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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 1 Interfere with Inhibit fast Na+ channels 1A Quinidine, Disopyramide, Procainamide depolarisation 1B Lignocaine, Mexilitine, Phenytoin 1C Flecainide 2 Beta Blockers Inhibit beta adrenergic receptors Metoprolol, Atenolol, Propranolol, 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 Blockers 1A Quinidine, Disopyramide, Procainamide 1B Lignocaine, Mexilitine, Phenytoin 1C Flecainide 2 3 4 Beta Blockers Metoprolol, Atenolol, Propranolol K+ efflux blockers Amiodarone, Bretylium, Sotalol 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 Lignocaine CLASS MECHANISM Class 1b USES/DOSE VT and VF Fast Na+ channel blocker Reduces automaticity Negative inotrope No effect AV node Rx: IV 100mg slow push, then IV infusion @ 2 - 4 mg/min. SIDE EFFECTS /INTERACTS S/E’s: Proarrhythmic, dizziness, paraesthesiae, seizures, hypotension, resp depr, coma Metab: hepatic Inter: Flecainide: negative inotrope. Electrolyte disturbances: correct before use C/Ix AV Block, CCF Class1c DRUG Flecainide CLASS Class 1c MECHANISM USES/DOSE INTERACTS Incr Refractory period esp His-Purk Negative inotrope SVT, AFlutter, Reverts PAF,( equiv to Amiodarone.) 2nd line for refractory VT/VF S/E’s: Neg inotrope, Proarrhythmic Electrolyte disturbances: correct before use, may cause heart block Rx: IV 100mg slow push in 5% Dextrose, oral 50100mg at onset AF symptoms, Maint oral 50mg bd C/Ix AV Block, CCF, SSS Inter: C/Ix with 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 sites in the myocardium Variable Mechanisms of Beta Blocker Actions Representative Beta Blocker 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 interval (class 3) Sotalol Mixed Beta and Alpha-1 Blocker effect Labetalol 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 Activity” Insignificant Beta Agonist effect Pindolol, Alprenolol, also Oxprenolol ??helpful in CCF Comparing beta blockers DRUG RECEPTORS BLOCKED ISA (antagonist and partial agonist) METABOLISM DOSES/DAY Atenolol Beta 1 0 renal 1 Metoprolol Beta 1 0 liver 1-2 Sotalol Beta 1 beta 2 0 liver 2 Pindolol, Oxprenolol Beta 1 beta 2 +++ ?Better in PVD; does not help survival after MI liver 2-3 Propranolol Beta 1 beta 2 0 liver 2-3 Beta Blockers and arrhythmias DRUG Beta receptor blocked MECHANISM DOSE SIDE EFFECTS Arrhythmias /INTERACTS used for Propranolol Beta 1 and 2 Blocks adrenaline binding at the receptor Reduced myoc contractility, slowed SA AV automaticity and cond veloc 10 -40mg o tds S/Es: bradycardia, bronchospasm, cool peripheries, nightmares, depression, fatigue Sinus tachy including hyperthyroidism, rate control AF, increase AV block in AFlutter Metoprolol Beta 1 “ IV 1mg increments; usually 50100mg oral q1224h “ “ “ also exercise induced VT Atenolol Beta 1 “ 25-50mg oral daily “ “ “ also exercise induced VT Sotalol Beta 1 and 2, “ ”, and Slows Refractory Period: Atria, AV.Ventricles, 40-160mg oral bd Proarrhythmic including long QT and ventric torsades. Brady/ Most Atrial, ventricular tachyarrhythmias; not effective in and Prolongs RP 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 noncardioselective beta adrenergic blocking effect Amiodarone DRUG Amiodarone CLASS MECHANISM DOSE SIDE EFFECTS /INTERACTS Class 3 K+ channel blocker Also some Na+ channel blocker (Class 1), Also some beta blocker and CCB effect. Structurally similar to Thyroxine. Long acting half life 30-120 days Not negative inotrope so is useful in CCF. Decreases SA and AV node automaticity. Prolongs Refractory period of all myocardium. Weak beta blocker effect on rate. IV 300mg then infusion 15mg/kg over 24 hrs, in 5%Dextrose Oral 100-400mg daily Many. Proarrhythmic. Photosensitisatio n, skin pigment, corneal deposits, thyroid,pulm fibrosis, Periph Neuropathy , long QT and torsades. Hepatotoxic, nausea. Interacts: potentiates Digoxin levels and Warfarin C/Ix Cardiogenic shock C/Ix AV Block Arrhythmias used for Equivalent to Flecainide in reverting PAF; VT reversion; VF after Defib; PVCs; SVT incl WPW; Aflutter; prevent PAF C/Ix AV Block C/Ix Cardiogenic shock 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 /INTERACTS Arrhythmias used for Prevent and treat SVT, rate control in AF, STc Verapamil Phenylalkylamine Block L-type Calcium channels Reduces HR Conduction velocity. Negative Inotrope 40-80 mg tds: Hypotension, C/Ix in CCF, peripheral oedema, headache, flushing Nifedipine Amlodipine Dihydropridines Block L-type Calcium channels Relaxes peripheral vascular smooth muscle Nifed:10-30mg daily for HT Amlod: 5-10mg; used for HT Reflex tachycardia, Not for arrhythmias peripheral oedema, headache, flushing Diltiazem Benzothiazepine Block L-type Calcium channels Mixed effects 60mg tds antianginal Similar to above Anti-anginal; some effects STc SVT Adenosine DRUG Adenosine CLASS nucleoside MECHANISM DOSE SIDE EFFECTS /INTERACTS Arrhythmias used for Depresses conduction AV node Metabolised by cellular uptake into erythrocytes. 3-6mg rapid IV bolus and flush. 12mg if not successful Rapid onset and offset ~ half life is 10 seconds. Bronchospasm, headache, anxiety Relative C/Ix with Verapamil or Digoxin as may rarely cause VF Dipyridamole and carbemazepine enhance adenosine heart bl;ock effect Use Midazolam 1- C/Ix Bradycardia 2mg IV as or CHB premed to reduce anxiety Reverts SVT including WPW. Diagnostic in Aflutter Transient AV blockade in AF. No effect on Ventricular arrhythmias Which conduction disorder is this? Atropine DRUG Atropine CLASS Anticholinergic: MECHANISM DOSE SIDE EFFECTS /INTERACTS Arrhythmias used for Competitive blockade muscarinic ACh receptors in CNS and parasympathetic NS Bradycardia with compromised haemodynamics: -IV 1 mg (adult); repeat x 2 as needed (total 3mg) Asystole: 6mg IV once only S/E’s: tachycardia, dry mouth, mydriasis, photophobia, urinary retention, delirium, fever Bradyarrhythmia s with haemodynamic compromise Adrenaline is the initial drug of choice for asystole Also for organophosphat e poisoning with bradycardia. Digoxin DRUG Digoxin CLASS Cardiac glycoside MECHANISM DOSE Increases force of contraction and inhibits AV node conduction IV: 0.5mg IV over 5 mins 4-6 hourly to total 1.5mg. Oral 0.1250.25mg daily. SIDE EFFECTS /INTERACTS Arrhythmias used for Yellow vision, bradycardia, atrial tachy with bundle block, vomiting, proarrhythmic AF rate control SVT reversion or prevention of PAF CCF at lower doses Therapeutic level Renal excretion 1.0-2.6 nmol/L 70% Isoprenaline DRUG Isoprenaline CLASS Beta AGONIST (beta 1 and beta 2) MECHANISM DOSE SIDE EFFECTS /INTERACTS Positive inotrope, chronotrope. Increases automaticity and AV conduction. Increases systolic BP; decreases diastolic BP due to peripheral vasodilatation. Coronary vasodilator. IV: 20mcg IV over 2 mins; infusion 0.0510mcg/kg/min titrated to heart rate. Headache, tachycardia, BP up or down, angina. It increases cardiac workload and oxygen demand like all sympathomimetic agonists. Arrhythmias used for Bradycardia, complete heart block, adjunct in septic or cardiogenic shock. Use vasopressors as well and fluid. Use with CHB while arranging urgent pacing. Questions?
