To use a larger pharmacokinetic computer simulation system to look at the effect of changing physiological conditions on drug pharmacokinetics.
MacDope is a large pharmacokinetic simulation program which is loaded on the R & E computer system. It will generate printer plots of concentration versus time or tables of concentration versus time data after single or multiple drug administration. The effect of changing physiological parameters or patient characteristics can be studied.
The program recognizes a number of drugs:
Aspirin, Digoxin, Salicylate, Gentamicin, Inulin, Phenobarbitone, Lidocaine, Digitoxin, Pentobarbitone, Thiopentone, Amitriptyline, Propranolol, Amphetamine, Procainamide, Phenytoin, Penicillin G
You can start 1) with a normal young adult male volunteer, 2) with one of a number of preset patients, (infant, young child, female 23 yrs, hockey hero, octogenarian, female with renal failure) or 3) from scratch specifying a number of patient characteristics including:
Sex, height, weight, and age.
With any of these subject types you can then alter a variety of physiological parameters including:
gastric emptying rate (to influence absorption of PO medication), gastric pH (stability), plasma albumin (protein binding), plasma volume, body fat (distribution of lipid drugs), interstitial space, intracellular space, hepatic function (metabolism rate compared to normal 70 kg male), glomerular filtration rate (for drugs excreted by the kidney, fe approaching 1, 7.5 L/hr is 120 ml/min), urine pH (which affects tubular re-absorption of weak acid or base drugs), urine output, and renal tubule function (ratio to normal for 70 kg man).
Drug parameters can also be altered to modify one of the built-in compounds to mimic other similar compounds. The parameters considered are:
pKa, parenteral absorption (probably for IM or SC but not clearly specified), lipid/water partition, plasma to lipid rate (rate at which drug partitions with lipid), interstitial fluid to plasma ratio, intracellular equilibration rate, intestinal absorption, first pass effect, and renal tubular permeability.
As you are starting to see the program has considerable flexibility.
To start the program.
Log on to the computer as usual. At the ')' prompt enter
Throughout the program it is better if you have the 'Caps Lock' pressed.
Press 2 <return>
to get a brief introduction. Enter your signature as two letters or something brief, the program will require this throughout to confirm your answers.
Choose the normal volunteer the first time through
Enter 1 <return>
To the prompt PRESC# A.. you may wish to enter 'Q', then 'QQ' to get more information about the drug list and the prescription format. The prescription has to be entered completely correctly to be recognized. Type slowly and carefully.
The dose units are G, MG, MMG (microgram), or MG PER HOUR (iv drip - iv infusion)
Drug route includes SC, IM, IV, IVDRIP (infusion), or PO
Some possible entries for dosing frequency include:
STAT = immediately
Q6H = every 6 hours at 8 am, 2 p.m., 8 p.m., and 2 am
QID = four times daily at 8 am, 12 noon, 6 p.m., and 10 p.m.
TID = three times a day at 8 am, 2 p.m., and 10 p.m.
BID = twice a day at 8 am and 8 p.m.
PER MINUTE or PER HOUR for IVDRIP
AC = before meals
PC = after meals
The limit on doses can specify how many doses or for how long the doses should be given.
End the prescription entry by entering your INITIALS (as capital letters) in place of the next prescription.
1) Change allows you to alter the prescriptions, the run type (the graph scale and what is plotted), patient factors, and drug factors.
2) Continue, will continue the simulation, more time points are displayed.
3) Restart, gets you back to the start, with standard normal volunteer or preset subjects.
5) Stop gets you out of the program. Control-C together probably will as well but not as nicely.
A) Give ASPIRIN multiple dose PO in two patients who are the same except for urine pH. Try urine pH values from 4.5, 5.5, 6.5, 7.5 and 8.5. Look at the plasma disappearance curves (may be easier as tables), calculate the observed kel, and plot observed kel versus urine pH.
B) PENTOBARB is highly lipid soluble. Try patients with different body fat weight and look for the effect of altered distribution of pentobarb.
C) PHENYTOIN is eliminated by saturable metabolism. Alter dose and/or hepatic function to see what happens to the elimination kinetics. The drug is also protein bound so plasma albumin may have an effect on its disposition.
D) As I have mentioned in class GENTAMICIN is extensively excreted in the kidney as unchanged drug. Thus glomerular filtration rate will have a considerable effect on this drug's elimination, especially after multiple doses. Enter a suitable single dose of gentamicin, from the data represented calculate the elimination rate constant. Restart and change the GFR. Simulate new data and calculate the new elimination rate constant. Try GFR in the range 10 - 20 ml/min, 40 - 60 ml/min, and 100 - 120
E) Calculate iv infusion rates to achieve a suitable steady concentration for LIDOCAINE, quickly.
Briefly describe the exercise, giving the conditions tried and the results you observed.
Copyright 2001 David W.A. Bourne