Transcript Antiarrhythmic Drugs (continued)

Antiarrhythmic Drugs
October 6, 2006
Frank F. Vincenzi
Antiarrhythmic drug list
•
•
•
•
•
•
•
adenosine (Adenocard®) •
amiodarone (Cordarone®) •
atropine
•
bretylium (Bretylol®)
•
digoxin (Lanoxin®)
•
diltiazem (Cardizem®)
•
isoproterenol (Isuprel®)
lidocaine (Xylocaine®)
procainamide (Pronestyl®)
propranolol (Inderal®)
quinidine (Quinidex®)
verapamil (Calan®, Isoptin®)
Fundamental features of cardiac
excitation
• Automaticity
capacity for self excitation
• Excitability
ability to respond to stimuli and conduct action potentials
Refractory period
time following excitation during which a second
action potential can not be elicited and conducted
Membrane responsiveness
relationship between membrane activation voltage and
the maximal rate of rise of the action potential
Excitable tissues in heart
Slow response tissues (mainly Ca channels)
SA node
AV node
Fast response tissues (mainly Na channels)
atrium
ventricle
bundle of His
Purkinje fibers
Typical action potential in SA nodal cells
Typical action potential in AV nodal cells
Typical action potential in cardiac muscle cells
Influence of diastolic membrane potential
on action potential upstroke rate in a given cell:
‘Membrane Responsiveness’
Treatment for bradyarrhythmias
• Atropine
prevents vagally-induced inhibition of
supraventricular pacemakers and vagally
induced inhibition of AV nodal conduction
• Isoproterenol
increases automaticity of all parts of the heart
and promotes AV nodal conduction
• Artificial pacemaker - transvenous or
or implantable
Treatment for tachyarrhythmias
• Decrease automaticity of ectopic pacemakers
(e.g., reflex activation of vagus, adenosine,
quinidine, beta blockers, Ca channel blockers)
• Prevent re-entry excitation (lidocaine, amiodarone,
quinidine, etc.)
• Partially block AV nodal conduction of
supraventricular arrhythmias (digitalis, betablockers, Ca channel blockers)
Agents which partially block AV nodal
conduction may be useful in the treatment of
supraventricular tachyarrhythmias
• Digitalis - by increasing vagal tone increases AV
nodal refractory period
• Beta blockers - by preventing sympathetically
mediated increases in AV nodal conduction slow
or block conduction, also depress catecholamine
augmented automaticity
• Ca channel blockers - by inhibiting Ca channels
depress AV nodal conduction velocity and increase
refractory period, also suppress automaticity
adenosine (unclassified)(suppresses automaticity)
Metabolite of ATP, etc., released in heart under
conditions of ischemia
(rapidly causes vasodilation)
Increases potassium conductance and inhibits
cAMP mediated increase in calcium influx
Useful in the acute treatment of supraventricular
tachyarrhythmias
Extremely short half life, used IV only
(also used as a test for coronary dilation)
Vaughan Williams Classification of
Antiarrhythmic Drugs
I. Drugs with direct membrane action (e.g., Na channel
blockade
A. moderate phase 0 depression
B. minimal phase 0 depression, usually shorten repolarization
C. marked phase 0 depression, little effect on repolarization
II. Sympatholytic drugs
III. Drugs that prolong repolarization
IV. Calcium channel blockers
For a less arbitrary classification based on arrhythmogenic mechanisms
and potentially vulnerable parameters, see the report of the Task Force
of the Working Group on Antiarrhythmias of the European Society of
Cardiology, Circulation 84: 1831-1851, 1991
Examples of Antiarrhythmic Drugs According
to the Vaughan Williams Classification
• Class I
A - quinidine, procainamide
B - lidocaine
C - (encainide, flecainide)
• Class II - propranolol
• Class III - amiodarone, bretylium
• Class IV - verapamil, diltiazem
Antiarrhythmic drugs: a common theme
• Effective antiarrhythmic drugs increase the
refractory period compared to action potential
duration: ERP/APD
Relatively speaking, this gives ‘more time’ for recovery
of membrane potential and makes slow conduction
less likely. Slow conduction is a formula for disaster.
quinidine (Class IA)
(moderate inhibition of Na channels)
• Generally useful in supraventricular arrhythmias
(decreases automaticity, increases refractory period)
• Atropine-like properties
(may promote AV conduction - paradoxical tachycardia)
• Mild adrenergic blockade
(hypotension)
• High doses promote bizarre cardiac arrhythmias,
torsades des pointes
• Cinchonism
GI upset, tinnitus, loss of hearing, blurred vision, headache,
diplopia, delerium, psychosis, rarely thrombocytopenia
Quinidine decreases membrane responsiveness
(moderate inhibition of Na channels)
Quinidine
Membrane Responsiveness:
Relation between membrane activation
voltage and max dV/dt
procainamide (Class IA)
(moderate inhibition of Na channels)
• Generally useful in ventricular arrhythmias
• Little or no atropine-like properties
• Cardiac toxicity, hypotension, CNS effects, rarely
agranulocytosis or systemic lupus erythematosus
(SLE)-like syndrome
lidocaine (class IB)
(minor inhibition of [normal] Na channels)
• Useful mainly in ventricular arrhythmias
• Minor effects on normal automaticity or
membrane responsiveness, greatly suppresses
membrane responsiveness in ‘sick’ fibers
(by binding to inactive Na channels)
• Major toxicity in CNS; disorientation,
convulsions, respiratory arrest
Lidocaine decreases membrane responsiveness
(selective inhibition of Na channels in depolarized cells)
Lidocaine
Class IC antiarrhythmics
(major inhibition of Na channels)
• Flecainide for prevention of paroxysmal atrial
fibrillation (PAF) and paroxysmal supraventricular
tachycardia (PSVT) prevention and ventricular
arrhythmias.
•
Flecainide and encainide (off market?) were
associated with increased mortality
CAST, Cardiac Arrhythmia Suppression Trial
Echt et al., Mortality and morbidity in patients receiving encainide,
flecainide, or placebo, New Engl. J. Med. 324: 781-788, 1991.
Class IC antiarrhythmics: major inhibition of
membrane responsiveness
(major inhibition of Na channels)
Flecainide or encainide
beta-blockers (class II)
• Decrease cardiac automaticity and contractility, partly by
blocking beta-adrenergic receptors (& partly by direct
effects on cardiac cell membranes). Antagonize the effects
of catecholamines on Ca channels (reduce automaticity and
slow conduction in partially depolarized cells and decrease
myocardial contractility)
• Useful in supraventricular arrhythmias
• Increase effective refractory period of AV node
• AV block, asystole, sudden withdrawal can precipitate
angina, arrhythmias or myocardial infarction
• Contraindicated in asthma (relatively for beta-1 selective),
may mask tachycardia of hypoglycemia, CNS effects
amiodarone (Class III)
(but also has Class I, II and IV effects)
• A ‘dirty drug’, inhibits K channels, (delays repolarization),
Na channels and Ca channels (slight), blocks betareceptors non-competitively, blocks alpha receptors, potent
suppressor of ectopic automaticity (only rarely causes
torsades des pointes), and some vagolytic effects.
• Approved for ventricular tachycardia, ventricular
fibrillation and paroxysmal supraventricular tachycardia,
used in other arrhythmias as well; has anti-anginal
properties
• Adverse reactions (too many to list) occur in about 70% of
patients, sufficient to cause discontinuation in 5-20%.
• Extremely long, biphasic, half life (initial about 10 days,
terminal about 50 days), metabolized in liver, Vd ~ 70 l/kg
Amiodarone: selected adverse reactions
(far too many to list)
•
•
•
•
•
•
•
•
•
•
ARDS
Ataxia
AV block
Bronchiolitis obliterans
Dyspnea
Epididymitis
Heart failure
Hepatitis
Hyper/hypothyroidism
Macular degeneration
•
•
•
•
•
•
•
•
•
•
Optic neuritis
Pancreatitis
Peripheral neuropathy
Pneumonitis
QT prolongation
Sinus bradycardia
Thrombocytopenia
Torsade de pointes
Toxic epidermal necrolysis
Vasculitis
Amiodarone in out-of-hospital Resuscitation of REfractory sustained ventricular
Tachyarrhythmias (ARREST)
(504 pts, out of hospital arrest, >= 3 precordial shocks, 1 mg EPI, IV then:
Kudenchek et al., NEJM 341:871-878, 1999
bretylium (class III)
• Effects on cardiac (ventricle >> atrium) cell
membranes in addition to its effects on adrenergic
nerve terminals
• Useful in drug resistant ventricular fibrillation
(with cardioversion) or sustained ventricular
tachycardia in intensive care situations
• Classified as an agent that prolongs action
potential duration; actually increases ERP more
than APD
verapamil (class IV)
• Blocks mainly L-type calcium channels
• Decreases SA and Purkinje fiber automaticity,
slows conduction through and increases refractory
period of AV node
• Useful mainly in supraventricular arrhythmias or
ventricular arrhythmias caused by coronary spasm
• GI disturbances, cardiac toxicity including heart
failure, AV block
diltiazem (class IV)
• Blocks mainly L-type calcium channels
• Decreases SA and Purkinje fiber automaticity,
slows conduction through and increases refractory
period of AV node
• Useful mainly in supraventricular arrhythmias or
ventricular arrhythmias caused by coronary spasm
• GI disturbances, cardiac toxicity, including heart
failure, AV block
Long QT syndrome: genetic &/or drug-induced
Oral erythromycin and the risk of sudden
death from cardiac causes*
• Erythromycin is metabolized by CYP3A4
• Commonly prescribed drugs increase the AUC of
erythromycin by at least 2-fold:
– Nitroimidazole antifungals
– Diltiazem, Verapamil
• Incidence ratio of sudden cardiac death was 5.35
(1.72-16.64, 95% CI) in patients using
erythromycin and a CYP3A inhibitor
*Ray et al., NEJM 351:1089-1096, 2004
Drugs and the QT Interval - Caveat Doctor*
• 1A2
Amitriptyline, haloperidol, imipramine, clozapine
• 2C9
Amitriptyline, tamoxifen
• 2D6
Amitriptyline, desipramine, imipramine, haloperidol,
thioridazine, tamoxifen
• 3A4
Cisapride, disopyramide, quinidine, pimozide, tamoxifen,
erythromycin, clarithromycin
*Liu & Juurlink, NEJM 351: 1053-1056, 2004