7, 8. Molecular Mechanisms of Arrhythmias and Drugs

Question 1

Cardiac arrhythmias are acquired subsequent to what 7 things?

Answer 1

MI, ischemia, acidosis, alkalosis, electrolyte abnormalities, drug toxicitiy, or excessive catecholamine exposure

Question 2

Name a cardiac glycoside that can cause arrhythmias.

Answer 2

digoxin

Question 3

Name some antihistamines that can cause arrhythmias.

Answer 3

astemizole, terfenadine

Question 4

Name an antibiotic that can cause arrhythmias.

Answer 4

sulfamethoxazole

Question 5

What are the 1a targets of antiarrhythmic drugs?

Answer 5

1. cardiac Na+ channels (INa)
   2, Ca2+ channels (ICa-L)
2. K+ channels (IKs and IKr)
3. β-adrenergic receptors

Question 6

What drugs can reduce the incidence of sudden cardiac death?

Answer 6

β-blockers

Question 7

What is familial long QT syndrome?

Answer 7

a genetic prolongation of the duration of the cardiac AP (phase 2 plateau phase in the QT interval) that can lead to ventricular arrhythmia and death

Question 8

What is torsades de pointes?

Answer 8

a polymorphic ventricular tachycardia that can degenerate into v-fib

Question 9

What triggers torsades de pointes?

Answer 9

an abrupt increase in sympathetic tone

Question 10

How are long QT patients treated?

Answer 10

β-adrenergic receptor blockers (β-blockers)

Question 11

What is Brugada syndrome?

Answer 11

an inherited v-fib with only 40% survival to age 5- caused by mutations in Na+ channels

Question 12

What is yotiao?

Answer 12

a protein that normally targets PKA, the effector of β receptors in cardiac Ca and K channels

Question 13

What are the 2 general mechanisms of arrhythmia generation?

Answer 13

1. inappropriate impulse initiation at the SA node or ectopically
2. disturbed impulse conduction in nodes, Purkinje cells, or myocytes

Question 14

Why do ectopic foci occur?

Answer 14

SA nodal pacemaker is abnormally slow or ectopic focus is abnormally fast; infarct

Question 15

What does EAD stand for?

Answer 15

early afterdepolarizations

Question 16

When do EADs occur?

Answer 16

in late phase 2 or early phase 3

Question 17

What causes EADs?

Answer 17

re-activation of Ca2+ channels in response to elevated Ca2+

Question 18

What does DAD stand for?

Answer 18

delayed afterdepolarizations

Question 19

When do DADs occur?

Answer 19

during early phase 4

Question 20

What causes DADs?

Answer 20

initiated by elevated [Ca2+]in and elevated Na+/Ca2+ exchange

Question 21

What is NCX?

Answer 21

the sodium-calcium exchanger

Question 22

What is the current the NCX generates?

Answer 22

I NCX

Question 23

Re-entrant arrhythmias require what two conditions?

Answer 23

1. uni-directional conduction block in a functional circuit

2. conduction time around the circuit is longer than the refractory period

Question 24

In many cases, arrhythmia is triggered by _____ but is maintained by _____.

Answer 24

afterdepolarizations; re-entry

Question 25

Why does increased sympathetic tone increase the likelihood of triggered afterdepolarizations?

Answer 25

Ca2+ influx is enhanced by β-adrenergic receptor activity

Question 26

What is the mechanism of action of Class I Anti-arrhythmic Drugs?

Answer 26

voltage-gated Na+ channel blockers

Question 27

All Na+ channel blockers decrease _____ and | nearly all increase _____.

Answer 27

conduction rate; refractory period

Question 28

All _____ decrease conduction rate and nearly all increase refractory period.

Answer 28

Na+ channel blockers

Question 29

Class I action results in _____.

Answer 29

slowed upstroke

Question 30

_____ action results in slowed upstroke.

Answer 30

Class I

Question 31

_____ drugs slow upstroke and also decrease action potential duration.

Answer 31

Class Ib

Question 32

Class Ib drugs slow _____ and also decrease _____.

Answer 32

upstroke; action potential duration

Question 33

_____ and _____ drugs delay phase 3 onset by blocking K+ channels.

Answer 33

Class Ia; class Ic

Question 34

Class Ia and class Ic drugs delay ____ onset by blocking K+ channels.

Answer 34

phase 3

Question 35

Class Ia and class Ic drugs delay phase 3 onset by blocking _____.

Answer 35

K+ channels

Question 36

Name 3 specific class 1a Na+ channel blockers.

Answer 36

quinidine, procainamide, disopyramide

Question 37

All ____ drugs slow the upstroke of the fast response, and they also delay the onset of repolarization.

Answer 37

class Ia

Question 38

All class Ia drugs slow the _____, and they also delay the ____.

Answer 38

upstroke of the fast response; onset of repolarization

Question 39

Class Ia drugs prolong the refractory period via two processes: _______ and _____.

Answer 39

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

Question 40

Quinidine has important effects not related to Na+ channel block, including ____, ____, and ____.

Answer 40

1. blocks K+ channels particularly well, thereby prolonging action potential duration 2. it is a vagal inhibitor (anti-cholinergic) 2. it is an α-adrenergic receptor antagonist

Question 41

Name 3 specific Class Ib Na+ channel blockers.

Answer 41

lidocaine, mexiletine, phenytoin

Question 42

Lidocaine, mexiletine, and phenytoin are all what kind of drug?

Answer 42

Class Ib Na+ channel blockers

Question 43

How are class 1b drugs similar to class 1a drugs?

Answer 43

they are use-dependent blockers of voltage-gated Na+ channels

Question 44

In contrast to class Ia drugs, ____ drugs do not prolong phase 2 of the action potential.

Answer 44

class Ib

Question 45

In contrast to class Ia drugs, class Ib drugs do not ____.

Answer 45

prolong phase 2 of the action potential

Question 46

What is the most important class 1b drug for the treatment of arrhythmias?

Answer 46

lidocaine

Question 47

Name 3 specific Class Ic Na+ channel blockers.

Answer 47

propafenone, flecainide, encainide

Question 48

Propafenone, flecainide, and encainide are all what kind of drug?

Answer 48

Class Ic Na+ channel blockers

Question 49

_____ produce the most pronounced slowing of upstroke rate; the net effect is powerful prolongation of tissue refractory period.

Answer 49

Class Ic drugs

Question 50

Class Ic drugs produce the most pronounced slowing of upstroke rate; the net effect is powerful ____.

Answer 50

prolongation of tissue refractory period

Question 51

What does it mean that class 1c drugs preferentially target cells?

Answer 51

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 myocyte

Question 52

What is the mechanism of action for class 1c drugs that allows their preferential targeting?

Answer 52

the channel must be open

Question 53

_____ is the fundamental mechanism of prolongation of cellular refractory period.

Answer 53

Prolongation of channel inactivation

Question 54

How do use-dependent channel blockers prolong the refractory period?

Answer 54

they stabilize the inactive state after entering the open channel