Cardiac Arrhythmias

Agents Uesd in Cardiac Arrhythmias

1. Disturbance of impulse formation (abnormal automaticity) Interval between depolarization of a pacemaker cell 1) duration of the action potential 2) duration of the diastolic interval (1) maximum diastolic potential (2) slope of phase 4 depolarization (3) threshold potential vagal discharge: (1) and (2) ↓ beta blocker: (2) ↓ hypokalemia, beta-stmulation: (2)↑

Phae 3: early afterdepolarization (EAD) EAD: ⇐ haert rate ↓ long QT-related arrhythmias

Phase 4: delayed afterdepolarizationr (DAD) DAD:⇐ haert rate↑ intracellular Ca increased digitalis catecholamine myocardiac ischemia

2. Disturbance of Impulse conduction (reentrant) 1) obstacle 2) unidirectional block 3) conduction time

Atrioventricular nodal reenty (supraventricular tachycardia) Torsade de pointes long OT interval

II. Basic Pharmacology of the Antiarrhythmic Agents Mechanisms of Action 1. Automaticity of Ectopic Pacemakers: channel blocker

Use-dependent State-dependent

2. Reentry arrhythmias 1) reduces the excitatory current to a level below that required for propagation 2) Increase the effective refractory period

III. Specific Antiarrhythmic Agents

Miscellaneous: adenosine digitalis potassium ion magnesium ion

III. Specific Antiarrhythmic Agents Class I : sodium channel block class IA: lengthen the action potential duration quindine, procainamide, disopyramide class IB: shorten it: lidocaine, mexiletine, tocainide, phenytoin claas IC: no effect or may minimally increase action potential duration: flecainide IB : interact rapidly sodium channel IC: interact slowly IA: intermediate Class II: sympathoplegic Class III: prolongs the effective refractory period Class IV: block of cardiac calcium current

Sodium Channel-Blocking Drugs (Class IA) 1. Block Na channel ⇒ conduction ↓ ⇒ QRS duration ↑ 2. Block K channel ⇒ action potential duration ↑ ⇒ QT interval ↑ effective refractory period↑

Quindine Procainamide Disopyramide Amiodarone

Block of Na Refractory Ca Channel period channel norma depolarized normal depolarized blokade l cell cell cell cell + ++ 0 ↑ ↑ ↑ + +++ ↑ ↑ ↑ ↑ 0 + +++ + ↑ ↑ + +++ + ↑ ↑ ↑ ↑

Effect on Sympapacemake tholytic r action activity + ↓ ↓ + ↓ 0 + ↓ ↓

Effect on Effect on PR QRS QT Usefulness SA Nodal AV nodal interval duration interval Supra- Ventricu Rate refractory ventricu lar period lar 1,3 3 3 Quindine + +++ ↑ ↓ ↑ ↓ ↑ ↓ ↑ ↑ ↑ ↑ 1 3 3 Procainamide + +++ ↓ ↑ ↓ ↑ ↓ ↑ ↑ ↑ ↑ 1,3 3 3 Disopyramide + +++ ↑ ↓ ↑ ↓ ↑ ↓ ↑ ↑ ↑ ↑ 1 amiodarone +++ ↓ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ +++ 1: May suppress diseased sinus nodes 3: Anticholinergic effect and direct depressant action 4: Especially in Wolff-Parkinson-White syndrome 5: May be effective in atrial arrhythmias caused by digitalis. 6: Half-life of active metabolites much longer.

T 1/2

6h 3-4 h 6-8 h weeks

Quinidine 1. Cardiac Effects pacemaker rate ↓ conduction and excitability↓ 1) blocked activated sodium channel 2) block of potassium channel: action potential duration ↑ 3) QT interval ↑ ⇒torsade de pointes 2. Extracardiac Effects α-adrenoceptor-blocking⇒ vasodilation SA nodal rate↑ (reflex)

3. Toxicity A) Cardiac 1) antimuscarinic actions AV conduction ↑ ⇒ventricular rate ↑ (in atrial fibrillation or flutter) calcium-blocker, beta-blocker, digitalis 2) quindine syncope ⇐ torsade de pointes light headedness, fainting 3) cardaic depression (toxic concentrations) arrhythmias or asytole ( sick sinus) contractility ↓ blood pressure ↓

B) Extracardiac 1) G-I: diarrhea, nausea, vomiting (1/3 - 1/2 of patients) 2) cinhonism: headache, dizziness, tinnitus 3) digitalis toxicity ↑ ⇐ digoxin plasma level ↑ 4) allergic reactions (thrombocytopenic purpura) 4. Therapeutic Use 1) every form of arrhythmias most common: atrial fibrillation and flutter occasionally: ventricular tachycardia 2) malaria (i.v.)

Procainamide 1. Cardiac Effects 1) electrophysiologic effect: quinidine like 2) antimuscarinic action procainamide < quinidine 2. Extracardiac Effects ganglion-blocking: hypotension 3. Toxicity A) Cardiac antimucarinic and direct depressant ⇒new arrhythmias

B) Extracardiac 1) long-term therapy: a) reversible lupus-related symptoms (1/3 patients) (consiting arthralgia and arthritis) b) serologic abnormalities: (all patients) 2) others: nausea, diarrhea (10 %)

3. Pharmacokinetics 1) N-acetylprocainamide (NAPA): class III activity 2) NAPA accumulation ⇒ torsade de pointes 3) rapidly acetylates ⇒ NAPA↑ ⇒lupus syndrome ↓

4) slow-release formulation 5) renal failure: NAPA is eliminated by the kidneys 6) congestive heart failure ⇒ volume of distribution ↓ renal clearance ↓ reduction in dosage 7) measure plasma levels of both procainamide and NAPA 4. Therapeutic Use 1) atrial and ventricular arrhythmias 2) to avoid long-term therapy 3) sustained ventricular arrhythmias associated with acute myocardial infaraction second choice after lidocaine

Disopyramide 1. Cardiac Effects 1) quinidine like 2) cardiac antimuscarinic effects: disopyramide > quinidine 2. Toxicity A) Cardiac 1) quinidine like 2) left ventricular dysfunction: negative inotropic actions Contraindication: congest heart failure B) Extracardiac 1) atropine-like activity 3. Therapeutic Use only for the ventricular arrhythmias not used as a first-line antiarrhythmic agent

Quindine Procainamide Disopyramide Amiodarone

Block of Na Refractory Ca Channel period channel norma depolarized normal depolarized blokade l cell cell cell cell + ++ 0 ↑ ↑ ↑ + +++ ↑ ↑ ↑ ↑ 0 + +++ + ↑ ↑ + +++ + ↑ ↑ ↑ ↑

Effect on Sympapacemake tholytic r action activity + ↓ ↓ + ↓ 0 + ↓ ↓

Effect on Effect on PR QRS QT Usefulness SA Nodal AV nodal interval duration interval Supra- Ventricu Rate refractory ventricu lar period lar 1,3 3 3 Quindine + +++ ↑ ↓ ↑ ↓ ↑ ↓ ↑ ↑ ↑ ↑ 1 3 3 Procainamide + +++ ↓ ↑ ↓ ↑ ↓ ↑ ↑ ↑ ↑ 1,3 3 3 Disopyramide + +++ ↑ ↓ ↑ ↓ ↑ ↓ ↑ ↑ ↑ ↑ 1 amiodarone +++ ↓ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ +++ 1: May suppress diseased sinus nodes 3: Anticholinergic effect and direct depressant action 4: Especially in Wolff-Parkinson-White syndrome 5: May be effective in atrial arrhythmias caused by digitalis. 6: Half-life of active metabolites much longer.

T 1/2

6h 3-4 h 6-8 h weeks

Class IB 1. Reduce action potential 2. Effective refractory peroid (- or prolong) 3. little effect on normal cardiac tissue

Block of Na Refractory period Channel normal depolarized normal depolarized cell cell cell cell Lidocaine 0 +++ ↓ ↑ ↑ Tocainide 0 +++ 0 ↑ ↑ Mexiletine 0 +++ 0 ↑ ↑

Effect on SA Nodal Rate Lidocaine Tocainide Mexiletine

None1 None1 None1

Ca Effect on Sympachannel pacemake tholytic blokade r action activity 0 ↓ ↓ 0 +++ ↓ ↓ 0 0 ↓ ↓ 0

Effect on PR QRS QT Usefulness AV nodal interval duration interv Supra- Ventri refractory al ventricu cular period lar None 0 0 0 None5 +++ None 0 0 0 None +++ None 0 0 0 None6 +++

T 1/2

1-2 h 12 h 12 h

Lidocaine 1. Cardiac Effects 1) Both activated and inactivated Na channel quindine: activated state 2) Inactivated state block long action potential: Purkinje ventricular 3) Selective depression of conduction in depolarized cells

2) Toxicity a) Cardiac 1) exacerbates ventricular arrhythmias in fewer than 10 % 2) acute myocardia infaraction: 1 % worsen impaired conduction 3) heart failure: hypotension b) Extracardiac 1) neurologic: paresthesia, convulsions elderly, drug is given too rapidly diazepam 3. Pharmacokinetics 1) first-pass hepatic metabolism: parenterally 2) myocardial infaraction: higher concentration α1-acid glycoprotein: binds lidocaine

3) congestive heart failure: loading and maintenance dose↓ volume of distribution and total body clearance 4) liver disease: maintenance dose ↓ 5) propranolol, cimetidine: decrease liver blood flow risk of toxicity↑ 4. Therapeutic Use i.v. or i.m. ventricular arrhythmias 1) recurrence 2) associated with acute myocardial infaraction do not use the prophylactically in myocardial infaraction

Mexiletine 1. Congeners of lidocaine 2. Oral route: resistant to first-pass hepatic metabolism 3. Treatment of ventricular arrhythmias 4. Toxicity: neurologic(tremor, blurred vision) 5. Mexiletine: relieving chronic pain pain due to diabetic neuropathy and nerve injury

Block of Na Refractory period Channel normal depolarized normal depolarized cell cell cell cell Lidocaine 0 +++ ↓ ↑ ↑ Tocainide 0 +++ 0 ↑ ↑ Mexiletine 0 +++ 0 ↑ ↑

Effect on SA Nodal Rate Lidocaine Tocainide Mexiletine

None1 None1 None1

Ca Effect on Sympachannel pacemake tholytic blokade r action activity 0 ↓ ↓ 0 +++ ↓ ↓ 0 0 ↓ ↓ 0

Effect on PR QRS QT Usefulness AV nodal interval duration interv Supra- Ventri refractory al ventricu cular period lar None 0 0 0 None5 +++ None 0 0 0 None +++ None 0 0 0 None6 +++

T 1/2

1-2 h 12 h 12 h

Class IC 1. have no effect on ventricular action potential duration or the QT interval 2. Slow conduction velocity in atrial and ventricular cells increase QRS duration

Block of Na Refractory Ca Effect on SympaChannel period channel pacemaker tholytic action normal depolarized norma depolarized blokade activity cell cell l cell cell Flecainde + +++ 0 0 ↑ ↑ 0 ↓ ↓ Propafenone + ++ + ↑ ↑ ↑ + ↓ ↓ Moricizine + ++ 0 0 ↓ ↓ ↓ ↓ Effect on Effect on PR QRS QT Usefulness SA Nodal AV nodal interval duration interval Supra- Ventricu Rate refractory ventricu lar period lar Flecainde None +4 ++++ ↑ ↑ ↑ ↑ ↑ 0 propafenone 0 + +++ ↑ ↑ ↑ ↑ ↑ 0 moricizine None None 0 None +++ ↑ ↑ ↑

T 1/2

20 h 5-7 h 2-6 h6

Class IC drugs are now restricted to use in arrhythmias that fail to respond to other drugs Flecainide 1. Blockers of sodium and potassium channels 2. No antimuscarinic effect 3. Clinical uses: supraventricular arrhythmias premature ventricular contraction↓ 4. Exacerbation of arrhythmias: preexisting ventricular tachyarrhythmia previous myocardial infaraction ventricular ectopy

Propafenone 1. Structure similarities to propranolol 2. Weak beta-blocking activity 3. Action: quinidine-like 4. Potency: flecainide like 5. Supraventricular arrhythmias 6. Metallic taste and constipation Moricizine 1. Potent Na channel blocker 2. Not prolong action potential duration 3. Ventricular arrhythmias

Class II: Beta Adrenoceptor-blocking drugs 1. Selectivity for cardiac β1 receptors AV node: PR interval ↑ 2. Prevent recurrent infaraction and sudden death acute myocardial infarction 3. Esmolol: short acting intraoperative and other acute arrhythmias 4. Sotalol: nonselective beta-blocking drug prolong the action potential

Block of Na Refractory Ca Channel period channel normal cell depolarized normal depolarized blokade cell cell cell Esmolol 0 + 0 NA2 0 Proprnolol 0 + ↓ ↑ ↑ 0 Sotalol 0 0 ↑ ↑ ↑ ↑ ↑ 0

Effect on SA Nodal Rate Esmolol Propranolol Sotalol

↓ ↓ ↓ ↓ ↓ ↓

Effect on AV nodal refractory period

Effect on Sympapacemake tholytic r action activity ↓ ↓ +++ ↓ ↓ +++ ++ ↓ ↓

PR QRS QT Usefulness interval duration interval Supra- Ventricula ventric r ular 0 + + ↑ ↑ ↑ ↑ 0 0 0 + + ↑ ↑ ↑ ↑ 0 ↑ ↑ ↑ ↑ ↑ ↑ ↑ +++ +++

T 1/2

10 min 8h 7h

Class III: Prolong Effective Refractory Period by Prolonging AP 1. Quinidine and Amiodarone: Na channel 2. Bretylium and Sotalol: autonomic effect 3. Ibutilide and Dofetilide: pure class III

Amiodarone (Class IA or III) 3. Cardiac Effect 1 ) blocking K channel: action potential duration↑ against tachycardia 1) blocker of Na channel inactivated state > activated state 3) calcium channel: weak 4) β adtrenoceptor blocker greast AP-prolonging effect (Calss III) rarity of torsade de pointes 2. Extracardiac Effect peripheral vascular dilation

3. Toxicity A) Cardiac 1) bradycardia or heart block (sinus or AV nodal disease) 2) hart failure B) Extracardiac 1) fatal pulmonary fibrosis 2) concentrated in tissue: cornea: yellowish-brown microcrystals, halos skin: photodermatitis grayish-blueskin discoloration 3) adverse neurologic effect: paresthesias

4) thyroid dysfunction: both hypo- and hyperthyroidism thyroid function 5) G-I tract: constipation 20 %, hepatocellular necrosis 4. Pharmacokinetics extremely longer half-life (13 - 103 days) toxicity persist long after drug administration is discontinuted CYP3A4

5. Therapeutic Use 1) both supraventricular and ventricular arrhythmias quite effective against supraventricular arrhythmias in children 2) paroxysmal atrial fibrillation 3) recurrent ventricular tachycardia or fibrillation (i.v.) antiadrenergic properties phlebitis physical compatibility with other drugs (i.v.) 4) use only in serious ventricular arrhythmias (USA) Effective in most types of arrhythmias Mechanisms: broad spectrum Secondary choice

Bretylium 1. Cardiac effect 1)↑ ventricular action potential duration ↑ effective refractory period ischemic cells 2) initial release of catecholamine: inotropic action ventricular arrhythmias 2. Extracardiac Effect postural hypotension: tricyclic antidepressant 3. Therapeutic Use 1) i.v. only 2) recurrent ventricular fibrillation when lidocaine and cardioversion have failed

Sotalol 1. Nonselective beta-blocker: slows repolarization prolong the action potential 2. Used in supraventricular and ventricular arrhythmias 3. Toxicities: beta blockade torsade de points (higher dosage) 4. Atrial fibrillation : lower dosage 5. Renal failure

Dofetilide 1. Ikr-blocker 2. Maintaining sinus rhythm: atrial fibrillation and flutter 3. Toxicity: torsade de pointes Ibutilide 1. Enhancing an inward sodium current blocking Ikr or both 1. i.v.: atrial flutter and atrial fibrillation

Clinical Uses bretylium: recurrent ventricular fibrillation sotalol: supraventricular and ventricular arrhythmias ibutilide and dofetilide: atrial flutter and fibrilation Toxicities bretylium: hypotension sotalol: torsade de pointes, asthma ibutilide and dofetilide: torsade de pointes

Bretylium Dofetilide Ibutilide Sotalol

Block of Na Refractory Ca Effect on Channel period channel pacemake normal depolarized normal depolarized blokade ractivity cell cell cell cell 1 0 0 ↑ ↓ ↑ ↑ ↑ ↑ ↑ ↑ 0 0 0 ? 0 0 ↑ 0 0 ? 0 0 ↑ 0 0 ↑ ↑ ↑ ↑ ↑ 0 ↓ ↓

Effect on SA Nodal Rate Bretylium Dofetilide Ibutilide Sotalol

2 ↑ ↓ ? ↓ ? ↑ ↓ ↓

Sympatholytic action ++ 0 0 ++

Effect on PR QRS QT Usefulness AV nodal interval duration interval refractory SupraVentricula ventricular r period 2 ↑ ↓ 0 0 ↑ ↑

0 0 0 ↑ ↑

0 0 0 0

0 ↑ ↑ ↑ ↑ ↑ ↑ ↑

0 ++ ++ +++

+ none ? +++

T 1/2

4h 7h 6h 7h

Class IV: Calcium Channel-Blocking Drugs

Diltiazem Verapamil Adenosine

Block of Na Refractory Ca Effect on SympaChannel period channel pacemaker tholytic action normal depolarized normal depolarized blokade activity cell cell cell cell 0 0 0 0 +++ 0 ↓ ↓ 0 + 0 +++ + ↑ ↓ ↓ 0

Effect on SA Nodal Rate

0

0

0

0

0

+

Effect on AV nodal refractory period

Diltiazem Verapamil

↑ ↓ ↓ ↓

PR QRS QT Usefulness T 1/2 interval duration interval Supra- Ventricula ventric r ular 0 0 +++ 4-8 h ↑ ↑ ↑ 0 +++ 7h ↑ ↑ ↑ ↑ 0

Adenosine

Little

↑ ↑ ↑ ↑ ↑ ↑ 0

0

+++

?

<10 s

Class IV: Calcium Channel-Blocking Drugs Verapamil 1. Cardiac Effects 1) blocks activated and inactivated calcium channel SA and AV node 2) AV nodal conduction and effective refractory period↑ 3) direct action: SA node↓ 4) a small increase of SA nodal rate⇐ hypotension 5) ↓ early and delayed afterdepolarization 2. Extracardiac Effects peripheral vasodilation

3. Toxicity A) cardiac 1) ventricular tachycardia: hypotension and ventricular fibrillation 2) disease heart: negative inotropic effects 3) atrioventricular block: treated with atropine, beta stimulanr, calcium 4) sinus node disease: sinus arrest B) Extracardiac: Constipation 4. Pharmacokinetcs bioavailability 20 %: hepatic dysfunction 5. Therapeutic Use 1) reentrant supraventricular tachycardia 2) reduce the ventricular rate in atrial fibriallation and flutter 3) ventricular tachycardia: hemodynamic collapse (i.v.)

Miscellaneous Antiarrhythmic Agents Adenosine 1. Hal-life < 10 second 2. inward K conductance↑ Ca influx ↓ 3. AV nodal conduction ↓ the AV nodal refractory period ↑ 4. paroxysmal supraventricular tachycardia high efficacy and very short duration 5. Adenosin receptor blockers: theophylline , caffeine 6. Adenosine uptake inhibitors: dipyridamole 7. Toxicities: flushing, shortness of breath or chest burning

Diltiazem Verapamil Adenosine

Block of Na Refractory Ca Effect on SympaChannel period channel pacemaker tholytic action normal depolarized normal depolarized blokade activity cell cell cell cell 0 0 0 0 +++ 0 ↓ ↓ 0 + 0 +++ + ↑ ↓ ↓ 0

Effect on SA Nodal Rate

0

0

0

0

0

+

Effect on AV nodal refractory period

Diltiazem Verapamil

↑ ↓ ↓ ↓

PR QRS QT Usefulness T 1/2 interval duration interval Supra- Ventricula ventric r ular 0 0 +++ 4-8 h ↑ ↑ ↑ 0 +++ 7h ↑ ↑ ↑ ↑ 0

Adenosine

Little

↑ ↑ ↑ ↑ ↑ ↑ 0

0

+++

?

<10 s

Magnesium 1. Digitalis-induced arrhythmias; hypomagnesemic 2. Serum Mg is normal torsade de pointes Potassium 1. hypokalemia⇒early and delayed afterdepolarization ectopic pacemaker activity 2. hyperkalemia ⇒depression of ectopic pacemakers slowing of conduction 3. Potassium therapy: normalizing K gradients and pools in the body

OBJECTIVES 1. Describe the distingushing features of the four major classess of antiarrhythmic drugs and adenosine. 2. List two of three of the most important drugs in each of the four classess. 3. List the major toxicities of those drugs. 4. Describe the mechanism of selective depression by local anesthetic antiarrhythmic agents. 5. Explain how hyperkalemia, hypokalemia, or antiarrhythmic drug can cause an arrhythmia.