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Pharmacology Test #4 > Antiarrhythmic Drugs > Flashcards

Antiarrhythmic Drugs Flashcards

1
Q

What does it mean to say that pacemaker cells are physiologically depolarized?

A

they normally sit at a depolarized resting membrane potential compared to myocytes

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2
Q

Pacemaker cells exhibit action potentials that are dependent on what?

A

dependent on Ca2+ for the upstroke phase of the spike

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3
Q

Automaticity

A

the ability to generate action potentials regardless of input from outside of the cell (though outside influences certainly can change this automaticity)

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4
Q

How do ventricular myocytes differ from pacemaker cells?

A
  1. they are contractile cells
  2. they exhibit a more hyperpolarized resting membrane potential
  3. they exhibit much less automaticity
  4. the upstroke phase of the action potential is carried by sodium current passing through voltage gated sodium channels
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5
Q

Ventricular myocyte action potentials are dependent on what?

A

sodium current passing through voltage gated sodium channels

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6
Q

Describe Phase 0 of the SA node action potential

A

the “upstroke” of the action potential; mediated by L-type Ca2+ channels

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7
Q

Describe Phase 1 and 2 of the SA node action potential

A

not present in the SA node action potential

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8
Q

Where are Phase 1 and Phase 2 present?

A

present in Purkinje fiber and myocyte action potentials

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9
Q

Describe Phase 3 of the SA node action potential

A

repolarization; mediated by voltage gated K+ channels

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10
Q

Describe Phase 4 of the SA node action potential

A

diastolic depolarization or “pacemaker current”, where most automaticity mechanisms are found

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11
Q

What are the Phase 4 currents of the SA node action potential generated by?

A

“funny” currents i(f) are mediated by HCN channels

ACh-gated K+ channels mediate i(kAch)

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12
Q

i (f)

A

diastolic pacemaker current (phase 4) in SA node AP

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13
Q

i (K(Ach))

A

K+ current activated by vagus nerve (phase 4) in SA node AP

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14
Q

bAR stimulation results in

A

increased cAMP formation in SA node AP

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15
Q

What does increasing the activity of the HCN channels do?

A

increased depolarizing currents during phase 4 of the action potential and helps return the cell to firing threshold sooner

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16
Q

What does phosphorylation of the L-type voltage gated calcium channels do?

A

increases the amount of current these channels can pass, and also allows them to open at more negative membrane potentials

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17
Q

Which neurotransmitter acts on M1 receptors in the atrium and nodal cells?

A

Ach

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18
Q

What kind of channel is M1R

A

Gi-coupled

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19
Q

What do Gi-coupled channels do?

A

inhibit cAMP formation via Galpha and activates GIRK channels via Gbeta gamma

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20
Q

Why are GIRK channels odd K channels?

A

they conduct inward current better than outward current

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21
Q

GIRK inward K current is conducted at which membrane potentials

A

conducted at membrane potentials more negative than -90 mV

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22
Q

GIRK outward hyperpolarizing current are conducted at which membrane potentials?

A

conducted at membrane potentials more positive than -90 mV (which is most of the time in most cells)

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23
Q

Agonists that couple to GIRK channels

A

adenosine receptors or muscarinic receptors

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24
Q

Agonist activation of receptors that couple to GIRK channels increase what?

A

increases the otherwise small outward current through GIRK channels at potentials more positive than -90 mV

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25
Q

Inhibition of cAMP reduces?

A

HCN current (phase 4 depolarization), and reduces the amplitude of Ca2+ dependent spikes in nodal cells

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26
Q

Activating GIRK channels does what to the membrane potential?

A

hyperpolarized

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27
Q

Acetylcholine effects on atrium and SA/AV nodal cells?

A

decreased HCN and Ca2+ current

hyperpolarization (GIRK)

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28
Q

Describe phase 0 of the myocyte action potential

A

“upstroke” and involves a rapid increase in conductance due to opening of sodium channels

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29
Q

Describe phase 1 of the myocyte action potential

A

brief repolarization, often called the “notch”

current causing this feature is “transient outward”

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30
Q

Describe phase 2 of the myocyte action potential

A

plateau phase, involving many inward Ca2+ currents with some contribution from sodium and potassium as well

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31
Q

Ca2+ entry during phase 2 of the myocyte action potential is critical for?

A

permitting actual myocyte contraction

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32
Q

Describe phase 3 of the myocyte action potential

A

repolarization phase, where potassium current dominate and serve to return the membrane potential back to the resting membrane potential

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33
Q

Describe phase 4 of the myocyte action potential

A

the intervening time between action potentials, and there is slight depolarizing current during this time (though much less in nodal cells)

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34
Q

Which channels are key in mediating the phase 0 upstroke of myocyte cells?

A

voltage gated Na+ channels

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35
Q

What happens when voltage gated Na+ channels are depolarized?

A

they open, allowing rapid inward current that gives rise to phase 0 of the action potential

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36
Q

When do voltage gated Na+ channels inactivate?

A

a few msec after opening

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37
Q

What are the two voltage gated sodium channel gates called?

A

“m” gate and the “h” gate

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38
Q

When is the voltage gated sodium channel closed?

A

in the “closed” state at hyperpolarized resting membrane potentials, such as -80 mV
(“m” gate is closed and the “h” gate is open)

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39
Q

What happens when the voltage gated sodium channels are depolarized?

A

“m” gate opens; sodium rushes into the cell and further depolarizes it

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40
Q

Describe an inactivated voltage gated sodium channel

A

“m” gate is open, “h” gate is closed

“h” gate precludes the channel from conducting any more current; channels cannot open in response to depolarization

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41
Q

Voltage gated sodium channels inactivation occurs during which period?

A

absolute refractory period

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42
Q

Phase 2 (plateau phase) of the myocyte action potential is mediated by opening of?

A

voltage gated Ca2+ channels (L-type Ca2+ channels)

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43
Q

What balances the inward current of the L-type Ca2+ channel during the myocyte action potential?

A

outward current from the voltage-gated K+ channels;

why the membrane potential is at a “plateau” during phase 2

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44
Q

What happens with the channels during phase 3 of the myocyte AP

A

the voltage gated Ca2+ channel currents are declining and the voltage gated K+ current are increasing

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45
Q

Why does repolarization happen during phase 3? (myocyte AP)

A

because the K+ channels are the dominant channel and are relatively unopposed by Ca2+ channels

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46
Q

What would happen to the EKG if you decrease the activity of the L-type voltage gated Ca2+ channels in the AV node

A

increase the R-R interval

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47
Q

What would happen to the EKG if you block a minority of the voltage-gated Na+ channels in the ventricular myocardium?

A

decreased QRS amplitude

48
Q

What would happen to the EKG if you slow the phase 3 of the ventricular myocyte AP?

A

increase the QT interval

49
Q

When does torsades de pointe occur?

A

when ion channels (K+ channels) active during phase 3 of the myocyte action potential are blocked

50
Q

Most common way that antiarrhythmic drugs are classified?

A

Vaugh Williams Singh scale

51
Q

Vaugh Williams Singh scale is based on

A

electrophysiological effect the drug has

52
Q

Briefly describe bAR signaling in pacemaker cells

A

bAR stimulation results in increased cAMP -> increases HCN activity -> increase depolarizing currents during phase 4 of action potential -> helps return cell to firing threshold sooner

53
Q

bAR signaling and cAMP formation also increases?

A

protein kinase A activity -> increases phosphorylation of L-type voltage gated calcium channels -> increases amount of current these channels can pass -> allows them to open at more negative membrane potentials

54
Q

Class 2 Antiarrhythmics summary

A
  • bAR blockers
  • slow pacemaker and Ca2+ currents in SA/AV node
  • increase refractoriness of SA/AV node
  • increase P-R interval
  • Arrhythmias involving catecholamines
55
Q

Class 4 Antiarrhythmics summary

A
  • Ca2+ channel blockers
  • Frequency-dependent block
  • increase refractoriness of AV node and P-R interval
  • Protect ventricular rate from atrial tachycardia
56
Q

bAR blockers used as Antiarrhythmics

A
  1. Esmolol
  2. Acebutolol
  3. Propanolol
  4. Sotalol
57
Q

Cardioselective beta blockers preferentially inhibit?

A

beta1 adrenergic receptors in the heart (NOT beta 2 or alpha receptors)

58
Q

When are beta blockers often used as antiarrhythmics

A

often used when the underlying arrhythmia involves catecholamines, such as when there is an increase in sympathetic tone or when sensitivity to catecholamines has increased

59
Q

Beta blockers have a large effect on which cells? What is the clinical significance of this?

A

large effect on pacemaker cells; they are often used in atrial arrhythmias to protect the ventricular rate

60
Q

Esmolol

A

cardioselective (beta1 AR); very short half life; given IV

61
Q

Acebutolol

A

cardioselective; weak partial agonist at beta1AR (sympathomimetic); weak Na+ channel blockade

62
Q

Propanolol

A

non-selective; weak Na+ channel blockade

63
Q

Clinical uses of betaAR blockers used as antiarrhythmics

A
  1. arrhythmias involving catecholamines
  2. atrial arrhythmias (protect ventricular rate)
  3. post-MI prevention of ventricular arrhytmias
  4. prophylaxis in long QT syndrome (catecholamine sensitive)
64
Q

Ca2+ channel blockers used as antiarrhythmics

A
  1. Verapamil

2. Diltiazem

65
Q

What kind of blockade do verapamil (and to a less extent) diltiazem exhibit

A

frequency-dependent blockade; meaning that these drugs only begin to block the channel as it is being opened

66
Q

Which calcium channels are most susceptible to blockade by verapamil and diltiazem?

A

calcium channels that are opening and closing more often; includes calcium channels in the pacemaker cells

67
Q

Verapamil and diltiazem blockade will accumulate in which tissue?

A

rapidly depolarizing tissue, such as heart tissue exhibiting tachycardia

68
Q

Clinical uses of Ca2+ channel blockers used as antiarrhythmics

A
  1. block re-entrant arrhythmias involving AV node

2. protect ventricular rate in atrial flutter and atrial fibrillation

69
Q

What happens when Ca2+ channel blockers increase the refractoriness of the AV node?

A

atrial arrhythmias cannot transmit as readily to the ventricles

70
Q

Mechanism of action summary for verapamil and diltiazem?

A

frequency-dependent block of Cav1.2 channels; selective block for channels opening more frequently; accumulation of blockade in rapidly depolarizing tissue (i.e. tachycardia)

71
Q

List the Vaughan-Williams-Singh Scale classes

A

Class 1 - Na+ channel blockers
Class 2 - Beta adrenergic antagonists
Class 3 - K+ channel blockers (agents that prolong refractory period)
Class 4 - Ca2+ channel blockers

72
Q

Describe class 1A antiarrhythmics

A

mixed block: Na+ and K+ channels; blocks open state; moderate to slow dissociation (secs); widens QRS and prolongs QT interval

73
Q

Describe class 1B antiarrhythmics

A

pure Na+ channel block; blocks open and inactivated state; rapid dissociation (milisecs); narrows the AP due to block of persistent sodium current

74
Q

Describe class 1C antiarrhythmics

A

strong Na+ channel block; only blocks the open state; very slow dissociation (>10 sec); marked widening of the QRS complex

75
Q

Class 1A antiarrhythmic drugs

A

quinidine; procainamide; disopyramide

76
Q

Class 1B antiarrhythmic drugs

A

lidocaine; tocainide; mexilitine

77
Q

Class 1C antiarrhythmic drugs

A

propafenone; flecainide

78
Q

Quinidine

A

2-8% risk of Torsades de pointes

anti-muscarinic activity

79
Q

Procainamide

A

Lupus-like syndrome

ganglionic blocker

80
Q

Disopyramide

A

anti-muscarinic activity

81
Q

Lidocaine

A

IV only; top choice for rapid control of ventricular arrhythmias; ONLY ventricular, not atrial

82
Q

Mexiletine

A

orally available; similar to lidocaine in efficacy

83
Q

Flecainide

A

ventricular and supraventricular; orally available

84
Q

Propafenone

A

ventricular and supraventricular; bAR blocking activity; orally available

85
Q

Class 3 antiarrhythmics block

A

potassium channels and have a significant effect on i (Kr), the rapid component of the delayed rectifier potassium current that is responsible for repolarization

86
Q

What do class 3 agents do to the AP?

A

prolong the AP, making the cell dwell a little longer at voltages that favor sodium channel inactivation; prolongs the effective refractory period of the cell

87
Q

When are re-entry circuits possible?

A

when the conduction time around the circuit is slower than the effective refractory period of any one cell in the circuit

88
Q

How do class 3 antiarrhythmics terminate a re-entry circuit/the arrhythmias that arose from it?

A

increased effective refractory period greater than conduction time around circuit

89
Q

Two ways that Torsades de pointes can arise?

A
  1. due to administration of class 3 agents

2. severe toxicity reaction that can occur for other drugs that also block the HERG potassium channel

90
Q

What is the HERG potassium channel?

A

the major voltage gated potassium channel that gives rise to the rapid component of the delayed rectifier potassium current i (Kr) that is responsible for the phase 3 repolarization during the cardiac AP

91
Q

Class 3 drugs block which channel

A

HERG channel - can therefore slow repolarization and prolong the AP duration

92
Q

What happens in a cell that dwells too long in the depolarized range and if the inward currents start to be greater than outward potassium currents?

A

an early after depolarization (EAD) can develop

93
Q

EADs are capable of giving rise to?

A

triggered upstrokes and ectopic action potentials, potentially setting up a re-entry arrhythmia

94
Q

What kind of arrhythmia is TdP characterized as?

A

polymorphic ventricular tachycardia

95
Q

Class 3 antiarrhythmics drugs

A
  1. Amiodarone
  2. Dronedarone
  3. Ibutilide
  4. Sotalol
  5. Dofetilide
96
Q

“Shotgun” drug because it has class 3, but also class 1, 2, and 4 activity

A

Amiodarone

97
Q

Amiodarone used to

A

suppress emergency ventricular and atrial arrhythmias; prevention of atrial fibrillation

98
Q

Adverse effects of amiodarone

A

hypothyroidism, pulmonary fibrosis, photosensitization

99
Q

Dronedarone

A

amiodarone analog used for atrial fibrillation prevention; reduced toxicity and shorter half life

100
Q

Ibutilide

A

2% incidence of TdP; rapid conversion of atrial fibrillation/flutter to normal rhythm

101
Q

Sotalol

A

2% incidence of TdP; one isomer has bAR blocking activity; life-threatening ventricular arrhythmias or maintenance of normal sinus rhythm after atrial fibrillation/flutter

102
Q

Dofetilide

A

High (10%) risk of TdP; very restricted and used infrequently; atrial arrhythmias

103
Q

Acquired LQTS

A

drug-induced; electrolyte imbalances; block of HERG channel

104
Q

Which drugs should you not give to patients with congenital LQTS?

A

drugs known to precipitate TdP

105
Q

Drugs that have a risk for TdP

A

antiarrhythmics, antibiotics, antiemetics, antineoplastics, Ca2+ channel blockers, gastric pro-motility, opiates, antihistamines, antipsychotics, antidepressants, diuretics

106
Q

Clinical use of amiodarone

A

top choice for rate control in A-fib, suppression of post-MI ventricular arrhythmias

107
Q

Clinical use of dronedarone

A

A-fib

108
Q

Clinical use of sotalol

A

prevent A-fib reoccurance

109
Q

Clinical use of ibutilide

A

convert A-fib to sinus rhythm

110
Q

Misc. antiarrhythmics drugs/agents

A
  1. digoxin
  2. magnesium chloride
  3. potassium chloride
  4. adenosine
111
Q

Digoxin

A

direct inhibition of AV node

112
Q

Magnesium chloride

A

treat hypomagnesemia; convert TdP; prevent MI and digoxin associated arrhythmias

113
Q

Potassium chloride

A

hypokalemia reduces i (Kr) current, which can prolong action potentials and be pro-arrhythmic

114
Q

Adenosine

A

similar to M2 muscarinic activation; depresses pacemaker cells; suppress atrial tachycardia; short half-life; given IV

115
Q

What does hypokalemia do in regards to arrhythmias?

A

reduce i (Kr), delays repolarization and lengthens APD, thereby causing it to be proarrhythmic

116
Q

First-line for promptly stopping paroxysmal AV nodal reentrant tachycardia

A

adenosine

117
Q

Best choice drug for normalizing sinus bradycardia rate without initiating any other arrhythmias?

A

atropine

Pharmacology Test #4 (9 decks)

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