core v - cardiovascular core

7/30/2019 Core V - Cardiovascular Core

1/35

Pathophysiology

Conduction System

SA node conduction begins (electrical automaticity) Atrial contraction Fibers sitting b/w atria 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) contractionWhat 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 formationorfrom alterations in impulse conductionor 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 escapebeat If another region of the heart develops an intrinsic automatic firing rate that exceeds the SA node leading to

an ectopicbeat. (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 beatAutomaticity: 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


2/35

If catecholamine concentrations are increased locally at a group of abnormal or diseased cardiac cells with latentpacemaker 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 of60 mV,automaticity can be demonstrated even among these non-pacemaker cells.

Mechanisms: Triggered Activity

Under certain conditions, the action potential of cellular depolarization can triggera second action potential calledafterdepolarizations, 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 afterrepolarization has been completed.

At faster heart rates, the amplitude of afterdepolarizations increases and may lead to self-perpetuating runs oftachyarrhythmias

TDP:

A second type of afterdepolarization is called the delayed or late afterdepolarizations that occur afterrepolarization has been completed. known to cause DAD: digoxin

At faster heart rates, the amplitude of afterdepolarizations increases and may lead to self-perpetuating runs oftachyarrhythmias.

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 theyconduct electricity and how long does it take to repolarize/ another beat): ischemia would causedifferential between the two tissues that would cause disfigured re-entry circuit


3/35

Reentry

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 ifpresent 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)

Reentry

Reentry tachycardia is most commonly seen in the AV node but can also occur within the atrium and is themechanism 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

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 theventricles 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)


4/35

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 (


5/35

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 causePremature 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 toxicityUnifocal 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


6/35

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 antithrombotictherapy

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


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


Losing CO push; ventricle beats so quickly will use more oxygen and not enough to fill properly so lose CO (pulse islower 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 whichcan 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 withoutatrial fibrillation

Valvular (mitral) even greater risk for strokeA 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


7/35

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 7days Permanent: Cardioversion (trying to get patient back to normal sinus rhythm) not indicated or attempted or failed Lone: 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 RAAtrial Fibrillation Diagnosis: Simple Lab Tests

Complete blood counts Anemia

Low hemoglobin Low red blood cell count Low hematocrit


8/35

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 inthe 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 annulusof the right atrium

Single loop (circles the tricuspid and right atrium) doesnt allow for full contraction of atria (also risk ofthrombus 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 defectAtrial Flutter: Signs & Symptoms

Depend principally on ventricular rate Asymptomatic Palpitations Fatigue Poor exercise tolerance Dyspnea (congestion) Angina Dizziness Syncope Tachycardia Hypotension Rales, S3, edema


9/35

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


10/35

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 itdoes 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 PACone 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 men Most patients have structurally normal hearts Can occur in patients with rheumatic heart disease, pericarditis, MI or mitral valve prolapse


11/35

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) 2nd 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

pathwaybridging the atrium and ventricles outside of the AV node

AVRT usually composed of one accessory pathway and the AV nodeAV 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 toventricle 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 anaccessory 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 AVRTinscribes a bizarre wide complex tachycardia (doesnt connect through the AV node) can look at ventricular

tachycardia (it is associated with AVRT)

AVRT


12/35

Pre-excitation

Accessory pathways can conduct either from the atrium to the ventricle (antegrade) or from the ventricle to theatrium (retrograde)

Antegrade conduction through the accessory pathway occurring earlier than the AV node conduction is known a spre-excitationbeat 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 ( 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 blockmake 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


13/35

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 areassociated with an increased risk of death


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


14/35

Major manifestations are hypotension, syncope, loss of consciousness due to low cardiac output or cardiac arrestrequiring immediate cardioversion


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)


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


After a myocardial infarction, the risk of death is 5 to 10%, with a large portion of these patients dying of anarrhythmia 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


15/35

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)

Three degrees of types of AV block: 1st, 2nd & 3rd degreeAtrioventricular Block 1

stdegree (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 RxAtrioventricular Block 2

nddegree 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

Atrioventricular Block 2nd

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 May progress to 3rd degree AV block Pacemaker is therefore necessary

Atrioventricular Block 3rd

degree (no relationship b/w atria and ventricle firing)


16/35

Complete failure of conduction between the atria and ventricles Most common causes: acute MI, drug toxicity and chronic degeneration of the conduction pathway 3rd 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 sodiumo 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 tauworks 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 rhythmo Atrial fibrillation normal sinus rhythmo 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.


17/35

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 quinidinePotassium 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 Produces 1st 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 fibrillationand 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 tachycardiaAmiodarone: Mechanisms of antiarrhythmic actions1. 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 atrialfibrillation 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; and2. 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 arrestMajor 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:


18/35

1. Calcium channel blockers.2. Beta blockers3. Digitalis glycosides4. Amiodarone5. Adenosine

Ion channel blockers in heart (affecting the ion flow in the cardiac cells/ vascular smooth muscle cells)

These ion channels control movement of ions (Na+, K+, Ca2+), which control conductance, in cardiac cells and vascularsmooth 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) IV. Voltage-gated slow calcium channels (Ca2+)

(blocked by calcium channel blockers = class IV antiarrhythmics) V. Sodium/potassium-ATPase (Na+/K+ exchange)

(blocked by digoxin and other cardiac glycosides) = class VLearning Objectives

Understand the sequence of Calcium ion channel opening and closing in smooth muscle contraction. (Na+ channeland K+ channel work similarly)

List the molecular target of each of the five Vaughan-Williams antiarrhythmic drug classes, and the major drugs withineach class. Recognize structural features.

Compare and contrast the drugs within each class as to structure and effects.Ion movement in smooth muscle contraction

Action potentialo Resting: more K+ inside and theres Na+ and Ca+ outsideo Depolarization: sodium influx through fast inward Na+ channelso 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 ofrecovery 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, phenytoin1A: 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


19/35

Parent drug causes lupus-like syndrome More prominent in slow N-acetylators

Procainamide1B: 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

Two types of channels/receptors control intracellular Ca2+ 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

Ca2+

channel VS b-receptor

Calcium channel and b-receptor are both transmembrane proteins. The Calcium Channel forms a hole (pore) in the membrane to directly move Ca2+ 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.

Indirectly causes movement of Ca2+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 Also decreases Ca2+ 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+ channelAmiodarone = 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

Mechanism of action: Competitively inhibit influx of Ca2+ into vascular smooth muscle and cardiac (heart) cellsthrough slow calcium channels by plugging the channel.


20/35

Bind only to open and closed-inactive conformations of L-type Ca2+ 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). Large conductance (lots of Ca2+ 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

Voltage gated Ca2+

channels: 3 conformations (activated by action potentials)

I. Closed/ resting (apocalmodulin blocks intracellular side of channel); alpha helices block the extracellular portion ofthe 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

Structure-function of calcium ion channels Side view of docked CCBs in L-type Ca2+ 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 togethershe cant even find the fourth p helix coming together They are just coming into the membrane a little so they are able to shift


21/35

CCB only block the open formdont block resting state because have to be partially open Drug binds inside channel

needs access from extracellular side

This is why Ca2+ 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 withdipine suffix).

Non-dihydropyridines Phenylalkylamine

verapamil (Verapamil SR, Calan SR). Benzothiazepine

diltiazem (Cardizem CD). Diarylaminopropylether

Bepridil (removed from market 2003) Phenylalkylamines: verapamil First Ca2+ channel blockers developed, in 1960s. Act at L-type channels in vascular smooth muscle and cardiac muscle.

L-type Ca2+ channels are most sensitive to phenylalkylamines. at higher concentrations, phenylalkylamines also block

other types of Ca2+ 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)

At higher concentrations, diltiazem also blocks other voltage-gated Ca2+ 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. Also blocks receptor operated Ca2+ 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 6-

positions 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


22/35

Need something bulky phenyl, or a nitro The R6 can be an ester or something as small as methyl

Clinical effects of metabolism of Ca2+ 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 increasedintracellular 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 andOHs 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 withineach 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


23/35

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 highlightedAntiarrhythmics: 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)


24/35

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 (


25/35

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? 2011ACC/AHA: Class IIb recommendationDirect 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


26/35

AHA/ACC Class I indication for stroke prevention in patients with non-valvular atrial fibrillation (cannot havesevere renal dysfunction (CrCl < 15 ml/min or liver disease impairing clotting function)

Dont give in patients with (1) valvular atrial fibrillation, (2) CrCl


27/35

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 beenstopped.

Antithrombotic-anticoagulant therapy: STILL BE ON ANTITHROMBOTIC THERAPY With rate control or rhythm control group: same increased stroke risk with either INR was sub-

therapeutic 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 mortalitybenefit with antiarrhythmics over rate control in this population

Rate control is a reasonable approach in older patients with persistent AF and concurrent hypertension orheart 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 fromrhythm 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 antiarrhythmicInitial 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 orHF 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) Cardioversionmore 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


28/35

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 whohave an accessory AV pathway (other agents will cause harm)

Patient: accessory bundle (conduit of fibers allows anagrade conduction)AF: Outpatient Rate ControlGoal: Resting ventricular rate


29/35

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 ofwarfarin (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 failureDronedarone

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


30/35

Premature discontinuation due to safety points not statistically significant; Safety profile may bebetter with D (thyroid effects; concurrent warfarin treatment

ACC/AHA 2011: Class Iia; Reasonable for use in preventing CV events in patients with paroxysmal orpersistent 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 patientsNon-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


31/35

*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 accessorypathway

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


32/35

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)


33/35

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 trialSecondary 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; Althoughsubgroup 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


34/35

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 minIntravenous 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 choiceIntravenous 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


35/35

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

core v - cardiovascular core

Documents