Antiarrhythmic Drugs

Dr. Sachana KC
1st year Resident
Department of Anesthesia
Overview
 Normal cardiac AP
 Classification of Anti-arrhythmic Drugs
 MOA
 Amiodarone
 Pharmacokinetics
 Uses and doses
 Drug interactions
 Side effects
 Interactions
Cardiac Electrophysiology

 The cardiac action potential results from the interplay of multiple inward
and outward currents via specific ion channels responsible for each of
the five phases.

Drugs and Cardiac AP

 The effects of cardiac antiarrhythmic drugs on the action potential and
effective refractory period of the cardiac action potential determine the
clinical effect of these drugs.
Cardiac Action Potential Phases

 Phase 0 represents rapid depolarization as a result of opening of Na channels

and closing of K channels.
 Phase 1 is the period of initial repolarization that results from closure of Na
and opening of K channels.
 Phase 2 is the plateau phase that results from the sustained Ca current that
began with the initial depolarization.
 Phase 3 is repolarization due to opening of K and closure of Ca channels.
 Phase 4 is the resting potential during which time K channels are open and
Na and Ca channels are closed.
 The effective refractory period (ERP) is the time during which the cell cannot
be depolarized again.
Figure : The physiologic basis of the cardiac action potential.
Antiarrhythmic Drugs

 Antiarrhythmic drugs produce pharmacologic effects by blocking

passage of ions across sodium, potassium, and calcium ion channels
present in the heart.
Classification
 Cardiac arrhythmic drugs are most commonly classified into four
groups based primarily on the ability of the drug to control
arrhythmias by blocking specific ion channels and currents during
the cardiac action potential.
Contd…

Class I (inhibit fast sodium ion channels)

Class IA Class IC
 Quinidine  Flecainide
 Procainamide  Propafenone
 Disopyramide
 Moricizine
Class IB

 Lidocaine
 Tocainide

Contd…

Class II (decrease rate of depolarization)

 Esmolol
 Propranolol
 Acebutolol
Class III (inhibit potassium ion channels)
 Amiodarone
 Sotalol
 Ibutilide
 Dofetilide
 Bretylium
Contd…

Class IV (inhibit slow calcium channels)

 Verapamil
 Diltiazem
MOA Of Antiarrythmic Drugs

 Produce pharmacologic effects by blocking passage of ions across

sodium, potassium, and calcium ion channels present in the heart.
Figure : Drugs affecting on different phases of Cardiac AP
Class I Drugs

 inhibit fast sodium channels during depolarization (phase 0) of the

cardiac action potential.
 decreases in depolarization rate and conduction velocity.

Class I A drugs
 lengthen both the action potential duration and the effective
refractory period by sodium channel inhibition and prolonged
repolarization owing to potassium channel blockade.
 Eg; quinidine, procainamide, disopyramide, moricizine
Contd…

Class IB drugs
 less powerful sodium channel blockers and, unlike class IA drugs,
shorten the action potential duration and refractory period in
normal cardiac ventricular muscle.
 In ischemic tissue, lidocaine may block adenosine triphosphate
(ATP)–dependent channels, preventing ischemia-mediated
shortening of ventricular depolarization.
 Ex ; lidocaine, mexiletine, tocainide, phenytoin
Contd…

Class IC drugs
 Are potent sodium channel blockers - markedly decrease the rate of
phase 0 depolarization and speed of conduction of cardiac impulses.
 Little effect on the duration of the cardiac action potential and the
effective refractory period in ventricular myocardial cells but do
shorten the duration of the action potential in Purkinje fibers.
 Inhomogeneity effects - may contribute to the proarrhythmic effects.
 Ex; flecainide, propafenone
Contd…

Class II drugs
 are beta-adrenergic antagonists.

 decrease the rate of spontaneous phase 4 depolarization - decrease

autonomic nervous system activity – suppress ventricular arrhythmia
during myocardial ischemia and reperfusion.

 slow the speed of conduction of cardiac impulses through atrial tissues

resulting in prolongation of the P-R interval on the ECG
Contd…

 duration of action of the cardiac action potential in ventricular

myocardium is not altered.

 decreasing the incidence of arrhythmia-related morbidity and

mortality (exact mechanism for effect remains unclear).

 Ex ; Esmolol, Propranolol, Acebutolol

Contd…

Class III drugs

 Block potassium ion channels – causes prolongation of cardiac
depolarization, action potential duration, and the effective refractory
period.
 Prevent cardiac arrhythmias - by decreasing the proportion of the cardiac
cycle (when myocardial cells are excitable -susceptible to a triggering
event)
 Suppress Reentrant tachycardias - by prolonging action potential
duration than the cycle length of the tachycardia circuit.
Contd…

 Amiodarone exhibits sodium channel blockade (class I), b blockade

(class II), and calcium channel blockade (class IV) : so used treatment
of refractory ventricular arrhythmias , prevention of supraventricular
and ventricular arrhythmias
 Sotalol : long-acting, non-cardioselective beta-blocking drug consisting
of a racemic mixture of levorotatory (L) and dextrorotatory (D) isomers
that possess similar class III effects.
 The reduced incidence of proarrhythmia effects seen with amiodarone
or racemic sotalol treatment may be related to beneficial class II effects.
Contd…

Class IV drugs
 calcium channel blockers : inhibits inward slow calcium ion currents
that may cause tachycardia.
 Used for treatment of supraventricular tachyarrhythmias and
idiopathic ventricular tachycardia. (verapamil, diltiazem )
 The dihydropyridine calcium blockers (nifedipine, nicardipine,
nimodipine) do not have antiarrhythmic action.
Effects Of Anti-arrhythmic Drugs

Proarrhythmic Effects
 This is described as bradyarrhythmias or tachyarrhythmias that
represent new cardiac arrhythmias associated with antiarrhythmic
drug treatment.
 These include :
 Torsades de pointes (most common),
 Incessant ventricular tachycardia,
 Wide complex ventricular rhythm.
Torsades de Pointes

 Is triggered by early afterdepolarizations in a setting of delayed

repolarization and increased duration of refractoriness manifesting
as prolongation of the QTc interval on the ECG.
 Class IA and class III drugs prolong the QTc interval by potassium
channel blockade predisposing to torsades de pointes.
 Drug-induced torsades de pointes : a/w bradycardia because the
QTc interval is longer at slower heart rates.
Incessant Ventricular Tachycardia

 Precipitated by drugs that slow conduction of cardiac impulses (class IA

and class IC drugs) causes continuous ventricular tachycardia circuit
(reentry).
 Occur with high doses of class IC drugs and in patients with a history of
sustained ventricular tachycardia and poor left ventricular function.
 VT due to this mechanism is slower because of the drug effect but may be
resistant to drugs or electrical therapy.
 Rarely a/w class IB drugs : because of weaker blocking effect of sodium
channels.
Wide Complex Ventricular Rhythm

 Usually a/w class IC drugs with h/o structural heart disease.

 Excessive plasma concentrations of the drug or change in the dose
may cause arrhythmia.
 Wide complex ventricular rhythm is thought to reflect a reentrant
tachycardia and easily degenerates to ventricular fibrillation.
Amiodarone

 Potent antiarrhythmic drug (class III) with a wide spectrum of activity

against refractory supraventricular and ventricular tachyarrhythmias.
 A benzofurane derivative, is 37% iodine by weight and structurally
resembles thyroxine.
 Mechanism of Action

 A class III antiarrhythmic drug, but it possesses electrophysiologic

characteristics of all four Vaughan Williams classes.
 Like class I drugs, amiodarone blocks sodium channels at rapid pacing
frequencies,
 Like class II drugs, amiodarone exerts a noncompetitive antisympathetic
action.
 Like class III effect, with prolonged administration, it lengthen the
cardiac action potential.
 The negative chronotropic effect of amiodarone in nodal tissues is similar
to the effect of class IV drugs.
Contd…

 By blocking sodium channels, amiodarone blocks myocardial potassium

channels, which contributes to slowing of conduction and prolongation of
refractoriness.
 The antisympathetic action - block of calcium and potassium channels are
responsible for the negative dromotropic effects on the sinus node and for the
slowing of conduction and prolongation of refractoriness in the atrioventricular
(AV) node.
 Its vasodilatory action can decrease cardiac workload and consequently
myocardial oxygen consumption.
 It acts as an antianginal drug by dilating coronary arteries and increasing
coronary blood flow.
 Metabolism and Excretion

 A prolonged elimination half-time and large volume of distribution.

 Minimally dependent on renal excretion - an unchanged elimination half-time in
the absence of renal function.
 Principal metabolite, Desethylamiodarone, is pharmacologically active and
has a longer elimination half-time than the parent drug, resulting in
accumulation of this metabolite with chronic therapy.
 Protein binding of amiodarone is extensive, and the drug is not easily removed
by hemodialysis.
Pharmacokinetic

 Bioavailability- 22 to 95 %.
 Absorption is enhanced with food.
 Lipid soluble and is stored in high concentrations in fat and muscle, liver, lungs,
& skin.
 Plasma peak concentrations, 3 to 7 hours after single oral dose.
 Minimal first-pass effect.
 Elimination by hepatic excretion.
 Therapeutic blood concentrations of amiodarone are 1.0 to 3.5 mg/mL.
 Extensive hepatic metabolism with Desethylamiodarone as a metabolite.
Contd…

 Myocardium concentration 10 to 50 times of plasma.

 Plasma clearance is low, and Renal excretion is negligible
 Doses modification not requried in renal disease.
 Amiodarone and desethylamiodarone not dialyzable
 Large Volume of distribution (60 liter/kg).
 Highly protein bound (96%).
 Crosses the placenta and Measurable levels in breast milk.
 Desethylamiodarone (DEA) have antiarrhythmic properties.
 Elimination half-life is 58 days (range 15 to 142 days) for amiodarone and 36
days (range 14 to 75 days) for the active metabolite (DEA).
Electrophysiologic effects

 Prolongs the QT interval

 Slows heart rate and atrioventricular nodal conduction
 Prolongs refractoriness (via potassium and sodium channel
blockade)
 Slows intracardiac conduction (via sodium channel blockade).
Doses
Usual Adult Dose for Arrhythmias
 starting dose should be adequate to suppress life-threatening arrhythmias
Intravenously (IV)
Initial dose:
 1000 mg over the first 24 hours of therapy, delivered by the following infusion
regimen:
 Loading infusions: 150 mg over the first 10 minutes (15 mg/min), followed by
360 mg over the next 6 hours (1 mg/min)
 Maintenance infusion: 540 mg over the remaining 18 hours (0.5 mg/min)
Contd…

Maintenance dose:
 After the first 24 hours, continue the maintenance infusion rate of
0.5 mg/min; may increase infusion rate to achieve effective
arrhythmia suppression.
 Supplemental infusions: 150 mg over 10 minutes (15 mg/min) for
breakthrough episodes of ventricular fibrillation (VF) or
hemodynamically unstable ventricular tachycardia (VT)
Contd…

 Maximum dose: Initial infusion rate: 30 mg/min

 Duration of therapy: Until ventricular arrhythmias stabilize (most
patients require 48 to 96 hours); maintenance infusion of up to 0.5
mg/min can be continued for up to 3 weeks.
 Use: Initiation of treatment and prophylaxis of frequently recurring VF
and hemodynamically unstable VT in patients refractory to other
therapy.
Oral doses.

 Loading dose: 800 to 1600 mg orally per day for 1 to 3 weeks

(occasionally longer) until adequate arrhythmia control is achieved or if
side effects become prominent, then switch to adjustment dose
 Adjustment dose: 600 to 800 mg orally per day for 1 month, then
switch to maintenance dose
 Maintenance dose: 400 mg orally per day
 Maintenance dose should be determined according to antiarrhythmic
effect as assessed by patient tolerance as well as symptoms, Holter
recordings, and/or programmed electrical stimulation; some patients
may require up to 600 mg/day while some can be controlled on lower
doses.
Contd…

 May be administered once a day; twice a day dosing is

recommended for total daily doses of 1000 mg or more or in
patients who experience gastrointestinal tolerance.
 Close monitoring is indicated during the loading phase and
surrounding any dose adjustments.
 Use: Treatment of life-threatening recurrent VF or life-threatening
recurrent hemodynamically unstable VT in patients refractory to
adequate doses of other antiarrhythmics or those intolerant of
alternative agents.
Contd…
Contd…

 After initiation of oral therapy, a decrease in ventricular tachyarrhythmias occurs

within 72 hours.
 The maintenance dose can usually be gradually decreased to about 400 mg daily
for suppression of ventricular tachyarrhythmias and 200 mg daily for
suppression of supraventricular tachyarrhythmias.
 Administered IV over 2 to 5 minutes, a dose of 5 mg/kg produces a prompt
antiarrhythmic effect that lasts up to 4 hours.
 After discontinuation of chronic oral therapy, the pharmacologic effect of
amiodarone lasts for a prolonged period (up to 60 days), reflecting the prolonged
elimination half-time of this drug.
Indications

Long-term treatment
 Secondary prevention of life-threatening VT.
 For patients who have survived sustained VT & with left ventricular
dysfunction
 For primary prevention of SCD
 As an adjunct to reduce the frequency of ICD shocks
Contd…

 Treatment of atrial fibrillation, although the FDA has not approved this
indication.
 Hypertrophic cardiomyopathy
 Non-ischemic dilated cardiomyopathy
 Ventricular tachyarrhythmia during and after resuscitation from cardiac
arrest.
 Asymptomatic ventricular arrhythmias after myocardial infarction
Contd…

Acute treatment
 IV amiodarone for the emergency treatment of VT
 Onset of action with IV therapy in less than 30 minutes
 ACLS recommended for the initial treatment of hemodynamically
stable wide-complex tachycardia.
 In patients who require long-term treatment, intravenous dosing should
be switched to oral dosing.
 Hemodynamically unstable atrial fibrillation, AF with rapid ventricular
rates and AF with impaired renal function.
Contd…

 Preoperative oral administration of amiodarone decreases the incidence of atrial

fibrillation after cardiac surgery.
 Effective for suppression of tachyarrhythmias associated with Wolff- Parkinson-
White syndrome - depresses conduction in the atrioventricular node and the
accessory bypass tracts.
 Prolongs the effective refractory period in all cardiac tissues, including the SA
,AV node, His–Purkinje system, ventricle, and, in the case of Wolff- Parkinson-
White syndrome, accessory bypass tracts.
Figure : Role of Amiodarone in cardiac arrest in ACLS
 Side Effects

 Side effects is seen more in patients with – if daily maintenance dose exceeds
400 mg.
 Therapeutic blood concentrations- 1.0 to 3.5 mg/mL so > 3.5 mg/mL is toxic.

Pulmonary Toxicity
 Most serious side effect of amiodarone is pulmonary alveolitis (pneumonitis)
 Incidence is 5% to 15% of amiodarone treated patients.
Contd…

 Causes : it may enhance production of free oxygen radicals in the lungs

that in turn oxidize cellular proteins, membrane lipids, and nucleic acids.

 high-inspired oxygen concentrations may accelerate such reactions.

So restrict the inspired concentration of oxygen in patients receiving

amiodarone and undergoing GA to the lowest level capable of
maintaining adequate systemic oxygenation.
Contd…

Two distinct types of presentation seen

 More common form of pulmonary toxicity consists of a slow insidious
onset of progressive dyspnea, cough, weight loss, and pulmonary
infiltrates on the chest x-ray.
 The second form of pulmonary toxicity has a much more acute onset of
dyspnea, cough, arterial hypoxemia, and occasionally fever that may
mimic an infectious pneumonia.
Postoperative pulmonary edema attributed to amiodarone-induced
pulmonary toxicity reflects this acute form of onset.
Treatment of pulmonary toxicity

 Withdrawal of amiodarone
 Supportive care
 Corticosteroids
 Toxicity is reversible.
Cardiovascular

 May prolong the QTc interval on the ECG - increased incidence of

ventricular tachyarrhythmias, torsades de pointes (proarrhythmic effect)
 Slow HR - resistant to treatment with atropine
 Catecholamines and SNS stimulation is decreased - drug induced
inhibition of a- and b-adrenergic receptors. (Direct myocardial depressant
is minimal)
 IV amiodarone - Hypotension (most likely reflecting the peripheral
vasodilating effects of this drug)
- Atrioventricular heart block may occur.
 Contd…

 The negative inotropic effects of amiodarone may be enhanced in the

presence of GA, b-adrenergic blockers, and calcium channel blockers.
 Drugs that inhibit automaticity of the sinoatrial node (lidocaine) could
accentuate the effects of amiodarone – may increase sinus arrest.

GI
 Gastrointestinal side effects of amiodarone include nausea, anorexia, and
constipation. These symptoms often are dosage related and usually improve
when the dosage is reduced.
Ocular, Dermatologic, Neurologic, and Hepatic
 Corneal micro-deposits – Occur 100% if used longer than 6 months.
 Optic neuropathy has been found in 1.8% of patients treated with
amiodarone.Discontinuation shows improvement in visual acuity.
 Visual impairment is unlikely.
 Photosensitivity and rash develop in up to 10% of patients.
 Rarely, cyanotic discoloration (slate-gray pigmentation) of the face that persists
even after the drug is discontinued.
 Neurologic toxicity – peripheral neuropathy, tremors, sleep disturbance,
headache, or proximal skeletal muscle weakness.
 Mild increases in plasma transaminase concentrations- may cause fatty liver
infiltration.
 Endocrine

 Contains iodine and has effects on thyroid metabolism, causing either

hypothyroidism or hyperthyroidism in 2% to 4% of patients.
 Patients with preexisting thyroid dysfunction - more likely to develop
amiodarone-related alterations in thyroid function.
 Hyperthyroidism has occurred up to 5 months after discontinuation of
amiodarone.
 Hyperthyroidism – detected by increased plasma concentration of
triiodothyronine.
 Hypothyroidism – detected by increased plasma concentration of TSH
Contd..

Amiodarone-induced hyperthyroidism
 Inhibit the peripheral conversion of T4 to T3
 Slight increase in T4, reverse T3, and thyroid-stimulating hormone (TSH) and
a slight decrease in T3 levels
 Reverse T3 concentration, used as an index of drug efficacy
Treatment –
 Surgical thyroidectomy provides prompt metabolic control.
 Bilateral superficial cervical plexus blocks have been described for
anesthetic management of subtotal thyroidectomy in these patients.
Copyright@ : Baruah MP, Singh RJ. Effects of drugs on thyroid function. Thyroid Research and Practice. 2012 Jan 1;9(1):3.
 Protocol of treatment of amiodarone-
induced thyroid disease
Type 1 Amiodarone induced thyrotoxicosis
 Thioamides (carbimazole 30-60 mg/day or methimazole 30-40 mg/ day)
in combination with potassium-perchlorate (1 g/day for 16-40 days).
 Discontinue amiodarone if possible.
 After restoration of euthyroidism and normalization of urinary iodine
excretion, definitive treatment of the underlying thyroid abnormalities by
either radioiodine or thyroidectomy.
 If amiodarone cannot be withdrawn and medical therapy is unsuccessful,
consider total thyroidectomy.

Copyright@ : Baruah MP, Singh RJ. Effects of drugs on thyroid function. Thyroid Research and Practice. 2012 Jan 1;9(1):3.
 Contd…

Type 2 Amiodarone induced thyrotoxicosis

 Glucocorticoids for 2 to 3 months (starting dose, prednisone 40 mg/ day or
equivalent).
 Discontinue amiodarone if possible.
 In mixed forms add thioamides and potassium perchlorate (a short course of
1 g/day for 10-30 days).
 After restoration of euthyroidism, follow-up for possible spontaneous
progression to hypothyroidism.
 If amiodarone cannot be withdrawn and medical therapy is unsuccessful,
consider total thyroidectomy.
Copyright@ : Baruah MP, Singh RJ. Effects of drugs on thyroid function. Thyroid Research and Practice. 2012 Jan 1;9(1):3.
 Contd…

Amiodarone-induced hypothyroidism
 In presence of underlying thyroid abnormalities (usually Hashimoto’s
thyroiditis), amiodarone therapy can be continued, and levothyroxine
replacement to be started.
 In presence of apparently normal thyroid gland, and if amiodarone cannot be
discontinued, levothyroxine replacement is initiated.
 If amiodarone is withdrawn, strict follow-up is required for possible
spontaneous restoration of euthyroidism. A short course of potassium
perchlorate (1 g/day for 10-30 days) can be given to accelerate return to
euthyroidism.

Copyright@ : Baruah MP, Singh RJ. Effects of drugs on thyroid function. Thyroid Research and Practice. 2012 Jan 1;9(1):3.
Drug Interaction

 Amiodarone inhibits hepatic P450 enzymes resulting in increased

plasma concentrations of digoxin, procainamide, quinidine, warfarin,
and cyclosporine.
 Amiodarone also displaces digoxin from protein-binding sites – dose
should decreased as much as 50% when given with amiodarone.
 Amiodarone also increases the plasma concentrations of quinidine,
procainamide, and phenytoin.
 The anticoagulant effects of warfarin are potentiated because amiodarone
may directly depress vitamin K–dependent clotting factors.
Contd…

 Volatile Anesthetic Agents: Patients who are on amiodarone therapy

may be more sensitive to the myocardial depressant and conduction
defects of halogenated inhalational anesthetics.
 Histamine H1 antagonists:
Loratadine, a non-sedating antihistaminic, is metabolized primarily by
CYP3A. QT interval prolongation and TdP have been reported with the
co-administration of loratadine and amiodarone.
 Histamine H2 antagonists:
Cimetidine inhibits CYP3A and can increase serum amiodarone levels.
Contd…

 Antidepressants:
Trazodone, an antidepressant, is metabolized primarily by CYP3A.
QT interval prolongation and TdP have been reported with the
coadministration of trazodone and amiodarone.
 Antibiotics:
Rifampin is a potent inducer of CYP3A. Administration of rifampin
concomitantly with oral amiodarone has been shown to result in
decreases in serum concentrations of amiodarone and
desethylamiodarone.
Contd…

 Immunosuppressives:
Cyclosporine(CYP3A substrate) administered in combination with oral
amiodarone has been reported to produce persistently elevated plasma
concentrations of cyclosporine resulting in elevated creatinine, despite
reduction in dose of cyclosporine.
 HMG-CoA Reductase Inhibitors:
Simvastatin (CYP3A substrate) in combination with amiodarone has
been associated with reports of myopathy/rhabdomyolysis.
Figure : Important Amiodarone intreaction
Contraindications

Amiodarone is contraindicated in patients with:

 Known hypersensitivity to any of the components of amiodarone,
including iodine. Hypersensitivity reactions may involve rash,
angioedema, cutaneous/mucosal hemorrhage (bleeding), fever,
arthralgias (joint pains), eosinophilia (abnormal blood counts), urticaria
(hives), thrombotic thrombocytopenic purpura, or severe periarteritis
(inflammation around blood vessels).
 Cardiogenic shock.
 Marked sinus bradycardia.
 Second- or third-degree atrio-ventricular (AV) block unless a
functioning pacemaker is available.
Monitoring

 Perform close perioperative monitoring in patients undergoing general

anesthesia who are on amiodarone therapy as they may be more sensitive to
the myocardial depressant and conduction defects of halogenated inhalational
anesthetics.
 Thyroid function tests, every 3 months for first year. Once or twice yearly,
thereafter.
 Pulmonary toxicity symptoms.
 Screening tests, such as chest radiographs and tests for pulmonary function,
thyroid stimulating hormone, liver function, coagulation profile (PT/INR) are
recommended.
Contd…

 Followed regularly.
 Assess ongoing need.
 Efficacy of the drug.
 Appropriateness of dosage.
 Adverse effects.
 Potential drug interactions.
Figure : Pharmacokinetics of Antiarrythmic drugs
References

 Amiodarone: Guidelines,for Use and Monitoring, LYLE A.

SIDDOWAY, M.D., York Hospital, York, Pennsylvania, December 1,
2003 / Volume 68, Number 11 www.aafp.org/afp, American Family
Physician.
 Stoelting’s Pharmacology and Physiology in Anesthetic Practice 5th
Edition (2015).
 Images- Google image.
Thank you