Molecular Mechanisms of Arrhythmias & Anti-Arrhythmic Drugs (complete) Flashcards Preview

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Flashcards in Molecular Mechanisms of Arrhythmias & Anti-Arrhythmic Drugs (complete) Deck (24):
1

Describe the gene defects and molecular basis of long QT syndrome

- Prolongation of the QT interval (repolarization occurred too late)
- Can be caused by genetics or drugs
- >200 mutations identified
- K+ mutations => reduce # of K+ channels
- Na+ mutations => prevent channels from inactivating

2

What are the primary causes of almost all arrhythmias?

- MI
- Ischemia
- Acidosis
- Alkalosis
- Electrolyte abnormalities

3

What are the various anti-arrhythmic drugs?

1) Class I (a, b, c)
2) Class II
3) Class III
4) Class IV

4

Describe Class Ia drugs

- Targets voltage-gated cardiac Na+ channels
- Slow the upstroke of fast response (phase 0)
- Prolongs refractory period (phase 4) b/c depolarization (phase 2) is prolonged
- Delays onset of repolarization

5

Describe Class Ib drugs

- Na+ channel blockers
- slow phase 0
- mildly shorten phase 2
- prolong phase 4

6

Describe Class Ic drugs

- Na+ channel blockers
- Pronounced slowing of phase 0
- Mildly prolong phase 2

7

Describe Class II drugs

- Targets β-adrenergic receptors
- aka β-blockers
- Reduces rate of diastolic phase 4 depolarization in pacing cells
- Reduces upstroke rate
- Slows repolarization

8

Describe Class III drugs

- K+ channel blockers
- Drugs that prolong fast response phase 2 by delaying repolarization
- Prolong refractory period
- Just because it is Class III, doesn't mean it can't act on Class I targets

9

Describe Class IV drugs

- Targets voltage-gated cardiac Ca++ channels
- Slow Ca++-dependent upstroke in slow response tissue
- Prolong refractory period (repolarization)

10

Describe the cellular mechanism of triggers afterdepolarizations

- During prolonged phase2 => Ca++ triggers further Ca++ release from sarco reticulum
- Elevates intracellular Ca++ level => increased Na/Ca exchange (NCX1 exchanger)
- W/ 3Na+ in and 1 Ca++ out => adds one (+) charge to inside of myocyte
- This depolarizes myocyte
- Initiates delayed or early afterdepolarizations

11

Describe how a re-entrant (or circus) arrhythmia originates

- Loop of current flowing => can occur in circuits made up of every type of cell in heart
- Small or large, atria or ventricles

Requires 2 conditions:
- uni-directional conduction block in functional circuit
- conduction time around circuit > refractory period

12

Describe the basis of use-dependent block of Na+ channels by class I anti-arrhythmic drugs

- More abnormal AP firing rates or abnormal depolarized membranes => greater degree of Na+ channel blocks!
- Channels must open before they can be blocked
- Blocker enters pore, binds, and blocks the channel
- Mechanism is identical to anesthetic block of neuronal Na+ channels

13

Describe how class I anti-arrhythmic drugs increase Na+ channel refractory period. Do they prolong the phase 2 of the fast response?

- These drugs have a higher affinity for inactivated state of Na+ channel => blockers stabilize inactivated state
- This prolongs time channel spends in inactivated state
- Overall prolongs refractory period

alternative mechanism:
- Class III blocks K+ channels => prolongation of phase 2
- Leads to inactivation of Na+ channels

14

Describe how β-adrenergic receptor blockers help suppress arrhythmias

- Reduce pacing rate
- Prolong refractory period
- Decrease I(f) current, L-type Ca++ current, K+ current
- This decreases diastolic depolarization in pacing cells
- Also decreases upstroke rate
- Slows depolarization in AV nodal myocytes

Terminate arrhythmias involved in AV nodal re-entry and control ventricular rate during atrial fibrillation

15

Describe how class III drugs increase refractory period

- Blocks K+ channel
- Prolongation of refractory period b/c of prolongation of phase 2 => increases inactivation of Na+ channels

16

Describe how class IV anti-arrhythmic drugs (Ca++ channel blockers) reduce re-entry via effects on conduction velocity through the AV node and refractory period of the AV node

- use-dependent blocks of L-type Ca++ channels
- principal effects are on Ca++ channels in nodal cells
- Slowing conduction velocity => terminates re-entry w/ decreased upstroke rate

17

Describe how increasing the refractory period may help suppress re-entrant arrhythmias

- Refractory tissue will not generate an AP
- Re-entrant wave of excitation is extinguished

18

Describe how some anti-arrhythmic drugs can suppress arrhythmias by decreasing cardiac automaticity

- Decreases rate at which a cell fires
- This ensures non-pacemaker cells (those outside of SA & AV nodes) do not generate their own "pacemaking" activity => suppresses arrhythmias

19

Describe how adenosine can help suppress cardiac arrhythmias

- Acute therapy ---- short t1/2 (used in emergencies)
- Increases K+ current & decreases L-type Ca++ current and I(h) in SA and AV nodes
- Not a β-blocker => but works via Gi-coupled receptor
- Induces changes that cause reduction in SA and AV nodes' firing rate & reduce conduction rate in AV node

20

What is the long QT type for I(Na) channels? What are the effects?

LQT3

Incomplete I(Na) inactivation

21

What is the long QT type for I(Ca-L) channels? What are the effects?

LQT8

Incomplete I(Ca) inactivation

Also, autism => Timothy syndrome

22

What is the long QT type for I(Kr) channels? What are the effects?

LQT2, 6

Decreased K+ current

23

What is the long QT type for I(Ks) channels? What are the effects?

LQT1, 5

Decreased K+ current

slows K+ channels --- reduces current amplitude

24

What is the long QT type for I(K1) channels? What are the effects?

LQT7

Decreased K+ current (during diastole)