Drugs used to treat Ventricular

Tachyarrhythmias

Stefano Nardi MD, PhDStefano Nardi MD, PhDArrhythmia, EP Center and Cardiac Pacing Unit Arrhythmia, EP Center and Cardiac Pacing Unit

Thoracic Surgery and Cardiovascular Department Thoracic Surgery and Cardiovascular Department

S. Maria General Hospital, TerniS. Maria General Hospital, Terni

Definition: a variation in either the site or rate of cardiac impulse formation, and/or a variation in the sequence of cardiac impulse propagation.

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

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

Cardiac Na+ channels

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

Cell-Membrane Resting Potential

+

-

needle electrode

membrane

reference electrode outside of cell

Advance needle electrode across the cell membrane….

BIOPOTENTIALS

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….

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….

-

--- -- ---

---

----

--- -

---

-

-- -

++++

++++

+++

+++++++

++++

++

Cell Membrane Action Potential (AP)

+

-

Stimulate the cell….

0 mV

….a transmembrane “AP” is observed with 5 characteristic

phases (Φ)

Cell Membrane Action Potential (AP)

+

-

Stimulate the cell….

Φ0 – Upstroke

Φ2 – Plateau (absolute

refractory)Φ3 – Recovery

(relative refractory)

Φ4 – Resting

Φ1 – Initial Recovery

0 mV

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

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

Cell Membrane Ion Channels

Voltage-gated, ion-selective channels open and close to generate the AP

NH2

COOH

“unroll” channel....

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

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

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

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

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

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

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)

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)

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)

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+

+

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+

Contraction of atria

Contraction of ventricles

Repolarization of ventricles

Passive Ligand-gated

Voltage-gated

R

Na+ K+

Na+ K+

-90 mV

inside

outside

Na +

Ca 2+

Ca 2+

K +

K +

4

0

12

3

4

K+

Na+

Na/K ATPase

The fast cardiac action potential

-90 mV

+55 mV

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

4

0

12

3

4

K +

K +

Refractory Period

Effect of drugs that block K channels

Increase action potential duration (APD)

4

0

2

3

4

Ca2+

Ca2+

K+

If

Na, K

Slow cardiac action potential (AP)

4

0

2

3

4

Ca2+

Slope of phase 0 = Conduction velocity

Effect of Ca 2+ channel blockers

Refractory Period

4

0

2

3

4β agonist

Muscarinic agonists, Adenosine

Drugs affecting automaticity

• 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!

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)

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

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

Afterdepolarizations

Disorders of impulse conduction• May result in

– Bradycardia (if have AV block)– Tachycardia (if reentrant circuit occurs)

Reentrant circuit

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

Therapeutic overview

• Na+ channel blockade• β-adrenergic receptor blockade• Prolong repolarization• Ca2+ channel blockade

• Adenosine• Digitalis glycosides

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

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

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

Classification of AADs(based on mechanisms of action)

• Class II – β–adrenergic blockers– Based on two major actions

1) blockade of myocardial β–adrenergic receptors2) 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

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

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