2. Cardio-vascular Pharmacology By Professor Doctor: Abd Al Rahman Abd Al Fattah Yassin Professor and head of clinical pharmacology department Mansura university

3. ANTIARRHYTHMIC DRUGS

4. CARDIAC ARRHYTHMIAS It is an abnormality of rate, site of origin of cardiac impulse or disturbance in conduction that causes alteration in normal sequence of activation of the atria and ventricles. All arrhythmia Result From Disturbance of impulse formation Abnormalities of impulse conduction. Both. Disturbance of Impulse Formation This occurs due to either enhancement or failure of normal automaticity.

5. Arrhythmias can be precipitated by: hypoxia,acidosis,alkalosis,electrolyte disturbances,excess catecholamines, drug toxicity (e.g. quinidine sotalol, phenothia-zine and cisapride), overstretching of cardiac fibers.

6. Arrhythmias may be one of the following: 1. Sinus tachycardia. 2. Sinus bradycardia 3. Extra systoles 4. Atrial flutter 5. Atrial fibrillation 6. Paroxysmal atrial tachycardia 7. Paroxysmal ventricular tachycardia 8. Ventricular fibrillation

7. 9. Heart block It may result from congenital, ishaemic heart disease, overdose of digitalis or potassium intoxication. It is classified into 3 grades. 8. Bundle branch block Block of conduction in one of the two main branches of bundle of His. N.B. Wolf-Parkinson-White Syndrome (WPW): It is due to an accessory atrioventricular pathway which conduct more rapidly than normal pathway and one ventricle is excited early. Rrespiratory sinus arrhythmias: heart rate increase during inspiration and decrease during expiration.

8. ANTIARRHYTHMIC DRUGS Non-pharmacological techniques for arrhythmia treatment are preferred because: Arrhythmogenic effect of the drugs used in treatment of arrhythmias. Efficacy of these methods.

9. Non Pharmacological techniques Ablation technique.. Implantable cardiovector defibrillator. Artificial pacemaker.

10. Mechanistic Classifications CLASS I (SODIUM CHANNEL BLOCKERS) Ia:.e.g. Quinidine, disopyramide, procainamide. Ib:..e.g. Lidocaine, mexilitene, aprinidine, tocainide. Ic: e.g. flecainide, lorcainide or encainide.

11. CLASS II (BETA-BLOCKERS) They include esmolol, metoprolol and propranolol. CLASS III (POTASSIUM CHANNEL BLOCKERS).e.g.: Amiodarone, bretylium, ibulilide and sotalol. CLASS IV Calcium channel blockers e.g. verapamil, diltiazem Potassium channel openers e.g. adenosine, cromakalim, pinacidil.

12. Therapeutic Classification of Antiarrhythmic Drugs Supraventricular arrhythmias: adenosine, verapamil, digoxin or beta-blockers Ventricular arrhythmias: Lidocaine, mexiletine, disopyramide or sotalol. Supraventicular and ventricular arrhytmias: Amiodarone, quinidine or beta adrenoceptor blockers.

13. CLASS Ia ANTIARRHYTHMICS QUINIDINE It is an alkaloid of Cinchona bark. It is dextroisomer of quinine. Pharmacokinetics Absorption from the gut is about 70%... The half-life is 7-9 hours. Protein binding 80-90% Metabolized in the liver. Plasma levels for antiarrhythmic effects are 2-5  g/ml.

14. Pharmacodynamics Its antiarrhythmic action: block sodium channels. Quinidine has atropine like action. and alpha adrenoceptor blocking properties..

15. Pharmacological Effects Effects on the cardiovascular system Cardiac effects Negative inotropic effect. Depression of excitability. ENHANCE conductivity in the A-V node and bundle of His. It suppresses enhanced automaticity. Effect on the E.C.G: Prolongation of Q-T interval. Prolongation of P-R interval Decrease in amplitude or inversion of T wave Widening of Q.R.S. complex.

16. Effect on blood vessels and BP: vasodilatation and hypotension with large dose. Autonomic effects Quinidine has atropine like effect and alpha adrenocepetor blocking properties. Other pharmacological actions It possesses antimalarial, antipyretic, analgesic, oxytocic and skeletal muscle relaxant, but it is not used clinically for these purposes.

17. Therapeutic Indications Atrial fibrillation (of less than 6 months duration). Patient should be digitalized before quinidine to prevent the possible occurrence of "Paradoxical tachycardia". Atrial flutter : It is less active than in atrial fibrillation and can be used when digitalis fails. Paroxysmal atrial tachycardia. Extrasystoles. Atrial and ventricular. Ventricular tachycardias. Maintenance of sinus rhythm after successful direct current cardioversion.

18. Side Effects and Toxicity Idiosyncrasy. Cinchonism. Embolism. Paradoxical tachycardia. Quinidine syncope. Hypotension: particularly if given intravenously.

19. Contraindications Complete A.V block with an A.V. pacemaker or idioventricular rhythm. Old standing atrial fibrillation. Prolongation of Q.T. interval. Congestive heart failure. Hypotension. Hypersensitivity. Myasthenia gravis.

20. Preparations and Dosage Oral: Quinidine sulphate, available as 0.2 gm tab. or capsules. A test dose is given at first. The usual schedule is as follows: 0.2 gm, 2 hourly for 5 doses which may be increased to 0.4 gm, on the next day..). Parenteral: Quinidine gluconate administered i.m, or i.v. in emergencies.

21. PROCAINAMIDE Pharmacological Effects Cardiac effects: Similar to quinidine Autonomic effects: It has weaker anticholinergic effects.it has a ganglion blocking effect. Therapeutic Uses Ventricular arrhythmias Supraventricular arrhythmias.

22. CLASS Ib ANTIARRHYTHMICS LIDOCAINE Its oral administration results in a very low plasma concentration due to its massive first-pass metabolism Pharmacological Effects. It decrease pacemaker activity of Purkinjie fibers. It has no effects on SAN Lidocaine decreases membrane excitability of Purkinjie fibers..

23. Therapeutic Uses In most ventricular arrhythmias. In digitalis induced arrhythmias Adverse Effects It is the least cardio toxic of antiarrhythmic but it may worsen impaired conduction Perioral paresthesia, tremors, dizziness, and slurred speech Dosage : It is given in loading dose of 1-2 mg /kg as an I.V bolus injection followed by a maintenance infusion of 2-4 mg/min. A constant infusion would take 5-9 hours to achieve therapeutic level.

24. PHENYTOIN (DIPHENYLHYDANTOIN, DPH) It is effective in treating epileptic seizures as well as ventricular arrhythmias. Pharmacokinetics It is slowly absorbed after oral administration It is inactivated by microsomal enzymes in the liver. About 90 % is bound to plasma protein

25. PHARMACOLOGICAL EFFECTS Effect on the heart: similar to lidocaine Effect on the autonomic nervous system: It exerts a depressant effect on sympathetic centers in the CNS. THERAPEUTIC USES Digitalis induced cardiac arrhythmias Ventricular arrhythmias. Antiepileptic drug.

26. ADVERSE EFFECTS CNS side effects: nystagmus, vertigo, dysarthria and confusion. Hepatotoxicity, lymphadenopathy, gingival hyperplasia, hirsutism, megaloblastic anaemia, hypotension. DOSAGE: IVI 50-100 MG/5 MINUTES THEN MAINTAIN ON 400 MG/DAY ORALLY AFTER CONTROL OF ARRHYTHMIAS.

27. CLASS Ic ANTIARRHYTHMICS FLECAINDIE and ENCAINIDE PROPAFENONE It is class Ic antiarrhythmic drug with some beta- blocking, class III, and class IV activities. Uses: ventricular, supraventricular arrhythmia and WPW syndrome. Side effects: A-V block, visual disturbance, metallic taste, and constipation.

28. CLASS II BETA-ADRENOCEPTOR BLOCKERS. The antidysrythmic effects of these drugs is probably due to beta receptor blockade.Beta-blockers slow automaticity in sinus and ectopic pacemakers. The principal effect is the depression of phase –4 depolarization. Propranolol has class I & IV properties, sotalol has class III properties. Therapeutic Uses : Supraventricular arrhythmias. In digitalis - induced ventricular arrhythmias. It is the drug of choice for chest pain and arrhythmias of mitral valve prolapse.

29. CLASS III AMIODARONE It is well absorbed orally. Extensively bound to tissues and slowly metabolized by the liver. Pharmacological Effects It produces prolongation of action potential duration through blockade of potassium channel. Blocking Na + channels (Class I activity). Blocking  and  adrenergic receptors (Class II activity). Weak Ca ++ channel blockers (Class IV activity). Amiodarone is a potent smooth muscle relaxant, producing marked coronary and peripheral vasodilatation.

30. Therapeutic Uses Supraventricular and ventricular arrhythmias. Arrythmias associated with WPW syndrome. Control of recurrent ventricular tachycardia or fibrillation in patients resistant to other aniarrhythmic drugs. Adverse Effects Corneal microdeposists, alteration of thyroid function, photosensitivity, pulmonary infiltration, myopathy, peripheral neuropathy, hepatotoxicity, sleeplessness, A- V block and sinus bradycardia. Dosage: It is given once per day. A loading dose of 0.8 - 1.2 gm/day is given for 2-4 weeks and maintain on 0.2 - 0.8 gm/day.

31. CLASS IV CALCIUM CHANNEL BLOCKERS The pharmacology of this class of drugs was discussed. Calcium channel blockers that are used are verapamil and diltiazem. VERAPAMILIS EFFECTIVE PREVENTING SUPRAVENTRICULAR TACHYCARDIA AND IN REDUCING THE VENTRICULAR RATE IN ATRIAL FIBRILLATION AND FLUTTER. MECHANISM OF ACTION: It acts by delaying impulse transmission through the A.V node as a result of blocking calcium channels.

32. OTHER ANTIARRHYTHMICS ADENOSINE It is a potassium channel opener. It is used in AV tachycardia in WPW syndrome. Adenosine also has been used to produce controlled hypotension during some surgical procedures and in the diagnoses of coronary artery disease. DIGOXIN.. Digoxin is used to control the ventricular response rate in atrial fibrillation and flutter.

33. MAGNESIUM SULFATE Magnesium sulfate is administered intravenously to suppress drug- induced torsade de pointes, to treat digitalis-induced ventricular arrhythmias, and to treat supraventricular arrhythmias associated with magnesium deficiency. ELECTRIC SHOCK THERAPY Direct current electric shock applied externally can be used to convert cardiac arrhythmias to normal sinus rhythm.it has been successfully applied to arrest atrial flutter and fibrillation, supraventricular and ventricular tachycardia and ventricular fibrillation. It is a method of choice in the emergency treatment of these arrhythemias. It is dangerous in presence of digitalis toxicity.

34. CLINICAL APPLICATIONS OF ANTIARRHYTHMIC DRUGS Atrial Fibrillation Emergency Treatment Digitalis IV is the drug of choice. Cardioversion can be used. Non-emergency Treatment Digitalis is given orally. Quinidine may be used to convert atrial fibrillation to sinus rhythm

35. Atrial Flutter Emergency Treatment Cardioversion or I.V. digitalis Non-Emergency Treatment Digitalis is given orally.

36. Wolf-Parkinson-White (WPW) Syndrome Amiodarone Sotalol or propranolol plus procainamide or quinidine Cardioversion should be used if the patient shows signs of CHF or angina. Junctional Tachycardias Vagotonic maneuvers.. I.V. verapamil, esmolol and adenosine are the drugs of choice and the response is usually diagnostic. Class Ia or Ic antiarrthythimcs are also useful. Avoid recurrence by the use of class Ia, III or IV antiarrhythmics.

37. Ventricular Tachycardias Emergency Treatment Lidocaine is the first choice if the patient is haemodynamically stable. Recently I.V. amiodarone has been used to suppress ventricular tachycardias. Cardioversion is used if ventricular tachycardia persists after lidocaine provided it is not due to digitalis toxicity and if the patient is unstable. Prophylaxis I.V. drips lidocaine should be continued for at least 48-72 after the return of sinus rhythm. Oral quinidine should be continued for at least 3 months especially if there is acute myocardial infarction.

38. Torsade de pointes Patients with this arrhythmia may be treated by intravenous administration of magnesium sulfate, cardiac pacing. Ventricular fibrillation Lidocaine, procainamide, or bretylium has been used as an adjunct treatment and is usually administered before and between attempts at electrical defibrillation. Recently, amiodarone has also been used for this purpose. Long- term preventive therapy may include an implantable cardioverter–defibrillator. Bradyarrhythmias and Heart Block Cardiac pacemaker.. Atropine I.V.. Hydrocortisone I.V. in acute cases of heart block e.g. following infarction hydrocortisone suppresses inflammatory reaction in the conducing tissue.