Anti-arrhythmia drugs

[Ref: SH(H)2:p375]

 

General principles

Tow major physiological mechanism for ectopic arrhythmias
* Reentry
* Enhanced automaticity

 

Beta-blocker decreases mortality after acute MI
--> Mechanism not known

 

Classification of antiarrhythmic drugs

Voughan Williams' classification

Class I (blocks fast sodium channels)

Further subdivided based on actions on refractory periods

Class IA (Refractory period prolonged)

• Quinidine
• Procainamide
• Disopyramide
• Moricizine

Class IB (Refractory period shortened)

• Lidocaine
• Tocainide
• Mexiletine

Class IC (No effect on refractory period)

• Flecainide
• Propafenone

Class II (beta-blockade, decreases rate of depolarisation)

• Esmolol
• Propranolol
• Acebutolol

Class III (blocks potassium channels)

Prolongs AP duration

• Amiodarone
• Sotalol
• Ibutilide
• Dofetilide
• Bretylium

Class IV (blocks slow calcium channels)

• Verapamil
• Diltiazem

 

Prodysrhythmic effects

Patients on class IC drugs experience higher incidence of sudden cardiac death
--> Treatment with amiodarone results in fewer life-threatening cardiac events

Torsade De Pointes

Associated with class IA (quinidine, disopyramide) and class III (amiodarone)

Predisposing factors:
* Hypokalaemia
* Hypomagnesaemia
* Poor LV function
* Other drugs that prolong QTc

Incessant ventricular tachycardia

Precipitated by class IA and class IC
--> Continuous venticular tachycardia re-entry circuit

Wide complex ventricular tachycardia

Often associated with class IC in the setting of structural heart disease

 

Class IA

• Sodium channel blocker
• Prolongs the refractory period

 

• Quinidine and procainamide are rarely used during anaesthesia
  --> Due to propensity to produce hypotension
  * (???) Secondary to myocardial depression
• Disopyramide also causes myocardial depression
  * Especially in LV dysfunction cases
  * More so than quinidine and procainamide
• Moricizine is reserved for life-threatening cases of ventricular dysarrhythmia due to its proarrhythmic effect

 

Quinidine

For treatment of acute and chronic SVT

Decreases the slope of phase 4 depolarisation

Low therapeutic index

 

Procainamide

As effective as quinidine in treatment of ventricular tachyarrhythmia

Not as effective in treatment of atrial tachyarrhythmia

 

Class IB

• Sodium channel blocker
• (???) Shortens the refractory period

 

Lidocaine

Used principally for suppression of ventricular arrhythmias

Minimal effects on supraventricular tchyarrhythmias

Delays rate of spontaneous phase 4 depolarsation
* By preventing the gradual decrease in K+ ion permeability

Metabolised by liver
* Metabolite may possess antiarrhythmic property

Side effects include:
* Hypotension
* Bradycardia
* Seizures
* CNS depression, apnoea, cardiac arrest

Tocainide and mexiletine

Used from chronic suppression of ventricular tachyarrhythmias

 

Phenytoin

• (???) Part of class IB as well
• Effective in suppression of ventricular arrhythmias associated with digitalis toxicity
• Side effects include:
  * Cerebellar disturbances (ataxia, nystagmus, confusion)
  * Hyperglycaemia (inhibition of insulin secretion)
  * Thrombocytopenia (bone marrow suppression)
  * Skin rash

 

 

Class IC

Flecainide

Fluorinated local anaesthetic analog of procainamide

Suppresses ventricular premature beats and ventricular tachycardia
* More effective than quinidine and disopyramide

Also effective in treating atrial tachyarrhythmias

Significant proarrhythmic side effect

 

Class II (Beta-blockers)

Effective for treatment of arrhythmias due to enhanced activities of sympathetic nervous system
* e.g. Perioperative stress, thyrotoxicosis, pheochromocytoma

Mechanism of action

Prevants the cardiac beta-receptor from responding to sympathetic nervous system stimulation and the circulating catecholamines
--> Spontaneous phase 4 depolarisation is decreased and SA node discharge decreased

Side-effects of beta-blocker

• Bradycardia
• Hypotension
• Myocardial depression
• Bronchospasm
• CHF
• Heart block
  * Do not administer beta-blocker to patients with pre-existing heart block
• Mental depression
• Worsening of Raynaud's disease
• Up-regulation of beta-adrenergic receptors
  --> Can lead to SVT when treatment abruptly discontinued

 

 

Propanolol

Propanolol (PO) is extensively metabolised in liver

Variation in liver metabolism accounts for variation in plasma concentration

Readily crosses the blood-brain barrier

Principle metabolite is 4-hydroxypropranolol
--> Weak beta-adrenergic antagonist activity

 

Class III (Inhibits K+ channel)

Amiodarone

Structurally similar to thyroxine

Has anti-adrenergic effect
* Non-competitive blockade of alpha and beta-receptors
* Minor negative inotropic effect

Effective against refractory supraventricular and ventricular tachyarrhythmias

 

Administration

5mg/kg IV over 2-5 minutes
--> Antiarrhythmic effect lasting up to 4 hours

Effect may last 60 days after discontinuation

 

Pharmacokinetics

Elimination half-time = 29 days

Large Vd

Principle metabolite is desethylamiodarone
* Pharmacologically active
* Longer elimination half-time than amiodarone

Side effects

Pulmonary toxicity
--> Pulmonary alveolitis (5-15% of patients)
* Gradual onset of dyspnoea, cough, and pulmonary infiltrates on XRay
* Acute onset (???)

Cardiotoxicity
* Prolonged QTc interval
* AV heart block

Inhibition of P-450 enzymes
--> Could lead to increased plasma concentration of digoxin and warfarin

Endocrine effects
* Hypothyroidism
* Hyperthyroidisim (as late of 5 months after discontinuation)

Others
* Corneal micro deposits
* Photosensitivity
* Peripheral neuropathy
* Increase in plasma transaminase

Sotalol

Used for treating sustained ventricular tachycardia or ventricular fibrillation

At low dose
--> Non-selective beta-blocker

At high dose
--> Prolongs cardiac action potential in atria, ventricles, and accessory pathway

Proarrhymic potential
--> Used only in life-threatening cases

Renally excreted

Onset of action faster than amiodarone

Bretylium

No longer recommended for treatment of VF during CPR

Amiodarone is more effective and has less side effects

Class IV (Calcium channel blockers)

Verapamil and diltiazem have the greatest efficacy for treatment of cardiac arrhythmias

Inhibition of slow calcium channel on smooth muscles and cardiac cells
--> Decreased rate of spontaneous phase 4 depolarisation

Side effects

• AV heart block
• Direct myocardial depression
• Hypotension (due to vasodilation)
• Potentiation of anaesthetic-induced myocardial depression
• Potentiation of muscle relaxants

Verapamil

• IV verapamil is highly effective in terminating SVT
  * 75-150microgram/kg over 1 to 3 minutes
  * Followed by infusion of 5 microgram/kg/min
• Does not depress accessory tracts
  --> Does not slow HR in Wolff-Parkinson-White syndrome
• Substantial depressant effect on AV node
• Negative chronotropic effect on SA node
• 70% eliminated by kidney

Other antiarrhythmic drugs

 

Digitalis

Stablise atrial electrical activity

Treatment of atrial tachyarrhythmias

Adenosine

Slows conduction through AV node

An effective alternative to calcium channel blockers (e.g. verapami) in treatment of paroxysmal SVT
* Also depresses accessory pathways
--> Can be used in WPW syndrome (unlike verapmil)

NOT effective in treating AF, atrial flutter, and VT

Mechanism of action

Stimulates cardiac adenosine1 receptors
--> Increase potassium flow
--> Hyperpolarise cardiac cell membrane
--> Shortens AP

Short duration of action
* Elimination half-time = 10 seconds
* Due to carrier-mediated cellular uptake

Metabolised to inosine by adenosine deaminase

Side effect of adenosine

• Flushing
• Headache
• Dyspnoea
• Chest discomfort
• Nausea
• AV heart block
• Bronchospasm