drugs acting on the heart: anti-arrhythmics
Post on 29-Nov-2016
215 Views
Preview:
TRANSCRIPT
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
Anat
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-
ic s
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
emen
t of
vag
al b
rady
card
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
ate
(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
te a
rrhy
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
ary
arte
ry c
athe
ter; T
caD, tric
yclic
ant
idep
ress
ants
; 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
© 2009 Elsevier ltd. all rights reserved.
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
© 2009 Elsevier ltd. all rights reserved.
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.
© 2009 Elsevier ltd. all rights reserved.
top related