Anti-Arrhythmic Drugs

Question 1

What is the concept of use-dependence in Class I antiarrythmic drugs.

Recall: Class I is Na+ Channel blocker

Answer 1

Use-dependence: Target the sodium channels that are more active - i.e. membranes more actively firing or depolarizing

• Explained: This allows selective targeting (to a degree) of Na+ channels in the myocytes with abnormally high firing rates or abnormally depolarized membranes (which are the myocytes inducing the arrythmia)

Question 2

What is the basis of use-dependent block of Na+ channels by class I antiarrythmics?

Answer 2

• Channels must open before they can be blocked.
  
  • The channel must be open for the blocker to enter the pore, bind and thereby block the Na+ channel

Question 3

How do Class I antiarrhythmetics increase the Na+ channel refractory period?

(regardless if they prolong phase 2 of the fast response)

Answer 3

Class I have a _higher affinity for inactivated state of Na+ channe_l.

• Use-dependent blockers stabilize the inactivated state
  
  • i.e they prolong the refractory period

Alternative mechanism:

• Prolonging phase 2: Myocyte membrane is depolarized for longer period of time -> more Na+ channels become inactivated -> refractory period longer

Question 4

How do beta-adrenergic recepetor blockers help supress arrythmias?

Answer 4

Reduction of Ih, ICaL and IK reduces the rate of diastolic depolarization in pacing cells, reduces the upstroke rate and slow repolarization.

• Refractory period is prolonged (reentry) in the SA and AV nodal cells

Question 5

During what kind of arrhythmia’s would one Rx a beta blocker?

Answer 5

Beta-blockers are used to terminate arrhythmias that involve AV nodal re-entry, and in controlling ventricular rate during atrial fibrillation.

Question 6

How do Class III drugs increase the refractory period?

Answer 6

Blocking cardiac K+ channels

• Consequences
  
  • Prolongation of fast response phase 2
  • Prominent prolongation of refractory period ( ̄ reentry)
    
    • Prolonged duration of phase 2 leads to an increased inactivation of Na+ channels.

Question 7

What are the two ways in which antiarrhythmetics supress reentry?

*Hint*: Think about the two different requirements for a re-entry arrhythmia to occur.

Answer 7

1. Terminating re-entry by slowing conduction velocity and upstroke rate -> slower conduction velocity
   
   • Slower conducting action potentials are more likely to fail to propagate through a depressed region.
2. Terminating re-entry by prolonging refractory period
   • If tissue is still in refractory it cannot generate a new AP

Question 8

How does reducing cardiac automaticity supress some arrhythmias?

Answer 8

Some arrhythmias arise from rogue myocytes that generate AP w/out direction from the AV/SA nodes.

• Decreasing automaticity, ensures that cells do not generate their own “pacemaking” activity thereby suppressing these arrhythmias
• Class II (beta blockers) and Class III (K+ channel blockers) drugs are particularly good at this.

Question 9

What class antiarrhthmetic is adenosine described as?

Answer 9

TRICK QUESTION! It’s unclassfied.

Question 10

How does adenosine help supress arrhythmias?

Answer 10

• Increases* a K+ current, while also decreasing both L-type Ca2+ current and Ih in SA and AV nodes.
• Adenosine induced changes cause a reduction in SA node and AV node firing rate as well as a reduced conduction rate in the AV node