Antidysrhythmic Agents

Tachyarrhythmias

Mechanisms: http://www.lhsc.on.ca/uwodoc/pages/arrmech.htm
Altered Impulse Formation http://www.cvphysiology.com/Arrhythmias/A008a.htm
Altered Impulse Conduction http://www.cvphysiology.com/Arrhythmias/A008b.htm

1. Increased automaticity
2. Triggered Activity (afterdepolarizations)
3. Conduction Abnormalities
   • Blocks
   • Re-entry

Figure 1. "Re-entry" mechanisms for tachyarrhythmias

Drug Selection

Drugs are grouped by mechanism of action against the arrhythmias. (Combining drugs from the same group should be questioned).

Drugs are selected by considering cardiac side effects and administration problems

Setting Therapeutic Objectives

1. Maintain cardiac output and "critical organ perfusion" (this can be evaluated)
2. Prevent progression of the arrhythmia (this cannot be evaluated)
3. Return the EKG to normal activity (this can be evaluated but may not be possible)

Vaughn-Williams Class I

Action

All agents in Class:

• Slow the maximum rate of phase 0 depolarization (Figure 2)
• Slow conduction velocity
• Slow rate and force of contraction
• Refractory period effects are secondary to changes in action potential.

Figure 2. Action potentials in normal cardiac (left) and pacemaker cells (right).

Differential effects:

• Ia prolong refractory period
  
• Ib shorten action potential and refractory period (Figure 2.)
• Ic do not effect refractory period Decrease automaticity in pacemaker cells
  
• Ib affect on abnormal cells greater than normal

Mechanism(s) of Action

• Block Na influx through fast Na channels
  
• Alter activity of (some) K channels (Ib only)

Quinidine (Ia)

Routes of Administration

• Intravenous - severe hypotension with rapid administration
• Intramuscular - suitable
• Oral - slow release oral forms available (little veterinary need)

Metabolism and Excretion

• Considerable metabolism occurs
• Approximately 40% eliminated unchanged (urine)
• Protein binding extensive (see interactions)

Toxicity

1. Hypotension (particularly IV)
   • Myocardial contractility depression leads to decreased cardiac output
   • Direct effect on blood vessels (vasodilation)
2. Enhanced AV conduction (therapeutic doses - indirect, atropine-like)
3. AV block (high doses - direct effect)

Drug Interactions

• Increases concentration of concurrently administered cardiac glycosides
• Increased urinary pH (antacids) increases reabsorption (increases quinidine concentrations)
  
• Barbiturates enhance metabolism (decreases quinidine concentrations)
  
• Potentiates NMJ block of skeletal muscle relaxants and aminoglycosides

Clinical Uses

1. Primary - conversion of horses with atrial fibrillation to normal sinus rhythm
   
2. Secondary - alone or in combination with other antiarrhythmics for refractory:
   • PVCs
   • Ventricular tachycardia

Procainamide (Ia)

Routes of Administration

• Oral, IM - most suitable
  
• IV - caution , hypotension with rapid administration

Metabolism and Excretion

• Metabolism in veterinary species not well worked out
  
• N-acetylprocainamide (associated with immunologic side effects) is not produced in the dog

Toxicity

1. Hypotension (particularly IV)
   • Myocardial contractility depression leads to decreased cardiac output
   • Direct effect on blood vessels (vasodilation)
2. Vagolytic effect (see quinidine)
   
3. Induces antinuclear antibody (ANA)in humans some Veterinary species??
   

Drug Interactions

• Additive GI upset with other Ia antidysrhythmics
• Additive mycardial depression with other Ia
• None are documented

Lidocaine (Ib)

Routes of Administration

• FIRST IV bolus administration fairly safe
• Continuous infusion necessary to maintain effective concentrations
• IM doses must be given every 1 - 2 hours to maintain effect
• IM form is higher concentration (decreases volume that must be given)
• Studies of IM form in veterinary patients have not been done
• Lidocaine patches have no role in treatment of dysrhthmia.

Metabolism and Excretion

• Extensive metabolism and extraction by liver
• Pronounced first-pass effect
• Active metabolites contribute to efficacy and toxicity

Toxicity

1. Neurologic
   
   • Depression, muscle tremors, convulsions
   • Convulsions controlled with diazepam, phenobarbital
     
   • Nausea and vomiting (extension of neurologic?)
   • Rapidly abate when infusion slowed
2. Cardiac
   • May potentiate disease-induced deficiencies in automaticity, contractility, AV conduction
     
   • Associated with cardiac standstill (rare) may occur with multiple boluses

Drug Interactions

1. Reduced liver blood flow:
   • Clearance of lidocaine reduced by coadministration of: propranolol, pentobarbital, gas anesthesia, cimetidine
2. Reduced metabolism:
   Clearance of lidocaine reduced with coadministration of: chloramphenicol, quinidine

Tocainide, Mexilitine (Ib)

Routes of Administration

• Oral

Metabolism and Excretion

1. Steric hindrance to metabolism
   • Decreased first-pass effect
2. Hepatic metabolism still dominates as route of elimination though the half-life prolonged as compared to lidocaine

Toxicity

• Similar to lidocaine

Drug Interactions

• Have not been reported

Phenytoin (Ib)

Routes of Administration

• Oral - Absorption slow, incomplete and may be dose dependent
  
• IV - rapid injection not recommended as vehicle is cardiodepressant
  
• IM - discouraged because of low systemic availability

Metabolism and Excretion

• Metabolism by microsomal enzymes is rapid
• Dose-dependent (partial saturation) possible

Toxicity

• Postural ataxia and hypermetric gates at high serum concentrations

Drug Interactions

1. Chloramphenicol increases serum concentrations by 20%
2. Barbiturates
   • Acutely decrease phenytoin clearance (competitive)
   • Long-term enzyme induction increases clearance

Vaughn-Williams Class II

Mechanism of action

1. Blockade of b- receptors (beta blockers)
2. Inhibition of norepinephrine release (bretylium)

Propranolol

Routes of Administration

• Oral
  • Considerable first pass metabolism
  • Availability increases with 2nd and subsequent doses
• IV-caution: may produce excessive myocardial depression

Metabolism and excretion

• Largely hepatic metabolism
• T_1/2 approximately 2 hours

Toxicity

1. Decreased cardiac output - the significance depends on a number of factors
   
   • Acutely beta blockade decreases sympathetic component of compensation for CHF (Use with extreme caution in these patients)
   • Chronically
     1. chronic sympathetic overdrive (reflexes) reduce number of beta receptors (before the propranolol)
     2. sympathetic component of reflex becomes ineffective
     3. moderate-dose beta blockade (propranolol) induces up-regulation of receptor numbers
     4. sympathetic component of reflex becomes effective again
2. Bradyarrhythmias, heart block (esp. combined with digoxin)
   • Contraindicated with supraventricular bradycardia, AV block
3. Hypotension (depends on significance of contractility effects)
4. Bronchoconstriction (may promote bronchospasm if chronic obstructive pulmonary disease or bronchial asthma exist)
5. Hypoglycemia (in insulin dependent diabetics)

Drug Interactions

• Decreases clearance of drugs dependent upon liver blood flow (see Lidocaine above)
• Antacids decrease oral absorption
• Barbiturates increase metabolism (enzyme induction)
  
• Excessive a adrenergic activity (hypertension) if epinephrine or drugs resulting in its release (clonidine) are used

Metoprolol

Clinical Advantage

• b-1 Selectivity - No Bronchochostriction

Disadvantage

• Lack of Veterinary experience
• It's metabolized much like propranolol

Clinical Uses

• Asthmatics, patients where bronchoconstriction a problem

Atenolol

Clinical Advantage

• Consistant Kinetics (renal elimination)
• Beta Selectivity (No Bronchochostriction)

Disadvantage

• Lack of Veterinary experience

Clinical Uses

• Asthmatics, patients where bronchoconstriction a problem

Vaughn-Williams Class III

Action

• Prolong action potential and affiliated refractory period.
  
  

Mechanism of Action

• Do not alter normal fast Na conductance
• Do not compete for beta receptors

Bretylium

Possibly useful for arrhythmias refractory to other antiarrhythmic agents. Veterinary experience and use is limited.

Amiodarone

Possibly useful for arrhythmias refractory to other antiarrhythmic agents. Veterinary experience and use is limited.

Being investigated for management of atrial fibrillation in dogs.

Saunders AB, Miller MW, Gordon SG, Van De Wiele CM. Oral amiodarone therapy in dogs with atrial fibrillation. J Vet Intern Med. 2006 Jul-Aug;20(4):921-6.
Abstract:

The medical records of client-owned dogs in which amiodarone was used to manage atrial fibrillation (AF) were reviewed. Data analyzed included signalment, history of heart failure, presenting complaint, clinical diagnosis, prescription drug history, number of re-examinations, outcome, and laboratory analysis including serum biochemical analysis, CBC, and thyroid function testing. Specific data for amiodarone included loading and maintenance dose, duration of loading dose, adverse effects, and reason for decreasing dose or discontinuation of amiodarone therapy. Follow-up data for 17 dogs were included in the analysis. Various cardiac diseases including cardiomyopathy, valvular endocardiosis, and congenital heart disease were diagnosed in the dogs. Median loading and maintenance dosages of amiodarone were 16.5 and 9.0 mg/kg of body weight/d, respectively. A >20% decrease in heart rate was achieved in 13 dogs (76%). Conversion to sinus rhythm was achieved and maintained in 6 dogs (35%). Amiodarone was discontinued in 5 dogs, and the dose was decreased because of symptomatic bradycardia (n = 1), asymptomatic (n = 1) and symptomatic (n = 3) increases in hepatic enzyme activities, and for unknown reason (n = 1). On the basis of >20% decrease in heart rate in 76% of the dogs and conversion to sinus rhythm in 35%, it was concluded that amiodarone may be useful in managing AF in dogs. The use of amiodarone in the medical management of AF in dogs warrants further investigation.

Vaughn-Williams Class IV

Action

• Slow automaticity and increase conduction velocity

Mechanism of Action

• Selectively block slow Ca Channels
  1. Inhibit slow inward Ca current during phase 2
     
     
     
     • Decrease rate of phase 4 depolarization
     • Effect on the "pacemaker in charge" (SA NODE as long as it's the pacemaker)
  2. Depress conduction velocity in purkinji sytem and AV NODE
  3. Decrease contractility in myocardium (lowered intracellular calcium)
  4. Vasodilation (lower intracellular calcium in arterial muscle)

Verapamil

Pharmacokinetics

Routes of Administration

• Oral - extensive first pass metabolism
• IV - CAUTION: Extreme hypotension possible

Metabolism and Excretion

• Clearance is high
• Substantial first-pass elimination limits oral availability

Toxicity

1. Depression of contractility
   • Decreased cardiac output
   • Contraindicated with pre-existing CHF
2. Hypotension (vasodilation + contractility)
3. Bradyarrhythmias
   • third-degree AV block
   • nodal rhythms
   • Asystole

Drug Interactions

Not commonly reported
Additive depression of conduction and contractility with other antiarrhythmics can be expected

Diltiazem

• Some antiarrhythmic activity in supraventricular tachychardia
• Good combination of anti-arrhythmic/contractility/vasodilator effects (cats - hypertrophic cardiomyopathy)

Other Antiarrhythmics (for tachyarrhythmias)

Cardiac Glycosides

Potassium

Treatment of Bradyarrhythmias

• Sinus Bradycardia
• Sinoatrial Arrest
• Atrioventricular Block

Antidysrhythmic Agents

Isoproterenol

Ephedrine (Pseudoephedrine)

Dopamine

Atropine

Glycopyrillate

Topic Summary (Treatment of Arrhythmias)

1. a. Choose VW I, VW II, VW III agents
   
   Relative advantages:

   • Lidocaine - low cardiac and vascular depression
   • Procainamide - intermediate CV depression
     • all routes of administration
     • accumulated experience
   • Quinidine - none
   • Propranolol - experience in felines
   • Amiodarone - unique mechanism Relative disadvantages
   • Lidocaine - difficult to administer (IV infusion)
   • Procainamide - intermediate CV depression
   • Quinidine - severe CV depression
   • Propranolol - CV depression
   • Amiodarone - lack of veterinary experience

   b. begin with single agent therapy.

   c. combine agents from different classes if refractory

2. Treatment of Atrial Tachyarrhythmias

   a. Choose VW IV, VW I(a) agents.
   
   Quinidine - atrial fibrillation horses
   Verapamil - atrial, sinus tachyarrhythmia
   - refractory a. fib?