Anti-Arrhythmic Drugs (Arrhythmia)

DEFINITION

Arrhythmia is defined as the variation of the heart from normal rhythm. Disturbances in the rhythm, heart rate, impulse generation, or conduction of electrical impulses are responsible for membrane depolarization. These changes can escort to alterations in overall cardiac function that can be life-threatening.

MECHANISMS OF ARRHYTHMIAS

• Disturbances in the generation of impulse may be due to:

Abnormal automaticity.

Delayed after depolarization.

• Disturbances in conduction of impulse:

By causing repeated activation (re-entry), the impulse may recirculate in the heart.

Blocks conduction.

CLASSIFICATION OF ANTIARRHYTHMIC DRUGS

Class I: Block Na+ channels	Ia (quinidine, Disopyramide, Lidocaine, Mexiletine, procainamide, Propafenone) Ib (lignocaine, phenytoin, mexiletine) Ic (flecainide)
Class II: ß-adrenoceptor antagonists	Atenolol, Esmolol, Metoprolol, Propranalol.
Class III: K+ channel blocker-prolong action potential and prolong refractory period.	Amiodarone, Dofetilide, Sotalol, Dronedarone, Ibutilide.
Class IV: Ca2+ channel antagonists	Verapamil, Diltiazem.
Other anti-arrhythmic drugs	Adenosine.

Classification based on Clinical use:

• Drugs used for supraventricular arrhythmias.

Adenosine, verapamil, diltiazem.

• Drugs used for ventricular arrhythmias.

Lignocaine, mexiletine, bretylium.

• Drugs used for both supraventricular and ventricular arrhythmias.

Amiodarone, β-blockers, disopyramide, procainamide.

Na+ Channel Blocker:

• Bind to and block Na+ channels (and K+ also).
• Act on initial rapid depolarisation (slowing effect).
• Local Anaesthetic (higher concentration): block nerve conduction.
• Do not alter resting membrane potential (Membrane Stabilisers).
• At times, post repolarization refractoriness.
• Bind preferentially to the open channel state.
• Use Dependence: The more the channel is in use, the more drug is bound.

CLASS IA

Quinidine:

• D-isomer of quinine obtained from cinchona bark.
• A historically first antiarrhythmic drug was used.

MOA:

• Blocks sodium channels.
• Decreases automaticity, conduction velocity, and prolong S repolarization.
• Decreases phase 0 depolarization, increases action potential duration (APD), and effective refractory period (ERP).

Other actions:

• Decreases BP (α-block), skeletal muscle relaxation.

Clinical Pharmacokinetics

• Well absorbed.
• 80% bound to plasma proteins (albumin).
• Extensive hepatic oxidative metabolism.
• 3-hydroxyquinoline is nearly as potent as quinidine in blocking cardiac Na+ Channels and prolonging cardiac action potentials.

Uses:

• To maintain sinus rhythm in patients with atrial flutter or atrial fibrillation.
• To prevent recurrence of ventricular tachycardia or VF.

Adverse Effect:

Non-cardiac:

• Diarrhea, thrombocytopenia.
• Cinchonism and skin rashes.

Cardiac:

• Marked QT-interval prolongation and torsades de pointes (2-8%).
• Hypotension.
• Tachycardia.

Drug Interactions:

• Metabolized by CYP450.
• Increases digoxin levels.
• Cardiac depression with beta-blockers.
• Inhibits CYP2D6.

Disopyramide:

MOA:

Disopyramide produces negative ionotropic effects that are greater than the weak effect exerted by quinidine and procainamide, and unlike the latter drugs, disopyramide causes peripheral vasoconstriction.

Adverse Effects:

• Precipitation of glaucoma.
• Constipation, dry mouth.
• Urinary retention.
• Myocardial depression.

Drug Interactions:

Both metabolism of disopyramide and the accumulation of its metabolite are increased, in the presence of phenytoin, thus escalating the probability of anticholinergic properties.

Use:

• Ventricular tachycardia.
• Atrial flutter (AF) and Atrial fibrillation (AFI).

Procainamide:

• Procaine derivative, quinidine-like action.

MOA:

• Procainamide binds to open and inactivated Na+ channels and prevents sodium influx, slowing the rapid upstroke during phase 0.

Adverse Effect:

• Hypotension.
• Hypersensitivity reaction.

Drug interactions:

• Cimetidine inhibits the metabolism of procainamide.

Uses:

• Premature atrial contractions.
• Paroxysmal atrial tachycardia.

CLASS IB

• They shorten Phase 3 repolarization.
• ↓ the duration of the cardiac action potential.
• Prolong phase 4.

IBL:

Lidocaine:

MOA

• It shortens phase 3 repolarization and decreases the duration of the action potential.

Pharmacokinetics:

• High first-pass metabolism.
• Metabolism is dependent on hepatic blood flow.
• T½ = 8 min – distributive, 2 hrs – elimination.
• Propranolol decreases the half-life of lignocaine.
• Dose = 50-100 mg bolus followed by 20-40 mg every 10-20 min i.v.

Adverse Effects:

• Drowsiness.
• Slurred speech.
• Confusion and convulsions.

Drug Interaction:

• Propranolol increases its toxicity.
• The myocardial depressant effect of lidocaine is enhanced by phenytoin administration.

Uses:

• VA.
• Digitalis toxicity.

Phenytoin:

Phenytoin was originally introduced for the control of convulsive disorders but has now also been shown to be effective in the treatment of cardiac arrhythmias.

Adverse Effects:

• Respiratory arrest.
• Hypotension.

Drug Interaction:

• In the presence of chloramphenicol, disulfiram, and isoniazid, the plasma concentration of phenytoin is increased, since the later drugs inhibit the hepatic metabolism of phenytoin.

Uses:

• Anesthesia.
• Open heart surgery.
• Digitalized induced and ventricular arrhythmia in children.

Mexiletine:

MOA

• By the oral route, it acts as a local anesthetic as well as an active antiarrhythmic; chemically and pharmacologically similar to lidocaine.
• It reduces automaticity in Purkinje Fibres (PF), both by decreasing phase IV slow and by increasing threshold voltage.
• It may convert a one-way block to a two-way block by reducing the rate of 0 phase depolarization in ischemic PF.

Adverse Effects:

• Tremor
• Hypotension
• Bradycardia

Drug Interactions:

• When mexiletine is administered with phenytoin or rifampin, these drugs stimulate the hepatic metabolism of mexiletine, reducing its plasma concentration.

Uses:

• VA
• Congenital long QT syndrome.

CLASS IC

• Markedly slow Phase 0 depolarization.
• Slow conduction in the myocardial tissue.
• Minor effects on the duration of action potential and ERP.
• Reduce automaticity by increasing threshold potential rather than decreasing the slope of Phase 4 depolarization.

FLECAINIDE

MOA

• Flecainide suppresses phase 0 upstroke in Purkinje and myocardial fibers.
• This causes marked slowing of conduction in all cardiac tissues, with a minor effect on the duration of the action potential and refractoriness.
• Automaticity is reduced by an increase in the threshold potential rather than a decrease in the slope of phase 4 depolarization.
• The potent blocker of Na & K channels with slow unblocking kinetics.
• Maintain sinus rhythm in supraventricular arrhythmias.

Adverse Effect:

• Torsades de point, visual disturbances & headache.

Uses:

• Ventricular arrhythmia.

Class II Drugs: β- Blockers

PROPRANOLOL, METOPROLOL, ESMOLOL, ACEBUTOLOL

β-receptor stimulation:

• Increase automaticity.
• Decrease AV conduction velocity.
• Increase refractory period.
• β-adrenergic blockers competitively block catecholamine-induced stimulation of cardiac β-receptors.

β-blockers:

• Depress phase 4 depolarization of pacemaker cells,
• Slow sinus as well as AV nodal conduction: Decrease Heart Rate (HR), Increase Pulse Rate (PR).
• Increase ERP, prolong Action Potential (AP) Duration by Decrease AV conduction
• Reduce myocardial oxygen demand.

Propranolol

MOA

• Propanolol decreases the slope of phase 4 depolarization.
• Prolong the ERP of the A-V node.

Adverse Effect:

• Hypoglycemia (infants)
• Asthma
• Bronchospasm

Uses:

• Atrial Fibrillation.
• Digitalis induced arrhythmias

Esmolol:

MOA

• Esmolol is a short-acting β1-selective adrenoreceptor blocker.
• It doesn’t possess membrane-stabilizing activity.
• Route of administration is through i.v.

Adverse Effects:

• Nausea
• Hypotension
• Headache

Uses:

• Supraventricular tachyarrythmias.

Class III Drugs:

Amiodarone:

• Iodine containing long-acting drugs.

MOA: (Multiple actions)

• Prolongs APD by blocking K+ channels.
• Blocks inactivated sodium channels.
• β blocking action, Blocks Ca2+ channels.
• Decrease conduction, decrease ectopic automaticity.

Pharmacokinetics:

• Variable absorption 35-65%.
• Slow onset 2 days to several weeks.
• Duration of action: weeks to months.
• Many drug interactions.

Uses:

• Can be used for both supraventricular and ventricular tachycardia.

Adverse effects:

• Cardiac: hypotension, bradycardia, QT prolongation, heart block, cardiac failure.
• Pulmonary: pneumonitis leading to pulmonary fibrosis.
• Bluish discoloration of the skin.
• GIT disturbances, hepatotoxicity.
• Causes hypothyroidism or hyperthyroidism by blocking the peripheral conversion of T4 to T3.

Bretylium:

• Adrenergic neuron blocker used in ventricular arrhythmias.

Sotalol:

• Beta-blocker.

Dofetilide:

• Selective K+ channel blocker, less adverse events.
• Oral use in AF to convert or maintain sinus rhythm.

Ibutilide:

• K⁺  channel blocker used as an IV infusion in AF.

Class IV: Ca2+ channel Blockers

• Inhibit the inward movement of calcium.
• Decrease contractility, automaticity, and AV conduction.

Verapamil:

Uses:

• Terminate PSVT.
• Control ventricular rate in atrial flutter or fibrillation.

Drug interactions:

• Displaces digoxin from binding sites.
• Decrease renal clearance of digoxin.

Anti Arrhythmic Drugs:

Class	Mechanism	Action	Notes
I.	Na+ channel blocker	Change the slope of phase 0.	Can abolish tachyarrhythmia caused by reentry circuits.
II.	β-blocker	Increase heart rate and conduction velocity.	Can indirectly alter K+ and Ca2+ conductance.
III.	K+ channel blocker	1. Increase action potential duration (APD) or effective refractory period (ERP). 2. Delay repolarization.	Inhibit re-entry tachycardia
IV.	Ca++ channel blocker	Slowing the rate of rising in phase 4 of the SA node.	Decrease conduction velocity in SA and AV node.

OTHER ANTI-ARRHYTHMIC

Adenosine:

• Purine nucleotide having short and rapid action.

MOA:

• It activates ACh-sensitive K⁺ channels and causes membrane hyperpolarization through interaction with A1 type of adenosine GPCRs on SA node coronaries.

Adverse events:

• Nausea, dyspnoea, flushing, headache.

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