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2009 terni, università di medicina, i farmaci nel trattamento delle tachicardie ventricolari
1. Drugs used to treat
Ventricular Tachyarrhythmias
Stefano Nardi MD, PhDStefano Nardi MD, PhD
Arrhythmia, EP Center and Cardiac Pacing UnitArrhythmia, EP Center and Cardiac Pacing Unit
Thoracic Surgery and Cardiovascular DepartmentThoracic Surgery and Cardiovascular Department
S. Maria General Hospital, TerniS. Maria General Hospital, Terni
2. Definition: a variation in either the site or
rate of cardiac impulse formation, and/or a
variation in the sequence of cardiac impulse
propagation.
3. Electrophysiology
resting potential
• A transmembrane electrical gradient (potential) is
maintained, with the interior of the cell negative with
respect to outside the cell
• Caused by unequal distribution of ions inside vs.
outside cell
– Na+
higher outside than inside cell
– Ca+
much higher “ “ “ “
– K+
higher inside cell than outside
• Maintenance by ion selective channels, active pumps
and exchangers
4. Cardiac Action Potential
• Divided into five phases (0,1,2,3,4)
– Phase 4 - resting phase (resting membrane potential)
• Phase cardiac cells remain in until stimulated
• Associated with diastole portion of heart cycle
• Addition of current into cardiac muscle causes
– Phase 0 – opening of fast Na channels and rapid
depolarization
• Drives Na+
into cell (inward current), changing membrane
potential
• Transient outward current due to movement of Cl-
and K+
– Phase 1 – initial rapid repolarization
• Closure of the fast Na+
channels
• Phase 0 and 1 correspond to the R and S waves of the ECG
6. Cardiac Action Potential
• Phase 2 - plateau phase
– sustained by the balance between the inward movement of Ca+
and
outward movement of K +
– Has a long duration compared to other nerve and muscle tissue
– Normally blocks any premature stimulator signals (other muscle
tissue can accept additional stimulation and increase contractility in
a summation effect)
– Corresponds to ST segment of the ECG.
• Phase 3 – repolarization
– K+
channels remain open,
– Allows K+
to build up outside the cell, causing the cell to repolarize
– K +
channels finally close when membrane potential reaches certain
level
– Corresponds to T wave on the ECG
8. Cell-Membrane Resting Potential
+
-
0 mV
….a “resting” potential of -90 mV is
observed inside the cell with respect to
outside the cell
Advance needle electrode
across the cell membrane….
9. Cell-Membrane Resting Potential
+
The resting potential is maintained by an ATP
powered sodium-potassium “pump” within the
membrane that transports Na+
ions outward
and K+
ions inward (3 Na+
per 2 K+
).
Na+
K+ Na+
Na+
The gradient of ion-concentration separates
charge across the membrane with an equal and
opposite electrical gradient of -90 mV.
-
K+
Advance needle electrode
across the cell membrane….
-
-
-- --
---
--
-
-
---
-
---
--
-
-
-- -
+
+
+
+
+++
+
+
+
+
+++
+
+
+
+
+
+
+
+
+
+
10. Cell Membrane Action Potential (AP)
+
-
Stimulate the cell….
0 mV
….a transmembrane “AP” is observed
with 5 characteristic phases (Φ)
12. Cell Membrane Ion Channels
Voltage-gated, ion-selective
channels open and close to
generate the AP
Many types of channels
are known, each selective
to a specific species of
Na+
, K+
, and Ca++
ions
13. Cell Membrane Ion Channels
Voltage-gated, ion-selective
channels open and close to
generate the AP
….with 4 “phases” of
protein groups (I-IV)….
….including 1 “P-loop”
polypeptide chain
….and 6 “sub-groups”
within each phase….
All channels have a
common structure that
spans the membrane….
inside outsidemembrane
14. Cell Membrane Ion Channels
Voltage-gated, ion-selective
channels open and close to
generate the AP
NH2
COOH
“unroll” channel....
15. Cell Membrane Ion Channels
Flattened view presents
clearer view of the channel
structure
NH2
COOH
membrane
(phospholipid bilayer)
amino-end
carboxy-end
IN OUT
IN OUT
16. Cell Membrane Ion Channels
NH2
COOH
….are repeated,
forming each of the
4 phases (I-IV)
subgroups S1-S6….
Flattened view presents
clearer view of the channel
structure
IN OUT
IN OUT
17. Cell Membrane Ion Channels
NH2
COOH
“P-loops” form the
narrowest part of
the channel
responsible for
gating ion-flow
Flattened view presents
clearer view of the channel
structure
IN OUT
IN OUT
18. Cell Membrane Ion Channels
Functional and structural
evidence suggests that P-
loops are central to….
NH2
COOH
• sensing voltage
• filtering ion species
• mechanical actuation
S6
S5
19. Cell Membrane Ion Channels
S6
S5
Functional and structural
evidence suggests that P-
loops are central to actuation
• P-loops extend (or twist)
for channel activation
20. Cell Membrane Ion Channels
S6
S5
Functional and structural
evidence suggests that P-
loops are central to actuation
• P-loops retract (or
twist) for channel
inactivation
21. Na+
Cell Membrane Ion Channels
Transmembrane AP formation
follows an organized sequence in
response to stimulation:
Φ0 – Upstroke
1) Fast, inward Na+
channels open, rapidly
depolarizing the membrane and triggering
closure of the channels (Φ0 – upstroke and
overshoot)
22. K+
Na+
Cell Membrane Ion Channels
Φ1 – Initial Recovery
Transmembrane AP formation
follows an organized sequence in
response to stimulation:
2) Slower, outward K+
channels sense the
rising voltage and open, diminishing the
overshoot (Φ1 – Initial Recovery)
23. Cell Membrane Ion Channels
Φ2 – Plateau
(absolute refractory)
K+
Ca++
Transmembrane AP formation
follows an organized sequence in
response to stimulation:
3) Slower, inward Ca++
channels open, matching
outward K+ and maintaining the membrane
near 0 mV (Φ2 – Plateau)
24. Cell Membrane Ion Channels
Φ3 – Recovery
(relative refractory)
K+
K+
Transmembrane AP formation
follows an organized sequence in
response to stimulation:
4) K+
conduction increases and Ca++
decreases,
repolarizing the membrane (Φ3 – Recovery)
Ca++
25. Cell Membrane Ion Channels
Transmembrane AP formation
follows an organized sequence in
response to stimulation:
5) Na+
– K+
pump helps converge and maintain
resting potential near -90 mV (Φ4 – Resting)
Φ4 – Resting
Na+
K+ Na+
Na+
K+
29. Na +
Ca 2+
Ca 2+
K +
K +
4
0
1
2
3
4
K+
Na+
Na/K ATPase
The fast cardiac action potential
-90 mV
+55 mV
30. Na + Refractory Period
Effect of local anesthetics on the
fast cardiac action potential
Slope phase 0 = conduction velocity Longer RP due to slower
recovery from inactivation
Increased threshold
36. • VAs are common in most people and are usually not a
problem but…VA’s are most common cause of SCD
• Majority of SCD occurs in pts with neither a previously
known HD nor history of VA’s
• AADs which decrease incidence of VA’s do not decrease
(and may increase) the risk of SCD treatment may be
worse then the disease!
37. Differences between non-PM and PM
cell action potentials
• PCs - Slow, continuous depolarization during rest
• Continuously moves potential towards threshold for a new
action potential (called a phase 4 depolarization)
38. Mechanisms of
Cardiac Arrhythmias
• Result from disorders of impulse
formation, conduction, or both
• Causes of arrhythmias
– Cardiac ischemia
– Excessive discharge or sensitivity to autonomic
transmitters
– Exposure to toxic substances
– Unknown etiology
39. Disorders of impulse
formation
• No signal from the pacemaker site
• Development of an ectopic pacemaker
– May arise from conduction cells (most are capable of spontaneous
activity)
– Usually under control of SA node if it slows down too much
conduction cells could become dominant
– Often a result of other injury (ischemia, hypoxia)
• Development of oscillatory afterdepolariztions
– Can initiate spontaneous activity in nonpacemaker tissue
– May be result of drugs (digitalis, norepinephrine) used to treat other
cardiopathologies
41. Disorders of impulse conduction
• May result in
– Bradycardia (if have AV block)
– Tachycardia (if reentrant circuit occurs)
Reentrant
circuit
42. Antiarrhythmic drugs
• Biggest problem – AADs can cause
arrhythmia!
– Example: Treatment of a non-life threatening
tachycardia may cause fatal VTs
– Must be vigilant in determining dosing, blood
levels, and in follow-up when prescribing AADs
44. Classification of AADs
(based on mechanisms of action)
• Class I – blocker’s of fast Na+
channels
– Subclass IA
• Cause moderate Phase 0 depression
• Prolong repolarization
• Increased duration of action potential
• Includes
– Quinidine – 1st
antiarrhythmic used, treat both atrial and
ventricular arrhythmias, increases refractory period
– Procainamide - increases refractory period but side
effects
– Disopyramide – extended duration of action, used only for
treating ventricular arrthymias
45. Classification of AADs
(based on mechanisms of action)
• Subclass IB
– Weak Phase 0 depression
– Shortened depolarization
– Decreased action potential duration
– Includes
• Lidocane (also acts as local anesthetic)
– blocks Na+ channels mostly in ventricular cells, also good
for digitalis-associated arrhythmias
• Mexiletine
- oral lidocaine derivative, similar activity
• Phenytoin
– anticonvulsant that also works as antiarrhythmic similar to
lidocane
46. Classification of AADs
(based on mechanisms of action)
– Subclass IC
• Strong Phase 0 depression
• No effect of depolarization
• No effect on action potential duration
Includes
– Flecainide (initially developed as a local anesthetic)
» Slows conduction in all parts of heart,
» Also inhibits abnormal automaticity
– Propafenone
» Also slows conduction
» Weak β – blocker
» Also some Ca2+
channel blockade
47. Classification of AADs
(based on mechanisms of action)
• Class II – β–adrenergic blockers
– Based on two major actions
1) blockade of myocardial β–adrenergic receptors
2) Direct membrane-stabilizing effects related to Na+
channel blockade
– Includes
• Propranolol
– causes both myocardial β–adrenergic blockade and membrane-stabilizing
effects
– Slows SA node and ectopic pacemaking
– Can block arrhythmias induced by exercise or apprehension
– Other β–adrenergic blockers have similar therapeutic effect
• Metoprolol
• Nadolol
• Atenolol
• Acebutolol
• Pindolol
• Stalol
• Timolol
• Esmolol
48. Classification of AADs
(based on mechanisms of action)
• Class III – K+
channel blockers
– Developed because some patients negatively
sensitive to Na channel blockers (they died!)
– Cause delay in repolarization and prolonged
refractory period
– Includes
• Amiodarone – prolongs action potential by delaying K+
efflux
but many other effects characteristic of other classes
• Ibutilide – slows inward movement of Na+
in addition to delaying
K +
influx.
• Bretylium – first developed to treat hypertension but found to
also suppress ventricular fibrillation associated with myocardial
infarction
• Dofetilide - prolongs action potential by delaying K+
efflux with
no other effects
49. Classification of AADs
(based on mechanisms of action)
• Class IV – Ca2+
channel blockers
– slow rate of AV-conduction in patients
with atrial fibrillation
– Includes
• Verapamil – blocks Na+
channels in addition to
Ca2+;
also slows SA node in tachycardia
• Diltiazem