ANTI-ARRHYTHMIC DRUGS Pharmacology (Lecture) | Study notes Pharmacology

Irelia: The Blade Dancer; Jicama

ANTI-ARRHYTHMIC DRUGS

Pharmacology (Lecture)

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 5

CARDIAC ARRHYTHMIAS

Ø 25% treated with digitalis

Ø 50% anesthetized patients

Ø 80% patients with AMI

Ø Reduced cardiac output

Ø Srugs or nonpharmacologic: pacemaker,

cardioversion, catheter ablation, surgery

Ø Result from

• Disturbance in impulse formation

• Disturbance in impulse conduction

• Both

ELECTROPHYSIOLOGY OF NORMAL CARDIAC RHYTHM

Ø SA node à atria à AV node à His-Purkinje system

à ventricles

IONIC BASIS OF MEMBRANE ELECTRICAL ACTIVITY

Ø The movement of these ions produces currents that

form the basis of the cardiac action potential: sodium,

calcium, potassium

Table 1. Effects of Potassium

Hyperkalemia

Hypokalemia

• Reduced AP duration

• Slowed conduction

• Decreased pacemaker

rate

• Decrease pacemaker

(arrhythmogenesis)

• Prolonged AP duration

• Increased pacemaker

rate

• Increase pacemaker

(arrhythmogenesis)

Table 2. Types of Arrhythmias

Supraventricular

Hypokalemia

• Atrial tachycardia

• Paroxysmal tachycardia

• Multifocal atrial

tachycardia

• Atrial fibrillation

• Atrial flutter

• Wolff-Parkinson-White

(preexcitation

syndrome)

• Ventricular tachycardia

• Ventricular fibrillation

• Premature ventricular

contraction

CLASSES OF ANTI-ARRHYTHMIC DRUGS

Ø Class I: Sodium Channel Blocking Drugs

Ø Class II: Beta-blockers

Ø Class III: Potassium Channel Blockers

Ø Class IV: Calcium Channel Blockers

Ø Miscellaneous

SODIUM CHANNEL BLOCKING DRUGS

Ø IA

• Lengthen AP duration

• Intermediate interaction with Na+ channels

• Quinidine, Procainamide, Disopyramide

Ø IB

• Shorten AP duration

• Rapid interaction with Na+ channels

• Lidocaine, Mexiletene, Tocainide, Phenytoin

Ø IC

• No effect or minimal ⁭ AP duration

• Slow interaction with Na+ channels

• Flecainide, Propafenone, Moricizine

CLASS IA

Ø Procainamide

Ø Quinidine

Ø Disopyramide

PROCAINAMIDE

Ø Prolongs APD

Ø Slows upstroke of AP, slows conduction, prolongs the

QRS duration of the ECG

Ø Direct depressant actions on SA amd AV nodes

Ø More effective in blocking Na+ channels in

depolarized cells

Ø Extracardiac: ganglion-blocking properties à

reduces PVR à hypotension

Ø Toxicity:

• Cardiotoxic: excessive AP prolongation, QT

interval prolongation, torsade de pointes,

syncope, excessive slowing of conduction

• Ppt. new arrhythmias

• LE-like syndrome (arthralgia, arthritis)

• ↑ ANA

• Pleuritis, pericarditis, parenchymal pulmonary

disease

• Nausea, DHA, rash, fever, hepatitis,

agranulocytosis

Ø Pharmacokinetics

• IV, IM, Oral

• Metabolite N-acetylprocainamide (NAPA) has

class 3 activity à accumulation may induce

torsades de pointes

Overview

I. Cardiac Arrhythmias

II. Treatment

III. Sodium Channel Blockers

IV. Beta- Adrenergic Blocking Agents

V. Potassium Channel Blockers

VI. Calcium Channel Blockers

VII. Miscellaneous Anti-Arrhythmic Agents and

Other Drugs that act on Channels

VIII. Selection of Rhythm Control Therapies

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ANTI-ARRHYTHMIC DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 5

CARDIAC ARRHYTHMIAS

Ø 25% treated with digitalis Ø 50% anesthetized patients Ø 80% patients with AMI Ø Reduced cardiac output Ø Srugs or nonpharmacologic : pacemaker, cardioversion, catheter ablation, surgery Ø Result from

Disturbance in impulse formation
Disturbance in impulse conduction
Both ELECTROPHYSIOLOGY OF NORMAL CARDIAC RHYTHM Ø SA node à atria à AV node à His-Purkinje system à ventricles IONIC BASIS OF MEMBRANE ELECTRICAL ACTIVITY Ø The movement of these ions produces currents that form the basis of the cardiac action potential: sodium, calcium, potassium Table 1. Effects of Potassium Hyperkalemia Hypokalemia
Reduced AP duration
Slowed conduction
Decreased pacemaker rate
Decrease pacemaker (arrhythmogenesis)
Prolonged AP duration
Increased pacemaker rate
Increase pacemaker (arrhythmogenesis) Table 2. Types of Arrhythmias Supraventricular Hypokalemia
Atrial tachycardia
Paroxysmal tachycardia
Multifocal atrial tachycardia
Atrial fibrillation
Atrial flutter
Wolff-Parkinson-White (preexcitation syndrome)
Ventricular tachycardia
Ventricular fibrillation
Premature ventricular contraction CLASSES OF ANTI-ARRHYTHMIC DRUGS Ø Class I : Sodium Channel Blocking Drugs Ø Class II : Beta-blockers Ø Class III : Potassium Channel Blockers Ø Class IV : Calcium Channel Blockers Ø Miscellaneous SODIUM CHANNEL BLOCKING DRUGS Ø IA
Lengthen AP duration
Intermediate interaction with Na+ channels
Quinidine, Procainamide, Disopyramide Ø IB
Shorten AP duration
Rapid interaction with Na+ channels
Lidocaine, Mexiletene, Tocainide, Phenytoin Ø IC
No effect or minimal AP duration
Slow interaction with Na+^ channels
Flecainide, Propafenone, Moricizine CLASS IA Ø Procainamide Ø Quinidine Ø Disopyramide PROCAINAMIDE Ø Prolongs APD Ø Slows upstroke of AP, slows conduction, prolongs the QRS duration of the ECG Ø Direct depressant actions on SA amd AV nodes Ø More effective in blocking Na+ channels in depolarized cells Ø Extracardiac: ganglion-blocking properties à reduces PVR à hypotension Ø Toxicity:
Cardiotoxic : excessive AP prolongation, QT interval prolongation, torsade de pointes, syncope, excessive slowing of conduction
Ppt. new arrhythmias
LE - like syndrome (arthralgia, arthritis)
↑ ANA
Pleuritis, pericarditis, parenchymal pulmonary disease
Nausea, DHA, rash, fever, hepatitis, agranulocytosis Ø Pharmacokinetics
IV, IM, Oral
Metabolite N - acetylprocainamide (NAPA) has class 3 activity à accumulation may induce torsades de pointes Overview I. Cardiac Arrhythmias II. Treatment III. Sodium Channel Blockers IV. Beta- Adrenergic Blocking Agents V. Potassium Channel Blockers VI. Calcium Channel Blockers VII. Miscellaneous Anti-Arrhythmic Agents and Other Drugs that act on Channels VIII. Selection of Rhythm Control Therapies

ANTI-ARRHYTHMIC DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 5

Metabolism : hepatic
Elimination : renal
Half-life : 3 – 4 hours
Dosage : Loading dose – 12mg/kg IV at 0.3mg/kg/min
Maintenance dose : 2 – 5 mg/min
Plasma concentration > 8 mcg/ml or NAPA >20 mcg/ml : GI or cardiac toxicity
Dose to control ventricular arrhythmia : 2 - 5 g/day
Renal disease : reduce dose Ø Therapeutic use
Drug of 2 nd^ or 3 rd^ choice (after Lidocaine or Amiodarone) in most coronary care units for the treatment of sustained Ventricular Arrhythmias associated with Acute Myocardial Infarction
Atrial and Ventricular Arrhythmias QUINIDINE Ø Pharmacokinetics
Oral → rapid GI absorption
80% plasma protein binding
20% excreted unchanged in the urine → enhanced by acidity
t½ = 6 hours
Parenteral → hypotension
Dosage : 0.2 to 0.6 gm 2 - 4X a day
Slows the upstroke of the AP, slows conduction, prolongs QRS duration Ø Toxic cardiac effects
Excessive QT-interval prolongation
Induction of torsades de pointes
Excessive Na+ blockade à slows conduction Ø Therapeutic Uses :
Atrial flutter and fibrillation
Ventricular tachycardia
IV treatment of malaria Ø Drug Interaction : increases digoxin plasma levels Ø Toxicity
Antimuscarinic actions → inhalation à vagal effects
Quinidine syncope (lightheadedness, fainting)
Ppt. arrhythmia or asystole
Depress contractility and ↓ BP
Widening QRS duration
Diarrhea, nausea, vomiting
Cinchonism (HA, dizziness, tinnitus)
Rare : rashes, fever, hepatitis, thrombocytopenia DISOPYRAMIDE Ø More marked cardiac antimuscarinic effects than quinidine → slows AV conduction Ø Pharmacokinetics
Oral administration
Extensive protein binding
t½ = 6 to 8 hours
Dosage : 150 mg TID up to 1 gm/day Ø Therapeutic Use : Ventricular arrhythmias Ø Toxicity : negative inotropic action (HF without prior myocardial dysfunction) Ø Urinary retention, dry mouth, blurred vision, constipation, worsening glaucoma CLASS IB Ø Lidocaine Ø Mexiletene Ø Tocainide Ø Phenytoin LIDOCAINE Ø Intravenous route only Ø Blocks activated and inactivated Na+ channels Ø Little effect in normal sinus rhythm Ø Shorten AP, prolonged diastole → extends time available for recovery Ø Suppresses electrical activity of DEPOLARIZED, ARRHYTHMOGENIC tissues only Ø Pharmacokinetics
Extensive first-pass hepatic metabolism
T½ = 1 to 2 hours
Dosages : LD- 150 to 200 mg; MD: 2 - 4 mg
Therapeutic plasma level : 2 – 5 mcg/m and Ml and acute illness à higher doses needed due to ↑ ⍶ 2 - acid glycoprotein that binds lidocaine Ø Therapeutic use : agent of choice for termination of ventricular tachycardia and prevent ventricular fibrillation after cardioversion in the setting of acute ischemia Ø Toxicity
Patients with preexisting HF HYPOTENSION (due to ↓ myocardial contractility)
Neurologic : most common ü Paresthesias, tremor, nausea, lightheadedness, hearing disturbances, slurred speech, convulsions ü Seizures : IV diazepam
Proarrhythmic effects : uncommon ü SA node arrest, worsening of impaired conduction, ventricular arrhythmia MEXILETENE Ø Orally active congener of lidocaine Ø Therapeutic use : ventricular arrhythmias Ø Elimination t½ = 8 to 20 hours (2-3x/day) Ø Dosage : Mexiletene – 600 to 1200 mg/day Ø S/E : Neurologic - tremors, blurred vision, lethargy, nausea, Ø Off-label : treatment of chronic pain esp. due to diabetic neuropathy and nerve injury (450-750mg/day) CLASS IC Ø Flecainide Ø Propafenone Ø Moricizine FLECAINIDE Ø Initially developed as a local anesthetic Ø Cause severe exacerbation of arrhythmia in
Preexisting ventricular tachyarrhythmia
Previous MI
Ventricular ectopy Ø Potent blocker of Na+ and K+ channels

ANTI-ARRHYTHMIC DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 5

Ø Doubles the interval between episodes of AF recurrence in patients with paroxysmal or persistent AF Ø Half-life : 24 hours (administered b.i.d.) Ø No thyroid or pulmonary toxicity Ø 1 st^ antiarrhythmic drug to demonstrate reduction in mortality or hospitalization in patients with AF CELIVARONE Ø Non-iodinated benzofuran derivative similar to Dronaderone Ø Clinical trials for prevention of ventricular tachycardia recurrence SOTALOL Ø Nonselective beta-blocker à slows repolarization and prolongs AP duration Ø Treatment of life-threatening ventricular arrhythmias Ø Maintains normal sinus rhythm in patients with AF Ø Supraventricular and ventricular arrhythmias in pediatric age group Ø Depress LV function in overt heart failure Ø Oral Ø 100% bioavailability Ø Renal excretion Ø t½ = 12 hours Ø Dosage : 80 – 320 mg bid Ø Toxicity : torsades de pointes DOFETILIDE Ø Prolongs action potential

dose dependent blockade of the rapid component of the delayed rectifier Ikr current
blockade of Ikr in hypokalemia Ø Clinical uses
Maintenance of normal sinus rhythm in AF
Restoring NSR in patients with AF Ø Dosage based on creatinine clearance Ø Toxicity: Torsade de pointes IBUTILIDE Ø Prolongs cardiac action potentials Ø MOA: slows cardiac repolarization and enhance slow inward Na+ current by blocking Ikr- Ø Routes: oral, IV (1 mg over 10min) Ø Clinical uses
IV : acute conversion of atrial flutter and AF to NSR
More effective in converting atrial flutter to NSR than atrial fibrillation Ø Hepatic metabolism, renal excretion Ø Elimination t½ = 6 hours Ø Toxicity : excessive QT interval prolongation, torsades de pointes CALCIUM CHANNEL BLOCKERS Ø Blocks cardiac calcium currents
Low conduction
Increase refractory period Ø *esp. in Ca++ dependent tissues (i.e. AV node) Ø Verapamil, Diltiazem, Bepridil

VERAPAMIL

Ø Blocks both activated and inactivated L-type calcium channels Ø Prolongs AV nodal conduction and effective refractory period Ø Suppress both early and delayed after-depolarizations Ø May antagonize slow responses in severely depolarized tissues Ø Peripheral vasodilatation → HPN and vasospastic disorders Ø Pharmacokinetics

Oral administration → 20% bioavailability
t½ = 4-7 hours
Liver metabolism
Dosage:
IV : 5-10 mg every 4-6 hours or infusion of 0. ug/kg/min
Oral: 120-640 mg daily, divided in 3-4 doses Ø Therapeutic Uses
Supraventricular tachycardia à major arrhythmia indication
Reduce ventricular rate in atrial fibrillation and flutter Ø Toxicity
Hypotension and ventricular fibrillation: IV administration in patients with ventricular tachycardia
Negative inotropic effects
Induce AV block in large doses and in patients with AV nodal disease
Extracardiac : constipation, lassitude, nervousness, peripheral edema DILTIAZEM Ø Similar efficacy with verapamil in management of SV arrhythmias Ø IV : used in AF à rarely cause hypotension 0r bradycardia MISCELLANEOUS ARRHYTHMIC AGENTS AND OTHER DRUGS THAT ACT ON CHANNELS Ø Adenosine Ø Ivabradine Ø Ranolazine Ø Vernakalant Ø Magnesium Ø Potassium DIGITALIS Ø Indirectly alters autonomic outflow by increasing parasympathetic tone and decreasing sympathetic tone Ø Results in decreased conduction time and increased refractory period in the AV node ADENOSINE Ø A nucleoside that occurs naturally in the body Ø t½ < 10 seconds Ø MOA : Activation of an inward rectifier K+^ current and inhibition of Ca++^ current à results in marked hyperpolarization and suppression of Ca++^ dependent

ANTI-ARRHYTHMIC DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 5

AP

Ø IV bolus : directly inhibits AV nodal conduction and ↑ AV nodal refractory period Ø DOC for prompt conversion of paroxysmal SVT to sinus rhythm due to its high efficacy and very short duration of action Ø Dosage : 6-12 mg IV bolus Ø Drug indications

Theophylline, caffeine : adenosine receptor blockers
Dipyridamole : adenosine uptake inhibitor Ø Toxicity : flushing, SOB or chest burning, AF, headache, hypotension, nausea, paresthesia IVABRADINE Ø Selective blocker of I f in the SA node Ø Slows pacemaker activity by decreasing diastolic depolarization of sinus node cells Ø Reduces HR without affecting myocardial contractility, ventricular repolarization or intracardiac conduction Ø Incomplete block of If à retained autonomic control of sinus node pacemaker Ø Direct bradycardic agent Ø Anti-anginal and anti-ischemic effects: CAD and chronic stable angina Ø Reduces mean HR à LV dysfunction, HR >70/bpm Ø Slows HR in Inappropriate Sinus Tachycardia Ø Dosage : 5-10 mg as needed Ø Use : visual disturbances RANOLAZINE Ø Inhibits persistent or late inward Na+ current ( I Na) and the rapid component of the delayed rectifier K+^ current (Ikr) à leads to reductions in elevated IC Ca++^ levels à prolongation of APD and QT interval Ø Metabolic modulator Ø Prevents induction of and may terminate AF Ø Atrial and ventricular arrhythmias VERNAKALANT Ø Multi-ion channel blocker developed for the treatment of Atrial Fibrillation Ø Prolongs atrial refractory period and slows conduction over the AV node à by blocking Ikur, IACh, and Ito which play a key role in atrial repolarization Ø Ventricular effective refractory period unchanged Ø Clinical use: IV for rapid termination of AF in patients with no or minimal structural heart disease Ø Toxicity : dysgeusia, sneezing, paresthesia, cough, hypotension, bradycardia Ø Pharmacokinetics
Oral : 900 mg b.i.d.
IV : metabolized in liver by CYP2D
t½ = 2 hours
Effective in converting recent-onset AF to normal sinus rhythm in 50% of patients MAGNESIUM Ø Effective in patients with recurrent episodes of torsades de pointes (MgSO 4 1 to 2 g IV) and in digitalis-induced arrhythmia Ø MOA : unknown → influence Na+/K+^ ATPase, Na+ channels, certain K+ and Ca++ channels POTASSIUM Ø Therapy directed toward normalizing K+^ gradients and pools in the body Ø Effects of increasing serum K+
Resting potential depolarizing action
Membrane potential stabilizing action Ø Hypokalemia
↑ risk of early and delayed afterdepolarization
↑ ectopic pacemaker activity especially if (+) digitalis Ø Hyperkalemia
Depression of ectopic pacemakers
Slowing of conduction SELECTION OF RHYTHM CONTROL THERAPIES R E F E R E N C E S

Anti-Arrhythmic drugs. Dr. Serrano, 2021. (Annotated Lecture)
Basic and Clinical Pharmacology. (14th^ ed). Katzung.

ANTI-ARRHYTHMIC DRUGS Pharmacology (Lecture), Study notes of Pharmacology

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Partial preview of the text

Download ANTI-ARRHYTHMIC DRUGS Pharmacology (Lecture) and more Study notes Pharmacology in PDF only on Docsity!

ANTI-ARRHYTHMIC DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 5

CARDIAC ARRHYTHMIAS

ANTI-ARRHYTHMIC DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 5

ANTI-ARRHYTHMIC DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 5

VERAPAMIL

ANTI-ARRHYTHMIC DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 5

AP