Nursing Pharmacology: Pharmacology of Antiarrhythmic Agents

Nursing Pharmacology Chapter 8: Antiarrhythmic Agents

Introduction: Arrhythmias and Drug Therapy

Atrial fibrillation may result in a high ventricular following rate (tachycardia).

"Tachycardia: Update for 2011"

Kunz MG Tachycardia: Update for 2011 with Nursing Educator Michele G. Kunz, MSN, ANP, RN-BC. Dickson Keanaghan, LLC Presentation, Produced by Joseph C. Kunz, Jr (©) 2011 Dickson Keanaghan, LLC https://www.youtube.com/watch?v=vTR1T0Jbeww .

Accordingly, drugs which may reduce ventricular rate by reducing AV nodal conduction include:

Calcium channel blockers (verapamil (Isoptin, Calan), diltiazem (Cardiazem))

β-adrenergic receptor blockers (propranolol (Inderal)), and

Digitalis glycosides.

Treatment of atrial fibrillation: Verapamil (Isoptin, Calan) and Diltiazem (Cardiazem)

Blocks cardiac calcium channels in slow response tissues, such as the sinus and AV nodes.

Useful in treating AV reentrant tachyarrhythmias and in management of high ventricular rates secondary to atrial flutter or fibrillation.

Major adverse effect (i.v. administration) is hypotension. Heart block or sinus bradycardia can also occur.

Treatment of atrial fibrillation: Propranolol (Inderal)

Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade.

Normally, sympathetic drive results in increased in Ca²⁺, K⁺ ,and Cl^- currents.

Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated arrhythmias.

These effects are blocked by beta-adrenergic receptor blockers.

β-adrenergic receptor blockers increase AV conduction time (takes longer) and increase AV nodal refractoriness, thereby helping to terminate nodal reentrant arrhythmias.

β-adrenergic receptor blockade can also help reduce ventricular following rates in atrial flutter and fibrillation, again by acting at the AV node.

Adverse effects of β blocker therapy can lead to fatigue, bronchospasm, depression, impotence, and attenuation of hypoglycemic symptoms in diabetic patients and worsening of congestive heart failure.

Drugs assist in restoring and maintaining normal sinus rhythm include quinidine and procainamide.
- Quinidine (Quinidine gluconate (Quinaglute, Quinalan))
  - Although classified as a sodium channel blocker, quinidine also blocks K+ channels.
    - Most antiarrhythmic agents have such multiple actions.
  - Sodium channel blockade results in
    - An increased threshold
    - Decreased automaticity.
  - Potassium channel blockade results in action potential (AP) prolongation (width increases).
  - Quinidine gluconate-Clinical Use:
    - Maintains normal sinus rhythm in patients who have experienced atrial flutter or fibrillation.
    - Prevents ventricular tachycardia or fibrillation.
  - Quinidine gluconate (Quinaglute, Quinalan) administration results in vagal inhibition (anti-muscarinic) and alpha-adrenergic receptor blockade.
  - Adverse effects include cinchonism (headaches and tinnitus), diarrhea.
  - Quinidine is also associated with torsades de pointes, a ventricular arrhythmias associated with marked QT prolongation.
    - This potentially serious arrhythmia occurs in 2% - 8% if patients, even if they have a therapeutic or subtherapeutic quinidine blood level.
- Procainamide (Procan SR, Pronestyl-SR)
  - Quinidine and Procainamide exhibit similar electrophysiological properties.
  - By contrast to quinidine, procainamide does not exhibit either vagolytic or alpha-adrenergic blocking activity.
  - Useful in acute management of supraventricular and ventricular arrhythmias.
  - Long term use is associated with side effects, including a drug-induced lupus syndrome which occurs at a frequency of 25% to 50%.
    - In slow acetylators the procainamide-induced lupus syndrome occurs more frequently and earlier in therapy than in rapid acetylators.

Paroxysmal supraventricular tachyarrthymias (PSVT) may be managed, depending upon clinical presentation, by increasing the vagal tone at the AV node.

The red dot highlights the AV node

Paroxysmal supraventricular tachyarrthymias (PSVT)

PSVT: Eastside Arrhythmia Services, Overlake Hospital Medical Center

https://www.youtube.com/watch?v=dlyziCbeCog

Interventions that may terminate paroxysmal supraventricular tachyarrthymias (PSVT) arrthytmias
- Valsalva maneuver
- α-adrenergic receptor agonist administration
- digoxin administration
- By administration of drugs that reduce AV transmission:
  - Adenosine (Adenocard), verapamil (Isoptin, Calan), diltiazem (Cardiazem), esmolol (Brevibloc) or DC cardioversion.
    - Adenosine (Adenocard)
      - Effects mediated through G protein-coupled adenosine receptor.
      - Activates acetylcholine-sensitive K+ current in the atrium and sinus and A-V node.
      - Decreases action potential duration, reduces automaticity
      - Increases A-V nodal refractoriness
      - Rapidly terminates re-entrant supraventricular arrhythmias (I.V)
    - Verapamil (Isoptin, Calan) and Diltiazem (Cardiazem)
      - Blocks cardiac calcium channels in slow response tissues, such as the sinus and AV nodes.
      - Useful in treating AV reentrant tachyarrhythmias and in management of high ventricular rates secondary to atrial flutter or fibrillation.
      - Major adverse effect (i.v. administration) is hypotension. Heart block or sinus bradycardia can also occur.
    - Esmolol (Brevibloc)
      - Esmolol is a very short acting, cardioselective beta-adrenergic receptor antagonist.
      - i.v. administration is used for rapid beta-receptor blockade in treatment of atrial fibrillation with high ventricular following rates.
      - Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade. Normally, sympathetic drive results in increased in Ca²⁺,K⁺and Cl^- currents.
      - Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated arrhythmias.
        
        These effects are blocked by β-adrenergic receptor blockers.
      - β-adrenergic receptor blockers
        
        increase AV conduction time
        
        increase AV nodal refractoriness, thereby helping to terminate nodal reentrant arrhythmias.

Three mechanisms have been associated with many tachyarrhythmias.

Enhanced Automaticity
- Enhance automaticity is associatied with an increase in the slope of phase 4 depolarization results in
  - As a result of the increase in phase 4 slope the cell reaches threshold more often per minute resulting in higher heart rate.
  - Factors that increase automaticity include
    - Mechanical stretch
    - β-adrenergic stimulation
    - Hypokalemia
    - Ischemia can induce abnormal automaticity, i.e. automaticity that occurs in cells not typically exhibiting pacemaker activity.
Triggered Automaticity
- Triggered automaticity occurs when a second depolarization occurs prematurely.
  - One type of triggered automaticity is a delayed afterdepolarization (DAD).
    - If this late depolarization reaches threshold (a) second beat(s) may occur.
  - Factors that predispose to delayed afterdepolarizations include:
    - Excessive adrenergic activity
    - Digitalis toxicity
    - High intracellular Ca²⁺
- A second type of triggered automaticity is Early Afterdepolarization (EAD) which is associated with significant prolongation of the action potential duration.
  - In this case, during a prolonged phase 3 repolarization, the repolarization is interrupted by a second depolarization.
  - Factors that predispose to Early Afterdepolarizations include:
    - Bradycardia
    - Low extracellular K⁺
    - Certain drugs, including some antiarrhythmics
- Torsades de pointes, a polymorphic ventricular arrhythmia- associated with
  - Prolongation of cardiac repolarization (prolonged Q-T interval)
  - Possibly induced by early afterdepolarizations.
- The antiarrhythmic drug quinidine gluconate (Quinaglute, Quinalan) can cause this arrhythmia.
  - Many other drugs can also cause this effect.

Reentry is the most common cardiac conduction abnormality leading to arrhythmias.

**Reentry Arrhythmia**

PF: Branched Purkinje Fiber terminating on ventricular muscle (VM). Shaded Area: Depolarized region with unidirectional (one-way) block (Decremental conduction, impulse slowly dies out) slowed conduction may be due to depression of Na⁺ or Ca²⁺ currents (e.g. AV node) Retrograde impulses (wavy line) propagate slow enough such that cells in branch 1 are no longer refractory and can be activated by the re-entry potential. Drugs that terminate reentry may further depress conduction, converting the "unidirectional" block to a "bidirectional" block A reentrant circuit involves a pathway that bifurcates into two branches. One pathway is blocked to anterograde conduction, but can be excited in a retrograde manner by the impulse that traversed the unblocked path. Retrograde conduction occurs until excitation of now non-refractory tissue re-initiates the process.

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton and Lange, 1998, pp 216-241.