Antiarrhythmic drugs - drdhriti

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  • Antiarrhythmic DrugsDepartment of PharmacologyNEIGRIHMS, Shillong

  • ContentPhysiology of normal cardiac rhythmDefinition and mechanisms of arrhythmiasClassification of drugs to treat arrhythmiasImportant anti-arrhythmic drugs (mechanism and pharmacological characteristics)Arrhythmias in clinical practice

  • Cardiac PhysiologyRecall: to function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchronicityRelaxation 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

  • Cardiac Physiology Myocardial Cells2 types Pacemaker and non pacemakerPacemaker and conducting cells SAN, AVN, Bundle of His and Purkinje`s fibresNon pacemaker Working Myocardial Cell (WMC) or CMCSinus rhythm means rhythm originates in SANSinus tachycardia means tachycardia but rhythm originates in SAN fever, exercise etc.Tachycardia = heart rate > 100 per minuteBradycardia = heart rate < 60 per min.

  • Cardiac Electrophysiology 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 cellNa+ higher outside than inside cellCa+ much higher K+ higher inside cell than outsideMaintenance by ion selective channels, active pumps and exchangers

  • Cardiac Action Potential - WMCs

  • 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 stimulatedAssociated 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 potentialTransient outward current due to movement of Cl- and K+

    Phase 1 initial rapid repolarizationClosure of the fast Na+ channelsPhase 0 and 1 together correspond to the R and S waves of the ECG

  • Cardiac Na+ channels

  • Cardiac Action Potential contd.Phase 2 - plateau phasesustained by the balance between the inward movement of Ca+ and outward movement of K+ Has a long duration compared to other nerve and muscle tissueNormally 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 repolarizeK + channels finally close when membrane potential reaches certain levelCorresponds to T wave on the ECG

  • Cardiac Action Potential Pacemaker Cells PCs - Slow, continuous depolarization during restSlow depolarization during 0 phase Continuously moves potential towards threshold for a new action potential (called a phase 4 depolarization)Funny current (If)

  • Cardiac Electrophysiology contd.ECG (EKG) showing wave segmentsContraction of atria

    Contraction of ventriclesRepolarization of ventricles

  • The Normal EKGRight ArmLeft Leg

  • Cardiac arrhythmias

  • Cardiac ArrhythmiasCardiac dysrhythmia (arrhythmia)Large and heterogeneous group of conditions in which there is abnormal electrical activity in the heartThe hearts too fast or too slow, and may be regular or irregularResults in rate and/or timing of contraction of heart muscle that is insufficient to maintain normal cardiac output (CO)Result from disorders of impulse formation, conduction, or both Causes of arrhythmiasCardiac ischemiaExcessive discharge or sensitivity to autonomic transmittersExposure to toxic substancesUnknown etiology

  • Cardiac Arrhythmias Clinical ClassificationHeart rate (increased / decreased)Tachycardia heart rate fast (>100 beats/min)Bradycardia heart rate slow (
  • Normal Vs Atrial ArrhythmiaNormal RhythmAtrial Rhythm

  • Ventricular ArrhythmiaVentricular arrhythmias are common in most people and are usually not a problem butVAs are most common cause of sudden deathMajority of sudden death occurs in people with neither a previously known heart disease nor history of VAsMedications which decrease incidence of VAs do not decrease (and may increase) the risk of sudden death treatment may be worse then the disease!

  • Cardiac Arrhythmias - MechanismEnhanced or ectopic pacemaker activityCatecholamine over activityInjury current in damaged myocardial cells, e.g. Myocardial ischemiaOscillatory After-depolarizationEAD: depolarization at phase 3 interrupted and MP oscillatesDAD: Related to Ca++ current. After attaining RMP premature action potential develops, e.g. digitalis toxicityReentry Phenomenon

  • After depolarization EAD and DAD

  • Cardiac Arrhythmias - Reentry PhenomenonProbably the cause of most arrhythmiasCommon abnormality of conduction also called circus movementOne impulse reenters and excites areas of heart more than oncePath of re-entering impulses may be small areas of heart (near AV node) Large (atrial or ventricular wall) atrial and ventricular fibrillationAnatomically determined (WPW syndrome) reentry circuit consists of atrial tissue, AV node, ventricular wall and accessory ventricular connection (a bypass tract)

  • Reentry Phenomenon Functional reentry

  • Reentry Phenomenon Accessory pathway (WPW syndrome)

  • Arrhythmia ConditionsExtrasystole: abnormal automaticity/after depolarizationParoxysmal Supraventricular Tachycardia: 150-200/minute (1:1), reentry phenomenon (AV node) Atrial Flutter: 200-350/minute (2:1), reentrant circuit in right atriumAtrial Fibrillation: 350-550/min, electrophysiological inhomogenicity of atrial muscles (bag of worms)Ventricular tachycardia: 4 or more consecutive extrasystole of ventriclesVentricular Fibrillation: rapid irregular contractions fatal (MI, electrocution)Torsades de pointes: polymorphic ventricular tachycardia, rapid asynchronous complexes, rise and fall in baseline of ECG Atrio-ventricular Block (A-V Block): vagal influence or ischaemia - 1st, 2nd and 3rd degree

  • Antiarrhythmic DrugsBiggest problem antiarrhythmics can cause arrhythmia!Example: Treatment of a non-life threatening tachycardia may cause fatal ventricular arrhythmiaMust be vigilant in determining dosing, blood levels, and in follow-up when prescribing antiarrhythmicsMechanism of action:Sodium channel blockadeBlockade of sympathetic autonomic effectsBlockade of Effective Refractory Period (ERP) increase ERP/APD ratioCalcium Channel Blockade

  • Antiarrhythmic DrugsVaugham-Williams classification:

    Class I Na+ Channel Blockers Class II - Beta-adrenergic Blockers Class III Prolong Repolarization Class IV Calcium Channel Blocker

  • Class I - antiarrhythmics Class IA Class IB Class ICClass I antiarrhythmics are further classified to IA, IB and ICQuinidineProcainamideDisopyramideLidocainePhenytoinFlecainidePropafenone

  • Subclass I A

    Lengthen action potentialSlow rate of rise of phase 0Prolong repolarizationProlong refractoriness by blocking several types of potassium channelProlong PR, QRS, QTModerate-marked sodium channel blockade in Open stateE.g, quinidine, procainamide, disopyramide

  • Shorten action potentialLimited effect on rate of rise of phase 0Shorten repolarizationShorten QTRaise fibrillation threshold in ventricular tissuesMild-moderate sodium channel blockadeLittle effect on refractoriness since there is essentially no blockade of potassium channelsE.g, lignocaine, mexilitine, phenytoin, propafenone

    Subclass - IB

  • Subclass IC No effect on length of action potentialMarkedly reduces rate of rise of phase 0Little effect on repolarizationMarkedly prolongs PR and QRSRefractory period of AV node is increasedMarked Na+ channel blockadeProlong refractoriness by blocking outward-rectifying potassium channelsUsed in life threatening ventricular fibrillation since they have highest affinity to Na+ channelsE.g, flecainide

  • Antiarrhythmic Drugs - QuinidineDextroisomer of Quinine: N+ channel blocking and antivagal actionActions: Inhibition of Na channel slanted O phase and Decreases phase 4Net result is delay in conductivity and increase in refractorinessOther actions include alpha blockade, decreased skeletal muscle contractility, vomiting and diarrhoea etc Kinetics: well absorbed orally, half life 10 HrsUses: Broad spectrum antiarrhythmic Atrial fibrillation and flutter, AF after direct current cardioversion to maintain sinus rhythm, prevention of PSVT and prevention of ventricular tachycardiaAdverse effects: Not used now for adverse effects like Proarrhythmia (torsades de pointes), sudden cardiac arrest, cinchonism etc.

  • Antiarrhythmic Drugs - ProcainamideProcaine derivative (amide)Identical action with quinidine except:Minimal antivagal actionLesser suppression of ectopic automaticityLesser depression of automaticity and AV conductionNo alpha blocking actionKinetics:Absorbed orally and bioavailability is 80%Metabolized in liver to N-acetyl-procainamide (NAPA) blocks K channel and prolongs repolarizationDosage 250 mg tabs and 1gm/ml injections Antiarrhythmic 0.5 to 1 gm oral followed by 0.25-0.50 mg every 2 HrsUses: Mainly for monomorphic VTs and to prevent recurrences

  • Antiarrhythmic Drugs - LidocainePopular antiarrhythmic and also local anaestheticActions:Suppression of automaticity in ectopic foci Slowing of O phase and shortening of pha