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CVPR > CV - molecular mechanisms of arrhythmias and anti arrhythmic drugs > Flashcards

CV - molecular mechanisms of arrhythmias and anti arrhythmic drugs Flashcards

1
Q

fundamentally there are two types of problems leading to arrhythmia generation. what are they?

A

1 inappropriate impulse generation in the SA node or elsewhere (ectopic focus)
2 disturbed impulse conduction in the nodes, conduction cells (purkinje cells) or myocytes

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2
Q

what are the causes of inappropriate impulse initiation? (2)

A

ectopic foci
triggered afterdepolarizations triggered by action potential (early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs))

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3
Q

what are the causes of disturbed impulse conduction? (2)

A 
conduction block (primary, secondary or tertiary)
reentry
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4
Q

what are the broader causes for cardiac arrhythmias? (6)

A 
myocardial infarction
ischemia
acidosis/alkalosis
electrolyte abnormalities
excessive catecholamine exposure
drug toxicity
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5
Q

in ectopic foci, the SA nodal pacemaker is abnormally ___________ OR an ectopic focus is abnormally ___________.

A

slow

fast

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6
Q

in what phase of the cardiac action potential do early afterdepolarizations (EADs) appear?

A

late phase 2 and phase 3

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7
Q

in what phase of the cardiac action potential do delayed afterdepolarizations (DADs) appear?

A

early phase 4

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8
Q

early afterdepolarizations (EADs) are largely dependent on reactivation ___________ in response to elevated ___________.

A

Ca2+ channels

[Ca2+]in

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9
Q

during an EAD, the prolongation of ___________ contributes to elevated [Ca2+]in.

A

phase 2

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10
Q

delayed afterpolarizations (DADs) are initiated by elevated ___________ and, consequently, elevated ___________.

A

[Ca2+]in

Na+/Ca2+ exchange

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11
Q

the Na+/Ca2+ exchanger (NCX) generates ___________ current by moving ___________ Na+ ions ___________ the cell and ___________ Ca2+ ions ___________ the cell.

A 
I_NCX
3
into
1
out of
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12
Q

prolongation of the QT interval leads to ___________ and ___________.

A

afterdepolarizations

arrhythmia

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13
Q

what two conditions are required to cause a reentrant arrhythmia?

A

1 unidirectional conduction block in a functional circuit

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

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14
Q

in many cases, arrhythmia is triggered by ___________ and maintained by ___________.

A

afterdepolarizations

reentry

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15
Q

describe torsades de pointes

A

a polymorphic ventricular tachycardia initiated by a prolongation of the plateau phase (phase 2) of the fast response cardiac action potential in ventricular myocytes

the term “twisting of points” describes the appearance of the abnormal ECG typically triggered by an abrupt increase in sympathetic tone as occurs with emotional excitement, fright, or physical activity, also associated with pathological heart failure such as long QT syndrome

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16
Q

___________ is believed to be responsible for the premature beat that initiates torsades de pointes

A

EAD-induced extra systole

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17
Q

describe congenital long QT syndrome

A

congenital long QT syndrome is a prolongation of the duration of the cardiac action potential (QT interval) that can lead to ventricular arrhythmia and sudden death

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18
Q

Romano-Ward syndrome (RWS)

A

autosomal dominant form of long QT syndrome

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19
Q

while RWS is genetically heterogeneous, the most prevalent mutations identified are found in the ___________ channel, the ___________ channel, and the ___________ channel.

A

slow cardiac K+
rapid cardiac K+
cardiac Na+

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20
Q

Jervell-Lang-Nielson syndrome (JLNS)

A

autosomal recessive form of long QT syndrome

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21
Q

what is the mutation associated with JLNS?

A

homozygous mutations in I_Ks, the slow cardiac K+ channel

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22
Q

what is the additional phenotype associated with homozygosity of the I_Ks mutation in JLNS?

A

congenital deafness

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23
Q

what is the affect of long QT mutations in cardiac K+ channel subunits?

A

generally reduce the number of K+ channels expressed in the myocyte plasma membrane (loss of function mutations), thereby reducing the size of the K+ current (I_Kr + I_Ks) that helps terminate the plateau phase of the fast response cardiac action potential and return the membrane to resting potential

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24
Q

what is the affect of long QT mutations in cardiac Na+ channels?

A

prevent Na+ channels from inactivating completely (gain of function mutations), thereby prolonging phase 2 of the fast response action potential

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25
Q

anti arrhythmic drugs should be selected based on the specific ___________ of long QT syndrome.

A

molecular basis

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26
Q

with which ion channel and current is the LQT1 mutation associated?

A

slow cardiac K+

I_Ks

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27
Q

what is the functional effect of the LQT1 mutation?

A

decrease in K+ current

reduced current amplitude

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28
Q

with which ion channel and current is the LQT2 mutation associated?

A

rapid cardiac K+

I_Kr

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29
Q

what is the functional effect of the LQT2 mutation?

A

decrease in K+ current

reduced current amplitude

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30
Q

with which ion channel and current is the LTQ3 mutation associated?

A

cardiac N+

I_Na

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31
Q

what is the functional effect of the LQT3 mutation?

A

incomplete I_Na inactivation

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32
Q

what is the general drug therapy recommended for patients with LQT3 mutations?

A

drugs that block Na+ channels

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33
Q

what is the general (theoretical) drug therapy recommended for patients with LQT1 and LQT2 mutations?

A

drugs that open K+ channels

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34
Q

with which ion channel and current is the LQT5 mutation associated?

A

slow cardiac K+

I_Ks

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35
Q

what is the functional effect of the LQT5 mutation?

A

decrease in K+ current

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36
Q

with which ion channel and current is the LQT6 mutation associated?

A

rapid cardiac K+

I_Kr

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37
Q

what is the functional effect of the LQT6 mutation?

A

decrease in K+ current

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38
Q

with which ion channel and current l is the LQT8 mutation associated?

A

cardiac Ca+

I_Ca-L

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39
Q

what is the functional effect of the LQT8 mutation?

A

incomplete I_Ca activation

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40
Q

with what syndrome and phenotype is the LQT8 associated?

A

Timothy Syndrome

autism

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41
Q

with which ion channel and current is the LQT7 mutation associated?

A

inward rectifier K+ current

I_K1

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42
Q

what is the functional effect of the LQT7 mutation?

A

decrease in K+ current during diastole

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43
Q

the primary targets of anti arrhythmic drugs are which channels or receptors?

A

cardiac Na+ channels (I_Na)
Ca2+ channels (I_Ca-L)
K+ channels (I_Ks and I_Kr)
beta-adrenergic receptors

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44
Q

to date, which anti arrhythmic drugs have been demonstrated to reduce the incidence of sudden cardiac death?

A

beta-blockers

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45
Q

describe Brugada syndrome (BrS)

A

mutations in the cardiac Na+ channel reduce peak inward Na+ current, affecting the drive of the action potential upstroke in ventricular myocytes and causing ventricular fibrillation

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46
Q

the plateau of the fast response (phase 2 of the cardiac action potential) can be prolonged either by ___________ or ___________.

A

increased inward current (incompleteNa+ channel inactivation in LQT3)
decreased outward current (smaller K+ current in LQT1, LQT2)

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47
Q

Ca2+ entry during the resulting prolonged QT interval can result in ___________ via ___________ or ___________ via ___________.

A

EADs
Ca2+ channel reactivation
DADs
NCX-dependent depolarization

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48
Q

Ca2+ channel reactivation and Ca2+ entry during a prolonged QT interval can result in ___________.

A

EADs

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49
Q

NCX-dependent depolarization and Ca2+ entry during a prolonged QT interval can result in ___________.

A

DADs

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50
Q

increased sympathetic tone (startled, excited) increases the likelihood of ___________ because Ca2+ influx is enhanced by ___________ activity.

A

triggered afterdepolarizations

beta-adrenergic receptor

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51
Q

all class I drugs act primarily by what mechanism?

A

blocking voltage-gated Na+ channels

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52
Q

the primary action of class I drugs is on ___________ cells, though they also affect ___________ cells.

A

fast-response

slow-response

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53
Q

the effect of class I drugs on slow-response cells probably occurs because these drugs also block ___________ channels.

A

L-type Ca2+

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54
Q

all Na+ channel blockers decrease ___________ and increase ___________.

A

conduction rate

refractory period

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55
Q

class Ia Na+ channel blockers (3)

A

quinidine
procainamide
disopyramide

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56
Q

all class Ia drugs slow the ___________ of the fast response and delay ___________.

A

upstroke

onset of repolarization

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57
Q

slowed upstroke of the fast response due to the action of class Ia drugs results from the block of ___________ channels.

A

Na+

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58
Q

delay of repolarization due to the administration of class Ia drugs results from the block of ___________ channels, which is actually a class ___________ effect.

A

K+

III

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59
Q

what are the two processes by which class Ia drugs prolong refractory period?

A

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

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60
Q

what are the effects of quinidine not related to Na+ channel block? (3)

A

1 blocks K+ channels particularly well, thereby prolonging action potential duration and delaying the onset of repolarization
2 vagal inhibition (anti-cholinergic)
3 alpha-adrenergic receptor antagonization

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61
Q

class Ib Na+ channel blockers (3)

A

lidocaine, mexiletine, phenytoin

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62
Q

like class Ia drugs, class Ib drugs are use-dependant blockers of ___________ channels.

A

voltage-gated Na+

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63
Q

class Ib drugs ___________ and ___________, but more mildly than class Ia or Ic drugs.

A

slow upstroke

prolong refractory period

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64
Q

in contrast to class Ia drugs, class Ib drugs do not ___________.

A

prolong phase 2 of the action potential

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65
Q

___________ drugs show the purest form of class I action on the fast response.

A

class Ib

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66
Q

in treating arrhythmias, ___________ is the most important of the class Ib drugs.

A

lidocaine

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67
Q

what does it mean for a channel block to be use-dependent?

A

channel must be open (be used, or activated) for the blocker to enter the pore, bind, and thereby block the Na+ channel

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68
Q

what is the importance of the use-dependant property of class I anti arrhythmic drugs?

A

the block of Na+ channels by class I anti arrhythmic drugs is optimized so that 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

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69
Q

the mechanism of block of cardiac Na+ channels is identical to what mechanism involving neuronal Na+ channels?

A

local anesthetic block of neuronal Na+ channels

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70
Q

use-dependent blockers include both ___________ ___________ channel blockers and ___________ ___________ channel blockers.

A

class I
Na+
class IV
Ca+

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71
Q

what is the primary mechanism by which use-dependent channel blockers prolong the refractory period?

A

these drugs actually block initially by entering the open channel, but they have a higher affinity for the inactivated state of the channel, meaning that these use-dependent blockers stabilize the inactivated state, thus prolonging the time the channel spends in its inactivated state

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72
Q

most use-dependent channel blockers have a higher affinity for the ___________ state of the channel.

A

inactivated

73
Q

the primary mechanism of use-dependent channel blockers is to stabilize the ___________ state of the channel they are blocking.

A

inactivated

74
Q

what is the the primary mechanism of prolongation of cellular refractory period by class I drugs?

A

the prolongation of channel inactivation via the stabilization of the inactivated state of the ion channel

75
Q

what are two examples of channels that may be stabilized in their inactive state by use-dependent channel blockers, thus prolonging the refractory period?

A

Na+ channels in non-pacemaker cells

Ca+ channels in SA nodal or AV nodal cells

76
Q

what is the secondary mechanism of prolongation of the cellular refractory period by class I drugs?

A

prolongation of phase 2 and delay of depolarization, which is a class III action exerted by class Ia drugs in particular

77
Q

prolonging phase 2 means that the myocyte membrane is ___________ for a longer period of time and therefore more ___________ channels become inactivated, prolonging the refractory period.

A

depolarized

Na+

78
Q

reentry can be terminated by converting a ___________ block to a ___________ block and prolonging the ___________.

A

unidirectional
bidirectional
refractory time

79
Q

by what two mechanisms can unidirectional blocks be converted to bidirectional blocks?

A

1 slowing action potential conduction velocity

2 prolonging refractory period

80
Q

do steeper upstrokes of action potentials cause a faster or slower propagation of the action potential?

A

faster

81
Q

steeper upstrokes of action potentials correspond to what change in voltage gradient along the conduction pathway?

A

steeper

82
Q

steeper voltage gradient along a conduction pathway have what effect on the flow of action current?

A

increase

83
Q

a drug-induced reduction in upstroke rate results in a ___________ conduction velocity.

A

slower

84
Q

slowed conduction velocity is an easy-to-measure reporter of ___________.

A

action current density, or drug-mediated block of some of the Na+ channels in the reentrant circut

85
Q

partial block of I_Na by drugs such as lidocaine means that ___________ or ___________ conduction is more likely to fail.

A

retrograde

circus

86
Q

why does prolonging the refractory period help suppress reentrant arrhythmias?

A

prolonged refractoriness can help suppress reentrant arrhythmias for the straightforward reason that refractory tissue will not generate an action potential

87
Q

T/F refractory tissue wil generate an action potential

A

false

88
Q

class II anti arrhythmic drugs: beta-blockers (3)

A

propranolol
metaprolol
esmolol

89
Q

what is the action of class II drugs?

A

reduction of I_f current (I_f)
reduction of L-type Ca2+ current (I_Ca-L)
reduction of K+ current (I_Ks)

90
Q

reduction of I_f, I_Ca-L and I_Ks currents reduces the rate of ___________ in pacing cells, reduces ___________, and slows ___________ in AV nodal myocytes.

A

diastolic depolarization
upstroke rate
repolarization

91
Q

class II drugs have what two general effects in SA and AV nodal cells?

A

1 reduction of pacing rate

2 prolongation of refractory period

92
Q

beta-blockers are used to terminate arrhythmias due to ___________, and in controlling ___________ during atrial fibrillation.

A

AV nodal reentry

ventricular rate

93
Q

class III anti arrhythmic drugs: prolongation of phase 2 (5)

A 
ibutilide
dofetilide
amiodarone
sotalol
bretylium
94
Q

what is the primary mechanism of prolongation of the refractory period by class III drugs?

A

prolongation of the fast response phase 2 due to blocking of K+ channels

95
Q

prolongation of phase 2 leads to increased inactivation of ___________ channels.

A

Na+

96
Q

in addition to K+ channel block, what are the additional mechanisms of the class III anti arrhythmic drug amiodarone?

A

decreases potential for reentry via reduction of conduction velocity and prolongation of the refractory period by blocking Na+ channels
decreases automaticity via a decrease in the rate of diastolic depolarization (phase 4) in automatic cells, thus reducing the firing rate

97
Q

in addition to K+ channel block, what is an additional mechanism of the class III anti arrhythmic drug sotalol?

A

beta-adrenergic receptor blocker

98
Q

class IV anti arrhythmic drugs: Ca2+ channel blockers (2)

A

verapamil

diltiazem

99
Q

the principal effect of class IV anti arrhythmic drugs is exerted by what action?

A

blockage of Ca2+ channels in nodal cells

100
Q

what is a secondary action of class IV anti arrhythmic drugs?

A

blockage of Ca2+ channels in fast response myocytes

101
Q

all Ca2+ channel blockers slow the Ca2+-dependent upstroke in ___________ tissue (normal or abnormal), which in turn has hat effect on the conduction velocity?

A

slow response

slows conduction velocity

102
Q

where is the slowing of conduction velocity by Ca2+ channel blockers most significant?

A

AV node

103
Q

just as in the case of class I blockers of Na+ channels, class IV Ca2+ channel blockers have what effect on the refractory period?

A

prolong the refractory period

104
Q

due to their effect on prolongation of the refractory period, class IV Ca2+ channel blockers can thereby suppress ___________ arrhythmias, particularly in which node?

A

reentrant

AV node

105
Q

a decrease in reentry is the result of what two mechanisms of class IV Ca2+ channel blockers?

A

1 decrease in conduction velocity of the AV node

2 prolongation of the effective refractory period of the AV node

106
Q

what is the effect of the unclassified anti arrhythmic drug adenosine?

A

increase a K+ current while also decreasing both L-type Ca2+ current (dihydropyridine-sensitive, slow inward current) and I_f in SA and AV nodes

107
Q

via what receptor does adenosine act?

A

A1 adenosine receptor

108
Q

the action of adenosine is similar to that of what class of anti arrhythmic drugs?

A

class II anti arrhythmic drugs: beta-adrenergic receptor blockers

109
Q

what is the mechanism of adenosine that results in similar effects to beta-blockers?

A

adenosine, via a Gi-coupled receptor, inhibits adenylyl cyclase and thus cAMP production

110
Q

the adenosine-induced changes in membrane current have what effects on the SA node and AV node?

A

reduce SA node and AV node firing rates

reduce conduction rate in AV node

111
Q

what molecule-receptor interaction also activates the K+ channel activated by adenosine?

A

acetylcholine binding to muscarinic receptors

112
Q

anti arrhythmic drugs are primary therapy for ___________ only, while ablation or ICD are thought to be equal or superior in the management of all other arrhythmias.

A

atrial fibrillation

113
Q

from what arrhythmic incident does paroxysmal supraventricular tachycardia (PSVT) pathophysiology arise?

A

reentry

114
Q

what is the recommended treatment for acute PSVT?

A

adenosine

115
Q

what is the recommended treatment for chronic PSVT?

A 
AV nodal blockers (class II, class IV, class III or digoxin)
catheter ablation of ectopic focus
116
Q

from what arrhythmic incident does atrial fibrillation pathophysiology arise?

A

reentry

117
Q

what is the recommended treatment for acute atrial fibrillation?

A

AV nodal blockers

electrical cardioversion

118
Q

what is the recommended treatment for chronic atrial fibrillation?

A 
AV nodal blockers combined with long-term anticoagulation (warfarin)
electrical cardioversion and maintenance of sinus rhythm with drug therapy with class III or Ic AV nodal blockers
119
Q

from what arrhythmic incident do ventricular tachycardias/fibrillation pathophysiology arise?

A

afterdepolarizations AND reentry

120
Q

what is the recommended treatment for acute ventricular tachycardia/fibrillation?

A

amiodarone
lidocaine
procainamide

(class Ia, class Ib or class III anti arrhythmic drugs)

121
Q

what drugs show a proven benefit in the drug prevention of sudden cardiac death?

A

beta-blockers

122
Q

what drugs show a potential benefit in the drug prevention of sudden cardiac death?

A

amiodarone, digoxin

123
Q

what drugs are potentially harmful in causing sudden cardiac death?

A 
class I drugs (Na+ channel blockers) 
class IV drugs (Ca2+ channel blockers)
124
Q

excluding drug therapies, what are the typical treatments for arrhythmias?

A

catheter ablation of ectopic foci

implantable, cardioverter-debrillator devices

125
Q

in light of their arrhythmogenic properties, why are pharmaceuticals still used?

A

they are a good first-line treatment and can be used in conjunction with ICDs to decrease frequency of arrhythmic episodes

126
Q

what are the primary, direct drug targets of anti arrhythmic drugs? (4)

A

Na+ channels
beta-adrenergic receptors
K+ channels
Ca2+ channels

127
Q

what are the indirect targets of drugs influencing the beta-adrenergic pathway?

A

I_f
I_Ca-L
I_Ks

128
Q

class Ic Na+ channel blockers (3)

A

propafenone, flecainide, encainide

129
Q

how does the effect of class Ic drugs on the upstroke rate compare to the effect of class Ia and Ib drugs?

A

class Ic drugs produce the most pronounced slowing of the upstroke rate

130
Q

what is the net effect of class Ic drugs on the tissue refractory period?

A

powerful prolongation

131
Q

what class of drugs are used to treat long QT patients?

A

beta-blockers

132
Q

what arrhythmia might torsades de pointes degenerate to?

A

ventricular fibrillation

133
Q

where are nearly all mutations implicated in torsades de pointes?

A

ion channels

134
Q

mutations in which ion channels are most prevalent in torsades de pointes patients? (3)

A

slow cardiac K+ (I_Ks)
rapid cardiac K+ (I_Kr)
cardiac Na+ (I_Na)

135
Q

what are the two categories of long QT syndrome?

A

autosomal dominant Romano-Ward Syndrome (RWS)

autosomal recessive Jervell-Lang-Nielson syndrome (JLNS)

136
Q

how do mutations in K+ channels in long QT syndrome affect phase 2 of the cardiac action potential?

A

a reduction in the number of expressed K+ channels (loss of function mutation) leads to a reduction in the amplitude of the K+ current

the K+ current is required for the termination of the phase 2 plateau and depolarization of the cell membrane, thus, a reduction of the K+ current leads to the prolongation of phase 2 of the cardiac action potential

137
Q

how do mutations in Na+ channels lead to long QT syndrome?

A

gain of function mutations in Na+ channels prevent Na+ channels from inactivating completely, prolonging phase 2 of the fast response.

138
Q

which ion channel is typically mutated in BrS?

A

Na+ channel

139
Q

what is the effect of the mutation in Na+ channels in BrS?

A

reduced amount of peak inward Na+ current that drives action potential upstroke in ventricular monocytes, leading to a decreased upstroke and ventricular fibrillation

140
Q

what is the normal function of the yotiao protein?

A

yotiao targets protein kinase A (PKA), an effector of beta adrenergic receptors, to cardiac Ca2+ and K+ channels, by binding directly to these channels

141
Q

a mutation in yotiao protein has what effect on cardiac ion channel activity?

A

a mutation in the yotiao protein affects the K+ channel binding site, impairing binding and diminishing beta adrenergic receptor up regulation of K+ channel activity

cells with this yotiao mutation have preserved beta adrenergic receptor up regulation of cardiac Ca2+ channels but not cardiac K+ channels

142
Q

what is the pathophysiology that results from the mutation in the yotiao protein that impairs beta adrenergic receptor upregulation of cardiac K+ channels?

A

during periods of increased sympathetic activity there is insufficient repolarizing K+ current to match the depolarizing Ca2+ current, resulting in a prolongation of phase 2 and an increase in Ca2+ levels in the cytosol that trigger afterdepolarizations and arrhythmias

143
Q

how is inappropriate impulse initiation identified?

A

abnormally depolarized diastolic membrane potential

144
Q

what are two causes of inappropriate impulse generation?

A

1 ectopic foci due to abnormally slow SA nodal firing or abnormally fast ectopic foci firing causing membrane depolarization
2 triggered afterdepolarizations triggered by action potential

145
Q

describe early afterdepolarizations (EADs)

A

EADs appear during late phase 2 and phase 3 and are dependent on the reactivation of Ca2+ channels in response to elevated Ca2+ levels due to prolonged phase 2 (long QT)

146
Q

describe delayed afterdepolarizations (DADs)

A

DADs appear during early phase 4 and are initiated by elevated inward movement of Ca2+, which drives increased Na+/Ca2+ exchange via the NCX exchanger, resulting in a net increase in positive charge in the cytosol of myocytes and abnormal depolarization of the cells

147
Q

what is the treatment for a complete heart block?

A

implantable pacemaker

148
Q

what is reentry?

A

a loop current flowing in a functional circuit of the heart, often caused by damage to the heart resulting in a unidirectional block

also called a “circus rhythm”

149
Q

T/F reentry can occur in circuits made up of every type of cell in the heart

A

true

150
Q

T/F reentrant circuits may involve a combination of atria and ventricles

A

true

151
Q

what are the two conditions that lead to the generation of a reentrant arrhythmia?

A

1 unidirectional block of a functional circuit of the heart

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

152
Q

what is the fundamental issue in reentry?

A

conduction time around a circuit is longer than the refractory period of the circuit, causing repeated activation of the current or a circus rhythm

153
Q

what are two factors that can prolong phase 2 of the cardiac action potential and their corresponding mutations?

A

incomplete Na+ channel inactivation (LQT3 mutation)

reduced amplitude of K+ currents I_Ks and I_Kr (LQT1 and LQT2 mutations, respectively)

154
Q

what might be the result of increased Ca2+ entry during a prolonged phase 2?

A

EADs due to Ca2+ channel reactivation

DADs due to NCX-dependent depolarization

155
Q

increased sympathetic tone (startled, excited) increases the likelihood of what type of afterdepolarizations? why?

A

EADs

Ca2+ influx is enhanced by beta-adrenergic receptors, which are activated as part of the sympathetic response

156
Q

how does the activation of beta-adrenergic receptors influence Ca2+ influx?

A

beta-adrenergic receptor activity increases/enhances the influx of Ca2+

157
Q

what are two injuries to heart tissue that may cause reentry?

A

myocardial infarction (total heart block) or drugs that block K+ channels

158
Q

what are the four classes of anti arrhythmic drugs?

A 
class I: sodium channel blockers
class II: beta-adrenergic receptor antagonists (beta blockers)
class III: K+ channel blockers causing prolongation of refractory period
class IV: Ca2+ channel blockers
159
Q

what cells are primarily affected by Na+ channel blockers?

A

fast-response cells

160
Q

what are the two effects of Na+ channel blockers?

A

decrease conduction rate

prolong refractory period

161
Q

what is the functional effect of class Ia drugs?

A 
slow upstroke of the fast response via blocking of Na+ channels
delay repolarization via blocking of K+ channels, technically a class III effect
162
Q

what are the two mechanisms by which class Ia drugs prolong the refractory period?

A

1 classic, use-dependent mechanism of inactive state stabilization, similar to local anesthetic affects on neuronal Na+ channels
2 prolongation of depolarization (phase 2)

163
Q

what is an old school drug that was originally used to treat arrhythmias, and why is it no longer the primary therapy?

A

quinidine, a class Ia anti arrhythmic drug, also blocks K+ channels and prolongs the duration of the action potential, exhibits vagal inhibition, and is an agonist of alpha-adrenergic receptors

non-selectivity of action

164
Q

name three class Ib anti arrhythmic drugs

A

lidocaine, mexiletine, phenytoin

165
Q

what is the mechanism and effect of class Ib Na+ channel blockers?

A

use-dependent blockage of voltage-gated Na+ channels

slow upstroke and prolong refractory period

166
Q

how do class Ia and Ib anti arrhythmic drugs differ?

A

class Ib anti arrhythmic drugs DO NOT PROLONG PHASE 2 but instead shorten phase 2 and prolong the refractory period

167
Q

name three class Ic anti arrhythmic drugs

A

propafenone, flecainide, encainide

168
Q

what is the mechanism and effect of class Ic anti arrhythmic drugs?

A

use-dependent blockage of voltage-gated Na+ channels
produce the most pronounced slowing of upstroke rate and mildly prolong phase 2, resulting in a net effect of powerful prolongation of the tissue refractory period

169
Q

which of the class Ic anti arrhythmic drugs is no longer marketed? why?

A

encainide

1989 Cast study showed increased mortality

170
Q

order the three subsets of class I anti arrhythmic drugs by their exhibited degree of Na+ voltage-gated channel blocking

A

1c - marked
1a - moderate
1b - mild

171
Q

what does it mean for a drug to exhibit use-dependent blockage?

A

use-dependent refers to the use of the channel; the channel must be open (used, activated) in order for a use-dependent drug to enter the pore, bind and thereby block the channel

use-dependent drug behavior preferentially targets overactive cells or cells that have abnormally depolarized resting potentials

172
Q

charged, hydrophilic drugs may only enter and exit an ion channel when the channel is in its ___________ state.

A

open/active

173
Q

T/F neutral, hydrophobic drugs, at a much slower rate, can reach the local anesthetic site even when the channel is closed or inactivated.

A

true

174
Q

what is the major distinction between charged and uncharged drugs with regards to their abilities to enter ion channels?

A

charged drugs can only enter or exit ion channels when the channel is open or active, and cannot enter or exit ion channels when the channel is closed or in its inactive state
neutral/uncharged drugs can access local anesthetic sites even when the channel is closed or inactivated

175
Q

which two classes of drugs are use-dependent blockers of ion channels, and what are their respective ion channel targets?

A 
class I - Na+ channel blockers
class IV - Ca2+ channel blockers
176
Q

name three common beta adrenergic receptor antagonists

A

propanolol, metaprolol, esmolol

177
Q

what three currents are reduced by beta-blockers?

A

I_f
I_Ca-L
I_Ks

178
Q

what are the net effects of beta-blocker reduction of the I_f, I_Ca-L and I_Ks currents?

A

reduces rate of diastolic depolarization in pacemaker cells
reduces upstroke rate
slows repolarization

179
Q

what is the primary location of the net effects of beta-blocker?

A

AV node

CVPR (14 decks)

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