Download dysrhythmics

Cardiovascular Pharmacology - Antidysrhythmic Drugs
Edward JN Ishac, Ph.D.
Professor, Pharmacology and Toxicology
Smith 742, 828-2127, e-mail: [email protected]
OBJECTIVES
1.
2.
3.
4.
5.
6.
7.
8.
I.
a.
Understand how, in general antidysrhythmic drugs suppress electrical disorders that result
from problems in cardiac impulse generation or conduction
Recognize how drugs differentially suppress firing in abnormal vs. normal cardiac tisssue
Recognize concept of state dependent drug action and it’s significance for
antidysrhythmic action
Recall the Vaughan-Williams classification of antidysrhythmic drugs and its limitations
Be able to cite prototype drugs from each of the four Vaughan-Williams classes.
Understand the mechanism of action/electrophysiological effects, autonomic effects,
pharmacokinetic effects, toxicity and non-cardiac actions of the prototype drugs.
Know names of each non-prototype and uniqueness of each one.
Understand representative clinical uses of each class.
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.
Sino-atrial node (SA) sets the pace (ie. pace maker) for the electrical activity of the heart
Dr. Ishac
Antidysrhythmic Agents
2
d.
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).
d.
Abnormal heart tissue is usually depolarized, which reduces Na current, decreases dV/Dt
and decreases conduction velocity.
e.
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), set 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:
a.
b.
c.
d.
2.
flutter – very rapid but regular depolarizations
tachycardia – increased rate
bradycardia – decreased rate
fibrillation – disorganized depolarization activity
sites involved:
a.
b.
c.
d.
e.
ventricular
atrial
sinus
AV node
Supraventricular (atrial myocardium or AV node)
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Antidysrhythmic Agents
Schematic diagram of ion permeability
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Dr. Ishac
III.
Antidysrhythmic Agents
Mechanisms of arrhythmias
1.
Abnormal impulse generation (abnormal automaticity)
a.
automaticity of normally automatic cells (SA, AV, His)
b.
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)
2.
Abnormal impulse conduction (more common mechanism)
- damaged tissue usually depolarized   conduction velocity
a.
b.
AV block – ventricle free to start own pacemaker rhythm
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
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Antidysrhythmic Agents
C.
IV.
5
Alter the refractory period (usually want to increase)
i.
increase Phase 2 plateau
ii.
increase Phase 3 repolarization
iii.
Increase action potential duration
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
Mechanism
Examples
IA.
Na channel blockers
Moderate block Ph.0; slow conduction; increase APD
Quinidine
Procainamide
IB.
Na channel blockers
Minimal block Ph 0; slow conduction; shorten phase 3
repolarization, decrease APD
Lidocaine
Tocainide
Phenytoin
IC.
Na channel blockers
Marked block Ph.0; slow conduction.; no change APD or
repolarization. Increased suppression of Na channels
Flecainide
Encainide
Class II
Beta blockers
decrease adrenergic input . No effect APD, suppress
phase 4 depolarization, slow conduction.
Class III
K channel blockade
Prolong repolarization/refractory period other means than
exclusively INa block (mainly K channel blockade), ↑QT.
Class IV
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)
Verapamil
Diltiazem
Nifedipine
Adenosine, Digoxin, Mg and K ions
Not part of
VW table
Others
Propranolol
Metoprolol
Sotalol
others
Amiodarone
Sotalol
Bretylium
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Antidysrhythmic Agents
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B. 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).
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.
2.
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
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.
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Dr. Ishac
Antidysrhythmic Agents
3.
Extracardiac
a.
b.
4.
8
blocks alpha-adrenoreceptors to yield vasodilatation.
blocks muscarinic receptors (ie. blurred vision, dilated pupils)
Adverse Effects/Toxicity
a.
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)
b.
Extracardiac
- GI - diarrhea, vomiting
- CNS - headaches, nausea, dizziness, tinnitus (quinidine
“Cinchonism”)
5.
Pharmacokinetics/therapeutics
a.
b.
c.
d.
e.
Oral, rapidly absorbed, 80% bound to membrane proteins
Hydroxylated in liver; T1/2 = 6-8 h
Drug interaction: displaces digoxin from binding sites
Some active metabolites of quinidine
Effective in treatment of nearly all dysrhythmias, including:
1)
Premature atrial contractions
2)
Paroxysmal atrial fibrillation and flutter
3)
Intra-atrial and A-V nodal reentrant dysrhythmias
4)
Wolff-Parkinson-White tachycardias (short PR, long QRS)
5)
PVCs, nonsustained VTs
f.
Useful in chronic dysrhythmias requiring outpatient treatment
Dr. Ishac
B.
Antidysrhythmic Agents
Procainamide (Class 1A)
1.
Cardiac effects
a
b.
2.
3.
Ganglionic blocking reduces peripheral vascular resistance
Toxicity
a.
b.
4.
Very similar to quinidine in general but less blockade of
muscarinic and adrenergic receptors.
Has negative inotropic action
Extracardiac effects
a.
Cardiac: Similar to quinidine; cardiac depression
Syndrome resembling lupus erythematosus (inflammatory disease,
reversible, significiant with long-term therapy)
Pharmacokinetics/therapeutics
a.
b.
c.
d.
C.
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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.
T1/2 = 3-4 hours; necessitates frequent dosing; kidney chief
elimination path. NAPA has longer T1/2 and accumulates readily.
Usually used short-term.
Lidocaine (Class IB prototype; other Phenytoin, Tocainide, Mexiletine)
a.
b.
c.
d.
Use as antidysrhythmic agent in emergency care (AHA 2001) decreased
Given I-V; commonly used in ICU (old DOC; “Drug of Choice”).
Very low toxicity, good therapeutic index
A local anesthetic, works on nerve at higher doses.
Dr. Ishac
Antidysrhythmic Agents
2.
Cardiac effects
a.
b.
c.
d.
3.
10
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
4.
D.
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 (atrial flutter).
d.
Suppresses ventricular dysrhythmias; prevents ventricular
fibrillation after acute MI; rarely used in supraventricular
arrythmias. But in recent years, antiarrythmic use has been limited.
Phenytoin (Class IB)
1.
Non-sedative anticonvulsant used in treating epilepsy
2.
Limited efficacy as antidysrhythmic (second line antiarrythmic)
3.
Suppresses ectopic activation by blocking Na and Ca channels
4.
Especially effective against digitalis-induced dysrhythmias
5.
T1/2 = 24 hr - metabolized in liver
6.
Use associated with gingival hyperplasia
Dr. Ishac
E.
Antidysrhythmic Agents
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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.
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
Dr. Ishac
Antidysrhythmic Agents
2.
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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.
Non-cardiac: Hypotension
4.
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; inhibits ectopic foci
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.
G.
Amiodarone (Class III; others: Ibutilide, Bretylium, Sotalol, Dronedarone)
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; 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.
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Antidysrhythmic 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.
ii.
iii.
Sinus bradycardia
Negative inotropic action due to block of Ca channels and beta
receptors; but can improve heart failure via vasodilation.
A-V block, paradoxical VTs., ↑QT interval
b. Non-cardiac:
i.
ii.
iii.
iv.
v.
vi.
vii.
viii.
ix.
Deposits into almost every organ
Reduces clearance of drugs like procainamide, flecainide, digitalis,
quinidine and diltiazem.
Thyroid dysfunction (hypo or hyperthyroidism)
Pulmonary fibrosis is most serious adverse effect
Paresthesias (tingling, pricking, or numbness, “pins and needles”)
Photosensitivity
Corneal microdeposits and blurred vision
Ataxia, dizziness, tremor
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)
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
Dr. Ishac
H.
Antidysrhythmic Agents
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.
3.
Extracardiac effects: Hypotension (from block of NE release)
4.
Pharmacokinetics/therapeutics
a.
b.
c.
d.
I.
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IV or intramuscular
Excreted mainly by the kidney
Usually emergency use only: ventricular fibrillation when lidocaine
and cardioversion therapy fail. Increases threshold for fibrillation.
Decreases tachycardias and early extrasystoles by increasing
effective refractory period
Ibutilide (Class III). Prolongs cardiac action potential without additional effects.
1. 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 flutter than fibrillation
4. Generally well tolerated
J.
Sotalol (Class III and Class II)
5. Non-selective beta blocker, also increases action potential duration.
6. Increases APD, ↑QT interval
7. Used for dysrhythmias of supraventricular and ventricular origin
Dr. Ishac
K.
Antidysrhythmic Agents
15
Verapamil (Class IV, Ca channel blockers; other eg. diltiazem)
1.
Cardiac
a.
b.
c.
d.
e.
2.
Extracardiac
a.
b.
c.
3.
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 Ca channel blockers are poor
antiarrythmics
Peripheral vasodilatation via effect on smooth muscle
Used as antianginal, antihypertensive
Hypotension may increase HR reflexively.
Toxicity
a. Cardiac
i.
Too negative inotropic for damaged heart, depresses contractility
ii.
Can produce complete A-V block
b. Extracardiac
i.
ii.
iii.
Hypotension
Constipation
Nervousness
Dr. Ishac
4.
Antidysrhythmic Agents
16
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. Blocks reentrant supraventricular tachycardia ("A-V nodal reentrant
tachycardia"), 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. Naturally occurring nucleoside which is often used in the field by rescue squads as
well as in the hospital.
2. Activates P1 purinergic receptors (subtype A1) coupled to cardiac K channels,
especially in nodal tissue.
3. Has sympatholytic action
4. 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.
5. Effective in slowing or abolishing A-V nodal dysrhythmias, may also produce a
period of asystole.
6. T1/2 very short, 15 seconds; rapid elimination of the drug
7. 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.
ii.
Can depress conduction
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
V.
A.
These drugs must be used very carefully
B.
Sometimes interactions can be counter-intuitive
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
VII.
Antidysrhythmic Agents
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Summary of Effects of Antiarrhythmic Drugs
Drug
Quindine
Procainamide
Disopyramide
Lidocaine
Phenytoin
Tocainide
Mexiletine
Flecainide
Propafenone
Propranolol
Acebutolol
Esmolol
Sotalol
Amiodarone
Bretylium
Verapamil
Diltiazem
Digitalis
Adenosine
Class
IA
IA
IA
IB
IB
IB
IB
IC
IC
II
II
II
II/III
III
III
IV
IV
Auto
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓↑
↓
↓
↑
↓
CV
↓
↓
↓
0
0
0
0
↓
↓
↓
↓
↓
↓
↓
0
↓
↓
↓
↓
RP
↑
↑
↑
↓
↓
↓
↓
↑
↑
↓
↓
↓
↑
↑↑
↑↑
↑
↑
↓↑
↑
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
Lidocaine
Tocainide
Mexiletine
Flecainide
Propafenone
Propranolol
Acebutolol
Esmolol
Sotalol
Amiodarone
Bretylium
Verapamil
Adenosine
Class
Plasma Binding
%
T1/2
(hrs)
IA
IA
IA
IB
IB
IB
IC
IC
II
II
II
II/III
III
III
IV
60
15
39-95
40
10
65
45
85
90
25
(esterase)
6
4
5
2
14
12
15
5
4
3
9 min
9
25 days
9
5
15 secs
95
5
90
Drug
Excretion
Unchanged
20-40%
60%
50-70%
<10%
40%
10%
40%
<1%
<1%
40%
<1%
80%
<1%
80%
2%
Dr. Ishac
Antidysrhythmic Agents
IX.
Dysrhythmics treatment summary:
X.
1.
2.
Recommended:
Basic and Clinical Pharmacology, B.G. Katzung, 11th ed., 2009, pp. 225-249.
Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Hardman and
Limbird, 11th ed., 2005, pp. 899-932.
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