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

Question 1

Describe the gene defects and molecular basis of long QT syndrome

Answer 1

• 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

Question 2

What are the primary causes of almost all arrhythmias?

Answer 2

• MI
• Ischemia
• Acidosis
• Alkalosis
• Electrolyte abnormalities

Question 3

What are the various anti-arrhythmic drugs?

Answer 3

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

Question 4

Describe Class Ia drugs

Answer 4

• 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

Question 5

Describe Class Ib drugs

Answer 5

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

Question 6

Describe Class Ic drugs

Answer 6

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

Question 7

Describe Class II drugs

Answer 7

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

Question 8

Describe Class III drugs

Answer 8

• 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

Question 9

Describe Class IV drugs

Answer 9

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

Question 10

Describe the cellular mechanism of triggers afterdepolarizations

Answer 10

• 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

Question 11

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

Answer 11

• 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

Question 12

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

Answer 12

• 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

Question 13

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

Answer 13

• 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

Question 14

Describe how β-adrenergic receptor blockers help suppress arrhythmias

Answer 14

• 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

Question 15

Describe how class III drugs increase refractory period

Answer 15

• Blocks K+ channel

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

Question 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

Answer 16

• 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

Question 17

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

Answer 17

• Refractory tissue will not generate an AP

- Re-entrant wave of excitation is extinguished

Question 18

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

Answer 18

• 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

Question 19

Describe how adenosine can help suppress cardiac arrhythmias

Answer 19

• 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

Question 20

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

Answer 20

LQT3

Incomplete I(Na) inactivation

Question 21

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

Answer 21

LQT8

Incomplete I(Ca) inactivation

Also, autism => Timothy syndrome

Question 22

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

Answer 22

LQT2, 6

Decreased K+ current

Question 23

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

Answer 23

LQT1, 5

Decreased K+ current

slows K+ channels — reduces current amplitude

Question 24

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

Answer 24

LQT7

Decreased K+ current (during diastole)