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) obstacle2) unidirectional block3) conduction time

Atrioventricular nodal reenty (supraventricular tachycardia)

Torsade de pointes long OT interval

II. Basic Pharmacology of the Antiarrhythmic Agents Mechanisms of Action1. Automaticity of Ectopic Pacemakers: channel blocker

Use-dependentState-dependent

2. Reentry arrhythmias1) reduces the excitatory current to a level below that required for propagation2) Increase the effective refractory period

Miscellaneous: adenosine digitalis potassium ion magnesium ion

III. Specific Antiarrhythmic Agents

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: sympathoplegicClass III: prolongs the effective refractory periodClass 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

Block of Na

ChannelRefractory

periodnormal cell

depolarizedcell

normalcell

depolarizedcell

Cachannelblokade

Effect onpacemakeractivity

Sympa-tholytic

action

Quindine + ++ 0 +Procainamide + +++ 0 +Disopyramide + +++ + 0Amiodarone + +++ + +

Usefulness Effect onSA NodalRate

Effect onAV nodalrefractoryperiod

PRinterval

QRSduration

QTinterval

Supra-ventricular

Ventricular

T 1/2

Quindine 1,3 3 3 + +++ 6 hProcainamide 1 3 3 + +++ 3-4 hDisopyramide 1,3 3 3 + +++ 6-8 hamiodarone 1 +++ +++ weeks

1: May suppress diseased sinus nodes3: Anticholinergic effect and direct depressant action4: Especially in Wolff-Parkinson-White syndrome5: May be effective in atrial arrhythmias caused by digitalis.6: Half-life of active metabolites much longer.

Quinidine1. 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

-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 < quinidine2. 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 formulation5) renal failure: NAPA is eliminated by the kidneys6) congestive heart failure volume of distribution renal clearance reduction in dosage7) 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

Disopyramide1. Cardiac Effects 1) quinidine like 2) cardiac antimuscarinic effects: disopyramide > quinidine2. 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

Block of Na

ChannelRefractory

periodnormal cell

depolarizedcell

normalcell

depolarizedcell

Cachannelblokade


Sympa-tholytic

action

Quindine + ++ 0 +Procainamide + +++ 0 +Disopyramide + +++ + 0Amiodarone + +++ + +



PRinterval

QRSduration

QTinterval

Supra-ventricular

Ventricular

T 1/2

Quindine 1,3 3 3 + +++ 6 hProcainamide 1 3 3 + +++ 3-4 hDisopyramide 1,3 3 3 + +++ 6-8 hamiodarone 1 +++ +++ weeks

1: May suppress diseased sinus nodes3: Anticholinergic effect and direct depressant action4: Especially in Wolff-Parkinson-White syndrome5: May be effective in atrial arrhythmias caused by digitalis.6: Half-life of active metabolites much longer.

Class IB1. Reduce action potential2. Effective refractory peroid (- or prolong)

3. little effect on normal cardiac tissue

Block of Na

ChannelRefractory period

normalcell

depolarizedcell

normalcell

depolarizedcell

Cachannelblokade


Sympa-tholytic

action

Lidocaine 0 +++ 0 0Tocainide 0 +++ 0 +++ 0Mexiletine 0 +++ 0 0 0



PRinterval

QRSduration

QTinterval Supra-

ventricular

Ventricular

T 1/2

Lidocaine None1 None 0 0 0 None5 +++ 1-2 hTocainide None1 None 0 0 0 None +++ 12 hMexiletine None1 None 0 0 0 None6 +++ 12 h

Lidocaine1. Cardiac Effects1) Both activated and inactivated Na channel quindine: activated state2) Inactivated state block long action potential: Purkinje ventricular3) 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 1-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

Mexiletine1. Congeners of lidocaine2. Oral route: resistant to first-pass hepatic metabolism3. Treatment of ventricular arrhythmias4. Toxicity: neurologic(tremor, blurred vision)5. Mexiletine: relieving chronic pain pain due to diabetic neuropathy and nerve injury

Block of Na

ChannelRefractory period

normalcell

depolarizedcell

normalcell

depolarizedcell

Cachannelblokade


Sympa-tholytic

action

Lidocaine 0 +++ 0 0Tocainide 0 +++ 0 +++ 0Mexiletine 0 +++ 0 0 0



PRinterval

QRSduration

QTinterval Supra-

ventricular

Ventricular

T 1/2

Lidocaine None1 None 0 0 0 None5 +++ 1-2 hTocainide None1 None 0 0 0 None +++ 12 hMexiletine None1 None 0 0 0 None6 +++ 12 h

Class IC1. have no effect on ventricular action potential duration or the QT interval2. Slow conduction velocity in atrial and ventricular cells increase QRS duration

Block of Na

ChannelRefractory

periodnormalcell

depolarizedcell

normal cell

depolarizedcell

Cachannelblokade


Sympa-tholytic

action

Flecainde + +++ 0 0 0Propafenone + ++ + +Moricizine + ++ 0 0



PRinterval

QRSduration

QTinterval

Supra-ventricular

Ventricular

T 1/2

Flecainde None 0 +4 ++++ 20 hpropafenone 0 0 + +++ 5-7 hmoricizine None None 0 None +++ 2-6 h6

Class IC drugs are now restricted to use in arrhythmias that fail to respond to other drugs

Flecainide1. Blockers of sodium and potassium channels2. No antimuscarinic effect3. Clinical uses: supraventricular arrhythmias premature ventricular contraction4. Exacerbation of arrhythmias: preexisting ventricular tachyarrhythmia previous myocardial infaraction ventricular ectopy

Propafenone1. Structure similarities to propranolol2. Weak beta-blocking activity3. Action: quinidine-like 4. Potency: flecainide like5. Supraventricular arrhythmias6. Metallic taste and constipation

Moricizine1. Potent Na channel blocker2. Not prolong action potential duration3. Ventricular arrhythmias

Class II: Beta Adrenoceptor-blocking drugs1. Selectivity for cardiac 1 receptors AV node: PR interval 2. Prevent recurrent infaraction and sudden death acute myocardial infarction3. Esmolol: short acting intraoperative and other acute arrhythmias4. Sotalol: nonselective beta-blocking drug prolong the action potential

Block of NaChannel

Refractoryperiod

normal cell depolarizedcell

normalcell

depolarizedcell

Cachannelblokade


Sympa-tholytic

action

Esmolol 0 + 0 NA2 0 +++Proprnolol 0 + 0 +++Sotalol 0 0 0 ++



PRinterval

QRSduration

QTinterval

Supra-ventricular

Ventricular

T 1/2

Esmolol 0 0 + + 10 minPropranolol 0 0 + + 8 hSotalol 0 +++ +++ 7 h

Class III: Prolong Effective Refractory Period by Prolonging AP 1. Quinidine and Amiodarone: Na channel2. Bretylium and Sotalol: autonomic effect3. Ibutilide and Dofetilide: pure class III

Amiodarone (Class IA or III)

1. 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) adtrenoceptor blocker greast AP-prolonging effect (Calss III) rarity of torsade de pointes2. Extracardiac Effect peripheral vascular dilation

3. ToxicityA) Cardiac 1) bradycardia or heart block (sinus or AV nodal disease) 2) hart failureB) 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 function5) 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 Use1) both supraventricular and ventricular arrhythmias quite effective against supraventricular arrhythmias in children2) paroxysmal atrial fibrillation3) 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 arrhythmiasMechanisms: broad spectrumSecondary choice

Bretylium1. Cardiac effect 1) ventricular action potential duration effective refractory period ischemic cells2) initial release of catecholamine: inotropic action ventricular arrhythmias2. Extracardiac Effect postural hypotension: tricyclic antidepressant3. Therapeutic Use 1) i.v. only 2) recurrent ventricular fibrillation when lidocaine and cardioversion have failed

Sotalol1. Nonselective beta-blocker: slows repolarization prolong the action potential2. Used in supraventricular and ventricular arrhythmias3. Toxicities: beta blockade torsade de points (higher dosage)4. Atrial fibrillation : lower dosage5. Renal failure

Dofetilide1. Ikr-blocker2. Maintaining sinus rhythm: atrial fibrillation and flutter3. Toxicity: torsade de pointes

Ibutilide1. Enhancing an inward sodium current blocking Ikr or both1. 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



PRinterval

QRSduration

QTinterval

Supra-ventricular

Ventricular

T 1/2

Bretylium 2 2 0 0 0 0 + 4 hDofetilide ? 0 0 0 ++ none 7 hIbutilide ? 0 0 0 ++ ? 6 hSotalol 0 +++ +++ 7 h

Block of NaChannel

Refractoryperiod

normalcell

depolarizedcell

normalcell

depolarizedcell

Cachannelblokade


Sympa-tholytic

action

Bretylium 0 0 0 1 ++Dofetilide 0 0 ? 0 0 0Ibutilide 0 0 ? 0 0 0Sotalol 0 0 0 ++

Class IV: Calcium Channel-Blocking Drugs

Block of NaChannel

Refractoryperiod

normalcell

depolarizedcell

normalcell

depolarizedcell

Cachannelblokade


Sympa-tholytic

action

Diltiazem 0 0 0 0 +++ 0Verapamil 0 + 0 +++ +

Adenosine 0 0 0 0 0 0 +



PRinterval

QRSduration

QTinterval

Supra-ventricular

Ventricular

T 1/2

Diltiazem 0 0 +++ - 4-8 hVerapamil 0 0 +++ - 7 h

Adenosine Little 0 0 +++ ? <10 s

Class IV: Calcium Channel-Blocking Drugs

Verapamil1. 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 dysfunction5. 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

Adenosine1. Hal-life < 10 second2. inward K conductance Ca influx 3. AV nodal conduction the AV nodal refractory period 4. paroxysmal supraventricular tachycardia high efficacy and very short duration5. Adenosin receptor blockers: theophylline , caffeine6. Adenosine uptake inhibitors: dipyridamole7. Toxicities: flushing, shortness of breath or chest burning

Block of NaChannel

Refractoryperiod

normalcell

depolarizedcell

normalcell

depolarizedcell

Cachannelblokade


Sympa-tholytic

action

Diltiazem 0 0 0 0 +++ 0Verapamil 0 + 0 +++ +

Adenosine 0 0 0 0 0 0 +



PRinterval

QRSduration

QTinterval

Supra-ventricular

Ventricular

T 1/2

Diltiazem 0 0 +++ - 4-8 hVerapamil 0 0 +++ - 7 h

Adenosine Little 0 0 +++ ? <10 s

Magnesium1. Digitalis-induced arrhythmias; hypomagnesemic 2. Serum Mg is normal torsade de pointes

Potassium1. hypokalemiaearly and delayed afterdepolarization ectopic pacemaker activity2. 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.

Cardiac Arrhythmias

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