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Antiarrhythmics

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Anti-arrhythmics

Arrhythmogenic mechanisms

Classification

Site of action

Further reading

Adenosine

Amiodarone

Bretylium

Disopyramide

Flecainide

Lignocaine

Procainamide

Propafenone

Quinidine

Sotalol

Arrhythmogenic mechanisms

Enhanced abnormal automaticity
- due to enhancement of slow depolarisation seen in phase 4
Abnormal automaticity
- mechanism by which spontaneous impulses are generated in fibres that are partially depolarized because of some pathological process
- characteristics of abnormal automaticity are a function of of the magnitude of membrane depolarization. At high levels of membrane potential in the Purkinje system pacemaker current is If, an inward Na current while at low levels (eg during severe ischaemia) phase 4 depolarization is caused by decay of repolarizing K currents and action potentials generated depend primarily on Ica
Triggered activity
- arrythmias that arise as a result of afterdepolarizations
- occurrence of afterdepolarizations depends of the prior impulse (or series of impulses)
- afterdepolarizations can either interrupt the process of repolarization (early: EAD) or occur after completion (delayed: DAD)
- several mechanims for EADs. All result in change in net membrane inward current that delays or interrupts depolarization
- EAD most often arises at slow heart rates or after long pauses in the present of intervetnions that prolong the action potential
- DAD caused by intracellular Ca overload that results in repetitive release of Ca from SR. Resulting oscillatory changes in intracellular Ca activity cause an inwared depolarizing current that underlies the DAD

Re-entry

Classification

NB classification incomplete - some agents (eg digoxin, adenosine not included Other agents have more than one anti-arrhythmic action

Class I - membrane stabilizers

- depress depolarization of cardiac cell membrane by restricting entry of fast sodium current resulting in reduction in the maximum rate of rise of phase 0 of the action potential. This leads to slower rate of conduction, increased threshold for excitation and prolongation of the effective refractory period.
- also reduce rate of phase 4 diastolic depolarization, at doses which have no other effects, causing a reduction in spontaneous automaticity.
- class I drugs further subdivided by their effect on the duration of the action potential:

Ia

- lengthen action potential
- slow rate of rise of phase 0
- prolong repolarization
- prolong refractoriness by blocking several types of potassium channel
- prolong PR, QRS, QT
- moderate-marked sodium channel blockade
- eg quinidine, procainamide, disopyramide

Ib

- shorten action potential
- limited effect on rate of rise of phase 0
- shorten repolarization
- shorten QT
- raise fibrillation threshold
- mild-moderate sodium channel blockade
- little effect on refractoriness since there is essentially no blockade of potassium channels
- eg lignocaine, mexilitine, phenytoin, propafenone

Ic

- no effect on length of action potential
- markedly reduces rate of rise of phase 0
- little effect on repolarization
- markedly prolongs PR and QRS
- marked Na channel blockade
- prolong refractoriness by blocking outward-rectifying potassium channels
- eg flecainide

Class II

- decrease potential for arrhythmias to develop in response to catecholamines
- eg bretylium: blocks release of sympathetic transmitters
- beta blockers: competitive antagonists and also block possible arrhythmogenic effect of cAMP
- indirect blockade of Ca channel opening by attenuating adrenergic activation

Class III

- K channel blockers: prolong duration of action potential with resulting prolongation of effective refractory period
- eg amiodarone, sotalol, disopyramide, bretylium

Class IV

- calcium channel blockers
- inhibit slow inward calcium mediated current and depress phase 2 and 3
- slow SAN pacemaker cells and AVN conduction by direct blockade of Ca channels
- have inportant effects on upper and middle parts of the AV node
- may have particular value in blocing one limb of a re-entry circuit

Site of action

SAN, atrium

- Ia eg quinidine, disopyramide
- II beta blockers
- III eg amiodarone
- IV ? verapamil
- ? digoxin

AVN

- Ia ? disopyramide
- Ic eg flecainide
- II beta blockers
- III amiodarone
- IV verapamil
- digoxin

Anomalous pathway

- Ia disopyramide, quinidine
- Ic flecainide (most effective)
- III amiodarone

Ventricle

- Ia disopyramide, quinidine
- Ib lignocaine, mexilitine
- Ic flecainide
- II bretylium
- III amiodarone

Individual drugs

Quinidine

Class Ia

Mechanism of action

- decrease maximum rate of rise of phase 0
- depresses spontaneous phase 4 depolarization in automatic cells (results in prolonged QT)
- in general slows conduction through atrial, ventricular and Purkinje fibres causing QRS prolongation but usually has no effect on sinus rate or R interval
- antivagal action may accelerate AVN conduction

Pharmacokinetics

Admin: PO - absorption rapid and almost complete. SR preparations available bu their bioavailability may be lower than that of the standard formulation Never given IV as may cause severe hypotension and myocardial depression
Distrib: peak plasma concentrations at 2-3 hrs. 80% bound to albumin. Volume of distribution reduced in cardiac failure resulting in higher plasma levels which may lead to toxicity
Elim: 85-90% hydroxylated in liver to metabolites with less anti-arrhythmic activity. t1/2 5-7 hours. Only 10-15% excreted unchanged in the urine but renal excretion can be usefully increased if urine is acidified. Conversely heart failure or the administration of antacids or thiazides may lead to metabolic alkalosis and cause toxicity

Clinical uses

- limited by lack of IV preparation to prophylaxis after cardioversion or after acute administration of lignocaine. Effectively maintains sinus rhythm after cardioversion from AF but mortality is increased
- effective against both atrial and ventricular arrhythmias. However enhanced AV conduction may result in dangerously increased ventricular rates in atrial fibrillation or flutter and pre-treatment with digoxin must thus be given prior to any attempt to convert these arrhythmias with quinidine
- use should probably be restricted to patients with life-threatening arrhythmias in whom quinidine has been "proven" to be effective by EPS

Adverse effects

- high plasma levels cause myocardial depression, vasodilatation and hypotension
- sinus arrest
- AV dissociation
- QT prolongation and hence torsades de pointes. All type 1a drugs associated with risk of torsades but quinidine appears to be the worst offender
- nausea, vomiting and diarrhoea are common
- cinchonism: headaches, tinnitus, partial deafness, disturbed vision and nausea
- hypersensitivity reactions: fever, purpura, thrombocytopaenia, hepatic dysfunction
- may ppt haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency

Drug interactions

- diuretic induce hypokalaemia can produce life-threatening arrhythmias in patients on drugs which prolong QT interval. Characteristic arrhythmia is VT
- may increase serum digoxin levels
- cimetidine and some beta blockers reduce hepatic blood flow and may cause toxic concentrations
- concentrations decreased by hepatic enzyme inducers (eg phenytoin , phenobarbitone)

Procainamide

Class Ia

Mechanism of action

- as for quinidine

Clinical use

- atrial, junctional and ventricular arrhythmias - may be more effective than lignocaine in the treatment of VT
- use limited by short half-life

Pharmacokinetics

Admin: IV/PO. 85% bioavailable with rapid absorption - peak levels occur 1 hr after administration
Distrib: 15% plasma protein bound. Concentration in heart and most other tissue > plasma
Metab: 30% metabolized to active metabolite N-acetyl procainamide. Slow acetylators require smaller maintenance doses
Elim: 90% in urine unchanged or acetylated. Excretion decreased in renal failure, alkaline urine and CCF. t1/2 2-3.5 hrs - slow release preparation available

Adverse effects

Cardiac
- rapid IV injection may decrease CO and cause vasodilatation resulting in hypotension
- increases PR interval +/- increase degrees of heart block. compared with disopyramide and procainamide exerts least vagolytic effect
- may result in QRS and QT prolongation especially in slow acetylators

Others
- long term oral use associated with drug-induced SLE
- GI disturbance (less common than with quinidine)

Drug interactions

- diuretic induced hypokalaemia can cause life threatening arrhythmias in patients on drugs which prolong the QT interval. Characteristic arrhythmia is VT.

Disopyramide

Class Ia and III

Mode of action

- similar to quinidine
- increases atrial } abolishes ectopic &
refractory period } re-entrant atrial
- decreases sinus node }arrhythmias
refractory period
- anti-cholinergic effect (> quinidine/procainamide): antagonizes vagal actions and may be useful in suppressing supra-ventricular arrhythmias
- slows conduction in accessory pathway and sometimes prolongs His-Purkinje refractory period, although it has little effect on PR, QT, or QRS duration
- some Ca blocking effects

Pharmacokinetics

Admin: PO/IV. Following MI patients achieve lower plasma levels after oral dose.
Distrib: peak levels within 2 hrs. 25% plasma protein bound but binding saturable and depends both on disopyramide and metabolite concentrations - contributes to its unusual pharmacokinetic property of higher renal clearance at higher plasma levels. Volume of distribution decreases following MI
Metab: liver - 40% metabolized to a metabolite which is only slightly less active against atrial arrhythmias but is inactive against ventricular arrhythmias
Elim: drug and metabolite excreted in urine - decrease dose in severe renal failure. t1/2 4-6 hrs, increased following MI

Clinical uses

- AV nodal, AV re-entry and ventricular arrhythmias. Should not be used to treat AF or atrial flutter without prior control of ventricular rate with beta blockers or verapamil
- useful in preventing paroxysms of AF

Adverse effects

Cardiac
- myocardial depression; may be clinically important. Related both to plasma levels and rate of administration. Contra-indicated in heart failure, severe LV dysfunction
- prolongs QT -predisposes to re-entrant VT and especially torsades de pointes
- sinus node depression

Other
- anticholinergic activity may lead to urinary retention, dry mouth, blurred vision etc
- may precipitate glaucoma

Lignocaine

Class Ib anti-arrhythmic. Also has local anaesthetic actions.

Pharmacokinetics

Admin: IV
Distrib: volume of distribution 1.5 l/kg in normals, 0.5 l/kg in heart failure
Elim: 70-80% metabolized by liver. However hepatic clearance decreases when blood flow to the liver decreases as it does after MI. Metabolites have less anti-arrhythmic effect but may have greater CNS excitatory properties and may be responsible for some of the undesirable effects

Clinical use

- first line drug for VT after acute MI and cardiac surgery

Adverse effects

- high concentrations may cause bradycardia, hypotension and even asystole
- -ve inotrope
- in 10% of patients may induce ventricular arrhythmias
- GI upset with nausea and vomiting
- CNS: parasthesiae, twitching and generalized tonic-clonic seizures

Injection rate may be important in precipitating toxic reactions, which are also related to free drug concentration, which is particularly determined by the concentration of acute phase protein alpha-1 acid glycoprotein. Latter increases after MI so that although long-term infusions may lead to increasing total lignocaine concentrations the free drug level may remain fairly constant.
- crosses placenta rapidly but information on its use in pregnancy is limited. No reports of teratogenicity

Drug interactions

- hepatic clearance reduced in patients receiving cimetidine, propranolol or halothane

Flecainide

Class Ic

Mode of action

- depresses phase 0 and slows conduction throughout the heart
- delays repolarization in (canine) vnetricular muscle with significant prolongation of intracardiac monophasic action potential
- causes concentration related increase in PR, QRS and intra-atrial conduction intervals and prolongs effective ventricular refractory period
- sinus node function may also be affected particularly in patients with intrinsic sinus node disease

Pharmacokinetics

- admin: PO/IV; well absorbed with peak plasma concentrations after 3 hrs
- elim: 70% metabolised in liver to 2 major metabolites, one of which is active (1/5 of potency of parent). Remainder excreted directly in urine
– t1/2: 12-27 hrs

Clinical use

- life-threatening tachyarrhythmias: supra-ventricular or ventricular
- most effective drug at blocking conduction by anomalous pathways

Adverse effects

- up to 30% of patients
- -ve inotrope: exacerbation of CCF
- proarrhythmic effects: more common in patients with severe underlying cardiac dysfunction and more malignant arrhythmias. Torsades may occur even in patients without structural heart disease
- dizziness
- visual disturbance eg blurring
- headache
- nausea
- tremor
- diarrhoea
- conduction blocks including bundle branch block, complete heart block
- sinus arrest
- increase in pacing thresholds
- increased difficulty in cardioversion of tachyarrhythmias

Use in pregnancy

- have been a few reports of safe and effective use in pregnancy. Crosses placenta readily
- lack of toxic fetal effects possibly due to a lower sensitivity of immature cardiac tissue to its electrophysiological effects

Drug interactions

- results in minimal increase in digoxin levels
- both flecainide and propranolol levels are increased by co-administration of these drugs

Encainide

- haemodynamic, electrophysiological and adverse effects similar to flecainide
- shorter elimination t1/2

Propafenone

- similar to flecainide and encainide

Beta-blockers

Anti-arrhythmic properties appear to be a class effect with no one drug being intrinsically superior

Mode of action

- reduce slope of phase 4 in pacemaker cells thus prolonging their refractoriness
- slow conduction in AVN
- refractoriness and conduction in the His-Purkinje system are unchanged

Clinical use

- most effective in arrhythmias associated with increased cardiac adrenergic stimulation (eg TTX, phaeochromocytoma, exercise or emotion)
- SVT: may terminate re-entry tachycardias when the AVN is part of the re-entry circuit but less effective than adenosine or verapamil. Slow ventricular response to other SVTs
- VT: generally ineffective for the emergency treatment of sustained VT. Role in VT prevention not clear

Adverse effects

- cross placenta readily. Fetal bradycardia, hypoglycaemia, hyperbilirubinaemia and intrauterine growth retardation are concerns. Most reports have not shown significant adverse fetal effects but beta-blockers are probably best avoided in known intrauterine growth retardation

Bretylium

Class III

Mode of action

- increases action potential duration and refractory period of cardiac cells
- antifibrillatory effect on ventricular muscle - may be more important than class III effects in emergency treatment of malignant ventricular arrhythmias
- initially causes noradrenaline release and then produces the equivalent of a sympathectomy, preventing noradrenaline release (class II effect)

Clinical use

- useful adjunct to DC shock in managing life-threatening ventricular arrhythmias, especially refractory VF
- theoretical advantages of lignocaine but no advantage has been demonstrated clinically

Dose

5mg/kg IV over 15-20 min but in an emergency often given over 1-2 min

Adverse effects

Postural hypotension most significant side effect. Nausea and vomiting possible

Amiodarone

Mode of action

  • class III anti-arrhythmic with weak class I, II (b blocker) and class IV actions
  • prolongs effective refractory period of myocardial cells, AV node and anomalous pathways
  • depresses automaticity of SA and AVN
  • may also be a non-competitive blocker of a and b receptors
  • haemodynamic effects: coronary vasodilator (direct effect on smooth muscle, Ca channel blockade, and a blockade), peripheral vasodilator, negative inotrope

Pharmacokinetics

Administration: IV/PO.

Distribution: enormous apparent volume of distribution (70 l/kg). Stored in fat and other tissues. T1/2 after multiple dosing of 54 days

Elimination: metabolized in liver and excreted via biliary and intestinal tracts

Clinical uses

  • effective against most tachyarrhythmias
  • patients with poor LV function or patients with frequent ventricular ectopics post MI although did reduce "arrhythmia deaths"

Adverse effects

  • bradycardia, heart block and proarrhythmic effects. Latter are mild compared to other anti-arrhythmics
  • congestive cardiac failure (2-3%)
  • hypotension (28% following IV administration. Not dose related)
  • increases defibrillation threshold
  • corneal microdeposits which cause visual haloes and photophohia. Dose related and resolve when drug discontinued
  • hyperthyroidism, hypothyroidism, interference with thyroid function tests
  • photosensitivity
  • eosinophilic lung infiltration (early, fever, SOB, cough)
  • pulmonary fibrosis
  • hepatitis
  • tremor, ataxia, peripheral neuropathy, fatigue, weakness. Usually occur during loading. Dose related
  • skin discolouration

Drug interactions

  • displaces digoxin from binding sites and, more importantly, interferes with elimination
  • inhibits warfarin metabolism
  • b blockers and Ca antagonists augment the depressant effect of amiodarone on SA and AVN function as well as negative inotropic effects
  • raises quinidine and phenytoin concentrations

Sotalol

Class III (& II)

Mode of action

- prolongs action potential duration in atria, ventricles, AVN and accessory AV pathways
- potent non-cardioselective beta blocker
- antifibrillatory actions which are superior to those of conventional beta blockers

Pharmacokinetics

- admin: IV/PO
- elim: renal
- t1/2 15 h

Clinical use

- SVT: less effective than adenosine and verapamil in treatment of AVNRT and AVRT. Will prevent recurrence.
- AF & atrial flutter: probably ineffective as chemical cardiovertor but effective in preventing recurrence after cardioversion
- VT: as safe and more effective than lignocaine to terminate sustained VT when given IV. Use to prevent recurrence should be guided by Holter or EPS testing

Dose

- dose required to prolong cardiac repolarisation higher than that required to cause beta blockade
- IV dose: 0.5-1.5 mg/kg over 5-20 min
- PO: start at 80 mg bd and increase to 160 mg bd

Adverse effects

- adverse effects of beta blockers. Negative inotropic effect of beta blockade slightly offset by weak positive inotropism due to prolongation of action potential, allowing more time for calcium influx into myocardial cells
- QT prolongation
- crosses placenta readily. Fetal bradycardia, hypoglycaemia, hyperbilirubinaemia and intrauterine growth retardation are concerns. Most reports have not shown significant adverse fetal effects but beta-blockers are probably best avoided in known intrauterine growth retardation

Adenosine

Mode of action

- stimulates specific A1 receptors on the surface of cardiac cells thus influencing adenosine sensitive K channel cAMP production
- slows sinus rate
- prolongs AVN conduction, usually causing high degree AV block

Pharmacokinetics

- admin: IV
- elim: taken up by RBCs and deaminated in plasma
– t1/2 < 2 secs

Clinical use

- narrow complex tachycardia: drug of choice to terminate AVRT or AVNRT. Will not revert AF and may transiently increase ventricular rate in AF associated with WPW
- wide complex tachcardia: useful in assisting diagnosis. SVT with aberrant conduction will usually terminate with adenosine whereas few VTs will revert

Dose

6 then 12 then 18 mg

Drug interactions

- antagonized by methylxanthines, especially aminophylline
- dipyridamole potentiates effect by blocking uptake

Adverse effects

- flushing, dyspnoea and chest discomfort may occur transiently
- may precipitate bronchospasm in asthmatic patients

Use in pregnancy

- minimal placental transfer and short duration of action make it suitable for use in pregnancy

More on adenosine

Further reading

Alexander J.P., Anti-arrhythmic drugs. In Dundee J.W., Clarke R.S.J. and McCaughey W. (eds.) Clinical Anaesthetic Pharmacology, Chap 22, pg 367-83. Churchill Livingstone, Edinburgh, 1991

Ben-David J and Zipes DP, Torsades de pointes and proarhythmia. Lancet, 1993; 341:1578-1582

Commitee on safety of medicines, Current problems, Dec 1989.

Donovan KD, Hockings BEF. Antiarrhythmic drugs. In Oh TE (ed) Intensive Care Manual (4th ed). In press

Gillies H.C. et al, A textbook of clinical pharmacology, 2nd edn. Hodder and Stoughton, London, 1986.

Hillis W.S. and Whiting B., Antiarrhythmic drugs. British Medical Journal 286: 1332-6, 1983.

Katz A.M., Cardiac ion channels. N Eng J Med, 1993; 328:1244-1251

Medical Clinics of N. America 72(2): 291, 1988

Laurence DR, Bennett PN. Clinical pharmacology. 7th ed, 1992

Podrid PJ. Amiodarone: reevaluation of an old drug. Ann Intern Med, 1995; 122:689-700

 


© Charles Gomersall July 1999

 

©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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