Antiarrythmic Drugs pdf - D. Hussein Adaia

BASIC ELECTROPHYSIOLOGY

Antiarrhythmic Drugs

 Myocardial cells maintain transmembrane ion gradients by movement of the

, Ca

and K

through membrane channels.

 The resting potential of a cardiac cell is– 85 mV compared to the extracellular

environment.

 Depolarization is initiated by a rapid influx of Na

(phase 0).

In the AV node depolarization is due to the
slower influx of calcium ions.

This results in slower conduction of the
impulse through the AV node than in other
parts of the heart.

During the period between phase 0 and the end of phase 2, the cell is refractory to the
further depolarization (absolute refractory period) since the sodium channels are
inactivated.

During phase 3, a sufficiently large stimulus can open enough sodium channels to over-
come the potassium efflux. This is the relative refractory period.

The cardiac action potential

Arrhythmia

Heart condition where disturbances in

  Pacemaker impulse formation
  Contraction impulse conduction
  Combination of the two

Results in rate and/or timing of contraction of heart muscle that is insufficient to
maintain normal cardiac output (CO)

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!

ECG (EKG) showing wave segments

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

o Na

higher outside than inside cell

o Ca

much higher “ “ “ “

o K

higher inside cell than outside

o Maintenance by ion selective channels, active pumps and exchangers

Cardiac Action Potential

 Divided into five phases (0,1,2,3,4)

o 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

o 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

o 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 Na+ channels

Differences between nonpacemaker and pacemaker cell action potentials

 PCs - Slow, continuous depolarization during rest
 Continuously moves potential towards threshold for a new action potential

(called a phase 4 depolarization)

Cardiac Action Potential (con’t)

 Phase 2 - plateau phase

o sustained by the balance between the inward movement of Ca

and outward movement of K

o Has a long duration compared to other nerve and muscle tissue
o Normally blocks any premature stimulator signals (other muscle

tissue can accept additional stimulation and increase contractility
in a summation effect)

o Corresponds to ST segment of the ECG.

 Phase 3 – repolarization

o K

channels remain open,

o Allows K

to build up outside the cell, causing the cell to repolarize

o K

channels finally close when membrane potential reaches certain

level

o Corresponds to T wave on the ECG

Mechanisms of Cardiac Arrhythmias

 Result from disorders of impulse formation, conduction, or both
 Causes of arrhythmias

o  Cardiac ischemia
o  Excessive discharge or sensitivity to autonomic transmitters
o  Exposure to toxic substances
o  Unknown etiology

Disorders of impulse formation

 No signal from the pacemaker site
 Development of an ectopic pacemaker

o May arise from conduction cells (most are capable of spontaneous activity)
o Usually under control of SA node  if it slows down too much conduction

cells could become dominant

o Often a result of other injury (ischemia, hypoxia)

 Development of oscillatory afterdepolariztions

o  Can initiate spontaneous activity in nonpacemaker tissue
o  May be result of drugs (digitalis, norepinephrine) used to treat other
o  cardiopathologies

Afterdepolarizations

Disorders of impulse conduction

 May result in

o Bradycardia (if have AV block)
o Tachycardia (if reentrant circuit occurs)

Reentrant circuit

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

Therapeutic overview

 Na

channel blockade

  β-adrenergic receptor blockade
  Prolong repolarization
  Ca

channel blockade

 Adenosine
 Digitalis glycosides

Classification of antiarrhythmics (based on mechanisms of action)

 Class I – blocker’s of fast Na

channels

o Subclass IA

  Cause moderate Phase 0 depression
  Prolong repolarization
  Increased duration of action potential

 Includes

 Quinidine – 1

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

Class IA - Na+ Channel Blockers
Procainamide/Quinidine/Disopyramide

 Mode of action

o Depress conduction and prolong refractoriness

 Atrial, His-Purkinje, ventricular tissue

o  Peripheral alpha block
o  Vagolytic
o  Negative inotrope

 ECG changes

o  Increase PR, QRS (Diso:  PR á > QRS á )
o  Toxicity: QTc increases by 30% or QT > 0.5 sec
o  Ca

channel blockade / potent anticholinergic (Diso)

 Uses

o SVT (reentry) or VT
o Afib/flutter (on digoxin)

 Drug interactions-Decrease metabolism of Amiodarone
 Dose

o IV: load 15 mg/kg over 1 hour, then 30-80 mg/kg/min

 (level 5-10 ng/ml)

o PO: 30-70 mg/kg/day

 Side effects: Lupus- in slow acetylators

o ANA + : 50-90% Symptoms: 20-30 %

Arrhythmia Therapy

 Procainamide has been a long-used intravenous

o infusion for a wide range of dysrhythmias:
o Narrow complex tachycardia:

 Atrial tachycardia, resistant re-entrant tachycardia

o Wide-complex tachycardia:

 Ventricular tachycardia

 Downside:

o Side effects, negative inotrope, pro-arrhythmic

Subclass IB

  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

Class IB
Lidocaine/Mexiletine/Phenytoin

 Mode of action

o  Little effect on normal tissues
o  Decreases Purkinje ERP/ automaticity
o  Increases Ventricular fibrillation threshold
o  Depresses conduction, esp. at high rates (Mexiletine)
o  Suppresses dig-induced delayed afterdepolarizations (Phenytoin)

 ECG changes

o Slight ↓ QTc (Lidocaine/Phenytoin)

Class IB Lidocaine

 Use: VT (acute)

o Acts rapidly; no depression of contractility/AV conduction

 Kinetics

o t

1/2

: 5-10 min (1st phase); 80-110 min (2nd phase)

 Drug interactions

o Decreased metabolism w/ CHF/hepatic failure, propranolol, cimetidine
o Increased metabolism w/ isuprel, phenobarbital, phenytoin

 Dose

o 1 mg/kg, then 20-50 mg/kg/min (level: 2-5 mg/ml)

 Side effects

o CNS toxicity w/ levels > 5 mg/ml

Class IB Mexiletine

 Use: VT (post-op CHD)
 Kinetics: t

1/2

= 8 - 12 hrs

 Drug interactions- rare
 Dose

3-5 mg/kg/dose (adult 200-300mg/dose) po q 8 hrs

 Side effects

Nausea (40%)
CNS - dizziness/tremor (25%)

Class IB Phenytoin

 Uses

VT (post-op CHD), digoxin-induced arrhythmias

 Drug interactions

Coumadin- á PT; Verapamil- á effect (displaces from protein)

 Dose

PO: 4 mg/kg q 6 hrs x 1 day, then 5-6 mg/kg/day ÷ q 12hr
IV: bolus 15 mg/kg over 1 hr; level 15-20 mg/ml

 Side effects

Hypotension, gingival hyperplasia, rash

Arrhythmia-focused Therapy

  Class IB antiarrhythmics are very effective and very safe.
  Little or no effect on “normal” tissues
  First line for ischemic, automatic arrhythmia's (Ventricular tachycardia)
  Not a lot of effect on normal conduction tissue – not a good medicine for reentry

and atrial tachycardias.

Subclass IC

  Strong Phase 0 depression
  No effect of depolarization
  No effect on action potential duration

Includes

1.  Flecainide  (initially developed as a local anesthetic)
  Slows conduction in all parts of heart,
  Also inhibits abnormal automaticity
2.  Propafenone

  Also slows conduction
  Weak β – blocker
  Also some Ca

channel blockade

Class IC
Flecainide/Propafenone/Ethmozine

 Mode of action

o  Depresses abnormal automaticity (Flec/Ethmozine)
o  Slows conduction in AV node, AP, ventricle (Flec/Prop)
o  Shortens repolarization (Ethmozine)
o  Negative inotrope (Propafenone)
o  Prolongs atrial/ventricular refractoriness (Propafenone)

 ECG changes

o ↑ PR, QRS
o ↑ QTc (Propafenone)

 Uses: PJRT, AET, CAT, SVT, VT, Afib
 Kinetics

1/2

= 13 hrs (shorter if between 1-15 mos old)

 Drug interactions

Increases digoxin levels (slight)
Amiodarone: increases flecainide levels

 Dose

70-225 mg/m

/day ÷ q 8-12 hr

Level: 0.2-1.0 mg/ml

 Side effects

Negative inotrope- use in normal hearts only (NO POST-OPs)
PROARRHYTHMIA - 5-12% (CAST)

Arrhythmia –focused Therapy

• IC’s have a lot of side effects that make them appropriate for use only by

experienced providers.

Class II – β–adrenergic blockers

Based on two major actions

1. blockade of myocardial β–adrenergic receptors
2. Direct membrane-stabilizing effects related to Na

channel blockade

Includes

 Propranolol

• causes both myocardial β–adrenergic blockade and membrane-stabilizing

effects

•  Slows SA node and ectopic pacemaking
•  Can block arrhythmias induced by exercise or apprehension
•  Other β–adrenergic blockers have similar therapeutic effect

  Metoprolol
  Nadolol
  Atenolol
  Acebutolol
  Pindolol
  Stalol
  Timolol
  Esmolol

Class III – K

channel blockers

1. Developed because some patients negatively sensitive to Na channel

blockers (they died!)

2. 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

 Ibutilide – slows inward movement of Na

in addition to delaying K

influx.

 Bretylium – first developed to treat hypertension but found to also suppress

ventricular fibrillation associated with myocardial infarction

 Dofetilide - prolongs action potential by delaying K

efflux with no other effects

Can be very powerful antiarrhythmics but limited indications for first-line use – beyond
the spectrum of primary care providers

Amiodarone: may become a first-line medicine for a broad spectrum of arrhythmias,
currently still high-risk

Class IV – Ca

channel blockers

slow rate of AV-conduction in patients with atrial fibrillation

Includes

 Verapamil – blocks Na

channels in addition to Ca

2+;

also slows SA node in

tachycardia

 Diltiazem

Purinergic Agonists
Adenosine

Mode of action

•  Vagotonic
•  Anti-adrenergic
•  Depresses slow inward Ca

current

• Increases K

conductance (hyperpolarizes)

ECG/EP changes

• Slows AV node conduction

Uses

• SVT- termination of reentry
• Aflutter- AV block for diagnosis

Kinetics

• t

1/2

= < 10 secs

• Metabolized by RBCs and vascular endothelial cells

Dose

• IV: 100-300 mg/kg IV bolus

Drug interactions

• Methylxanthines (caffeine/theophylline)

Side effects

•  AFib/ sinus arrest/ sinus bradycardia
•  Bronchospasm
•  Flushing/headache
•  Nausea

Great medicine: quick onset, quick degradation.

Digoxin

Mode of action

•  Na-K ATPase inhibition
•  Positive inotrope
•  Vagotonic

ECG changes

•  Increases PR interval
•  Depresses ST segment
•  Decreases QT interval

Use: SVT (not WPW)

Kinetics

• t

1/2

= preemie (61hrs), neonate (35hrs), infant (18hrs), child (37hrs), adult

(35-48hrs )

Interactions

  Coumadin- ↑ PT
  ↑ Digoxin level
  Quinidine, amiodarone, verapamil
  ↓ renal function/renal tubular excretion (Spironolactone)
  Worse with ↓ K

, ↓ Ca

Digoxin Toxicity

Nausea/vomiting, lethargy, visual changes

Metabolic

• Hyper K

, Ca

• Hypo K

, Mg

• Hypoxemia
• Hypothyroidism

Proarrhythmia

•  AV block- decreased conduction
•  SVT- increased automaticity
•  VT- delayed afterdepolarizations

Digoxin Toxicity
Treatment

• GI decontamination

o Ipecac/lavage/charcoal w/ cathartic

• Arrhythmias

o  SA node /AV node depression- Atropine; if dig > 6, may need pacing
o  SVT- Phenytoin or b -blocker
o  VT- Lidocaine (1 mg/kg) or Phenytoin

• DC Cardioversion may cause refractory VT/VF!!

Mubark A. Wilkins