Pharmacology of antiarrhytmic drugs

Dr. DATTEN BANGUN MSc,SpFK Dr. HASANUL ARIFIN Bagian Farmakologi dan Terapeutik, Fakultas Kedokteran Universitas Sumatera Utara

What is an Arrhythmia ?

Irregular rhythm Abnormal Rate Conduction abnormality

What causes an arrhythmia?

Changes in automaticity of the PM Ectopic foci causing abnormal APs Reentry tachycardias Block of conduction pathways Abnormal conduction pathways (WPW) Electrolyte disturbances and DRUGS Hypoxic/Ischaemic tissue can undergo spontaneous depolarisation and become an ectopic pacemaker

Normal heartbeat and atrial arrhythmia

Normal rhythm
AV septum

Atrial arrhythmia

Definition of arrhythmia
Cardiac arrhythmia is an abnormality of the heart rhythm Bradycardia heart rate slow (<60 beats/min) Tachycardia heart rate fast (>100 beats/min) Clinical classification of arrhythmias
= Heart rate (increased/decreased) = Heart rhythm (regular/irregular) = Site of origin (supraventricular / ventricular) = Complexes on ECG (narrow/broad)

Mechanisms of arrhythmia production

Re-entry (refractory tissue reactivated due to conduction block, causes abnormal continuous circuit. eg accessory pathways linking atria and ventricles in Wolff-Parkinson-White syndrome) Abnormal pacemaker activity in nonconducting/conducting tissue (eg ischaemia) Delayed after-depolarisation (automatic depolarisation of cardiac cell triggers ectopic beats, can be caused by drugs eg digoxin)

Electrophysiology - resting potential

A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cell Caused by unequal distribution of ions inside vs. outside cell Na+ higher outside than inside cell Ca+ much higher K+ higher inside cell than outside Maintenance by ion selective channels, active pumps and exchangers

Differences between nonpacemaker and pacemaker cell action potentials

PCs - Slow, continuous depolarization during rest Continuously moves potential towards threshold for a new action potential (called a phase 4 depolarization)

Spontaneous depolarisation

Cardiac Action Potential

Divided into five phases (0,1,2,3,4)
Phase 4 - resting phase (resting membrane potential) Phase cardiac cells remain in until stimulated Associated with diastole portion of heart cycle

Addition of current into cardiac muscle (stimulation) causes

Phase 0 opening of fast Na channels and rapid depolarization Drives Na+ into cell (inward current), changing membrane potential Transient outward current due to movement of Cl- and K+

Phase 1 initial rapid repolarization Closure of the fast Na+ channels Phase 0 and 1 together correspond to the R and S waves of the ECG

Cardiac Action Potential (cont)

Phase 2 - plateau phase
sustained by the balance between the inward movement of Ca+ and outward movement of K + Has a long duration compared to other nerve and muscle tissue Normally blocks any premature stimulator signals (other muscle tissue can accept additional stimulation and increase contractility in a summation effect) Corresponds to ST segment of the ECG.

Phase 3 repolarization
K+ channels remain open, Allows K+ to build up outside the cell, causing the cell to repolarize K + channels finally close when membrane potential reaches certain level Corresponds to T wave on the ECG

ECG (EKG) showing wave segments

Contraction of atria

Contraction of ventricles

Repolarization of ventricles

Cardiac Na+ channels

Therapeutic overview
Na+ channel blockade -adrenergic receptor blockade Prolong repolarization Ca2+ channel blockade

Adenosine Digitalis glycosides

Vaughan-Williams Classification
Class I II III IV Mechanism Na channel blockers Membrane Stabilisers Beta Blockers K channel blockers Ca channel blockers Example Lignocaine Metoprolol Amiodarone Verapamil

Other Digoxin. Adenosine. MgSO4. Atropine

Electrophysiological effects

Drug Class Class IA Class IB (Affect ischemic tissues) Class IC (Affect ventricular conduction)

Example Quinidine Lidocaine Flecainide

Sodium Channel Affinity Open > inactivated Inactivated > open Open > inactivated

Rate of Dissociation Slow Rapid Very slow

Classification of antiarrhythmics
(based on mechanisms of action)

Class I blockers of fast Na+ channels

Subclass IA
Cause moderate Phase 0 depression Prolong repolarization Increased duration of action potential Includes Quinidine 1st antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory period Procainamide - increases refractory period but side effects Disopyramide extended duration of action, used only for treating ventricular arrthymias

Kinidin - prototip dari klas I A Adalah d isomer dari kinin, memiliki semua sifat kinin seperti : - anitimalaria - antipiretik - oxitosik - skeletal muscle relaxant
Kinidin juga memiliki efek antikholinergik, yang jelas nyata pada awal terapi atau pada dosis rendah. Setelah tercapai konsentrasi terapi efek langsug(direct effect ) yang bekerja . Kinidin juga memiliki efek MSA (membrane stabilizing activity) sifat anestesi lokal

Efek hemodinamik . - negative inotropic effect - vasodilatasi -adrenergik blockade ECG : P R interval QRS Comp Q T interval Memanjang

T.D.

torsade de pointes.

Farmakokinetik: - diserap per-oral komplit - 80 % berikatan dengan plasma protein

Kontra Indikasi
A.V Block C.H.F Hipotensi

Hati hati :
pemberian digitalis hiperkalemia miastenia gravis == why ?

Prokainamid :
- efek hampir = kinidin dengan perbedaan - sumber - antimuskarinik << - asetilasi dilever ada yang fast ada yang rapid acetylator. - menimbulkan lupus (80% akan mendapat titer anti nuklear yang tinggi 30% lupus )., dose-related, biasanya pada yang slow acetylator. - dosis besar : agranulositosis.

Classification of antiarrhythmics
(based on mechanisms of action)
Subclass IB Weak Phase 0 depression Shortened depolarization Decreased action potential duration Includes Lidocane (also acts as local anesthetic) blocks Na+ channels mostly in ventricular cells, also good for digitalis-associated arrhythmias Mexiletine - oral lidocaine derivative, similar activity Phenytoin anticonvulsant that also works as antiarrhythmic similar to lidocane

Lignocaine (Lidocaine)
Class Ib (blocks Na+ channels, reduces AP duration) Ventricular arrhythmias (acute Rx) IV infusion only (2 hour half life, high first pass metabolism) Hepatic metabolism (inhibited by cimetidine, propranolol) SE mainly CNS - drowsiness, disorientation, convulsions, hypotension

Classification of antiarrhythmics
(based on mechanisms of action)
Subclass IC Strong Phase 0 depression No effect of depolarization No effect on action potential duration Includes Flecainide (initially developed as a local anesthetic) Slows conduction in all parts of heart, Also inhibits abnormal automaticity

Propafenone Also slows conduction Weak blocker Also some Ca2+ channel blockade

Flecainide
Class Ic (block Na+ channels, no change to AP) Slows conduction in all cardiac cells Acute Rx /prophylaxis Supraventricular tachycardias Paroxysmal atrial fibrillation Ventricular tachycardias Oral/IV Long acting (T1/2 14 hours) Hepatic metabolism, urinary elimination

Flecainide
CAST (Cardiac Arrhythmia Suppression Trial) 1989 increased mortality post MI (VF arrest) Side-effects: = cardiac failure,= ventriculararrhythmias,blurred vision, abdominal discomfort, nausea, paraesthesia, dizzyness, tremor, metallic taste

Classification of antiarrhythmics
(based on mechanisms of action)
Class II adrenergic blockers
Based on two major actions 1) blockade of myocardial adrenergic receptors 2) Direct membrane-stabilizing effects related to Na+ channel blockade Includes Propranolol causes both myocardial adrenergic blockade and membrane-stabilizing effects Slows SA node and ectopic pacemaking Can block arrhythmias induced by exercise or apprehension Other adrenergic blockers have similar therapeutic effect Metoprolol Nadolol Atenolol Acebutolol Pindolo Stalol Timolol Esmolol

Classification of antiarrhythmics
(based on mechanisms of action)

Class III K+ channel blockers

Developed because some patients negatively sensitive to Na channel blockers (they died!) Cause delay in repolarization and prolonged refractory period Includes
Amiodarone prolongs action potential by delaying K+ efflux but many other effects characteristic of other classes Ibutilide slows inward movement of Na+ in addition to delaying K + influx. Bretylium first developed to treat hypertension but found to also suppress ventricular fibrillation associated with myocardial infarction Dofetilide - prolongs action potential by delaying K+ efflux with no other effects

Amiodarone
Class III - increases refractory period and AP Major effect acutely is depression of AV node Acute Rx/prophylaxis Atrial and ventricular arrhythmias Oral or IV (central line) Loading and maintenance doses T1/2 ; 54 days Large volume of distribution Accumulates Hepatic metabolism- biliary and intestinal excretion

Amiodarone adverse effects

Photosensitive rashes Grey/blue discolouration of skin Thyroid abnormalities 2% Pulmonary fibrosis Corneal deposits CNS/GI disturbance Pro-arrhythmic effects (torsade de pointes) Heart block Nightmares 25% Interacts with digoxin, warfarin (reduces clearance)

Classification of antiarrhythmics
(based on mechanisms of action) Class IV Ca2+ channel blockers slow rate of AV-conduction in patients with atrial fibrillation

Includes Verapamil blocks Na+ channels in addition to Ca2+; also slows SA node in tachycardia Diltiazem

Verapamil
Class IV (calcium channel blocker) Prolongs conduction and refractoriness in AV node, slows rate of conduction of SA node Used IV/oral SUPRAVENTRICULAR NOT VENTRICULAR ARRHYTHMIAS (cardiovascular collapse) Do not use IV verapamil with - blocker (heart block) T1/2 6-8 hours

Verapamil- adverse effects

Heart failure Constipation Bradycardia Nausea

Adenosine
Purine nucleoside Acts on A1 adenosine receptors Opens Ach sensitive K channels Inhibits Ca in current Suppresses Ca dependent AP (Nodal) Increases K out current Hyperpolarisation Inhibits AVN > SAN Increases AVN refractory period

ADENOSINE
Interrupts re-entry and aberrant pathways through AVN Diagnosis and Treament Drug for narrow complex PSVT SVT reliant on AV node pathway NOT atrial flutter or fibrillation or VT Contraindications: VT Hypotension and deterioration High degree AV block Poison or drug induced tachycardia Bronchospasm but short DOA

ADENOSINE
Carotid massage and vagal maneuvers first Rapid IV push 6mg 12 mg 12 mg Flush with 20ml N/S Record rhythm strip FLUSHING CHEST PAIN ASYSTOLE/BRADY VENTRICULAR ECTOPY

Adenosine- adverse effects

Feeling of impending doom! Flushing, dyspnoea, chest pain, transient arrhythmias Contraindicated in asthma, heart block

Digoxin
Not in Vaughan Williams class

Cardiac glycoside (digitalis, foxglove)

Act on Na/K-ATPase of cell membrane (inhibits Na+/K+ pump, increases intracellular Na+ and calcium)/ increases vagal activity Increase cardiac contraction and slows AV conduction by increasing AV node refractory period

Digoxin
Atrial fibrillation or flutter (controls ventricular rate) Acute Rx/prophylaxis Oral/IV Loading and maintenance doses T1/2 36 hours Excreted by kidneys Narrow therapeutic index Therapeutic drug monitoring Reduce dose in elderly/renal impairment

Digoxin adverse effects

Arrhythmias, heart block, anorexia, nausea, diarrhoea, xanthopsia, gynaecomastia, confusion, agitation Adverse-effects potentiated by hypokalaemia and hypomagnesaemia Overdose Digibind (digoxin binding antibody fragments), phenytoin for ventricular arrhythmias, pacing, atropine

Anti-bradycardia agents
1. -adrenic receptor activator 2. M-cholinergic receptor blocker 3. Non-specific activator

Dalam keadaan denyut jantung amat melambat ( bradikardia ):

- atropin(M-cholinergic receptor blocker)

- stimulator (-adrenic receptor activator)

- pacemaker (pacu jantung )

Pacemakers
Surgical implantation of electrical leads attached to a pulse generator Over 175,000 implanted per year 1.Leads are inserted via subclavicle vein and advanced to the chambers on the vena cava (right) side of the heart 2. Two leads used, one for right atrium, other for right ventricle 3. Pulse generator containing microcircuitry and battery are attached to leads and placed into a pocket under the skin near the clavicle 4. Pulse generator sends signal down leads in programmed sequence to contract atria, then ventricles * Pulse generator can sense electrical activity generated by the heart and only deliver electrical impulses when needed. * Pacemakers can only speed up a heart experiencing bradycardia, they cannot alter a condition of tachycardia

Summary
Anti-arrhythmic drugs are classified by their effect on the cardiac action potential

Not all drugs fit this classification

In clinical practice treatment of arrhythmias is determined by the type of arrhythmia (SVT, VT) and clinical condition of the patient Anti-arrhythmic drugs are efficacious but may have serious adverse effects Not all arrhythmias are treated with drug therapy alone

Take-Home Message
Anti-arrhythmics are also proarrhythmics Dangerous side effects If patient is unstable rather cardiovert Enlist expert help Stick to drugs you know Limited choice in SA anyway