ANTI-ARRHYTHMIC DRUGS Cardiac Electrophysiology

Cardiac cell at rest transmembrane potential is 80-90 mV negative to exterior Na channels are closed K can move thru inward rectifier channel Na channel opening initiates the action potential Transmembrane potential to +60mV SA node Pacemaker of the heart Automaticity Fires between 60 100 times per minute AV node His-Purkinje fiber system Voltage-gated and time dependent currents

Na current rapid depolarizing phase of atrial, ventricular muscles and Purkinje fibers (-) in SA and AV node Ca current SA and AV node depolarization K current repolarization phase of all cardiomyocytes pacemaker current pacemaker activity of SAN, AVN and Purkinje fibers Phases of Cardiac Action Potential

Phase O = upstroke of AP phase 1 = rapid depolarization component phase 2 = plateau (ventricular muscles) calcium phase 3 = repolarization phase phase 4 = electrical diastolic phase ECG: rough guide to some cellular properties of the cardiac tse

Heart rate Reflects sinus node automaticity PR interval Reflects AV node conduction time

QRS duration Reflects conduction time in the ventricles QT interval Measure of ventricle action potential duration Mechanism of cardiac arrhythmias

Enhanced automaticity afterdepolarization and triggered automaticity re-entry Enhanced automaticity

occurs in cells that display spontaneous diastolic depolarization SA node AV node His-Purkinje fibers automatic behaviour can occur in tissues that lack spontaneous pacemaker activity venticles >>Modulation of pacemaker activity (boron table) ----lessen heart rate (decrease automaticity of SA node) = prolong your phase 4 -decreased rate of depolarization -negative shift in maximum diastolic potential -positive shift in threshold Afterdepolarization and triggered automaticity

delayed afterdepolarization (intracellular Ca overload) myocardial ischemia adrenergic stress digitalis intoxication heart failure Early afterdepolarization (marked prolongation of cardiac action potential) Anti-arrhythmic drugs Torsades de pointes >>>abnormal automaticity in ventricular muscles (pic) >>>look for DAD Re-entry (it will go back, normally it is just one way)

anatomically defined re-entry Wolff-Parkinson-White syndrome accessory pathway = bundle of kent

Functional defined or leading circle no anatomic pathway or excitable gap circuit does not remain in same anatomic site >>>Abnormal conduction (boron pic) AV node -> purkinje -> fascicles ...... Mechanisms of Antiarrhythmic drug action

increased maximum diastolic potential adenosine acetylcholine decreased phase 4 slope beta-blockers increase threshold slope CCB Na channel blockers increase action potential duration K channel blocker delayed afterdepolarizations early afterdepolarizations inhibition of the development of afterdepolarization verapamil interference with inward current (Na or Ca) quinidine (Na+B) Mg+ re-entry weak-link (AV node) >>>>A mechanistic approach to antiarrhythmic therapy (GG table) 34-2 Classification of antiarrhythmic drugs (TABLE)

Na channel blocker threshold excitability is decreased decrease conduction velocity increase QRS duration action potential prolongation K channel blocker

Ca channel blocker SAN, AVN Block of Beta adrenergic receptors Decrease magnitude of Ca current and slows its activation Decrease magnitude of repolarizing K+ and Cl- currents Decrease pacemaker current Decrease DAD- and EAD-mediated arrhythmias Inhibit afterdepolarization-mediated automaticity >>Major electrophysiological actions of antiarrythmic drugs Principle in the clinical use of Antiarrhythmic Drugs

identify and remove precipitating factors establish goals of treatment some arrhythmias should not be treated symptoms due to arrhythmias choosing among therapeutic approaches minimize risk antiarrhythmic drugs can induce arrhythmias monitor plasma concentration patient specific contraindication electrophysiology of the heart as a moving target autonomic tone, myocardial ischemia and stretch >>>> GG table 34-4 Patient specific antiarrhythmic drug contraindication QUESTION: why use with caution digoxin, verapamil, diltiazem with Wolff-parkinson-white syndrome? ANSWER: AV node is blocked with Digoxin, verapamil, diltiazem the impulse remains in the bundle of kent -- so it generates another bout of arrhythmia Condition exclude/use with caution heart failure disopyramide, flecainide sinus or AV node dysfxn digoxin, verapamil, diltiazem, B adrenergic receptor antagonist, amiodarone wolff parkinson white syndrome digoxin, verapamil, diltiazem (risk of extremely rapid rate if atrial fibrillation develops) Na channel blockers bretylium infranodal conduction dse flecainide

aortic subaortic stenosis quinidine, procainamide history of MI disopyramide, sotalol, dofetilide prolonged QT interval ibutilide, amiodarone cardiac transplant adenosine diarrhea quinidine prostatism, glaucoma disopyramide arthritis chronic procainamide (drug induced lupus) lung dse amiodarone (only safe drug na you can use for heart failure, but it can cause interstitial fibrosis coz it can cause COPD) tremor mexiletine, tocaidine constipation verapamil Antiarrhythmic drugs

adenosine effects mediated by its interaction with specific G protein-coupled adenosine receptor activates acetylcholine- sensitive K current reduces Ca current slows sinus rate slows AV nodal conduction velocity increases AV nodal refractoriness inhibiting DAD short lived effects potentiated by dipyridamole (adenosine-uptake inhibitor) and inhibited by methylxanthines cardiac glycoside inotropic action results from increase intracellular CA hyperpolarization and shortening of atrial action potential increase in AV nodal refractoriness increase sympathetic activity and hypoxia can risk of toxicity amiodarone structural analog of thyroid hormone highly lipophilic Flecainide blocks Na current and delayed rectifier K current prolongs the duration of PR, QRS and QT intervals class 1 channel blocker dose related blurred vision exacebration of lethal arrhythmias indicated for SVT and AFib lidocaine local anesthetic block open and inactivated Na channels decreases automaticity by reducing the slope of phase 4 and alter threshold for excitability no significant effect on PR or QRS large doses can cause seizure, tremor and altered consciousness

metabolized in liver Propafenone Na channel blocker and K channel blocker Slow conduction in fast-response tissues Prolong PR and QRS duration Maintains SVT and AFib to sinus Can induce arrhythmias Eliminated by both kidneys and liver Undergo first and second pass metabolism with production of less active metabolites use with no structural heart dse sotalol K channel blocker non selective beta adrenergic antagonist prolongs the action potential duration of heart (QT) decreases automaticity, AV nodal conduction and prolongs AV refractoriness prescribed as racemic eliminated in kidneys torsades de pointes major toxicity with overdose >>>>pharmocokinetic char and doses of antiarrhythmic drugs (table) >>>>Drug induced cardiac arrhythmias (table) *do not give digoxin in renal failure pts, non dialyzable