Antiplatelet drugs (Antiaggregatory drugs) Antiplatelet therapy decreases among patients with AP risk of complications (MI, sudden heart death) by 23 %. Antiplatelet drugs devided according to mechanism of action 1. Inhibition of TXA A2 formation through prostaglandin pathway - inhibition of COX-1 (aspirin) 2. Inhibition of TXA A2 formation through increasing level of cAMP in thorbocyte - inhibition of fosfodiesterase (dipyridamole) - stimulation of adenylatcyclase (prostacyclin) 1. 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) 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 Ticlopidine • Inhibition of platelet activation, mediated by adenosindiphosphate, starting after several days • 2 times per day 250 mg • Risk of leukopenia 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 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 • 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 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) Glyceryl trinitrate (GTN) • Different application forms • At sublingual administration pain subsides in 1-5 minutes • At peroral administration effect starts in 2040 minutes and lasts 2-6 hours • Used mainly at acute episodes • ADR: headache, flushing, palpitations, ortosthatic disturbances Long-acting nitrate preparations • GTN, isosorbide dinitrate, isosorbide mononitrate (all come in long-acting preparations) • Prevention of angina pectoris • KI: acute circulatory failure, cardiogenic shock, systolic blood pressure below 90 mm Hg, the use of sildenafil, tadalafil, verdenafil 2+ Ca 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) - benzothiazepins (diltiazem) 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 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 Selectivity of CCB Nifedipine • The oldest Ca2+CB • If nowadays administered, only as slow-release 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, who 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 treshold Antiarrhytmic effect Stopping of administration can´t be abrupt KI BB • Atrial bradycardia • Bradycardia below 50 per min • Ischemic 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 Trimetazidine • 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 Ivabradin • Is blocker of sinus node, in which it blocks If flow • Causes atrial bradycardia Ranolazine • Mechanism of action is not absolutely known • Can have some antianginal effects due to inhibition of late sodium current in heart cells 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 Dyslipidemia Is disorder of plasmatic protein metabolism Can have different manifestation. Disorder can have genetic or dietetic reason, or other disease. Classification of Lipids Target levels of lipids according to CVS risk (2005) mmol/l TOTAL CH 5 NON-HDL-CH 4 LDL-CHOLESTEROL Patients with high CVS risk Patients with very high CVS risk 3 2,5 1,8 TRIACYLGLYCEROLS 2 HDL-CH 1 2011 – important is level of LDL! Hypolipidemics 1. Affecting mainly cholesterol - - Statins – atorvastatin Bile acid-binding resins – cholestyramine (bind bile acids in the small intestine, reduce CH in the liver and increase the catabolism of LDL) 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 and decreases concentration of LDL • pravastatine ≤ lovastatine ≤ flluvastatine ≤ simvastatine ≤ atorvastatine ≤ rosuvastatine • statins total and coronary mortality • have pleiotropic effects (endothelium, inflammation, coagulation,...) Statins ADR • Myopathy biggest problem, check CK th CERIVASTATIN 16 – 80x more frequently => deregistration higher risk: at combination of statins with drugs increasing concentration of statins, or myotoxic drugs rhabdomyolysis – 5-10 cases / million treated • drugs inhibiting metabolism of statins (CYP3A4), increase occurance of statin toxicity, important dose reduction at combination therapy: - ERYTHROMYCIN, CYKLOSPORIN, AZOLES • Neuropathy - manifested by sensory and sensorimotor disturbances - association with DM, the main difficulties in the differential diagnosis of neuropathy • Rebound effect - sudden discontinuation of statin therapy can result in worsening of the underlying disease - increase of pathological levels of lipids (LDL cholesterol, TG) - increased incidence of thromboembolic events (AP, MI,) Combination Therapy with Statins • Ezetimibe • Fenofibrate • ?CEPT inhibitors • ?PSCK9 inhibitors Ezetimibe • drug that lowers plasma cholesterol levels by decreasing cholesterol absorption in the small intestine • I: combination with statints at patients where with monotherapy aren´t reached normal values = dual inhibition Fibrates Bind as ligand to PPAR α – receptor activated with peroxisome proliferator Increase lipolysis of lipoprotein lipases Fibrates ADRs: NAUSEA, DIARRHEA, NAUSEA MYOPATHY (MORE FREQUENT AT RENAL DISEASES) LDL-CH. TOTALCH. TG HDL-CH. FENOFIBRAT E ALSO URIC ACID CIPROFIBRATE FIBRINOGEN BEZAFIBRATE IMPROVES GLUCOSE TOLLERANCE GEMFIBROZIL FIBRINOGEN Therapy of stable AP- improving prognosis • Antiplatelet therapy (mainly ASA and clopidogrel) • Hypolipidemics (statins) • ACE inhibitors • Betablockers (at patients after MI) Therapy of stable APtherapy/prevention of symptoms •Nitrates •Betablockers •Calcium channel blockers •Others (nicorandil, ivabradine, molsidomine, ranolazine)