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CVPR Unit 1 > Molecular Mechanisms of Arrhythmias & Antiarrhythmic Drugs > Flashcards

Molecular Mechanisms of Arrhythmias & Antiarrhythmic Drugs Flashcards

1
Q

What 2 forms of long QT syndrome?

A
  • autosomal dominant: Romano-Ward Syndrome (RWS)

- Autosomal Recessive: Jervell-Lange-Nielson (JLNS)

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2
Q

T of F: RWS is genetically heterogenous

A

True, more than 200 mutations have been identified

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3
Q

What are the most prevalent mutations found in RWS?

A
  • Slow cardiac K+ channel (LQT1)
  • Rapid cardiac K+ channel (LQT2)
  • Cardiac Na+ Channel (LQT3)
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4
Q

T or F: heterozygous carriers of mutations in slow K+ channels in JLNS are asymptomatic

A

True, however, homozygous carriers also suffer from congenital deafness

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5
Q

Mechanism of Class I drugs

A

Blocks Na channels, slow upstroke

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6
Q

Mechanism of Class II drugs

A

β-adrenergic receptor blockers (“β blockers”)

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7
Q

Mechanism of Class III drugs

A

drugs that prolong fast response phase 2 by delaying repolarization

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8
Q

Mechanism of Class IV drugs

A

blockers of voltage-gated cardiac Ca2+ channels

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9
Q

Imp unclassified drug

A

Adenosine

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10
Q

What is Vaughan Williams classification?

A

This scheme describes the effects of drugs, rather than truly classifying drugs themselves.

  • Drugs can―and do―have more than one class of action.
  • Drugs are generally referred to according to their dominant mechanism of action
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11
Q

T or F: almost all arrhythmias are acquired

A

True, myocardial infarction (MI), ischemia, acidosis, alkalosis, electrolyte abnormalities.

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12
Q

What is a common cause of arrhythmias?

A

Drug toxicity:

  • cardiac glycosides
  • some antihistamines (astemizole, terfenadine) and
  • antibiotics (sulfamethoxazole).
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13
Q

What is very often used in place of drugs to treat arrhythmias?

A

catheter ablation of ectopic foci and implantable cardioverter-debrillator devices (ICDs)

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14
Q

Name the primary targets of antiarrhythmic drugs

A
  • cardiac Na+ channels
  • cardiac Ca2+ channels
  • cardiac K+ channels
  • β-adrenergic receptors
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15
Q

What are the indirect targets via the B adrenergic receptors?

A
  • If
  • ICa-L
  • IKs
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16
Q

Result of LQT mutations in Cardia K+ channel subunit

A

Reduces # of K+ channels in membrane, thus reducing the size of current that terminates the plateau phase

  • LQT1&5=Ks
  • LQT2&6=Kr
  • LQT7=IK1 (during diastole)
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17
Q

Result of LQT mutations in Cardia Na+ channel

A

LQT3 Prevents channels from inactivating completely, thereby prolonging phase 2 of fast response

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18
Q

LQT8 mutation

A

incomplete ICa++ inactivation,

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19
Q

What is Burgada syndrome?

A
  • ventricular fibrillation (survival rate of only 40% by 5 years of age)
  • > 30 mutations in the cardiac Na+ channel are linked to Brugada
  • many mutations reduce peak inward Na+ current
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20
Q

What is Finnish familial arrhythmia?

A

Mutation in IKs channels that prevents the binding of yotiao (which anchors PKA), thus mutant K+ is not properly upregulated by β receptor activity.

  • during ↑ sympathetic activity (exercise, emotion): not enough repolarizing K+ current to match the increased depolarizing Ca2+ current.
  • Phase 2 is prolonged, cytosolic Ca2+ levels rise, triggering afterdepolarizations and arrhythmia.
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21
Q

What are the 2 origins of arrhythmia?

A

(1) inappropriate impulse initiation in SA node or elsewhere (ectopic focus), and
(2) disturbed impulse conduction in nodes, conduction (Purkinje) cells or myocytes

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22
Q

Two major sources of inappropriate impulse initiation:

A
  • Ectopic foci

- triggered afterdepolarizations

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23
Q

what is Triggered activity?

A

Triggered activity occurs when abnormal action potentials are triggered by a preceding action potential

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24
Q

When do you find early afterdepolarizations (EADs)?

A

appear during late phase 2 and phase 3, result of increased ICa-L

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25
T or F: EADs are dependent on re-activation of Ca2+ channels in response to ↑[Ca2+]in
True
26
When do you see delayed afterdepolarizations (DADs)?
during early phase 4
27
What causes DADs?
↑[Ca2+]in and, consequently, ↑Na+/Ca2+ exchange (NCX contributes to depolarization)
28
Briefly describe the process of triggered afterdepolarizations
Prolonged phase 2-->excess Ca++ entry-->triggers excess Ca++ release from SR [EADs]-->↑[Ca2+]in drives increased Na/Ca exchange via NCX [DADs]
29
What are the causes of Disturbed impulse conduction?
a. ) conduction block (1°, 2°, 3°) | b. ) re-entry
30
What is re-entry?
means loop current flowing – also called “circus rhythm” can occur in circuits made up of every type of cell in heart
31
Re-entrant arrhythmias require two conditions:
i) uni-directional conduction block in a functional circuit | ii) conduction time around the circuit > refractory period
32
NOTE: In many cases, arrhythmia is triggered by afterdepolarizations, but is maintained by re-entry
Note that shit
33
What are the causes a prolonged fast phase 2?
- Increased inward current: Incomplete Na+ channel inactivation in LQT3 - decreased outward current: Smaller K+ current in LQT1&2
34
T or F: ↑ sympathetic tone (startle) ↑ likelihood of triggered afterdepolarizations
True, because Ca2+ influx is enhanced by β-adrenergic receptor activity.
35
T or F: heart failure decreases the frequency of occurrence of triggered afterdepolarizations
False, it increase the frequency (even without LQT mutations).
36
How does DADs and EADs lead to death?
An EAD or DAD initiates re-entry, resulting in torsades de pointes which can degenerate into ventricular fibrillation and sudden cardiac death.
37
What is the common ground with all the following: atrial flutter and fibrillation, torsades de pointes and ventricular fibrillation.
Re-entry
38
Amiodarone
class III drug that has, important for its utility, class I action too
39
All class I drugs do what?
↓ conduction velocity & ↑refractory period, thereby ↓re-entry
40
T or F: Class Ib drugs show pure class I action
True, slows upstroke, decrease AP duration
41
Class Ia & Class Ic are also capable of doing what?
delay phase 3 onset via K+ channel block
42
Class Ia drugs
quinidine, procainamide, disopyramide
43
Class Ib
lidocaine, mexiletine, phenytoin
44
Class Ic
propafenone, flecainide, encainide
45
What is use dependance?
The block of ion channels is done to a greater degree in myocytes with abnormally high firing rates or abnormally depolarized membrane, include both class I and class IV drugs
46
How can you defeat re-entry?
(1) converting uni- to bi-directional block | (2) or by prolonging refractory time
47
Unidirectional block can be converted to bi-directional block by:
(1) slowing action potential conduction velocity or | (2) by prolonging refractory period
48
T or F: Larger action current pushes adjacent regions to firing threshold sooner
True
49
Drug-induced ↓ in upstroke rate results in what?
↓ conduction velocity
50
T or F: Conduction velocity reports action current density
yes, easier to measure conduction velocity than action current
51
How is a Unidirectional block is converted to bi-directional block?
Drug-induced ↓ in upstroke rate results in ↓ conduction velocity (keep in mind that Slower action potentials may not propagate through a depressed region) so smaller action current fails to excite tissue beyond depressed region. So a partial block of INa cause retrograde conduction to fail, resulting in a bidirectional block.
52
How does prolonged refractoriness suppress re-entrant arrhythmias?
* refractory tissue will not generate an action potential | * and so the re-entrant wave of excitation is extinguished
53
slowing conduction velocity makes it ____ likely that conduction time around the circuit will be shorter than the refractory period.
Less (the fundamental means of combating re-entry are conflicting processes)
54
How is the refractory period prolonged?
use dependent drugs actually have a higher affinity of the inactivated state of the channel, stabilizing them in the inactivated state.
55
Class II antiarrhythmic drugs
propranolol, metoprolol, esmolol (β-blockers)
56
Action of class II drugs
↓ rate of diastolic depolarization in pacing cells | ↓ upstroke rate, and slows repolarization, particularly in AV nodal myocytes
57
End result of Class II drugs
Pacing rate is reduced, and in addition, refractory period is prolonged in SA and AV nodal cells.
58
uses of class II drugs
terminate arrhythmias that involve AV nodal re-entry, and in controlling ventricular rate during atrial fibrillation.
59
Class III drugs
ibutilide, dofetilide, amiodarone, sotalol, bretylium
60
Action of Class III drugs
- Block K+ channels ibutilide and dofetilide specifically block IKr channels - K+ channel block prolongs fast response phase 2 - and prominently prolongs refractory period (leads to ↑ inactivation of Na+ channels)
61
T or F: Amiodarone, but not other class III drugs, reduces conduction velocity
True
62
What class III drug also acts as a β-blocker
Sotalol
63
Why does Amiodarone ↑ refractory period
by blocking Na+ channels.
64
How does Amiodarone reduce firing rate>
↓ rate of diastolic depolarization in automatic cells
65
Class IV drugs
verapamil, diltiazem
66
Mechanism of class IV drugs action
- use-dependent blockers of L-type Ca2+ channels | - principal effects are on Ca2+ channels in nodal cells also fast response myocytes to lesser extent
67
What is the effect of blocking Ca++ channels?
↓ upstroke rate in slow response tissue this in turn ↓ conduction velocity, particularly in the AV node
68
How does Class IV drugs supress re-entry arrhythmia?
class IV Ca2+ channel blockers prolong refractory period and thereby suppress re-entrant arrhythmias
69
How do class IV drugs prolong reploarization?
results indirectly from L channel block: the reduced amplitude of the action potential activates fewer K+ channels.
70
Actions of adenosine
↑ K+ current ↓ L-type Ca2+ current (dihydropyridine-sensitive, slow inward current) ↓ If (funny current) in SA and AV nodes
71
End result of adenosine
↓ SA node and AV node firing rate | ↓ conduction rate in the AV node
72
adenosine works by inhibiting ___________ and thus cAMP production
adenylyl cyclase
73
Antiarrhythmic drugs are primary therapy for ___________
atrial fibrillation
74
How do you treat Paroxysmal supraventricular tachycardia (PSVT)?
``` Acute: adenosine (short half-life is advantageous) Chronic: AV nodal blockers -Class II (β-blockers) -Class IV (Ca2+ channel blockers) -Class III (amiodarone, sotalol) -catheter ablation of ectopic focus ```
75
How do you treat Atrial fibrillation?
Acute: AV nodal blockers, electrical cardioversion Chronic: -AV nodal blockers + long-term anticoagulation (warfarin) -Cardioversion (electrical/ibutilide) + drug maintenance of rhythm -Class III (amiodarone)
76
How do you treat Ventricular tachycardias/fibrillation?
Acute: amiodarone, lidocaine
77
Pathology of Ventricular tachycardias/fibrillation
afterdepolarizations + re-entry
78
Pathology of Atrial fibrillation
re-entry
79
Pathology of Paroxysmal supraventricular tachycardia (PSVT)
re-entry
80
pharmacokinetic properties of Lidocaine
Class Ib | t0.5 = 1-2 hrs
81
pharmacokinetic properties of Esmolol
t0.5 = 10 min (metabolize by blood esterase) Class II
82
pharmacokinetic properties of Amiodarone
t0.5 = 13-100 days side-effects: heart block, thyroid dysfunction, corneal deposits, pulmonary fibrosis Class III
83
pharmacokinetic properties of Verapamil
t0.5 = 7 hrs | Class IV
84
pharmacokinetic properties of Adenosine
t0.5 = 10 sec | IV bolus

CVPR Unit 1 (27 decks)

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