Pathophysiology Conduction System SA node conduction begins (electrical automaticity) Atrial contraction Fibers sitting b/w atria and

and ventricles that block propagation of electrical conduction AV node (electrical automaticity) Bundle of His (electrical automaticity) different from AV that it is not controlled by vagus (cholinergic stimulation affects SA) Left Bundle Branch Right Bundle Branch Purkinje fibers Ventricular (mechanical) contraction What are Arrhythmias: impulse formation (abnormality with automaticity) impulse conduction (muscles start conducting) Mechanisms of rhythm disorders are classically thought to occur either from alterations in impulse formation or from alterations in impulse conduction or from both Impulse Formation: Automaticity Automaticity is defined as a cells ability to depolarize itself to threshold and generate an action potential. SA node (100-60x), AV node (40x-60x), bundle of His (40-60x), bundle branches (20-40x) and Purkinje fibers (20-40x) all has a natural automaticity. SA node depolarizes spontaneously: calcium dependent Leaky sodium channel brings to 1 calcium channel leads to 2 which causes potassium efflux Normal Impulse Formation: Automaticity The fastest intrinsic automaticity are: SA node with an inherent firing rate of 60 (bradycardia) to 100 beats (tachycardia) per minute AV node 40 to 60 beats per minute. Bundle of His 40 to 60 beats per minute. Purkinje network 20 to 40 beats per minute. SA node functions as primary pacemaker Damage to SA node, the AV node will take over Remainder of conduction system are latent pacemakers Altered Impulse Formation: Automaticity Altered impulse formation can develop If the SA node becomes suppressed and fires less frequently than normal leading to an escape beat If another region of the heart develops an intrinsic automatic firing rate that exceeds the SA node leading to an ectopic beat. (ventricular ectopy ventricular tissue firing faster than the SA node) Altered Impulse Formation: Automaticity (rhythm strip arrhythmia detection) Ectopic beat is premature Escape beat terminates the pause caused by cessation of the normal firing of the SA node Several ectopic beats in series is called an ectopic rhythm Several escape beats in series is called an escape rhythm

Premature beat (prior to SA node firing off)

PQRS-T wave no p-wave so the atria didnt depolarize so the SA node didnt beat Automaticity: Physiologic Mechanisms Automaticity can increase and decrease either through normal physiologic mechanisms or as a result of cell injury Most important influence increasing normal automaticity of the SA node is the adrenergic nervous system using beta-blockers think about affect *Increase in rate with increase in slope of phase 4 of depolarization Automaticity: Pathologic Mechanism

If catecholamine concentrations are increased locally at a group of abnormal or diseased cardiac cells with latent pacemaker potentials, the automaticity of these cells could be enhanced, resulting in an ectopic tachyarrhythmia originating from that site. Automaticity: Pathologic Mechanisms ACS arrhythmias Ischemia injures the membranes of myocytes allowing the cells to become leaky and unable to maintain normal ion concentration gradients. This results in a less negative resting membrane potential and if reduced close to the threshold potential of 60 mV, automaticity can be demonstrated even among these non-pacemaker cells.

Mechanisms: Triggered Activity Under certain conditions, the action potential of cellular depolarization can trigger a second action potential called afterdepolarizations, and if the amplitude of the second action potential reaches a threshold potential, they can lead to repetitive firing. Triggered: EAD (early after depolarization), Prolong repolarization can cause TDP (QT-interval) Triggered Activity A second type of afterdepolarization is called the delayed or late afterdepolarizations that occur after repolarization has been completed. At faster heart rates, the amplitude of afterdepolarizations increases and may lead to self-perpetuating runs of tachyarrhythmias TDP:

A second type of afterdepolarization is called the delayed or late afterdepolarizations that occur after repolarization has been completed. known to cause DAD: digoxin At faster heart rates, the amplitude of afterdepolarizations increases and may lead to self-perpetuating runs of tachyarrhythmias. Mechanisms of Arrhythmias Abnormal Impulse Formation Automaticity Triggered Activity Abnormal Impulse Conduction Reentry Altered Impulse Conduction: Reentry (most ventricular tachycardia the mechanism is likely re-entry) Paroxysmal supraventricular tachycardia re-entry Several things have to set up: o Premature beat that will come down the two pathways (alpha & beta: difference is that how fast they conduct electricity and how long does it take to repolarize/ another beat): ischemia would cause differential between the two tissues that would cause disfigured re-entry circuit

Reentry

Reentry Reentry tachycardia is most commonly seen in the AV node but can also occur within the atrium and is the mechanism for the frequently seen rhythms such as paroxysmal supraventricular tachycardia, atrial flutter and atrial fibrillation. Long QRS indicates block of bundle of his Supraventricular tachycardia, atrial fibrillation, atrial flutter

In order for reentry to occur, there must be an area of unidirectional block to conduction. 1. Impulse coming down and has 2 ways to go alpha is still refractory (long time for it to allow impulse to come down) while beta is not so it goes the other direction Inverted p-wave when the fast conduction will block the SA node (turns off the SA node from firing if present in AV node) Conduction then proceeds through the heart and reenters the area of the block. Slow conduction through the area of unidirectional block then sets up the reentrant circuit. Dependent upon different tissues (how fast and how long it takes to repolarize)

Altered Impulse Conduction: Reentry Using Bypass Tracts In some individuals, there is an additional tract of conducting tissue that bypasses the AV node and depolarizes the ventricles earlier than normal. Tubes of conduction not under vagal control that would cause propagation from atria down to the ventricle (accessory pathway) ECG: Intervals & Complexes PR P (atrial depolarization and not the SA node firing; normally its from SA node but could be result of other pacemaker)

o Dont see atria repolarizing) Q (negative deflection) R S T (ventricular depolarization) QT interval (takes into account depolarization and repolarization) concerned about ST interval (ventricular repolarization)

ECG: Grid What is interpreted on the ECG Rate, rhythm, QRS axis, PR, QRS, QT intervals, P wave morphology, QRS morphology, ST segment, T wave PR: 3-5 boxes QRS: 0.1s (2.5 boxes) Horizontal axis=time Thick line to thick line = .2 seconds Each intervening thin line =.04 seconds Vertical axis= amplitude

ECG: Determining the rate Count # of QRS complexes in 6 seconds and multiply by 10. In this example, HR= 8x10 or 80 bpm ECG: Determine the rhythm What is the rhythm? Is the rhythm regular or irregular? Are there P waves before each QRS complex? If no P waves, is the QRS complex narrow (<.12 sec.) or wide (.12 sec.)? Sinus Tachycardia (heart has increased rate exceeding 100 bpm) Tachycardia: Rate exceeding 100 beats per minute

Sinus tachycardia 100 to 180 beats per minute Higher in extreme exertion Enhanced automaticity, catecholamines, exertion, Increase # of pacemaker channels opening during phase 4 depolarization Sinus Tachycardia Normal reaction to a variety of physiological or pathophysiological stresses Fever Hypotension Hyperthyroidism Anemia Anxiety Exertion Hypovolemia Myocardial ischemia Pulmonary embolism CHF (decreased CO body tries to increase HR) Shock Drugs Atropine Catecholamines Thyroid medications Alcohol Caffeine Nicotine Cocaine Treatment is directed not at the tachycardia but at the underlying cause Premature Atrial Complexes: PACs

Originates within the atrial myocardium but outside the SA node Occurs before the next expected sinus discharge Associated with other supraventricular arrhythmias (with development) MAT (multi-focal atrial tachycardia): pulmonary disease PSVT (paroxysmal supraventricular tachycardia) Atrial fibrillation What is causing it? Atrial Tachycardia (not in SA node vs. sinus tachycardia) Caused by (1) enhanced automatic activity or (2) reentry properties in atrial sites other than the SA node Heart rates 150 to 200 beats/min Displays warm-up (beats slowly increase in how fast they are going) Occurs most commonly in patients with structural heart disease CAD, MI, Cor pulmonale (pulmonary disease with stretch of right atria), hypokalemia, digoxin toxicity Unifocal Atrial Tachycardia (coming from one spot) Doesnt respond to BB or CCBs tissue generating impulse is not automatic Ectopic atrial tachycardia Single p wave morphology different from that of sinus rhythm Structural heart disease, severe lung disease and drug toxicity (e.g. digitalis) Alcohol, pneumonia, sepsis & metabolic abnormalities Accounts for 5% of all cases of SVT Does not respond to beta blockers, calcium blockers or vagal maneuvers Multifocal Atrial Tachycardia (MAT) Irregular chaotic rhythm resulting from random firing of several different atrial foci Characterized on the EKG by 3 different P wave morphologies (p-waves look different from each other) Commonly seen in the elderly patients with COPD and CHF Multiple reentry mechanism

 Started and stopped by PAC Affects men > women Therapy directed at the underlying cause (manage the HF or COPD) Atrial Fibrillation Most common clinically significant cardiac arrhythmia; most drugs used and choices being used with antithrombotic therapy Found more often in men than in women Affects approximately 2.5 million Americans every year Prevalence .4% of the general population Incidence increases with age from .2%-.3% in individuals < 40 years of age to 5% in the 50-59 year old age group, to 10% among those 80-89 years old Atrial Fibrillation

Multiple reentry (loops) wavelets propagating in different directions Causes disorganized atrial depolarizations without effective atrial contraction ECG (no discernable p-waves, irregularly irregular) Small undulating waves 350 to 600 beats per minute Irregularly irregular ventricular response conducting between 100 and 160 beats per minute (AV node filters) Atrial Fibrillation: Symptoms Determined by multiple factors Underlying cardiac status HF w/ low CO: atrial fibrillation (lower contractile force) so patients HF can worsen Rapid ventricular rate (not filling with enough blood so reducing CO) Loss of atrial contraction Underlying CHF or hypertensive heart disease Atrial contraction provides 20-25% of the LV stroke volume Loss of atrial contraction Shortness of breath Orthopnea Weakness, fatigue Atrial Fibrillation: Symptoms Palpitations (a-fib: may be asymptomatic) Most common symptom Chest pain/pressure Underlying obstructive coronary artery disease leads to decrease in coronary blood flow Increased heart rate from atrial fibrillation leads to increase in myocardial oxygen Imbalance between supply and demand Leads to symptoms of angina pectoris Atrial Fibrillation: Symptoms Losing CO push; ventricle beats so quickly will use more oxygen and not enough to fill properly so lose CO (pulse is lower then what you measure on the ECG because ineffective at generating pulse) Systemic embolization (a-fib and a-flutter: atria not contracting will result in thrombus formation in the cavity which can dislodge thereby causing a stroke) clot in left atrium causes stroke Transient ischemic attack (TIA) Cerebrovascular accident (CVA) or stroke Patients with nonvalvular atrial fibrillation have a 5 to 7 times greater risk of having a stroke than patients without atrial fibrillation Valvular (mitral) even greater risk for stroke A Fib: Stroke Rheumatic heart disease (ex. Disease of valve) and a fib had a 17-fold increase risk of stroke 80,000 strokes per year in the U.S. related to a fib 1 of every 6 strokes occur in patients with a fib

 Left atrial appendage (out-pouching) is a particularly important area in thrombus generation Noncontracting atrium stagnant blood flow clot formation left atrial appendage embolizing to the brain Atrial Fibrillation: Classification Parosxymal: episodes lasting < 7 days (most <24 hours) that can revert spontaneously and recur infrequently (short lived a-fib) Persistent: episodes lasting >7days Permanent: Cardioversion (trying to get patient back to normal sinus rhythm) not indicated or attempted or failed Lone: <60 years old and no clinical or echo evidence of cardiovascular disease Recurrent: 2 or more episodes (happened before) Atrial Fibrillation Risk factors: HTN Age CAD CHF (atrial stretch; atrial enlargement) Mitral valve disease Associated medical conditions: Increased catecholamines associated with severe illness single episode related to specific condition Hyperthyroidism (in elderly patient) Hypoxemia Chronic ETOH Diabetes Stimulant drugs (Decongestants, caffeine, cocaine etc.) A Fib: Diagnosis (1) Characterize the pattern of arrhythmia (e.g. paroxysmal, persistent) Determine its cause (e.g. CAD, HTN etc) Define associated factors (e.g. thyroid, valvular etc.) History Physical Exam EKG CXR (enlarged heart, pulmonary disease) Simple Lab Tests CBC (electrolyte/ anemia) Chem 7 Thyroid function tests Echocardiogram (1) Transthoracic see the valves and chambers of the heart (2) Transesophageal person swallows probe and it sits behind the heart and pictures are taken on the backside of the heart (visualize left atrial appendage and see if there is a clot there) Atrial Fibrillation Diagnosis: ECG Characterized by an irregularly irregular rhythm (important to know how to take pulse: an inconsistent pattern) with no discernable p waves QRS is normally narrow (normal his-purkinje system; absence of bundle block) Useful in ischemic heart disease and chamber enlargement such as left ventricular hypertrophy from hypertension and dilatation from valvular heart disease Atrial Fibrillation Diagnosis: Chest X-ray Evaluate for lung parenchymal disease such as pneumonia Assess for chamber enlargement Transverse diameter of the heart is >50% transverse diameter of the thorax Heart half diameter or thorax (right atrial enlargement); pulmonary congestion related to HF, lung volume in COPD patients Atrial enlargement as suggested by the prominent shadow labeled LA and RA Atrial Fibrillation Diagnosis: Simple Lab Tests Complete blood counts Anemia Low hemoglobin Low red blood cell count Low hematocrit

Infection Elevated white blood cell count Electrolytes, BUN, Cr, Glucose Hypokalemia Renal failure Diabetes Thyroid function tests Occult hyperthyroidism Atrial Fibrillation Diagnosis: Echocardiogram Sound waves directed into the chest from a transducer The high-frequency sound waves bouncing off of the hearts walls & valves reflect back at different frequencies Electronically plotted to produce a picture of the heart and its anatomic structure Identifies valvular heart disease, left and right atrial size, left ventricular size and function, left ventricular hypertrophy and pericardial disease Enlarged left atrium: etiologies of development of a-fib (wont be able to see thrombus) Atrial Fibrillation Diagnosis: Transesophageal Echocardiogram (TEE) see thrombus in atrial appendage Obtains images of the heart from inside the esophagus Placement of long probe with transducer at the tip sending ultrasound waves reflecting off various parts of the heart Echos are converted into moving images of the heart structures and blood flow A Fib Diagnosis: TEE Thrombus formation due to loss of organized mechanical contraction during atrial fibrillation arises most frequently in the LA appendage (LAA) TTE does not reliably detect LAA thrombi TEE provides a sensitive and specific method assessing LAA and detecting thrombi Atrial Flutter: Pathophysiology (use anti-thrombotic therapy) re-entry loop Due to a large reentrant circuit that involves the lower lateral right atrium essentially encircling the tricuspid annulus of the right atrium Single loop (circles the tricuspid and right atrium) doesnt allow for full contraction of atria (also risk of thrombus formation) Atrial Flutter: Causes Can occur at any age Can occur in patients without structural heart disease More commonly seen in the elderly patient with underlying heart disease Hypertension Ischemic heart disease Cardiomyopathy Rheumatic heart disease Pulmonary embolism Hyperthyroidism Alcoholism Pericarditis Post surgery for Coronary artery disease Congenital heart disease Atrial septal defect Atrial Flutter: Signs & Symptoms Depend principally on ventricular rate Asymptomatic Palpitations Fatigue Poor exercise tolerance Dyspnea (congestion) Angina Dizziness Syncope Tachycardia Hypotension Rales, S3, edema

Peripheral embolization TIA CVA (stroke) Lower extremity emboli A Flutter (no p-waves instead flutter waves regular)

EKG demonstrates characteristic flutter waves forming the classic sawtooth pattern Atrial depolarization occurs ~300 beats/min usually conducting through the AV node in a 2:1 or 4:1 ratio Atrial flutter unlike atrial fibrillation tends to be a very regular rhythm

Classic re-entry: paroxysmal supraventricular arrhythmia o Normally SA node fire enough of time between each beat for both pathways to accept a beat (when it does beat itll cancel each other out) AV Nodal Reentrant Tachycardia (AVNRT) (premature atrial complex PAC) Both side of conduction in reentry loops reside in AV node Abrupt onset and termination Triggered by a PAC one of the pathway is still refractory (cant conduct) impulse will come down one side and itll go up and starts reentry circuit) Narrow QRS complex tachycardia (QRS <.12 seconds) everything happening in AV node everything is going through his-purkinje system 150-250 beats/min Occurs in the young & healthy w/o heart disease Women >men Most patients have structurally normal hearts Can occur in patients with rheumatic heart disease, pericarditis, MI or mitral valve prolapse

AVRT
AV Reentrant Tachycardia (AVRT) one path in AV node and another side of pathway in accessory pathway No N (so a bundle of fibers that connects atria to ventricle) nd 2 most common form of PSVT Results from presence of 2 conducting pathways creating a reentry circuit AVRT different from AVNRT orthodromic conduction (NOT AS BAD) Reentry circuit with AVNRT contained within the AV node Reentry circuit with AVRT requires both atrium and ventricle and conducting tissue called an accessory pathway bridging the atrium and ventricles outside of the AV node AVRT usually composed of one accessory pathway and the AV node AV Reentry Tachycardia (AVRT) Incidence of AVRT in the general population is .1 to .3% AVRT is more common in males than in females (2:1) Patients with AVRT commonly present at a younger age than patients with AVNRT Most patients with AVRT do not have any evidence of structural heart disease AVRT A reentry circuit is most commonly established by impulses traveling in an antegrade (they go down from atria to ventricle through AV node and through accessory pathway orthodromic) manner through the AV node and in a retrograde manner through the accessory pathway called orthodromic AVRT AVRT (antidromic DANGEROUS: atrial beat can stimulate ventricle) A reentry circuit may also be established by a premature impulse traveling in an antegrade manner through an accessory pathway and in a retrograde manner through the AV node called antidromic AVRT

AVRT

While orthodromic AVRT is typically a narrow complex tachycardia (connects through AV node), antidromic AVRT inscribes a bizarre wide complex tachycardia (doesnt connect through the AV node) can look at ventricular tachycardia (it is associated with AVRT)

Pre-excitation Accessory pathways can conduct either from the atrium to the ventricle (antegrade) or from the ventricle to the atrium (retrograde) Antegrade conduction through the accessory pathway occurring earlier than the AV node conduction is known as pre-excitation beat from SA node will come down through accessory pathway which travels faster to ventricle than AV node EKG findings include delta wave and short PR interval (<.12 sec); less narrow QRS, lump on the QRS interval (delta wave: early electrical conduction) Pre-excitation Wolfe-Parkinson-White Syndrome (WPW) (anagrade conduction from atria to ventricle through accessory pathway)

WPW (risk of paroxysmal ventricular tachyarrythmia) Prevalence of WPW pattern .1 to .3% Men > Women (2:1) Incidence of arrhythmia in patients with WPW pattern vary widely 12-80% Present at birth, sporadic & genetic Often asymptomatic and found incidentally Associated with ASD, MVP, IHSS Sxs occur during adolescence or adulthood Ventricular Arrhythmias Premature Ventricular Complexes (PVCs) (wide QRS: problem in his-purkinje possible block make from one side over traveling a greater distance to depolarize either ventricle if impulse is generated in a muscle cell it has to travel throughout the ventricle depolarizing it but because it isnt in the fast conducting his-purkinje system it will take a greater time) Width and physical difference in the QRS

Premature comes before the next expected beat from nodal tissue Monomorphic ventricular tachycardia (associated as a pro-arrhythmia with class IC antiarrythmic ex. Flecainade)

Ventricular Tachycardia

Ventricular Fibrillation Chaotic contractions no physical contraction (no CO; BP; perfusion)

Premature Ventricular Complexes (PVCs) Most common of the ventricular arrhythmias May arise from a ventricular focus with (1) enhanced automaticity or may represent a form of (2) reentry Also known as VPBs or VPCs PVC Wide QRS >.12 sec (more than 3 boxes) Bizarre QRS morphology (abnormal QRS) Followed by compensatory pause Isolated or in groups (complex PVCs) Two consecutive PVCs termed a couplet Three or more consecutive PVCs at rate >100 beats/min termed ventricular tachycarida Sustained or non-sustained Bigeminy (PVC every other beat): normal, abnormal, normal, abnormal Trigeminy (PVC every third beat): 2 normal beats and then an abnormal beat Multiform (PVCs with 2 or more different morphologies: at least 2 spots within ventricle that have abnormal automaticity or reentrant activity PVC Single PVCs, sporadic or in a periodic pattern, are sometimes referred to as simple ventricular ectopy Multiform PVCs, ventricular couplets, and non-sustained ventricular tachycardia are referred to as complex ventricular ectopy (complex increases risk) PVCs increase in frequency with age Can occur inpatients with and without structural heart disease PVC frequency and complexity have NO prognostic significance for patients WITHOUT structural heart disease Patients with prior myocardial infarction, both frequent PVCs (>10 PVCs/hr) and complex ventricular ectopy are associated with an increased risk of death Ventricular Tachycardia Series of three or more PVCs in a row Divided arbitrarily into two categories Sustained: V tach persisting > 30 seconds or requires termination because of severe symptoms Nonsustained 3 or more consecutive PVCs lasting <30 seconds not requiring acute termination Commonly associated with structural heart disease Ventricular Tachycardia Symptoms vary depending on the duration of the tachycardia, the rate, and the underlying condition of the heart

Major manifestations are hypotension, syncope, loss of consciousness due to low cardiac output or cardiac arrest requiring immediate cardioversion Ventricular Tachycardia QRS >.12 sec 100-200 beats/min QRS may all be of the same shape monomorphic or as continually changing forms polymorphic Mechanism of VT Enhanced automaticity Reentry (this is the cause in majority of patients) Ventricular Tachycardia Most common cause of VT is IHD (IHD increase intracellular cation concentration) In setting of an acute MI you have a reason for that patients VT Sustained VT occurring within first 48 hrs. do not convey an increased risk of recurrence VT occurring beyond the first 48hrs after an MI has a high recurrence rate (annual risk 30%) Patients with recurrent symptomatic VT More than half have IHD Prior MI with depressed LV function Cardiomyopathy (structural change predisposes to VT) Dilated congestive (systolic heart failure) Hypertrophic (diastolic failue) Primary electrical disorders Long QT syndrome (repolarization of the ventricle prolonged increases risk for triggered automaticity and development of TDP-VT) Mitral valve prolapse Valvular heart disease Congenital heart disease Ventricular Tachycardia After a myocardial infarction, the risk of death is 5 to 10%, with a large portion of these patients dying of an arrhythmia and the largest risk being in patients with poor LV function Patients with a prior MI and nonsustained VT have a 2-year mortality of 30% Patients with inducible VT have a 50% 2-year mortality In patients with heart failure, up to 50% may die suddenly In patients who survive a cardiac arrest, the mortality is 20% at 1 year Ventricular Fibrillation Life-threatening Disordered rapid stimulation of the ventricles preventing coordinated contraction Major cause of death with MI ECG: chaotic irregular complexes of varying amplitude & morphology without discrete QRS waveforms Treatment: Cardioversion Torsades de Pointes (polymorphic tachycardia)

Twisting of the points Form of ventricular tachycardia Varying amplitudes of QRS twising about the baseline Mechanism: Afterdepolarizations or triggered activity in diseased tissues Prolonged QT interval (repolarization of ventricle making it vulnerable to a trigger from the ventricle; EAD) Antiarrhythmic drugs: potassium blocker (class III antiarrhythmic: sodalol), CCB; (class Ias: quinidine) Electrolyte imbalance (Low K and Mg) Congenital prolongation of the QT interval Usually symptomatic but self-limited (decreased BP) Syncope Ventricular fibrillation Heart Block

Alterations of impulse conduction Conduction blocks can occur anywhere within the specialized conducting system Between sinus node and atrium (SA block) Between atrium and ventricle (AV block) With atrium (intratrial block) Within ventricles (intraventricular block) Atrioventricular Block Conduction blocks between the atria and ventricles are termed AV block AV block exists when the atrial impulse is conducted with delay or is not conducted at all to the ventricle Commonly seen in clinical practice Caused by ischemia (SA/ AV node right coronary artery; his bundle left anterior descending), fibrosis, trauma & drugs (BBs, CCBs) st nd rd Three degrees of types of AV block: 1 , 2 & 3 degree st Atrioventricular Block 1 degree (start of P wave and R or QRS) Prolongation of the normal delay between the atrial and ventricular depolarization PR interval >0.2 sec (>5 small boxes) Transient influences Heightened vagal tone Transient AV ischemia Beta/Calcium blockers Structural MI Chronic degenerative disease Benign, asymptomatic that requires no Rx nd Atrioventricular Block 2 degree Mobitz I

Intermittent failure of AV conduction, such that not every P wave is followed by a QRS complex Periodic loss of the QRS (intermittent) Mobitz I also termed Wenchebach block EKG: Increase PR interval from one beat to the next until a single QRS complex is absent, and then the cycle starts anew AV node is almost always the site of this form of block Usually benign (children, trained athletes, increased vagal tone) Can occur during acute IMI, because of vagal stimulation, but is usually transient nd Atrioventricular Block 2 degree Mobitz II

More ominous More likely from a disease within bundle branches related to abnormal conduction system (need for pacemaker) Periodic completely absent conduction AV conduction intermittently ceases unexpectedly without warning PR prolongation in previous beats Block may persists for 2 or more beats (high degree AV block) Usually indicates disease more distally in the His-Purkinje system QRS complexes may be abnormally wide May arise from extensive infarction or chronic degeneration of the conduction pathway rd May progress to 3 degree AV block Pacemaker is therefore necessary rd Atrioventricular Block 3 degree (no relationship b/w atria and ventricle firing)

Complete failure of conduction between the atria and ventricles Most common causes: acute MI, drug toxicity and chronic degeneration of the conduction pathway rd 3 degree AV block divides the heart into two unconnected zones There is no relationship between the P waves and the QRS complexes Atria depolarize in response to SA node activity, while an escape rhythm drives the ventricles independently at an intrinsic rate of 30 to 50 beats per minute Symptoms of lightheadedness or syncope Permanent pacemaker is almost always necessary

Pharmacology Major Categories of antiarrhythmic drugs Fast-response: His-purkinje cells, myocardial muscle cell Slow-response: nodal cell Examples of Each Drug Category 1. Sodium channel blockers (Class I): Lidocaine, disopyramide, flecainide, others. 2. Beta blockers (Class II): Propranolol, esmolol, others. 3. Potassium channel blockers (Class III): Ibutilide, others. 4. Calcium channel blockers (Class IV): Verapamil, diltiazem, bepridil. 5. Multi-channel blockers: Amiodarone. 6. Vagus activators: Digitalis glycosides. 7. Adenosine Sodium channel blockers: Effects on fast-response action potentials Prolongs the time the sodium channel is open causes greater influx of sodium o Decreases responsiveness (slope of phase 0 decrease velocity of conduction through his-purkinje and muscle cells widening of QRS) Sodium channel blockers: Effects on arrhythmias Short tau and long tau agents Short and some of the long tau works on partially depolarized muscle cells and his-purkinje cells (zone of ischemia) Either fix it or shut it down (block it completely class I drugs) o Lidocaine corrects ventricular tachycardia to produce normal sinus rhythm o Atrial fibrillation normal sinus rhythm o Counterproductive (long tau/ class I): proarrhythmia Class I agents and quenching of reentrant arrhythmias Most likely mechanism: (1) slow conduction velocity Further slowing conduction and increasing refractoriness (cant be stimulated early) of damaged and partially depolarized fast-response cells in the ischemic zone. This would convert a unidirectional to a bidirectional block through the damaged zone. Two types of sodium channel blockers State-dependent channel blockade: Drug has either higher affinity for either open vs. inactive channel Drug either lets go quickly or holds on longer (short vs. long recovery) Long tau agents: e.g. flecainide (tau = rate of recovery) 1. Higher affinity for open sodium channels. 2. Blocks channels in both healthy and diseased cells. 3. Slower rate of recovery from blockade. 4. Same extent of sodium channel blockade at low and high heart rates. 5. Therefore, these agents generally are less useful class I agents. Short tau agents: e.g. lidocaine (1) selective for damaged cells, (2) works better at high HR 1. Higher affinity for inactive sodium channels. 2. More selective blockade of sodium channels in diseased myocardium. 3. Faster rate of recovery from blockade (why its called short tau) 4. Better blockade at higher heart rates.

5. Therefore, more useful class I agents, especially for arrhythmias associated with severe ischemia or m.i. Adverse effects of sodium channel blockers (by blocking sodium channels gets calcium out and sodium in; weaken the heart especially long tau agents) 1. Cardiodepression: Reverse of effects of digitalis glycosides. 2. Proarrhythmias: More prevalent with long tau agents. 3. Anticholinergic effects (e.g. quinidine), which would accelerate AV conduction and therefore exacerbate ventricular arrhythmias in atrial fibrillation (want to produce partial AV block). 1. Give BB or CCB to slow down HR first before administering quinidine Potassium Channel Blockers (class III) (1) decrease rate of activation, (2) decreased rate of recovery ONLY INCREASE REFRACTORINESS Potassium channels start out open; establishing resting membrane potential At the plateau they close down and to repolarize they slowly open again Increase the duration of action potential increases refractory period (rate of recovery and reopening) Decreases automaticity of fast response cells (phase 4 depolarization especially purkinje cells) o QRS to T wave prolonged) Counter therapeutic: marked QT prolongation Torsades de Pointes Quenching reentrant arrhythmias by class III agents Most likely mechanism: Increase in refractoriness of partially depolarized fast-response cells in the ischemic zone. This converts a unidirectional to a bidirectional block in the affected area. Beta blockers: Effects on fast- and slow-response action potentials Triggered activity caused by high sympathetic drive Class II agents: mechanisms of antiarrthymic actions 1. Slowing conduction and increasing refractoriness in AV node (stabilizes ventricular rhythm in atrial fibrillation). 2. Suppressing of abnormal automaticity and triggered activity in fast-response cells, quenching ventricular tachyarrhythmias. Calcium channel blockers: Effects on slow-response action potentials Shortens the fast cell action potential st Produces 1 degree AV block Class IV agents: Mechanisms of antiarrhymic actions 1. Decreased conduction and increased refractoriness in the AV node, normalizing ventricular rhythm in atrial fibrillation and terminating reentrant arrhythmias involving nodal tissue. 2. Suppression of triggered activity (delayed afterdepolarizations) in fast-response cells. Amiodarone: The multi-purpose tool in the box Atrial flutter, ventricular tachycardia Amiodarone: Mechanisms of antiarrhythmic actions 1. Decreased conduction and increased refractoriness of partially depolarized fast-response cells, quenching reentrant arrhythmias (classes I and III effects). 2. Decreased conduction and increased refractoriness of AV nodal tissue, normalizing ventricular rhythm in atrial fibrillation and quenching reentrant rhythms involving nodal tissue (Classes II and IV effects). Digitalis glycosides: Effects on arrhythmias Digitalis glycosides: Major mechanism of antiarrhythmic action The digitalis glycosides increase the actions of, and sensitivity to, the vagus nerve on slow-response (nodal) cells in the heart. This has two major consequences: 1. Slowing conduction through the AV node, normalizing ventricular rhythm in atrial fibrillation; and 2. Decreasing heart rate, relieving oxygen demand. Treatment of atrial fibrillation Quinidine and disopyramide increases AV conduction Slow AV conduction A-fib may continue but normal ventricular contraction Effects of adenosine on slow-response cells Temporary cardiac arrest Major Objective in Treating Atrial Fibrillation Main objective: Slow conduction through the AV node. Rationale: To slow down and normalize ventricular rhythm, even if the atrial fibrillation persists. Mechanism: Fewer action potentials move more regularly through the AV node to the bundle branches when the AV node is partially blocked. Drugs that can slow conduction through the AV node Drugs that can be useful to treat atrial fibrillation because they all can slow conduction through the AV node:

1. 2. 3. 4. 5.

Calcium channel blockers. Beta blockers Digitalis glycosides Amiodarone Adenosine

Ion channel blockers in heart (affecting the ion flow in the cardiac cells/ vascular smooth muscle cells) + + 2+ These ion channels control movement of ions (Na , K , Ca ), which control conductance, in cardiac cells and vascular smooth muscle cells. KNOW MAJOR TARGETS + I. Class I (main target): Fast inward sodium (Na ) channels (blocked by class I antiarrhythmics = local anesthetics) II. Beta-adrenergic receptor blockers = class II (beta receptors) + III. Potassium (K ) efflux channel (blocked by amiodarone*, dofetilide = class III) 2+ IV. Voltage-gated slow calcium channels (Ca ) (blocked by calcium channel blockers = class IV antiarrhythmics) + + V. Sodium/potassium-ATPase (Na /K exchange) (blocked by digoxin and other cardiac glycosides) = class V Learning Objectives Understand the sequence of Calcium ion channel opening and closing in smooth muscle contraction. (Na+ channel and K+ channel work similarly) List the molecular target of each of the five Vaughan-Williams antiarrhythmic drug classes, and the major drugs within each class. Recognize structural features. Compare and contrast the drugs within each class as to structure and effects. Ion movement in smooth muscle contraction Action potential o Resting: more K+ inside and theres Na+ and Ca+ outside o Depolarization: sodium influx through fast inward Na+ channels o Plateau: slow calcium channel cause calcium influx while opening K+ open channels open causes potassium efflux Class I Antiarrhythmics: sodium channel blockers These are generally local anesthetics which + Block the fast inward sodium (Na ) channels 1A: Quinidine, procainamide, disopyramide, ajmaline, prajmaline 1B: Lidocaine, mexiletine, phenytoin, (tocainide) 1C: Flecainide, encainide, propafenone, moricizine. Indecainide, lorcainide Differences defining subclass: 1A vs. 1B vs. 1C: DIFFERENT? Different ability to block open channel vs. closed channel (1A vs. 1B). (State-dependent channel blockade) + Procainamide (1A) blocks open Na channel + Lidocaine (1B) blocks open and IN-active (closed) state of Na channel Differences defining subclass: 1A vs. 1B vs. 1C Different rates of recovery from block (B (short) vs. A&C (long)) Long t = slow recovery; short t = fast recovery Flecainide (1C) has very slow recovery from block, and Slows conductance even in normal tissues at normal rates. Lidocaine (1B) has very fast recovery from block, + results in substantial Na block in ischemic tissues (but less in normal tissues) Most 1A & 1C agents = long t Disopyramide, quinidine, flecainide, propafenone, moricizine 1B agents = short t Lidocaine, mexiletine, tocainide, phenytoin 1A: Quinidine, procainamide, disopyramide 1A electrophysiological actions, but different side effects Quinidine is also alpha-antagonist Disopyramide has anticholinergic actions (the dries) Explains glaucoma, constipation, dry mouth + Also blocks outward K current

Parent drug causes lupus-like syndrome More prominent in slow N-acetylators Procainamide 1B: Lidocaine, mexiletine, phenytoin 1B electrophysiological actions, but different side effects Lidocaine used only IV or IM (not oral) Because of extensive and variable first-pass metabolism (N-dealkylation) Mexiletine Analog of lidocaine with much less first pass metabolism, permitting oral therapy Phenytoin is most well-known for its anti-seizure action 1C: Flecainide, encainide, propafenone, moricizine 1C electrophysiological actions, but different other details + Both flecainide and propafenone also block K channels Propafenone is metabolized extensively by CYP2D6 Poor CYP2D6 metabolizers have more adverse effects (aromatic hydroxylation) across from ether Cellular calcium levels 2+ Two types of channels/receptors control intracellular Ca 1. Receptor-operated calcium channels (b-receptor blocker): Class II Not directly blocked by calcium channel blockers b-blockers directly block the b receptors Indirectly affect intracellular calcium levels (via adenylyl cyclase) 2. Calcium channels: Class IV blocked directly by calcium channel blockers Also called...Voltage-gated or potential-dependent. Also called slow calcium channels Also called L-type calcium channels 2+ Ca channel VS b-receptor Calcium channel and b-receptor are both transmembrane proteins. 2+ The Calcium Channel forms a hole (pore) in the membrane to directly move Ca from outside cell to inside cell. B-adrenergic receptor is a G-protein-coupled receptor (GPCR). The b-agonist binds to the receptor outside the cell, activates adenylyl cyclase. 2+ Indirectly causes movement of Ca Class II: b-blockers Fundamentals covered last semester Certain ones used for arrhythmias Esmolol (very short acting minutes (hydrolyzed by plasma esterases), given by slow IV) Sotolal (dual action, also K+ channel blocker) Remember how b-receptors affect the heart? Class III (plus) = Amiodarone + MAJOR EFFECT: Blocks potassium (K ) efflux channels, but also blocks additional channels 2+ Also decreases Ca current (class IV) + Also decreases inward Na current (class I) Through weak sodium channel blocking Also has non-competitive b-adrenergic blocking action + Amiodarone binds to and blocks IN-active state of K channel Amiodarone = class III plus Highly lipophilic, eliminated very slowly (days, weeks) Active metabolite (N-desethyl) is also eliminated slowly Is a structural analogue of thyroid hormone, and some of its side effects may be caused by nuclear thyroid hormone activity. Amiodarone decreases metabolism and elimination of other drugs Inhibition of CYP3A4, CYP2C9, p-glycoprotein transporter Explains need for dosage adjustment of warfarin (2C9), flecainide, digoxin Calcium channel blockers = class IV Calcium channel blockers = class IV 2+ Mechanism of action: Competitively inhibit influx of Ca into vascular smooth muscle and cardiac (heart) cells through slow calcium channels by plugging the channel.

Bind only to open and closed-inactive conformations of L-type Ca channels. ApoCalmodulin (ooo) in the resting channel prevents binding of channel blockers to the closed-resting conformation. Apo (means without bound calcium): bound or not bound (Apo means that it is without calcium) Voltage-gated Calcium ion channels Six known subtypes, present in many tissues, affect many cellular processes. T, -Transient, low voltage. N, -Neuronal P, -Perkinje cells Q, R, -bind polypeptide toxins L : see below L-type, blocked by calcium channel blockers. Present in skeletal, cardiac cells, vascular smooth muscle. High voltage (activated above 40 mV). 2+ Large conductance (lots of Ca moves through). Recover slowly, called slow calcium channels (recovery is rather slow) Structure of Calcium Channels (L-type) Completely closed Completely open Intracellular and Extracellular domains of calcium channels (L-type) Cartoon model of calcium channel structuremultiple subunits 4-membrane domains Calmodulin binds to an intracellular domain 2+ Voltage gated Ca channels: 3 conformations (activated by action potentials) I. Closed/ resting (apocalmodulin blocks intracellular side of channel); alpha helices block the extracellular portion of the channel 2a. open intracellular side (voltage activation) 2b. open extracellular side o Fully opened 3. Extracellular closes; S6 helices close intracellular side of channel o Helices have to relax and open (recovery) Structure-function of calcium ion channels

2+

Structure-function of calcium ion channels 2+ Side view of docked CCBs in L-type Ca channel Ligands are represented as orange sticks, channel protein represented as gray ribbons. (I love dr. king yay! ) We are only seeing the alpha helices that are the membrane portion in ribbon form! This is so dumb! We have four of these coming together she cant even find the fourth p helix coming together They are just coming into the membrane a little so they are able to shift

CCB only block the open form dont block resting state because have to be partially open Drug binds inside channel needs access from extracellular side 2+ This is why Ca channel blockers do not block the resting state Calcium channel blockers (chemical classes) Dihydropyridines they have a state that is resting and ready to be opened nifedipine (Procardia, Adalat), amlodipine (Norvasc), (~5 others with dipine suffix). Non-dihydropyridines Phenylalkylamine verapamil (Verapamil SR, Calan SR). Benzothiazepine diltiazem (Cardizem CD). Diarylaminopropylether Bepridil (removed from market 2003) Phenylalkylamines: verapamil 2+ First Ca channel blockers developed, in 1960s. Act at L-type channels in vascular smooth muscle and cardiac muscle. 2+ L-type Ca channels are most sensitive to phenylalkylamines. at higher concentrations, phenylalkylamines also block 2+ other types of Ca channels, + + Na and K channels. Verapamil has active metabolite, some indication for adjusting in renal because of the active metabolite Ionized nitrogen (+) at physiologic pH, pKa 8.9. Active metabolite (N-desmethyl). Active metabolite is eliminated renally, thus dosage adjustment in renal impaired patients. Diltiazem (a benzothiazepine) 2+ At higher concentrations, diltiazem also blocks other voltage-gated Ca channels. pKa 7.7, basic. Active metabolite (N-deacetyl). Renal eliminationdosage adjustment in renal impaired patients. Bepridil (diarylaminopropylether) for a while it was thought to be fab but it was removed from the market Newest agent, (but removed from market in 2003) + Also blocks fast Na channels. 2+ Also blocks receptor operated Ca channels (b-receptors). Basic compound, pKa 10, ionized at physiologic pH (pyrrolidine ring N). Unionized form very lipophilic, oral absorption 90%. First pass metabolism reduces oral bioavailability to 60%. But Active metabolite improves action. Dihydropyridines Developed beginning in 1970s. Many similar ones on market currently. All have 1,4-dihydropyridine structural nucleus but have different substituents on the 3-, 4-, 5- and 6positions on the dihydropyridine ring. Unionized at pH 7, except those with side-chain basic nitrogen (amlodipine, nicardipine). Dihydropyridines-pharmacophore The dihydropyridine (reduced form) is required for activity (oxidative metabolism to pyridine = inactive). aromatic ring at C4 is required for good activity. bulky substituent (X) on the phenyl ring is optimal, locks the two rings perpendicular to one another, ortho and meta positions best for this (see 3D structures). ester groups at C3 and C5 optimize activity. substituent needed at C6, may be methyl or larger. Dihydropyridines Most of them have this phenyl ring

Need something bulky phenyl, or a nitro The R6 can be an ester or something as small as methyl 2+ Clinical effects of metabolism of Ca channel blockers First pass may reduce bioavailability: CYP3A4 metabolism in gut Felodipine, isradipine, nimodipine, nisoldipine, 5-20% bioavailable Nicardipine, 35% bioavailable Nifedipine, 30-60% bioavailable Amlodipine, 60-80% bioavailable, not much first pass Half-life affected by rate of liver metabolism Nicardipine & nifedipine, 2-4 hr, "fast" metabolism Amlodipine, 30-50 hr., also has an active metabolite All oxidized by CYP3A4 to pyridine (inactive) Inducers, inhibitors Liver impairment + + Na -K -ATPase pump blockers: Digoxin, digitoxin + + Bind to a site on the extracellular portion of the Na -K -ATPase pump in the membrane of heart cells (myocytes). + + + + Inhibits the Na -K -ATPase pump responsible for Na -K exchange in heart cells + + This Na -K exchange normally reestablishes the action potential. Energy for the exchange is provided by the + + Na -K -ATPase. + + Net result of inhibition of Na -K -ATPase is reduced sodium exchange with potassium, leaving increased + intracellular Na . Digoxin, digitoxin Called cardiac glycosides Three sugar residues aglycone (name for portion without sugar residues) -genin, is name for aglycone portion alone (digitoxigenin, digoxigenin) Therapeutic activity is due to the aglycone Both Digoxin and Digitoxin are natural products, from plants (digitalis). Difference: Digoxin has extra -OH (digitoxin = H) Differences of digoxin and digitoxin Pharmacokinetic difference Caused by different number of sugars and OHs The extra -OH in digoxin makes digoxin more polar Digoxin 81.5 (partition coefficient) Digitoxin 96.5 Cardiac glycosides with more lipophilic character (i.e., digitoxin) are absorbed faster and exhibit longer duration of action as a result of slower urinary excretion rate. Active conformation: digoxin, digotoxin Fused ring system is different than most steroids Forces the molecule into U-shape Also called cardenolides because of lactone ring Remember the objectives Understand the sequence of Calcium ion channel opening and closing in smooth muscle contraction. (Na+ channel and K+ channel work similarly) List the molecular target of each of the five Vaughan-Williams antiarrhythmic drug classes, and the major drugs within each class. Recognize structural features. Compare and contrast the drugs within each class as to structure and effects.

Pharmacotherapy: Therapeutics Outline: Supraventricular Arrhythmias and Conduction Abnormalities Overview of Antiarrhythmic Drugs Atrial Fibrillation Definitions and Patterns Prevention of Thromboembolism Rate Control vs. Rhythm Control Cardioversion of Atrial Fibrillation Maintenance of Sinus Rhythm Atrial Flutter

Outline (cont.) Paroxysmal Supraventricular Tachycardia (PSVT) (AV reentrant tachycardia) Acute treatment Chronic management AV Nodal Blockade Association with drug therapy Approaches to management

IB: Lidocaine alternative to amiodarone in patients with MI with VA IC: A-fib, VA, III: amiodarone (back of hand), dronedarone (appropriate use, how is it different from amiodarone), dofetilide (a lot of restrictions), sotalol (sotalol and amiodarone biggest in a-fib; renal elimination prolongs repolarization/ QT) o Supraventricular arrhythmias highlighted Antiarrhythmics: Thought Process for Use Risk vs. Benefit Ask: How important is the arrhythmia? Are patients likely to die or have significant morbidity? Ask: Is the drug effective for the arrhythmia? Does it act at the site in question (e.g., the atria or ventricle)? Role: Has it been shown to be clinically effective at treating the arrhythmia in question? How effective is it compared to other treatments? Ask: What risk is associated with the antiarrhythmic? (Class I and III can be proarrhythmics) Can it cause significant harm (cardiovascular or non-cardiovascular) in the patient? Does the drug have significant interactions with other drugs? Is the drug difficult to acquire / dose / administer? Antiarrhythmics: Dosing; Interactions; Adverse Events Refer to Detailed Listings in DiPiro tables Medications to Focus On Outpatient: Amiodarone, Dronedarone, Sotalol, Propafenone, Flecainide, Dofetilide Inpatient: Amiodarone, Procainamide, Lidocaine (not in supraventricular arrhythmias) Atrial Fibrillation definitions(AHA/ACC 2006)

 1=episodes lasting >30 seconds to 7days; 2=episodes lasting > 7days 3=cardioversion failed or not attempted 4=both paroxysmal and persistent AF may be recurrent *Recurrent AF = 2 or more episodes *Secondary AF= treating underlying condition terminates the arrhythmia *Lone AF= AF in young (<60yo) without CV dx including HTN Who Develops Atrial Fibrillation - Importance for Determining Management Secondary or Reversible Causes E.g., CABG, pulmonary embolism, hyperthyroidism Successful treatment of underlying condition often terminates the atrial fibrillation- long term management not required Who Develops Atrial Fibrillation - Importance for Determining Management Conditions Associated with Development of Atrial Fibrillation Increased Age Hypertension (esp. in the presence of LV hypertrophy) Ischemic Heart Disease Heart Failure and other structural heart disease Systolic HF: Treat a-fib by slowing AV nodal conduction digoxin, verapamil, diltiazem, BB Diabetes Obesity Valvular Heart Disease Lone Atrial Fibrillation ASK: how do these patient characteristics impact on your choice of treatment? Antiarrhythmics: Thought Process for Use Risk vs Benefit Ask: How important is the arrhythmia? Are patients likely to die or have significant morbidity? Ask: Is the drug effective for the arrhythmia? Does it act at the site in question (e.g., the atria [or ventricle or AV node)? Node: digoxin, BB, V and D Has it been shown to be clinically effective at treating the arrhythmia in question? How effective is it compared to other treatments? Ask: What risk is associated with the antiarrhythmic? Can it cause significant harm (cardiovascular or non-cardiovascular) in the patient Does the drug have significant interactions with other drugs Is the drug difficult to acquire / dose / administer What are the Risks of Atrial Fibrillation? (1)Thromboembolic Risk = Increased Risk of Stroke Rheumatic heart disease afib risk: 17-fold increase Non-valvular atrial fibrillation risk: 7-fold increase Risk increases with age Risk increases with concurrent HTN Risk increases with LV systolic dysfunction (2) Increased Deaths due to Heart Failure

 Heart failure promotes development of atrial fibrillation Atrial fibrillation (with fast ventricular rate) worsens heart failure Development of atrial fibrillation increases mortality in patients with HF Increased Heart Rate = Ischemia/Necrosis / Other Symptoms Decreased Blood Pressure Overall Management Strategy for AF Prevent Thromboembolism Based on Stroke Risk NOT on Pattern of AF (AHA/ACC 06)

High Risk Factors: Previous stroke, TIA or embolism, mitral stenosis or prosthetic heart valve Moderate Risk Factors: Age 75 yrs, hypertension, heart failure, LVEF 35%, diabetes mellitus Weaker/Less Validated Risk Factors: Female gender, age 65-74yrs, coronary artery disease, thyrotoxicosis (1: ASA or Warfarin) If patient has a mechanical valve replacement, INR range=2.5-3.5 with a target of 3.0 Dependent only on patient stroke risk nothing to do with transient or persistent AT Stroke Risk in Atrial Fibrillation Questions to Ask to Determine Risk/Benefit Balance: Who is Most at Risk for a Stroke? (CHADS2 score) What Antithrombotic Therapies are Most Effective at Decreasing Stroke Risk? What Antithrombotic Therapies are Least Associated with Adverse Outcomes / Poor Patient Adherence? Are There Any New Options? Combining Aspirin with Clopidogrel for Stroke Prevention in Patients with Atrial Fibrillation (ACTIVE W) ACTIVE W (Lancet 2006;367:1903) 3371 pts with atrial fibrillation with 1 risk factor for stroke Mean CHADS2 score =2 Clopidogrel 75mg + ASA 75-100mg daily vs vitamin K antagonist (INR=2-3). Trial ended early at 1.3 yrs: Oral anticoagulation superior (stroke/non-CNS embolus/MI/vascular death): annualrisk of 5.6% (C/A) vs 3.9% (OA); especially imp: stroke Combining Aspirin with Clopidogrel for Stroke Prevention in Patients with Atrial Fibrillation (ACTIVE A) ACTIVE A 7554 pts with atrial fibrillation; Not considered candidates for oral anticoagulation by enrolling physician Mean CHADS2 score =2 Aspirin plus Clopidogrel 75mg/day vs Aspirin alone Same endpoints at ACTIVE W; Treated 3.6 years Results: (annual event rates) Composite endpoint: C/A: 6.8% A: 7.6% (RR=0.89; 0.81-0.98) Stroke: C/A: 2.4% A: 3.3% (RR=0.72; 0.62-0.83) Major Bleeding: C/A: 2.0% A: 1.3% (RR=1.57; 1.29-1.92) Should clopidogrel be added to aspirin therapy in patients who cannot receive oral anticoagulation? 2011 ACC/AHA: Class IIb recommendation Direct Thrombin Inhibitor-Dabigatran Dabigatran (Pradaxa, Rendix): RE-LY non-inferiority trial (NEnglJMed 2009;361:1139) >18,000 atrial fibrillation pts (Mean CHADS2 score =2): use warfarin over aspirin alone Dabigatran 110mg or 150mg twice daily or warfarin Endpoint: Stroke or systemic embolism Results at 2 years: Lower dose= non-inferior; Higher dose= superior with similar risk of major hemorrhage

AHA/ACC Class I indication for stroke prevention in patients with non-valvular atrial fibrillation (cannot have severe renal dysfunction (CrCl < 15 ml/min or liver disease impairing clotting function) Dont give in patients with (1) valvular atrial fibrillation, (2) CrCl <15ml/min, (3) liver disease Considerations: (RENAL FXN) Costs- drug vs monitoring (warfarin a little less expensive even with monitoring) Issues for Switching to/from Warfarin Dosing in patients with renal dysfunction: CrCl <15ml/min CrCl: 15-30ml/min there is a renal dosing (75mg Dabigatran bid) GI bleeding ; Lack of antidote Dabigatran has less hemorrhagic stroke risk but greater risk of GI bleeding Is there a connection to Myocardial Infarctions? Doesnt reduce risk for MI as much as warfarin does More immediate effect as compared to warfarin When INR drops below 2: initiate Dabigatran Dabigatran warfarin: how fast does the effect of Dabigatran dissipates when initiating warfarin Half-life increased in patients with renal dysfunction (stop earlier because of the need to add warfarin) A direct Factor Xa inhibitor for AF Rivaroxaban (Xarelto) ROCKET-AF non-inferiority/superiority trial vs warfarin for prevention of stroke in afib patients NEnglJMed 2011; 365:883-891 14,264 pts with atrial fibrillation; mean CHADs=3.48 Rivoroxaban 20 mg qd or Warfarin (INR 2-3) Median time of INR 2-3 in Warfarin group= 55% of time Primary outcome of stroke or systemic embolism 1.7%/yr (R) and 2.2%/yr (W) ; non-inferior Bleeding rates similar FDA approved indication for prevention of stroke and systemic embolism in patients with nonvalvular afib Another direct Factor Xa inhibitor Apixaban (Not yet approved; Eliquis) AVERROES (NEnglJMed 2011; 364:806-817) Apixaban 5mg bid vs ASA 81-324mg qd in 5599 afib patients in whom warfarin was considered unsuitable; Mean CHADS score =2 Study ended early, mean follow-up 1.1 years with reduced stroke/systemic embolism with apixaban ARISTOTLE (NEnglJMed 2011; 365:981-992): comparison with warfarin therapy Apixaban 5 mg bid vs Warfarin (INR 2-3) in 18,201 afib patients; Mean CHADs score= 2.1 Median time of INR 2-3 in Warfarin group= 66% of time Primary outcome of stroke or systemic embolism = 1.27%/yr(A) vs 1.6%/yr (W) Reduced rates of major bleeding Arrhythmia Management Strategy for Atrial Fibrillation (AV node slow down ventricular rate; not doing anything about afib)) vs. (antiarrhythmic to get rid of conduction and go to normal sinus rhythm) Decision of Rate Control (i.e., slow down the ventricular rate using AV nodal blocking drugs) or Rhythm Control (i.e., giving an antiarrhythmic to achieve normal sinus rhythm) Considerations: Duration of AF: Ongoing for several years: unlikely that even if get to normal sinus rhythm it will be unlikely person will remain in normal sinus rhythm Type and Severity of Symptoms Associated Cardiovascular Disease Potential for Change in Cardiac Function over Time If a-fib continues rapid ventricular rate, can precipitate HF Is Rate Control or Rhythm Control better at decreasing mortality in patients with AF? Rate vs. Rhythm Control: no mortality benefit of either one AFFIRM trial (NEnglJMed 2002; 347:1825-33) Randomized comparison rate control vs. rhythm control in 4060 patients with atrial fibrillation Mean age: 70yrs; 38% with CAD; est. 26% with HF; old patients with few patients with HF Rate control: digoxin, beta-blockers, diltiazem most common, frequently combined Rhythm control: amiodarone; sotalol Mean follow-up: 3.5 yrs; Primary endpoint: total mortality

Results: No difference in total mortality (more hospitalizations/ADR in rhythm control group) or in stroke rate between groups Increased stroke rate in both groups when INR was sub-therapeutic or warfarin had been stopped. Antithrombotic-anticoagulant therapy: STILL BE ON ANTITHROMBOTIC THERAPY With rate control or rhythm control group: same increased stroke risk with either INR was subtherapeutic or if warfarin is stopped Patients with a-fib many of the times: from normal sinus rhythm a-fib, many are asymptomatic and they are at a greater risk Patients with Atrial Fibrillation and Systolic Heart Failure Important Recent Trial: AF-CHF (NEnglJMed 2008;358: 2667-77) Premise: Pts with Afib (paroxysmal/persistent) and HF would have reduced mortality if NSR was restored and maintained 1376 pts ; mean age 67 yrs; NYHA class II-IV; EF=27% Rhythm control (Amiodarone) or rate control (BB/Digoxin) Standard treatments given for HF (ACE-I/ARB; BB) 90% on oral anticoagulation Results: 3-yr CV Mortality: 27% (rhythm) vs 25% (rate) Rate vs Rhythm Control Considerations: Although AFFIRM was the largest trial addressing the question, it was performed in older patients, few of whom had heart failure. Further study in patients with heart failure (AF-CHF (NEnglJMed 2008;358: 2667-77)) showed no mortality benefit with antiarrhythmics over rate control in this population Rate control is a reasonable approach in older patients with persistent AF and concurrent hypertension or heart disease Rate vs Rhythm Control Considerations (cont): Have to consider the potential risks of antiarrhythmic therapy vs. the potential benefit of maintaining NSR in individual patients: Patients with continued symptoms despite appropriate rate control agents may benefit from rhythm control Rhythm control may be an appropriate option in younger patients with lone atrial fibrillation Rhythm control might be considered appropriate for younger patients with heart failure that would worsen over time if atrial fibrillation persisted Beta-blocker and digoxin/ CCB: still symptomatic attempt antiarrhythmic Initial Approach to Patients with AF (1) Identify and manage secondary causes (2)Determine need for emergency electrical cardioversion to normal sinus rhythm: AF with rapid ventricular response with ECG evidence of acute MI or symptomatic hypotension, angina or HF not promptly responding to pharmacologic measures for rate control (Class I) (caveat: there is a risk of thromboembolism if AF present for > 48 hrs) Do it (a-fib, v-fib) based upon patients symptoms and risk for adverse event A-fib, v-fib with MI Symptoms associated with CO (hemodynamically need to get out of rhythm) Most patients: first step is to slow down ventricular rate (rate control) Cardioversion more than 48hrs (assume there is a clot in left atrial appendage) RISK FOR STROKE IV heparin concurrent (reduce stroke risk) AF: Inpatient Rate Control Goal: Resting ventricular rate <110 bpm (60-80 bpm in patients with HF) Desire: Effective, rapid response with easy dosing, low adverse effect profile and low expense Examples of intravenous agents: Diltiazem 0.25 mg/kg IV over 2 min; then 5-15mg/hr (Class I*) Esmolol 0.5 mg/kg IV over 1 min; then 0.05-0.2 mg/kg/min (Class I) Superfast acting BB Verapamil 0.075-0.15 mg/kg IV over 2 min (Class I*) Class I: CCB V&D and BB

Digoxin 0.25 mg IV every 2 hours up to 1.5 mg; then 0.125-0.375mg qd (or dose using kinetics) (Class I in patients with heart failure, otherwise less effective due to slow onset ) Slow onset of effect Patient: patients with systolic HF/ decompensated HF Amiodarone 150mg over 10min, then 0.5-1.0 mg/min (Class I in patients with heart failure or who have an accessory AV pathway (other agents will cause harm) Patient: accessory bundle (conduit of fibers allows anagrade conduction)

AF: Outpatient Rate Control Goal: Resting ventricular rate <110 bpm (60-80 bpm in patients with HF) Desire: Effective, maintaining ventricular response with easy dosing, low adverse effect profile and low expense First Line: (AHA/ACC Class I) Beta-blockers (most effective overall for HR control). Examples: Atenolol, Metoprolol and Propranolol Diltiazem or Verapamil (preferred over BB if bronchospasm or COPD) Digoxin for sedentary individuals or those with HF (however it is ineffective for paroxysmal AF; must also use caution re: dosing and drug interactions) AF: Outpatient Rate Control Goal: Resting ventricular rate <110 bpm (60-80 bpm in patients with HF) Second Line: Combination of digoxin with BB or CCB (AHA/ACC Class IIa) Amiodarone to control rate if others unsuccessful (AHA/ACC Class IIb)(many adverse effects associated with this drug) Side effects and drug interactions associated with Third Line: Catheter-directed ablation of the AV node and pacemaker placement Cut the AV node so no electricity going through the node Other options Elective Cardioversion of Atrial Fibrillation to Normal Sinus Rhythm Methods for Initial Conversion Electrical cardioversion Pharmacologic cardioversion Consideration of Maintenance Antiarrhythmic Therapy Young patient, symptomatic Elective Cardioversion of Atrial Fibrillation Electrical: STABLE PATIENTS: Patients without hemodynamic instability when symptoms of AF are unacceptable (Class I) or as part of long-term management strategy (Class IIa) (contraindicated in pts with digoxin toxicity or hypokalemia high risk of ventricular arrhythmia) Initial dose: 200 J; max= 400 J Requires sedation/anesthesia Small chance of asystole (more significant ventricular arrhythmias can occur with digoxin toxicity and hypokalemia) no beat comes back Faster and more effective than pharmacologic cardioversion (70-90% effective) Pretreat: amiodarone several week before cardioversion Antiarrhythmic pre-treatment may improve efficacy Elective Cardioversion of Atrial Fibrillation Pharmacologic Cardioversion Inpatient Administration of Appropriate Drugs: IV Ibutilide (class I): 1mg over 10 min, can repeat x1 Alone or with cardioversion PO Propafenone (class I*): 450-600 mg single dose PO Flecainide (class I*): 200-300 mg single dose PO Dofetilide (class I): dose dependent upon renal function IV/PO Amiodarone (class IIa): IV: 5-7mg/kg over 30-60 min then 1.2-1.8 grams per day (IV or oral) until 10 grams total, then 200-400 mg/d Takes quite a while for Cardioversion to occur Different in dosing in v-fib and loading for a-fib

Do not use sotalol in cardioversion Used to maintain normal sinus rhythm *Class IIb if AF >7 days (i.e., less effective) Elective Cardioversion of Atrial Fibrillation Pharmacologic Cardioversion Comparison of therapies- patient characteristics and adverse event profiles Risk of proarrhythmia: varies by antiarrhythmic Outpatient administration in very selected pts with propafenone or flecainide pill in pocket or amiodarone (class IIa) do not do in patients with heart disease Prevention of Thromboembolism Associated with Cardioversion Patients with 48 hours of atrial fibrillation: (cant really tell) For elective cardioversion: warfarin (INR target 2.5, range 2-3) for 3 weeks prior to cardioversion then 4 weeks afterwards If patients has CHAD score (appropriate to be on anticoagulation afterwards continuous) If patient is just on aspirin still need the warfarin; EKG might be normal but contractility of heart doesnt come back For emergency cardioversion: intravenous heparin (aPTT of 50-70 seconds) ; transition to 4 weeks of warfarin (INR as above) Patients with known AF duration < 48 hours: For low stroke-risk patients: anticoagulation not needed (low CHAD score) If patient has higher CHAD score: IV heparin; trans-esophageal echo to check for thrombus For high stroke-risk patients: intravenous heparin with/without TEE (transesophageal echocardiogram) or delay cardioversion for 1 month, anticoagulation Maintenance of Sinus Rhythm Relapse rates very high in patients with persistent AF receiving DCC: 23% in normal sinus rhythm (NSR) at one year Have to add an antiarrhythmic Benefits of maintaining NSR Risks of using antiarrhythmics- patient considerations Comparisons of Adverse Effects A Substitute for Amiodarone? Unlike other antiarrhythmics, amiodarone does not increase mortality in patients with concurrent heart failure but Pharmacokinetics Drug Interactions Thyroid Dysfunction Electrophysiologic Effects Should Dronedarone be a substitute? Dronedarone The Good News ATHENA (NEnglJMed 2009;360:668) Large-scale trial of paroxysmal/persistent atrial fibrillation Dronedaone 400mg bid vs placebo Mean age 71 years; 21% with HF (II/III) Results at 21months: Primary endpoint of death and first cardiovascular hospitalization reduced (36.9% vs 39.4%). The Bad News ANDROMEDA (NEnglJMed 2008;358:2678) 627 patients with severe heart failure Study stopped at 2 months: Increased mortality from dronedarone 400mg bid vs placebo (8.1% vs 3.8%); primarily deaths from worsening heart failure Dronedarone The ?? News DIONYSOS Study (J Cardiovasc Electrophysiol 2010; 21: 597-605) 504 Patients with Atrial Fibrillation (persistent); Mean age=64years; 19% with NYHA I/II HF Dronedarone 400mg bid vs Amiodarone LD + 200mg qd Composite efficacy (prevent recurrence of afib) and safety endpoint Results: (12 months) Composite Endpoint: 75.1% (D) vs 58.8% (A); atrial fibrillation recurrence primary reason

Premature discontinuation due to safety points not statistically significant; Safety profile may be better with D (thyroid effects; concurrent warfarin treatment ACC/AHA 2011: Class Iia; Reasonable for use in preventing CV events in patients with paroxysmal or persistent atrial fibrillation (in NSR at initiation); Not indicated for patients with NYHA class IV HF or recent exacerbation Therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation

Maintenance of Sinus Rhythm Examples: (See DiPiros) Amiodarone 100-400 mg/d (can be used in patients with HF, CAD, or HTN with LV hypertrophy(LVH)) Dronedarone 400 mg bid (not for patients with severe HF) Dofetilide: 500-1000 mcg/d (can be used in patients with HF or CAD) Sotalol: 240-320 mg/d (use in patients with CAD) Flecainide: 200-300 mg/d (only if no structural heart disease, including LVH) Propafenone: 450-900 mg/d (only if no structural heart disease, including LVH) What is Next? Premise still holds that normal sinus rhythm is better than atrial fibrillation--- the strategy just needs to be improved: Better achievement of normal sinus rhythm Better identification of patients likely to have recurrent afib so risk/benefit correctly considered Lesser toxicity of antiarrhythmic strategy Ablation therapy of tissue surrounding the pulmonary veins can eliminate atrial fibrillation in some patients Non-pharmacologic Treatment for Atrial Fibrillation: Catheter Ablation AHA/ACC 2011: Class I recommendation as useful for maintaining NSR in selected patients:

*Significantly symptomatic paroxysmal atrial fibrillation

*Failure of treatment with antiarrhythmic drug *Normal or mildly dilated left atria *Normal or mildly reduced LV function *No severe pulmonary disease Atrial Flutter Comparison to Atrial Fibrillation Less common; similar pathogenesis Acute management: Rate/Rhythm control Anticoagulation Chronic management: Rate/Rhythm control Anticoagulation Paroxysmal Supraventricular Tachycardia (PSVT) Requirements for Development/Propagation (targets for drug/device intervention): Premature atrial complex (PAC) Two electrically distinct pathways with differing conduction/refractory periods At least one pathway in the AV node Two forms when considering therapy: AV Nodal Re-Entry AV Re-Entry (e.g., Wolff-Parkinson-White syndrome) Orthodromic (down AV node; up accessory pathway) Antidromic (down accessory pathway; up AV node) Acute Management of PSVT Vagal maneuvers Electrical Cardioversion (25 J) Patients with severe symptoms Pharmacologic Cardioversion (based upon ECG evaluation): Narrow QRS complex, regular tachycardia: Adenosine 6-12 mg rapid IVP Verapamil 5-10mg IVP Wide QRS complex, regular tachycardia: Adenosine as above Amiodarone (150mg over 10 min; repeat up to 2.2gm/24hrs) Wide QRS complex, irregular tachycardia: Could be atrial fibrillation with conduction through accessory pathway NO AV nodal slowing agents Use Amiodarone or Procainamide Preventive Therapy for PSVT Therapy indicated if: Frequent episodes needing intervention Infrequent but severely symptomatic episodes Choices: AV Nodal Blockers: Beta-blockers, Diltiazem, Verapamil (Digoxin) Drugs that alter retrograde fast pathways: e.g., Flecainide Risks and Benefits Catheter Ablation: (See DiPiro figure 19.10) Patients with antidromic AV re-entry ? All patients with symptomatic PSVT A-V Block First Degree (prolonged PR interval) Not a contraindication to drugs that prolong AV conduction Second Degree (periodic loss of ventricular beats) Type I (Wenkebach)= drug induced --stop drug Type II= structural abnormality below AV node: not secondary to AV nodal blocking drugs Third Degree (no connection between atria and ventricles) Either within the AV node or below

 Can be drug induced-- stop offending drugs Treatment: Atropine and Pacemakers Lecture Outline: Ventricular Arrhythmias Overview of antiarrhythmic drugs Chronic outpatient management of ventricular arrhythmias Categorization of arrhythmias and relative risk Appropriate management with drugs and ICDs Evidence-based justification Current issues Drug-induced ventricular arrhythmias Antiarrhythmic causes Non-antiarrhythmic causes Management Lecture Outline: Ventricular Arrhythmias (cont.) Out-of-hospital cardiac arrest Community response Automatic External Defibrillators ACLS procedures for ventricular fibrillation and pulse-less ventricular tachycardia Stable ventricular tachycardia Vaughan Williams Classification

Structurally Normal Hearts- Arrhythmia Management Isolated PVCs, rarely more complex or numerous Asymptomatic or palpitations (flipping sensation) Catecholamine excess, caffeine etc. Also consider low potassium, magnesium These persons are not at increased CV risk Remove cause, rarely need beta-blockers for symptoms Patients with Prior Myocardial Infarction Historical: Ventricular arrhythmias following hospital discharge after MI have been associated with increased CV risk. Risk increases with complexity of the arrhythmia (e.g., VT greater than PVCs) and presence of heart failure Prior MI with small decrease in EF and asymptomatic PVCs (no VT)

Management: Give magnesium and/or potassium if low Beta-blockers (decrease sudden death and overall mortality) Other antiarrythmics not indicated AVOID: Any class I antiarrhythmic because of increased risk of death from proarrhythmia Evidence: CAST I and II trials (encainide, flecainide, morcizine) (Dipiro pp.300-301) Other data: propafenone, quinidine Prior MI, reduced EF, nonsustained VT and sustained VT with EPS Approximately 30% of these subjects have sustained VT when electrically induced in an EPS (electrophysiology study) lab Management: Electrolytes (Mag/Potassium) and Beta-Blockers Implantable Cardioverter-Defibrillator (ICD) (DiPiro figure 19.12) ?Amiodarone as alternative to ICD AVOID: Class I antiarrhythmics Evidence: MUSTT trial Secondary Prevention (Patients with prior cardiac arrest) Episode in absence of known trigger (e.g., acute MI, electrolyte abnormalities) Most have CAD or history of prior MI Highest risk group for future episode of ventricular fibrillation/pulse-less VT (life-threatening ventricular arrhythmias) Secondary Prevention (Patients with prior cardiac arrest) Treatment: ICD ICD better than amiodarone Amiodarone or sotalol may be used to reduce firings in patients who receive an ICD Give beta-blocker as well Evidence: AVID trial and others Heart Failure Patients (Primary Prevention) SCD-HeFT trial (N Engl J Med 2005;352:225-37) 2521 Pts with NYHA II-III ; median EF=25% 52% with ischemic cardiomyopathy Randomization: Placebo, amiodarone (wt based 200-400mg/d), or ICD Median follow-up of 46mo: Death from any cause: P=29%, A= 28%, ICD=22% (relative reduction of 23% compared to P; 95%CI= 0.62-0.96) Conclusions: ICD reduced mortality. No apparent benefit from amiodarone in this population; Although subgroup analysis showed ICD better in NYHA II than NYHA III patients, inconsistent with other smaller studies ICD Considerations Inpatient Hospital Cost: $159K (2012 AHA Heart and Stroke Facts) Medicare Coverage (updated 1/05): Prior cardiac arrest (VF) not due to transient or reversible cause Documented sustained VT, not associated w/ MI or transient or reversible cause Prior MI + EF<0.35 + EPS-induced sVT or VF Prior MI + EF <0.30 Pts like those of SCD-HeFT (ischemic/nonischemic cardiomyopathy, EF <0.35 Economic Impact: 2-3x more pts eligible (approx. 500,000) Need more registry data to help determine who will obtain the greatest benefit from this treatment Ventricular Proarrhythmia Monomorphic Ventricular Tachycardia Usually associated with Type Ic antiarrythmics such as flecainide or propafenone. Can become incessant (unremitting) and resistant to resuscitation Increased risk in patients with ischemic heart disease, LV dysfunction, underlying ventricular arrhythmias; high concentrations may predispose

Ventricular Proarrhythmia Polymorphic Ventricular Tachycardia EXAMPLE: Torsade de Pointes Associated with prolonged repolarization on the ECG (lengthened QTc interval) Usually associated with class Ia and III drugs (amiodarone=rare) Frequently concentration dependent (sotalol, ibutilide) Other factors and drugs may cause Torsade de Pointes (See DiPiros) Examples of risk factors for prolonged QTc interval (See DiPiros) Electrolyte Imbalance: low potassium and magnesium Cardiac abnormalities: MI, myocarditis, cardiomyopathy, severe bradycardia Genetic: congenital long QT syndrome Drugs: Type Ia, III antiarrhythmics, phenothiazines, TCAs, erythromycin, others Management of Torsade de Pointes Discontinue/treat offending cause Correct electrolyte imbalances Electrical cardioversion if patient unstable Magnesium sulfate IV bolus 1 to 2 g over 1-2 minutes followed by an infusion of 1 to 2 g/h Secondary Management: Temporary transvenous pacing to increase heart rate 90 120 bpm (shortens QT) Isoproterenol infusion Out-of-hospital cardiac arrest Chain of Survival (time is life) Rapidly activate EMS (call 911) Rapidly initiate CPR Rapidly Defibrillate Rapidly initiate advanced care (airway/drugs) Outcomes Automatic External Defibrillators ACLS Treatment Protocol: V-Fib or Pulse-less VT CPR (go to Shock first if witnessed arrest) 1 Shock (360J); resume CPR 5cycles 1 Shock (360J); resume CPR Airway Drugs Epinephrine 1 mg IVP, repeat q 3-5 min OR Vasopressin 40 U IVP single dose 1 Shock (360J); resume CPR Consider Antiarrhythmics (before/after shock) Amiodarone 300mg IV; consider additional 150mg (first choice- (ACC Class I)) Lidocaine 1-1.5 mg/kg first dose, then 0.6-0.75mg/kg to a maximum of 3mg/kg Magnesium (1-2 g if torsades de pointes) Continue CPR; rhythm check/shock approx every 2 min Intravenous Amiodarone Drug of choice for VF and pulseless VT Shown to improve survival to hospital by 29% when given in rescue to shock-resistant patients as compared to placebo. No improvement in survival to hospital discharge (ARREST trial) However, electrical shocks are most important and should not be delayed by drug administration Sustained ventricular tachycardia ACLS 2005 standards: drug of choice Intravenous Amiodarone (II) Dosing for ventricular tachycardia: 150mg IV over 10min, then 1mg/min infusion for 6 hrs, then 0.5mg/min maintenance. Can administer second 150mg bolus if needed. Maximum dose is 2200 mg in 24 hours Administration issues -IV compatibility Acute side effects of IV administration: bradycardia and hypotension (infusion rate can be reduced) Intravenous Procainamide

Acceptable choice for stable ventricular tachycardia (except pts. with heart failure) Loading dose 2030 mg/min until suppression of arrhythmia, hypotension or QRS prolongation of >50% baseline or 17 mg/kg given. Maintenance dose= 1-4 mg/min Precautions Note: Not suitable for VF/ pulseless ventricular tachycardia because of the need for a slow infusion Intravenous Lidocaine Second line therapy to amiodarone (VF and pulseless VT) and third line to amiodarone and procainamide (stable VT) Dosing: Bolus 1-1.5 mg/kg; give second bolus 0.5 mg/kg after 10 minutes due to redistribution of drug. MD= 2-4 mg/min Considerations Pharmacokinetics Neurologic and other adverse effects