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HST-151 1 
I. Ventricular muscle cell action potential 
a. Phase 0: Upstroke 
b. Phase 1: Early-fast repolarization 
c. Phase 2: Plateau 
d. Phase 3: Repolarization 
e. Phase 4: Diastole 
Harvard-MIT Division of Health Sciences and Technology 
HST.151: Principles of Pharmocology 
Instructor: Dr. Jeremy RuskinHST-151 2 
II. Cardiac arrhythmia: 
a. Abnormal impulse formation 
i. Early afterdepolarizations (EADs): interrupts phase 3 -
exacerbated at slow heart rates and may contribute to development 
of long QT-related arrhythmias 
ii. Delayed afterdepolarizations (DADs): interrupts phase 4 - occurs 
when intracellular calcium is increased; is exacerbated by fast 
heart rates, may relate to digitalis excess, catecholamines, and 
myocardial ischemia 
b. Abnormal impulse propagation: 
i. Abnormal depolarization (QRS) 
ii. Abnormal repolarization (QTc) 
III. Cellular mechanism of arrhythmia: 
a. Enhanced automaticity: sinus and AV node, His-Purkinje system 
i. Beta-adrenergic stimulation, hypokalemia, mechanical stretch 
increase phase 4 slope & pacemaker rate 
b. Reentry: impulse reenters and excites areas of the heart more than once 
i. Obstacle for homogeneous conduction (anatomic, physiologic) 
ii. Unidirectional block in conduction circuit 
iii. Path length X conduction velocity > refractory period HST-151 3 
c. Polymorphic ventricular tachycardia (Torsades de Pointes): ("twisting of 
the points") or drug-induced long QT syndrome (DILQTS) 
ƒ Polymorphic arrhythmia that can rapidly develop into ventricular 
ƒ Associated with drugs that have Class III actions (potassium 
channel blockers) 
ƒ Also seen with other drugs such as terfenadine, cisapride, 
under certain circumstances 
ƒ Usually occurs within the first week of therapy 
ƒ Preexisting prolonged QTc intervals may be indicator of 
ƒ Potentiated by bradycardia 
ƒ Often associated with concurrent electrolyte disturbances 
(hypokalemia, hypomagnesemia) 
IV. Classification of Antiarrhythmic drugs: 
• Although several of the drugs used to treat cardiac arrhythmias have been used for 
many years (e.g.- quinidine and digitalis since the early 1900s), most of the agents 
approved for use today have only been available for a decade or less. 
• Research in recent years has provided much information regarding the cellular 
mechanisms of arrhythmias and the mechanisms by which some of the 
antiarrhythmic drugs act, but the general approach to antiarrhythmic therapy 
remains largely empirical. 
• The recent results of several clinical trials, including the Cardiac Arrhythmia 
Suppression Trial (CAST), have indicated that many antiarrhythmic drugs may 
significantly increase mortality compared to placebo. 
• All of the antiarrhythmic drugs act by altering ion fluxes within 
excitable tissues in the myocardium. The three ions of primary 
importance are Na+
, Ca++, and K+
. Antiarrhythmic drugs can be 
classified by their ability to directly or indirectly block flux of one or HST-151 4 
more of these ions across the membranes of excitable cardiac muscle 
• Class I drugs, those that act by blocking the sodium channel, are subdivided into 3 
subgroups, IA, IB, and IC based on their effects on repolarization and potency 
towards blocking the sodium channel 
o Subclass IA drugs have high potency as sodium channel blockers (prolong 
QRS interval), and also usually prolong repolarization (prolong QT 
interval) through blockade of potassium channels 
o Subclass IB drugs have the lowest potency as sodium channel blockers, 
produce little if any change in action potential duration (no effect on QRS 
interval) in normal tissue, and shorten repolarization (decrease QT 
o Subclass IC drugs are the most potent sodium channel blocking agents 
(prolong QRS interval), and have little effect on repolarization (no effect 
on QT interval) 
• Class II drugs act indirectly on electrophysiological parameters by blocking betaadrenergic receptors (slow sinus rhythm, prolong PR interval, little effect on QRS 
or QT intervals) 
• Class III drugs prolong repolarization (increase refractoriness) by blocking 
outward potassium conductance (prolong QT interval), with typically little effect 
on the rate of depolarization (no effect on QRS interval) 
• Class IV drugs are relatively selective AV nodal L-type calcium-channel blockers 
(slow sinus rhythm, prolong PR interval, no effect on QRS interval) 
• Miscellaneous In addition to the standard classes, IA-C, II, III, and IV, there is 
also a miscellaneous group of drugs that includes digoxin, adenosine, magnesium, 
alinidine (a chloride channel blocker) and other compounds whose actions don't 
fit the standard four classes HST-151 5 
Ventricular Action Potential 
Class I Class I & III* 
Table 1. Vaughan Williams Classification of Antiarrhythmic Drugs 
Class Action Drugs 
I Sodium Channel Blockade 
IA Prolong 
repolarization Quinidine, procainamide, disopyramide 
IB Shorten 
Lidocaine, mexiletine, tocainide, 
IC Little effect on 
Encainide, flecainide, propafenone, 
II Beta-Adrenergic Blockade Propanolol, esmolol, acebutolol, l-sotalol 
Prolong Repolarization 
(Potassium Channel 
Blockade; Other) 
Ibutilide, dofetilide, sotalol (d,l), 
amiodarone, bretylium 
IV Calcium Channel Blockade Verapamil, diltiazem, bepridil 
Miscellaneous Miscellaneous Actions Adenosine, digitalis, magnesium HST-151 6 
Table 2. Class Toxicities of Antiarrhythmic Drugs (Adapted from Woosley, 1991) 
Class I Class II Class III Class IV 
Proarrhythmic effects: 
• IA- Torsades de 
Negative inotropic effect 
Infranodal conduction 
Sinus bradycardia 
AV block 
Depression of LV 
Sinus bradycardia 
Torsades de pointes 
Sinus bradycardia 
AV block 
Negative inotropic effect 
V. Mechanism of antiarrhythmic drugs: 
Antiarrhythmic drugs act by altering the flux of ions across the membranes of excitable 
cells in the heart. The primary mechanisms of action correspond to the mechanisms used 
in developing the Vaughan Williams classification system, and include inhibition of 
sodium channels (Class I drugs), inhibition of calcium channels (Class IV drugs), 
inhibition of potassium channels (Class III drugs), and blockade of beta-adrenergic 
receptors in the heart (Class II drugs). 
a. Sodium Channel Blockade 
• Sodium channels are responsible for the initial rapid (Phase 0) depolarization of 
atrial, Purkinje, and ventricular cells. 
• Sodium channel activation (opening) is voltage-dependent 
• The sodium current entering the cell during phase 0 depolarization is very intense, 
but brief 
• Activation (opening) and inactivation (closing) of cardiac sodium channels is very 
• Blockade of sodium channels: 
o Slows the rate and amplitude of phase 0 depolarization 
o Reduces cell excitability 
o Reduces conduction velocity 
• SA and AV nodal cells have relatively few sodium channels and therefore lack a 
rapid phase 0 depolarization. HST-151 7 
b. Calcium Channel (L-type) Blockade 
• Calcium channels (L-type) are responsible for the prolonged plateau phase (Phase 
2) seen in the action potential of atrial, Purkinje, and ventricular cells. 
• L-type calcium channel opening is voltage-dependent, but requires a more 
positive membrane potential than cardiac sodium channels 
• The calcium current entering the cell during phase 2 is intense and prolonged 
• L-type calcium channels are slow to activate (open) and slow to inactivate (close) 
• Blockade of calcium channels reduces the amplitude and length (time) of phase 2 
in atrial, Purkinje, and ventricular cells 
• In SA and AV nodal cells, calcium entry through L-type channels represents the 
major ion flux during depolarization. 
c. Potassium Channel Blockade 
• Potassium channels, particularly the channel giving rise to the "delayed rectifier 
current", are activated during the repolarization (Phase 3) of the action potential. 
• Blockade of potassium channels prolongs action potential duration. 
o Prolongation of action potential duration usually results in an increase in 
effective refractory period 
d. Use (Rate)-Dependent Blockade by Channel Blockers 
• An ideal antiarrhythmic drug should target ectopic pacemakers and rapidly 
depolarizing tissue to a greater extent than normal tissues of the heart 
• Many of the sodium (Class I) and calcium (Class IV) channel blockers have this 
property because they preferentially block sodium and calcium channels in 
depolarized tissues (cf, Modulated Receptor Hypothesis in preceding lecture). 
• Enhanced sodium or calcium channel blockade in rapidly depolarizing tissue has 
been termed "use-dependent blockade" and is thought to be responsible for 
increased efficacy in slowing and converting tachycardias with minimal effects on 
tissues depolarizing at normal (sinus) rates 
• Many of the drugs that prolong repolarization (Class III drugs, potassium channel 
blockers) exhibit negative or reverse rate-dependence 
o These drugs have little effect on prolonging repolarization in rapidly 
depolarizing tissue 
o These drugs can cause prolongation of repolarization in slowly 
depolarizing tissue or following a long compensatory pause, leading to 
repolarization disturbances and torsades de pointes HST-151 8 
VI. Acute Treatement of VT: 
II & IV 
a. Lidocaine (50-75 mg bolus, 1-3 mg/min) 
b. Procainamide ( 500 mg – 1 g over 40-60 min, 1-4mg/min) 
c. Amidodarone (100 mg over 10 min, 1mg/min) 
d. Bretylium (300 mg over 1 hr, 1 mg/min) 
e. Magnesium sulfate 
f. DC cardioversion/defibrillation 
VII. Classification of SVT: 
a. Sinus tachycardia: 
i. Physiologic 
ii. Nonphysiologic: 
1. Inappropriate sinus tachycardia (IST) 
2. Sinus node reentry (SNR) 
b. AV Node independent (Atrial) 
i. PACs 
ii. Atrial tachycardia 
iii. Atrial flutter 
iv. Atrial fibrillation 
c. AV node dependent (junctional) 
i. AV node reentry 
ii. AV reentry 
d. Junctional ectopic tachycardia (JET) HST-151 
IX. Antiarrhythmic drug effects in SVT: 
a. AVN independent: 
i. Prevent/terminate tachycardia 
ii. Slow ventricular rate 
b. AVN depedendent: 
i. Prevent/terminate tachycardia 
X. Radiofrequency (RF) catheter ablation of left free wall accessory AV 
a. Radiofrequency (RF) catheter ablation has recently replaced surgical 
ablation in nearly all cases of ablation for cardiac arrhythmias. It is now a 
first-line therapy and highly effective in treating: 
V1 V1 
VIII. SVT : ECG correlation: HST-151 10 
i. Wolff-Parkinson-White syndrome 
ii. AV nodal reentry 
iii. Atrial ectopic tachycardia 
b. RF ablation is also useful in treating: 
i. Atrial fibrillation 
ii. Several types of monomorphic ventricular tachycardias 
XI. Clinical studies: 
a. Cardiac Arrhythmia Suppression Trial (CAST): encainide or flecainide vs 
placebo HST-151 11 
XII. Antiarrhythmic in structural HD (VT) 
a. Beta blocker 
b. Sotalol 
c. Amiodarone 
XIII. Non-pharmacological Therapy 
a. Surgery 
b. Catheter ablation 
c. Implantable cardioverter-defibrillator (ICD) 
XIV. Automatic implatable cardioverter/defibrillator devices (ICDs) therapy 
circa 1980: 
Large devices, abdominal site 
a. Thoracotomy, multiple incisions 
b. Long hospital stay 
c. General anesthesia 
d. Complication from major surgery 
e. Perioperative mortality up to 5% 
f. Nonprogrammable therapy 
g. High energy shock only 
h. Device longevity ~ 1.5 years 
i. Fewer than 1000 implants/year 
XV. ICD therapy present: 
a. Can now be implanted without thoracotomy
b. Current generation devices terminate arrhythmias by anticardiac pacing, 
cardioversion, and defibrillation 
c. Considered by some experts to be the therapy of first choice in patients 
with ventricular tachycardias based on a number of recent clinical trials 
comparing ICD therapy to antiarrhythmic drug therapy (both Class I and 
Class III drugs) 
d. A significant fraction of patients receiving an ICD may still require 
antiarrhythmic drug therapy to decrease the frequency of arrhythmic 
episodes (to prolong battery life) and to reduce the number of 
inappropriate (energy-consuming and painful) shocks. Improvements in 
ICD design may reduce or eliminate the need for concurrent drug therapy. 
XVI. Conclusions: 
a. Antiarrhythmic drugs are first line therapy for the acute management of 
most supraventricular and ventricular arrhythmias 
b. Catheter ablation is curative for most forms of recurrent SVTs HST-151 12 
c. Life threatening ventricular arrhythmias are best managed with ICDs and 
adjunctive drug therapy when necessary 
• It is often problematic to determine the best drug for a given patient due to the 
unknown etiology of many arrhythmias, patient-to-patient variability, and the 
multiple actions of many antiarrhythmic drugs. Three trial-and-error approaches 
are widely used: 
o Empiric. That is, based upon the clinician's past experience. 
o Serial drug testing guided by electrophysiological study (EPS). This 
invasive technique requires cardiac catheterization and induction of 
arrhythmias by programmed electrical stimulation of the heart, followed 
by a delivery of drugs to predict the most efficacious drug(s) to use for a 
given patient. 
o Drug testing guided by electrocardiographic monitoring (Holter 
monitoring). This noninvasive technique involves 24-hour recording of a 
patient's ECG before and during each drug treatment to predict optimal 
efficacy. The recent Electrophysiologic versus Electrocardiographic 
Monitoring (ESVEM) study concluded that there may not be any 
significant difference between the predictive value of this technique 
compared to programmed electrical stimulation. 
• Before beginning therapy: 
o Any factor that might predispose a patient to arrhythmias (electrolyte 
abnormalities, hypoxia, proarrhythmic drugs, underlying disease states) 
should be eliminated 
o A firm diagnosis should be made before beginning therapy and a baseline 
ECG should be established to monitor the efficacy of treatment 
• Monitoring during therapy should include: 
o Continuous and careful monitoring for efficacy and adverse effects 
o Monitoring plasma concentrations of drug, including free vs. proteinbound because of the narrow therapeutic index of most antiarrhythmic 
drugs HST-151 13 
Table 3. Drugs of Choice for Cardiac Arrhythmias (Adapted from The Medical Letter 
(1996) 38, 75-82) 
(Links point to 
Drug of Choice 
(Non-drug therapy) 
(Non-drug therapy) 
• (Cardioversion) 
• Verapamil, diltiazem, or 
beta-blocker to slow 
ventricular response 
• Digoxin to slow 
ventricular response 
• Class IA, IC drugs for 
long-term suppression 
• Ibutilide for termination 
• Low dose amiodarone for 
• Dofetilide for prevention 
• (RF ablation) 
• Adenosine, verapamil, or 
diltiazem for termination 
• (RF ablation) 
• Class II drugs or digoxin 
for termination 
• (Cardioversion or atrial 
• Class IA, IC, II, or IV 
drugs or digoxin for longterm suppression 
PVCs or nonsustained ventricular 
• No drug therapy for 
asymptomatic patients 
• Class II drugs for 
symptomatic patients 
Sustained ventricular 
• (Cardioversion or chest 
thump is the safest and 
most effective treatment) 
• Lidocaine for acute 
• Procainamide, bretylium 
or amiodarone for acute 
• Sotalol, amiodarone, Class 
IA, IB, II, III can be used 
for long-term suppression 
• (RF ablation or ICD) 
• (Defibrillation is 
treatment of choice) 
• Amiodarone, 
procainamide or bretylium HST-151 14 
• Lidocaine to prevent 
to prevent recurrence 
• (RF ablation or ICD) 
• Digibind for lifethreatening toxicity 
• Lidocaine 
• Phenytoin 
• Avoid cardioversion 
except for ventricular 
• Potassium (if 
Torsades de pointes • Magnesium sulfate 
• Remove causative agents 
• Isoproterenol 
• Potassium (if 
• (Cardiac pacing) 
Table 4. Relative Efficacies of Antiarrhythmic Drugs by Class (Adapted from 
Melmon and Morelli, 3rd ed.) 
Drug Class Efficacy 
IA Atrial fibrillation 
Ventricular arrhythmias 
IB Ventricular arrhythmias 
AV nodal reentry 
WPW-related arrhythmias 
Ventricular arrhythmias (can increase mortality despite suppressing PVCs) 
II Atrial fibrillation/flutter 
(Ventricular arrhythmias) 
III Atrial fibrillation/flutter 
Ventricular arrhythmias 
IV Atrial fibrillation/flutter 
Atrial automaticities HST-151 15 
AV nodal reentry 
Adenosine AV nodal reentry 
Orthodromic tachycardia 
Digitalis AV nodal reentry 
Atrial fibrillation/flutter 
Magnesium Torsades de pointes 
Table 5. Adverse Extra-Cardiac Effects of Selected Antiarrhythmic Drugs (Adapted 
from The Medical Letter 33:55-60 and Katzung, 8th ed.) 
Drug (Class) Adverse Extra-Cardiac Effects and Toxicities 
Quinidine (IA) 
• GI disturbances in 30-50% of patients: diarrhea, nausea, 
• Cinchonism 
• Hypotension (due to alpha-adrenergic blocking activities) 
• Can elevate serum digoxin concentrations, resulting in digitalis 
• Hypersensitivity reactions: rashes, fever, angioneurotic edema, 
• Reversible thrombocytopenia 
• Hypotension (due to ganglionic blocking activity) 
• Long-term use results in a lupus-like syndrome in 15-30% of 
patients consisting of arthralgia and arthritis (pleuritis, 
pericarditis, parenchymal pulmonary disease also occur in some 
• GI symptoms in 10% of patients 
• Adverse CNS effects: giddiness, psychosis, depression, 
• Hypersensitivity reactions: fever, agranulocytosis (can lead to 
fatal infections), Raynaud's syndrome, myalgias, skin rashes, 
digital vasculitis 
Lidocaine (IB) • Lowest incidence of toxicity of currently used antiarrhythmic HST-151 16 
• CNS depression: drowsiness, disorientation, slurred speech, 
respiratory depression, nausea 
• CNS stimulation: tinnitus, muscle twitching, psychosis, seizures 
• Concurrent use of tocainide or mexiletine can cause additive 
CNS toxicity, including seizures (seizures respond to i.v. 
Tocainide (IB) 
Mexiletine (IB) 
• GI effects: nausea, vomiting 
• CNS effects: dizziness, disorientation, tremor 
• Hematological effects (0.2%) with tocainide: agranulocytosis, 
bone marrow suppression, thrombocytopenia; can lead to death 
• Concurrent use of either of these drugs and quinidine in 
combination may be effective at lower doses than either drug 
alone and thereby minimize adverse effects of both drugs 
Flecainide (IC) 
• CNS effects in 10-15% of patients: dizziness, tremor, agitation, 
headache, visual disturbances 
• GI upset 
• Although this drug is highly effective in treating many 
arrhythmias, its large number adverse effects limits its clinical 
• Adverse effects are common (more than 75% of patients 
receiving drug) and increase after a year of treatment; some 
toxicities result in death 
• Half-life of 25-110 days can prolong toxicity 
• Pulmonary toxicity and fibrosis (10-15%, can cause death in 
10% of those affected); can be irreversible 
• Constipation in 20% of patients) 
• Hepatic dysfunction; can be irreversible 
• Asymptomatic corneal deposits occur in all patients 
• CNS effects (ataxia, dizziness, depression, nightmares, 
• Hypothyroidism or hyperthyroidism (5% of patients) HST-151 17 
• Cutaneous photosensitivity (25% of patients) and blue-grey 
discoloration of skin (less than 5% of patients) 
• Peripheral neuropathy 
• Substantial increases in LDL-cholesterol concentrations often 
seen; phospholipidosis 
• Enhances the effect of warfarin and increases the serum 
concentrations of digoxin, quinidine, procainamide, flecainide, 
theophylline and other drugs 
Digitalis (Misc.) 
• Many adverse non-cardiac effects (anorexia, nausea, vomiting, 
diarrhea, abdominal pain, headache, confusion, abnormal vision) 
• Adverse effects may indicate digitalis toxicity 
• Short half-life in blood (less than 10 seconds) 
• Causes hypotension, flushing in 20% of patients 
• Transient dyspnea, chest discomfort (non-myocardial) in > 10% 
• Metallic taste 
• Headache, hypotension, nausea, paresthesias are less common 
Recommended Reading 
• Katzung (8th ed.) Chapt. 14 or 
• Goodman & Gilman (9th ed.), Chapt. 35 
Supplemental Reading 
o "Antiarrhythmics-from cell to clinic: past, present, and future," Heart 
84:14-24 (2000) 
o Symposium Proceedings: "Changing Trends in Antiarrhythmic Therapy," 
Am. J. Cardiol. (1997) 80(8A):1G-104G 
ƒ "Controlling cardiac arrhythmias: an overview with a historical 
perspective," Am J Cardiol. (1997) 80(8A): 4G-15G. Review. 
o "Drugs for cardiac arrhythmias," The Medical Letter (1996), 38: 75-82 
o Clinical Pharmacology (Melmon & Morrelli) (3rd ed.) Chapt. 6