Edward JN Ishac, Ph.D.
Professor, Pharmacology and Toxicology
Smith 742, 828-2127, e-mail: eishac@vcu.edu
OBJECTIVES
1.
Understand how, in general antidysrhythmic drugs suppress electrical disorders that result from problems in cardiac impulse generation or conduction
2.
Recognize how drugs differentially suppress firing in abnormal vs. normal cardiac tisssue
3.
Recognize concept of state dependent drug action and it’s significance for antidysrhythmic action
4.
Recall the Vaughan-Williams classification of antidysrhythmic drugs and its limitations
5.
Be able to cite prototype drugs from each of the four Vaughan-Williams classes.
6.
Understand the mechanism of action/electrophysiological effects, autonomic effects, pharmacokinetic effects, toxicity and non-cardiac actions of the prototype drugs.
7.
Know names of each non-prototype and uniqueness of each one.
8.
Understand representative clinical uses of each class.
I. a.
Brief review of physiological concepts:
The heart contains specialized cells that exhibit automaticity, ie. generate rhythmic action potentials in the absence of external stimuli (sino-atrial node, AV node). Optimal mechanical performance requires well-synchronized repetitive electrical activity Fig. 1).
Figure 1.

c. d.
Dr. Ishac b.
Antidysrhythmic Agents 2
The response of cells to excitatory electrical stimuli is a function of the number of available sodium (Na) channels. An index of the number of open Na channels is dV/dt (of
Phase 0) of the cardiac action potential (AP).
Abnormal heart tissue is usually depolarized, which reduces Na current, decreases dV/Dt and decreases conduction velocity.
Voltage-dependent Na channel availability results from Voltage (Vm) -dependent Na channel states. Recovery time of Na channels from excitation/depolarization strongly contributes to the refractory period and is increased by many drugs (See Fig 2).
Figure 2: What this means:
1. Conduction in damaged/abnormal heart tissue is decreased
2. Antidysrhythmics work better on Na channels in depolarized cells and decrease recovery.
II. Characteristics of dysrhythmias
1.
2. normal sinus rhythm (60-100bpm), controlled by SA node pacemaker arrhythmia; any abnormality of firing rate, regularity or site of origin of cardiac impulse or disturbance of conduction that alters normal sequence of activity of atria and ventricles.
Classification of dysrhythmias, characteristic or sites involved:
1. characteristics:
2. a. b. c. flutter – very rapid but regular depolarizations tachycardia – increased rate bradycardia – decreased rate d. fibrillation – disorganized depolarization activity sites involved: a. b. ventricular atrial c.
sinus d.
AV node e.
Supraventricular (atrial myocardium or AV node)

Dr. Ishac Antidysrhythmic Agents
Schematic diagram of ion permeability
3

Dr. Ishac Antidysrhythmic Agents
III. Mechanisms of arrhythmias
1. Abnormal impulse generation (abnormal automaticity) a. b. automaticity of normally automatic cells (SA, AV, His) generation of impulses in normally non-automatic cells i.
phase 4 depolarization in normally non-automatic cells ii.
‘triggered activity’ due to afterdepolarizations
early afterdepolariztion (EADs)
delayed afterdepolarization (DADs)
4
2.
Abnormal impulse conduction (more common dysrhythmia mechanism)
- damaged tissue usually depolarized
 
conduction velocity a. AV block – ventricle free to start own pacemaker rhythm b. Re-entry: re-excitation around a conducting loop, which produces tachycardia i.
unidirectional conduction block ii.
establishment of new loop of excitation iii.
conduction time that outlasts refractory period
IV. General strategy of antidysrhythmic drugs
Suppression of dysrhythmias
A. Alter automaticity (usually want to decrease) i. decrease slope of Phase 4 depolarization ii. increase the threshold potential iii. decrease resting (maximum diastolic) potential
B. Alter conduction velocity (usually want to decrease) i. mainly via decrease slope of Phase 0 upstroke ii. decrease rate of rise of Phase 4 depolarization ii. decrease membrane resting potential and responsiveness

Dr. Ishac Antidysrhythmic Agents
C. Alter the refractory period (usually want to increase) i. increase Phase 2 plateau ii. increase Phase 3 repolarization iii. Increase action potential duration
IV. Classification of Antidysrhythmic Drugs
A. Vaughan-Williams classification (1970), subsequently modified by Harrison.
1.
2.
3.
4. based on the pattern of electrophysiological actions in normal tissue presumes a mechanism of action of antidysrhythmic drugs consists of four main classes and three subclasses does not include agents (ie. Adenosine, digoxin) that act at other sites
Table 1. Class I - directly block Na channels. All behave like local anaesthetics.
Subclasses based on differing effects on AP duration (APD) and degree of Na channel block (Phase 0).
Subclass
IA
IB
IC
.
.
.
Class II
Others
Class III
Class IV
Mechanism
Na channel blockers
Moderate block Ph.0; slow conduction; increase APD
Na channel blockers
Minimal block Ph 0; slow conduction; shorten phase 3 repolarization, decrease APD
Na channel blockers
Marked block Ph.0; slow conduction.; no change APD or repolarization. Increased suppression of Na channels
Beta blockers decrease adrenergic input . No effect APD, suppress phase 4 depolarization, slow conduction.
K channel blockade
Prolong repolarization/refractory period other means than exclusively INa block (mainly K channel blockade),
↑
QT.
Ca channel blockers
Slow conduction and increase effective refractory period in normal tissue (A-V node) and Ca-dependent slow responses of depolarized tissue (atria, ventricle, Purkinje)
Adenosine, Digoxin, Mg and K ions
Examples
Quinidine
Procainamide
Lidocaine
Tocainide
Phenytoin
Flecainide
Encainide
Propranolol
Metoprolol
Sotalol
Esmolol
Amiodarone
Sotalol
Ibutilide
Bretylium
Verapamil
Diltiazem
Nifedipine
VW table
Not part of
5

Dr. Ishac Antidysrhythmic Agents 6
B. Cardiac Membrane Effects of Antiarrhythmic Drugs
Drug
Quinidine
Procainamide
IA
IA
+
+
Na-Block
N Dep N
RP
Dep
++
+++
↑
↑
↑↑
↑↑↑
Ca
Block
Pacemaker activity
0
0
↓↓
↓
Disopyramide
Lidocaine
Phenytoin
Mexiletine
Flecainide
Propafenone
Propranolol
Metoprolol
Esmolol
Sotalol
Amiodarone
Ibutilide
Verapamil
Diltazem
Digitalis
Adenosine
IV
IV
II
II/III
III
III
IC
IC
II
II
IA
IB
IB
IB
+++
++
+
+
+++
+++
+
+++
↑
↓
+
0
+
0
0
↑↑
+++ ↑↑
0 ↑
0
0
↓
↓
0
↑
↓
0
↑
↓
0
0
+
0
0
0
0
0
+
+
0
0
+
0
↓
↓
↑
0
↑↑↑
↑↑
↑
↑↑
↑↑
↑↑
↑↑
↑↑
↓
↑↑
+++
+++
↓ ↑
↑
+
0
0
0
0
0
0
+
0
0
+
0
↓↓
↓↓
↓ ↑
↑
↓↓
↓↓
↓↓
0
0
↓↓
↓↓
↓↓
↓
↓↓
↓↓
↓↓
ANS effects
M-block,  -block
M-block,  -block
M-block,  -block
 -block
 -block
 -block
 -block
 -,  -block vagal stimulation
N = Normal cells, Dep = Depolarized cells, RP = Refractory Period
C. Shortcomings of Vaughan-Williams system (V-W):
1.
The classification (excluding Class II) is mainly based on drugs which modify the electrophysiological characteristics of normal cardiac tissue. In diseased tissue, where dysrhythmias are more likely to occur, channels and receptors, and their responses to drugs, are modified.
2.
V-W is incomplete, and does not include adenosine, digitalis, cholinergic agonists, alpha adrenergic blockers or agents that modulate gap junctions, ion pumps or exchangers. It also ignores actions of metabolites of the drugs.
3.
Some drugs have properties of several classes (amiodarone, for example, has properties of classes I-IV).

Dr. Ishac Antidysrhythmic Agents 7
V.
Key Aspects of Antidysrhythmic Drug Action and Therapy a.
Antidysrhythmic drug action is state-dependent ; drug effects depend on the molecular states of the channel (i.e. open, closed, or inactivated). Two current models: a.
modulated receptor hypothesis: different states have different affinities b.
guarded receptor hypothesis: channel gate limits drug access to site b.
Dysrhythmic drugs selectively affect firing and CV in abnormal/depolarized cells.. c.
Since transitions between different states are dependent on membrane voltage and cell firing frequency, drug action is also dependent on membrane voltage and spike frequency . In addition, by binding to inactivated states and slowing recovery from inactivation, some drugs can increase the time needed for recovery from inactivation.
d.
Can be prodysrhythmic under certain circumstances e.
May have significant cardiac and extracardiac toxicity; many Class 1A drugs, for example, can seriously depress cardiac contractility directly by acting on heart muscle f.
often affect the autonomic nervous system , and have hemodynamic effects and effects on cardiovascular reflexes
D.
Antidysrhythmic drugs also selectively affect different parts of the heart
1.
Ca channel blockers (Class IV) are selective for A-V and S-A nodes, where Ca action potentials predominate. This explains why Class IV drugs are so useful for treating
A-V re-entrant tachycardias for example.
2.
Lidocaine (Class IB) has been useful for treating PVCs in Purkinje fibers, since longer
APDs in Purkinje yield more inactivated Na channels. Lidocaine selectively blocks inactivated state Na channels. Lidocaine has little effect, in constrast, on atrial tissue.
3.
Quinidine affects both atrial and ventricular dysrhythmias (but has been mostly used to treat atrial fibrillation).

Dr. Ishac Antidysrhythmic Agents
DRUGS USED FOR DYSRHYTHMIAS
I.
Specific examples of drugs from each Vaughan-Williams class and their key aspects
A. Quinidine (Class IA prototype; others: Procainamide, Disopyrimide)
1. General properties: a. b. c. use decreasing, significant side effects an alkaloid, D-isomer active
As with most of the Class I agents
- moderate block of sodium channels
- decreases automaticity of pacemaker cells
- increases effective refractory period/AP duration
8
2.
3.
Cardiac effects of quinidine a. b. c. d. e. f.
Decreases automaticity, conduction velocity and excitability
Preferentially blocks open Na channels
Recovery from block slow in depolarized tissue; lengthens refractory period
All effects are potentiated in depolarized tissues
Increases action potential duration (APD) and prolongs AP repolarization via block of K channels; decreases reentry,
↑
QT
Indirect action: anticholinergic effect (accelerates heart), which can speed A-V conduction.
Extracardiac a. b. blocks alpha-adrenoreceptors to yield vasodilatation. blocks muscarinic receptors (ie. blurred vision, dilated pupils)

Dr. Ishac Antidysrhythmic Agents
4.
5.
Adverse Effects/Toxicity a. b.
Cardiac
- "Quinidine syncope"(fainting)- due to disorganized ventricular tachycardia
- associated with greatly lengthened Q-T interval; can lead to
Torsades de Pointes (TdP, precursor to ventricular fibrillation)
- negative inotropic action (decreases contractility)
Extracardiac
- GI - diarrhea, vomiting
- CNS - headaches, nausea, dizziness, tinnitus (quinidine
“Cinchonism”)
Pharmacokinetics/therapeutics a. b.
Oral, rapidly absorbed, 80% bound to membrane proteins
Hydroxylated in liver; T
1/2
= 6-8 h c. d. e. f.
Drug interaction: displaces digoxin from binding sites
Some active metabolites of quinidine
Effective in treatment of nearly all dysrhythmias, including:
Useful in chronic dysrhythmias requiring outpatient treatment
B. Procainamide (Class 1A)
1. Cardiac effects a b.
Very similar to quinidine in general but less blockade of muscarinic and adrenergic receptors.
Has negative inotropic action
2. Extracardiac effects a. Ganglionic blocking reduces peripheral vascular resistance
3. Toxicity a. b.
Cardiac: Similar to quinidine; cardiac depression
Syndrome resembling lupus erythematosus (inflammatory disease, reversible, significant with long-term therapy)
4. Pharmacokinetics/therapeutics a. b. c. d.
Administered orally, I-V
Major liver metabolite is N-acetylprocainamide (NAPA), a weak
Na+ channel blocker with class III activity. Bimodal distribution in population of rapid acetylators, accumulate high levels of
NAPA.
T
1/2
= 3-4 hours; necessitates frequent dosing; kidney chief elimination path. NAPA has longer T
1/2 and accumulates readily.
Usually used short-term.
9

Dr. Ishac Antidysrhythmic Agents
C. Lidocaine (Class IB prototype; other Phenytoin, Tocainide, Mexiletine) a. c. d.
Given I-V; (previous ICU “Drug of Choice”).
Very low toxicity, good therapeutic index
A local anesthetic, works on nerve at higher doses.
10
2.
3.
4.
Cardiac effects a. b. c. d.
Generally decreases APD, hastens AP repolarization, decreases automaticity and increases refractory period in depolarized cells.
Exclusively acts on Na channels in depolarized tissue by blocking open and inactivated Na channels
Potent suppresser of abnormal activity
Most Na channels of normal cells rapidly unblock from lidocaine during diastole; few electrophysiological effects in normal tissue
Toxicity: - least cardiotoxic, high dose can lead to hypotension
- tremors, nausea, slurred speech, CNS stimulation & convulsions
Pharmacokinetics/therapy a.
Usually given I-V, since extensive first pass hepatic metabolism b.
T1/2 = 0.5-4 hours; rapid onset and short duration of action. c.
Very effective in suppressing dysrhythmia associated with depolarized tissue (ischemia; digitalis toxicity); ineffective against dysrhythmias in normal tissue d.
Suppresses ventricular dysrhythmias; prevents ventricular fibrillation after acute MI; rarely used in supraventricular arrythmias. Generally second line therapy that is refractory

Dr. Ishac Antidysrhythmic Agents 11
D. Phenytoin (Class IB)
5.
6.
7.
1.
2.
3.
4.
Non-sedative anticonvulsant used in treating epilepsy
Limited efficacy as antidysrhythmic (second line antiarrythmic)
Suppresses ectopic activation by blocking Na and Ca channels
Especially effective against digitalis-induced dysrhythmias
T
1/2
= 24 hr - metabolized in liver
Use associated with gingival hyperplasia
Pregnancy Category D; Use not recommended
E. Flecainide (Class IC prototype)
Other examples: Lorcainide, Propafenone , Indecainide, Moricizine. Depress rate of rise of AP without change in refractoriness or APD in normally polarized cells
1.
Decreases automaticity and conduction in depolarized cells.
2.
Marked block of open Na channels (decreases Ph. 0); little or no change in repolarization.
3.
Relatively new compared to other antidysrhythmics
4.
Used primarily for ventricular dysrhythmias, but effective for atrial and supraventricular arrythmias, and prevention of atrial fibrillation/flutter.
5.
No antimuscarinic action
6.
Suppresses premature ventricular contractions
7.
Associated with significant mortality (CAST study); marked tendency to exacerbate or precipitate dysrhythmias. Thus, use limited to last resort applications like treating ventricular tachycardias.
8.
Significantly negative inotropic effect.

Dr. Ishac Antidysrhythmic Agents 12
F. Propranolol (Class II, beta adrenoreceptor blockers; other examples: esmolol, sotalol , acebutolol; metoprolol (beta-1 blocker); or carvedilol (alpha- and beta-blocker).
- Beta blockers are now often the drugs of choice for rate control, along with Ca channel blockers for supraventricular tachycardias.
- Generally beta-blockers with partial agonist (ISA) ie Pindolol are not used
1. General properties of all Class II agents: a. b. c.
Slow A-V conduction
Prolong A-V refractory period
Suppress automaticity
2. Cardiac effects (of propranolol), a non-selective beta blocker a. b. c. d. e.
Main mechanism of action is block of beta receptors;

Ph 4 slope. which decreases automaticity under certain conditions
Some direct local anesthetic effect by block of Na channels
(membrane stabilization)-at higher doses
Increases refractory period in depolarized tissues
Increases K channel current
Increases A-V nodal refractory period
3.
4.
Non-cardiac: Hypotension
Therapeutics a. b. c. d. e.
Blocks abnormal pacemakers in cells receiving excess catecholamines (e.g. pheochromocytoma) or having up-regulated betas (thyroid disorder)
Blocks A-V nodal reentrant tachycardias
Beta-blockers are used to treat supraventricular tachydysrhythmias; objective to slow the ventricular rate by beta affects on A-V conduction rather than abolish dysrhythmias.
Propranolol is contraindicated in patients with ventricular failure; can lead to A-V block.
Oral (propranolol) or IV. Extensive metabolism in liver.

Dr. Ishac Antidysrhythmic Agents
G. Amiodarone (Class III; others : Ibutilide, Bretylium, Sotalol, Dronedarone
Dofetilide )
1.
General a.
A Class III drug which prolongs refractory period by blocking potassium channels; structural analog of thyroid hormone which interacts with nuclear thyroid hormone receptors; contains iodine, very lipophilic. b.
Also member of Classes IA, II, III, IV since blocks Na, K, Ca channels and alpha and beta adrenergic receptors c.
Dronedarone ( ↓ adverse effects?) similar to Amiodarone, approved Jul 2009. d.
Among most widely used and effective dysrhythmic agents.
13
2.
Cardiac effects: a.
Block Na channels, but low affinity for open channels; mainly blocks inactivated Na channels b.
Block most pronounced in tissue with long APs or more depolarized diastolic potential c.
Weak Ca channel blocker also (Class IV activity) d.
A powerful inhibitor of abnormal automaticity, decreases conduction, increases refractory period and APD, increases QT interval e.
Has antianginal effects (blocks alpha/beta receptors and Ca channels)
3.
Extracardiac effects: Vasodilation via block of Ca channels and alpha receptors
4.
Adverse Effects: a.
Cardiac i.
Sinus bradycardia ii.
Negative inotropic action due to block of Ca channels and beta receptors; but can improve heart failure via vasodilation. iii.
A-V block, paradoxical VTs., ↑ QT interval

Dr. Ishac Antidysrhythmic Agents 14 b.
Non-cardiac: i.
Deposits into almost every organ ii.
Reduces clearance of drugs like procainamide, flecainide, digitalis, quinidine and diltiazem. iii.
Thyroid dysfunction (hypo or hyperthyroidism), contains iodine iv.
Pulmonary fibrosis is most serious adverse effect v.
Paresthesias (tingling, pricking, or numbness, “pins and needles”) vi.
Photosensitivity vii.
Corneal microdeposits and blurred vision viii.
Ataxia, dizziness, tremor ix.
Anorexia, nausea
5.
Pharmacokinetics and therapeutics a.
T1/2 = 13-103 days (weeks) very long for one dose; very lipid soluble; metabolized in liver. Dronedarone 24 hrs (does not contain iodine)) b.
Effective against many arrythmias: atrial, A-V and ventricular dysrhythmias; prevention of atrial fibrillation/flutter; PVCs, nonsustained and sustained VTs. c.
There exist multiple interactions with other drugs such as: i. Amiodarone is a CYP3A4 substrate and inhibitor and thus may enhance the effect of other CYP3A4 substrates eg. Warfarin , Simvastatin, Verapamil ii. Amiodarone may increase the serum concentration of Cardiac Glycosides
H.
3.
4.
Bretylium (Class III, K channel blockers; others ibutilide )
1. General: originally used as an antihypertensive agent, availability limited
2. Cardiac effects a. b. c. d. e.
Direct antidysrhythmic action
Increases ventricular APD and increases refractory period; decreases automaticity
Most pronounced action in ischemic cells having short APD
Initially stimulates and then blocks neuronal catecholamine release from adrenergic nerve terminals
Blocks cardiac K channels to increased APD.
Extracardiac effects: Hypotension (from block of NE release)
Pharmacokinetics/therapeutics a. b. c. d.
IV or intramuscular
Excreted mainly by the kidney
Usually emergency use only: ventricular fibrillation. Increases threshold for fibrillation.
Decreases tachycardias and early extrasystoles by increasing effective refractory period

Dr. Ishac Antidysrhythmic Agents 15
I. Ibutilide (Class III. ). Also Dofetilide
1.
↑ APD. Mechanism incompletely understood but it known to increase inward Na current and decrease repolarizing K current in cardiac cells.
2.
Can be administered I-V. Most effective current agent to convert atrial fibrillation and flutter of recent onset to normal rhythm. Low incidence of Torsades (about
2%), compared to other drugs.
3.
More effective for atrial flutter than fibrillation
4.
Generally well tolerated
J.
5.
Dofetilide (atrial flutter and fibrillation)
Sotalol (Class III and Class II)
1. Non-selective beta blocker, also increases action potential duration.
2. Increases APD, ↑ QT interval
3. Used for dysrhythmias of supraventricular and ventricular origin
K. Verapamil (Class IV, Ca channel blockers; other eg. Diltiazem)
1. a. b. c. d. e.
Cardiac
Block active and inactivated L-type Ca channels, prevents Ca entry
More effective on depolarized tissue, tissue firing frequently or areas where activity dependent on Ca channels (SA node; A-V node)
Increases A-V conduction time and refractory period; directly slows SA and A-V node automaticity suppresses oscillatory depolarizing after depolarizations due to digitalis
Note that dihydropyridine (DHPs) Ca channel blockers (ie. Nifedipine) are poor antiarrythmics

Dr. Ishac Antidysrhythmic Agents 16
2. Extracardiac a. Peripheral vasodilatation via effect on smooth muscle b. c.
Used as antianginal, antihypertensive
Hypotension may increase HR reflexively, more likely with DHPs.
3. Toxicity a.
Cardiac i.
Negative inotropic for damaged heart, depresses contractility ii.
Can produce complete A-V block b.
Extracardiac
4. i.
Hypotension ii.
Constipation iii.
Nervousness
Pharmacokinetics/Therapeutics a. T1/2 = 7h, b. Metabolized by liver c.
Oral administration; also available parenterally d.
Great caution for patients with liver disease e.
Decrease reentrant supraventricular tachycardia (decrease A-V node conduction), decreases atrial flutter and fibrillation f.
Only moderately effective against ventricular arrythmias g.
Can inhibit oscillatory depolarizing afterdepolarizations due to digitalis toxicity
II.
Examples of antidysrhythmic agents that do not fit the Vaughan-Williams classification
A.
Adenosine
1.
Activates P1 purinergic receptors (subtype A1) coupled to cardiac K channels, especially in nodal tissue.
2.
Given as IV bolus to quickly slow conduction in A-V node and increase A-V refractory period. Decreases the rate of discharge of pacemaker cells.
3.
Effective in slowing or abolishing A-V nodal re-entry, may also produce a period of asystole.
4.
T1/2 very brief, 15 seconds; rapid elimination of the drug
5.
Toxicity a.
Flushing (due to vasodilation) b.
Hypotension c.
Shortness of breath or burning sensation in chest

Dr. Ishac Antidysrhythmic Agents 17
B.
Potassium ions (K+)
1.
Depress ectopic pacemakers
2.
Can suppress hypokalemia-induced dysrhythmias
3.
Toxicity a.
Cardiac i.
Can depress conduction ii.
Can lead to reentrant dysrhythmias
C.
Digoxin
1.
Used to treat atrial flutter and fibrillation, since it slows ventricular responses by slowing A-V node conduction; vagomimetic. Digoxin can also itself produce VTs, which can be treated with digoxin antibodies (first line) or drugs such as phenytoin or lidocaine.
D.
Mg: Used to treat Torsades de pointes, plus overdrive pacing if needed.
E.
Autonomic agents : Beta-agonists (ie. Isoproterenol)), anticholinergics (Atropine), used to treat AV block
III.
Current Drugs of Choice for Treatment of Some Dysrhythmias (see also Figure IX.
Dysrhythmics treatment summary:
This is a complex and advanced clinical issue and must be individualized to the patient and the situation
IV.
Drug interactions involving antidysrhythmics
A.
These drugs must be used very carefully
B.
Sometimes interactions can be counter-intuitive
V.
Problems with selecting drugs
A.
Do not always know the cause of the dysrhythmia, thus what to treat?
B.
Multiple mechanisms of dysrhythmogenesis
C.
Drugs are both anti- and pro-dysrhythmias
D.
Drugs do not really fix the damage; usually they restore function by breaking something else
VI. Important considerations for treating Dysrrhythmias
1.
2.
Acute vs chronic treatment
Ventricular vs supraventricular

Dr. Ishac Antidysrhythmic Agents
VII. Summary of Effects of Antiarrhythmic Drugs
Drug
Quindine
Procainamide
Disopyramide
Lidocaine
Phenytoin
Tocainide
Mexiletine
Flecainide
Propafenone
Propranolol
Acebutolol
Esmolol
Class Auto
IA ↓
IA
IA
IB
IB
IB
IB
IC
IC
II
II
II
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
CV
0
0
0
↓
↓
↓
↓
↓
↓
↓
↓
0
RP
↑
↑
↑
↓
↓
Sotalol
Amiodarone
Bretylium
Verapamil
Diltiazem
Digitalis
Adenosine
II/III
III
III
IV
IV
↓
↓
↓ ↑
↓
↓
↑
↓
↓
↓
0
↓
↓
↓
↓
↑
↑↑
↑↑
↑
↑
↓ ↑
↑
↓
↓
↑
↑
↓
↓
↓
APD
↑
↑
↑
↓
↓
↓
↓
0
0
↓
↓
↓
↑
↑↑
↑↑
↑
↑
↓ ↑
↑
ANS effects vagal,

-block vagal,

-block vagal,

-block

-block

-block

-block

-block

-,

-block sympatholytic vagal stimulation
VIII. Summary of Pharmacokinetic Properties of Antiarrhythmic Drugs
Drug
Quindine
Procainamide
Disopyramide
Class
IA
IA
IA
Plasma Binding
%
60
15
39-95
T
1/2
(hrs)
6
4
5
Drug
Excretion
Unchanged
20-40%
60%
50-70%
Lidocaine
Tocainide
Mexiletine
Flecainide
Propafenone
IB
IB
IB
IC
IC
II
40
10
65
45
85
90
2
14
12
15
5
4
<10%
40%
10%
40%
<1%
<1% Propranolol
Acebutolol
Esmolol
II
II
II/III
25
(esterase)
3
9 min
9
40%
<1%
80% Sotalol
Amiodarone
Bretylium
Verapamil
Adenosine
III
III
IV
95
5
90
25 days
9
5
15 secs
<1%
80%
2%
18

Dr. Ishac Antidysrhythmic Agents
IX. Dysrhythmics treatment summary:
19
X. Recommended :
1. Basic and Clinical Pharmacology, B.G. Katzung, 11th ed., 2009, pp. 225-249.
2. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Hardman and
Limbird, 11th ed., 2005, pp. 899-932.