BIOE 425

 

Case studies III,

Infusions, volume of distributions, therapeutic index

1.               Anemic rheumatoid arthritis patient (true story).http://www.atpcenter.org/physicians/cases_of_interest_archive_detail.cfm?ID=19

A 56-year-old male was seen in consultation in the ATP Center at Johns Hopkins Medical Center for evaluation prior to having a hip replacement. He had a long history of rheumatoid arthritis, and he could no longer perform his usual activities as a computer specialist. He was taking several aspirin a day for pain relief. His general medical health was good. He had no history of heart disease or shortness of breath. He was told that he had mild anemia and occasionally took iron pills. Because the anticipated blood loss for hip replacement was 2000 ml and since he was already anemic, the hematologist seeing the patient recommended that the patient be treated for anemia.   He was instructed to stop taking aspirin so that platelet function would return to normal and that there would not be excessive bleeding.

It was recommended that the Hb value be increased to 14 gm/dl by the use of recombinant erythropoietin

Recombinant human Erythropoietin (EPO) is a glycosylated protein used to increase red blood cell formation in patients with end-stage renal disease. After subcutaneous administration of 40 units/kg to a 60kg patient,  the AUC was found to be 1372 units-hr/L

A   Calculate bioavailability of EPO if after a 50 unit/kg  i.v. dose, the volume of distribution was 7.7 L, and the clearance was 1.5.1L/hr.(assume first order elimination, one compartmental model).

 

 

 

 

2.    After a leisurely cruise accompanied by excessive eating and drinking, a bioengineering graduate student Pat (name has been changed to protect the innocent or not so innocent), has come down with a case of intractable, explosive diarrhea.  The doctors cannot figure out the cause and they fear that it may be life threatening.  They have decided to administer the new experimental drug called  Stoptheruns® that is given by infusion for serious diarrhea .  This drug has a volume of distribution of 250 L and a normal clearance of 75 L/hour with a fe of 0.5.  The Minimum Effective Concentration (MEC) is 8mg/L. Concentrations greater than 100 mg/L may cause psychotic, murderous episodes.

 

 

At what rate of infusion should the physicians start to pump in the drug to achieve a therapeutic steady state plasma concentration?

 

 

At this rate, when should Pat’s diarrhea stop?

 

 

3.         Ms. Ima Reality is suffering from health problems after falling off a tightrope over the Snake River Canyon (filled with real snakes) when appearing on Fear Factor.   She received a compound fracture from the fall and she was bitten 10 times by the cobras.  She was given a high dose of the antivenin and recovered from the snakebites.  Unfortunately, the break has become severely infected with unknown bacteria after she decided to go in the Hot Tub that had been used on The Bachelor  (without it being cleaned).  She has been admitted to a Houston hospital and is being treated with amino glycoside (and needs to recover quickly for her American Idol tryout)

 

Gentamicin is an aminoglycoside used to treat a wide variety of infections. However, due to its toxicity, its use must be restricted to the therapy of life-threatening infections and those for which a less toxic antimicrobial agent is ineffective. Gentamicin follows a one-compartment body model with first-order elimination. Protein binding is low for gentamicin (depending on the test performed, binding is reported to be 0-30%).

 

A Calculate the initial IV dose if the desired concentration of drug in the plasma is 6 mg/L.  

 

 

B   To maintain a constant blood level, an infusion needs to be started. What should the infusion rate be to maintain the desired 6-mg/L plasma concentrations?

 

 

C What is the half-life of the drug?

 

 

 

D What is the Cp after 3 hours?

 

 

 

E It turns out in a TV twist ending that the antivenin may have damaged her kidney function.  Aminoglycosides are eliminated via glomerular filtration. Any change in GFR will affect the clearance of gentamicin.   How can you evaluate renal function?

 

4.   Following their adventures, Shrek, the Donkey and Princess Fiona all need something for their sore muscles.  Their physician decides to give them each some FAIRYPAINRelief®  using a portable intravenous infusion pump.  This drug has a MEC of 12 ug/L but at concentrations above 50 ug/L (MTC) it can cause dizziness, confusion, seizures and pimples.  In humans like Princess Fiona, FairyPainrelief® has a Vd of 200L, Cl =60 L/hr

And fe 0.05.  However its pharmacokinetics in Ogres (Shrek) and donkeys is not known.

 

A)  What rate of infusion (R)   should the physician recommend that princess Fiona’s pump be set to in order to achieve Cp ss=20 ug/L ?

 

 

B)    At this rate, when should the princess feel no pain?

 

C)    Calculate Shreks total body clearance and the drugs half life in ogres using the following data that was obtained with the physician set Shreks infusion pump to 4 times Princess Fiona’s.

 

T hours      Cp ug/L

0                           0

1                           10

2                           18

3                           24

4                           28

 

 

D)  You get the donkey to evaluate and donkeys like to complain.  You plan to give a 6 mg IV bolus injection of FairyPainrelief® and then start infusion 1200ug/hr

 Unfortunately the donkey gets dizzy immediately and complains of being confused (more than usual) right after the IV dose, so no infusion is started.   Calculate the Donkey’s total body clearance, apparent volume of distribution and half-life. Blood samples are obtained as below

 

T hr     Cp ug/L

0                 60

2            40

5            22

8            12

18            1.6

 

B) New research shows that FairyPainrelief® is metabolized exclusively in the liver in patients with normal CYP3A4 and CYP2D6 to inactive metabolites.  20% of the dose is metabolized by CYP3A4 to hydroxymetabolite whereas 75% is demethylated by CYP2D6.  5% of the drug is excreted unchanged in the urine.  

The drug is 90% bond to the plasma proteins (primarily albumin) and show linear protein binding.

If you gave the Princess a dose of 6 mg I.V. dose, what is the total amount of unmetabolized drug you could collect in urine (over the next 24 hours)?

 

5  A 35 year old male (70kg) was readmitted to the Psychiatric Hospital for the 5th time because of  mental problems. His wife reported that he has now started claiming to be the Pope and that has purchased $5,000 of religious garments at a department store. On the previous admissions the patient was diagnosed as having a bipolar manic-depressive disorder and/ or schizophrenia and has been on every known therapy.   He now believes that he is the target of a large conspiracy and very agitated, unstable and should be institutionalized.  But his wife claims he cannot miss any more classes teaching at a local university or they will lose their insurance . It is decided that he is to be given an experimental new antipsychotic drug called Bpsycho ®.  To control his agitation so that he does not harm himself or others, the physician decided give him a  loading dose via IV injection to rapidly reach the therapeutic dose  and to maintain a constant Cp  with IV infusion.

 Because of enzymatic inhibition  you want a 50% higher Cp from the loading dose than the steady state IV infusion.

(Data: Vd of Psycho ® is 3L/kg; therapeutic levels are 1-5mg/L and the clearance is 6ml/min/kg).

A.    Calculate the loading dose to rapidly achieve a therapeutic level.

 

B.    Calculate the desired infusion rate