Cardiac Glycosides Flashcards
Which ions shift into the cardiac myocytes during depolarization and how?
Na and Ca enters the cell, through Na+ channels and L type Ca channels.
Once inside the cardiac myocyte, what is the role of the cytoplasmic Ca? What happens next?
It causes the Ca induced Ca release by binding to the Ryr (Ryanodine) receptor in the sarcoplasmic reticulum, which in turn releases even more Ca, which would react with troponin C and cause actin and myosin to contract.
What happens during myocyte repolarization?
Ca gets shuttled back into the SR via the SERCA2 pump (it’s a Ca ATP-ase), and shuttled out of the cell via the NCX (3 Na in, 1 Ca out) and to a lesser extent, sarcolemmal Ca/ATP ase.
What is the main way Ca gets shuttled back into the SR?
Via the SERCA 2.
Main way Ca is shuttled out of the cell? 2nd way?
Mainly via the NCX, and to a lesser degree the Ca/ATP ase.
In what direction is the NCX pump working during depolarization and repolarization?
During depol the direction can reverse (Ca in 3 Na out) but otherwise its 3 Na in 1 Ca out.
What do ß adrenergic agonists and PDE inhibitors do for the RyR and L-type Ca channels?
Basically doubles the probability of opening the L type Ca channels and the RyR channels, by increasing the intracellular cAMP levels which activates PKA, which then phosphorylates Phospholamban (PL, the alpha subunit of L-type) and regulatory channels of RyR.
What is “positive inotripic effect” refer to?
It means, “faster rate of tension development to a higher level of tension, followed by a faster rate of relaxation.
What is the basic cite of action for cardiac glycosides and its MOA?
They phosphorylate the alpha subunit of the Na/K ATPase, preventing Na from leaving the cell and increasing intracellular Na. This screws up the Na gradient inside the cell, recall that Na would’ve been used in the NCX to shuttle more Na in and kick out Ca. Because there is already a high intracellular [Na], less Na can be pushed in, so less Ca can be kicked out, resulting in more intracellular Ca, which gets taken up by the SERCA 2 and stored in the SR. Thus when the myocyte next depolarizes, the SR will release more Ca (since it has more stored) and increase contractility.
Describe how the drug Digoxin can become less effective.
If the Na/K pump is inhibited, less K+ is entering the cell, so extracellular [K+] increases, (hyperkalemia). In this case the ATPase will be dephosphorylated which will alter the binding site of digoxin –> less effect.
What electrophysical activity does digoxin have?
It increases vagal tone (parasympathetics) and inhibits sympathetic activity –> decreases automaticity and increases the maximal diastolic resting membrane potential in AV node and atrial tissues. Also, effective refractive period is prolonged and decreases conduction velocity in AV node.
Given the electrophysical effects, what are some side effects of digoxin as a direct result of their electrophysical effects?
Sinus bradycardia (increased vagal tone), sinus arrest, prolonged AV conduction and high grade AV block.
Contrary to its intended therapeutic effect, what does digoxin do at increased levels?
Instead of decreasing sympathetic tone it will increase it, leading to increased cardiac muscle automacity –> atrial and ventricular arrythmias, esp considering you are also increasing Ca loading into the SR. Increased chance of malignant ventricular arrythmias.
Why is there increased sympathetic activity in CHF?
Abbarant atrial baroreceptors detect reduced cardiac output so they induce SNS to increase HR and blood pressure (increase renin, NE and vasopressin).
PK of Digoxin? (half life and clearance?) What should we watch out for in digoxin clearance? Main reservoir of digoxin in the body?
Half life 36-48 hours, renally excreted 2/3 of which remains unchanged. However, vasodilator and sympathomimetic therapy will increase renal excretion of digoxin. Stored mainly in skeletal muscles not adipose tissues.
