J.

ONACRUZ,MD,MHPED,FPOGS
PHYSIOLOGY OF CARDIAC
CONTRACTION
ARRHYTHMIAS
ANTI-ARRHTYMIC DRUGS:
CLASSES I IV
OTHER ANTI-ARRHYTHMICS
ADENOSINE
DIGOXIN
Action Potential in SA Nodal Cells
ACTION POTENTIAL OF VENTRICULAR MYOCYTES
OUTSIDE CELL INSIDE CELL
Na+ Na+ Na+
Na+ Na+
Na+ Na+ Na+
Na+ Na+ Na+
Cell Membrane
Cell Membrane
OUTSIDE CELL INSIDE CELL
Na+
K+ K+ K+ K+
Cell Membrane
OUTSIDE CELL INSIDE CELL
Ca++
Ca++
Ca++
K+ K+ K+ K+
Ca++
K+ K+ K+ K+
Cell Membrane
OUTSIDE CELL INSIDE CELL
Increasing depolarization results from
gradual increase in permeability to sodium
Resting membrane potential is
restablished
SA Node- native pacemaker
AV Node- latent pacemaker
Bundle of His-latent pacemaker
Purkinje-latent pacemaker


1.Rate of spontaneous depolarization in
phase 4
2.Threshold potential
3.Resting membrane potential
Impulse formation and/or
Impulse conduction
Altered automaticity (increased activity of
pacemakers)
Triggered Activity (EADs. DADs)
Physiologic
Pathologic
latent pacemakers takeover
escape, ectopic beats
direct tissue injury
Afterdepolarizations: occur when a normal
action potential triggers an EXTRA
depolarization

Simple block
Reentry or circus movement
Accessory Tracts
Bundle of Kent
1. Sodium channel blockade
2. Blockade of sympathetic autonomic
effects in the heart
3. Prolongation of effective refractory period
4. Calcium channel blockade
Ion channels can change into various
conformational states
Changes in membrane permeability to a
particular ion is mediated by
conformational changes in the channels
through which that ion passes
Antiarrhythmic agents often have
different affinities for different
conformational states of the ion
channel
Ectopic pacemakers
Depolarized tissues, ischemic tissues
Activated channels (phase 0) or
inactivated channels (phase 2)- use or
state dependent drug action

Reduction of phase 4 slope by blocking
sodium or calcium
Increase threshhold
Blockade of positive chronotropic action of
norepinephrine in the heart (beta blockers)
Slows conduction by:
1. steady state reduction of available
unblocked channels
2. prolongation of recovery time of
channels that are able to reach rested and
available state (increased refractory
period)
As dose of antiarrhythmics are increased,
they begin to suppress conduction in
normal polarized tissue of the heart
Therapeutic concentrations may also be
proarrhythmic in settings of fast heart
rates, acidosis, hyperkalemia, ischemia
SA NODAL EFFECTS:
decreases automaticity by increasing
threshold potential and decreasing slope
of phase 4 depolarization

Ventricular Myocyte effects:
decreases upstroke velocity (slope) of
phase 0, for some also prolongs
repolarization (increases ERP)



Generally decrease reentry and prevent
arrhythmia by:
1.decreasing conduction velocity
2.increasing the refractory period
Although all three subclasses have similar
effects on action potential in the SA node,
there are important differences in their
effects on ventricular action potential
Moderate sodium channel blockade
(Moderate reduction in slope of phase 0)
Prolongs repolarization in both SA node
and ventricles
Prolongs action potential duration
Increases Effective Refractory Period
duration
Weak sodium channel blockade (Small
reduction in phase 0 slope)
Shortens action potential duration in some
tissues of the heart
Decreases effective refractory period
Strong sodium blockade
Pronounced reduction in slope of phase 0
No effect on APD or ERP
Sodium Blockade
IC>IA>IB
ERP
IA-increase, IB-shortens, IC-no effect
Action Potential Duration (K+
repolarization current)
IA > IB IC-no effect
Slows phase 4 depolarization thereby
decreasing abnormal automaticity
Increases threshold for excitation in atrium
and ventricles- direct depressant actions
EXTRACARDIAC EFFECTS
ganglion blocking propertiesreduces
peripheral vascular resistance*
hypotension (esp.IV)
CARDIAC
excessive slowing of conduction
precipitation of new arrhythmias such
as torsades de pointes*
syncope
EXTRACARDIAC
lupus-like syndrome
nausea and diarrhea
rash
fever
hepatitis
agranulocytosis

WEAK ANTICHOLINERGIC EFFECTS
IV,IM, PO(good absorption)
NAPA metabolite- Class III activity*
Liver metabolism and renal excretion
Half life is 3-4 h (frequent dosaging)
Dose reduction in renal failure and heart
failure
Atrial and ventricular arrhythmias
Sustained ventricular arrhythmias with
acute MI (second choice)
CARDIAC EFFECTS
similar to procainamide
more cardiac antimuscarinic effects
than procainamide
Cardiac toxicities- excessive QT
interval prolongation, torsades de
pointes, excessive slowed conduction
EXTRACARDIAC EFFECTS
diarrhea, nausea, vomiting
cinchonism (headache, dizziness,
tinnitus)
thrombocytopenia
hepatitis
angioneurotic edema
fever
Rapid absorption after oral intake
Binds to albumin and alpha glycoprotein
Hepatic metabolism
Half life 6-8 hrs
Slow release formulations
Occasional: atrial flutter/fib
CARDIAC EFFECTS
similar to procainamide and quinidine
greater cardiac antimuscarinic effect than
quinidine*
CARDIAC TOXICITIES
similar to quinidine
precipitation of heart failure*
EXTRACARDIAC TOXICITIES
ATROPINE-LIKE EFFECTS-
urinary retention
dry mouth
blurred vision
constipation
glaucoma worsening
Oral
Reduced dose in renal failure

Ventricular arrhythmias
Low incidence of toxicity
Highly effective for arrhythmias in acute
MI
IV use only
CARDIAC EFFECTS
greater effects on purkinje and ventricular
cells than atrial

Selective depression of conduction in
depolarized and not in resting cells
CARDIAC
least cardiotoxic among class I
uncommon proarrhythmic effects
hypotension in large doses (heart failure
cases)*
EXTRACARDIAC
Neurologic*
paresthesia, tremor, nausea
lightheadedness, hearing disturbances
slurred speech, seizures
Extensive first pass hepatic metabolism*
Parenteral (infusion)
Half-life 1-2h (can be as short as 20 mins)
Higher concentration may be needed in
some cases of MI or other acute illness**

Doses are decreased in those with heart
failure, liver disease
Drug interaction:*
propranolol
cimetidine
(Renal disease has no effect)
DOC- tx for ventricular tachycardia and
prevention of ventricular fibrillation after
cardioversion in acute MI
Oral active congener of lidocaine
Adverse effects are dose-related and
frequently occur at therapeutic doses
(neurologic)*
Elimination half-life is 8-20 h*

Ventricular arrhythmias
Chronic pain conditions
Potent sodium and potassium blocker*
Does not prolong APD or QT interval
Well absorbed orally
Half-life- 20h
Hepatic metabolism, renal elimination
No antimuscarinic effects
TOXICITY:
severe arrhythmia exacerbation*

USE:
Supraventricular arrhythmias,PVCs
With weak beta blocking action
Structural similarity: propranolol
Spectrum of action: Quinidine
Liver metabolism
TOXICITY:
metallic taste
constipation
arrhythmia exacerbation

USE:
supraventricular arrhythmias
Potent sodium channel blocker
No APD prolongation
Many metabolites*

TOXICITY:
Dizziness
Nausea
Arrhythmia exacerbation

USE:
ventricular arrhythmias
Cardiac Effects: anti-arrhythmic
beta receptor blockade
direct membrane effects


Well tolerated but less effective than
sodium channel blockers*

Prevention of recurrent infarction and
sudden death in post-MI
Propranolol
Esmolol
Sotalol*

Drugs that prolong effective refractory
period via prolongation of action potential
Blocks K+ channel or enhance inward
currents of sodium

reverse-use dependence*
CARDIAC EFFECTS:
marked prolongation of the APD and QT
interval by blocking I
k


blocking effect occurs in all ranges of
heart rates*-the exception


broad range of actions- Class I-IV actions





CARDIAC EFFECTS
slows heart rate and AV node conduction
highly efficacious, low risk of torsades
even if QT is prolonged
EXTRACARDIAC EFFECTS
Peripheral vasodilatation*

USES
ventricular arrhythmias, tachycardia
supraventricular arrhythmias (atrial fib)

Accumulates in many tissues (heart, lung,
liver, skin, tears)



TOXICITY: CARDIAC
symptomatic bradycardia and heart block*
arrhythmia aggravation
TOXICITY:EXTRACARDIAC

dose-related pulmonary fibrosis
abnormal liver function tests and hepatitis
photodermatitis, gray blue discoloration of
exposed skin

asymptomatic corneal microdeposits
optic neuritis (rare)
anomalies in thyroid function*
KINETICS
bioavailability 35-65%
hepatic metab: desethylamiodarone*
elimination half-life
50% rapid component (3-10days)
50% slow (weeks)

*effects are maintained up to 3 months
after d/c
KINETICS
drug interaction
increase with cimetidine
decrease with rifampicin
increases levels of warfarin and digoxin
Direct antiarrhythmic effect and inhibitor of
neuronal catecholamine release

CARDIAC EFFECTS
lengthens ventricular* APD and ERP esp.
in ischemic tissues- reverses shortening
of APD due to ischemia
CARDIAC EFFECTS
initial positive inotropic effect*

EXTRACARDIAC EFFECTS
postural hypotension**
nausea and vomiting
KINETICS
available for IV use

USES (rare)
emergency- resuscitation from ventricular
fibrillation after failure of lidocaine and
cardioversion (amiodarone preferred)
Class 3 (APD prolongation) and Class 2
(beta blocker) actions
Racemic mixture:
*Beta blocking effect is in the l-isomer
APD prolongation in d- and l-isomers
KINETICS
100% bioavailability
excreted unchanged in the kidneys
half-life of 12 h
few direct drug interactions

CARDIAC TOXICITIES
torsades des pointes*
further depression of LV function**

USES
life threatening ventricular arrhythmias
maintaining sinus rhythm in atrial fib
supraventricular and ventricular
arrhythmias in pedia
Dose dependent blockade rapid
component of delayed rectifier potassium
current I
kr*
(esp. in hypokalemia)

Ability to block is independent on
stimulation frequency due to slow rate of
recovery from the blockade*
KINETICS
100% bioavailability
Drug interaction-
Verapamil*
Cimetidine**
80% excreted renally unchanged
20% excreted as inactive metabolites

dosage is based on creatinine clearance
Contraindication:
baseline QT interval of > 450ms,
intraventricular delay, bradycardia of <50
beats, hypokalemia

USE:
maintenance or restoration of normal
sinus rhythm in atrial fibrillation

Blockade of rapid component of delayed
rectifier potassium current and activation
of slow inward sodium current
KINETICS
rapid by hepatic metabolism
renal excretion
half-life 6 h

USES
acute conversion of atrial fibrillation and
flutter
CARDIAC TOXICITY
extreme prolongation of QT interval
torsades des pointes
Initially introduced for management of
angina pectoris
CARDIAC EFFECTS
blocks activated and inactivated L-type
calcium channels especially in rapidly
firing tissues, less completely polarized at
rest, those whose activation depends
more on calcium channels*

SA and AV NODES
CARDIAC EFFECTS
suppression of EAD and DAD

EXTRACARDIAC EFFECTS
Peripheral vasodilatation
TOXICITY: CARDIAC*
hypotension and ventricular fibrillation
when given for a misdiagnosed SVT**

negative inotropic effect
AV block
sinus arrest


TOXICITY: EXTRACARDIAC
constipation
lassitude
nervousness
peripheral edema
KINETICS
half life 7 h
extensive liver metabolism
20% bioavailability

USES
SVT (also adenosine)
reduction of ventricular rate in atrial fib or
flutter
Ventricular arrhythmias (occasional)
Similar to verapamil
Naturally occuring nucleoside
Half life 10 mins

Activates inward K+ rectifier current and
inhibits Ca current: marked
hyperpolarization and suppression of
calcium dependent action potentials
Bolus inhibits AV node conduction and
increases AV node refractory period*
DOC- prompt conversion of paroxysmal
SVT to sinus rhythm

Interactions
caffeine, theophylline
dipyridamole
TOXICITY:
flushing in 20%
shortness of breath, chest burning in 10%
brief AV block
atrial fibrillation

headache, hypotension, nausea, paresthesias
Effects on Na+/K+ ATPase, sodium
channels, calcium channels

USES:
Digitalis-induced arrhythmias in
hypomagnesemic patients
Torsades des pointes
Hypokalemia and hyperkalemia are both
arrhythmogenic

Therapeutic goal: normalization of
potassium gradients and pools in the body