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Anti-arrhythmics
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
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