Na+ channel blocker:

•Na+ channel block depends on:

HR

Membrane potential

Drug specific physiochemical characteristic- recovery

•Blockade of Na+ channels results in:

Threshold for excitability is increased (more current)

Increase in pacing and defibrillation threshold

Decrease conduction velocity in fast response tissues

Increase QRS interval (due to conduction slowing in ventricles)

Some drugs tend to prolong PR interval- flecainide (possibly Ca2+ channel blockade)

•Some sodium channel blockers shorten the PR interval (quinidine; vagolytic effect)

•APD unaffected or shortened

•Increase in threshold for excitation also decreases automaticity

•Can also inhibit DAD/EAD

•Delays conduction so can block re-entry

•In some cases, it can exacerbate re-entry by delaying conduction

•Shift voltage dependence of recovery of sodium channels from inactivated state to more negative potentials and so increases refractoriness

•Net effect- whether it will suppress or exacerbate re-entry arrhythmia depends on its effect on both factors- conduction velocity and refractoriness

•Most Na+ channel blockers bind to either open or inactivated state and have very little affinity for channels in closed state, drug binds to channels during systole & dissociates during diastole

•ADRs:

Decrease in conduction rate in atrial flutter- slows rate of flutter and increases HR due to decrease in AV blockade

Especially common with quinidine due to its vagolytic property; also seen with flecainide and propafenone

Cases of ventricular tachycardia due to re-entrant rhythm following MI may worsen due to slowing of conduction rate

Slowing of conduction allows the re-entrant rhythm to persist within the circuit so that complicated arrhythmias can occur

Several Na+ channel blockers have been reported to exacerbate neuromuscular paralysis by d-tubocurarine

•Na+ channel blockers lidocaine, phenytoin and mexiletine have only sodium channel blocking activity

•Lidocaine blocks Na+ channels more in open than in inactive state

•Phenytoin blocks them in inactivated state

•Quinidine blocks Na+ channels in open state

•It also has vagolytic and blocking activity

•Procainamide, disopyramide, propafenone block sodium channels in open state

•Sotalol is a blocker with Na+ channel blocking activity

•Amiodarone and dronedarone block sodium channels in inactivated state and produce non-competitive blockade of receptors

•Phenytoin is an anti-epileptic drug that blocks sodium channels and is used for treatment of digitalis induced tachyarrhythmias

•Reasons:

Does not aggravate AV block

Does not produce hypotension

It is a potent hepatic microsomal enzyme inducer

Toxicity- gum hyperplasia

•Mexiletine is an oral analogueof lidocaine, does not undergo first pass metabolsm

•It is preferred for treatment of ventricular arrhythmias associated with previous MI

•Lidocaine, a local anaesthetic is given as i.v. loading dose of 150-200 mg in 15 min followed by maintenance dose

•Lidocaine is extensively metabolized in the liver so not given orally

•Toxicity- drowsiness, convulsions, slurred speech, confusion, paresthesia

•Quinidine, due to vagolytic action, can potentiate ventricular tachycardia if given in the presence of rapid heart rate

•In addition to antiarrhythmic effect, it has antimalarial, antipyretic and skeletal muscle relaxant actions

•Procainamide is a derivative of procaine, a LA with actions similar to that of quinidine

•Quinidine is contraindicated in cases of:

AV block (because it slows conduction)

QT prolongation (already slow conduction is there)

CHF and hypotension due to its negative inotropic effects

Digitalis intoxication and hyperkalemia that potentiate the decrease in conduction velocity by quinidine

Digitalis toxicity because it has negative inotropic effects so antagonizes positive inotropic effects of digitalis

Myasthenia gravis (may be aggravated due to its muscle relaxant property

Atrial flutter & fibrillation (rapid HR)- quinidine can potentiate ventricular tachycardia due to its vagolytic action on AV node

•ADRs of quinidine:

•Diarrhoea

•Reversible thrombocytopenia due to formation of plasma protein-quinidine complex which forms antibodies against circulating platelets

•Quinidine syncope- loss of consciousness due to ventricular arrhythmias)

•Large doses (toxicity) may cause cinchonism- tinnitus, headache, nausea, blurring of vision and vertigo

•Interactions:

•Increases plasma levels of digoxin & precipitates its toxicity

•Enzyme inducers facilitate its metabolism- plasma concentration

•Mg hydroxide & CaCO3 elevate its plasma concentration

•K+ Channel blockers:

Prolong APD (QT interval) and reduces automaticity

Increase in APD also increases refractoriness

Effective in treating re-entrant arrhythmias

Reduce energy requirement for defibrillation

Inhibit ventricular arrhythmias in cases of myocardial ischemia

Many K+ channel blockers also have blocking activity also like sotalol

Disproportionate prolongation of APD can result in torsaides de pointes, specially when basal HR is slow

•Drugs included in this group are amiodarone, dronedarone, ibutilide, dofetilide, bretylium and sotalol

•They prolong APD and ERP without affecting phase 0 depolarization or resting membrane potential

•Amiodarone is an iodine containing analogue of thyroid hormone

•It is highly lipohilic drug

•It blocks inactivated Na+ channels, Ca2+ channels and K+channels

•Bretylium is a adrenergic neurone blocker with K+ channel blocking activity

•It was introduced as antihypertensive –obsolete now

•Used i.v. for treatment of resistant ventricular arrhythmias

•CCBs:

Major effect on nodal tissues

Verapamil, diltiazem and bepridil cause slowing of HR, nifedipine and other dihydropyridines reflexly increase HR

Decrease AV nodal conduction so PR interval increases

AV nodal block occurs due to decremental conduction and increase in AV nodal refractoriness

DAD leading to ventricular tachycardia respond to verapamil

Verapamil and diltiazem are recommended for treatment of PSVT

Bepridil increases APD in many tissues and can exert antiarrhythmic action in atria and ventricles but it use is associated with increased incidence of torsades de pointes- rarely used

•Verapamil and diltiazem block both open and inactivated L-type of calcium channels

•They decrease the rate of phase 4 depolarization in SA and AV nodes decrease conduction in AV node

•Adenosine: Naturally occuring neucleotide

Administered as rapid i.v. bolus for acute termination of re-entrant supraventricular arrhythmias

Also used to produce controlled hypotension for some surgical procedures

Effects are mediated through G-protein coupled adenosine receptors

It activates ACh sensitive K+ current in atrium, SA and AV nodes

Shortens APD, hyperpolarization and slowing of automaticity

•It also reduces Ca2+ currents and increases nodal refractoriness thereby acts as antiarrhythmic

•t½ is in seconds

•Magnesium sulphate: to terminate torsaides de pointes, mechanism unknown

•Vernakalant:

•Blocks several ion channels in atria

•Mainly blocks ultra rapidly acting delayed rectifier K+ channels

•Also blocks other K+ currents, Na+ current and L-type of Ca2+ current

•Does not significantly affect ventricular refractoriness

•Used for treatment of atrial fibrillation as i.v. infusion