Lec 35 Anti Arrhythmic Pharm Flashcards
What is main determinant of conduction velocity [in ventricles]?
Ina
speed of upstroke = proportional to speed of conduction
slower upstroke –> also have longer delay between APs
What is physiology of the Na channel opening/closing?
- channels open in response to increase in membrane voltage [depolarization]
- channels automatically close [inactivate] even when voltage is maintained
What are the 3 states of Na channel?
- closed but available
- open
- inactivated and unavailable
AT -80 mV what is probability of each of the 3 Na channel states?
- 0% open
- 85% closed
- 15%
What is sequence of Na channel events during action potential?
- diastole: 85% of channels closed but available
- upstroke/plateau: transition to open then inacivated
- diastole: return to 85% closed but available [depending on how much time in diastole]
What is effect of time in diastole on Na channels?
determines whether there is time to redistribute back to mostly closed but available from mostly inactivated
What is most drug’s preference for the 3 channel states?
- most preferentially bind at open and inactivated and have weaker binding at closed
What do atrial flutter/fib tell you?
only some atrial excitations are propagating into the ventricles
What are the 3 primary mechanisms of arrhythmia initiation?
- early after depolarizations [EADs]
- delayed after depolarizations [DADs]
- reentry
What is an early after depolarization? What current?
second upstroke in the middle of the depolarization phase
due to reactivation of Ica –> can propagate and cause PVC
What puts at risk for early after depolarization?
longer action potential / slower rate
What is a delayed after depolarization? What current?
right after repolarization of AP
first phase = spontaneous release of intracellular Ca from SR –> slow depolarization due to NCX exchange [1 Ca out for 3 Na in]
second phase = if NCX high enough, activates Na channel and causes full AP
What puts at risk for delayed after-depolarization?
- fast HR
- B adrenergic stimulation
- high intracellular Ca
What happens in reentry?
- stimulus delivered late will propagate on both side and collide
- if longer AP on R compared to L –> premature stimulus from will encounter refractory tissue and be blocked only be right; will propagate slowly on left –> by the time if propagates around the bottom, right side recovered
premature stimulus = EAD or DAD
What is the center “block” in the diagram model of reenty?
- can be anatomically defined [e.g by AV node]
- can be functional block due to damaged tissue or temporary difference in refractory
What is mech of arrhythmias?
- arrhythmia initiated by EADs/DADs and maintained by reentry
What is [are] theoretic place for blocking EAD?
- EAD is from Ca channel –> block Ca current
What is [are] theoretical place for blocking DAD?
- DAD is from spontaneous release of Ca then trigger of second AP
–> block B adrenergic signal to decrease HR and decrease likelihood of spontaneous Ca release
–> block Na channels to decrease likelihood of trigger
What is normal conduction velocity?
50 cm/s
What is normal AP duration?
300 ms
What is normal heart AP wavelength?
6 inches = same scale as heart itself
What happens if wavelength < path length vs > wave length?
wavelength > path length –> reentry will spontaneously terminate
wavelength < path length –> reentry can continue indefinitely
What is action of class I anti-arrhythmics?
block Na current
What is action of class II anti-arrhythmics?
Block B-adrenergic receptors
What is action of class III anti-arrhythmics?
Block K currents, prolong APD
What is action of class IV anti-arrhythmics?
Block Ca currents
What is strategy of class I anti-arrhythmics?
prevent spontaneous release of Ca and DADs from triggering action potential
What is mech class II anti-arrhythmics?
block Beta –> decrease cAMP/protein kinase –> block positive inotropy + phosportylation of L type Ca channels that allows more Ca pumped into sarcoplasmis reticulum
slow or block conduction
–lower HR; prevent Ca overload and DADs
What is mech of class III anti-arrhythmic?
block K channel –> increase wavelength/AP duration –> so reentrant arrhythmias self-terminate
What is mech of class IV anti-arrhythmics?
block Ca –> slow conduction between AV node and longer delay between APs
–> suppress reentrant SVT dependent conduction through AV node
–> for AFib allow fewer atrial impulses to get conducted
What are class IV anti-arrhythmics used to treat?
- SVT
- AFib
How do class IA, IB, IC drugs differ?
rate of Na channel unblock during diastole
block of other targets such as K channels
For class IA drugs: [procainamide]
- rate of unblock
- K block
- effects on APD, upstroke velocity
- rate of unblock: medium
- K block: strong
medium reduction in upstroke velocity
longer APD
For class IB drugs: [Lidocaine]
- rate of unblock
- K block
- effects on APD, upstroke velocity
- rate of unblock: fast
- K block: weak
small reduction in upstroke velocity
decrease in APD
For class IC drugs: [Flecainide]
- rate of unblock
- K block
- effects on APD, upstroke velocity
- rate of unblock: slow
- K block: weak
large reduction in upstroke velocity
little change in APD
How do effects of Class I drugs change with depolarization?
- bigger effect on depolarized [ischemic] cells
What happens to membrane polarization, AP length in ischemia?
- shorter AP
- membrane depolarized slightly
What is pharmacokinetics of lidocaine?
metabolized quickly [1-2 hr 1/2 life] so have to administer as IV in the hospital
What type of drug is lidocaine?
class IB anti-arrhythmic
use it for VT
What type of drug is procainimide?
class IB
use it for WPW w/ AFib
What are non-cardiac side effects specific to procainamide?
- reversible lupus-like symptoms,
anti-nuclear antibodies
What are non cardiac side effects common to all class IA drugs?
antimuscarinic activity
can cause fluid retention, dry mouth, constipation
Which of the class I drugs are most dangerous?
Class 1C –> unbind so slowly –> most dangerous and used infrequently
How are class I drugs pro-arrhythmic?
increase AP duration
BUT decrease conduction velocity
wavelength = APD * CV
overall they shorten wavelength –> promote reentry
How are class III drugs pro-arrhythmic?
increase APD –> increase wavelength so prevent reentry
BUT –> increase APD encourages EADs
made worse b/c they prolong APs more at slower rates when it is most dangerous/least beneficial
What is reverse rate dependence?
class III drugs are reverse rate dependent
–> prolong AP more at slow rate where this is bad; prolong AP less at fast rate where this could be beneficial
