Mechanism and Pharmacological Effects of Quinidine

Quinidine Overview

• Class 1A antiarrhythmic drug.
• Mechanism: Blocks activated Na+ channels, decreasing phase-0 depolarization, excitability, and increasing action potential duration (APD) and effective refractory period (ERP).
• Effects: Vagal stimulation leads to increased AV conduction at low doses; direct action decreases AV conduction at therapeutic doses.
• Additional actions: Blocks muscarinic and α receptors causing vagolytic effects and hypotension.
• Indications: Previously used for supraventricular and ventricular arrhythmias and to maintain sinus rhythm post-atrial flutter and fibrillation; usage has declined due to availability of safer alternatives.

Adverse Effects and Precautions

• Cinchonism: Symptoms include tinnitus, headache, blurred vision, vomiting, and diarrhea.
• Hypotension: Can occur after rapid IV infusion due to α-receptor blockade.
• Paradoxical tachycardia: Quinidine's atropine-like action can increase AV conduction and cause "paradoxical tachycardia."
• Risk factors: Associated with arrhythmias in hypertrophic obstructive cardiomyopathy (HOCM) and mitral valve prolapse.

Amiodarone Overview

• Class III antiarrhythmic drug, structurally similar to thyroxine, containing ~40% iodine.
• Mechanism: Blocks K+ channels, slowing phase 3 and increasing ERP; blocks Na+ channels and Ca2+ channels.
• Pharmacokinetics: Long half-life and large volume of distribution lead to accumulation and various adverse effects.
• Indications: Used for both supraventricular and ventricular arrhythmias, including Wolff-Parkinson-White (WPW) syndrome and refractory arrhythmias.

Adenosine Overview

• Purinergic A1 receptor agonist, opens K+ channels and inhibits Ca2+ channels, causing hyperpolarization and inhibiting AV nodal conduction.
• Extremely short half-life of 8-10 seconds.
• Drug of choice for immediate termination of paroxysmal supraventricular tachycardia, administered as a 6 mg IV bolus followed by 12 mg if necessary.
• Less effective with adenosine receptor blockers (e.g., theophylline, caffeine) and contraindicated in asthma patients due to potential bronchospasm.

Non-Pharmacological Methods

DC Cardioversion

• Direct current delivery via electric shock for emergency control of arrhythmias, especially unstable rapid AF.
• Patients should be heparinized prior to the procedure and anticoagulated post-procedure for at least 4 weeks.

Laser Ablation

• Catheter insertion into specific heart areas, where energy is applied to abnormal rhythm-causing tissue.
• Laser radiofrequency ablation is definitive treatment for WPW syndrome.

Artificial Pacemakers and Implantable Cardioverter-Defibrillators

• Battery-powered devices implanted under the skin or in the chest cavity to monitor and pace the heart.

Quinidine (Subclass 1A)

• Blocks activated Na+ channels, decreasing phase-0 depolarization rate, excitability, increases action potential duration (APD) and effective refractory period (ERP).
• Inhibits muscarinic and α receptors, leading to atropine-like vasodilatory effects and hypotension.
• Effects on AV conduction are complex:
  • Low doses enhance AV conduction due to predominant vagolytic action.
  • Therapeutic doses reduce AV conduction via direct action.
• Exhibits negative inotropic effects and has anti-malarial properties against Plasmodium falciparum.
• Must administer digitalis or verapamil prior to quinidine to control AV conduction and heart rate.
• Can prolong QT interval, posing a risk for serious arrhythmias (like Torsades de Pointes).
• Contraindicated in patients with long QT syndrome.

Procainamide (Subclass 1A)

• Comparable antiarrhythmic agent to quinidine with akin cardiac and toxic effects; currently used less frequently.
• Metabolized by hepatic acetylation; 30% of patients (slow acetylators) may develop drug-induced systemic lupus erythematosus (SLE) with long-term use.
• Effective for arrhythmias associated with hypertrophic obstructive cardiomyopathy (HOCM) and supraventricular arrhythmias (such as atrial fibrillation).

Amiodarone (Class III)

• Structurally related to thyroxine with approximately 40% iodine content; dronedarone is a similar compound without iodine.
• Long half-life and high volume of distribution lead to tissue accumulation and various adverse effects.
• Mechanism of action:
  • Mainly blocks K+ channels, slowing phase 3 depolarization, thus increasing ERP.
  • Also blocks Na+ channels, reducing excitability.
  • Blocks Ca2+ channels, leading to negative inotropic and chronotropic effects.
• Used for both supraventricular and ventricular arrhythmias, as well as Wolff-Parkinson-White (WPW) syndrome.
• Adverse effects include dose-related pulmonary toxicity (fibrosis), hepatic toxicity, thyroid dysfunction, corneal microdeposits (reversible), bradycardia, heart block, and photosensitivity leading to skin discoloration.

Calcium Channel Blockers (Class IV: Verapamil and Diltiazem)

• Mechanism of action: decrease activity in the Sinoatrial Node (SAN) and AV conduction.
• Primarily used to reduce heart rate in supraventricular tachycardia and arrhythmias linked to HOCM.
• Not recommended for chronic management of ventricular tachycardia (VT).
• Acute use in VT is contraindicated due to potential for hemodynamic collapse.

Management of Cardiac Arrest

• Cardiac arrest characterized by cessation of mechanical heart activity, confirmed by absence of circulation signs (absent pulse and apnea).
• Common causes include coronary heart disease (~80%), cardiac conditions (HOCM, Brugada syndrome), arrhythmias (especially ventricular), trauma, electrolyte imbalances, electrical shock, and drug-related issues.
• Patterns of cardiac arrest:
  • Asystole: Flat line on ECG.
  • Ventricular fibrillation: ECG shows fibrillation waves.
  • Pulseless electrical activity (PEA): Electrical activity present without detectable pulse.
• Treatment aims to preserve life with early CPR (30:2 cycles).
• Additional management steps include:
  • Electrical defibrillation at 360J followed by 2 minutes of CPR.
  • If no response, administer epinephrine 1 mg IV every 3-5 minutes with CPR.
  • If still unresponsive, apply DC shocks and continue CPR for 2 minutes.
  • Administer amiodarone 300 mg IV if no response persists.

Quinidine (Class 1A)

• Blocks activated Na+ channels, leading to decreased phase-0 depolarization, reduced excitability, increased action potential duration (APD), and increased effective refractory period (ERP).
• Inhibits muscarinic and α-adrenergic receptors, producing atropine-like (vagal) effects and causing hypotension.
• Exhibits complex effects on AV conduction:
  • At low doses, vagolytic action increases AV conduction.
  • At therapeutic doses, direct action decreases AV conduction.
• Has a negative inotropic effect and is an effective antimalarial against Plasmodium falciparum.

Lidocaine (Class 1B)

• A selective Na+ channel blocker, primarily acting on damaged cardiac tissues; not administered orally due to extensive first-pass metabolism.
• Used intravenously for acute ventricular arrhythmia management, particularly after myocardial infarction (MI). Typical dose is 50-100 mg IV, repeat half dose after 5-10 minutes if required.
• Has no effect on AV conduction; not suitable for supraventricular arrhythmias.
• Adverse effects are predominantly neurologic.
• Mexiletine, similar to lidocaine, is orally available for long-term ventricular arrhythmia treatment post-MI.
• Phenytoin, an antiepileptic with Class 1B activity, primarily treats digitalis-induced tachyarrhythmia and has limited use for other ventricular arrhythmias. IV loading dose is 250 mg over 10 minutes.

Flecainide (Class 1C)

• Blocks both Na+ and K+ channels, decreasing phase-0 depolarization and slowing AV conduction; APD remains unchanged.
• Utilized for atrial and ventricular arrhythmias and maintaining sinus rhythm post-conversion from atrial flutter and fibrillation.
• Increases risk of ventricular fibrillation and sudden death post-MI (proarrhythmic effect), contraindicated in ischemic or structurally compromised hearts.

Class II: Beta Blockers

• Reduce sympathetic stimulation by inhibiting phase 4 depolarization, decreasing automaticity, prolonging AV conduction, decreasing heart rate, and lowering contractility.

Therapeutic Uses of Beta Blockers

• Effective for arrhythmias induced by sympathetic overactivity, thyrotoxicosis, hypertrophic obstructive cardiomyopathy (HOCM), supraventricular arrhythmias like atrial fibrillation, and arrhythmias associated with mitral valve prolapse.

Amiodarone (Class III)

• Structurally related to thyroxine with ~40% iodine content; Dronedarone is similar but iodine-free.
• Long half-life and large volume of distribution lead to accumulation in various tissues, causing diverse adverse effects.
• Mechanism of action:
  • Primarily blocks K+ channels, slowing phase 3 depolarization, increasing ERP.
  • Also inhibits Na+ channels, reducing excitability, and blocks Ca2+ channels, producing negative inotropic and chronotropic effects.

Therapeutic Uses of Amiodarone

• Treats both supraventricular and ventricular arrhythmias, including Wolff-Parkinson-White syndrome and arrhythmias resistant to other drugs.
• Patients may require heparinization prior to procedures and anticoagulation for at least 4 weeks after electrical cardioversion.

Laser Ablation

• Involves catheter insertion into specific heart areas; utilizes directed energy to treat abnormal rhythms.
• Radiofrequency ablation is the definitive treatment for WPW syndrome.

Artificial Pacemakers and Implantable Cardioverter Defibrillators

• Battery-powered devices implanted under the skin or in the chest to monitor and regulate heart rhythm.

Management of Cardiac Arrest

• Cardiac arrest signifies cessation of mechanical cardiac activity with no circulation signs (absent pulse and apnea).
• Major causes include coronary heart disease (~80%), cardiac conditions (e.g., HOCM, Brugada syndrome), arrhythmias, trauma, electrolyte imbalances, and drugs.

Patterns of Arrest

• Complete asystole: ECG displays a flat line.
• Ventricular fibrillation: ECG presents fibrillation waves.
• Pulseless electrical activity (PEA): Some electrical activity present without detectable pulse.

Management Protocol for Cardiac Arrest

• Initial goal: preserve life through early CPR (30 chest compressions followed by 2 rescue breaths).
• Initiate electrical defibrillation (360J), then resume CPR for 2 minutes.
• If unresponsive, administer epinephrine (1 mg IV every 3-5 minutes with CPR).
• Continue with direct current (DC) shock if no response; administer amiodarone (300 mg IV) with ongoing CPR.

Therapeutic Uses of Antiarrhythmic Drugs

• Quinidine: Historically used for supraventricular and ventricular arrhythmias; now rarely prescribed due to availability of more effective, less toxic alternatives.
• Procainamide: Comparable to quinidine; limited use due to similar effects and risk of drug-induced systemic lupus erythematosus (SLE) in some patients.
• Lidocaine: Selectively blocks Na+ channels, primarily used intravenously for acute ventricular arrhythmias, especially post-myocardial infarction (MI). Oral administration is avoided due to extensive first-pass metabolism.
• Flecainide: Blocks both Na+ and K+ channels, suppressing atrial and ventricular arrhythmias. Risks include increased chances of ventricular fibrillation and sudden death after MI, making it contraindicated for patients with ischemic or structural heart disease.

Class II: Beta Blockers

• Reduce sympathetic stimulation, which inhibits phase 4 depolarization and depresses automaticity.
• Therapeutic applications: Manage arrhythmias induced by sympathetic overactivity, thyrotoxicosis, hypertrophic obstructive cardiomyopathy (HOCM), atrial fibrillation (AF), and mitral valve prolapse.

Class III: Amiodarone

• Structurally related to thyroxine, contains about 40% iodine; dronedarone shares similar properties but without iodine.
• Long half-life and large volume of distribution allow tissue accumulation, leading to diverse side effects.
• Mechanism: Primarily blocks K+ channels, slowing phase 3 repolarization, and also blocks Na+ and Ca2+ channels, reducing excitability and providing negative inotropic and chronotropic effects.
• Used for a wide range of arrhythmias, including supraventricular and ventricular types, Wolff-Parkinson-White (WPW) syndrome, and refractory rhythms.

Laser Ablation Therapy

• Utilizes a catheter inserted into specific heart areas; energy is directed to ablate abnormal cardiac tissue responsible for irregular rhythms.
• Effective in treating various arrhythmias and is the definitive treatment for WPW syndrome.

Implantable Devices

• Artificial pacemakers and implantable cardioverter-defibrillators (ICDs) are battery-powered devices implanted under the skin to monitor heart rhythms and provide pacing as needed.

Quinidine (Subclass 1A)

• Blocks activated Na+ channels, reducing phase-0 depolarization, excitability, while increasing action potential duration (APD) and effective refractory period (ERP).
• Antagonizes muscarinic and α receptors resulting in atropine-like vagolytic and hypotensive effects.
• Exhibits dual actions on AV conduction:
  • At low doses, it enhances AV conduction due to vagolytic activity.
  • At therapeutic doses, it decreases AV conduction due to direct action.
• Has negative inotropic effects and anti-malarial properties against Plasmodium falciparum.
• Prior administration of digitalis or verapamil may help control AV conduction rate.
• Prolongs QT interval and predisposes patients to torsades de pointes; contraindicated in patients with long QT syndrome.

Procainamide (Subclass 1A)

• Comparable to quinidine as an antiarrhythmic agent with similar cardiac effects and toxicity.
• Limited usage in modern medicine.
• May cause drug-induced systemic lupus erythematosus (SLE) in slow acetylators after long-term therapy.

Lidocaine (Subclass 1B)

• Exclusively a Na+ channel blocker, highly selective for damaged tissues.
• Undergoes extensive first-pass metabolism; not suitable for oral administration.
• Administered intravenously for acute ventricular arrhythmias associated with myocardial infarction (MI).
• Does not affect AV conduction; not indicated for supraventricular arrhythmias.
• Common adverse effects are primarily neurological.
• Mexiletine, related to lidocaine, is orally effective for long-term ventricular arrhythmia management.
• Phenytoin, an antiepileptic, has class 1B activity useful in digitoxin-induced tachyarrhythmias.

Flecainide (Subclass 1C)

• Blocks both Na+ and K+ channels, slowing phase-0 depolarization and AV conduction without altering action potential duration.
• Indicated for atrial and ventricular arrhythmias and maintenance of sinus rhythm post-conversion from atrial flutter/fibrillation.
• Increases risk of ventricular fibrillation and sudden death post-MI; contraindicated in patients with ischemic or structural heart disease.

Class II: Beta Blockers

• Reduce sympathetic stimulation, inhibit phase 4 depolarization, decrease automaticity, prolong AV conduction, increase heart rate, and reduce contractility.
• Used for arrhythmias induced by sympathetic overactivity and those related to thyrotoxicosis.

Adenosine

• Acts as a purinergic A1 receptor agonist, enhancing K+ channel opening and inhibiting Ca2+ channels, leading to hyperpolarization in the AV system.
• Short half-life of 8-10 seconds.
• First-line treatment for rapid termination of paroxysmal supraventricular tachycardia, administered as an i.v. bolus.
• Efficacy reduced in the presence of adenosine receptor blockers such as theophylline or caffeine.
• Should not be used in patients with asthma due to bronchospasm risk.

Non-Pharmacological Methods

DC Cardioversion

• Application of direct current shock to the chest wall for rapid arrhythmia control, especially in unstable patients.
• Important to anticoagulate patients post-procedure.

Laser Ablation

• Targets specific cardiac areas via catheter insertion to treat various arrhythmias by disconnecting abnormal impulse pathways.
• Radiofrequency ablation is the definitive treatment for Wolff-Parkinson-White syndrome.

Artificial Pacemakers and Implantable Cardioverter-Defibrillators

• Battery-powered devices implanted under the skin or in the chest cavity to monitor and regulate heart rhythms.

This quiz focuses on the pharmacological effects and mechanisms of Quinidine, a medication used in treating cardiac arrhythmias. It covers its action on activated Na+ channels, effects on phase-0 depolarization, excitability, and action potential duration. Dive in to test your understanding of this vital topic in pharmacology.