Answer provided by Jeffrey Stark,
Graduate StudentCase Study 2
PHA 5127 Fall 1998
Reminder: When monitoring drug levels for a patient, the plasma concentration reported is almost always for the total conc (bound + unbound). The same is true for the values given for a therapeutic range. However, since only the free drug is active (for the desired pharmacological effect as well as side effects), it is important to consider what changes may occur in plasma protein or tissue binding due to the disease state or drug-drug interaction.
Warm-up questions (T or F; Justify your response)
(1) The maximum volume of distribution possible for a drug which shows neither plasma protein or tissue binding is the volume of the body.
(2) Assuming that the volume of tissue water (38L) may be substituted for the tissue volume, a Vd of around 41L indicates that there is neither significant plasma protein nor tissue binding.
Background information: Digoxin and Quinidine
Digoxin is a cardiac glycoside with a therapeutic range of 0.5 - 2.5 ng/ml. Plasma protein binding is negligible (~25%) but tissue binding - especially cardiac muscle - is significant (the cardiac muscle-to-plasma conc ratio is normally 70:1).
Quinidine is an antiarrhymthmic with a therapeutic range of 2.5 - 5 m g/ml. Approximately 70-90% is bound to plasma proteins (albumin and alpha-1-acid glycoprotein). Quinidine has a higher affinity than digoxin for tissue binding sites.
Case study: Mr. Jones (Mr. Jones and me - we tell each other fairy tales)
Mr. Jones, a 48 year-old male, is taken to the emergency room with shortness of breath and significant peripheral edema in the lower extremities (oooh, I hate it when that happens). He is diagnosed as having congestive heart failure and is treated with digoxin (and quinidine later on). For this patient, Vd of digoxin is 400L.
(1) Quinidine enhances the effect of digoxin due to a pharmacokinetic interaction. Using the information above, provide a feasible explanation for this.
(2) Suggest an oral loading dose of digoxin which will provide a total Cp0 in the middle of the therapeutic range. The bioavailability of the tablets is 0.68. Assume rapid dissolution and absorption.
(3) If the half-life for digoxin is around 36 hours, how much time is required for the plasma levels of this patient to fall below the therapeutic range?
(4) On the same graph, sketch a ln(Cp)-time profile for the digoxin dose given in question 2 with and without the addition of quinidine therapy (assume same Cl).
(5) If Mr. Jones has normal protein binding, what overall tissue binding is expected? Compare this value to cardiac muscle binding.