Antiarrhythmic DrugsAntiarrhythmic DrugsTypes of Cardiac Arrhythmias:Types of Cardiac Arrhythmias:

Abnormalities of Impulse Formation:Abnormalities of Impulse Formation:Rate disturbances.Rate disturbances.Triggered automaticity.Triggered automaticity.

Abnormalities of Impulse Conduction:Abnormalities of Impulse Conduction:Blocks.Blocks.Reentry.Reentry.

Causes of Cardiac ArrhythmiasCauses of Cardiac ArrhythmiasCardiac Causes:Cardiac Causes:

Ischemic heart disease.Ischemic heart disease.

Inflammation.Inflammation.

Trauma e.g. heart surgery. Trauma e.g. heart surgery.

Congestive heart failure.Congestive heart failure.

Hypotension.Hypotension.

Causes of Cardiac ArrhythmiasCauses of Cardiac Arrhythmias

Non Cardiac Causes:Non Cardiac Causes:Electrolyte imbalance.Electrolyte imbalance.Acid-Base imbalance.Acid-Base imbalance.Hypoxia.Hypoxia.Drugs: Digitalis, Anesthetics, Tricyclic, Drugs: Digitalis, Anesthetics, Tricyclic,

Diuretics, Diuretics, Bronchodilators.Bronchodilators.G.I. reflexes.G.I. reflexes.Neural reflexes. Neural reflexes.

Pre-requisites for ReentryPre-requisites for Reentry(Circus Movement)(Circus Movement)

Anatomic or physiologic obstacle.Anatomic or physiologic obstacle.

Unidirectional block.Unidirectional block.

Conduction time around the circuit must be Conduction time around the circuit must be longer than the effective refractory period.longer than the effective refractory period.

Torsade de PointesTorsade de PointesPolymorphic Ventricular TachycardiaPolymorphic Ventricular Tachycardia

LQT, syncope, and sudden death.LQT, syncope, and sudden death.Causes:Causes:

Familial long QT intervalFamilial long QT intervalDrug - Induced (drugs which prolong APD)Drug - Induced (drugs which prolong APD)

Mechanisms:Mechanisms:Increased inward current (GF), or Increased inward current (GF), or Decreased outward (LF) current during Decreased outward (LF) current during

the plateau.the plateau.Genetic Studies:Genetic Studies:

300 different mutations in at least 8 ion 300 different mutations in at least 8 ion channel genes. channel genes.

Torsade de PointesTorsade de PointesRisk Factors:Risk Factors:

Bradycardia.Bradycardia.Hypokalemia.Hypokalemia.Triggered upstrokes.Triggered upstrokes.Drugs which Drugs which APD. APD.

Treatment:Treatment:K+ K+ Triggered upstrokes (Triggered upstrokes ( Blockers or Blockers or Mg++)Mg++) APD (Pacemaker APD (Pacemaker oror isoproterenol). isoproterenol).

www.sads.orgwww.sads.org

Other Congenital ArrhythmiasOther Congenital ArrhythmiasShort QT Syndrome:Short QT Syndrome:– GF mutations in three potassium channel GF mutations in three potassium channel

genes(KCNH2, KCNQ1, and KCNJ2).genes(KCNH2, KCNQ1, and KCNJ2).

Chatecholaminergic Polymorphic Chatecholaminergic Polymorphic Ventricular Tachycardia (CPVT):Ventricular Tachycardia (CPVT):– Stress or emotion-induced syncope.Stress or emotion-induced syncope.– Caused by mutations in sarcoplasmic proteins Caused by mutations in sarcoplasmic proteins

that control calcium.that control calcium.

Other Congenital ArrhythmiasOther Congenital ArrhythmiasSick Sinus Syndrome:Sick Sinus Syndrome:– Mutations in HCN4 and SCN5AMutations in HCN4 and SCN5ABrugada Syndrome:Brugada Syndrome:– Ventricular fibrillation, persistent ST elevation, Ventricular fibrillation, persistent ST elevation,

and BBB.and BBB.– Linked to LF mutations in SCN5ALinked to LF mutations in SCN5AFamilial Atrial Fibrillation:Familial Atrial Fibrillation:– Linked to GF mutation in the potassium Linked to GF mutation in the potassium

channel gene, KCNQ1.channel gene, KCNQ1.

AfterdepolarizationsAfterdepolarizations(Triggered Automaticity)(Triggered Automaticity)

Require a normal action potential for their initiation.Require a normal action potential for their initiation.Early Afterdepolarizations (EAD):Early Afterdepolarizations (EAD):– Interrupt phase 3.Interrupt phase 3.– Exacerbated at low heart rates.Exacerbated at low heart rates.– Contribute to development of long QT-related Contribute to development of long QT-related

arrhythmias.arrhythmias.Delayed Afterdepolarizations (DAD):Delayed Afterdepolarizations (DAD):– Occur with increased intracellular calcium.Occur with increased intracellular calcium.– Exacerbated by fast heart rates.Exacerbated by fast heart rates.– Responsible for arrhythmias of digitalis, Responsible for arrhythmias of digitalis,

catecholamines, and ischemia.catecholamines, and ischemia.

Nonpharmacologic TherapyNonpharmacologic TherapySurgery.Surgery.

Radiofrequency Catheter Ablation.Radiofrequency Catheter Ablation.

Implantable Cardioverter- Defibrillator (ICD).Implantable Cardioverter- Defibrillator (ICD).

Mechanism of Action of Antiarrhythmic DrugsMechanism of Action of Antiarrhythmic DrugsReadily bind to activated channels or inactivated Readily bind to activated channels or inactivated channels, but bind poorly to rested channels. channels, but bind poorly to rested channels. i.e.: i.e.: Use –Dependent or State-Dependent.Use –Dependent or State-Dependent.

Channels in normal cells will rapidly lose the Channels in normal cells will rapidly lose the drug from the receptors during the resting drug from the receptors during the resting portion of the cycle.portion of the cycle.This selectivity is lost with increasing doses, This selectivity is lost with increasing doses, leading to drug-induced arrhythmias.leading to drug-induced arrhythmias.Also, these drugs may become”Also, these drugs may become” Proarrhythmic or Proarrhythmic or Arrhythmogenic” Arrhythmogenic” during fast heart rates, during fast heart rates, acidosis, hyperkalemia, or ischemia.acidosis, hyperkalemia, or ischemia.

Class 1A DrugsClass 1A Drugs

Quinidine:Quinidine:Prototype, Antimalarial.Prototype, Antimalarial.Cinchona tree Cinchona tree Antipyretic. Antipyretic.Inhibits Inhibits and muscarinic and muscarinic

receptors.receptors.Slows upstroke, conduction, and Slows upstroke, conduction, and

prolongs APD and QRS duration.prolongs APD and QRS duration.

QuinidineQuinidine

Use restricted to patients with normal Use restricted to patients with normal hearts but have atrial or ventricular hearts but have atrial or ventricular arrhythmias.arrhythmias.Occasionally used in acute severe Occasionally used in acute severe malaria.malaria.

QuinidineQuinidineSide Effects:Side Effects:

Nausea (18%), Diarrhea (33%).Nausea (18%), Diarrhea (33%). Headache, Dizziness, and tinnitus= Headache, Dizziness, and tinnitus= CinchonismCinchonism Hypersensitivity, fever, rash, angioedema.Hypersensitivity, fever, rash, angioedema.Thrombocytopenia.Thrombocytopenia.Excessive prolongation of QT interval, slowed Excessive prolongation of QT interval, slowed conduction and sudden death (TdP).conduction and sudden death (TdP).Hypotension.Hypotension.Serum Digoxin levels.Serum Digoxin levels. Warfarin effects.Warfarin effects.Sudden death.Sudden death.

Class 1A DrugsClass 1A Drugs

Procainamide: Procainamide: Oral, but has short t½.Oral, but has short t½.L.E. (30% of patients Tx over 6 L.E. (30% of patients Tx over 6

moths)moths)Acetylated Acetylated NAPA (Class III) action NAPA (Class III) action

DisopyramideDisopyramideMore anticholinergic effects but More anticholinergic effects but

less less diarrhea (X40) than quinidinediarrhea (X40) than quinidine

Class 1B DrugsClass 1B Drugs Lidocaine:Lidocaine:

High affinity to bind with activated and High affinity to bind with activated and inactivated Na+ channels with rapid inactivated Na+ channels with rapid kinetics.kinetics. Acts selectively on ischemic tissue to Acts selectively on ischemic tissue to promote conduction & block reentry.promote conduction & block reentry.

More effective with More effective with K+. K+.Not effective in atrial arrhythmias.Not effective in atrial arrhythmias.

Class 1B DrugsClass 1B DrugsLidocaine:Lidocaine:Kinetics:Kinetics:

Well absorbed, but ineffective orally, due to first Well absorbed, but ineffective orally, due to first pass effect.pass effect.

Well distributed, including the brain.Well distributed, including the brain.Side Effects:Side Effects:

Least cardiotoxic of the class, except for Least cardiotoxic of the class, except for hypotension hypotension with high doses due to depression with high doses due to depression of the of the myocardium. myocardium. CNS: parasthesia, tremor, nausea, slurred CNS: parasthesia, tremor, nausea, slurred speech, speech, and convulsions.and convulsions.

Was routinely given to all MI patients to prevent Was routinely given to all MI patients to prevent ventricular arrhythmias.ventricular arrhythmias.

Class 1B DrugsClass 1B DrugsTocainide:Tocainide:

Oral analog of lidocaine.Oral analog of lidocaine.CNS, GI and blood dyscrasia.CNS, GI and blood dyscrasia.

Mexiletine:Mexiletine:Oral analog of lidocaine.Oral analog of lidocaine.

Neurologic side effects.Neurologic side effects.Phenytoin:Phenytoin:

Digitalis induced arrhythmias.Digitalis induced arrhythmias. Epilepsy. Epilepsy.

Congenital heart surgery.Congenital heart surgery.Congenital prolonged QT interval. Congenital prolonged QT interval.

Class 1C DrugsClass 1C Drugs Flecainide:Flecainide:

Potent blocker of Na + and K+ channels.Potent blocker of Na + and K+ channels.Negative inotropic effect.Negative inotropic effect.Proarrhythmic Proarrhythmic ventricular. ventricular.Effective in supra ventricular Effective in supra ventricular

tachycardia with normal hearts.tachycardia with normal hearts.Side Effects:Side Effects: Ventricular arrhythmias, Ventricular arrhythmias, CNS, and sudden death.CNS, and sudden death.

Class 1C DrugsClass 1C Drugs

Propafenone:Propafenone: Blocks Na+ channels but also has some Blocks Na+ channels but also has some Beta blocking and Ca++ blocking Beta blocking and Ca++ blocking

activity.activity.No effect on QT interval.No effect on QT interval.

Used for supraventricular arrhythmias.Used for supraventricular arrhythmias. Side effects: metallic taste, Side effects: metallic taste, constipation, constipation, and arrhythmias.and arrhythmias.

Class II DrugsClass II Drugs Propranolol:Propranolol:

Besides beta blocking, membrane Besides beta blocking, membrane stabilization, and intrinsic sympathmimetic stabilization, and intrinsic sympathmimetic activities, has effective antiarrhythmic activities, has effective antiarrhythmic activity activity Very effective, well tolerated, and Very effective, well tolerated, and documented to reduce mortality after acute documented to reduce mortality after acute myocardial infarction by reducing myocardial infarction by reducing arrhythmias.arrhythmias.

Class II DrugsClass II Drugs Esmolol:Esmolol:Short acting, used in intraoperative and Short acting, used in intraoperative and acute arrhythmiasacute arrhythmiasββ1 selective1 selectiveNo membrane stabilization effect.No membrane stabilization effect.

Acebutolol:Acebutolol:Short acting, used in intraoperative and Short acting, used in intraoperative and acute arrhythmias.acute arrhythmias.ββ1-selective.1-selective.Also has direct membrane stabilizing.Also has direct membrane stabilizing.

Class III DrugsClass III Drugs Amiodarone:Amiodarone:

Blocks K+ channels and markedly prolongs Blocks K+ channels and markedly prolongs APD.APD.

Class I actions.Class I actions.Blocks Blocks and and Receptors. Receptors.Ca++ blocking actions.Ca++ blocking actions.

Reserved for life-threatening atrial and Reserved for life-threatening atrial and ventricular ventricular arrhythmias.arrhythmias. Only slows heart rate and AV conduction.Only slows heart rate and AV conduction. Low incidence of TdP despite significant Low incidence of TdP despite significant QT QT prolongation.prolongation. Peripheral vasodilator (only with IV). Peripheral vasodilator (only with IV).

Class III DrugsClass III DrugsAmiodarone:Amiodarone:

Given IV (Loading dose 10gm) and orally.Given IV (Loading dose 10gm) and orally.Slow kinetics (t½ 25-110 days), metabolized by CYP3A4 Slow kinetics (t½ 25-110 days), metabolized by CYP3A4 enzymes.enzymes.

Toxicity:Toxicity: mainly extracardiac and dose related.mainly extracardiac and dose related. Lungs (Fibrosis in 1%). Lungs (Fibrosis in 1%). CNS.CNS. Thyroid( hypo and hyper).Thyroid( hypo and hyper). GI and liver.GI and liver. Corneal deposits, Corneal deposits, Skin (photodermatitis and discoloration).Skin (photodermatitis and discoloration). Digoxin & Anticoagulants.Digoxin & Anticoagulants. Interactions: affected by CYP3A4 activity and can inhibit Interactions: affected by CYP3A4 activity and can inhibit other enzymes.other enzymes.

Class III DrugsClass III DrugsSotalol:Sotalol:

Beta blocker and Class III actions.Beta blocker and Class III actions.Atrial and ventricular arrhythmias.Atrial and ventricular arrhythmias.Bradycardia, HF, Prolongation of QT.Bradycardia, HF, Prolongation of QT.

Bretylium Tosylate:Bretylium Tosylate: Originally an antihypertensive, but tolerance Originally an antihypertensive, but tolerance develops.develops.

Releases NE, then Releases NE, then Release / Reuptake Release / ReuptakeRarely used except in the prevention of Rarely used except in the prevention of

ventricular fibrillation after cardiversion and ventricular fibrillation after cardiversion and lidocaine.lidocaine.

Hypotension, Parotid swelling.Hypotension, Parotid swelling.Ibutilide.Ibutilide.Dofetilide.Dofetilide.

Class IV DrugsClass IV Drugs(Ca++ Channel Blockers)(Ca++ Channel Blockers)

VerapamilVerapamilDiltiazemDiltiazem

Block activated and inactivated L-type Ca+= channels.Block activated and inactivated L-type Ca+= channels.Effects more marked in tissues that fire frequently, less Effects more marked in tissues that fire frequently, less completely polarized at rest and those dependant on Ca+ completely polarized at rest and those dependant on Ca+ (SA node and AV node).(SA node and AV node).Paroxysmal Supraventricular Tachycardia.Paroxysmal Supraventricular Tachycardia.Vasodilators and have negative inotropic effects.Vasodilators and have negative inotropic effects.Can cause severe AV block in diseased hearts.Can cause severe AV block in diseased hearts.Safe: Constipation, gastric discomfort, vertigo, headache, Safe: Constipation, gastric discomfort, vertigo, headache, nervousness, pruritis. nervousness, pruritis. Digoxin levels.Digoxin levels.

Properties of Several Recognized Voltage-Activated Calcium Channels.

TypeChannel Name

Where FoundProperties of the Calcium Current

Blocked By

LCaV1.1–CaV1.3 

Cardiac, skeletal, smooth muscle, neurons (CaV1.4 is found in retina), endocrine cells, bone 

Long, large, high threshold

Verapamil, DHPs, Cd2+,   -aga-IIIA 

TCaV3.1–CaV3.3 

Heart, neuronsShort, small, low threshold

sFTX, flunarizine, Ni2+, mibefradil1

 NCaV2.2

 Neurons, sperm2

 Short, high threshold

Ziconotide,3 gabapentin,4   -CTX-GVIA,   -aga-IIIA, Cd2+

 P/QCaV2.1

 NeuronsLong, high

threshold   -CTX-MVIIC,   -aga-IVA

RCaV2.3 

Neurons, sperm2

 PacemakingSNX-482,   -

aga-IIIA

Miscellaneous DrugsMiscellaneous Drugs

Digoxin:Digoxin:Old fashioned agent for atrialOld fashioned agent for atrial

arrhythmias.arrhythmias. Direct Actions.Direct Actions.

Vagotonic Effects.Vagotonic Effects. AV refractoriness.AV refractoriness.

Miscellaneous DrugsMiscellaneous DrugsMagnesium:Magnesium:

Works on Na+/K+ ATPase, Na+ channels, certain K+ Works on Na+/K+ ATPase, Na+ channels, certain K+ channels and Ca++ channels.channels and Ca++ channels.Effective IV in refractory digitalis- induced Effective IV in refractory digitalis- induced ventricular arrhythmias only in hypomagnesemic ventricular arrhythmias only in hypomagnesemic patients.patients.Also, in TdP patients even if serum Mg++ is normal.Also, in TdP patients even if serum Mg++ is normal.

Potassium salts:Potassium salts:In digitalis- induced arrhythmias wit hypokalemia.In digitalis- induced arrhythmias wit hypokalemia.Depress ectopic pacemakers and slow conduction. Depress ectopic pacemakers and slow conduction.

Miscellaneous DrugsMiscellaneous Drugs

Adenosine:Adenosine: Naturally occurring nucleoside.Naturally occurring nucleoside. Activates inward rectifier K+ current and Activates inward rectifier K+ current and

inhibits inhibits Ca++ current.Ca++ current. Very short acting (t1/2 10 seconds).Very short acting (t1/2 10 seconds). Phase 4 depolarization in SA node.Phase 4 depolarization in SA node. AV conduction.AV conduction. No effect on ventricles. No effect on ventricles.

Miscellaneous DrugsMiscellaneous DrugsAdenosine:Adenosine:

90-95% effective in supraventricular 90-95% effective in supraventricular tachycardia.tachycardia. Less effective in the presence of Less effective in the presence of adenosine adenosine receptor receptor blockers e.g. blockers e.g. theophylline and theophylline and caffeine. caffeine. Can cause very short –lived flushing (20%), Can cause very short –lived flushing (20%), chest chest tightness, AV block, headache, tightness, AV block, headache, hypotension, nausea, hypotension, nausea, and parasthesia. and parasthesia.