ANTI-ARRHYTHMIC

DRUGS

Mr. D.Raju, M.pharm,

Lecturer
ANTI – ARRHYTHMIC DRUGS

Cardiac Arrhythmias:
- 25% treated with digitalis
- 50% anesthetized patients
- 80% patients with AMI
¾ reduced cardiac output
¾ drugs or nonpharmacologic:
- pacemaker, cardioversion, catheter
ablation, surgery
ANTI – ARRHYTHMIC DRUGS

ELECTRO-PHYSIOLOGY OF NORMAL CARDIAC RHYTHM

SA node

ATRIA

AV node

His-Purkinje System

VENTRICLES
ANTI – ARRHYTHMIC DRUGS

¾ Transmembrane potential of cardiac cells

is determined by the concentrations of
the ff. ions:
« Sodium, Potassium, Calcium
¾ The movement of these ions produces
currents that form the basis of the
cardiac action potential
 ANTI – ARRHYTHMIC DRUGS

PHASES OF ACTION POTENTIAL

Phase 2
Phase 1
>Plateau Stage
>Limited depolarization
>Cell less permeable to Na+ Phase 3
>Inactivation of fast
>Ca++ influx through slow >Rapid repolarization
Na+ channels→ Na+
Ca++ channels >Na+ gates closed
ion conc equalizes
>K+ begins to leave cell >K+ efflux
>↑ K+ efflux & Cl- influx
>Inactivation of slow
Ca++ channels

Phase 0 Phase 4
>Rapid depolarization >Resting Membrane Potential
>Opening fast Na+ >High K+ efflux
channels→ Na+ rushes in >Ca++ influx
→depolarization
ANTI – ARRHYTHMIC DRUGS

MECHANISMS OF ARRHYTHMIA
ARRHYTHMIA – absence of rhythm
DYSRRHYTHMIA – abnormal rhythm

ARRHYTHMIAS result from:

1. Disturbance in Impulse Formation

2. Disturbance in Impulse Conduction

¾ Block results from severely depressed conduction
¾ Re-entry or circus movement / daughter impulse
ANTI – ARHYTHMIC DRUGS

ARRHYTHMIAS:
´ Supraventricular: ´ Ventricular:
- Atrial Tachycardia - Wolff-Parkinson-White
(preexcitation syndrome)
- Paroxysmal Tachycardia
- Ventricular Tachycardia
- Multifocal Atrial
Tachycardia - Ventricular Fibrillation
- Atrial Fibrillation - Premature Ventricular
Contraction
- Atrial Flutter
ANTI – ARRHYTHMIC DRUGS

CLASS I: SODIUM CHANNEL BLOCKING DRUGS

´ IA - lengthen AP duration
- Intermediate interaction with Na+ channels
- Quinidine, Procainamide, Disopyramide
´ IB - shorten AP duration
- rapid interaction with Na+ channels
- Lidocaine, Mexiletene, Tocainide, Phenytoin
´ IC - no effect or minimal  AP duration
- slow interaction with Na+ channels
- Flecainide, Propafenone, Moricizine
ANTI – ARRHYTHMIC DRUGS

CLASS II: BETA-BLOCKING AGENTS

´ Increase AV nodal conduction

´ Increase PR interval

´ Prolong AV refractoriness

´ Reduce adrenergic activity

´ Propranolol, Esmolol, Metoprolol,

Sotalol
ANTI – ARRHYTHMIC DRUGS

CLASS III: POTASSIUM CHANNEL BLOCKERS

´ Prolong effective refractory period by

prolonging Action Potential
« Amiodarone - Ibutilide
« Bretylium - Dofetilide
« Sotalol
ANTI – ARRHYTHMIC DRUGS

CLASS IV: CALCIUM CHANNEL BLOCKERS

z Blocks cardiac calcium currents

→ slow conduction
→ increase refractory period
*esp. in Ca++ dependent tissues (i.e. AV node)

z Verapamil, Diltiazem, Bepridil

ANTI – ARRHYTHMIC DRUGS

MISCELLANEOUS:
´ ADENOSINE → inhibits AV conduction &
increases AV refractory period

´ MAGNESIUM → Na+/K+ ATPase, Na+, K+,

Ca++ channels

´ POTASSIUM → normalize K+ gradients

ANTI – ARRHYTHMIC DRUGS

CLASS I: Sodium Channel Blocking Drugs

CLASS IA: QUINIDINE

´ Depress pacemaker rate
´ Depress conduction & excitability
´ Slows repolarization & lengthens AP duration
→ due to K+ channel blockade with reduction of repolarizing
outward current → reduce maximum reentry frequency →
slows tachycardia
´ (+) alpha adrenergic blocking properties → vasodilatation &
reflex ↑ SA node rate
ANTI – ARRHYTHMIC DRUGS

CLASS I: SODIUM CHANNEL BLOCKERS

CLASS IA: QUINIDINE

´ Pharmacokinetics:
« Oral → rapid GI absorption
« 80% plasma protein binding
« 20% excreted unchanged in the urine →
enhanced by acidity
« t½ = 6 hours
« Parenteral → hypotension

´ Dosage: 0.2 to 0.6 gm 2-4X a day

ANTI – ARRHYTHMIC DRUGS

CLASS I: SODIUM CHANNEL BLOCKERS

CLASS IA: QUINIDINE

z Therapeutic Uses:
– Atrial flutter & fibrillation
– Ventricular tachycardia
– IV treatment of malaria

z Drug Interaction:
– Increases digoxin plasma levels
ANTI – ARRHYTHMIC DRUGS

CLASS I: SODIUM CHANNEL BLOCKERS

CLASS IA: QUINIDINE

z Toxicity:
– Antimuscarinic actions → inh. vagal effects
– Quinidine syncope (lightheadedness, fainting)
– Ppt. arrhythmia or asystole
– Depress contractility & ↓ BP
– Widening QRS duration
– Diarrhea, nausea, vomiting
– Cinchonism (HA, dizziness, tinnitus)
– Rare: rashes, fever, hepatitis, thrombocytopenia,etc
ANTI – ARHYTHMIC DRUGS

CLASS II: BETA ADRENOCEPTOR BLOCKERS

´ ↑ AV nodal conduction time (↑ PR interval)

´ Prolong AV nodal refractoriness
« Useful in terminating reentrant arrhythmias that involve
the AV node & in controlling ventricular response in AF &
A.fib.
´ Depresses phase 4 → slows recovery of cells, slows
conduction & decrease automaticity
´ Reduces HR, decrease IC Ca2+ overload & inhibit after
depolarization automaticity
´ Prevent recurrent infarction & sudden death in patients
recovering from AMI
ANTI – ARHYTHMIC DRUGS

CLASS II: BETA ADRENOCEPTOR BLOCKERS

´ “membrane stabilizing effect”

¾ Exert Na+ channel blocking effect at high doses
¾ Acebutolol, metoprolol, propranolol, labetalol, pindolol
´ “intrinsic sympathetic activity”
¾ Less antiarrhythmic effect
¾ Acebutolol, celiprolol, carteolol, labetalol, pindolol
´ Therapeutic indications:
¾ Supraventricular & ventricular arrhythmias
¾ hypertension
ANTI – ARHYTHMIC DRUGS

CLASS II: BETA ADRENOCEPTOR BLOCKERS

Specific agents:
´ Propranolol – (+) MSA
´ Acebutolol – as effective as quinidine in
suppressing ventricular ectopic
beats
´ Esmolol - short acting hence used
primarily for intra-operative &
other acute arrhythmias
´ Sotalol – has K+ channel blocking
actions (class III)
ANTI – ARHYTHMIC DRUGS

CLASS III: POTASSIUM CHANNEL BLOCKERS

´ Drugs that prolong effective refractory period by

prolonging action potential
´ Prolong AP by blocking K+ channels in cardiac
muscle (↑ inward current through Na+ & Ca++
channels)
´ Quinidine & Amiodarone → prolong AP duration
´ Bretylium & Sotalol → prolong AP duration & refractory
period
´ Ibutilide & Dofetilide → “pure” class III agents
´ Reverse use-dependence
ANTI – ARHYTHMIC DRUGS

CLASS III: POTASSIUM CHANNEL BLOCKERS

SOTALOL
´ Nonselective beta-blocker that also slows repolarization
& prolongs AP duration
´ Effective antiarrhythmic agent
´ Used in supraventricular & ventricular arrhythmias in
pediatric age group
´ Renal excretion
´ Dosage: 80 – 320 mg bid
´ Toxicity: torsades de pointes
beta-blockade symptoms
ANTI – ARHYTHMIC DRUGS

CLASS IV: CALCIUM CHANNEL BLOCKERS

VERAPAMIL
´ Blocks both activated & inactivated calcium channels

´ Prolongs AV nodal conduction & effective refractory

period
´ Suppress both early & delayed afterdepolarizations

´ May antagonize slow responses in severely depolarized

tissues
´ Peripheral vasodilatation → HPN & vasospastic
disorders
ANTI – ARHYTHMIC DRUGS

CLASS IV: CALCIUM CHANNEL BLOCKERS

VERAPAMIL
´ Oral administration → 20% bioavailability
´ t½ = 7 hrs
´ Liver metabolism
´ Dosage:
IV: 5-10 mg every 4-6 hrs or infusion of 0.4 ug/kg/min
Oral: 120-640 mg daily, divided in 3-4 doses
´ Tptic use: SVT, AF, atrial fib, ventricular arrhythmias
´ Toxicity: AV block, can ppt. sinus arrest
constipation, lassitude, nervousness,
peripheral edema
ANTI – ARHYTHMIC DRUGS

MISCELLANEOUS ANTIARRHYTHMIC AGENTS:

DIGITALIS

´ Indirectly alters autonomic outflow by

increasing parasympathetic tone &
decreasing sympathetic tone
´ Results in decreased conduction time &
increased refractory period in the AV
node