IVMS-CV Pharmacology- Antiarrhythmics

CV PharmacologyAntiarrhythmic Agents : 

CV PharmacologyAntiarrhythmic Agents Presenter: Marc Imhotep Cray, M.D. Professor Pharmacology Recommended Reading: Antiarrhythmic Drugs Formative Assessment Practice question set #1 Clinical: E-Medicine Article Ventricular Fibrillation EKG Tutorial RnCeus Interactive

Electrophysiology and Cardiac Arrhythmias : 

2 Electrophysiology and Cardiac Arrhythmias Cardiac Rhythm Normal rate: 60-100 beats per minute Impulse Propagation: sinoatrial node   atrioventricular (AV node) His-Purkinje distribution throughout the ventricle Normal AV nodal delay (0.15 seconds) -- sufficient to allow atrial ejection of blood into the ventricles See Animated-Interactive Cardiac Cycle Hyper heart by Knowlege Weavers Adobe Shockwave Player

Electrophysiology and Cardiac Arrhythmias(2) : 

3 Electrophysiology and Cardiac Arrhythmias(2) Definition: arrhythmia -- cardiac depolarization different from previous slide sequence --  abnormal origination (not SA nodal)  abnormal rate/regularity/rhythm  abnormal conduction characteristics See: http://www.rnceus.com/ekg/ekgframe.html

Cardiac Electrophysiology : 

4 Cardiac Electrophysiology The cardiac action potential is a specialized action potential in the heart, with unique properties necessary for function of the electrical conduction system of the heart The cardiac action potential differs significantly in different portions of the heart This differentiation of action potentials allows different electrical characteristics of different portions of the heart For instance, the specialized conduction tissue of heart has special property of depolarizing without any external influence known as cardiac muscle automaticity See: Interactive animation illustrating the generation of a cardiac action potential

Cardiac Electrophysiology(2) : 

5 Cardiac Electrophysiology(2) In cardiac myocytes, the release of Ca2+ from the sarcoplasmic reticulum is induced by Ca2+ influx into cell through voltage-gated calcium channels on the sarcolemma This phenomenon is called calcium-induced calcium release and increases myoplasmic free Ca2+ concentration causing muscle contraction

Cardiac Electrophysiology(3) : 

6 Cardiac Electrophysiology(3)

Cardiac Electrophysiology(4) : 

7 Cardiac Electrophysiology(4) Note that there are important physiological differences between nodal cells and ventricular cells; the specific differences in ion channels and mechanisms of polarization give rise to unique properties of SA node cells, most importantly the spontaneous depolarizations (cardiac muscle automaticity) necessary for the SA node's pacemaker activity

Cardiac Electrophysiology(5) : 

8 Cardiac Electrophysiology(5) Calcium channels Two voltage-dependent calcium channels play critical roles in the physiology of cardiac muscle: L-type calcium channel ('L' for Long-lasting) and T-type calcium channels ('T' for Transient) voltage-gated calcium channels These channels respond differently to voltage changes across the membrane: L-type channels respond to higher membrane potentials, open more slowly, and remain open longer than T-type channels Also See Notes Page

Cardiac Electrophysiology(6) : 

9 Cardiac Electrophysiology(6) The resting membrane potential is caused by difference in ionic concentrations and conductances across the membrane of the cell during phase 4 of the action potential. The normal resting membrane potential in ventricular myocardium is about -85 to -95 mV This potential is determined by the selective permeability of the cell membrane to various ions The membrane is most permeable to K+ and relatively impermeable to other ions The resting membrane potential is therefore dominated by the K+ equilibrium potential according to the K+ gradient across the cell membrane The cardiac action potential has five phases

Cardiac Electrophysiology(7) : 

10 Cardiac Electrophysiology(7) The maintenance of this electrical gradient is due to various ion pumps and exchange mechanisms, including the Na+-K+ ion exchange pump, the Na+-Ca2+ exchanger current Remember: Intracellularly K+ is the principal cation, and phosphate and the conjugate bases of organic acids are the dominant anions. Extracellularly Na+ and Cl- predominate

Cardiac Electrophysiology(8) : 

11 Cardiac Electrophysiology(8) Transmembrane potential -- determined primarily by three ionic gradients:  Na+, K+, Ca 2+  water-soluble, -- not free to diffuse through the membrane in response to concentration or electrical gradients: depended upon membrane channels (proteins) Movement through channels depend on controlling "molecular gates"  Gate-status controlled by: Ionic conditions Metabolic conditions Transmembrane voltage Maintenance of ionic gradients:  Na+/K+ ATPase pump  termed "electrogenic" when net current flows as a result of transport (e.g., three Na+ exchange for two K+ ions)

Cardiac Electrophysiology(9) : 

12 Cardiac Electrophysiology(9) Initial permeability state -- resting membrane potential sodium -- relatively impermeable potassium -- relatively permeable Cardiac cell permeability and conductance:  conductance: determined by characteristics of ion channel protein  current flow = voltage X conductance  voltage = (actual membrane potential - membrane potential at which no current would flow, even with channels open)

Cardiac Electrophysiology(10) : 

13 Cardiac Electrophysiology(10) Sodium Concentration gradient: 140 mmol/L Na+ outside: 10 mmol/L Na+ inside; Electrical gradient: 0 mV outside; -90 mV inside Driving force -- both electrical and concentration -- tending to move Na+ into the cell In the resting state: sodium ion channels are closed therefore no Na+ flow through the membrane In the active state: channels open causing a large influx of sodium which accounts for phase 0 depolarization

Cardiac Electrophysiology(11) : 

14 Cardiac Electrophysiology(11) Cardiac Cell Phase 0 and Sodium Current Source: http://www.pharmacology2000.com/Cardio/antiarr/antiarrtable.htm

Cardiac Electrophysiology(12) : 

15 Cardiac Electrophysiology(12) Potassium: Concentration gradient (140 mmol/L K+ inside; 4 mmol/L K+outside) Concentration gradient -- tends to drive potassium out Electrical gradient tends to hold K+ in Some K+ channels ("inward rectifier") are open in resting state -- however, little K+ current flows because of the balance between the K+ concentration and membrane electrical gradients  Cardiac resting membrane potential: mainly determined By the extracellular potassium concentration and Inward rectifier channel state

Cardiac Electrophysiology(13) : 

16 Cardiac Electrophysiology(13) Spontaneous Depolarization (pacemaker cells)--  phase 4 depolarization Spontaneous Depolarization occurs because: Gradual increase in depolarizing currents (increasing membrane permeability to sodium or calcium) Decrease in repolarizing potassium currents (decreasing membrane potassium permeability) Both  Ectopic pacemaker: (not normal SA nodal pacemakers) -- Facilitated by hypokalemic states Increasing potassium: tends to slow or stop ectopic pacemaker activity

Cardiac Electrophysiology(14) : 

17 Cardiac Electrophysiology(14) Ca2+:  Channel Activation Sequence similar to sodium; but occurring at more positive membrane potentials (phases 1 and 2) Source: http://www.pharmacology2000.com/Cardio/antiarr/antiarrtable.htm

Cardiac Electrophysiology(15) : 

18 Cardiac Electrophysiology(15) Channel Inactivation, Re-establishing the Resting Membrane Potential Source: http://www.pharmacology2000.com/Cardio/antiarr/antiarrtable.htm

Cardiac Electrophysiology(15) : 

19 Cardiac Electrophysiology(15) Five Phases:cardiac action potential associated with HIS-purkinje fibers or ventricular muscle See Notes Page for Explainations

Influence of Membrane Resting Potential on Action Potential Properties : 

20 Influence of Membrane Resting Potential on Action Potential Properties Factors that reduce the membrane resting potential & reduce conduction velocity  Hyperkalemia  Sodium pump block  Ischemic cell damage

Influence of Membrane Resting Potential on Action Potential Properties(2) : 

21 Influence of Membrane Resting Potential on Action Potential Properties(2) Factors that may precipitate or exacerbate arrhythmias Ischemia Hypoxia Acidosis Alkalosis Abnormal electrolytes Excessive catecholamine levels Autonomic nervous system effects (e.g., excess vagal tone) Excessive catecholamine levels Autonomic nervous system effects (e.g., excess vagal tone) Drug effects: e.g., antiarrhythmic drugs may cause arrhythmias) Cardiac fiber stretching (as may occur with ventricular dilatation in congestive heart failure) Presence of scarred/diseased tissue which have altered electrical conduction properties

Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? : 

22 Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? Anti-arrhythmic drugs may work by: (a) Suppressing initiation site (automaticity/after-depolarizations) and/or (b) Preventing early or delayed afterdepolarizations and/or (c) By disrupting a re-entrant pathway Reference Resource Reader: Teaching Cardiac Arrhythmias: A Focus on Pathophysiology and Pharmacology/ PDF

Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? : 

23 Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? (a) Automaticity: Automaticity may be diminished by: (1) increasing the maximum diastolic membrane potential (2) decreasing the slope of phase 4 depolarization (3) increasing action potential duration (4) raising the threshold potential All of these factors make it take longer or make it more difficult for the membrane potential to reach threshold. (1) The diastolic membrane potential may be increased by adenosine and acetylcholine. (2) The slope of phase 4 depolarization may be decreased by beta receptor blockers (3) The duration of the action potential may be prolonged by drugs that block cardiac K+ channels (4) The membrane threshold potential may be altered by drugs that block Na+ or Ca2+ channels.

Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? : 

24 Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? (b) Delayed or Early Afterdepolarizations: Delayed or early afterdepolarizations may be blocked by factors that  (1) prevent the conditions that lead to afterdepolarizations.  (2) directly interfere with the inward currents (Na+, Ca2+) that cause afterdepolarizations.

Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? : 

25 Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? (c) Reentry For anatomically-determined re-entry such as Wolf-Parkinson-White syndrome (WPW) drugs the arrhythmia can be resolved by blocking action potential (AP) propagation In WPW-based arrhythmias, blocking conduction through the AV node may be clinically effective Drugs that  prolong nodal refractoriness and slow conduction include: Ca2+ channel blockers, beta-adrenergic blockers, or digitalis glycosides.

Intro to Arrhythmias and Drug Therapy(2) : 

26 Intro to Arrhythmias and Drug Therapy(2) Atrial fibrillation may result in a high ventricular following rate Atrial Fibrillation Accordingly, drugs which may reduce ventricular rate by reducing AV nodal conduction include:  calcium channel blockers (verapamil (Isoptin, Calan), diltiazem (Cardiazem))  beta-adrenergic receptor blockers (propranolol (Inderal)), and  digitalis glycosides

Arrhythmias and Drug Therapy (3)  calcium channel blockers : 

27 Arrhythmias and Drug Therapy (3)  calcium channel blockers Treatment of atrial fibrillation(2) Verapamil (Isoptin, Calan) & Diltiazem (Cardiazem) Blocks cardiac calcium channels in slow response tissues, such as the sinus and AV nodes. Useful in treating AV reentrant tachyarrhythmias and in management of high ventricular rates secondary to atrial flutter or fibrillation. Major adverse effect (i.v. administration) is hypotension Heart block or sinus bradycardia can also occur

Arrhythmias and Drug Therapy (4) beta-adrenergic receptor blockers : 

28 Arrhythmias and Drug Therapy (4) beta-adrenergic receptor blockers Treatment of atrial fibrillation:  Propranolol (Inderal)  Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade  Normally, sympathetic drive results in increased in Ca2+ ,K+ ,and Cl- currents

Arrhythmias and Drug Therapy (5) beta-adrenergic receptor blockers : 

29 Arrhythmias and Drug Therapy (5) beta-adrenergic receptor blockers Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated arrhythmias  These effects are blocked by beta-adrenergic receptor blockers

Arrhythmias and Drug Therapy (6) beta-adrenergic receptor blockers : 

30 Arrhythmias and Drug Therapy (6) beta-adrenergic receptor blockers Beta-adrenergic receptor blockers increase AV conduction time (takes longer) and increase AV nodal refractoriness, thereby helping to terminate nodal reentrant arrhythmias

Arrhythmias and Drug Therapy (7) beta-adrenergic receptor blockers : 

31 Arrhythmias and Drug Therapy (7) beta-adrenergic receptor blockers Beta-adrenergic receptor blockade can also help reduce ventricular following rates in atrial flutter and fibrillation, again by acting at the AV node.

Arrhythmias and Drug Therapy (8) beta-adrenergic receptor blockers : 

32 Arrhythmias and Drug Therapy (8) beta-adrenergic receptor blockers Adverse effects of beta blocker therapy can lead to fatigue, bronchospasm, depression, impotence, attenuation of hypoglycemic symptoms in diabetic patients worsening of congestive heart failure

Class I Antiarrhythmic Drugs : 

33 Class I Antiarrhythmic Drugs Class I: Sodium Channel Blockers Sodium channel blocking antiarrhythmic drugs are classified as use-dependent in that they bind to open sodium channels Their effectiveness is therefore dependent upon the frequency of channel opening.

Class I Antiarrhythmic Drugs Type Ia quinidine : 

34 Class I Antiarrhythmic Drugs Type Ia quinidine There are three classes or types of sodium channel blockers:  Type Ia: prototype: quinidine gluconate (Quinaglute, Quinalan Type Ia drugs slow the rate of AP rise and prolong ventricular effective refractory period

Quinidine : 

35 Quinidine Overview dextroisomer of quinine; quinidine gluconate (Quinaglute, Quinalan) also has antimalarial and antipyretic effects Pharmacokinetics: 80%-90%: bound to plasma albumin Rapid oral absorption; rapid attainment of peak blood levels (60-90 minutes) Elimination half-life: 5-12 hours IM injection, possible but not recommended due to injection site discomfort  IV administration: limited due to myocardial depression & peripheral vasodilation

Quinidine : 

36 Quinidine Metabolism: Hepatic: hydroxylation to inactive metabolites; followed by renal excretion 20% excreted unchanged in urine  Impaired hepatic/renal function: accumulation of quinidine and metabolites  Sensitive to enzyme induction by other agents-- decreased quinidine blood levels with phenytoin, phenobarbital, rifampin

Quinidine : 

37 Quinidine Mechanism of antiarrhythmic action-- primarily activated sodium channel blockade which results in: Depression of ectopic pacemaker activity Depression of conduction velocity may convert a one-way conduction blockade to a two-way (bidirectional) block -- terminating reentry arrhythmias Depression of excitability (particularly in partially depolarized tissue) also see notes page

Quinidine : 

38 Quinidine Effect on the ECG: QT interval lengthening Basis: quinidine-mediated reduction in repolarizing outward potassium current Result: Longer action potential duration Increased effective refractory period Reduces reentry frequency; reduced rate in tachyarrhythmias Sodium channel blockade results in an increased threshold decreased automaticity

Quinidine : 

39 Quinidine Quinidine Uses Used to manage nearly every form of arrhythmia especially acute and chronic supraventricular dysrhythmias Ventricular tachycardia Frequent indications:  Prevent recurrence of supraventricular tachyarrhythmias  Suppression ventricular premature contractions  Approximately 20% of patients with atrial fibrillation will convert to normal sinus rhythm following quinidine treatment  Supraventricular tachyarrhythmia due to Wolff-Parkinson-White syndrome -- effective suppression by quinidine also see notes page

Quinidine : 

40 Quinidine Quinidine Side Effects Cardiovascular--at (high) plasma concentrations (> 2ug/ml) Prolongation (ECG) of PR interval, QRS complex, QT interval Heart block likely with 50% increase in QRS complex duration (reduced dosage)  Quinidine syncope: may be caused by delayed intraventricular conduction, resulting in ventricular dysrhythmia  Patients with preexisting QT interval prolongation or evidence of existing A-V block (ECG): probably should not be treated with quinidine

Quinidine Side Effects (cont.) : 

41 Quinidine Side Effects (cont.) Quinidine is associated with Torsades de pointes, a ventricular arrhythmias associated with marked QT prolongation Torsades de pointes: Electrophysiological Features ventricular origin wide QRS complexes with multiple morphologies changing R - R intervals axis seems to twist about the isoelectric line This potentially serious arrhythmia occurs in 2% - 8% if patients, even if they have a therapeutic or subtherapeutic quinidine blood level

Quinidine Side Effects (cont.) : 

42 Quinidine Side Effects (cont.) Other quinidine adverse effects include: cinchonism blurred vision, decreased hearing acuity, gastrointestinal upset,headaches and tinnitus. Nausea, vomiting, diarrhea (30% frequency)  Drug-drug interaction:quinidine gluconate (Quinaglute, Quinalan)-digoxin (Lanoxin, Lanoxicaps) Quinidine increases digoxin plasma concentration; may cause digitalis toxicity in patients taking digoxin or digitoxin

Quinidine Side Effects (cont.) : 

43 Quinidine Side Effects (cont.) Effects on neuromuscular transmission: Quinidine gluconate (Quinaglute, Quinalan) interferes with normal neuromuscular transmission; enhancing the effect of neuromuscular-blocking drugs Recurrence of skeletal muscle paralysis postoperatively may be associated with quinidine administration

Class I Antiarrhythmic Drugs Type Ia Procainamide : 

44 Class I Antiarrhythmic Drugs Type Ia Procainamide Overview: Local anesthetic (procaine) analog Long-term use avoided because of lupus-related side effect

Procainamide : 

45 Procainamide Metabolism: Elimination: renal excretion & hepatic metabolism; procainamide is highly resistant to hydrolysis by plasma esterases 40%-60% excreted unchanged (renal) Renal dysfunction requires procainamide dosage reduction Hepatic metabolism -- acetylation cardioactive metabolite: N-acetylprocainamide (NAPA); NAPA accumulation may lead to Torsades de pointes

Procainamide : 

46 Procainamide Quinidine and Procainamide similar: electrophysiological properties  Possibly somewhat less effective in suppressing automaticity; possibly more effective in sodium channel blockade in depolarized cells Useful in acute management of supraventricular and ventricular arrhythmias. Drug of second choice for management of sustained ventricular arrhythmias (in the acute myocardial infarction setting) Effective in suppression of premature ventricular contractions & paroxysmal ventricular tachycardia rapidly following IV administration

Procainamide : 

47 Procainamide Most important difference compared quinidine: procainamide does not exhibit vagolytic (antimuscarinic) activity   Procainamide is less likely to produce hypotension, unless following rapid IV infusion Ganglionic-Blocking Activity

Procainamide Side Effects / Toxicities : 

48 Procainamide Side Effects / Toxicities Long term use is associated with side effects, including a drug-induced, reversible lupus erythematosus-like syndrome which occurs at a frequency of 25% to 50%. Consists of serositis, arthralgia & arthritis Occasionally: pluritis, pericarditis, parenchymal pulmonary disease Rare: renal lupus Vasculitis not typically present (unlike systemic lupus erythematosus) Positive antinuclear antibody test is common; symptoms disappear upon drug discontinuation In slow acetylators the procainamide-induced lupus syndrome occurs more frequently and earlier in therapy than in rapid acetylators. Nausea, Vomiting -- most common early, noncardiac complication

Class I Antiarrhythmic Drugs Type Ia Disopyramide (Norpace) : 

49 Class I Antiarrhythmic Drugs Type Ia Disopyramide (Norpace) Overview: Very similar to quinidine gluconate (Quinaglute, Quinalan) Greater antimuscarinic effects (in management of atrial flutter & fibrillation, pre-treatment with a drug that reduces AV conduction velocity is required) Approved use (USA): ventricular arrhythmias

Disopyramide (Norpace) : 

50 Disopyramide (Norpace) Metabolism: Dealkylated metabolite (hepatic); less anticholinergic, less antiarrhythmic effect compared apparent compound 50% -- excreted unchanged, renal Electrophysiological effects similar to quinidine gluconate (Quinaglute, Quinalan) Similar to quinidine gluconate (Quinaglute, Quinalan) in effective ventricular and atrial tachyarrhythmia suppression prescribed to maintain normal sinus rhythm in patients prone to atrial fibrillation and flutter and is also used to prevent ventricular fibrillation or tachycardia

Disopyramide (Norpace) Side Effects/Toxicity : 

51 Disopyramide (Norpace) Side Effects/Toxicity Adverse side-effect profile: different from qunidine's in that disopyramide (Norpace) is not an alpha-adrenergic receptor blocker but is anti-vagal Most common side effects: (anticholinergic) dry mouth urinary hesitancy Other side effects: blurred vision, nausea

Disopyramide (Norpace) Side Effects/Toxicity (cont.) : 

52 Disopyramide (Norpace) Side Effects/Toxicity (cont.) Cardiovascular: QT interval prolongation (ECG) paradoxical ventricular tachycardia (quinidine-like) Negative inotropism (significant myocardial depressive effects)--undesirable with preexisting left ventricular dysfunction (may promote congestive heart failure, even in patients with no prior evidence of myocardial dysfunction) Disopyramide is not a first-line antiarrhythmic agent because of its negative inotropic effects  If used, great caution must be exercised in patients with congestive heart failure Can cause torsades de pointes, a ventricular arrhythmia

Class I Antiarrhythmic Drugs Type Ib : 

53 Class I Antiarrhythmic Drugs Type Ib Class Ib agents are often effective in treating ventricular arrhythmias Example: lidocaine Type Ib agents exhibit rapid association and dissociation from the channel

Class I Antiarrhythmic Drugs Type Ib (Class IB, Sodium Channel Blocker) : 

54 Class I Antiarrhythmic Drugs Type Ib (Class IB, Sodium Channel Blocker) Mexiletine (Mexitil)  Overview Amine analog of lidocaine (Xylocaine), but with reduced first-pass metabolism Suitable for oral administration Similar electrophysiologically to lidocaine

Class I Antiarrhythmic Drugs Type Ib Mexiletine : 

55 Class I Antiarrhythmic Drugs Type Ib Mexiletine Clinical Use: Chronic suppression of ventricular tachyarrhythmias Combination with a beta adrenergic receptor blocker or another antiarrhythmic drug (e.g. quinidine gluconate (Quinaglute, Quinalan) or procainamide (Procan SR, Pronestyl-SR)): synergistic effects allow:  reduced mexiletine dosage  decreased side effect incidence

Class I Antiarrhythmic Drugs Type Ib Mexiletine (Cont.) : 

56 Class I Antiarrhythmic Drugs Type Ib Mexiletine (Cont.) Possibly effective: decreasing neuropathic pain when alternative medications have proven ineffective-- applications (on-label use): diabetic neuropathy nerve injury Side effects: Epigastric burning: usually relieved by a taking drug with food nausea (common) Neurologic side effects: diplopia, vertigo, slurred speech (occasionally), tremor

Class I Antiarrhythmic Drugs Type Ib (Class IB, Sodium Channel Blocker) : 

57 Class I Antiarrhythmic Drugs Type Ib (Class IB, Sodium Channel Blocker) Lidocaine (Xylocaine) Overview/Pharmacokinetics: Local anesthetic administered by i.v. for therapy of ventricular arrhythmias Extensive first-pass effect requires IV administration Half-life: two hours Infusion rate: should be adjusted based on lidocaine plasma levels Metabolism Hepatic;some active metabolites

Lidocaine (Xylocaine) (Class Ib, Sodium Channel Blocker) : 

58 Lidocaine (Xylocaine) (Class Ib, Sodium Channel Blocker) Factors influencing loading and maintenance doses: Congestive heart failure (decreasing volume of distribution and total body clearance) Liver disease: plasma clearance -- reduced; volume of distribution -- increased; elimination half-life substantially increased (3 X or more) Drugs that decrease liver blood flow (e.g. cimetadine, propranolol), decreased lidocaine clearance (increased possible toxicity)

Lidocaine (Xylocaine) (Class Ib, Sodium Channel Blocker) (Cont.) : 

59 Lidocaine (Xylocaine) (Class Ib, Sodium Channel Blocker) (Cont.) Cardiovascular Effects: Site of Action: Sodium Channels Blocks activated and inactivated sodium channels (quinidine blocks sodium channels only in the activated state) No significant effect on QRS or QT interval or on AV conduction (normal doses) Lidocaine (Xylocaine) decreases automaticity by reducing the phase 4 slope and by increasing threshold

Lidocaine (Xylocaine) (Cont.) : 

60 Lidocaine (Xylocaine) (Cont.) lidocaine is more effective in suppressing activity in depolarized, arrhythmogenic cardiac tissue but little effect on normal cardiac tissue -- the basis for this drug's selectivity Very effective antiarrhythmic agent for arrhythmia suppression associated with depolarization (e.g., digitalis toxicity or ischemia) Comparatively ineffective in treating arrhythmias occurring in normally polarized issue (e.g., atrial fibrillation or atrial flutter)

Lidocaine (Xylocaine) (Cont.) : 

61 Lidocaine (Xylocaine) (Cont.) Clinical Uses: Suppression of ventricular arrhythmias (limited effect on supraventricular tachyarrhythmias) May reduce incidence of ventricular fibrillation during the initial time frame following acute myocardial infarction Suppression of reentry-type rhythm disorders:  premature ventricular contractions (PVCs)  ventricular tachycardia

Lidocaine (Xylocaine) (Cont.) : 

62 Lidocaine (Xylocaine) (Cont.) Side Effect/Toxicities Overdosage: vasodilation direct cardiac depression decreased cardiac conduction -- bradycardia; prolonged PR interval; widening QRS on ECG Major side effect -- neurological  Large doses, rapidly administered can result in seizure. Factors that reduce seizure threshold for lidocaine: hypoxemia, hyperkalemia, acidosis Otherwise: CNS depression, apnea.

Cardiac Electrophysiology Animations and Interactive Tutorials : 

63 Cardiac Electrophysiology Animations and Interactive Tutorials Electro Cardio Gram by Knowlege Weavers Interpeting an EKG EKG Tutorial RnCeus Interactive Electrocardiogram -ECG Technician Nobel eMuseum Hyper heart by Knowlege Weavers The Arrhythma Center HeartCenterOnline

Tocainide  (Class I, Sodium Channel Blocker) : 

64 Tocainide  (Class I, Sodium Channel Blocker) Tocainide  Amine analog of lidocaine, similar to mexiletine, orally active --but with reduced first-pass metabolism. Used for chronic suppression of ventricular tachyarrhythmias Electrophysiologically similar to lidocaine Similar to mexiletine: tocainide + beta-adrenergic receptor blocker or another antiarrhythmic drug: synergism e.g.--Combination with quinidine may increase efficacy and diminish adverse effects.

Tocainide  (Class I, Sodium Channel Blocker) (cont) : 

65 Tocainide  (Class I, Sodium Channel Blocker) (cont) Side Effects: Profile similar to mexiletine suitable for oral administration, but RARELY USED due to possibly fatal bone marrow aplasia and pulmonary fibrosis  tremor and nausea are major dose-related adverse side effects Excreted by the kidney, accordingly dose should be reduced in patients with renal disease

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