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Cardiovascular Unit > Antiarrhythmic Drugs > Flashcards

Antiarrhythmic Drugs Flashcards

1
Q

Relationship between ion currents, cardiac action potentials, surface EKG: in cardiac myocytes

A

Cardiac myocytes actively maintain a resting membrane potential (Em) with interior of cell negative relative to exterior. Em is generated by unequal distribution of ions between intra and extra-cellular compartments, an energy-dependent process relying on selective ion channels, pumps and exchangers. The ion gradients across the cell membrane lead to electrical and chemical forces driving charged ions in or out of cells.

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2
Q

Relationship between ion currents, cardiac action potentials, surface EKG: in pacemaker cells (SA and AV nodes)

A

In pacemaker cells (SA and AV nodes), resting Em is less negative, thus Na+ channels are inactivated, and relatively slow phase 0 depolarization results from Ca2+ entering the cells through voltage-gated Ca2+ channels.

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3
Q

Relationship between ion currents, cardiac action potentials, surface EKG: in ventricular myocytes

A

In ventricular myocytes with more negative resting Em, Na+ channels are in resting state, available for activation by depolarization, with Na+ entry driving rapid phase 0 depolarization.

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4
Q

EKG points and phases of cardiac action potentials

A
  • P wave: atrial depolarization
  • QRS complex: ventricular depolarization
  • T wave: ventricular repolarization
  • PR: AV node conduction
  • QT: ventricular depolarization and depolarization
  • Phase 0: Na+ influx fast Na+ channel, or Ca2+ influx pacemaker cells,
    triggered by depolarization.
  • Phase 1: Transient repolarization K+ efflux
  • Phase 2: Ca2+ influx and K+ efflux, plateau due to small net current
    flow.
  • Phase 3: Repolarization mediated by K+ efflux, decline Ca2+ influx.
    Dominant repolarizing current is IKr, rapidly activating repolarizing current, carried by hERG-KCNE2 gene product. hERG is inhibited by large number of drugs causing action potential duration prolongation. IKs or the slowly activating repolarizing current also contributes to phase 3 repolarization, is carried by KCNO1-KCNE1 gene product, importance of this current increases under conditions of inhibition of IKr and at faster heart rates.
  • Phase 4: Restoration ionic balance Na+/K+ ATPase, Na+/Ca2+ exchanger and Ca2+ ATPase, return of nonpacemaker cells to resting potential; slow phase 4 depolarization in pacemaker cells as membrane potential slowly climbs to threshold for activation.
  • Funny Current If depolarizing current SA node, influx Na+, K+
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5
Q

Mechanisms of Arrhythmias

A
  • Increased automaticity
  • Afterdepolarizations
  • Reentry
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6
Q

Increased automaticity

A

Sinus node is normal site of automaticity in the heart, but other cardiac tissues can depolarize spontaneously. Automaticity is increased when there is a decrease in time from depolarization from maximal diastolic potential to threshold potential, such as occurs with increased slope phase 4, shift threshold potential to more negative value, or more positive maximum diastolic potential. Increased automaticity is observed with electrolyte abnormalities, hypoxia, and sympathetic stimulation.

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7
Q

Afterdepolarizations

A

Spontaneous action potentials during or immediately after phase 3 repolarization. Produced by abnormal Ca2+ influx during or after phase 3 of ventricular action potential, leading to premature ventricular contractions and ventricular tachycardia. Observed with digoxin toxicity and conditions that prolong QT interval.

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8
Q

how can quinidine therapy effect action potentials and EKGs?

A

Quinidine therapy resulting in action potential prolongation, increased QT duration, early afterdepolarizations and Torsade de Pointes (specific subtype polymorphic VT, “twisting around the point”).

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9
Q

Reentry

A

Reexcitation of a localized region of cardiac tissue by the same impulse, “circus movement”. Occurs in presence of bifurcating conduction pathways, requires 1) unidirectional block and 2) slow conduction through retrograde pathway, exceeding refractory period reentered tissue. Depending on differential speeds of conduction and refractory periods in two longitudinal pathways, antegrade propagation can be blocked in one pathway with subsequent retrograde propagation in that pathway after recovery from refractoriness, producing reentry.

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10
Q

Reentry in ventricular tissue

A

Reentry in ventricular tissue: with ischemia and hypoxia, Em is reduced, inactivation fast Na+ channels, slowing conduction velocity until conduction stops, may result in unidirectional block. In the presence of a bifurcating pathway, if impulse can conduct through second limb of pathway, may conduct antegrade direction, rhen renter the ventricular tissue through the second limb, provided the tissue is no longer refractory.

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11
Q

Reentry in atrioventricular node

A

most common mechanism causing supraventricular tachycardia. AV node may have two pathways, fast pathway with long refractory period and rapid conduction velocity, and slow pathway with short refractory period and slow conduction velocity. Premature atrial contraction may penetrate slow pathway antegrade direction but block antegrade in still-refractory fast pathway, upon reaching turn-around point, if fast pathway has recovered from refractory period, impulse penetrates fast pathway in retrograde direction.

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12
Q

characteristics of fast response cells: location

A

atria, ventricle, His-Purkinje

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13
Q

characteristics of fast response cells: rate of depolarization

A

fast

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14
Q

characteristics of fast response cells: conduction velocity

A

rapid

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15
Q

characteristics of fast response cells: major ionic species involved in depolarization

A

Na+

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16
Q

characteristics of fast response cells: inhibitors of depolarization

A

Class I anti-arrhythmic agents (quinidine)

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17
Q

characteristics of fast response cells: recovery of excitability

A

prompt, ends with repolarization

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18
Q

characteristics of fast response cells: catecholamines (SNS)

A

little effect on depolarization

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19
Q

characteristics of fast response cells: acetylcholine (PS)

A

no effect on depolarization

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20
Q

characteristics of slow response cells: location

A

SA and AV nodes

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21
Q

characteristics of slow response cells: rate of depolarization

A

slow

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22
Q

characteristics of slow response cells: conduction velocity

A

slow

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23
Q

characteristics of slow response cells: major ionic species involved in depolarization

A

Ca2+

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24
Q

characteristics of slow response cells: inhibitors of depolarization

A

calcium-entry blockers (verapamil, diltiazem)

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25
Q

characteristics of slow response cells: recovery of excitability

A

delayed; outlasts repolarization

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26
Q

characteristics of slow response cells: catecholamines (SNS)

A

enhance depolarization

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27
Q

characteristics of slow response cells: acetylcholine (PS)

A

significantly depresses depolarization

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28
Q

what are the three possible mechanisms of arrhythmias

A
  • Increased automaticity (inappropriately excitable cells)
  • Triggered automaticity (normal action potential is interrupted or followed by an abnormal depolarization; afterdepolarizations)
  • Reentry (abnormal impulse conduction)
29
Q

Class I anti-arrhythmic drugs and their actions

A

sodium channel blockers

  • Act on fast response cells
  • Reduce membrane responsiveness
  • Increase threshold for AP firing
  • Reduce Vmax (depress conduction velocity)
  • Prolong effective refractory period (ERP)
30
Q

Class Ia anti-arrhythmic drugs and their actions

A

Moderate phase 0 depression and slowed conduction (2+); prolong repolarization

Quinidine, Procainamide, Disopyramide

31
Q

Class Ib anti-arrhythmic drugs and their actions

A

Minimal phase 0 depression and slow conduction (0-1+); shorten repolarization

Lidocaine

32
Q

Class Ic anti-arrhythmic drugs and their actions

A

Marked phase 0 depression and slow conduction (4+); little effect on repolarization

Flecainide

33
Q

Class II anti-arrhythmic drugs and their actions

A

Beta-Adrenergic Blockers

Propranolol, esmolol

34
Q

Class III anti-arrhythmic drugs and their actions

A

K+ Channel Blockers (prolong repolarization)

Amiodarone, Sotalol, Dofetilide

35
Q

Class IV anti-arrhythmic drugs and their actions

A

Calcium Channel Blockers

Verapamil, Diltiazem

36
Q

Class 1A Drugs (Quinidine) - direct and indirect EP Effects

A

direct effects:

  • Increase AP threshold
  • decrease Vmax
  • increase ERP

indirect effects:

  • Blocks K+ channels–> early afterdepolarizations (EADs)
  • Vagolytic Effect
37
Q

Class 1A Drugs (Quinidine)- Use

A
  • Atrial flutter or fibrillation

- Prevent ventricular tachycardia and fibrillation

38
Q

Class 1A Drugs (Quinidine)- major side effects

A

-Severe GI effects - Diarrhea, cramps
-Heart – vagolytic
-Inhibits P450 system (metabolism of narcotics is reduced)
-Proarrhythmic – not necessarily related to the arrhythmia
being treated.
-Reduces the renal clearance of digitalis; increases plasma
levels of digitalis
–>Metabolized in liver; tolerated in patients with renal failure

39
Q

Class 1B Drugs (Lidocaine)- direct effects

A

-Increase AP threshold
-Block of Na+ channels (decrease Vmax)
at high HR (>120 bpm; use-dependent) and in depolarized cells (can target diseased (ischemic) cells)
-decrease AP duration and ERP

40
Q

Class 1B Drugs (Lidocaine)- side effects

A

dizziness, seizures

41
Q

Class 1B Drugs (Lidocaine)- uses

A
  • Ventricular tachycardia
  • Digitalis – induced arrhythmias
  • Safe for patients with Long QT Syndrome
42
Q

Class 1C Drugs (Flecainide)- direct effects

A
  • Increase AP threshold
  • decrease Vmax (conduction velocity)
  • Variable effects on ERP -Dissociates from Na+ channel slowly
43
Q

Class 1C Drugs (Flecainide)- side effects

A

Pro-arrhythmic (CAST Trial)

44
Q

Class 1C Drugs (Flecainide)- use

A

-Approved for used in life-threatening situations when supraventricular and ventricular
arrhythmias are resistant to other drugs

45
Q

Class II: B-Adrenoceptor antagonists (B-blockers)-drugs and effects

A

Propranolol – Long acting blocker (oral)
Esmolol – Short acting blocker (IV)

-Bind to ß-adrenergic receptors on cardiac cell membranes to
competitively inhibit epinephrine and norepinephrine binding.
-Antagonize effects of sympathetic stimulation.
-In the presence of catecholamines, the main action of Class II agents is to slow the rate of diastolic (phase 4) depolarization.

46
Q

Uses of B-Blockers

A

-Used for all atrial arrhythmias, ventricular tachycardia and fibrillation -
high levels of catecholamines present
-The beta blockers are currently the most useful antiarrhythmic drugs available due to their safety record and wide clinical applications.

47
Q

what are B-blocker effects on repolarization in ventricular tissues?

A

B-blockers do not prolong repolarization in ventricular tissues. They are safe for use in patients with Long QT Syndrome.

48
Q

major side effects of B-blockers

A
  • negative inotropic effect
  • heart block
  • bradycardia
  • bronchospasm.
49
Q

Class III: K+ Channel Blockers drugs and effects

A

amiodarone, sotalol

  • Main common property is K+ channel block; prolongs action potential repolarization (action potential duration increases); reverse use-dependence.
  • Among the many K+ channels, most common target is IKr (hERG channel).
  • Main common effect is increased ERP.
50
Q

actions of amiodarone

A
  • Potent K+ channel blocker (blocks both IKr and IKs)
  • Modest Na+ channel blocker
  • Modest Ca++ channel blocker
  • Modest B- adrenoreceptor blocker
51
Q

uses of amiodarone

A
  • Effective against ventricular tachyarrhythmias and fibrillation.
  • Also used in the prevention of recurrent paroxysmal atrial fibrillation or flutter
52
Q

amiodarone effects

A
  • Potent K+ channel blocker
  • increase AP duration
  • increase ERP
53
Q

Amiodarone – Major Side Effects

A
  • Triggered arrhythmias (EADs); but rarely associated with Torsades de Pointes
  • Altered thyroid function (inhibits conversion of T4 to T3) - hypothyroidism
  • Pulmonary fibrosis – often irreversible
54
Q

Sotalol-actions

A

-Major action is block of K+ channel (IKr).
-Also has B-adrenergic receptor blocking actions
(secondary effect).
-Most serious side effect: triggered arrhythmias, with Torsades de Pointes.

55
Q

uses of sotalol

A
  • Effective against ventricular tachyarrhythmias and fibrillation.
  • Also used against supraventricular tachycardias, atrial fibrillation
56
Q

Class IV: Ca2+ Channel Blockers drugs and effects

A

diltiazem (benzothiazepines), verapamil (phenylalkylamines)

-Acts primarily on slow response cells (SA & AV node), which are dependent on Ca++ influx for action potential depolarization.

57
Q

uses of 1,4-dihydropyridines in anti-arrhythmic treatment

A
  • amlodipine and nifedipine
  • 1,4-Dihydropyridines are generally not used as antiarrhythmic agents since they primarily target the vascular rather than cardiac cells.
  • 1,4-Dihydropyridines are sometimes prescribed for the treatment of chest pain (angina pectoris) to relieve arterial spasms.
58
Q

Major EP Effects of Ca2+ Channel Blockers

A
  • Increase threshold for AP firing in nodal cells
  • Increase nodal cell refractory period
  • Depress conduction velocity in the SA and AV nodes
59
Q

uses of Ca2+ channel blockers

A

-Atrial Tachycardias
-Paroxysmal supraventricular tachycardia
Note: Rarely used for
treatment of ventricular tachycardia

60
Q

Major Side Effects of Ca2+ Channel Blockers

A
  • Negative chronotropic effect – decreases automaticity of SA node (bradycardia)
  • Negative inotropic effect – decreases Ca++ influx during plateau phase of ventricular action potential
  • Hypotension – decreases Ca++ influx into vascular smooth muscle cells
61
Q

Major Side Effects of Ca2+ Channel Blockers–peripheral edema

A

Nifedipine-type mostly

62
Q

Major Side Effects of Ca2+ Channel Blockers–constipation

A 
decreases Ca2+ influx into GI smooth
muscle cells (Verapamil especially)
63
Q

Major Side Effects of Ca2+ Channel Blockers–Interacts with digitalis to slow conduction velocity in
the AV node –> heart block

A

Verapamil and Diltiazem

64
Q

Major Side Effects of Ca2+ Channel Blockers–Increase plasma digitalis levels by competing for renal excretion

A

Verapamil and Diltiazem

65
Q

Adenosine effects

A
  • Very rapidly activates K+ channels to slow phase 4 depolarization at AV node (T1/2=10 seconds)
  • Blocks cAMP-enhanced Ca2+ channel activity at the AV node
66
Q

Adenosine uses

A
  • Indicated for supraventricular tachycardia-slows AV conduction and heart rate
67
Q

Digitalis Glycosides

(Digoxin) effects

A

Enhances vagal parasympathetic activity to slow conduction at the AV node

68
Q

Digoxin uses

A

-Indicated for atrial fibrillation and supraventricular tachycardia to control ventricular response rate

Cardiovascular Unit (16 decks)

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