New Anti Arrythmic Drugs For AF

1
??? ???? ?????? ??????
??? ???? ??????
???? ?????? ??? 32
2
New Anti-Arrhythmic Drugs For Atrial Fibrillation
By Mohamed Maged Mahmoud Kharabish M.B., B.Ch.,
(2006) Faculty of Medicine - Zagazig University
3
Acknowledgement
4
Under Supervision of
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 Faculty of Medicine - Ain Shams
University
Dr. Amr Ahmed Ali Kasem Lecturer of
Anesthesiology and Intensive Care Faculty of
Medicine - Ain Shams University
5
Introduction
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).
6
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).
7
Anatomy of the Conductive System of the Heart
8
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).
9
Anatomy of the Conductive System of the Heart
Anatomy of cardiac conductive system (Heuser,
2007)
10
Anatomy of the Conductive System of the Heart
There are three intraatrial pathways. The
anterior internodal pathway begins at the
anterior margin of the sinus node and curves
anteriorly around the superior vena cava to enter
the anterior interatrial band, called the
Bachmann bundle. This band continues to the left
atrium, The middle intermodal (Wenchenbach's)
tract begins at the superior and posterior
margins of the sinus node, travels behind the
superior vena cava to the crest of the
interatrial septum, and descends in the
interatrial septum to the superior margin of the
Atrioventricular (A-V) node, the posterior
intermodal (Thorel's) tract starts at the
posterior margin of the sinus node and joins the
posterior portion of the A-V node (Martinez et
al., 2002).
11
Anatomy of the Conductive System of the Heart
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).
12
Anatomy of the Conductive System of the Heart
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).
13
Anatomy of the Conductive System of the Heart
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, which may send out extensions into the
central fibrous body. 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 unless the
ischemia is extensive (Basso et al., 2008).
14
Anatomy of the Conductive System of the Heart
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).
15
Anatomy of the Conductive System of the Heart
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. Purkinje fibers
tend to be less concentrated at the base of the
ventricle and at the papillary muscle tips (Ter
Keurs et al., 2007).
16
Anatomy of the Conductive System of the Heart
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. Ganglia, nerve
fibers, and nerve nets lie close to the A-V node.
Parasympathetic nerves to the A-V node region
enter the heart at the junction of the inferior
vena cava and the inferior aspect of the left
atrium (Schwartz and Zipes, 1999).
17
Physiology of the Electro-Conductive System of
the Heart
18
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).
19
Physiology of the Electro-Conductive System of
the Heart
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).
20
Physiology of the Electro-Conductive System of
the Heart

• 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.

21
Physiology of the Electro-Conductive System of
the Heart
Action potential in different areas of the heart
(Nerbonne and Kass, 2005)
22
Pathophysiology and Mechanisms of Atrial
Fibrillation
23
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.

24
Pathophysiology and Mechanisms of Atrial
Fibrillation
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).
25
Pathophysiology and Mechanisms of Atrial
Fibrillation

• Etiology
• Risk factors
• Hemodynamic Stress.
• Atrial Ischemia.
• Inflammation.
• Drug And Alcohol Use.
• Endocrine Disorders.
• Neurologic Disorders.
• Familial AF.
• Advancing age.

26
Pathophysiology and Mechanisms of Atrial
Fibrillation

• 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).

27
Non Pharmacological Management Of Atrial
Fibrillation
28
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.

29
Pharmacological Management of Atrial
Fibrillation with Current and New Anti-arrhythmic
Drugs
30
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).
31
Pharmacological Management of Atrial Fibrillation
with Current and New Anti-arrhythmic Drugs

• 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).

32
Pharmacological Management of Atrial Fibrillation
with Current and New Anti-arrhythmic Drugs

• Available Anticoagulants
• Warfarin.
• Dabigatran.
• Rivaroxaban.
• Apixaban.
• Emerging Anticoagulants
• Edoxaban
• Betrixaban
• Darexaban

33
Pharmacological Management of Atrial Fibrillation
with Current and New Anti-arrhythmic Drugs

• Rhythm Control
• Maintenance of sinus rhythm requires treatment of
  cardiovascular risk factors and any underlying
  disorder (i.e. hyperthyroidism) (Doyle and Ho,
  2009).

34
Pharmacological Management of Atrial Fibrillation
with Current and New Anti-arrhythmic Drugs

• 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).

35
Pharmacological Management of Atrial Fibrillation
with Current and New Anti-arrhythmic Drugs
36
Pharmacological Management of Atrial Fibrillation
with Current and New Anti-arrhythmic Drugs

• Class IA Anti-Arrhythmic Drugs
• Quindine.
• Disopyraimide.
• Procainamide.
• Class IB Anti-Arrhythmic Agents
• Flecainide.
• Propafenone.
• Moricizine.

37
Pharmacological Management of Atrial Fibrillation
with Current and New Anti-arrhythmic Drugs

• Class II Anti-Arrhythmic Agents
• Propranolol.
• Esmolol.
• Class III Anti-Arrhythmic Drugs
• Amiodarone.
• Bretylium Tosylate.
• Sotalol.
• Ibutilide.
• Dofetilide.
• Azimilide.

38
Pharmacological Management of Atrial Fibrillation
with Current and New Anti-arrhythmic Drugs

• Class IV Anti-Arrhythmic Agents
• Verapamil.
• Diltiazem.
• Other Unclassified Anti-Arrhythmic Drugs
• Digitalis.

39
New Anti-Arrhythmic Drugs For AF
40
New Anti-Arrhythmic Drugs For AF
Innovative strategies targeting different
mechanisms of AF development and maintenance
(Savelieva and camm, 2004).
41
New Anti-Arrhythmic Drugs For AF

• 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.

42
New Anti-Arrhythmic Drugs For 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.
• Dronedarone
• Dronedarone was specifically designed to overcome
  the side effects of its parent compound,
  amiodarone.

43
New Anti-Arrhythmic Drugs For AF

• Other Amiodarone Derivatives
• Celivarone
• ATI-2042
• PM101

44
New Anti-Arrhythmic Drugs For AF

• 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).

45
New Anti-Arrhythmic Drugs For AF

• 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).

46
New Anti-Arrhythmic Drugs For AF

• AVE0118
• AVE0118 blocks the IKur and several other
  currents such as Ito and the acetylcholine-activat
  ed 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).

47
New Anti-Arrhythmic Drugs For AF

• 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).

48
New Anti-Arrhythmic Drugs For AF
Ranolazine
Pilsicainide
49
New Anti-Arrhythmic Drugs For AF

• 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

50
New Anti-Arrhythmic Drugs For AF

• 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

51
New Anti-Arrhythmic Drugs For AF

• Na/Ca Exchanger Inhibitors
• KB-R7943
• SEA0400
• Stretch Receptor Antagonists
• Gadolinium
• GsMTx-4

52
New Anti-Arrhythmic Drugs For AF

• 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).

53
New Anti-Arrhythmic Drugs For AF

• 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.

54
New Anti-Arrhythmic Drugs For AF

• 5-Hydroxytryptamine-4 Receptor Antagonists
• ReninAngiotensin 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).

55
New Anti-Arrhythmic Drugs For AF

• 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).

56
Summary
57
Summary

• 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.

58
Summary

• 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-3polyunsaturat
  ed fatty acids (PUFAs) have theoretical
  advantages as potential novel therapeutic
  strategies.

59
THANK YOU