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Antiarrhythmic agents
- 1. ANTIARRHYTHMIC AGENTS Dr. Rajashree S. Chavan PDEA’s Seth Govind Raghunath Sable College of Pharmacy, Saswad
- 2. Arrhythmia Caused by a disturbance in impulse conduction through myocardial tissues or by disorders of impulse formation or by both Mechanism- 1. Ectopic foci 2. Re-entry 2
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- 7. Reasons Myocardial infarction causing death of pace maker or conducting cells Cardiac disorder Sympathetic or parasympathetic control changes Hypothyroidism, hyperthyroidism, hypoadrenalism, hypokalaemia, hyperkalaemia or other electrolyte disturbance 7
- 8. Classification Based on rate of beat and anatomical location 1. Sinus tachycardia 2. Atrial flutter and fibrillation 3. Sinus bradycardia 4. Sick sinus syndrome 5. AV block 6. Premature ventricular contraction 7. Paroxysmal Supraventricular tachycardia 8. Re-entry 9. Ventricular flutter 10. Ventricular fibrillation 8
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- 11. Signs and symptoms Dizziness or collapse because of poor supply to the brain Shortness of breath due to poor oxygenation Angina associated with a poor coronary circulation Increased cardiac workload arising from tachycardia Weakness and palpitation 11
- 12. ANTIARRHYTHMIC AGENTS Affect impulse conduction by altering conduction velocity and duration of refractory period of heart muscle tissue Depress spontaneous diastolic depolarization causing reduction of automaticity of ectopic foci 12
- 13. MOA May reduce rate of rise of action potential as well as magnitude of charge during phase 0 May diminish membrane responsiveness May decrease threshold potential May slow recovery of electrical excitability May alter the relationship between membrane potential during repolarization and recovery of excitability 13
- 14. Classification Based on MOA or pattern of their electrophysiological effect Cla ss Name Drugs MOA I A Membrane Depressant drugs (Decrease max rate of depolarization) Quinidine , Procainamide, Disopyramide duration of action potential I B Lidocaine , Phenytoin, Tocainide, Mexiletine Duration of action potential IC Flecainide, Encainide, Propafenone, Moricizine No change on duration of action potential, Slows conduction 14
- 15. Class Name Drugs MOA II β-adrenergic blockers (inhibition of sympathetic activity) Porpranolol Slows AV conduction time, Suppress automaticity III Repolarization prolongators Sotalol, Ibutilide, Bretylium, Amiodarone Prolongation of duration of action potential IV Calcium Channel Blockers Verapamil, Diltiazem, Bepridil Block slow inward calcium channels 15
- 16. PH and Activity Basic in nature with PKa - 7.5 to 9.5 Acidosis – Sodium channels get occupied by protonated form Small change in PH can affect effectiveness. Alkalosis reduce the effect of drug. 16
- 17. Class IA Antiarrhythmic N CHO H N H3CO H2C=HC H H QUINIDINE -Prototype of Class IA drugs -Dextrorotatory -Reduce Na+ current by binding the open ion channel (state A) -Depress phase 4 diastolic depolarization -Depress automaticity of ectopic foci -Decrease conduction velocity, prolongation of QRS -Prolongs action potential duration -Given orally or IM -Side effect- bradycardia -Available as Sulfates, Gluconates and Polygalacturonate 17
- 18. H2N C N H O CH2 CH2 N C2H5 C2H5 PROCAINAMIDE HCl p-amino-N-[2-(dimethylamino)ethyl]benzamide •More stable than procaine due to its amide nature •Aq. Soln- PH 5.5; stable to acid hydrolysis in PH range of 2-7 •Metabolite N-acetylprocainamide (has 25% of activity) •Less protein bound (peak level in 1 hr) •Quinidine used for atrial arrhythmias •Procainamide used for ventricular tachycardia 18
- 19. N C CH2CH2N C NH2 O CH(CH3)2 CH(CH3)2 DISOPYRAMIDE PHOSPHATE -[2(Diisopropylamino)ethyl]-phenyl-2-pyridineacetamide Given orally or IV Used to treat refractory, life threatening ventricular tachycardia Peak level in 2 hrs, 50% bound to protein 50% excreted unchanged in urine Shows cholinergic blocking actions as side effects 19
- 20. Class IB Antiarrhythmic CH3 CH3 NH C CH2 O N C2H5 C2H5 LIDOCAINE (XYLOCAINE) HCl 2-(Diethylamino)-2',6'-acetoxylidide -Used IV -Drug of choice for premature ventricular contraction -It does not decrease conduction velocity & increases membrane responsiveness to stimulation -It does not depress Na+ influx during diastole -Less protein bound and Rapid metabolism -Rapid action -Less cardiovascular side effects 20
- 21. CH3 CH3 NH C CH2 O N C2H5 C2H5 LIDOCAINE (XYLOCAINE) Microsomal oxidation CH3 CH3 NH C CH2 O N H C2H5 Microsomal Amidase NH2 + N H C2H5 CH2 COOH monoethylglycinexylilide METABOLISM OF LIDOCAINE 21
- 22. CH3 CH3 O H2 C C H N H H MEXILETINE HCl 1-Methyl-2-(2,6-xylyloxy)ethylamine CH3 N H H N O O PHENYTOIN SOD 5,5-Diphenyl-2,4-imidazolinedione Used to treat digitalis induced arrhythmias (supraventricular) Cause bradycardia, prolong PR interval oGiven orally or IV oEther in nature oHalf life- 10hrs oMetabolized by oxidative & reductive pathways in liver oEffective on Purkinje fibres oLong term oral prophylaxis of ventricular tachycardia 22
- 23. CH3 CH3 NH C C H O N H H TOCAINIDE HCl 2-Amino-2',6'-propionoxylidide CH3 - Analogue of Lidocaine - But less first pass metabolism in liver due to lack of ethyl grs - Used in ventricular ectopy & tachycardia 23
- 24. Class IC Antiarrhythmic S N C CH2CH2 N O NHCOC2H5 O O MORICIZINE Ethyl-10-(3-morpholinopropionyl)phenothiazine-2-carbamate •Phenothaizine derivative •Used to treat malignant arrhythmias •Higher affinity of inactivated state of sodium channels •Used to suppress life threatening ventricular arrhythmias24
- 25. OCH2CHCH2NH H2CH2CCO CH2CH2CH3 OH PROPAFENONE 2-[2'-Hydroxy-3-(propylamino)propoxy]-3-phenylpropiophenone •Racemic mix ; both R and S isomers active •But S isomer also produces β-adrenergic blockade •Thus S isomer is 40 % more potent •Polymorphic metabolism •5-hydroxy metabolite-active •Also blocks slow calcium channels •Protein bound, first pass metabolism, less bioavailability •Used for long term suppression of ventricular arrhythmias 25
- 26. F3CH2CO OCH2CF3 C NH O CH2 HN FLECAINIDE ACETATE N-(2-Piperidinylmethyl)-2,5-bis (2,2,2-trifluoroethoxy)benzamide Meta-o-dealkylated metabolite- half active Meta-o-dealkylated lactam metabolite – little activity Given orally to suppress chronic Ventricular ectopy & tachycardia CNS side effects 26
- 27. HN CH2CH2 C O H3CO ENCAINIDE 4-Methoxy-N-[2-[2-(1-methyl-2-piperidinyl)ethyl]phenyl]benzamide 27
- 29. Class II Antiarrhythmic Inhibit cardiac stimulation Depress adrenergically enhanced calcium flux thr β-receptor blockade Decrease neurologically induced automaticity at low dose At high dose, show anesthetic property (decreased excitability, decreased conduction velocity & prolonged refractory period) 29
- 30. O N H OH 1-(isopropylamino)-3-(naphthalen-1-yloxy)propan-2-ol PROPRANOLOL • Nonselective β- blocker • Prototype class II agent • Used to treat supraventricular arrhythmias including atrial flutter, paroxysmal supraventricular tachycardia & atrial fibrillation. • Effective in the treatment of digitalis induced ventricular arrhythmias 30
- 31. CHCH2NHCH(CH3)2H3CO2SHN OH SOTALOL 4'[1-Hydroxy-2-(isopropylamino)ethyl]methyl-sulfonanilide Nonselective β- blocker Shows class II and class III effects Used orally to suppress & prevent life threatening ventricular arrhythmias 31
- 32. Class III Antiarrhythmic Repolarization prolongators- prolongs refractory period Act through phase 3 of action potential by blocking potassium channels Bretylium- prototype 32
- 33. CH2 N CH3 C2H5 CH3 SO3 CH3 BRETYLIUM TOSYLATE (o-Bromobenzyl)ethyl dimethylammonium p-toluenesulfonate # Used in case of emergency, IV or IM (ICU) # Half life- 10 hrs # Side effect- orthostatic hypotension 33
- 37. Cl O H C N N O O (CH2)4 N N AZIMILIDE 37
- 38. Class IV Antiarrhythmic Calcium Channel Blockers Verapamil Diltiazem 38