Dr Laith M Abbas Al-Huseini Antiarrhythmic Drugs Dr Laith M Abbas Al-Huseini M.B.Ch.B, M.Sc., M.Res., Ph.D.

Antiarrhythmics ???? In a textbook  Interesting but sedative. Try it if you have insomnia In the lecture  Confusion ?????????? As always In the exam hall  Panic! Don’t worry rarely asked but it could happen!!!!!

Background To function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchronicity Relaxation must occur between contractions (not true for other types of muscle [exhibit tetany  contract and hold contraction for certain length of time]) Coordination of heartbeat is a result of a complex, coordinated sequence of changes in membrane potentials and electrical discharges in various heart tissues

Mechanisms of Cardiac Arrhythmias Results from: Faulty impulse initiation Faulty impulse conduction Combination of the above Results in rate and/or timing of contraction of heart muscle that is insufficient to maintain normal cardiac output (CO) To understand how anti-arrhythmic drugs work, need to understand electrophysiology of normal contraction of heart

Ventricular arrhytmia ARRHYTHMIAS Sinus arrythmia Atrial arrhythmia Nodal arrhythmia (junctional) Ventricular arrhytmia SVT

Ventricular Arrhythmia Ventricular arrhythmias are common in most people and are usually not a problem but… VA’s are most common cause of sudden death Majority of sudden death occurs in people with neither a previously known heart disease nor history of VA’s Medications which decrease incidence of VA’s do not decrease (and may increase) the risk of sudden death treatment may be worse then the disease!

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 outside than inside cell K+ higher inside cell than outside Maintenance by ion selective channels, active pumps and exchangers

ECG showing wave segments Contraction of ventricles Repolarization of ventricles Contraction of atria

Rapid Repolarization phase Early repolarization Inactivated Plateau phase +30 mV 1 2 0 mV Rapid Repolarization phase Na+ Phase zero depolarization open 3 Phase 4 resting membrane Resting 4 -80 mV RMP IS -90 MV Cardiac bounded by a lipoprotein membrane which has receptor channels crossing it WHEN AN ATRIAL OR VENTRICULAR CELL RECIEVES An action potential it starts depolarising in response to it..and sodium starts entering it Intracellular negativity starts diminishing When such depolarisation reaches a threshold potential, the sodium channels open abruptly Na enters cell in large quantities CELL MEMBRANE ACTION POTENTIAL CHANGES FROM -90 TO ALMOST +30MV Phase 0: rapid depolarisation…fast selective inflow of na ions During latter part, ca ions also enter the cell via na channels Frther in phase 1 and 2 ca ions enter thru slow ca channels THE CONFORMATION OF THE SODIUM CHANNELS HENCE CHANGES TO INACTIVE STATE The ca which enters the cell in dis manner causes release of ca from sarcoplasmic reticulumraising the conc of ca within the cells This intracellular free ca interacts with actin myocin system and causes contraction of heart Afetr this, phase 1: short rapid repolarisation due to beginning of outflow of potassium and entry of cloride ions into the cells, MEMBRANE CHARGE CHANGES FROM +30 TO ALMOST 0 MV IN VERY SHORT TIME Phase 2 : prolonged plateau phase.. Balance bw ca enterin the cell and k leavin the cell..VOLTAGE SENSITIVE SLOW l type CA CHANNELS OPEN …SLOW INWARD CA CURRENT BALANCED BY SLOW OUTWARD K CURRENT..DEPOLARISATION = REPOLARISATION Phase 3 : rapid repolarisation.. CA CHANNELS CLOSE…K CHANNELS OPEN..Contimued extrusion of k…RESUMES INITIAL NEGATIVITY FROM PHASE 0 TO 3 THERE HAS BEEN A GAIN OF NA AND A LOSS OF K ..THIS IS NOW REVERTED AND BALANCED BY NA K ATPASE Phase 4: resting phase..ELECTRICALLY STABLE… Ionic reconstitution of cell is reachieved by na k exchange pump RMP MAINTAINED BY OUTWARD K LEAK CURRENTS AND NA CA EXCHANGERS The cycle is then repeated Inactivation gates of sodium channels in resting membranes close over the potential range of -75 to -55mv Cardiac sodium channel protein shows 3 different conformations Depolarisation to threshold voltage results in opening of the activation gates of sodium channel thus causing markerdly increased sodium permeability Brief intense sodium current , conductance of fast sodium channel suddenly increases in response to depolarising stimulUs Very large influx of na accounts for phase 0 depolarisation Clusure of inactivation gates result Remain inactivated till mid phase 3 to permit a new propagated response to external stimulus…refractory period.. Cardiac calcium channels are L type Phase 1 and 2 : turning off nodium current, waxing and waning of calcium curent, slow development of repolarising potassium current, calcium enters ..potassium leaves.. Phase 3: complete inactivation of sodium and calcium currents and full opening of potassium 2 types of main potassium currents involved in phase 3 : ikr and iks Certain potassium channels are open at rest also…”inward rectifier” channels In addition there are 2 energy requiring exchange pumps in cardiac myocyte cell membrane…na k exchange pump…and and na-ca exchange pump Normally na ions concentrated extracellularly and vice versa for k cions Thus have a tendency odf diffusion along concentration gradient This diffusion is opposed by na k pump This pump operates contimuously and does not switch on and off during action potential of cardiac cells -90 mV Ca++ K+ K+ Na+ K+ K+ OUTSIDE Na+ Ca++ ATP MEMBRANE INSIDE K+ Na+

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 (con’t) 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

Causes of arrhythmias Cardiac ischemia Excessive discharge or sensitivity to autonomic transmitters Exposure to toxic substances Unknown etiology

Anti-arrhythmic drugs Biggest problem – anti-arrhythmics can cause arrhythmia! Example: Treatment of a non-life threatening tachycardia may cause fatal ventricular arrhythmia Must be vigilant in determining dosing, blood levels, and in follow-up when prescribing anti-arrhythmics

Classification of anti-arrhythmics (Vaughan-Williams-Singh) (based on mechanisms of action) Class I – Na+ channel blockers Subclass IA Increased duration of action potential and Prolong repolarization Includes Quinidine – 1st anti-arrhythmic used, increases refractory period, treats both atrial and ventricular arrhythmias, maintains sinus rhythm in patients with atrial flutter or atrial fibrillation, prevents recurrence of ventricular tachycardia or VF. SE: Diarrhea, thrombocytopenia, cinchonism , skin rashes, QT-interval prolongation, torsades de pointes, HOT and drug interactions.

Classification of anti-arrhythmics Subclass IA (con’t) Procainamide - increases refractory period, uses for supraventricular and ventricular arrhythmias. SE: less anticholinergic effects, cardiac adverse effects like quinidine, can cause SLE not recommended > 6 months Disopyramide – extended duration of action, well absorbed orally, negative ionotropic action, used only for treating ventricular arrhythmias, SE: prominent anticholinergic actions and heart failure.

Classification of anti-arrhythmics Subclass IB Shortened depolarization & Decreased action potential duration Includes Lidocane (also acts as local anesthetic) – blocks Na+ channels mostly in ventricular cells, extensive 1st pass metabolism. Used in arrhythmias associated with digitalis toxicity, MI and open heart surgery. SE: CNS like: drowsiness and convulsions. Mexiletine - oral lidocaine derivative, similar activity and uses Phenytoin – anticonvulsant and also works as anti-arrhythmic similar to lidocane Tocainide – Structurally similar to lignocaine but can be administered orally. Serious non cardiac side effects like pulmonary fibrosis limits its use.

Classification of anti-arrhythmics 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 Potent blocker of Na+ & K+ channels Used in life-threatening arrhythmias like sustained VT Propafenone Slows conduction Weak β–blocker and also some Ca2+ channel blockade Reserve drug for persistent ventricular arrhythmias Side effects: metallic taste, constipation and is proarrhythmic!

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

Classification of anti-arrhythmics Class III – K+ channel blockers Cause delay in repolarization and prolonged refractory period Includes Amiodarone – Iodine containing long acting drug acts by blocking K+ channels. Slow onset with t1/2 20-100 days. Used for SVT and VT. SE: cardiac e.g. bradycardia and A-V block, reversible pulmonary fibrosis and goiter. Bretylium – first developed to treat hypertension but found to also suppress resistant VF associated with myocardial infarction. SE: orthostatic HOT. Ibutilide – slows inward movement of Na+ in addition to delaying K+ influx. indicated for chemical cardioconversion of AF and atrial flutter of a recent onset to sinus rhythm. SE: can lead to arrhythmia and MI. Dofetilide - prolongs action potential by delaying K+ efflux with no other effects. Use in AF to convert or maintain sinus rhythm. May cause QT prolongation.

Classification of anti-arrhythmics 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

Other anti-arrhythmics Adenosine: Purine nucleoside having short and rapid action IV suppresses automaticity, AV conduction and dilates coronaries Drug of choice for Paroxysmal supraventricular tachycardia (PSVT) Adverse events: Nausea, dyspnoea, flushing, headache. CI in asthma. Atropine: Used in sinus bradycardia Digitalis: Atrial fibrillation and atrial flutter Magnesium SO4: digitalis induced arrhythmias

Drugs of choices S. No Arrhythmia Drug 1 Sinus tachycardia Propranolol 2 Atrial extrasystole Propranolol, 3 AF/Flutter Esmolol, verapamil ,digoxin 4 PSVT Adenosine ,esmolol 5 Ventricular Tachycardia Lignocaine , procainamide , Amiodarone 6 Ventricular fibrillation Lignocaine, amiodarone 7 A-V block Atropine , isoprenaline

Extra information

Impulse generation and transmission

Disorders of impulse formation No signal from the pacemaker site Development of an ectopic pacemaker May arise from conduction cells (most are capable of spontaneous activity) Usually under control of SA node  if it slows down too much conduction cells could become dominant Often a result of other injury (ischemia, hypoxia) Development of oscillatory after depolariztions Can initiate spontaneous activity in nonpacemaker tissue May be result of drugs (digitalis, norepinephrine) used to treat other cardiopathologies

Disorders of impulse conduction May result in Bradycardia (if have AV block) Tachycardia (if reentrant circuit occurs) Reentrant circuit

Pacemakers Surgical implantation of electrical leads attached to a pulse generator Over 175,000 implanted per year Leads are inserted via subclavicle vein and advanced to the chambers on the vena cava (right) side of the heart Two leads used, one for right atrium, other for right ventricle Pulse generator containing microcircuitry and battery are attached to leads and placed into a “pocket” under the skin near the clavicle 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