Cardiac Glycosides Flashcards
(33 cards)
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.
What bacteria contributes to the “drug tolerance” of digoxin and why? What form of digoxin has higher bioavilibility?
Eubacterium Lentum will break down digoxin, thus reducing the bioavilability. Liquid filled capsules have a higher bioavilibility than tablets.
What seems to be the only indication of Digoxin Tx today?
It is reserved for only people with LV systolic dysfunction and a fib or to patients in sinus rhythm who remain symptomatic despite receiving the first line tx (which is ACE inhibitors and adrenergic receptor antagonists).
What is the first line Tx of CHF?
ACE inhibitors and adrenergic receptor antagonist, due to their proven mortality benefits.
What can be used to treat digoxin induced toxicities?
The drugs digoxin immune fab, called DIGIFAB and DIGIBIND.
What are the electrophysical AE’s of digoxin that only needs dose adjustments?
Ectopic beats from AV junctions or ventricles, first degree AV block, slow ventricular response to a fib, or accelerated av junction pacemaker. However only dose adjustments are needed here.
When should digoxin tox be considered?
When patient presents with arrythmias, neurologic or GI symptoms present in patients taking cardiac glycosides.
What are some cardiac AE’s that might (rarely) require atropine administration?
Sinus bradycardia, SA arrest or exit block, 2nd or 3rd degree AV conduction delay.
How to treat patients who have AV junctional or ventricular automaticity? When should this tx not be used?
Administer potassium even if serum K+ levels are normal, however avoid K+ admin if high degree AV block.
What can be used to treat digoxin induced ventricular arrythmias that threaten hemodynamic comprimise?
Lidocaine or Phenytoin.
