Lectures 8-9: Mechanisms of Antiarrhythmics Flashcards
Summarize ion movements during ventricular AP
0: Na+ in; 1: Na+ in vs K+ out; 2: Ca2+ in vs K+ out; 3: K+ out; 4: K+ out vs NCX in
Three currents relevant for drugs
INa, ICa, IKr (rapid delayed rectifyer)
Na+ current is the main determination of…
Conduction velocity = speed of upstroke proportional to speed of conduction
Impaired Na+ current would lead to…(2)
Slower upstrokes and longer delays between APs
Na+ channel has three states. Describe.
- Resting (closed at negative voltage) –> 2. Open (“m” gates open due to depolarization) –> 3. Inactivated (“h” ball and chain blocking, despite “m” gates being open due to time)
If a cell is at -85 mV for a long time, about…(% in states)
85% channels will be closed, 0% open, and 15% will be inactivated
If a cell is at 0mV for a long time, about…(% in states)
0% channels will be closed, 0.5% will be open, 99.5% inactivated
Summarize channel states related to diastole and how this is related to time in diastole
- Diastole: ~85% channels closed but available; 2. Upstroke/Plateau: transition to open, then inactive; 3. Diastole: return to ~85% closed bu available IF THERE’S ENOUGH TIME
Most antiarrhythmic drugs bind how to different states…
Bind open, inactivated and UNBIND when CLOSED
Sinus bradychardia and tachycardia indicate a dysfunctional ________. How do you know it’s sinus?
SA node; normal P wave
Describe Paroxysmal Supraventricular Tachycardia. What does it indicate?
Tachycardia w/ narrow QRS complexes which indicate ventricular excitation through conduction system. Generally reflects reentry through two pathways in the AV node.
What does Paroxysmal mean?
Comes and goes
Describe Atrial Flutter/Fibrillation. What is of note here and what does it mean?
P waves are random/indistinct. Note that R-R intervals are irregular as well, which means that only SOME atrial excitations are propagating into ventricles.
Describe Premature Ventricular Contractions (PVCs)
Wide QRS complexes, which means that ventricles are exciting themselves
If two PVCs have different shapes this indicates?
Multiple ectopic foci
Describe Ventricular Tachycardia. If each one is similar, what do we call it?
Wide QRS complexes and tachycardic rate; monomorphic
What are three mechanisms that could initiate arrhythmia
- EADs, 2. DADs, 3. Reentry
Describe what is associated with Early Afterdepolarizations (EADs). What channel is involved? What can this cause?
Occur with a long AP and slow HRs; second upstroke due to reactivation of ICa; second upstroke can propagate and cause PVC
So, one of the first arrhythmic manifestations of EADs is a…
PVC (but other arrhythmias can manifest later on)
Describe the ion involvement in Delayed Afterdepolarizations (DADs).
Result from spontaneous release of intracellular Ca2+ from SR and occur when cells are overloaded with Ca2+
What can cause a cell to be overloaded w/ Ca2+
Fast HRs, beta-adrenergic stimulation
A smaller, slow depolarization is related to what current in DADs? Why?
Na+-Ca2+ exchange current (INCX); increaed intracellular Ca2+ leads to increased extrusion via NCX, and more intraceullar cations –> membrane depolarization
How could you get a full AP in in a DAD?
If Na+ current is activated
What is the textbook explanation for reentry
You have a region of heart tissue that cannot be excited by impulse in one direction (unidirectional block) but the impulse can travel through this region in the other direction, creating a loop
What is Dr. Sobie’s explanation for reentry?
Requires fibers w/ different AP lengths and an intervening blood island. If a premature stimulus occurs, AP will propagate on short AP side of the blood island but be blocked on the other. By the time it gets around the island, it can propagate up the long AP side –> loop
What is the “blood island”?
Can either be anatomical (AV node) OR functional (due to tissue damage OR to temporary differences in refractoriness)
What could the premature stimulus be?
EAD or DAD
Arrythmia mechanisms…
The important arrhythmias are initiated by EADs or DADs, maintained by reentry
Prevent EADs…
Since EADs result from reactivation of Ca2+ current, blocking Ca2+ current should inhibit EAD formation
Prevent DADs…
DADs require two steps: (1) spontaneous release of Ca2+ (2) triggering of a second action potential; Step (1) can be inhibited by blocking β-adrenergic signaling; Step (2) can be inhibited by blocking Na+ channels
How long is a cardiac AP?
300 ms
How do wavelengths relate to treating arrhythmias?
If you increase AP wavelength (via increase in duration) to larger than the path length, you won’t be able to generate a reentry loop
Class I blocks…
Na+ currents, to stop secondary AP, preventing DADs
Class II blocks…
Beta-blockers to lower heart rate, prevent Ca2+ overload and DADs
Class III blocks…
K+ currents to prolong APD to prevent reentry loops
Class IV blocks…
Ca2+ currents to reduce Ca2+ overload –> prevent EADs
Why are beta-blockers (Class II) antiarrhythmic?
Beta stimulation causes more Ca2+ into cell and into SR via phosphorylation by PKA; beta-blockers block this, decreasing spontaneous SR Ca2+ release and DADs
Why are Ca2+ channel blockers (Class IV) antiarrhythmic?
Blocking Ca2+ current allows for slower AP propagation in AV node (because AP upstrokes in AV node are ICa dependent); F
Class IA
Unblock: medium; IKR: strong block –> medium reduction in upstroke velocity, prolonged AP
Class IB
Unblock: fast; IKR: weak block –> small reduction in upstroke velocity, small decrease in APD (due to Na+ channel block)
Class IC
Unblock: slow; IKR: weak block –> large reduction in upstroke velocity, small decrease in APD (due to Na+ channel block)
If the cardiac cell is slight depolarized (~-70 mV), what will happen w/ Class I drugs?
All Class I bind more strongly to O and I states, so there will be more drug binding (ischemic cells)
Class I: Pharmacokinetics
Lidocaine (IB) is metabolized quickly so admin is IV
Class I: Non-cardiac SEs (2)
- Long-term procainimide (IA) treatment leads to anti-nuclear Abs and can cause lupus-like symptoms; 2. All Class IA drugs have some antimuscarinic activity and can cause fluid retention, dry mouth, constipation
Class I: Cardiac SEs
Because they unbind slowly, Class IC are the most dangerous and are used infrequently
What is the negative effect of Na+ channel blockers?
Reduce Na+ current, reduce CV, reduce wavelength, so if you get a reentry, it will “stick” –> arrhythmia
What is the negative effect of K+ blockers?
APD prolongation encourages EADs
What does reverse rate dependence mean?
Class III drugs prolong APs more at slow rates where the negative effect is more detrimental
