Pharmacology

Drugs acting on the heart: anti-arrhythmicsmarcus Wood

Jonathan Thompson

Abstractarrhythmias are common in patients undergoing anaesthesia and

surgery or in those in intensive care. They are associated with a variety

of underlying disorders or disease states. arrhythmias must be identi-

fied promptly and managed appropriately. In many cases, this involves

prevention or correction of precipitating factors and sometimes non-

pharmacological treatments (cardioversion or surgical ablation), but

anti-arrhythmic drugs are often required. These drugs are categorized

according to their mechanism of action using the Vaughan Williams

system. however, this is less useful in determining the choice of anti-

arrhythmic in clinical practice.

Keywords amiodarone; anti-arrhythmia agents; arrhythmias, cardiac;

digoxin; lidocaine; magnesium

Introduction

Abnormal cardiac rhythms are caused by abnormalities of impulse generation, impulse conduction or both, and can originate any­where in the heart. Symptoms may range from none (asympto­matic) or occasional palpitations to acute cardiovascular collapse. Although many drugs used in anaesthetic or intensive care practice affect heart rate and rhythm, the term anti­arrhythmic applies to drugs affecting ionic currents within cardiac con­ducting pathways. Urgent drug treatment may be required for rhythms which affect cardiac output, or those which may prog­ress to unstable tachyarrhythmias. Other arrhythmias might not require immediate therapy, but they require attention because they imply the presence of other abnormalities (Table 1).

To understand arrhythmias and their treatment, it is helpful to know the normal electrophysiology of the cardiac myocyte (Figure 1).

Marcus Wood FRCA is a Specialist Registrar and Honorary Lecturer in

Anaesthesia and Critical Care, University Hospitals of Leicester, UK. His

research interests include jet ventilation. Conflicts of interest: none

declared.

Jonathan Thompson BSc(Hons) MD FRCA is Senior Lecturer and Honorary

Consultant in Anaesthesia and Critical Care at the University of

Leicester and UHL NHS Trust, Leicester Royal Infirmary, UK. His main

clinical and research interests are cardiovascular pharmacology, critical

care medicine and anaesthesia for major vascular surgery. Conflicts of

interest: none declared.

aNaESThESIa aND INTENSIVE carE mEDIcINE 10:8 388

Classification

Anti­arrhythmic drugs can be classified according to their mode of action (Table 2). This classification has limitations, however, because it does not predict which drug to use for which arrhythmia. Furthermore, some drugs have more than one action, and some arrhythmias can be treated by drugs from more than one class.

In clinical practice, the treatment of arrhythmias depends on whether cardiac function is significantly compromised, the site of the arrhythmia (supraventricular or ventricular) and the poten­tial for progression to an unstable tachyarrhythmia. In many situations, non­pharmacological means (carotid sinus massage, withdrawal or correction of the underlying stimulus or trigger, etc.), surgical techniques (catheter ablation,4 implantable pace­makers/defibrillators) or electrical means (direct current (DC) cardioversion) are preferred. These techniques are outside the scope of this article.

Which drug to use?

The first step is to accurately diagnose the arrhythmia and treat any underlying or precipitating factors (i.e. supplemental oxy­gen/assisted ventilation in cases of hypoxia/hypercapnia). When the rhythm has been identified, the next question is whether the arrhythmia is acute or chronic. Patients can present with a chronic arrhythmia (i.e. atrial fibrillation (AF)), which can require drug treatment, but if cardiovascular function is acutely compromised then synchronized DC cardioversion should be performed. Note that these patients are likely to be on long­term anti­arrhythmic medication and thromboprophylaxis might be required.

Most of the arrhythmias requiring urgent treatment are tachy­cardias; the simplest way to classify these arrhythmias is as either supraventricular tachycardias (SVTs) or ventricular tachy­cardias (VTs).

Drugs to treat supraventricular tachycardiasAdenosine: a naturally occurring purine nucleoside that acts at specific A1 and A2 receptors. A1 receptors are coupled to potas­sium channels. Adenosine is used in the diagnosis and treatment of paroxysmal SVTs; it is given as a 6 mg intravenous bolus ini­tially, followed by 12 mg and a further 12 mg if necessary. It is quickly metabolized in red blood cells or vascular endothelium, leading to a very short plasma half­life of 10 seconds. Profound bradycardia might be induced, which can lead to ventricular excitation and ventricular fibrillation (VF).

Esmolol: a fast­onset (6 minutes), fast­offset (20 minutes) rela­tively selective β1­adrenoreceptor blocker used in the treatment of

after reading this article, you should be able to:

• draw the cardiac myocyte action potential and label anti-

arrhythmic sites of action

• identify at least 5 common causes of arrhythmias

• name at least 5 commonly used anti-arrhythmic drugs and the

arrhythmias they treat.

Learning objectives

© 2009 Elsevier ltd. all rights reserved.

Pharmacology

Caus

es o

f ar

rhyt

hmia

s in

pat

ient

s in

int

ensi

ve c

are

or tho

se u

nder

goin

g an

aest

hesi

a

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omic

alPh

ysio

logi

cal

Bio

chem

ical

Dis

ease

cong

enital

card

iac

isch

aem

iahyp

o/hy

perk

alae

mia

Seps

is

card

iac

abno

rmal

ity

hyp

oten

sion

hyp

ocal

caem

iaP n

eum

onia

mec

hani

cal (e

.g. cV

c /hic

kman

/Pa

cath

eter

ins

ertion

)au

tono

mic

dys

func

tion

hyp

omag

nesa

emia

Perica

rditis

hyp

oxia

Dru

gs (e.

g. e

pine

phrine

, Tc

aDs)

myo

card

itis

hyp

erca

pnia

hyp

er/h

ypot

hyro

id

hyp

othe

rmia

Vaga

l

Incr

ease

d Ic

P

In a

ll ca

ses,

tre

atm

ent of

arrhy

thm

ias

shou

ld b

e di

rect

ed a

t th

e ca

use,

whe

n kn

own.

cor

rect

ion

of the

se fac

tors

alo

ne m

ay b

e su

ffici

ent to

res

tore

a n

orm

al rhy

thm

, bu

t in

add

itio

n th

e ef

ficac

y of

ant

i-arrhy

thm

ic d

rugs

is

usu

ally

enh

ance

d if

pred

ispo

sing

fac

tors

are

tre

ated

firs

t. F

or e

xam

ple,

inc

reas

ed v

agal

ton

e ca

n oc

cur du

ring

stim

ulat

ion/

retrac

tion

on

the

perito

neum

, ex

trao

cula

r m

uscl

es o

r ut

erin

e ce

rvix

. Unc

ontrol

led

sym

path

et-

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tim

ulat

ion

can

caus

e ta

chyd

ysrh

ythm

ias,

e.g

. du

ring

lig

ht a

naes

thes

ia. Th

e m

anag

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t of

vag

al b

rady

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ias

is to

rele

ase

the

trac

tion

/stim

ulat

ion

of the

se a

reas

and

adm

inis

ter a

vago

lytic,

e.g

. at

ropi

ne (60

0 μg

) or

gly

copy

rrol

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(200

μg)

.Tr

eatm

ent of

acu

te a

rrhy

thm

ias

depe

nds

on c

linic

al u

rgen

cy (i.e

. is

the

car

diac

out

put or

blo

od p

ress

ure

com

prom

ised

, or

is

this

a p

recu

rsor

of a

mor

e se

riou

s dy

srhy

thm

ia?)

. Fo

r em

erge

ncy

trea

tmen

t of

acu

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th-

mia

s w

ithi

n th

e ho

spital

set

ting

, cu

rren

t re

susc

itat

ion

coun

cil (U

K) al

gorith

ms1

are

ava

ilabl

e from

ww

w.res

us.o

rg.u

k.cV

c, c

entral

ven

ous

cath

eter

; Pa

, pu

lmon

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athe

ter; T

caD, tric

yclic

ant

idep

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; Ic

P, int

racr

ania

l pr

essu

re.

Tabl

e 1

aNaESThESIa aND INTENSIVE carE mEDIcINE 10:8 389

acute SVT. It is given as an intravenous infusion (50–150 μg/kg/min), titrated to response. Esmolol is metabolized primarily by red cell esterases to methanol and an acid metabolite. Adverse effects include hypotension, bradycardia, bronchospasm and central nervous system disturbances.

Ibutilide: a pure class 3 drug because it works solely on the slow inward Na+ channels, causing a prolongation of the action potential and therefore an increased refractory period. Ibutilide is commonly used for recent­onset AF.5 It is administered as an intravenous infusion over 10 minutes, repeated if necessary; the dose is dependent on weight. It is metabolized by hepatic cyto­chrome P450 enzymes; adverse effects include chest pain and breathing difficulties.

Verapamil: causes a competitive block of the slow calcium ion channel, which leads to a decreased influx of calcium ions; this decreases automaticity and increases the refractory period. It is used to treat paroxysmal SVTs, AF and atrial flutter. Verapamil can be given orally (240–480 mg/day in three divided doses) or

Action potential of cardiac myocyte

The sinoatrial (SA) node is the cardiac pacemaker, which represents

functionally a small group of cells with an inherent rhythmicity that

spontaneously create action potentials. The rate of discharge of the SA

node is under fine control by the sympathetic (positive chronotropy) and

parasympathetic (negative chronotropy) systems, which increase and

decrease the rate of discharge respectively. The SA node action potential

has three distinct phases and, unlike the ventricular myocyte action

potential, does not have a resting membrane potential. The ventricular

myocyte action potential has a different shape and comprises five separate

phases that are due to cation and anion movements across the myocyte

cell membrane. The resting membrane potential is approx –50 to –60 mV

inside, relative to outside. After each action potential, there is a period of

time in which the myocyte is unable to depolarize despite normal amounts

of stimulation. This is called the refractory period. The refractory period

consists of an absolute refractory period during which no amount of

stimulus will cause an action potential and a relative refractory period

during which time a supramaximal stimulus will cause an action potential.

The refractory period is the inbuilt safety mechanism of the heart to

prevent uncontrolled myocyte stimulation. A, absolute refractory period;

B, relative refractory period.

Phase 0 Sudden influx of Na+ ions

Phase 1 Na+ channels start to close and slow Ca2+ channels open

Phase 2 Sustained Ca2+ channel opening

Phase 3 Efflux of K+

Phase 4 Return to resting membrane potential

Me

mb

ran

e p

ote

nti

al

(mV

)

Time

1

0

A B

4

3

2

0

–50

Resting potential

Depolarizationthreshold

Figure 1

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Pharmacology

Vaughan Williams classification of anti-arrhythmic drugs

Class Examples Mechanism Effects Indication

1a Disopyramide

Quinidine

Procainamide

moderate Na+ channel blockade

Decreased conduction velocity

Prolonged polarization

Increased aP duration

Increased refractory period

Widened QrS

moderate decrease in Vmax

Prevention of SVT, VT and atrial

tachydysrhythmias

Wolff–Parkinson–White syndrome

1b lidocaine

Tocainamide

mexiletine

mild Na+ channel blockade

Decreased conduction velocity

Shortened repolarization

Decreased aP duration

Decreased rP

QrS unchanged

mild decrease in Vmax

Prevention of VT/VF during

ischaemia

1c Flecainide

Propafenone

moricizine

marked Na+ channel blockade

Decreased conduction velocity

minimal change in aP or rP

 QrS widened

marked change in Vmax

conversion/prevention of

VT/VF/SVT

2 β -blockers β -adrenergic receptor blockade Decreased automaticity Prevention of sympathetically

mediated tachyarrhythmias

3 amiodarone

Sotalol

Dofetilide

Ibutilide

K+ channel blockade Prolonged repolarization

Increased aP and rP

QrS unchanged

Prevention of VT/VF/SVT

4 Verapamil ca2+ channel blockade Decreased action potential

duration and refractory period

rate control in aF

Prevention of aV node re-entrant

tachycardias

5 Digoxin Inhibition of Na+, K+-aTPase pump Positive inotropism and slowing

of ventricular response

Treatment of aF/flutter

adenosine agonist at a1, a2 receptors

coupled to K+ channels

Depression of Sa and aV nodal

activity

Diagnosis and treatment of

paroxysmal SVT

New anti-arrhythmic drugs under development include vernakalant hydrochloride (a K+ channel blocker used in the treatment and prevention of aF, currently awaiting approval by the Food and Drug administration2,3) and dronedarone3 (an experimental drug with an action similar to amiodarone but formulated without iodine and with a better adverse effect profile).aF, atrial fibrillation; aP, action potential; aV, atrioventricular; rP, refractory period; Sa, sinoatrial; SVT, supraventricular tachycardia; VF, ventricular fibrillation; VT, ventricular tachycardia.

Table 2

intravenously (5–10 mg over 30 seconds). It is metabolized in the liver. Adverse effects include first­ or second­degree heart block and VT/VF in patients with Wolff–Parkinson–White syndrome.

Digoxin: a glycoside used in the treatment of atrial flutter and fibrillation. It has direct and indirect effects. The direct effect is through inhibition of the Na+,K+­ATPase pump, thereby increas­ing intracellular Na+ concentration and decreasing intracellular K+ concentration. The increased intracellular Na+ alters the equilibrium of the Na+/Ca2+ exchanger; this causes a decrease in Ca2+ efflux and an increase in Ca2+ influx, leading to an increase in intracellular Ca2+ concentration. The decreased K+ concentration causes a slowing of atrioventricular (AV) conduc­tion. The indirect effect is through modifying autonomic func­tion, enhancing efferent activity. The loading dose of digoxin is 10–20 μg/kg (orally or parenterally) in three divided doses at 6­hour intervals until the desired effect has been established, fol­lowed by maintenance doses of 10–20 μg/kg/day. Therapeutic plasma concentrations must be monitored because digoxin toxic­ity causes several adverse effects, including junctional bradycar­dias, ventricular bigemini, second­ and third­degree heart block and visual disturbances. The dose is reduced in patients with

aNaESThESIa aND INTENSIVE carE mEDIcINE 10:8 390

renal failure, and toxicity is increased in the presence of hypoka­laemia, hypomagnesaemia, hypernatraemia or hypercalcaemia.

Amiodarone: acts by partial antagonism of adrenergic α and β receptors and also K+ channel blockade at the sinoatrial (SA) and AV nodes. It increases the refractory period and slows intracardiac conduction of the cardiac action potential, by slow­ing Na+ and Ca2+ channels. It is used for treating tachydysrhyth­mias, especially those resistant to other drugs. Amiodarone can be used to treat both supraventricular and ventricular arrhyth­mias. It is given as an intravenous bolus of 300 mg over 30 min­utes, followed by 900 mg over 23 hours or orally by means of 100 or 200 mg tablets. It is metabolized by the liver to an active metabolite. It has many adverse effects during chronic adminis­tration, most notably pulmonary fibrosis, corneal microdeposits, thyroid disorders, cirrhosis and peripheral neuropathy. During acute administration, it can precipitate cardiovascular collapse and AV block.

Drugs to treat ventricular tachycardiasLidocaine: an amide local anaesthetic that is predominantly used in the treatment of ventricular tachycardias. It is given as an

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Pharmacology

intravenous bolus of 1 mg/kg over 2 minutes followed by an infusion of 4 mg/min for 1 hour, 2 mg/min for 1 hour and finally 1 mg/min for 1 hour. It is metabolized in the liver. Allergic reac­tions are rare, but adverse effects of circumoral tingling, ecto­pic beats, respiratory depression and coma are dose dependent. Doses must not exceed 3 mg/kg intravenously.

Magnesium: a cofactor in many enzyme systems including Na+,K+­ATPase. It antagonizes atrial Ca2+ channels and also inhibits K+ channels, causing an increase in the refractory period. It is used to treat torsades de pointes and ventricular dysrhythmias. Various dosing regimens exist (e.g. 16 mmol over 20 minutes intravenously), but the dose should be titrated to pre­existing Mg2+ levels and serum Mg2+ concentrations should be monitored closely. Fifty per cent is excreted unchanged in the urine. Adverse effects include AV and intraventricular con­duction disorders and muscular and respiratory weakness. Toxic effects of hypermagnesaemia can be overcome by administration of calcium.

Amiodarone: can be used to treat a variety of ventricular dys­rhythmias; its pharmacology is described above. ◆

aNaESThESIa aND INTENSIVE carE mEDIcINE 10:8 391

REFEREnCEs

1 resuscitation council (UK). guidelines. also available at:

http://www.resus.org.uk/pages/gl5algos.htm (accessed 7 Feb 2009).

2 Dorian P, Pinter a, mangat I, et al. The effect of vernakalant

(rsd1235), an investigational antiarrhythmic agent, on atrial

electrophysiology in humans. J Cardiovasc Pharmacol 2007;

50: 35–40.

3 Savelieva I, camm J. Update on atrial fibrillation: part I.

Clin Cardiol 2008; 31: 55–62.

4 Jaïs P, cauchemez B, macle l, et al. catheter ablation versus

antiarrhythmic drugs for atrial fibrillation: the a4 study. Circulation

2008; 118: 2488–90.

5 Slavik rS, Tisdale JE, Borzak S, et al. Pharmacologic conversion

of atrial fibrillation: a systematic review of available evidence.

Prog Cardiovasc Dis 2001; 44: 121–52.

FuRThER READIng

mitchell lB. role of drug therapy for sustained ventricular

tachyarrhythmias. Cardiol Clin 2008; 26: 405–18.

Thompson JP. Drugs acting on the cardiovascular system.

In: aitkenhead ar, Smith g, rowbotham DJ, eds. Textbook of

anaesthesia, 5th edn. Edinburgh: churchill livingstone, 2007.

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