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):

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


What are the primary causes of almost all arrhythmias?

- MI
- Ischemia
- Acidosis
- Alkalosis
- Electrolyte abnormalities


What are the various anti-arrhythmic drugs?

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


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


Describe Class Ib drugs

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


Describe Class Ic drugs

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


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


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


Describe Class IV drugs

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


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


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


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


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


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


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


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


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


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


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


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


Incomplete I(Na) inactivation


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


Incomplete I(Ca) inactivation

Also, autism => Timothy syndrome


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

LQT2, 6

Decreased K+ current


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


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


Decreased K+ current (during diastole)