CV - molecular mechanisms of arrhythmias and anti arrhythmic drugs Flashcards
(179 cards)
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
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))
3
Q
what are the causes of disturbed impulse conduction? (2)
A
conduction block (primary, secondary or tertiary) reentry
4
Q
what are the broader causes for cardiac arrhythmias? (6)
A
myocardial infarction ischemia acidosis/alkalosis electrolyte abnormalities excessive catecholamine exposure drug toxicity
5
Q
in ectopic foci, the SA nodal pacemaker is abnormally ___________ OR an ectopic focus is abnormally ___________.
A
slow
fast
6
Q
in what phase of the cardiac action potential do early afterdepolarizations (EADs) appear?
A
late phase 2 and phase 3
7
Q
in what phase of the cardiac action potential do delayed afterdepolarizations (DADs) appear?
A
early phase 4
8
Q
early afterdepolarizations (EADs) are largely dependent on reactivation ___________ in response to elevated ___________.
A
Ca2+ channels
[Ca2+]in
9
Q
during an EAD, the prolongation of ___________ contributes to elevated [Ca2+]in.
A
phase 2
10
Q
delayed afterpolarizations (DADs) are initiated by elevated ___________ and, consequently, elevated ___________.
A
[Ca2+]in
Na+/Ca2+ exchange
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
12
Q
prolongation of the QT interval leads to ___________ and ___________.
A
afterdepolarizations
arrhythmia
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
14
Q
in many cases, arrhythmia is triggered by ___________ and maintained by ___________.
A
afterdepolarizations
reentry
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
16
Q
___________ is believed to be responsible for the premature beat that initiates torsades de pointes
A
EAD-induced extra systole
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
18
Q
Romano-Ward syndrome (RWS)
A
autosomal dominant form of long QT syndrome
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+
20
Q
Jervell-Lang-Nielson syndrome (JLNS)
A
autosomal recessive form of long QT syndrome
21
Q
what is the mutation associated with JLNS?
A
homozygous mutations in I_Ks, the slow cardiac K+ channel
22
Q
what is the additional phenotype associated with homozygosity of the I_Ks mutation in JLNS?
A
congenital deafness
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
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
25
anti arrhythmic drugs should be selected based on the specific ___________ of long QT syndrome.
molecular basis
26
with which ion channel and current is the LQT1 mutation associated?
slow cardiac K+
| I_Ks
27
what is the functional effect of the LQT1 mutation?
decrease in K+ current
reduced current amplitude
28
with which ion channel and current is the LQT2 mutation associated?
rapid cardiac K+
| I_Kr
29
what is the functional effect of the LQT2 mutation?
decrease in K+ current
reduced current amplitude
30
with which ion channel and current is the LTQ3 mutation associated?
cardiac N+
| I_Na
31
what is the functional effect of the LQT3 mutation?
incomplete I_Na inactivation
32
what is the general drug therapy recommended for patients with LQT3 mutations?
drugs that block Na+ channels
33
what is the general (theoretical) drug therapy recommended for patients with LQT1 and LQT2 mutations?
drugs that open K+ channels
34
with which ion channel and current is the LQT5 mutation associated?
slow cardiac K+
| I_Ks
35
what is the functional effect of the LQT5 mutation?
decrease in K+ current
36
with which ion channel and current is the LQT6 mutation associated?
rapid cardiac K+
| I_Kr
37
what is the functional effect of the LQT6 mutation?
decrease in K+ current
38
with which ion channel and current l is the LQT8 mutation associated?
cardiac Ca+
| I_Ca-L
39
what is the functional effect of the LQT8 mutation?
incomplete I_Ca activation
40
with what syndrome and phenotype is the LQT8 associated?
Timothy Syndrome
| autism
41
with which ion channel and current is the LQT7 mutation associated?
inward rectifier K+ current
| I_K1
42
what is the functional effect of the LQT7 mutation?
decrease in K+ current during diastole
43
the primary targets of anti arrhythmic drugs are which channels or receptors?
cardiac Na+ channels (I_Na)
Ca2+ channels (I_Ca-L)
K+ channels (I_Ks and I_Kr)
beta-adrenergic receptors
44
to date, which anti arrhythmic drugs have been demonstrated to reduce the incidence of sudden cardiac death?
beta-blockers
45
describe Brugada syndrome (BrS)
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
46
the plateau of the fast response (phase 2 of the cardiac action potential) can be prolonged either by ___________ or ___________.
increased inward current (incompleteNa+ channel inactivation in LQT3)
decreased outward current (smaller K+ current in LQT1, LQT2)
47
Ca2+ entry during the resulting prolonged QT interval can result in ___________ via ___________ or ___________ via ___________.
EADs
Ca2+ channel reactivation
DADs
NCX-dependent depolarization
48
Ca2+ channel reactivation and Ca2+ entry during a prolonged QT interval can result in ___________.
EADs
49
NCX-dependent depolarization and Ca2+ entry during a prolonged QT interval can result in ___________.
DADs
50
increased sympathetic tone (startled, excited) increases the likelihood of ___________ because Ca2+ influx is enhanced by ___________ activity.
triggered afterdepolarizations
| beta-adrenergic receptor
51
all class I drugs act primarily by what mechanism?
blocking voltage-gated Na+ channels
52
the primary action of class I drugs is on ___________ cells, though they also affect ___________ cells.
fast-response
| slow-response
53
the effect of class I drugs on slow-response cells probably occurs because these drugs also block ___________ channels.
L-type Ca2+
54
all Na+ channel blockers decrease ___________ and increase ___________.
conduction rate
| refractory period
55
class Ia Na+ channel blockers (3)
quinidine
procainamide
disopyramide
56
all class Ia drugs slow the ___________ of the fast response and delay ___________.
upstroke
| onset of repolarization
57
slowed upstroke of the fast response due to the action of class Ia drugs results from the block of ___________ channels.
Na+
58
delay of repolarization due to the administration of class Ia drugs results from the block of ___________ channels, which is actually a class ___________ effect.
K+
| III
59
what are the two processes by which class Ia drugs prolong refractory period?
1 via classic, use-dependent mechanism, similar to local anesthetics in action
2 because depolarization (phase 2) is prolonged
60
what are the effects of quinidine not related to Na+ channel block? (3)
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
61
class Ib Na+ channel blockers (3)
lidocaine, mexiletine, phenytoin
62
like class Ia drugs, class Ib drugs are use-dependant blockers of ___________ channels.
voltage-gated Na+
63
class Ib drugs ___________ and ___________, but more mildly than class Ia or Ic drugs.
slow upstroke
| prolong refractory period
64
in contrast to class Ia drugs, class Ib drugs do not ___________.
prolong phase 2 of the action potential
65
___________ drugs show the purest form of class I action on the fast response.
class Ib
66
in treating arrhythmias, ___________ is the most important of the class Ib drugs.
lidocaine
67
what does it mean for a channel block to be use-dependent?
channel must be open (be used, or activated) for the blocker to enter the pore, bind, and thereby block the Na+ channel
68
what is the importance of the use-dependant property of class I anti arrhythmic drugs?
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
69
the mechanism of block of cardiac Na+ channels is identical to what mechanism involving neuronal Na+ channels?
local anesthetic block of neuronal Na+ channels
70
use-dependent blockers include both ___________ ___________ channel blockers and ___________ ___________ channel blockers.
class I
Na+
class IV
Ca+
71
what is the primary mechanism by which use-dependent channel blockers prolong the refractory period?
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
72
most use-dependent channel blockers have a higher affinity for the ___________ state of the channel.
inactivated
73
the primary mechanism of use-dependent channel blockers is to stabilize the ___________ state of the channel they are blocking.
inactivated
74
what is the the primary mechanism of prolongation of cellular refractory period by class I drugs?
the prolongation of channel inactivation via the stabilization of the inactivated state of the ion channel
75
what are two examples of channels that may be stabilized in their inactive state by use-dependent channel blockers, thus prolonging the refractory period?
Na+ channels in non-pacemaker cells
| Ca+ channels in SA nodal or AV nodal cells
76
what is the secondary mechanism of prolongation of the cellular refractory period by class I drugs?
prolongation of phase 2 and delay of depolarization, which is a class III action exerted by class Ia drugs in particular
77
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.
depolarized
| Na+
78
reentry can be terminated by converting a ___________ block to a ___________ block and prolonging the ___________.
unidirectional
bidirectional
refractory time
79
by what two mechanisms can unidirectional blocks be converted to bidirectional blocks?
1 slowing action potential conduction velocity
| 2 prolonging refractory period
80
do steeper upstrokes of action potentials cause a faster or slower propagation of the action potential?
faster
81
steeper upstrokes of action potentials correspond to what change in voltage gradient along the conduction pathway?
steeper
82
steeper voltage gradient along a conduction pathway have what effect on the flow of action current?
increase
83
a drug-induced reduction in upstroke rate results in a ___________ conduction velocity.
slower
84
slowed conduction velocity is an easy-to-measure reporter of ___________.
action current density, or drug-mediated block of some of the Na+ channels in the reentrant circut
85
partial block of I_Na by drugs such as lidocaine means that ___________ or ___________ conduction is more likely to fail.
retrograde
| circus
86
why does prolonging the refractory period help suppress reentrant arrhythmias?
prolonged refractoriness can help suppress reentrant arrhythmias for the straightforward reason that refractory tissue will not generate an action potential
87
T/F refractory tissue wil generate an action potential
false
88
class II anti arrhythmic drugs: beta-blockers (3)
propranolol
metaprolol
esmolol
89
what is the action of class II drugs?
reduction of I_f current (I_f)
reduction of L-type Ca2+ current (I_Ca-L)
reduction of K+ current (I_Ks)
90
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.
diastolic depolarization
upstroke rate
repolarization
91
class II drugs have what two general effects in SA and AV nodal cells?
1 reduction of pacing rate
| 2 prolongation of refractory period
92
beta-blockers are used to terminate arrhythmias due to ___________, and in controlling ___________ during atrial fibrillation.
AV nodal reentry
| ventricular rate
93
class III anti arrhythmic drugs: prolongation of phase 2 (5)
```
ibutilide
dofetilide
amiodarone
sotalol
bretylium
```
94
what is the primary mechanism of prolongation of the refractory period by class III drugs?
prolongation of the fast response phase 2 due to blocking of K+ channels
95
prolongation of phase 2 leads to increased inactivation of ___________ channels.
Na+
96
in addition to K+ channel block, what are the additional mechanisms of the class III anti arrhythmic drug amiodarone?
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
in addition to K+ channel block, what is an additional mechanism of the class III anti arrhythmic drug sotalol?
beta-adrenergic receptor blocker
98
class IV anti arrhythmic drugs: Ca2+ channel blockers (2)
verapamil
| diltiazem
99
the principal effect of class IV anti arrhythmic drugs is exerted by what action?
blockage of Ca2+ channels in nodal cells
100
what is a secondary action of class IV anti arrhythmic drugs?
blockage of Ca2+ channels in fast response myocytes
101
all Ca2+ channel blockers slow the Ca2+-dependent upstroke in ___________ tissue (normal or abnormal), which in turn has hat effect on the conduction velocity?
slow response
| slows conduction velocity
102
where is the slowing of conduction velocity by Ca2+ channel blockers most significant?
AV node
103
just as in the case of class I blockers of Na+ channels, class IV Ca2+ channel blockers have what effect on the refractory period?
prolong the refractory period
104
due to their effect on prolongation of the refractory period, class IV Ca2+ channel blockers can thereby suppress ___________ arrhythmias, particularly in which node?
reentrant
| AV node
105
a decrease in reentry is the result of what two mechanisms of class IV Ca2+ channel blockers?
1 decrease in conduction velocity of the AV node
| 2 prolongation of the effective refractory period of the AV node
106
what is the effect of the unclassified anti arrhythmic drug adenosine?
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
via what receptor does adenosine act?
A1 adenosine receptor
108
the action of adenosine is similar to that of what class of anti arrhythmic drugs?
class II anti arrhythmic drugs: beta-adrenergic receptor blockers
109
what is the mechanism of adenosine that results in similar effects to beta-blockers?
adenosine, via a Gi-coupled receptor, inhibits adenylyl cyclase and thus cAMP production
110
the adenosine-induced changes in membrane current have what effects on the SA node and AV node?
reduce SA node and AV node firing rates
| reduce conduction rate in AV node
111
what molecule-receptor interaction also activates the K+ channel activated by adenosine?
acetylcholine binding to muscarinic receptors
112
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.
atrial fibrillation
113
from what arrhythmic incident does paroxysmal supraventricular tachycardia (PSVT) pathophysiology arise?
reentry
114
what is the recommended treatment for acute PSVT?
adenosine
115
what is the recommended treatment for chronic PSVT?
```
AV nodal blockers (class II, class IV, class III or digoxin)
catheter ablation of ectopic focus
```
116
from what arrhythmic incident does atrial fibrillation pathophysiology arise?
reentry
117
what is the recommended treatment for acute atrial fibrillation?
AV nodal blockers
| electrical cardioversion
118
what is the recommended treatment for chronic atrial fibrillation?
```
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
from what arrhythmic incident do ventricular tachycardias/fibrillation pathophysiology arise?
afterdepolarizations AND reentry
120
what is the recommended treatment for acute ventricular tachycardia/fibrillation?
amiodarone
lidocaine
procainamide
(class Ia, class Ib or class III anti arrhythmic drugs)
121
what drugs show a proven benefit in the drug prevention of sudden cardiac death?
beta-blockers
122
what drugs show a potential benefit in the drug prevention of sudden cardiac death?
amiodarone, digoxin
123
what drugs are potentially harmful in causing sudden cardiac death?
```
class I drugs (Na+ channel blockers)
class IV drugs (Ca2+ channel blockers)
```
124
excluding drug therapies, what are the typical treatments for arrhythmias?
catheter ablation of ectopic foci
| implantable, cardioverter-debrillator devices
125
in light of their arrhythmogenic properties, why are pharmaceuticals still used?
they are a good first-line treatment and can be used in conjunction with ICDs to decrease frequency of arrhythmic episodes
126
what are the primary, direct drug targets of anti arrhythmic drugs? (4)
Na+ channels
beta-adrenergic receptors
K+ channels
Ca2+ channels
127
what are the indirect targets of drugs influencing the beta-adrenergic pathway?
I_f
I_Ca-L
I_Ks
128
class Ic Na+ channel blockers (3)
propafenone, flecainide, encainide
129
how does the effect of class Ic drugs on the upstroke rate compare to the effect of class Ia and Ib drugs?
class Ic drugs produce the most pronounced slowing of the upstroke rate
130
what is the net effect of class Ic drugs on the tissue refractory period?
powerful prolongation
131
what class of drugs are used to treat long QT patients?
beta-blockers
132
what arrhythmia might torsades de pointes degenerate to?
ventricular fibrillation
133
where are nearly all mutations implicated in torsades de pointes?
ion channels
134
mutations in which ion channels are most prevalent in torsades de pointes patients? (3)
slow cardiac K+ (I_Ks)
rapid cardiac K+ (I_Kr)
cardiac Na+ (I_Na)
135
what are the two categories of long QT syndrome?
autosomal dominant Romano-Ward Syndrome (RWS)
| autosomal recessive Jervell-Lang-Nielson syndrome (JLNS)
136
how do mutations in K+ channels in long QT syndrome affect phase 2 of the cardiac action potential?
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
how do mutations in Na+ channels lead to long QT syndrome?
gain of function mutations in Na+ channels prevent Na+ channels from inactivating completely, prolonging phase 2 of the fast response.
138
which ion channel is typically mutated in BrS?
Na+ channel
139
what is the effect of the mutation in Na+ channels in BrS?
reduced amount of peak inward Na+ current that drives action potential upstroke in ventricular monocytes, leading to a decreased upstroke and ventricular fibrillation
140
what is the normal function of the yotiao protein?
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
a mutation in yotiao protein has what effect on cardiac ion channel activity?
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
what is the pathophysiology that results from the mutation in the yotiao protein that impairs beta adrenergic receptor upregulation of cardiac K+ channels?
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
how is inappropriate impulse initiation identified?
abnormally depolarized diastolic membrane potential
144
what are two causes of inappropriate impulse generation?
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
describe early afterdepolarizations (EADs)
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
describe delayed afterdepolarizations (DADs)
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
what is the treatment for a complete heart block?
implantable pacemaker
148
what is reentry?
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
T/F reentry can occur in circuits made up of every type of cell in the heart
true
150
T/F reentrant circuits may involve a combination of atria and ventricles
true
151
what are the two conditions that lead to the generation of a reentrant arrhythmia?
1 unidirectional block of a functional circuit of the heart
| 2 conduction time around the circuit is longer than the refractory period
152
what is the fundamental issue in reentry?
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
what are two factors that can prolong phase 2 of the cardiac action potential and their corresponding mutations?
incomplete Na+ channel inactivation (LQT3 mutation)
| reduced amplitude of K+ currents I_Ks and I_Kr (LQT1 and LQT2 mutations, respectively)
154
what might be the result of increased Ca2+ entry during a prolonged phase 2?
EADs due to Ca2+ channel reactivation
| DADs due to NCX-dependent depolarization
155
increased sympathetic tone (startled, excited) increases the likelihood of what type of afterdepolarizations? why?
EADs
| Ca2+ influx is enhanced by beta-adrenergic receptors, which are activated as part of the sympathetic response
156
how does the activation of beta-adrenergic receptors influence Ca2+ influx?
beta-adrenergic receptor activity increases/enhances the influx of Ca2+
157
what are two injuries to heart tissue that may cause reentry?
myocardial infarction (total heart block) or drugs that block K+ channels
158
what are the four classes of anti arrhythmic drugs?
```
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
what cells are primarily affected by Na+ channel blockers?
fast-response cells
160
what are the two effects of Na+ channel blockers?
decrease conduction rate
| prolong refractory period
161
what is the functional effect of class Ia drugs?
```
slow upstroke of the fast response via blocking of Na+ channels
delay repolarization via blocking of K+ channels, technically a class III effect
```
162
what are the two mechanisms by which class Ia drugs prolong the refractory period?
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
what is an old school drug that was originally used to treat arrhythmias, and why is it no longer the primary therapy?
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
name three class Ib anti arrhythmic drugs
lidocaine, mexiletine, phenytoin
165
what is the mechanism and effect of class Ib Na+ channel blockers?
use-dependent blockage of voltage-gated Na+ channels
| slow upstroke and prolong refractory period
166
how do class Ia and Ib anti arrhythmic drugs differ?
class Ib anti arrhythmic drugs DO NOT PROLONG PHASE 2 but instead shorten phase 2 and prolong the refractory period
167
name three class Ic anti arrhythmic drugs
propafenone, flecainide, encainide
168
what is the mechanism and effect of class Ic anti arrhythmic drugs?
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
which of the class Ic anti arrhythmic drugs is no longer marketed? why?
encainide
| 1989 Cast study showed increased mortality
170
order the three subsets of class I anti arrhythmic drugs by their exhibited degree of Na+ voltage-gated channel blocking
1c - marked
1a - moderate
1b - mild
171
what does it mean for a drug to exhibit use-dependent blockage?
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
charged, hydrophilic drugs may only enter and exit an ion channel when the channel is in its ___________ state.
open/active
173
T/F neutral, hydrophobic drugs, at a much slower rate, can reach the local anesthetic site even when the channel is closed or inactivated.
true
174
what is the major distinction between charged and uncharged drugs with regards to their abilities to enter ion channels?
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
which two classes of drugs are use-dependent blockers of ion channels, and what are their respective ion channel targets?
```
class I - Na+ channel blockers
class IV - Ca2+ channel blockers
```
176
name three common beta adrenergic receptor antagonists
propanolol, metaprolol, esmolol
177
what three currents are reduced by beta-blockers?
I_f
I_Ca-L
I_Ks
178
what are the net effects of beta-blocker reduction of the I_f, I_Ca-L and I_Ks currents?
reduces rate of diastolic depolarization in pacemaker cells
reduces upstroke rate
slows repolarization
179
what is the primary location of the net effects of beta-blocker?
AV node
