arrhythmia mech 3

Question 1

The plateau of the fast response can be prolonged either by

Answer 1

1. increased inward current during this time (e.g., incomplete Na+ channel inactivation in LQT3) or
2. by decreased outward current (e.g., smaller K+ current in LQT1, LQT2).

Question 2

Ca2+ entry during the resulting prolonged QT interval can result in

Answer 2

1. EADs (via Ca2+ channel reactivation) or

2. DADs (via NCX-dependent depolarization)

Question 3

Increased sympathetic tone (startled, excited) increases the likelihood of

Answer 3

triggered afterdepolarizations because Ca2+ influx is enhanced by β-adrenergic receptor activity.

Question 4

An EAD or DAD may be able to initiate

Answer 4

re-entry, resulting in torsades de pointes which can degenerate into ventricular fibrillation (disorganized contraction of ventricular muscle, poor ejection fraction) and sudden cardiac death.

Question 5

Re-entry can develop from many other insults, such as:

Answer 5

myocardial infarction, or drugs that block K+ channels.

Question 6

All class I drugs act primarily by

Answer 6

blocking voltage-gated Na+ channels.

Question 7

class I primary action

Answer 7

is on fast- response cells, but they also affect slow response cells (this latter effect probably occurs because these drugs also block, less effectively, L-type Ca2+ channels).

Question 8

All Na+ channel blockers

Answer 8

decrease conduction rate and nearly all increase refractory period; these effects underlie the clinical efficacy of the Na+ channel blockers.

Question 9

Class I action results in ___ upstroke.

Answer 9

slowed

Question 10

Class Ib drugs exhibit

Answer 10

1. pure class I action,
2. slowing upstroke and also
3. decreasing action potential duration

Question 11

class Ia and class Ic drugs

Answer 11

delay phase 3 onset by virtue of their block of K+ channels.

Question 12

Na+ current block:

Answer 12

1. lessens depolarization
2. decreases phase 2 Ca2+ current
3. hastens phase 3 repolarization.

Question 13

K+ channel blocking action of class Ia and Ic drugs is more effective in

Answer 13

prolonging phase 2 than is their Na+ channel blocking action in shortening phase 2.

Question 14

Class Ia Na+ channel blockers

Drugs:

Answer 14

1. quinidine
2. procainamide
3. disopyramide

Question 15

All class Ia drugs function to

Answer 15

1. slow the upstroke of the fast response
(from block of Na+ channels (class I action))
2.  delay the onset of repolarization 
(from K+ channel block (a class III effect))

Question 16

Class Ia drugs prolong refractory period, via two processes:

Answer 16

1. via classic, use-dependent mechanism, similar to local anesthetics in action
2. because depolarization (phase 2 duration) is prolonged

Question 17

Quinidine

Answer 17

1. has important effects not related to Na+ channel block
2. blocks K+ channels, thereby prolonging action potential duration
3. it is a vagal inhibitor (anti-cholinergic)
4. it is an α-adrenergic receptor antagonist
   5. these effects underscore the non-selectivity of action for antiarrhythmic drugs

Question 18

Class Ib Na+ channel blockers

Drugs:

Answer 18

1. lidocaine
2. mexiletine
3. phenytoin

Question 19

Class Ib Na+ channel blockers

Answer 19

1. use-dependent blockers of voltage-gated Na+ channels.
2. slow upstroke (more mildly than class Ia or Ic)
3. prolong refractory period
4. do not prolong phase 2 of the action potential despite shortened duration of phase 2,
5. refractory period increased
6. fast response
7. In treating arrhythmias, lidocaine is the most important of the Class Ib drugs.

Question 20

Class Ic Na+ channel blockers

Drugs:

Answer 20

1. propafenone
2. flecainide
3. encainide

Question 21

Class Ic Na+ channel blockers

Answer 21

1. use-dependent blockers of INa
2. produce the most pronounced slowing of upstroke rate,
3. mildly prolong phase 2
4. net effect is powerful prolongation of tissue refractory period
5. Encainide is no longer marketed: the 1989 CAST study showed increased mortality with encainide

Question 22

The block of Na+ channels by class I antiarrhythmic drugs is optimized so that

Answer 22

Na+ channels in myocytes with abnormally high firing rates or abnormally depolarized membranes will be blocked to a greater degree than are Na+ channels in normal, healthy myocytes.

Question 23

“use-dependent block”

Answer 23

preferentially target

(1) over-active cells or
(2) cells that have abnormally depolarized resting potentials

Question 24

mechanism of use-dependent ion channel block

Answer 24

(1) use-dependent channel block = channel must open (be used, or activated) before it can be blocked
(2) the channel must be open for the blocker to enter the pore, bind and thereby block the Na+ channel
(3) mechanism of block of cardiac Na+ channels is identical to local anesthetic block of neuronal Na+
channels.

Question 25

Mechanism of local anesthetic block of Na+ channels.

Answer 25

1. Charged, hydrophilic drug may enter and exit the channel when the channel is in the open state, and not when the channel is either closed or inactivated.
2. Neutral, hydrophobic drug, at a much slower rate, can reach the local anesthetic site even when the channel is closed or inactivated.

Question 26

Use-dependent blockers include

Answer 26

1. class I Na+ channel blockers

2. class IV Ca2+ channel blockers.