Flashcards in Pathophysiology and Pharmacology of Arrythmias Deck (46):
What are phases 0-4 of cardiac muscle action potential?
0- rapid depolarization due to Na influx
1- Na channels inactivate and there is transient outward K
2- Ca slow acting channels allow Ca to enter the cells, while K moves out (plateau phase)
3- K channels repolarize the cell
4- rest phase (modulated by Na/K pump (2K in and 3 Na out)
Na channels are maintained at the resting state only at the _________ membrane potential present in resting cells (_____mV)
Ath the negative membrane potential Na channels are closed.
Cell resting potential is -85mV which is maintained by Na/K ATPase pump
What channels are responsible for phase O depolarization?
Na channels. As the cell begins to depolarize, local currents cause the membrane potential to raise by a few mV to reach a threshold after which the Na channels rapidly switch from closed to open states.
The Na current in phase 0 depolarization is brief because the channels switch to ______ at membrane potential raises from ________ to _____ mV.
inactive state as the membrane raises from -75 to -55 mV.
When do Na channels switch from inactive to closed/resting state?
once the membrane starts to repolarize during phase 3.
It is inactive throughout the whole plateau phase (phase 2)
What is the switch from inactive Na channels to closed/resting Na channels called?
Recovery- an AP can fire in a region of myocardium where enough Na channels have recovered (switched from inactive to closed/resting).
Which channels are closed at cell resting membrane potential?
Na, K and Ca
The Na/K ATPase pump is at work though
What channels are responsible for the phase 2 plateau of cardiac myocyte AP?
When do the channels open? How fast?
Ca channels- they open as the membrane depolarizes but open at a more + membrane potential than Na channels.
They open fairly quickly (but slower than Na) and inactivate slowly so the channels are open for a long time
When do Ca channels switch from inactive back to resting/closed state?
During phase 3 depolarization
What channels play the largest role in impulse conduction at the SA and AV nodes?
What channels are responsible for phase 3 depolarization? When do they open?
K delayed-rectifiers are responsible for phase 3 depolarization. They open slowly during phase 2 and more from inside the cell to outside of the cell causing repolarization.
They do NOT inactivate but return to resting/closed state as the membrane nears resting potential (-85mV)
Which type of channels have inactive states? Which channels go directly to resting/closed?
K= directly to resting/closed
Na, Ca= inactive states
What is threshold?
What is the most important factor that determines the "threshold potential"?
What is the effect of antiarrhythmic drugs on AP?
The amount of depolarization necessary to elicit an AP. It is an all-or-none process.
The number of available channels determines the threshold potential. This is why antiarrhythmic drugs block Na or Ca channels. Fewer channels are available so the depolarization needed to induce an AP increases.
What is the effective refractory period?
What cell membrane potential usually has enough channels recovered to fire another AP?
Once cardiac tissue has been depolarized, the cells cannot excite again until they have recovered from inactivation.
Minimum # of channels must be available before an AP can be generated (threshold). This usually occurs at about -50mV
What are the two main forms of abnormal impulse generation?
1. enhanced automaticity- increased spontaneous firing from normal pacemaker tissue (SA, AV) or from ectopic sites (atrial myocytes, ventricular myocyte)
2. triggered activity- occur after a depolarization which triggers them. Early after-depolarization and delayed after-depolarization are the 2 types .
What is the mechanism by which delayed afterdepolarization (triggered activity) occurs?
What are the major causes?
What phase of depolarization do they occur in?
They occur in phase 4 depolarization and are associated with Ca overload (digoxin toxicity or metabolically stressed cells).
SR becomes overloaded with Ca and leaks it immediately following repolarization.
Na/Ca exchanger pumps excess Ca out in exchange for Na influx which can generate depolarization. If threshold is reached, another AP can fire.
How does a reentry pathway excite the rest of the heart (instead of just the myocytes in its path?
They send off daughter impulses that spread to the rest of the heart.
What is the difference between an anatomically defined reentry circuit and a functionally defined reentry circuit?
Anatomically defined reentry is when the conduction circles around an electrical dead spot. An example would be conduction around the tricuspid valve or an accessory pathway.
Functionally defined reentry is when the interior of the pathway is constantly depolarized by the daughter impulses of the reentry circuit CREATING an electrical dead spot
What are the 4 main mechanisms of antiarrhythmia drugs?
1. block Na channels
2. decrease adrenergic stimulation (b-blocker)
3. block Ca channels
4. block K channels
According to Vaughan-Williams classification, what are :
Class I anti-arrhythmic drugs?
I- Na channel blockers
II- B-blockers (esp.B1 selective)
III- K channel blockers - prolong AP
IV- Ca channel blockers
What is the serious drawback of Na and K channel blockers?
What has been used instead?
They have the potential to cause serious VT (including Torsades de Pointes).
This is not common, but still possible.
They also have bothersome side affects that limit their use.
Instead, we have been switching from drug to device and procedure based therapies which are safer and more effective.
What do Na channel blockers bind to?
They bind somewhat selectively to Na channels, but also can bind with low affinity to K or Ca channels as well as unidentified targets that can cause side effects
What states of Na channels do blockers bind to?
What is the mechanism of the blocker?
They bind with higher affinity to the inactive state or the open state than to the closed/rested state. This means that they are use dependent.
Once it binds the inactive state, it must dissociate before the channel can return to closed/rested. This increases the effective refractory period .
What do Na blockers do to the:
1. Effective refractory period
1. Increases the refractory period
2. no change to repolarization
3. decreases channels available (because the ones that are bound take longer to get to rested state) so less channels available for depolarization = higher threshold
4. conduction is slowed (an adverse effect)
What is meant by use-dependent?
Increases binding to Na channels happens at faster heart rates because this is where the most channels are open/inactive.
Resting heart rate has more time in the closed state so the drugs can't bind
What voltage are Na channels closed, open, and inactivated?
closed at -85
opened at -75
inactivated at -55
What voltages are Ca channels closed, open and inactivated?
closed at -85
opened at -40 (later than Na)
inactivated at +5
Na channel blockers reduce the total number of channels available which shifts the voltage-activation curve to the __________. This means the threshold is _______.
Why do Na channel blocker increase the effective refractory period without affecting the repolarization?
K+ channels are NOT affected so they will still depolarize.
The refractory period is lengthened because the Na channels are not going from inactive to rested.
Why is conduction slowed with a Na channel blocker? Why is this an adverse effect?
How is it seen on the EKG?
It is slowed because the speed of conduction is dependent on the amount of Na current (rapid upstroke at phase 0 depolarization).
This is adverse because it increases the risk of reentry.
Slower conduction can be seen in the EKG as a wide QRS wave
Conduction velocity is dependent on the _____ and ______ of the phase 0 depolarization of AP.
amplitude and slope.
Decreased Na channels will decrease the slope and amplitude of the phase O depolarization.
Decrease in conduction by Na channel blockers can increase the risk of _______.
When conduction is slow there is a greater chance of a wave encountering excitable tissue in the reentry circuit
What are the 2 main effects of Na channel blockers on treating arrhythmia?
1. Stop abnormal impulse generation
How do Na channel blockers inhibit abnormal impulse generation?
They increase the threshold for generation of an impulse.
Increased threshold can inhibit triggered activity due to delayed after depolarization
How do Na channel blockers block reentry circuits?
They increase the refractory period so there is a good chance tissue in the circuit will be refractory still when the reentry wave impulse reaches it so it will extinguish the circuit.
What specific channels are blocked by K channel blockers?
Are they use-dependent?
What other targets do these drugs interact with?
The delayed rectifier K channels.
Since these channels do not inactivate, they are not use dependent and there is a simple relationship between drugs and inhibition.
They interact with B-adrenergic receptors(sotalol) and other ion channels (amiodarone)
What are the 2 main electrophysiological actions of K channel blockers?
1. Increase refractory period and slow repolarization
2. Induce early after depolarizations
How do K channel blockers increase the effective refractory period?
They decrease the outward K current during phase 3 depolarization and decrease the rate of repolarization.
This prolongs the AP duration and increases the refractory period (because Na channels are dependent on repolarization to recover from inactivation)
What is seen on the EKG of someone who has taken a K channel blocker?
Extended QT segment due to the prolonged repolarization
What does the delayed repolarization due to a K channel blocker do to Na channels? Ca channels?
1. It takes longer for Na to go from inactive to rested/closed because this is dependent on repolarization. There is increased effective refractory period.
2. The delay allows time for Na channels to recover. If enough recover they can trigger reopening of Ca channels producing early after depolarization
What can the effect of K channel blockers on Ca channels do to the EKG?
Ca can recover and fire an EAD. This can lead to PVC and Torsades de Pointes.
What is the effect of K channel blockers on arrhythmia?
It can slow and terminate reentry because the prolonged AP duration increases refractory period. This will cause the propogating wavefront to encounter non-excitable tissue and extinguish.
What are the 4 molecular mechanisms of Ca channel blockers?
1. bind selectively to inactive/open Ca channels
2. block Ca movement
3. Raise threshold
4. slow voltage-dependent recovery of Ca channels
What are the main electrophysiological actions of Ca channel blockers?
1. slow response tissue like the SA and AV nodes
2. slow the HR
3. slow AV node conduction
4. increase AV node refractoriness
What are the 2 major effects of Ca channel blockers on arrhythmias?
1. reduce conduction through AV node to control ventricular rate
2. Increase refractoriness of AV node to terminate AVNRT