new antiarrythmic drugs for af

32سورة البقرة آية

By

Mohamed Maged Mahmoud Kharabish

M.B., B.Ch., (2006)

Faculty of Medicine - Zagazig University

Prof. Dr. Azza Mohamed Shafeek Abdel Mageed Professor of Anesthesiology and Intensive Care

Faculty of Medicine - Ain Shams University

Assist. Prof. Dr. Ayman Ahmed Abdellatif Assistant Professor of Anesthesiology and Intensive Care


Dr. Amr Ahmed Ali Kasem Lecturer of Anesthesiology and Intensive Care


Atrial fibrillation (AF) is a supraventricular

tachyarrhythmia characterized by uncoordinated atrial

activation with consequent deterioration of mechanical

function. Atrial fibrillation most often results from

sustained increases in left atrial (LA) afterload that cause

enlargement of the LA chamber. Conversely, progressive

LA dilatation also occurs in patients with atrial

fibrillation independent of alterations in LV function or

geometry (Suarez et al., 1991).

Introduction

Epidemiology:

Atrial fibrillation affects more than 0.07% of

population in the United States (Total population in

2004 is 292 millions). AF is strongly age-dependent,

affecting 4% of individuals older than 60 years and 8%

of persons older than 80 years. Approximately 25% of

individuals aged 40 years and older will develop AF

during their life time (Lloyd-Jones et al., 2004).

Introduction

Anatomy of the Conductive System of the Heart

The sinus node is a spindle-shaped structure composed

of a fibrous tissue matrix with closely packed cells, tending to

narrow caudally toward the inferior vena cava. It lies less

than 1mm from the epicardial surface, laterally in the right

atrial sulcus terminalis at the junction of the superior vena

cava and right atrium, the artery supplying the sinus node

branches from the right (60 %) or the left (40 %) circumflex

coronary artery (Musa et al., 2002).

Cardiac

Conductive

System


Anatomy of

cardiac

conductive

system (Heuser,

2007)


There are three intraatrial pathways:

> The anterior internodal pathway, called the

Bachmann bundle.

>The middle internodal (Wenchenbach's) tract

>The posterior internodal (Thorel's) tract.

(Martinez et al., 2002).

Internodal And

Intra-Atrial

Conduction


Atrioventricular Junctional Area And

Intraventricular Conduction System:

The normal A-V junctional area can be divided

into transient regions: the transitional cell zone, also

called nodal branches; the compact portion, or the A-

V node itself; and the penetrating part of the A-V

bundle (His bundle) (KO et al., 2004).


Atrioventricular Node:

The compact portion of the A-V node is a

superficial structure lying just beneath the right

atrial endocardium, and directly above the insertion

of the septal leaflet of the tricuspid valve. It is at the

apex of a triangle formed by the tricuspid annulus

and the tendon of Todaro (Kreuzberg et al., 2006).


Bundle of His (Penetrating Portion of the

Atrioventricular Bundle):

This structure connects with the distal part of the compact A-V

node, perforates the central fibrous body, and continues through the

annulus fibrosis, where it is called the nonbranching portion as it

penetrates the membranous septum. Connective tissue of the central

fibrous body and membranous septum encloses the penetrating portion of

the AV bundle. Branches from the anterior and posterior descending

coronary arteries supply the upper muscular interventricular septum

with blood, which makes the conduction system at this site more resistant

to ischemic damage(Basso et al., 2008).


Bundle Branches (Branching Portion of the

Atrioventricular Bundle):

These structures begin at the superior margin of the

muscular interventricular septum, where the cells of the left

bundle branch cascading downward as a continuous sheet

into the septum beneath the coronary aortic cusp. The right

bundle branch continues intramyocardially as an unbranched

extension of the AV bundle down the right side of the

interventricular septum to the apex of the right ventricle and

base of the anterior papillary muscle (Ter Keurs et al., 2007).


Terminal Purkinje Fibers:

These fibers connect with the ends of the bundle

branches to form networks on the endocardial surface

of both ventricles, which transmit the cardiac impulse

almost simultaneously to the entire right and left

ventricular endocardium (Ter Keurs et al., 2007).


Innervation Of Atrioventricular Node, His

Bundle, And Ventricular Myocardium:

The A-V node and His bundle region are innervated

by a rich supply of cholinergic and adrenergic fibers.

(Schwartz and Zipes, 1999).

Physiology of the Electro-Conductive System of the Heart

The primary function of the heart is to

generate and sustain an arterial blood pressure

sufficient to adequately perfuse organs, to do

this atrial and ventricular contractions must be

orderly and properly synchronized with each

other (Klabunde, 2012).


Cardiac Electrophysiology:

Electrical impulse in the heart involves the

passage of ion through ionic channels. The sodium,

potassium, calcium and chloride ions are the major

charge carriers and their movement across the cell

membrane creates a flow of current during action

potential (Le Winter and Osol, 2001).


Cardiac Cell Action Potential:

The cardiac action potential consists of five phases:

Phase 4: Resting membrane potential.

Phase 0: Rapid depolarization.

Phase 1: Partial repolarization.

Phase 2: Plateau period.

Phase 3: Repolarization.


Action potential in different areas of the heart

(Nerbonne and Kass, 2005)

Pathophysiology and Mechanisms of Atrial Fibrillation

Classification:

Classification of atrial fibrillation begins with

distinguishing a first detectable episode, irrespective of

whether it is symptomatic or self-limited. Published

guidelines from an American College of Cardiology

(ACC)/American Heart Association (AHA)/European

Society of Cardiology (ESC) committee of experts on the

treatment of patients with atrial fibrillation recommend

classification of AF into the following 3 patterns.


Paroxysmal

AF

Persistent

AF

Permanent

AF

Terminates

spontaneously

within 7 days

Lasts more than

7 days

Lasts more than

1 year

(Fuster et al., 2006).


Etiology:Risk factors Hemodynamic Stress.

Atrial Ischemia.

Inflammation.

Drug And Alcohol Use.

Endocrine Disorders.

Neurologic Disorders.

Familial AF.

Advancing age.


Pathophysiology:

Automatic Focus Hypothesis:

Studies have demonstrated that a focal source of AF

can be identified in humans and that isolation of this

source can eliminate AF (Welles et al., 2011).

Multiple Wavelet Hypothesis:

The multiple wavelet hypothesis proposes that

fractionation of wave fronts propagating through

the atria results in self-perpetuating "daughter

wavelets." (Nakao et al., 2002).

Non Pharmacological Management Of Atrial Fibrillation

Non-Pharmacological Therapy Includes Several

Different Treatment Modalities Includes:

Cardioversion.

Implantable Device Therapy.

AV (Atrio-Ventricular) Node Ablation and

Permanent Pacemakers.

Surgical Ablation Therapy.

Pharmacological Management of Atrial Fibrillation with Current and New Anti-arrhythmic Drugs

The main goals of treatment are to prevent

circulatory instability and stroke. Rate or

rhythm control are used to achieve the former,

while anticoagulation is used to decrease the

risk of the latter. If cardiovascularly unstable

due to uncontrolled tachycardia, immediate

cardioversion is indicated (Fuster et al., 2006).


Anticoagulation:

Anticoagulation can be achieved through a

number of means including the use of aspirin,

heparin, warfarin, and dabigatran. Which

method is used depends on a number issues

including: cost, risk of stroke, risk of falls,

compliance, and speed of desired onset of

anticoagulation (Leung et al., 2005).


Available Anticoagulants: Warfarin.

Dabigatran.

Rivaroxaban.

Apixaban.

Emerging Anticoagulants:

Edoxaban

Betrixa¬ban

Darexaban


Rhythm Control:

Maintenance of sinus rhythm requires

treatment of cardiovascular risk factors

and any underlying disorder (i.e.

hyperthyroidism) (Doyle and Ho, 2009).


Anti-Arrhythmic Drugs

Most of the available anti-arrhythmic drugs can be

classified according to whether they exert blocking

actions on sodium, potassium, or calcium channels

and block beta- adrenoreceptors. The commonly used

classification is Vaughan Williams classification which

based on the electro-physiological effect of the drug

(Nattel and Singh, 1999).


Class IA: Anti-Arrhythmic Drugs

Quindine.

Disopyraimide.

Procainamide.

Class IB: Anti-Arrhythmic Agents:

Flecainide.

Propafenone.

Moricizine.


Class II: Anti-Arrhythmic Agents:

Propranolol.

Esmolol.

Class III: Anti-Arrhythmic Drugs:

Amiodarone.

Bretylium Tosylate.

Sotalol.

Ibutilide.

Dofetilide.

Azimilide.


Class IV: Anti-Arrhythmic Agents:

Verapamil.

Diltiazem.

Other Unclassified: Anti-Arrhythmic Drugs:

Digitalis.

New Anti-Arrhythmic Drugs For AF

Innovative strategies targeting different

mechanisms of AF development and maintenance

(Savelieva and camm, 2004).


Newer and investigational class III

compounds:

Azimilide

Azimilide blocks both IKr, (rapid component of the

delayed rectifier potassium inward current, and IKs, slow

component of the delayed rectifier potassium in ward

current), and therefore is expected to be particularly

effective during high rates associated with AF.


Tedisamil

Tedisamil (Solvay) produces multiple potassium channel

blockade, including IKr, Ito (transient outward

potassium current), and IKATP.

Nifekalant

Nifekalant is a reverse use-dependent IKr blocker. it is

found that nifekalant prolongs the atrial effective

refractory period.

Dronedarone

Dronedarone was specifically designed to overcome the

side effects of its parent compound, amiodarone.


Other Amiodarone Derivatives

Celivarone

ATI-2042

PM101


Atrial Repolarization-Delaying Agents:

They Inhibit the IKur resulting in prolongation of the

atrial effective refractory period. Because the Kv1.5

channel proteins are expressed predominantly in the

atria, IKur blockers are expected to demonstrate atrial

selectivity without affecting the electrophysiological

properties of the ventricles. These investigational agents

are also known as atrial repolarization- delaying agents

(ARDAs) (Wettwer, 2007).


Vernakalant (RSD-1235):

Vernakalant is an atrial-selective anti-arrhythmic drug.

It is a mixed sodium and potassium channel blocker

(Roy et al., 2004).

XEN-D0101:

XEN-D0101 (Xention) selectively prolongs the atrial

effective refractory period and decreases the duration of

AF (Shiroshita et al., 2006).


AVE0118:

AVE0118 blocks the IKur and several other currents

such as Ito and the acetylcholine-activated

potassium current (IKACh). Studies have

demonstrated the ability of AVE0118 to prolong the

atrial effective refractory period and cardiovert AF

with little effect on ventricular refractoriness and

the QT interval (Blaauw et al., 2004).


AZD7009:

It is found to block multiple repolarizing potassium channels

including IKur, Ito, IKr and the IKs currents as well as the late

sodium depolarizing current (INa) (Carlsson et al., 2006).

NIP-141/142:

NIP-141/142 are multi-channel blockers with a high affinity to

Kv 1.5 channels (responsible for IKur, is associated with familial

AF), but it also affects Ito, IKACh and ICaL currents. (Tanaka

and Hashimoto, 2007).


Sodium Current Blockers

Pilsicainide Ranolazine


Agents with Novel Mechanisms of Action

Atrial Acetylcholine-Regulated Potassium Current (IKAch)

Inhibitors:

Blockade of IKAch may potentially be anti-arrhythmic and,

because IKAch is absent in the ventricles, its anti-arrhythmic

effect will be specific to the atria (Voigt et al., 2008).

For example

KB130015

NIP-151


Agents Targeting Abnormal Calcium Handling

Increased intracellular calcium (Ca++) concentrations

and abnormalities in Ca++ handling have been linked to

initiation of AF by promoting delayed and late phase

III early after depolarizations sufficient to initiate

ectopic activation (Chen et al., 2002).

For example

JTV519


Na+/Ca++ Exchanger Inhibitors

KB-R7943

SEA0400

Stretch Receptor Antagonists:

Gadolinium

GsMTx-4


Polynsaturated Fatty Acids (PUFAs)

Activation of stretch-activated channels depends on membrane

fluidity, which can be modified by polyunsaturated fatty acids

PUFAs. PUFAs incorporated in cell membranes increase

membrane fluidity and may reduce stretch-mediated

electrophysiological effects. Experiments on isolated Langedorff-

perfused hearts, (a predominant in vitro technique used in

pharmacological and physiological research using animals), from

rabbits fed with PUFA-rich diet have demonstrated an increased

resistance to stretch-mediated changes in atrial electro-

physiological properties (Ninio et al., 2005).


Gap Junction Modifiers

The mechanism of action is remodeling electro-

physiological and structural properties of the fibrillating

atria involves changes in junctions forming the atrial

intercalated disc: fascia adherens, the desmosomes, and

gap junctions and their proteins (N-cadherin, desmoplakin

and connexins) (Van et al., 2000).

Rotigaptide.

GAP-134.


5-Hydroxytryptamine-4 Receptor Antagonists

Renin–Angiotensin System Inhibitors

Pirfenidone

Pirfenidone is a newly developed anti-fibrotic agent which

inhibits collagen synthesis, downregulates production of pro-

fibrotic cytokines, and blocks cytokine-induced fibroblast

proliferation. The anti-arrhythmic potential of pirfenidone

has been shown in a canine model of heart failure induced by

rapid ventricular pacing (Lee et al., 2006).


3-Hydroxy-3-Methylglutaryl Co-Enzyme A

(HMG-CoA) Reductase Inhibitors (Statins)

Statin therapy was significantly associated with a

decreased risk of incidence or recurrence of AF.

Heterogeneity was explained by differences in statin

types, patient populations and surgery types. The benefit

of statin therapy seemed more pronounced in secondary

than in primary prevention (Fang et al., 2012).

Atrial fibrillation (AF) is an irregular heart rhythm, caused

by extremely rapid and chaotic electrical impulses that are

generated in the heart's atria This kind of rapid, chaotic

electrical activity is called "fibrillation."

AF is one of the most common cardiac arrhythmias, and it

can be one of the most frustrating to deal with. While AF is

not in itself a life-threatening arrhythmia, it often causes

significant symptoms, and it can lead to more serious

problems, such as stroke and worsening heart failure in

people with heart disease.

AF is often classified into 2 types: new onset or intermittent AF,

chronic or persistent AF.

Novel anti-arrhythmic drugs with conventional antiarrhythmic

mechanisms are under investigation in AF were discussed ,

including: newer multiple-channel blockers with a better safety

profile and specific agents targeting atrial repolarization. Agents

with unconventional modes of action are envisioned, such as:

stretch receptor antagonists, blockers of the sodium – calcium

exchanger, late sodium channel inhibitors, and gap junction

modulators, which may improve ‘the communication’ between cells

‘Upstream’ therapies with angiotensin-converting enzyme

inhibitors (ACEI), angiotensin receptor blockers (ARBs), statins,

and omega-3polyunsaturated fatty acids (PUFAs) have theoretical

advantages as potential novel therapeutic strategies.

new antiarrythmic drugs for af

Health & Medicine

right atrial endocardium

av node

left atrial la afterload

right atrial sulcus

intraatrial conductionanatomy

heartatrioventricular

sinus node branches

introduction anatomy