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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
Q

T or F: EADs are dependent on re-activation of Ca2+ channels in response to ↑[Ca2+]in

A

True

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26
Q

When do you see delayed afterdepolarizations (DADs)?

A

during early phase 4

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27
Q

What causes DADs?

A

↑[Ca2+]in and, consequently, ↑Na+/Ca2+ exchange (NCX contributes to depolarization)

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28
Q

Briefly describe the process of triggered afterdepolarizations

A

Prolonged phase 2–>excess Ca++ entry–>triggers excess Ca++ release from SR [EADs]–>↑[Ca2+]in drives increased Na/Ca exchange via NCX [DADs]

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29
Q

What are the causes of Disturbed impulse conduction?

A

a. ) conduction block (1°, 2°, 3°)

b. ) re-entry

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30
Q

What is re-entry?

A

means loop current flowing – also called “circus rhythm” can occur in circuits made up of every type of cell in heart

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31
Q

Re-entrant arrhythmias require two conditions:

A

i) uni-directional conduction block in a functional circuit

ii) conduction time around the circuit > refractory period

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32
Q

NOTE: In many cases, arrhythmia is triggered by afterdepolarizations, but is maintained by re-entry

A

Note that shit

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33
Q

What are the causes a prolonged fast phase 2?

A
  • Increased inward current: Incomplete Na+ channel inactivation in LQT3
  • decreased outward current: Smaller K+ current in LQT1&2
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34
Q

T or F: ↑ sympathetic tone (startle) ↑ likelihood of triggered afterdepolarizations

A

True, because Ca2+ influx is enhanced by β-adrenergic receptor activity.

35
Q

T or F: heart failure decreases the frequency of occurrence of triggered afterdepolarizations

A

False, it increase the frequency (even without LQT mutations).

36
Q

How does DADs and EADs lead to death?

A

An EAD or DAD initiates re-entry, resulting in torsades de pointes which can degenerate into ventricular fibrillation and sudden cardiac death.

37
Q

What is the common ground with all the following: atrial flutter and fibrillation, torsades de pointes and ventricular fibrillation.

A

Re-entry

38
Q

Amiodarone

A

class III drug that has, important for its utility, class I action too

39
Q

All class I drugs do what?

A

↓ conduction velocity & ↑refractory period, thereby ↓re-entry

40
Q

T or F: Class Ib drugs show pure class I action

A

True, slows upstroke, decrease AP duration

41
Q

Class Ia & Class Ic are also capable of doing what?

A

delay phase 3 onset via K+ channel block

42
Q

Class Ia drugs

A

quinidine, procainamide, disopyramide

43
Q

Class Ib

A

lidocaine, mexiletine, phenytoin

44
Q

Class Ic

A

propafenone, flecainide, encainide

45
Q

What is use dependance?

A

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
Q

How can you defeat re-entry?

A

(1) converting uni- to bi-directional block

(2) or by prolonging refractory time

47
Q

Unidirectional block can be converted to bi-directional block by:

A

(1) slowing action potential conduction velocity or

(2) by prolonging refractory period

48
Q

T or F: Larger action current pushes adjacent regions to firing threshold sooner

A

True

49
Q

Drug-induced ↓ in upstroke rate results in what?

A

↓ conduction velocity

50
Q

T or F: Conduction velocity reports action current density

A

yes, easier to measure conduction velocity than action current

51
Q

How is a Unidirectional block is converted to bi-directional block?

A

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
Q

How does prolonged refractoriness suppress re-entrant arrhythmias?

A
  • refractory tissue will not generate an action potential

* and so the re-entrant wave of excitation is extinguished

53
Q

slowing conduction velocity makes it ____ likely that conduction time around the circuit will be shorter than the refractory period.

A

Less (the fundamental means of combating re-entry are conflicting processes)

54
Q

How is the refractory period prolonged?

A

use dependent drugs actually have a higher affinity of the inactivated state of the channel, stabilizing them in the inactivated state.

55
Q

Class II antiarrhythmic drugs

A

propranolol, metoprolol, esmolol (β-blockers)

56
Q

Action of class II drugs

A

↓ rate of diastolic depolarization in pacing cells

↓ upstroke rate, and slows repolarization, particularly in AV nodal myocytes

57
Q

End result of Class II drugs

A

Pacing rate is reduced, and in addition, refractory period is prolonged in SA and AV nodal cells.

58
Q

uses of class II drugs

A

terminate arrhythmias that involve AV nodal re-entry, and in controlling ventricular rate during atrial fibrillation.

59
Q

Class III drugs

A

ibutilide, dofetilide, amiodarone, sotalol, bretylium

60
Q

Action of Class III drugs

A
  • 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
Q

T or F: Amiodarone, but not other class III drugs, reduces conduction velocity

A

True

62
Q

What class III drug also acts as a β-blocker

A

Sotalol

63
Q

Why does Amiodarone ↑ refractory period

A

by blocking Na+ channels.

64
Q

How does Amiodarone reduce firing rate>

A

↓ rate of diastolic depolarization in automatic cells

65
Q

Class IV drugs

A

verapamil, diltiazem

66
Q

Mechanism of class IV drugs action

A
  • 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
Q

What is the effect of blocking Ca++ channels?

A

↓ upstroke rate in slow response tissue this in turn ↓ conduction velocity, particularly in the AV node

68
Q

How does Class IV drugs supress re-entry arrhythmia?

A

class IV Ca2+ channel blockers prolong refractory period and thereby suppress re-entrant arrhythmias

69
Q

How do class IV drugs prolong reploarization?

A

results indirectly from L channel block: the reduced amplitude of the action potential activates fewer K+ channels.

70
Q

Actions of adenosine

A

↑ K+ current
↓ L-type Ca2+ current (dihydropyridine-sensitive, slow inward current)
↓ If (funny current) in SA and AV nodes

71
Q

End result of adenosine

A

↓ SA node and AV node firing rate

↓ conduction rate in the AV node

72
Q

adenosine works by inhibiting ___________ and thus cAMP production

A

adenylyl cyclase

73
Q

Antiarrhythmic drugs are primary therapy for ___________

A

atrial fibrillation

74
Q

How do you treat Paroxysmal supraventricular tachycardia (PSVT)?

A 
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
Q

How do you treat Atrial fibrillation?

A

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
Q

How do you treat Ventricular tachycardias/fibrillation?

A

Acute: amiodarone, lidocaine

77
Q

Pathology of Ventricular tachycardias/fibrillation

A

afterdepolarizations + re-entry

78
Q

Pathology of Atrial fibrillation

A

re-entry

79
Q

Pathology of Paroxysmal supraventricular tachycardia (PSVT)

A

re-entry

80
Q

pharmacokinetic properties of Lidocaine

A

Class Ib

t0.5 = 1-2 hrs

81
Q

pharmacokinetic properties of Esmolol

A

t0.5 = 10 min
(metabolize by blood esterase)
Class II

82
Q

pharmacokinetic properties of Amiodarone

A

t0.5 = 13-100 days
side-effects: heart block, thyroid dysfunction, corneal deposits, pulmonary fibrosis
Class III

83
Q

pharmacokinetic properties of Verapamil

A

t0.5 = 7 hrs

Class IV

84
Q

pharmacokinetic properties of Adenosine

A

t0.5 = 10 sec

IV bolus

CVPR Unit 1 (27 decks)

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