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Home , Amiodarone, Bretylium, Disopyramide, Flecainide, Procainamide, Sotalol

Anti arrhythmic drugs A/Prof Andrew Dean. May 2013 Drugs in

• Not all 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 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 )

• 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 (), beta blockers, ,

• Supraventricular and Ventricular arrhythmias: amiodarone, beta blockers, ,

• Ventricular arrhythmias: Amiodarone, Lignocaine Drugs for bradyarrhythmias

• Sinus : , ,

• Asystole: Adrenaline, Atropine Vaughan Williams Classification - by mechanism of action

Class 1: fast channel blockers

Class 2: reduce effect - beta blockers

Class 3: efflux

Class 4: blockers

Other: digoxin, adenosine, sulphate Beta blockers and CCBs

• The centrally acting CCBs (Verapamil and ) 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 , , 1 depolarisation 1B Lignocaine, Mexilitine, 1C Flecainide

2 Beta Blockers Inhibit beta adrenergic , , , receptors Sotalol ** 3 Prolong repolarisation Inhibit K+ efflux channels Amiodarone, , 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 mg/min. , 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 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 / skeletal muscle, uterine relaxation, reduced peripheral vascular resistance

• Beta 2 inhibition: , peripheral arteriolar vasoconstriction so use caution in , PVD !, inhibits glycogen breakdown in liver/skeletal muscle Why beta blockers rock

Long term use after MI reduces mortality by 25%, due to the reduction in cardiac workload and 02 demand, however 25% develop significant side effects including , 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 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 effect , , Activity” also ??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, , receptor cool peripheries, rate control AF, Reduced myoc nightmares, increase AV contractility, depression, block in AFlutter slowed SA AV 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 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 ,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 QT and torsades. similar to Refractory period C/Ix AV Block Hepatotoxic, C/Ix AV Block Thyroxine. of all . C/Ix Cardiogenic myocardium. Interacts: shock Weak beta potentiates blocker effect on Digoxin levels rate. and 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: , ; 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 , flushing Inotrope

Nifedipine Dihydropridines Block L-type Nifed:10-30mg Reflex , 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. rarely cause VF No effect on Ventricular arrhythmias Dipyridamole and Use Midazolam 1- C/Ix Bradycardia carbemazepine 2mg IV as or CHB enhance premed to reduce adenosine heart anxiety bl;ock effect Which conduction disorder is this? Atropine

DRUG CLASS MECHANISM DOSE SIDE EFFECTS Arrhythmias /INTERACTS used for

Atropine : Competitive Bradycardia with S/E’s: Bradyarrhythmia blockade compromised tachycardia, dry s with muscarinic ACh haemodynamics: mouth, haemodynamic receptors in CNS -IV 1 mg (adult); mydriasis, compromise and repeat x 2 as photophobia, parasympathetic needed (total , NS 3mg) delirium, fever Asystole: 6mg IV once only Adrenaline is the Also for initial drug of organophosphat choice for e poisoning with asystole bradycardia. Digoxin

DRUG CLASS MECHANISM DOSE SIDE EFFECTS Arrhythmias /INTERACTS used for

Digoxin Cardiac Increases force IV: 0.5mg IV over Yellow vision, AF rate control glycoside of contraction 5 mins 4-6 hourly bradycardia, SVT reversion or and inhibits AV to total 1.5mg. atrial tachy with prevention of node conduction Oral 0.125- bundle block, PAF 0.25mg daily. vomiting, CCF at lower proarrhythmic doses Therapeutic level Renal 1.0-2.6 nmol/L 70% Isoprenaline

DRUG CLASS MECHANISM DOSE SIDE EFFECTS Arrhythmias /INTERACTS used for

Isoprenaline Beta AGONIST Positive inotrope, IV: 20mcg IV over Headache, Bradycardia, (beta 1 and beta chronotrope. 2 mins; infusion tachycardia, BP complete heart 2) Increases 0.05- up or down, block, adjunct in automaticity and 10mcg/kg/min . septic or AV conduction. titrated to heart It increases cardiogenic Increases systolic rate. cardiac workload shock. Use BP; decreases and oxygen vasopressors as diastolic BP due demand like all well and fluid. Use to peripheral sympathomimetic with CHB while vasodilatation. . arranging urgent Coronary pacing. vasodilator. Questions?