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The Arrhythmias . Ibrahim Sales, Pharm.D . Assistant Professor of Clinical Pharmacy King Saud University isales@ksu.edu.sa. Key Concepts. Use of antiarrhythmic drugs in the US has declined due to major trials showing increased mortality associated with use - PowerPoint PPT Presentation

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The Arrhythmias

The Arrhythmias

Ibrahim Sales, Pharm.D.Assistant Professor of Clinical PharmacyKing Saud Universityisales@ksu.edu.sa1Key ConceptsUse of antiarrhythmic drugs in the US has declined due to major trials showing increased mortality associated with use recognition of proarrhythmia as significant adverse effectadvancements in nondrug therapy technologyablation implantable cardioverter-defibrillator (ICD)Antiarrhythmic medications frequently cause adverse effects, complex pharmacokinetics 2Normal ConductionElectrical activity initiated at sinoatrial (SA) nodehighest rate of spontaneous impulse generationMoves through cardiac tissue to ventricles at the atrioventricular (AV) nodeFlows down bundle of His to bundle branches & the Purkinje system2 bundle branches on left; 1 on the rightImpulse reaches refractory tissue (recently excited) & dies out SA node recovers & fires again3Normal Conduction of the HeartInherent HRSA node60-100 bpm

AV JUNCTION40-60bpm

VENTRICULAR 20-40 bpm

4

Electrical activity is initiated by the sinoatrial (SA) node As a result the action potential propagate through the cardiac cells and causes contraction and the cardiac cycle

Conduction system consist of SA nodeInter-ndal and inter-atrial pathwaysAV nodeBundle of HISPerkinjie fibers

4Normal ConductionPhase 0: initial, rapid depolarization of atrial & ventricular tissues; increase in cell Na+ permeability; Na+ influx; rapid depolarization overshoots electrical potential, brief period of repolarizationPhase 1: transient active K+ efflux; Ca2+ influx Phase 2: Ca2+ influx balanced by K+ efflux; plateauPhase 3: membrane permeable to K+ efflux; repolarizationPhase 4: gradual depolarization; constant Na+ leak to intracellular space balanced by K+ efflux556

Abnormal ConductionTachyarrhythmia: 2 categoriesabnormal impulse generation automatic tachycardiaabnormal impulse conduction reentrant tachycardia7Reentrant Tachycardias

8Three conditions required: two pathways for impulse conductionan area of unidirectional block (prolonged refractoriness) in one of these pathwaysslow conduction in the other pathway

Antiarrhythmic DrugsVaughan Williams classification limitationsincomplete, does not include digoxin, adenosinemany agents have properties of more than 1 class does not incorporate mechanism of tachycardia termination/prevention, clinical indications, side effectsagents labeled within a class 9Classification of Antiarrhythmic DrugsTypeDrugConduction Velocitya Refractory PeriodAutomaticityIon BlockIaQuinidineSodium (intermediate)ProcainamidePotassium

DisopyramideIbLidocaine0/

Sodium (fast on-off)MexiletineIcFlecainide0Sodium (slow on-off)Propafenoneb Potassiumd MoricizinecIIe -blockersCalcium (indirect)IIIAmiodaronef 00PotassiumDofetilideSotalolb IbutilideIVe VerapamilCalciumDiltiazem10aVariables for normal tissue models in ventricular tissue. bAlso has type II, -blocking actions. cClassification controversial. d Not clinically manifest. eVariables for SA & AV nodal tissue only. fAlso has sodium, calcium, -blocking actionsDiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.comAntiarrhythmic MedicationsVaughan-Williams Classification Mechanism of ActionDrugsIndicationIaNa+ channel block (intermediate association and dissociation)QuinidineProcainamideDisopyramideAtrial fib, Wolff-Parkinson-White syndrome, premature ventricular contractions, ventricular tachycardia**Paroxysmal supraventricular tachycardia-Disopyramide onlyIbNa+ channel block (fast association and dissociation)

LidocaineMexiletineTocainideVentricular arrhythmias only: Premature ventricular contractionsVentricular tachycardiaVentricular fibrillationIcNa+ channel block (slow association and dissociation)

Propafenone (class II activity)FlecainidePropafenone: Atrial fib, paroxysmal supraventricular tachycardia, life-threatening ventricular arrhythmias Flecainide: Atrial fib, paroxysmal supraventricular tachycardia, life-threatening ventricular arrhythmias, Wolff-Parkinson-White syndromeII-block (indirect Ca2+ block)-blockers (i.e. metoprolol)Atrial fib, atrial flutter, paroxysmal supraventricular tachycardiaIIIPrimarily K+ channel blockAmiodarone (class Ib, II, IV activity)Sotalol (class II activity)DofetilideIbutilideDronedarone (class Ib, II, IV activity)Wolff-Parkinson-White syndromeTreatment of Atrial fib and flutter*Sotalol: Maintenance only*Ibutilide: Conversion onlyAmiodarone or sotalol: Treatment and maintenance of life-threatening ventricular arrhythmiasIVCa2+ channel blockDiltiazemVerapamilAtrial fib, Atrial flutter, paroxysmal supraventricular tachycardiaAdditional agentsDirect nodal block; increases vagal activityDigoxinAtrial fibDirect nodal blockAdenosineTermination of AV nodal-dependent supraventricular tachycardias (AV nodal reentrant tachycardia)Contraindicated in ventricular tachycardias110 mV

AADs Have distinct Characteristics depending on which ion channels they block12Class II: Beta BlockersClass III: amiodarone, dofetilide, dronedarone, sotalol, ibulitideClass I: quinidine, procainamide, dispopyramide, lidocaineFlecainidepropafenoneK+Ca+Ca+Na+Class IClass IVClass IIIClass II-90mVClass IV: CCB12Type I AgentsBlock Na+ conduction: plug up channelsChannel state affinity lidocaine, flecainide: block during inactivated statequinidine: binds when channel is open/activatedBinding & unbinding specific to the receptor Type Ia: intermediate binding kineticsType Ib: fast receptor binding/dissociationType Ic: slow receptor binding/dissociation13Type Ia AntiarrhythmicsQuinidine, procainamide, disopyramideSlow conduction velocity, prolong refractoriness, decrease automatic properties of Na+ dependent conduction tissue reentry: transform area of unidirectional block into bidirectional block wave cannot get through pathway in retrograde fashion area still refractoryPrimarily Na+ channel blockerssome effects attributed to K+ channel blockadeused for supraventricular & ventricular arrhythmias

14Type Ib AntiarrhythmicsLidocaine, mexiletine: weak Na+ channel antagonists

Shorten refractoriness without affecting conduction velocity; improve antegrade conduction & eliminate unidirectional block

Used primarily in ventricular arrhythmias

15Type Ib AntiarrhythmicsLidocaineIndicated for Pulseless VT/VF conversion or VT with a pulse. VT maintenancePK: Reduce dose in those with HF, liver disease, low body weight and renal dysfunction and in the elderlyDI: Amiodarone (increased lidocaine levels)MexiletineVT maintenance

16Type Ic AntiarrhythmicsPropafenone, flecainideProfoundly slow conduction velocityRefractoriness relatively unaltered Eliminate reentry: slow conduction to point where impulse is extinguished & cannot propagate Potent Na+ blockersEffective for both ventricular & supraventricular arrhythmiasventricular arrhythmia use limited by proarrhythmia risk 17Type Ic AntiarrhythmicsPropafenone, FlecainideIndicated for patients with AF without structural heart disease. Avoid in patients with LV dysfunction and/or CAD. Can be initiated in an outpatient setting for patients with paroxysmal atrial fibrillation and no associated structural heart diseaseFollow-up: frequent ECG monitoring or via transtelephonic monitoring for potential signs of proarrhythmia.

18Type Ic Antiarrhythmics19

Type II Agents-blockersAntiarrythmic mechanism: anti-adrenergic actionsSA & AV nodes influenced by adrenergic innervationAdrenergic stimulation increases conduction velocity, shortens refractoriness & increases automaticity of nodal tissues-blockers antagonize these effectsuseful for exercise related tachycardias or other tachycardias induced by high sympathetic tone

20Non-Acute Setting and Chronic Maintenance Rate Control Therapy of Atrial FibrillationDrugLoading Dose (Oral)OnsetMaintenance Dose (Oral)Major Adverse EffectsRate ControlMetoprololSame as maintenance4-6 hours25-100mg BIDHypotension, bradycardia, HF and asthma exacerbation, heart blockPropanololSame as maintenance

60-90 minutes80-240mg in divided dosesHypotension, bradycardia, HF and asthma exacerbation, heart blockDiltiazemSame as maintenance

2-4 hours120-360mg daily in divided doses; slow release availableHypotension, HF exacerbation, heart blockVerapamilSame as maintenance

1-2 hours120-360mg daily in divided doses; slow release availableHypotension, HF exacerbation, heart blockRate control in patients with heart failure and without accessory pathwayDigoxin0.5mg daily2 days0.125-0.375mg dailyCardiac arrhythmias, headache, vision disturbances, nausea, vomiting, diarrhea Amiodarone800mg daily x 1 week600mg for 1 week400mg for 4-6 weeks1-3 weeks200mg dailyPulmonary fibrosis, hypothyroidism, hepatotoxicity, neurologic toxicity, TdP, AV block21Type III AgentsAmiodarone, sotalol, ibutilide, dofetilide

Prolong refractoriness in atrial & ventricular tissue

Delay repolarization: block K+ channels

Danger of blocking K+ channel too much: causes arrhythmias such as Torsades de Pointes (TdP)

22Type III AgentsAmiodarone & sotalol: effective in most supraventicular & ventricular tachycardias

Sotalol inhibits outward K+ movement during repolarization; nonselective -blocking actionsHospitalization mandatory for initiation, obtain QT 23 hours after first 5 doses, may increase dose after 3 days; NTE QT > 500 millisecondsNot effective for AF conversion

23Case 1A 52-year-old man comes into the clinic with a medical history significant for atrial fibrillation, diabetes, and hypertension. Current medications include metoprolol tartrate 100 mg twice daily, glyburide 10 mg twice daily, lisinopril 40 mg/day, and hydrochlorothiazide 25 mg/d