Antiarrhythmic drugs

Antiarrhythmic drugs

1. ANTIARRHYTHMIC DRUGS BY ANJITA KHADKA

2. Cardiac Arrhythmia Cardiac arrhythmia is an abnormality in: Rate Rhythm Site of origin and, The conduction of cardiac impulse Either - Bradyarrhythmia (<60 beats/min.) or , Tachyarrhythmia(>100 beats/min.)

3. Four mechanisms of Arrythmias Reentry (Most Common) Automaticity Parasystole Triggered activity

4. Fast Conduction Path Slow Recovery Slow Conduction Path Fast Recovery Reentry Requires… Electrical Impulse Cardiac Conduction Tissue 2 distinct pathways that come together at beginning and end to form a loop. A unidirectional block in one of those pathways. Slow conduction in the unblocked pathway.

5. Atrial Reentry atrial tachycardia atrial fibrillation atrial flutter Atrio-Ventricular Reentry WPW SVT Ventricular Re-entry ventricular tachycardia AV Nodal Reentry SVT Reentry Circuits SA Node

6. Automaticity Heart cells other than those of the SA node depolarize faster than SA node cells, and take control as the cardiac pacemaker. Factors that enhance automaticity include: CO 2 ,  O 2,  H + ,  stretch, hypokalemia and hypocalcaemia. Examples: Ectopic atrial tachycardia or multifocal tachycardia in patients with chronic lung disease OR ventricular ectopy after MI

7. Parasystole … Benign type of automaticity problem that affects only a small region of atrial or ventricular cells. 3% of PVCs

8. TRIGGERED ACTIVITY Myocardial damage - oscillations of the transmembrane potential at the end of the action potential. These oscillations, which are called 'after depolarizations ', may reach threshold potential and produce an arrhythmia. The abnormal oscillations can be exaggerated by pacing, catecholamines , electrolyte disturbances, and some medications. Examples as atrial tachycardias produced by digoxin toxicity

9. Classification of arrhythmias 1. Supraventricular arrhythmias: all arrhythmias above the bundle of His. Sinus bradycardia (rate <60 Beats/min.) Sinus tachycardia (rate>100 BPM) Paroxysmal supraventricular tachycardia (rate: 140-250 BPM) Atrial flutter (rate: 240-400 BPM) Atrial fibrilation Wolff-Parkinson white syndrome Premature atrial contraction

10. 2. Ventricular arrhythmias: all arrhythmias originating below the bundle of His Premature ventricular contractions Ventricular tachycardia ( Torsade de points) Ventricullar fibrillation

11. Note : Class IA agents also have class III property; Propranolol has class I acton as well; Sotalol and bretylium have both class II and class III actions.

12. Based on clinical use: Drugs used for supraventricular arrhythmias: Adenosine, verapamil , diltiazem Drugs used for ventricular arrhythmias: lignocaine , mexelitine , bretylium Drugs used for supraventricular as well as ventricular arrhythmias: Amiodarone , β -blockers, disopyramide , procainamide

13. 1. Lignocaine / Lidocaine First line drug for the suppression of ventricular tachycardias . Mechanism of action: inhibit the fast sodium current while shortening the action potential duration in nondiseased tissue es the depolarization automaticity and excitability in the ventricles during the diastolic phase directly acts on the tissues as the Purkinje network Acts selectively on diseased or ischemic tissue where they are thought to promote conduction block, thereby interrupting reentry circuits.

14. Lignocaine contd.. Indication : Ventricular arrhythmias especially after myocardial infarction. Cardiac manipulation Adverse effect: CNS: tremmor , confusion, restlessness, anxiety, light headedness, europhoria , apprehension, agitation CVS: cardiac arrest , cardiac dysrhythmia , hypotension, bradycardia , Respiratory: respiratory depression, respiratory arrest Ear: tinnitus Eye: double vision Methemoglobinemia , seizure, anaphylactic reactions, malignant hyperthermia

15. Lignocaine contd.. Contraindication: Hypersensitivity Adams-stokes syndrome Severe degrees of AV and SA Severe heart failure Prophyria Hepatic failure Wolff- parkinson -white syndrome Drug interaction: Β -blockers decrease the metabolism of lignocaine In patients receiving propranolol or halothane the hepatic clearance of lignocaine is reduced- toxicity

16. Pharmacokinetics of Lignocaine Bioavailability: 35% (PO) Onset: IV 45-90 sec Duration : 10-20 min Protein bound: 60-80% Vd : 119 L Metabolism- dependent on hepatic blood flow Extensive first pass effect (so requires iv administration). Half-life: 8 min. distributive and 2 hrs for elimination (prolonged in CHF, Liver disease) Excretion: urine (90%)

17. Dose of lignocaine : 1-1.5 mg/kg slow IV bolus over 2-3 min

18. Lignocaine contd.. Alert box: Lignocaine hydrochloride 2% injection for cardiac arrhythmias has a different formulation and should not be confused with lignocaine for anaesthesia . Lignocaine intravenous agent :used only for ventricular dysrrhythmias . It’s preparation is intended for IV administration and contain no preservative or catecholamines Preparation containing epinephrine or another catecholamines must never be administered intravenous. If so that can cause severe hypertension and life threatening dysrrhythmias .

19. 2. Amiodarone Mechanism of action: Inhibits movement of calcium ions across the cell membrane into vascular smooth muscles and myocytes Causes relief of angina by decreasing myocardial oxygen demand, similarly slow the sinus rate, increases PR and QT intervals, and decreases peripheral vascular resistance.

20. Amiodarone contd.. Indication : Life threatening ventricular arrhythmias unresponsive to conventional therapy with less toxic agents. Supraventricular arrhythmias unresponsive to conventional therapy.

21. Amiodarone contd.. Adverse effect: CNS: headache, dizziness, fatigue, malaise, poor concentration, tremor, involuntary movement CVS: pinresistant bradycardia , worsening of arrhythmias, sinus arrest, AV block GIT: nausea, vomiting, anorexia, constipation Respiratory: pulmonary fibrosis , interstitial pneumonitis , pulmonary oedema Endocrine: disturbances in thyroid function, increased triglycerides Liver: liver damage increased liver enzymes Muscular: phototoxicity

22. Amiodarone contd.. Drug interaction: It inhibits cytP450 enzymes and may increase plasma concentrations of digoxin , methotrexate , theophylline , procainamide , warfarin , and phenytoin resuliting in toxicities. Contraindication: Severe sinus node dysfunction 2 nd and 3 rd degree heart block Marked sinus bradycardia Cardiogenic shock Thyroid disease Severe respiratory failure

23. Pharmacokinetics of Amiodarone Bioavailability: 35-65% (PO) Effective plasma concentration: 1.2 mcg/ml Slow onset 2 days to several weeks. Duration of action= weeks to months Protein bound: 96% Vd : 4620 L Metabolism: liver with enterohepatic recirculation Half-life = 26 to 107 days Not dialyzable by hemodialysis or peritoneal dialysis Elimination: bile, urine

24. Dose of Amiodarone : IV: 150 mg IV over 10 min; Repaeted as needed to a maximum of 2.2g/24 hr Oral: Loading dose: 800-1600mg PO OD for 1-3 week; reduce dose to 600-800mg/day for 1 month Maintenance dose: 400mg PO OD

25. ADENOSINE MECHANISM OF ACTION: Ubiquitous in the body, in combination with phosphate (cyclic AMP) 2 types of specific adenosine receptor A1 and A2. A1: inhibition of AV nodal conduction, reduction of contractility, inhibition of neurotransmitter release in CNS and PNS, renal vasoconstriction and bronchoconstriction . A2: vasodilation , inhibition of platelet aggregation and stimulation of nociceptive neurones . It restores normal sinus rhythm by interrupting re-entrant pathways in the atrio ventricular node and also slow conduction time through the atrio ventricular node.

26. Adenosine contd.. Indication: Rapid reversion to sinus rhythm of paroxysmal supraventricular tachycardia. Adverse effect: CNS: headache, lightheadedness, dizziness, numbness, irritability, apprehension CVS: transient arrhythmia , heart block, haemodynamic disturbances, palpitation, chest pain hypotension, bradycardia GIT: nausea, tightness in throat Respiratory: dyspnoea , hyperventilation Blood: flushing

27. Adenosine contd.. Drug interaction: Dipyridamole inhibits Adenosine uptake. Aminophylline or Caffeine is potent inhibitors of adenosine. Contraindication: 2 nd and 3 rd degree heart block Sick sinus syndrome Asthma

28. Pharmacokinetics of adenosine Half-life : <10 sec Duration: 60- 90 sec Onset: 20-30 sec Metabolism: blood and tissue Total body clearance: 30 sec

29. Pharmacokinetics overview Drugs F (PO) Half-life Onset Vd Metabolism Elimination Lignocaine 35% 8 min (IV) 45-90 sec(IV) 119L liver urine Amiodarone 35-65% 26-107 days Several weeks 4620L liver Bile, urine Adenosine (IV) - <10 sec 20-30 sec - Blood and tissue sweat