Anti-arrhythmic Drugs and updates

Speaker: Dr. Md. Saiduzzaman

MD Resident (Neurology), Mymensingh Medical College Hospital.

What is an Arrhythmia?• The arrhythmias are altered cardiac rhythm

caused by abnormalities in-– impulse formation (abnormal automaticity)– conduction in the myocardium (reentry), – or combination of both.

However, in the cardiology ward, arrhythmias present as a complex family of disorders that show a variety of symptoms.

Why should we treat arrhythmia?

Arrhythmias can cause serious complications like-

1. Heart failure.2. Sudden cardiac death3. Syncope.4. Stroke.

Factors that precipitate arrhythmia:

− Cardiac ischemia,– Structural heart disease,– Hypoxia,– Acidosis, alkalosis– Electrolyte disturbances– Excessive catecholamine exposure– Exposure to toxic substances– Unknown etiology

The heart cavity from which the arrhythmia originates gives the name to the arrhythmia

1. Supraventricular • Ectopic (atrial or AV nodal)• Multifocal Atrial Tachycardia(MAT) • Atrial fibrillation and flutter

2. Ventricular • Ectopic (Extrasystole or PVC)• Tachycardia• Ventricular fibrillation

ARRHYTHMIAS

Sinus arrythmia

Atrial arrhythmia

Nodal arrhythmia(junctional)

Ventricular arrhytmia

SVT

+30 mV

0 mV

-80 mV

-90 mV

OUTSIDE

MEMBRANE

INSIDE

Na+

0

4

3

21

K+ Ca++ K+

Atp

K+Na+

K+

Ca++

Na+

K+

Na+

Resting

open

Inactivated

Phase zero depolarization

Early repolarization Plateau phase

Rapid Repolarization

phase

Phase 4 depolarization

Antiarrhythmic drugs

Vaughn william Classification:

Class I – blocker’s of fast Na+ channels

– Subclass IA • Cause moderate Phase 0 depression• Prolong repolarization• Increased duration of action potential• Includes

– Quinidine – 1st antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory period

– Procainamide - increases refractory period but side effects

– Disopyramide – extended duration of action, used only for treating ventricular arrhythmias

Quinidine-indications and MOA

• Indication: both VA and SVA• Blocks activated Na+ channel: ↓slope of phase 0 and 4• Inhibit K+ current:↑phase 3• Both above effects ↑ Action potential ↑ QT

interval• α-blocking vasodilation reflex tachycardia• Antimuscarinic effect

Quinidine-adverse effectsCardiac Adverse effects:• torsade depoints (↑QT interval) twisting of peak in ECG• Proarrhythmogenic effects, AV block or asystole (toxic

dose)Extracardiac Adverse effects:• GIT: Diarrhoea,Nausea,Vomiting• Cinchonism: headache, dizziness, confusion, tinnitus,

deafness, blurring of vision• Quinidine syncope because of VA (↑QT); light headedness and fainting

• Shortens depolarization.• Decreased action potential duration

–Lidocaine (also acts as local anesthetic) – blocks Na+ channels mostly in ventricular cells, also good for digitalis-associated arrhythmias.

–Mexiletine - oral lidocaine derivative, similar activity.

–Phenytoin – anticonvulsant that also works as antiarrhythmic similar to lidocaine.

Subclass IB: Lidocaine, mexiletine, tocainide, phenytoin

Class IB-Lidocaine

• t1/2 1-1.5 hr given by I.V loading dose followed by I.V infusion

• Block both activated & inactivated Na+ channel• ↓The slope of phase 0 & 4

Main uses: • Ventricular Arrhythmia following MI.

Dose :IV 75-200 mg flushing, then 2-4 mg/min for 24-

30 hrs.Flushing dose is given to saturate hepatic

enzymes.Dose reduction by half is required in conditions

where hepatic blood flow is reduced.(shock,beta-blocker,hepatic cirrhosis, severe

heart failure)

Lidocaine adverse effectsCNS: drowsiness, numbness, parathesia, slurred speeches, difficulty of swallowing,convulsions, nystagmus, tremor, Diplopia

Heart: • AV block• ↓contractility

• Strong Phase 0 depression• No effect of depolarization• No effect on action potential duration

– Flecainide (initially developed as a local anesthetic)» Potent blocker of Na+ shorten AP» Potent blocker of K+ prolong AP» Net result no change» Slows conduction in all parts of heart, » Also inhibits abnormal automaticityProarrhytmogenic : reserved for life threatening

SVA & VA in pts without myocardial structural abnormalities

Subclass IC: flecainide, propafenone, moricizine

Class IC- Flecainide, Propafenone & Moricizine– Propafenone

» Has some structural similarities to propranolol» Weak β – blocker» Also some Ca2+ channel blockade» Also slows conduction» VA & SVA: its spectrum of action similar to that

flecainide» AE: metallic taste & constipation

– Moricizine» Derivative of phenothiazine» Mechanism of action similar to flecainide-VA» Proarrhythmogenic

Class II – β–adrenergic blockers

– Based on two major actions

1) blockade of myocardial β–adrenergic receptors↓cAMP ↓ both Na+ & Ca+ current

2) Direct membrane-stabilizing effects related to Na+

channel blockade↓both automaticity & HR and suppression of abnormal

pacemaker activity

• The AV node is particularly sensitive to β-blockers• The PR interval is usually prolonged by β-blockers

Class II- β–adrenergic blockers • Propranolol

– Slows SA node and ectopic pacemaker– Can block arrhythmias induced by exercise or

apprehension– Other β–adrenergic blockers have similar

therapeutic effect • Metoprolol ,Nadolol, Atenolol, Acebutolol, Pindolol,

Sotalol, Timolol; prophylactic in MI• Esmolol (very short acting; I.V exclusively for acute

surgical arrhythmia)

Class III – K+ channel blockers – Cause delay in repolarization and prolonged refractory

period– Includes:

• Amiodarone – markedly prolongs action potential by delaying K+ efflux.

• Ibutilide – slows inward movement of Na+ in addition to delaying K + influx.

• Bretylium – is an older drug that combines general sympathoplegic actions & a K+ channel blocking effects in ischemic tissues.

• Dofetilide - is a newer K+ channel blocker prolongs action potential by delaying K+ efflux.

Class III-Amiodarone• Structurally related to thyroid hormone.• Effective in most types of arrhythmias & is most

efficacious of all antiarrhythmic, because of toxicities, mainly used in arrhythmias that are resistant to other drugs.

• Blocks Na+, Ca+2 & K+ channels and α-& β-receptors• Marked prolongs the QT interval & QRS duration, it

increases Atrial, AV and Ventricular refractory period.

Amiodarone: main clinical use

• It’s a unique wide spectrum anti-arrhythmic drug.• Pts with AF where rapid rhythm control is needed.• Recurrent ventricular fibrillation.• Recurrent haemodynamically unstable ventricular

tachycardia.

Dose: Oral loading dose 600-1200mg; maintenance

dose 200-400mg.IV 150 mg over 10 mins; then 350 mg over 6 hrs;

then 540 mg over 24 hrs.

Hepatic metabolism; lipid soluble with extensive distribution in body.

Amiodarone: contraindications

• Cardiogenic shock• Severe sinus node dysfunction• 2nd or 3rd degree AV block.• Bradycardia associated with syncope.

Amiodarone-adverse effects• Toxicity due to accumulation• Hepatic, cardiac, pulmonary fibrosis.• Thyroid hypo- or hyperthyroidism• Skin discoloration• Peripheral neuropathy• Corneal deposits• ↑Digoxin level• Development of new arrhythmia.

Class IV – Ca2+ channel blockersVerapamil & Diltiazem

• slows AV-conduction rate in patients with atrial fibrillation.

• ↑PR interval• Verapamil – blocks Na+ channels in addition to Ca2+; also

slows SA node in tachycardiaSuppression of SA node; bradycardiaSlowing of AV node: abolish AV reentry• DiltiazemClass IV: Drug of choice for SVA: flutter and fibrillation ?

Miscellaneous • Adenosine I.V bolus (6-12 mg), short t1/2 15 secs• Markedly slows or completely blocks conduction in

AV node.• Acts by hyperpolarizing AV node through ↑K+ (Ach-

sensitive K + channel in SA & AV node) and ↓Ca+2 currents.

• Adverse Effects : flushing, hypotension, dyspnea, chest pain, bronchospasm.

Drugs of choices

S. No

Arrhythmia Drug

1 Sinus tachycardia Propranolol2 Atrial extrasystole Propranolol,3 AF/Flutter Esmolol, verapamil ,digoxin 4 PSVT Adenosine ,esmolol,

amiodarone5 Ventricular Tachycardia Lignocaine , procainamide ,

Amiodarone 6 Ventricular fibrillation Lignocaine, amiodarone 7 A-V block Atropine , isoprenaline