Anti-arrhythmic drugs

Satarculova A.M.

Uploaded by: http://mbbshelp.com

 Arrhythmia
ARRHYTHMIAS result from:
1. Disturbance in Impulse Formation
2. Disturbance in Impulse Conduction
Block results from severely depressed
conduction
Re-entry or circus movement / daughter
impulse
To understand how antiarrhythmic drugs work, need
to understand electrophysiology of normal
contraction of heart

Uploaded by: http://mbbshelp.com

 Physiology of cardiac rate
and rhythm
Cardiac myocytes are electrically excitable
Resting intracellular voltage of myocardial
cells is negative -90mV (SA node is -40mV)
Resting state - K+ inside and Na+ outside cell
(Na+/K+ pump)
Action potential occurs when Na+ enters the
cell and sets up a depolarising current
Stimulation of a single muscle fibre causes
electrical activity to spread across the
myocardium
Uploaded by: http://mbbshelp.com
 Phases of action potential of
cardiac cells
Phase 0 rapid depolarisation
(inflow of Na+) Phase 1
Phase 1 partial repolarisation IV
(inward Na+ current deactivated, Phase 2
0 mV
outflow of K+)
Phase 2 plateau (slow inward III
Phase 0
calcium current) I Phase 3
Phase 3 repolarisation (calcium
current inactivates, K+ outflow)
-80mV Phase 4
Phase 4 pacemaker potential
(Slow Na+ inflow, slowing of K+ II
outflow) autorhythmicity
Refractory period (phases 1-3)

Uploaded by: http://mbbshelp.com

 Sinus rhythm

Sinoatrial node is
cardiac pacemaker
Normal sinus rhythm
60-100 beats/min
Depolarisation triggers
depolarisation of atrial
myocardium
Conducts more slowly
through AV node
Conducts rapidly
through His bundles
and Purkinje fibres

Uploaded by: http://mbbshelp.com

 ECG
Recording of electrical activity of the heart
Net sum of depolarisation and repolarisation
potentials of all myocardial cells
P-QRS-T pattern
P - atrial depolarisation
QRS - ventricular depolarisation
T - ventricular repolarisation

Uploaded by: http://mbbshelp.com

 Definition of arrhythmia
Cardiac arrhythmia is an abnormality of
the heart rhythm
Bradycardia heart rate slow (<60
beats/min)
Tachycardia heart rate fast (>100
beats/min)

Uploaded by: http://mbbshelp.com

 Clinical classification of
arrhythmias

Heart rate (increased/decreased)

Heart rhythm (regular/irregular)
Site of origin (supraventricular /
ventricular)
Complexes on ECG (narrow/broad)

Uploaded by: http://mbbshelp.com

 Mechanisms of arrhythmia
Result from disorders of impulse formation,
conduction, or both

Causes of arrhythmias
Cardiac ischemia
Excessive discharge or sensitivity to autonomic
transmitters
Exposure to toxic substances
Unknown etiology

Uploaded by: http://mbbshelp.com

Disorders of impulse conduction

Uploaded by: http://mbbshelp.com

 Vaughan Williams classification
of antiarrhythmic drugs
Class I: block sodium channels
Ia (quinidine, procainamide,
disopyramide) AP
Ib (lidocaine) AP Phase 1
Ic (flecainide) AP IV
Class II: -adrenoceptor Phase 2
0 mV
antagonists (atenolol, sotalol)
Class III: prolong action Phase 0 III
potential and prolong refractory I Phase 3
period (suppress re-entrant
rhythms) (amiodarone, sotalol)
-80mV
Class IV: Calcium channel Phase 4
blockers. Impair impulse II
propagation in nodal and
damaged areas (verapamil)
Class V: agents work by other
or unknown mechanisms
(adenosine, digoxin)
Uploaded by: http://mbbshelp.com
 Class IA blockers of fast Na+
channels
Cause moderate Phase 0 depression
Prolong repolarization
Increased duration of action potential
Includes
Quinidine 1st antiarrhythmic used, treat
both atrial and ventricular arrhythmias,
increases refractory period
Procainamide - increases refractory period
but side effects
Disopyramide extended duration of action,
used only for treating ventricular arrthymias

Uploaded by: http://mbbshelp.com

 QUINIDINE
Pharmacokinetics:
Oral rapid GI absorption
80% plasma protein binding
20% excreted unchanged in the urine enhanced by acidity
t = 6 hours
Parenteral hypotension
Drug Interaction:
Increases digoxin plasma levels
Toxicity:
Antimuscarinic actions inh. vagal effects
Depress contractility & BP
Diarrhea, nausea, vomiting
Cinchonism (HA, dizziness, tinnitus)
Rare: rashes, fever, hepatitis, thrombocytopenia,etc

Uploaded by: http://mbbshelp.com

Class IB blockers of fast Na+
channels
Weak Phase 0 depression
Shortened depolarization
Decreased action potential duration
Includes
Lidocane (also acts as local anesthetic) blocks Na+
channels mostly in ventricular cells, also good for
digitalis-associated arrhythmias
Mexiletine - oral lidocaine derivative, similar activity
Phenytoin anticonvulsant that also works as
antiarrhythmic similar to lidocane

Uploaded by: http://mbbshelp.com

 Lidocaine
Pharmacokinetics:
IV only
- Extensive first-pass hepatic metabolism
- t = 1 to 2 hrs
Drug Interaction:
propranolol, cimetidine reduce clearance
Therapeutic Use:
for suppression of recurrences of ventricular tachycardia &
fibrillation in the first few days after MI.
Toxicity:
Exacerbates ventricular arrhythmias
Hypotension in HF
Neurologic: paresthesias, tremor, nausea, lightheadedness,
hearing disturbances, slurred speech, convulsions

Uploaded by: http://mbbshelp.com

Class IC blockers of fast Na+
channels
Strong Phase 0 depression
No effect of depolarization
No effect on action potential duration

Includes
Flecainide (initially developed as a local anesthetic)
Slows conduction in all parts of heart,
Also inhibits abnormal automaticity

Propafenone
Also slows conduction
Weak blocker
Also some Ca2+ channel blockade

Uploaded by: http://mbbshelp.com

 Flecainide
Pharmacokinetics:
Oral/IV
Long acting (T1/2 14 hours)
Hepatic metabolism, urinary elimination
Therapeutic Use:
Supraventricular tachycardias,
Paroxysmal atrial fibrillation
Ventricular tachycardias
Side effects:
cardiac failure
ventricular arrhythmias
blurred vision
abdominal discomfort
nausea
paraesthesia
dizzinesstremor
metallic taste

Uploaded by: http://mbbshelp.com

Class II adrenergic blockers
Based on two major actions:
blockade of myocardial adrenergic receptors
Direct membrane-stabilizing effects related to Na+
channel blockade
Includes:
Propranolol
causes both myocardial adrenergic blockade and
membrane-stabilizing effects
Slows SA node and ectopic pacemaking
Can block arrhythmias induced by exercise or
apprehension
Other adrenergic blockers have similar therapeutic
effect
Metoprolol
Pindolol
Esmolol
Atenolol

Uploaded by: http://mbbshelp.com

Class III K+ channel blockers

Developed because some patients negatively

sensitive to Na channel blockers (they died!)
Cause delay in repolarization and prolonged
refractory period
Includes
Amiodarone prolongs action potential by
delaying K+ efflux but many other effects
characteristic of other classes
Bretylium first developed to treat hypertension
but found to also suppress ventricular fibrillation
associated with myocardial infarction

Uploaded by: http://mbbshelp.com

 Amiodarone
Pharmacokinetics:
Oral or IV (central line
T1/2 54 days
Large volume of distribution
Accumulates
Hepatic metabolism- biliary and intestinal excretion
Therapeutic Use: Atrial and ventricular arrhythmias
Side effects:
Photosensitive rashes
Grey/blue discolouration of skin
Thyroid abnormalities 2%
Pulmonary fibrosis
CNS/GI disturbance
Pro-arrhythmic effects (torsades de pointes)
Heart block
Nightmares 25%
Interacts with digoxin, warfarin (reduces clearance)

Uploaded by: http://mbbshelp.com

Class IV Ca2+ channel blockers

slow rate of AV-conduction in patients

with atrial fibrillation
Includes
Verapamil blocks Na+ channels in addition to
Ca2+; also slows SA node in tachycardia
Diltiazem

Uploaded by: http://mbbshelp.com

 Verapamil
Prolongs conduction and refractoriness in AV node, slows rate
of conduction of SA nod
Pharmacokinetics:
Used IV/oral
Do not use IV verapamil with - blocker (heart block)
T1/2 6-8 hour
Therapeutic Use: SUPRAVENTRICULAR NOT
VENTRICULAR ARRHYTHMIAS (cardiovascular collapse)
Side effects:
Heart failure
Constipation
Bradycardia
Nausea

Uploaded by: http://mbbshelp.com

 Class V
agents work by other or unknown mechanisms
Adenosine:
nucleoside that occurs naturally in the body
t 10 seconds
Mode of action: enhances K+ conductance & inhibits cAMP-
induced Ca++ influx results in marked hyperpolarization
& suppression of Ca++-dependent AP
Drug interaction:
theophylline, caffeine adenosine receptor blockers
Dipyridamole adenosine uptake inhibitor
Side effects:
flushing
atrial fibrillation
headache
hypotension
nausea
paresthesia

Uploaded by: http://mbbshelp.com

 Digitalis
Indirectly alters autonomic outflow by increasing
parasympathetic tone & decreasing sympathetic
tone
Results in decreased conduction time &
increased refractory period in the AV node

Uploaded by: http://mbbshelp.com

 Summary
Anti-arrhythmic drugs are classified by their
effect on the cardiac action potential
Not all drugs fit this classification
In clinical practice treatment of arrhythmias is
determined by the type of arrhythmia (SVT,
VT) and clinical condition of the patient
Anti-arrhythmic drugs are efficacious but may
have serious adverse effects
Not all arrhythmias are treated with drug
therapy alone