1. CLINICAL PHARMACOLOGY OF ANTIANGINAL DRUGS. CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC DRUGS

2. ISCHEMIC HEART DISEASE There are 35 risk factors for development of IHD 3 most important ones are – “big triple” hypercholesterolaemia arterial hypertension arterial hypertension smoking smoking 95 % of patients with IHD are observed to have aterosclerotic changes in coronary arteries

3. Antianginal (coronary active) drugs a group of drugs which using different mechanisms even out irregularities between myocardium need in oxygen and it’s blood supply by coronary arteries clinically it is manifested by removal or prevention of stenocardia attacks (improvement of disease current) and increasing of patients’ tolerance to physical load

4. ANTIANGINAL (CORONARY ACTIVE) DRUGS І. Nitrates and sidnonims which are close to the first ones ІІ. Bets-adrenoblockers ІІІ. Antagonists of calcium ions ІУ. Activators of potassium channels Inhibitors of ATE Antiaggregants and anticoagulants Drugs with metabolic influence on miocardium

5. NITRATES nitroglycerin isosorbid dinitrate isosorbid dinitrate isosorbid-5-mononitrate isosorbid-5-mononitrate

6. MECHANISM OF ACTION OF NITRATES Interaction with sulfhydryl (SH-) groups (nitrate receptors) inside cells of vascular smooth muscles Stimulation of formation of endothelial factor of relaxation of vessels (ЕRF) – nitrogen oxide (NO) Decreasing of ionized Са 2+ contents Relaxation, dilation of vessels, including coronary vessels

7. MECHANISM OF ACTION OF NITRATES Decreasing of tone of venules – decreasing of preloading (income of blood into heart during diastole) – decreasing of work of left ventricle and heart output Decreasing of tone of arterioles – decreasing of afterloading (decreasing of arterial pressure, end diastolic pressure in left ventricle and it’s volume, decreasing of tension of myocardium wall decreasing of heart need in oxygen improvement of blood float in ischemic zone of myocardium – redistribution of coronary blood circulation with increasing of perfusion of subendocardial areas dilation of large coronary vessels if they are in spasm or narrowed with aterosclerotic mass development of anastomoses between arteries in myocardium (in case of prolonged administration)

8. NITROGLYCERINE TabletsTablets (under the tongue) solution 1 % alcohol or oil solution (under the tongue) aerosolaerosol Latent period - 2-3 min Duration of action - 20-30 min ampoulesampoules 1 % solution – intravenously dropply 0,01% solution prolongedprolonged forms of nitroglycerine: trinitrolong, sustak, nitrong, ointment, plaster

9. Nitroglycerine Nitroglycerine Unique transdermal system in a form of plaster

10. SIDE EFFECTS OF NITROGLYCERINE bursting, pulsating headache decreasing of arterial pressure decreasing of arterial pressure (heartbeat, dizziness, collapse) (heartbeat, dizziness, collapse) skin redness, feeling of fever

11. Contraindications for nitroglycerine use Close-angled form of glaucoma increasing of intracranial pressure, insult acute myocardium infarction (in case of presence of hypotonia and collapse)

12. PROLONGED FORMS OF NITROGLYCERINE Trinitrolong – polymer films (0,001 g or 0,002 g of nitroglycerine) action develops immediately, lasts for 3-5 hours Sustac Sustaс-mite (contains 0,0026 g of nitroglycerine) and Sustac-forte (0,0064 g of nitroglycerine) beginning of action – after 10 min, maximal action – after 1 hour, duration of action – 4-5 hours Nitrong – microcapsule form of nitroglycerine of prolonged action latent period – 30-60 min, maximal effect - after 3-4 hours, action duration - 6-8 hours

13. Iso Mak Retard 20mg Iso Mak Retard 40mg Isomak Retard 60mg (isosorbid dinitrate)

14. Isoket Isosorbid dinitrate

15. SIDE EFFECTS OF NITRATES bursting, pulsating headache decreasing of arterial pressure (heartbeat, dizziness, collapse) skin redness, feeling of fever development of tolerance nitrate dependence syndrome of cancellation

16. Other nitrates Nitrosorbid – isosorbid dinitrate latent period 30-50 min, duration of action – 4-6 hours and more With sublingual administration of the drug latent period grows short to 3-5 min buccal form (Dinitrolslrbilong) tablets of prolonged action (Isoket-retard) ointment aerosol drugs for intravenous introduction Isosorbid-5-mononitrate - pharmacologically active metabolite of isosorbid dinitrate duration of action - from 6 till 24 hours

17. SYDNONIMS Molsydomin – corvaton - sydnopharm is metabolized in liver forming a substance – SIN-1a which contains free NО group (doesn’t need previous interaction with SH-groups) nitrogen oxide stimulates guanilatecyclase that activates synthesis of cGMP cGMP causes dilation of vessels 2 mg of molsydomin = 0,5 mg of nitroglycerine

18. Molsydomin latent period - 20 min (5-10 min – if administered sublingually), action duration - 6 hours. can be used for prophylaxis and releasing stenocardia attacks in patients with glaucoma (doesn’t increase intraoccular pressure) indicated for patients who make breaks in using nitrates to decrease tolerance towards them doesn’t lead to development of tolerance (doesn’t need previous combining with sulfhydryl groups) absence of cancellation syndrome

19. BETA-ADRENOBLOCKERS Mechanism of action during stenocardia blockade of  1 -adrenoreceptors of heart: decreasing of power and frequency of heart contractions and as follows cardiac need in oxygen decreasing of thrombocyte aggregation and prevention of thrombus formation increasing of diastole duration – improvement of coronary vessels saturation with blood – improvement of perfusion of ischemic areas of myocardium Decreasing of calcium ions accumulation – releasing of cardiac muscle tension, improvement of metabolic processes, increasing of ATP synthesis in case of acute myocardium infarction – increasing of blood supply of ischemic areas of heart, decreasing of size of infarction seat, prevention of development of cardiac arrhythmias

20. Anaprilin Anaprilin β 1 - β 2 adrenoblocker

21. Vasocardin 100 mg Methoprolol tartrate

22. Nadolol ( β1, β 2- adrenoblocker )

23. CALCIUM IONS ANTAGONISTS 1. Derivatives of difenilalkilamin (verapamil) 2. Derivatives of benzothiazepine (dylthiazem) 3. Derivatives of dyhydropyridine (nifedipin, amlodipin, nimodipin) Drugs of 1 and 2 groups dominantly influence on heart (depress automatism of sinus node, conductivity through conductive heart system), show antiarrhythmic, antiangina and hypotensive action. Derivatives of dyhydropyridine (group of nifedipin) – decrease blood pressure and cause dilation of coronary vessels, cause reflective tachycardia

24. Nifedipin - corinfar - fenigidin - adalate Doesn’t depress conductivity in myocardium, has a weak antiarrhythmic action Maximal concentration of the drug in blood occurs after 45-60 min after administration orally and after 2-3 min – if administered sublingually Effect lasts for 4-6 hours

25. Antagonists of calcium ions ІІ generation amlodipin Antagonists of calcium ions – derivatives of dyhydropyridine of ІІ generation (amlodipin, isradipin, nicardipin) almost don’t cause tachycardiaalmost don’t cause tachycardia are indicated for prolonged treatment of patients with stabile stenocardiaare indicated for prolonged treatment of patients with stabile stenocardia aren’t indicated in case of non stabile stenocardia (long lasting latent period)aren’t indicated in case of non stabile stenocardia (long lasting latent period)

26. Hypertension Verapamil Dylthiazem NifedipinFelodipinAmlodipin Stenocardia DylthiazemNifedipinAmlodipinVerapamil Supraventric ular tachy- arrhythmia VerapamilDylthiazem Possible combination with β-blockers DylthiazemNifedipinAmlodipin - recommended drug --should be used carefully Usage of calcium ions antagonists Illness Drugs Felodipin

27. Nifedipin (Са 2+ ions antagonist of dyhydropyrydine series)

30. ACTIVATORS OF POTASSIUM CANALS NICORANDIL activates Са 2+ -depending potassium canals causes relaxation of smooth muscles of vessels – coronary, arteriolar and venous vasodilation improvement of blood supply of myocardium, decreasing of pre- and afterloads of heart, decreasing of myocardial need in oxygen, separation of ischemic damage zone

31. Acetylsalicylic acid 80-100 mg per day – as antiaggregative drug, decreases risk of development of acute myocardium infarction and decreases mortality of patients with IHD In many world countries it is also used a basis treatment drug of IHD which can be used for years

32. ACUTE MYOCARDIUM INFARCTION one of the main reasons of disablement and mortality of people of employed age in many world countries, including Ukraine men suffer from MI almost 5 times more often than women Mortality of patients with MI during first two hours starting from the beginning of the process makes around 50 % of all mortal cases connected with MI the most often death causes – acute cardiac-vascular insufficiency (angina pectoris, lung edema, cardiogenic shock), heart rupture, heavy cardiac arrhythmia other complications of MI – thrombosis and emboli, acute and chronic heart aneurisms, Dresler’s syndrome, chronic cardiac insufficiency

33. TREATMENT OF MYOCARDIUM INFARCTION three stages Immediate treatment – decreasing pain and treatment of stop of heart beats Early treatment – separation of zone of infarction seat and prevention of early life threatening complications (cardiac arrhythmias, acute cardiac insufficiency) Further treatment – prevention and therapy of late complications of MI, prophylaxis of recurrent MI and death of the patients

34. TREATMENT OF ACUTE MYOCARDIUM INFARCTION Releasing of pain and prophylaxis of cardiogenic shock nitroglycerin (1 tablet under the tongue every 7-10 min.) Neuroleptanalgesia (fentanil with droperidol), morphine, omnopon, promedol (in combination with atropine, dimedrol, aminasine) nitrous oxide in combination with neuroleptics in case of remaining pain – non narcotic analgesics in combination with antihistamine and neuroleptic drugs to increase arterial pressure during cardiogenic shock – intravenously dropply dopamine (drugs of choice), noradrenalin, mesaton sometimes glucocorticosteroids are used

35. TREATMENT OF ACUTE MIOCARDIUM INFARCTION Size limitation of infarction seat Intravenous dropply introduction of 0,01 % nitroglycerin solution Administration of  -adrenoblockers

36. TREATMENT OF ACUTE MYOCARDIUM INFARCTION Treatment and prophylaxis of heart arrhythmias Treatment of ventricular arrhythmias – i.v. slowly 0,2 % solution of xycain, novocainamid intramuscularly Prophylaxis of ventricular extrasystolia and tachycardia – magnesium sulfate (intravenous dropping introduction of 4- 5 % solution),  -adrenoblockers Arrhythmias of atrial origin – heart glycosides, antagonists of calcium ions Bradycardia - isadrin, atropine sulfate, alupent (i.v.)

37. TREATMENT OF ACUTE MYOCARDIUM INFARCTION CORRECTION OF BLOOD CLOTTING thrombolytic drugsthrombolytic drugs streptokinase (1,5 mln OD), urokinase (2 mln OD), aktilise – recombinant tissue activator of plasminogen (100 mg) intravenous after performing of thrombolytic therapy – intravenous introduction of heparin, at first 10 000 OD, after 1000 OD per hour during 24-48 hours anticoagulants of indirect actionanticoagulants of indirect action acetylsalicylic acid acetylsalicylic acid (80-100-300 mg per day)

38. TREATMENT OF ACUTE MYOCARDIUM INFARCTION Treatment of heart insufficiency i.v. furosemid (40-120 mg); i.v. dropply nitroglycerine (12-20 hours), morphine i.v. dropply dopamin and dobutamin heart glycosides – in tachysystolic form of scintillating arrhythmia or fluttering of atria with moderate left-ventricular insufficiency General measures oxygen inhalation correction of acid-base balance

41. ANTIARRHYTHMIC DRUGS CLASSMechanism of ActionDrug name IANa + Channel blockerDisopyramide, procainamide, quinidine IBNa + Channel blockerLidocaine, mexiletine, tocainide ICNa + Channel blockerFlecainide, propafenone II  Adrenoreceptor blockerEsmolol, metoprolol, pindolol, propranolol IIIK + Channel blockerAmiodarone, bretylium, sotalol IVCa ++ Channel blockerDiltiazem, verapamil Other antiarrhythmic drugsAdenosine, digoxin