Anti arrhythmic drugs A/Prof Andrew Dean. May 2013 Drugs in arrhythmia • Not all arrhythmias need to be treated • Anti-arrhythmic drugs have significant side effects and some are pro-arrhythmic • None have been shown in drug trials to have long term mortality benefit with the exception of Amiodarone Classifying the drugs • Group antiarrhythmic drugs by their clinical effects/indications for use • Also group drugs by electrophysiological effects (for example: SA/ AV nodes, refractory periods, QT intervals, anatomical sites of action in the heart) • The Vaughan Williams classification is one of the latter. • No classification is ideal, as several drugs overlap the categories of actions Drugs for tachyarrhythmias • Supraventricular arrhythmias: glycosides (digoxin), beta blockers, adenosine, verapamil • Supraventricular and Ventricular arrhythmias: amiodarone, beta blockers, flecainide, sotalol • Ventricular arrhythmias: Amiodarone, Lignocaine Drugs for bradyarrhythmias • Sinus bradycardias: Atropine, Adrenaline, Isoprenaline • Asystole: Adrenaline, Atropine Vaughan Williams Classification - by mechanism of action Class 1: fast sodium channel blockers Class 2: reduce adrenergic effect - beta blockers Class 3: potassium efflux Class 4: calcium channel blockers Other: digoxin, adenosine, magnesium sulphate Beta blockers and CCBs • The centrally acting CCBs (Verapamil and Diltiazem) can be regarded as virtually identical to the beta blockers in their effects on conduction • Both reduce SA and AV node conduction speed, and may cause AV block, and reduce contractility and 02 demand. • They have slightly different roles. Vaughan Williams classification CLASS MECHANISM OF ACTION EXAMPLES Interfere with Inhibit fast Na+ channels 1A Quinidine, Disopyramide, 1 Procainamide depolarisation 1B Lignocaine, Mexilitine, Phenytoin 1C Flecainide 2 Beta Blockers Inhibit beta adrenergic Metoprolol, Atenolol, Propranolol, receptors Sotalol ** 3 Prolong repolarisation Inhibit K+ efflux channels Amiodarone, Bretylium, Sotalol ** 4 CCBs Inhibit slow calcium channels Verapamil, Diltiazem Unclassified Various mechanisms MgS04, Adenosine, Digoxin, Isoprenaline Antiarrhythmics commonly used Red shading = Commonly used VAUGHAN-WILLIAMS CLASS MECHANISM OF ACTION EXAMPLES 1 Fast Na+ Channel 1A Quinidine, Disopyramide, Blockers Procainamide 1B Lignocaine, Mexilitine, Phenytoin 1C Flecainide 2 Beta Blockers Metoprolol, Atenolol, Propranolol 3 K+ efflux blockers Amiodarone, Bretylium, Sotalol 4 Calcium Channel Blockers Verapamil, Diltiazem Unclassified Various mechanisms MgS04, Adenosine, Isoprenaline, Digoxin Class1: fast Na+ channel blockers Red shading = Commonly used drugs Vaughan Williams subdivides Type 1 into 1a: quinidine, procainamide, disopyramide 1b: lignocaine, mexilitine, phenytoin^^ 1c: flecainide ^^ phenytoin’s main use is for seizure prophylaxis Class1a Not commonly used Class1b DRUG CLASS MECHANISM USES/DOSE SIDE EFFECTS /INTERACTS Lignocaine Class 1b VT and VF S/E’s: Fast Na+ channel Proarrhythmic, blocker Rx: IV 100mg slow dizziness, Reduces push, then IV paraesthesiae, automaticity infusion @ 2 - 4 seizures, Negative inotrope mg/min. hypotension, resp No effect AV node depr, coma Metab: hepatic Inter: Flecainide: negative inotrope. Electrolyte disturbances: correct before use C/Ix AV Block, CCF Class1c DRUG CLASS MECHANISM USES/DOSE INTERACTS Flecainide Class 1c Incr Refractory SVT, AFlutter, S/E’s: Neg inotrope, period esp His-Purk Reverts PAF,( equiv Proarrhythmic Negative inotrope to Amiodarone.) Electrolyte 2nd line for refractory disturbances: VT/VF correct before use, may cause heart Rx: IV 100mg slow block push in 5% Dextrose, oral 50- C/Ix AV Block, CCF, 100mg at onset AF SSS symptoms, Inter: C/Ix with Maint oral 50mg bd Disopyramide Beta adrenergic receptor pharmacology – a quick review • Beta 1 stimulation: pos inotrope/chronotrope, pos automaticity, pos AV node conduction velocity, increases renin release>>increases aldosterone/angiotensin levels. • Beta 1 inhibition: neg inotrope/chronotrope, neg automaticity, inhibits conduction velocity AV node, inhibits renal renin release>>reduces aldosterone/angiotensin levels • Beta 2 stimulation: smooth muscle relaxation, vasodilatation in skeletal muscle and tremor, glycogenolysis in liver/ skeletal muscle, uterine relaxation, reduced peripheral vascular resistance • Beta 2 inhibition: bronchospasm, peripheral arteriolar vasoconstriction so use caution in ASTHMA, PVD !, inhibits glycogen breakdown in liver/skeletal muscle Why beta blockers rock Long term beta blocker use after MI reduces mortality by 25%, due to the reduction in cardiac workload and 02 demand, however 25% develop significant side effects including bradycardia, AV Block, asthma, hypotension Class 2: Beta Blockers Beta Blockers act at different Variable Mechanisms of Beta Representative Beta Blocker sites in the myocardium Blocker Actions examples Variable sites of action Slows AV conduction velocity Propranolol (NON SELECTIVE: BETA 1 AND BETA 2) Inhibits AV node conduction Metoprolol and Atenolol (BETA 1 SELECTIVE) Prolongs PR (class 2) and QT Sotalol interval (class 3) Mixed Beta and Alpha-1 Labetalol Blocker effect Beta blockers.. Effect Mechanism Examples Cardioselective Beta 1 receptor blockers Metoprolol, Atenolol Membrane stabilisers Prolong QRS Propranolol Alpha and beta blockade Block both adrenergic effects Labetalol “Intrinsic Sympathomimetic Insignificant Beta Agonist effect Pindolol, Alprenolol, Activity” also Oxprenolol ??helpful in CCF Comparing beta blockers DRUG RECEPTORS ISA (antagonist METABOLISM DOSES/DAY BLOCKED and partial agonist) Atenolol Beta 1 0 renal 1 Metoprolol Beta 1 0 liver 1-2 Sotalol Beta 1 beta 2 0 liver 2 Pindolol, Beta 1 beta 2 +++ liver 2-3 Oxprenolol ?Better in PVD; does not help survival after MI Propranolol Beta 1 beta 2 0 liver 2-3 Beta Blockers and arrhythmias DRUG Beta receptor MECHANISM DOSE SIDE EFFECTS Arrhythmias blocked /INTERACTS used for Propranolol Beta 1 and 2 Blocks 10 -40mg o tds S/Es: Sinus tachy adrenaline bradycardia, including binding at the bronchospasm, hyperthyroidism, receptor cool peripheries, rate control AF, Reduced myoc nightmares, increase AV contractility, depression, block in AFlutter slowed SA AV fatigue automaticity and cond veloc Metoprolol Beta 1 “ IV 1mg “ “ “ also increments; exercise induced usually 50- VT 100mg oral q12- 24h Atenolol Beta 1 “ 25-50mg oral “ “ “ also daily exercise induced VT Sotalol Beta 1 and 2, “ ”, and 40-160mg oral Proarrhythmic Most Atrial, and Slows bd including long ventricular Prolongs RP Refractory QT and ventric tachy- Period: Atria, torsades. arrhythmias; not AV.Ventricles, Brady/ effective in His-Purk system Heart blocks reverting PAF Class 3: K+ channel blockers Bretylium Amiodarone Sotalol Class 2 and 3: Sotalol • Sotalol: • Mimics Class 3 antiarrhythmics (The Class 3 agents are Amiodarone, Bretylium and Sotalol: they prolong myocardial refractoriness and repolarisation without affecting conduction) as well as having a non- cardioselective beta adrenergic blocking effect Amiodarone DRUG CLASS MECHANISM DOSE SIDE EFFECTS Arrhythmias /INTERACTS used for Amiodarone Class 3 K+ Long acting half IV 300mg then Many. Equivalent to channel blocker life 30-120 days infusion 15mg/kg Proarrhythmic. Flecainide in Also some Na+ Not negative over 24 hrs, in Photosensitisatio reverting PAF; channel blocker inotrope so is 5%Dextrose n, skin pigment, VT reversion; VF (Class 1), useful in CCF. Oral 100-400mg corneal deposits, after Defib; Also some beta Decreases SA daily thyroid,pulm PVCs; SVT incl blocker and CCB and AV node fibrosis, Periph WPW; Aflutter; effect. automaticity. C/Ix Cardiogenic Neuropathy , long prevent PAF Structurally Prolongs shock QT and torsades. similar to Refractory period C/Ix AV Block Hepatotoxic, C/Ix AV Block Thyroxine. of all nausea. C/Ix Cardiogenic myocardium. Interacts: shock Weak beta potentiates blocker effect on Digoxin levels rate. and Warfarin Calcium Channel Blockers Centrally acting: reduce heart rate, cardiac contractility, and conduction. Minimal peripheral effects. Phenylalkylamine class: Verapamil; Benzothiazepine class: Diltiazem*, Peripherally acting: relax vascular smooth muscle. Minimal effect on myocardium. Dihydropyridine class: Amlodipine, Nifedipine; also Benzothiazepine class: Diltiazem* Diltiazem overlaps central and peripheral effect Calcium Channel Blockers DRUG Examples CLASS MECHANISM DOSE SIDE EFFECTS Arrhythmias used /INTERACTS for Verapamil Phenylalkylamine Block L-type 40-80 mg tds: Hypotension, Prevent and treat Calcium channels C/Ix in CCF, SVT, rate control in Reduces HR peripheral AF, STc Conduction oedema, velocity. Negative headache, flushing Inotrope Nifedipine Dihydropridines Block L-type Nifed:10-30mg Reflex tachycardia, Not for arrhythmias Amlodipine Calcium channels daily for HT peripheral Relaxes Amlod: 5-10mg; oedema, peripheral used for HT headache, flushing vascular smooth muscle Diltiazem Benzothiazepine Block L-type 60mg tds anti- Similar to above Anti-anginal; some Calcium channels anginal effects STc SVT Mixed effects Adenosine DRUG CLASS MECHANISM DOSE SIDE EFFECTS Arrhythmias /INTERACTS used for Adenosine nucleoside Depresses 3-6mg rapid IV Bronchospasm, Reverts SVT conduction AV bolus and flush. headache, including WPW. node 12mg if not anxiety Diagnostic in Metabolised by successful Relative C/Ix with Aflutter cellular uptake Rapid onset and Verapamil or Transient AV into erythrocytes. offset ~ half life is Digoxin as may blockade in AF. 10 seconds.