Download Antiarrhythmic Drugs

Antiarrhythmic Drugs
Drug List
Class 1
Sodium Channel
Blockers
1a
Procainamide
Quinidine
1b
Lidocaine
Mexiletine
Phenytoin
1c
Flecainide
Class 2
Beta-blockers
Metoprolol
Propranolol
Class 3
Potassium
Channel
blockers
Amiodorone
Ibutilide
Dofetilide
Sotalol
Class 4
Calcium
Channel
Blockers
Verapamil
Diltiazem
Others
Adenosine
Magnesium
Digoxin
Physiology Review
• To function efficiently, heart needs to contract sequentially
(atria, then ventricles) and in synchrony
• Relaxation must occur between contractions
• Coordination of heartbeat is a result of pacemaker activity of
the SA node and transfer of impulses through AV node and
the purkinje system
Arrhythmia
A condition where there is a disturbance in
– Pacemaker impulse formation
– Impulse conduction
– Combination of the two
Results in change of heart rate or contraction of
heart muscle in a way that is insufficient to
maintain normal cardiac output
To understand how antiarrhythmic drugs work, need
to understand electrophysiology of normal
contraction of heart
Ventricular Arrhythmia
• Ventricular arrhythmias are common in most
people and are usually not a problem but…
• VA’s are most common cause of sudden death
• Majority of sudden death occurs in people with
neither a previously known heart disease nor
history of VA’s
• Medications which decrease incidence of VA’s do
not decrease (and may increase) the risk of sudden
death treatment may be worse then the disease!
Electrophysiology - resting potential
• A transmembrane electrical gradient (potential) is maintained,
with the interior of the cell negative with respect to outside
the cell
• Caused by unequal distribution of ions inside vs. outside cell
– Na+ higher outside than inside cell
– Ca+ much higher “ “
“
“
– K+ higher inside cell than outside
• Maintenance by ion selective channels, active pumps and
exchangers
ECG (EKG) showing wave
segments
Contraction of
atria
Contraction of
ventricles
Repolarization of
ventricles
Cardiac Action Potential
• Divided into five phases (0,1,2,3,4)
– Phase 4 - resting phase (resting membrane potential)
• Phase cardiac cells remain in until stimulated
• Associated with diastole portion of heart cycle
• Addition of current into cardiac muscle (stimulation) causes
– Phase 0 – opening of fast Na channels and rapid depolarization
• Drives Na+ into cell (inward current), changing membrane potential
• Transient outward current due to movement of Cl- and K+
– Phase 1 – initial rapid repolarization
• Closure of the fast Na+ channels
• Phase 0 and 1 together correspond to the R and S waves of the ECG
Cardiac Action Potential
• Phase 2 - plateau phase
– sustained by the balance between the inward movement of Ca+ and outward
movement of K +
– Has a long duration compared to other nerve and muscle tissue
– Normally blocks any premature stimulator signals (other muscle tissue can
accept additional stimulation and increase contractility in a summation effect)
– Corresponds to ST segment of the ECG.
• Phase 3 – repolarization
–
–
–
–
K+ channels remain open,
Allows K+ to build up outside the cell, causing the cell to repolarize
K + channels finally close when membrane potential reaches certain level
Corresponds to T wave on the ECG
Differences between nonpacemaker and pacemaker
cell action potentials
• Pacemaker Cells - Slow, continuous depolarization during
rest
• Continuously moves potential towards threshold for a new
action potential (called a phase 4 depolarization)
Mechanisms of Cardiac Arrhythmias
• 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
Types of arrhythmias
Tachyarrythmias
Bradyarrhythmia
Tachyarrythmias
Atrial: Afib
Nodal: Supraventricular Tachycardia
Sinus Tachycardia
ventricular: Ventricular Tachycardia
Ventricular fibrillation
Antiarrhythmic drugs
• Biggest problem – antiarrhythmics can cause
arrhythmia!
– Example: Treatment of a non-life threatening
tachycardia may cause fatal ventricular arrhythmia
– Must be vigilant in determining dosing, blood
levels, and in follow-up when prescribing
antiarrhythmics
Classification of Antiarrhythmic Drugs
Class I: Sodium channel blockers (membranestabilizing agents)
1 a: Block Na+ channel and prolong action potential
1 b: Block Na+ channel and shorten action potential
1 c: Block Na + channel with no effect on action
potential
Class II: β- blockers
Class III: Potassium channel blockers (main effect is
to prolong the action potential)
Class IV: Slow (L-type) calcium channel blockers
Class 1a Drugs
• They are the oldest group of antiarrhythmic drugs
and are still widely used.
Procainamide
• Blocks sodium channels, slows the upstroke of
the action potential, slows conduction, prolongs
the QRS duration of the ECG.
• The drug also prolongs the action potential
duration by nonspecific blockade of potassium
channels.
• Procainamide has direct depressant actions on
sinoatrial and atrioventricular nodes
Procainamide
Extracardiac Effects Procainamide has ganglion-blocking properties. This
action reduces peripheral vascular resistance and can cause hypotension,
particularly with intravenous use.
Pharmacokinetics:
Absorbed well orally. Metabolised in liver and excreted by kidney.
Toxicity :
QT interval prolongation, and induction of torsade de pointes arrhythmia and
syncope.
New arrhythmias can be precipitated.
Lupus erythmatosus, Pleuritis , pericarditis, or parenchymal pulmonary
disease. Nausea and diarrhea (in about 10% of cases), rash, fever, hepatitis (<
5%)
Therapeutic Use :
Therapeutic Use Atrial and ventricular arrhythmias
Quinidine
Similar to procainamide.
Also blocks K+ channels.
Adverse effects
Anticholinergic (i.e. anti-muscarinic), blocks α receptors.
Diarrhea , nausea
A syndrome of headache, dizziness, and tinnitus
(cinchonism) is observed at toxic drug concentrations.
Excessive QT interval prolongation and induction of
torsade de pointes arrhythmia. Toxic concentrations of
quinidine also produce excessive sodium channel
blockade with slowed conduction throughout the heart.
Not very commonly used these days
Class 1b Drugs
Lidocaine
Block Na + channel and shorten action potential duration.
Lidocaine has a low incidence of toxicity. A high degree of effectiveness
in arrhythmias associated with acute myocardial infarction. It is used
only by the intravenous route.
Cardiac Effects Lidocaine blocks activated and inactivated sodium
channels with rapid kinetics
Adverse effects: Lidocaine is one of the least cardiotoxic of the
currently used sodium channel blockers. Paresthesias, nausea of
central origin, lightheadedness, hearing disturbances. In preexisting
heart failure, lidocaine may cause hypotension
Pharmacokinetics:
Extensive first-pass hepatic metabolism Lidocaine must be given
parenterally Lidocaine has a half-life of 1–2 hours.
Therapeutic Use: Lidocaine is the agent of choice for termination of
ventricular tachycardia and prevention of ventricular fibrillation after
cardioversion in the setting of acute ischemia (Myocardial infarction)
Mexiletine (1b)
Mexiletine is given orally. Its electrophysiologic
and antiarrhythmic actions are similar to those
of lidocaine.
Therapeutic use: Treatment of ventricular
arrhythmias. Pain due to diabetic neuropathy
and nerve injury.
Adverse effects: Tremor, blurred vision, and
lethargy. Nausea
Class 1c Drugs
Flecainide
Blocks Na+ channel with no effect on action potential.
Flecainide is a potent blocker of sodium and potassium
channels. (Note that although it does block certain potassium
channels, it does not prolong the action potential or the QT
interval). It has no antimuscarinic effects.
Pharmacokinetics: Flecainide is well absorbed and has a halflife of approximately 20 hours. Elimination is both by hepatic
metabolism and by the kidney
Therapeutic Uses: Premature ventricular contractions. Atrial
fibrillation (AF), Wolf Parkinson White (WPW) syndrome
Toxicity: Arrhythmia
Class 2 Drugs. Beta Blockers
PROPRANOLOL: Suppress adrenergically mediated
ectopic activity. Drugs have antiarrhythmic properties by
virtue of their β -receptor–blocking action and direct
membrane effects Some of these drugs have selectivity
for cardiac β 1 receptors e.g. metoprolol, Some have
intrinsic sympathomimetic activity e.g. pindolol. Some
have marked direct membrane effects, and some prolong
the cardiac action potential
These agents can prevent recurrent infarction and sudden
death in patients recovering from acute myocardial
infarction.
Class 2 Drugs. Beta Blockers
Therapeutic Uses: Sinus tachycardia, Atrial/ nodal
extrasystole. Pheochromacytoma. Arryhthmia due to
halothane /digitalis. WPW syndrome
Esmolol is a short-acting β blocker used primarily as an
antiarrhythmic drug for intraoperative and other acute
arrhythmias
Sotalol is a nonselective β -blocking drug that prolongs the
action potential.
Class 3 Antiarrhythmic Drugs
Amiodarone
Amiodarone markedly prolongs the action
potential duration (and the QT interval on the
ECG) Amiodarone also significantly blocks
inactivated sodium channels.
Amiodarone also has weak anti-adrenergic and
calcium channel blocking actions
Extracardiac Effects Amiodarone causes
peripheral vasodilation.
Pharmacokinetics
Incompletely and slowly absorbed orally. It undergoes
hepatic metabolism, and the major metabolite,
desethylamiodarone, is bioactive. The elimination half-life
is complex. The drug accumulates in many tissues,
including the heart (10–50 times more so than in plasma),
lung, liver, and skin, and is concentrated in tears
Therapeutic Use: Recurrent ventricular tachycardia, atrial
fibrillation.
Rapid termination of supraventricular tachycardia (SVT),
ventricular tachycardia (VT) and WPW syndrome
Works on both supraventricular and ventricular
arrhythmias.
Amiodarone adverse effects
• Fatal pulmonary fibrosis
• Abnormal liver function tests and hepatitis
• Photodermatitis and a gray-blue skin
discoloration in sun-exposed areas (smurf skin)
• Corneal micro-deposits and discoloration
• Optic neuritis: Halos develop in the peripheral
visual fields, may progress to blindness
• Hypothyroidism or hyperthyroidism
• Bradycardia and heart block
Class 4 Antiarrhythmic Drugs
Calcium Channel-Blocking Drugs
Verapamil:
Cardiac Effects. Verapamil blocks both activated and
inactivated L-type calcium channels.
AV nodal conduction time and effective refractory period are
prolonged.
Slows the SA node by its direct action
Extracardiac Effects. Peripheral vasodilation (Less than
nifedipine)
Pharmacokinetics: Absorbed orally. It is extensively
metabolized by the liver
Therapeutic Use. Supraventricular tachycardia. Atrial
fibrillation and flutter
Miscellaneous Antiarrhythmic Agents
These include digitalis, adenosine, and magnesium
Adenosine
Mechanism of Action:
Adenosine is a nucleoside that occurs naturally throughout the body.
Its half-life in the blood is less than 10 seconds. Activation of
acetylcholine sensitive K + channels and inhibition of calcium current.
Atrioventricular nodal conduction and the atrioventricular nodal
refractory period. It is drug of choice (DOC) for conversion of
paroxysmal supraventricular tachycardia to sinus rhythm. High efficacy
(90–95%) and very short duration of action.
Adverse effects: Flushing, shortness of breath or chest burning, highgrade atrioventricular block. Atrial fibrillation may occur. Headache,
hypotension, nausea, and paresthesias
Magnesium
Mechanism of action is not known.
USES:
Digitalis -induced arrhythmias.
Torsade de pointes even if serum magnesium is
normal.
Pacemakers
•
•
Surgical implantation of electrical leads attached to a pulse
generator
Over 175,000 implanted per year
1)
2)
3)
4)
•
•
Leads are inserted via subclavian vein and advanced to the right side
of the heart
Two leads used, one for right atrium, other for right ventricle
Pulse generator containing microcircuitry and battery are attached
to leads and placed into a “pocket” under the skin near the clavicle
Pulse generator sends signal down leads in programmed sequence
to contract atria, then ventricles
Pulse generator can sense electrical activity generated by
the heart and only deliver electrical impulses when needed.
Pacemakers can only speed up a heart experiencing
bradycardia, they cannot alter a condition of tachycardia