antiarrhythmics Flashcards
Fast vs Slow response cells in the myocardium
Fast response: in the atria/ventricle/his-purkinje, rate of depolarization is fast, conduction velocity is fast, major ionic species in depolarization is Na, Sodium channel blockers (block the depolarization), Recovery of excitabilit is prompt and ends with repolarization, Catecholamines and acetylcholine have little effect on depolarization
Slow response: in Sa and Av nodes, rate of depolarization/conduction velocity is slow. CA is the depolirizer inhibited by Calcium channel blockers, recovery of excitability is delayed and outlasts repolarization, catecholamines enhance depolarization, Acetylcholine depresses depolarization
mechanisms of arrhythmias
abnormal automaticity (enhanced/reduced automaticity)
Triggered automaticity (normal AP is interrupted or followed by an abnormal depolarization, afterdepolarizations)
Reentry (abnormal impulse conduction)
Triggered automaticity
Early and delayed (late) afterdepolarizations
DAD: delayed afterdepolarization (occurs after repolarization)- if depolarization is big enough for it to reach threshold for action potentila generation, it can trigger an AP, Triggered by leaky ryanodine receptors.
EAD: early afterdepolarization (disrupts repolarization)- prolonged repolarization can allow the recovery of sufficient number of Na or Ca channels from their inactivated state to depolarize the membrane
Catecholaminergic polymorphic ventricular tachycardia (CPVT)
inherited arrhythmogenic disease, most common AD form of CPVT is caused by a genetic mutation in gene that encodes the caridac ryanodine receptor–> aberrent release of Ca from ssarcoplasmic reticulum
functionally defined reentry- reentry in ventricular tissue
Anatomic reentry- accessory pathway, wolff parkinsonwhite syndrome
extra electrical pathway in the heart, increases heart rate– delta waves
Antiarrhythmic drug therapy- ultimate goal is to restore normal cardiac rhythm
four ways by by which antiarrhythmics reduce spontaneous discharge in automic tissue
decrease the phase 4 slope, increase threshold, increased maximum diastolic potential, increase AP duration
Class 1 drugs
sodium (Na) channel blockers: act on fast response cells, reduce membrane responsiveness, increase threshold for AP firing, reduce Vmax (depress conduction velocity) can product effective refractory period
Class 1 A drugs
1A: quinidine, procainamide, disopyramide (Trump’s dispro quo)
Direclty increases AP threshold, decrease Vmax, increass ERP
Indirect effect: blocks K channels–> EADs, vagolytic effect
Used for Atrial FLutter/fibrillation, prevents ventricular tachycardia and fibrilation
SE: severe GIT effects, heart (vagolytic, at therapeutic levels could speed AV conduction, at high concentration could prolong Av conduction or induce AV block)
Proarrythmic- ventricular premature contractions,, v. Tach, prolonged QT
MEtabolizeded in liver (quinidine), tolerated in pt with renal failure (disopytamide and procainamide eliminated hepatic and renal path)– P450 metabolis (CPY2d6 narcotcs, digitalis)
Class 1 B drugs
Lidocaine, mexiletine
Direct effects: increase in AP threshold, increase Block of Na channels (dcrease V max), at high HR, and in depolarized cells ( has a high affinity for inactivated Na channels, can target diseased cells); decrease Ap duration and ERP
SE: CNS toxicity (dizziness, drowsiness, seizures, GIT toxicity
USE: V tach, digitalis (induced arrhythmias) Safe for pts with long QT syndrome
Lidocain is metabolized Cyp3A4 (cimetidine) increase toxicity
Mexiletine- potent Cyp1A2 inhibitor
lidocaine
Use-dependent block: drug binds to the Na channel when open, more frequent opening allows binding of drug to channel
Voltage dependent block: drug binds to inactivated state of the Na channel. these channels are inactivated at depolarization membrane potential
Class 1 C Drugs
Flecainide, propafenone (Pro.paflof and his flea dogs)
Direct effects: increase AP threshold, decrease Vmax, Variable effects on ERP, dissociates from Na channel slowly
SE: Flecainide: Proarrhythmic, can worsen heart failure, dizziness, nausea, brady cardia, Cyp 2D6
USE: approved for use in life threatening situations when SV and V arrhythmias are resistant to other drugs
Class 2
B-adrenoceptor antagonists (beta blockers) propranolol, esmolol, metoprolol
Bind to B-adrenergic receptors on cardiac myocytes to competitively inhibit Epi and Norepi binding
antagonizes effects of sympathetic stimulation
(in the presense of catecholamines (main action of Class 2 agents is to slow the rate diastolic phase 4 depolarization
USE: all atrial arrhythmias, V. tachy/fib, high levels of catecholamines. THE MOST USEFUL ANTIARRYHTHMICS
no prolonged repolarization, safe in pts with long QT, negative inotropic effect, heart block bradycardia, bronchospasm
Class 3
K Channel blockers: Amiodarone, sotalol, dofetilide
main common property is K channel block; prolongs AP repolarization( AP duration increases); reverse use-dependence
Among the many K channels, most common target is Ikr
Main common effect is increased ERP
Amiodarone
Potent K channel blocker (blocks both Ikr and IKS)
Modest Na channel blocker, Modest Ca channel blocker, modest B blocker
USE: effective against V tachycardia and fibrillation, prevents recurrence of life threatening Ventricular arrythmias, Prevents recurrent A flutte/fib
SE: triggered arrhythmias (EAD) but rarly associated with Torsades, Althered thyroid function (hypothyroidism), pulmonary fibrosis, liver disease
Drug interactions: inhibtion of P450 (2C9, 2D6, 3A4)–>
Sotalol
Blocks K channel (IKr), Beta block
SE: triggered arrhythmias w/torsades
Fatigue and brady cardia
USES: V tachyarrhythmias and fibrillation, SVT, a fib
(use with caution in pts that prolong QT interval)
