Molecular Mechanisms of Arrhythmias & Antiarrhythmic Drugs Flashcards Preview

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Flashcards in Molecular Mechanisms of Arrhythmias & Antiarrhythmic Drugs Deck (84):
1

What 2 forms of long QT syndrome?

-autosomal dominant: Romano-Ward Syndrome (RWS)
-Autosomal Recessive: Jervell-Lange-Nielson (JLNS)

2

T of F: RWS is genetically heterogenous

True, more than 200 mutations have been identified

3

What are the most prevalent mutations found in RWS?

-Slow cardiac K+ channel (LQT1)
-Rapid cardiac K+ channel (LQT2)
-Cardiac Na+ Channel (LQT3)

4

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

True, however, homozygous carriers also suffer from congenital deafness

5

Mechanism of Class I drugs

Blocks Na channels, slow upstroke

6

Mechanism of Class II drugs

β-adrenergic receptor blockers (“β blockers”)

7

Mechanism of Class III drugs

drugs that prolong fast response phase 2 by delaying repolarization

8

Mechanism of Class IV drugs

blockers of voltage-gated cardiac Ca2+ channels

9

Imp unclassified drug

Adenosine

10

What is Vaughan Williams classification?

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

11

T or F: almost all arrhythmias are acquired

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

12

What is a common cause of arrhythmias?

Drug toxicity:
-cardiac glycosides
-some antihistamines (astemizole, terfenadine) and
-antibiotics (sulfamethoxazole).

13

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

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

14

Name the primary targets of antiarrhythmic drugs

-cardiac Na+ channels
-cardiac Ca2+ channels
-cardiac K+ channels
-β-adrenergic receptors

15

What are the indirect targets via the B adrenergic receptors?

-If
-ICa-L
-IKs

16

Result of LQT mutations in Cardia K+ channel subunit

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)

17

Result of LQT mutations in Cardia Na+ channel

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

18

LQT8 mutation

incomplete ICa++ inactivation,

19

What is Burgada syndrome?

• 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

20

What is Finnish familial arrhythmia?

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.

21

What are the 2 origins of arrhythmia?

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

22

Two major sources of inappropriate impulse initiation:

-Ectopic foci
-triggered afterdepolarizations

23

what is Triggered activity?

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

24

When do you find early afterdepolarizations (EADs)?

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

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