LD = (Vd x Cp)/F (Vd x Cp)/F MD = (Css x CL x T)/F DR = (Css x (Vm-DR))/Km Css = (F x D)/(CL x T) (Km x DR)/(Vm DR)
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1 PHARMKIN WORKSHOP A PHARMACOKINETICS TEACHING SIMULATION Joseph K. Ritter, Ph.D. Associate Professor, Pharmacology and Toxicology MSB 536, , jritter@mail2.vcu.edu Tompkins-McCaw Libray Room PHARMKIN is a computer simulation of plasma drug levels. One goal is to determine the dose regimens of drugs that are required to maintain plasma drug levels in the therapeutic window (above and below the minimum effective concentration [MEC] and minimum toxic concentration [MTC], respectively). If the plasma drug level is too high (toxic) or too low (no response) the patient will not respond appropriately to the administered drug. It is important to understand that the patient s characteristics (age, weight, kidney function, liver function, etc.) influence the dose of drug required to produce the appropriate response. Another goal of this program is to help you understand how to calculate the loading dose (LD), maintenance dose (MD) and plasma plateau level (C SS ) of drugs cleared by first-order and zero-order kinetics. FIRST-ORDER ZERO-ORDER LD = (Vd x Cp)/F (Vd x Cp)/F MD = (Css x CL x T)/F DR = (Css x (Vm-DR))/Km Css = (F x D)/(CL x T) (Km x DR)/(Vm DR) Vd = volume of distribution; Cp = peak plasma level of drug; F = bioavailability; T = dose interval; CL = drug's clearance rate; D = dose of drug; DR = dose rate; Vm = maximum rate; Km = dose of drug that produces 50 % maximum rate (Vm). If you are working with a partner, take turns operating the computer. When you are not operating the computer, you should observe, offer advice and answer the questions. Make sure that you understand the basic concepts because this material will be on the exam. For example, what is the plateau principle and what factors influence the magnitude and time frame of a drug s plateau? The plasma level of all first-order cleared drugs will rise and plateau as long as the drug is repeatedly administered at intervals shorter than 4 half-lives. 100 (MTC) [plateau] = Css = F D CL T CSS by F or D, or by CL or T CSS by F or D, or by CL or T 50 (MEC) Time course of plateau is by CL [ t 1 / 2 ] or by CL [ t 1 / 2 ] t 1 / 2 = 50% 2t 1 / 2 = 75% 3t 1 / 2 = 88% 4t 1 / 2 = 94% 5t 1 / 2 = 97% 6t 1 / 2 = 99% 7t 1 / 2 = 100% Half-life intervals Drug clearance (CL) is decreased in elderly, infants, liver and kidney dysfunction and increased with induction (smoking, chronic alcohol intake, phenobarbital intake, etc.).
2 Dr. Ritter Pharmkin page 120 STARTING THE PHARMKIN PROGRAM: 1. Double click on PHARMKIN icon. Main Menu appears: CHOOSE DRUG PATIENT CHARACTERISTICS DOSAGE CHOICE / START SIMULATION 2. Select PATIENT CHARACTERISTICS [P], enter. 3. The patient s characteristics should be: Age (30), Sex (M), Weight (72 kg), Creatinine (1). Practice changing these parameters. What happens to creatinine clearance when the parameters are changed? A decrease (increased age or serum creatinine, gender change and decreased weight) in creatinine clearance [normal rate is 110 to 130 ml/min] means that drug clearance by the kidney is decreased and less drug should be administered under these conditions. An increase [increased weight] in creatinine clearance means that drug clearance by the kidney is higher and more drug must be administered to maintain the appropriate plasma level of drug. 4. Select EXIT WITH CHANGES, enter. 5. Select CHOOSE DRUG, enter. YOU ARE NOW READY TO START THE PROBLEM SET. CIRCLE THE APPROPRIATE ANSWERS ON YOUR PROBLEM SHEET AND ANSWER OTHER QUESTIONS AS INDICATED. PROBLEM 1 Select DIGOXIN, enter. Select DOSAGE CHOICE/START SIMULATION, enter. Select LOADING DOSE, enter 0. Select MAINTENANCE DOSE, enter 0.10 mg. Select TIME, enter 24 h (dose interval). Select START SIMULATION [computer will display graph on screen] A. Does the plasma DIGOXIN concentration reach therapeutic levels [above MEC and below MTC] using this dosage regimen? B. Select S to save displayed figure and then select DOSAGE CHOICE/START SIMULATION. Determine which of the following maintenance doses [0.1 to 0.6 mg] will maintain DIGOXIN levels in the therapeutic Use LD = O and DI = 24h. Save [S] each dose regimen on one graph. Circle appropriate dose (s):
3 Dr. Ritter Pharmkin page 121 C. Does the DIGOXIN plasma level plateau at all maintenance doses? D. Is the time course of the DIGOXIN plateau [Css] constant as the maintenance dose is increased? E. Is the magnitude of the DIGOXIN plasma plateau [Css] increased as the maintenance dose is increased? F. These results suggest that DIGOXIN is cleared by a [ FIRST-ORDER or ZERO-ORDER ] process. Explain the rationale of your decision: If a plateau is observed, the drug is being eliminated by first order kinetics. G. How many days does it take for DIGOXIN to reach a plasma plateau (Css)? Circle one: H. How many half-lives (t ½) does it take fordigoxin to reach a plasma plateau (Css)? Circle one: For 100% I. How many half-lives (t ½) does it take for DIGOXIN to reach 94% of Css? Circle one: J. What is the approximate half-life (t ½) of DIGOXIN in this patient? Circle one: 24 h 30 h 38 h 44 h 50 h K Explain how you determine the half-life of digoxin: Days to reach Css 7 x 24 h = 11 days x 24 hrs/day 7 = 38 hrs Select M [returns you to main menu] and select PATIENT CHARACTERISTICS. Change age to 80, exit with changes. Select DOSAGE CHOICE/START SIMULATION and enter a LD = 0, MD =.4 mg and DI = 24 h. Does DIGOXIN reach a steady-state level in the therapeutic [save figure] What maintenance dose is required to maintain digoxin levels in the therapeutic Circle one: Explain why an increase in age lowers the DIGOXIN maintenance dose: Aging decreases renal function (GFR). Digoxin clearance is proportionally reduced.
4 Dr. Ritter Pharmkin page 122 L. Select M, select PATIENT CHARACTERISTICS and change age to 30, creatinine to 3 and exit with changes. Select DOSAGE CHOICE/START SIMULATION and administer an LD = 0, MD = 0.4 mg at 24 h intervals (DI). Save [S] this figure. Does DIGOXIN reach a steady-state level in the therapeutic [save figure] What maintenance dose is required to maintain digoxin levels in the therapeutic Circle one: Explain why an increase in serum creatinine lowers the DIGOXIN maintenance dose: Increased serum creatinine indicates decreased creatinine clearance, digoxin clearance is proportionally reduced. M. Select M, select PATIENT CHARACTERISTICS, change creatinine to 1 and weight to 150 kg. Select DOSAGE CHOICE/START SIMULATION and administer an LD = 0, MD = 0.4 mg at 24 h intervals (DI). Does DIGOXIN REACH a steady-state level in the therapeutic [save figure] What maintenance dose is required to maintain digoxin levels in the therapeutic Circle one: Explain why an increase in weight increases the DIGOXIN maintenance dose: In summary, the same dose of DIGOXIN cannot be administered to all patients since patient characteristics determine the dose of DIGOXIN required to maintain the Css of DIGOXIN in the therapeutic window. Therefore, you need to learn how to calculate the appropriate dose of DIGOXIN to administer to a patient. Your patient is a 72 kg (158 lb), 30 year old male with normal kidney function (serum creatinine = 1 mg/100 ml). Use the pharmacokinetic information about DIGOXIN in TABLE 1 to solve the problems listed below and check your answers on the computer. Make sure that the patient characteristics on the computer are the same as your patient. Change body weight back to 72 kg.
5 Dr. Ritter Pharmkin page 123 TABLE 1 DIGOXIN (used to treat congestive heart failure [CHF]) A. Bioavailability (oral) [F] 0.7 B. Percent urinary excretion 60 C. Clearance (ml/min/kg normal) [NORMAL] 1.7 D. Volume of Distribution (L/kg) [Vd] 8.6 E. Half-life (hours) [t ½] 39 F. Effective Concentrations (mg/l) [MEC].001 G. Toxic Concentrations (mg/l) [MTC].002 H. Clearance (ml/min/kg) [CHF] 0.9 I. Clearance (ml/min/kg) [Elderly, Kidney Disease] 0.9 NOTE: You must always make sure that the volume of distribution [Vd] and clearance [CL] are multiplied by the body weight of the patient. [C]: [D]: [H]: [I]: CL = 1.7 ml/min/kg x 72 kg x 60 min/h / 1000 ml / L = 7.34 L / h [NORMAL] Vd = 8.6 L/ kg x 72 kg = 619 L [ALL PATIENTS] CL = 0.9 ml / min / kg x 72 kg x 60 min / h / 1000 ml / L = 3.9 L / h [CHF] CL = 0.9 ml/min/kg x 72kg x 60 min/h/1000 ml/l = 3.9 L/h [Elderly, Kidney Disease] A. Calculate the DIGOXIN loading dose and 24 h maintenance dose that would be required to achieve and maintain a serum concentration of mg/l in a normal patient. Check the doses on the computer and save [S] the figure. DI = 24 h LD = V d x C p /F = 619 L x mg/l / 0.7 = 1.33 mg MD = C ss x CL x T / F = mg/l x 7.34 L/h x 24 h / 0.7 = 0.38 mg If you just give the MD every 24 h how many days does it take before the plasma DIGOXIN level is in the therapeutic range? Circle one : How many days does it take before DIGOXIN reaches a steady-state plateau (Css)? Circle one : Explain how to shorten the time it takes for DIGOXIN to reach a steady-state plateau: Give a loading dose. B. Return to the main menu [M]. Calculate the DIGOXIN loading dose and 24 maintenance dose required to maintain a Css of.0015 mg/l in an elderly patient, a patient with congestive heart failure [CHF] or a patient with kidney dysfunction. Check the doses on the computer by selecting DRUG CHOICE and choosing [DIGOXIN- CONGESTIVE HEART FAILURE]. Enter the appropriate doses and save [S] the figure. LD = V d x C p /F = 619 L x mg/l / 0.7 = 1.33 mg MD = C ss x CL x T/F = mg/l x 3.9 L/h x 24 h / 0.7 = 0.2 mg
6 Dr. Ritter Pharmkin page 124 MD has to be educed to ccount for ecrease earance of igoxin in HF patients. If you give the MD every 24 h how many days does it take before DIGOXIN levels are in the therapeutic range? Circle one: How many days does it take before DIGOXIN reaches a steady-state plateau (Css)? Circle one: Explain why the maintenance dose is reduced and the time frame of DIGOXIN accumulation is increased in elderly patients and patients with CHF and kidney dysfunction. C. These results indicate that as kidney function decreases, the half-life of DIGOXIN INCREASES / DECREASES, the time course of the DIGOXIN plateau INCREASES / DECREASES and MORE / LESS DIGOXIN is required to maintain appropriate DIGOXIN levels. D. Which of the factors listed below reduce kidney function? PROBLEM 2 Circle ones: Infants Elderly CHF Kidney Disease Make sure that PATIENT CHARACTERISTICS are a 30 year old male weighing 72 KG with a creatinine of 1.0. Select EXIT WITH CHANGES, select CHOOSE DRUG and select PHENYTOIN and select DOSAGE CHOICE/START SIMULATION. A. Enter a LD = O mg, a MD = 200 mg and a DI = 12h. Does the plasma PHENYTOIN level reach therapeutic levels? B. How many days does it take before PHENYTOIN plasma levels are maintained in the therapeutic Circle one: C. Which of the following PHENYTOIN maintenance doses (100 to 300 mg) administered every 12h will maintain PHENYTOIN plasma concentrations in the therapeutic Save [S] all the dose regimens on the same graph. D. Circle appropriate one(s): E. Does the PHENYTOIN plasma level plateau at all maintenance doses? F. Is the time course of the PHENYTOIN plasma plateau constant? Explain why PHENYTOIN accumulation curves differ from those of DIGOXIN : At low phenytoin doses (non-saturating), elimination is first order or mixed first order-zero order. At high doses (saturating), elimination is zero order (no plateau observed).
7 Dr. Ritter Pharmkin page 125 G. What is the approximate half-life (h) of PHENYTOIN in this patient? Circle one: variable Explain the rationale of your decision: T1/2 is relatively constant at low phenytoin doses. But at higher doses (250 mg or higher), there is no plateau suggesting zero order kinetics of elimination. Half life would be variable (not constant) for drugs exhibiting zero order elimination. H. These results suggest that the clearance of PHENYTOIN is CONSTANT/ VARIABLE at high doses (saturating) and follows FIRST-ORDER / ZERO-ORDER kinetics. Indicate how you solve the problems listed below using the information in Table 2. Remember that your patient is a 72 kg, 30 year old male with normal kidney function. TABLE 2 PHENYTOIN (anticonvulsant) A. Bioavailability (F) 1 B. Percent urinary excretion 2 C. Clearance (dose-dependent) zero order kinetics D. Volume of distribution (L/kg) [Vd}.65 E. Half-life (dose-dependent) [t ½ ] Var. F. Effective Concentrations (mg/l) [MEC] 10 G. Toxic Concentrations (mg/l) [MTC] 20 H. Km (mg/l) 5.7 I. Vmax (mg/kg/12 h) [NORMAL] 3.75 J. Vmax (mg/kg/12 h) [LIVER CIRRHOSIS] 1.88 K. Vmax (mg/kg/12 h) [DRUG INDUCTION] 7.5 L. Vmax (mg/kg/12 h) [ELDERLY] 1.88 Vd =.65 L / kg x 72 kg = Vmax = 3.75 mg / kg x 72 kg [NORMAL] = 47 L 270mg Vmax = 1.88 mg / kg x 72 kg [CIRRHOSIS] = 135mg Vmax = 7.5 mg / kg x 72 kg [INDUCED] = Vmax = 1.88 mg/kg/ x 72 kg [ELDERLY] = 540mg 135mg
8 Dr. Ritter Pharmkin page 126 I. Calculate a loading dose and a 12 h maintenance dose that will reach and maintain a serum PHENYTOIN level of 15 mg/l in patients with normal, increased (induced) and decreased (cirrhosis and elderly) liver function. LD = V d x Cp / F = 47 L x 15 mg/l / 1 = 705 mg [ALL PATIENTS] DR = (C ss x [V m DR ] ) / Km = 15 mg / L [270 mg DR ] / 5.7 mg / L DR = 4050 mg 15 DR/ 5.7 mg / L 5.7 DR = 4050 mg - 15 DR 20.7 DR = 4050 mg DR = 4050 mg / 20.7 = 196 mg / 12h [Normal] DR = 15 mg / L [135 mg DR] / 5.7 mg /L 5.7 DR = 2050 mg - 15 DR 20.7 DR = 2050 mg DR = 2050 mg / 20.7 = 98 mg/ 12 h [Elderly, Cirrhosis] DR = 15 mg / L [540 mg DR] / 5.7 mg/l DR = 8050 mg 15 DR / 5.7 mg / L 5.7 DR = 8050 mg - 15 DR 20.7 DR = 8050 mg DR = 8100 mg / 20.7 = 392 mg / 12 h [Induced] These results indicate that decreased liver function [Elderly, Cirrhosis] reduces and increased liver function (induction by various agents such as smoking, phenytoin, chronic alcohol intake, etc.) increases the maintenance dose of phenytoin. J. Return to the main menu and select DOSAGE CHOICE. Enter LD = 705 mg, MD = 196 mg and DI = 12 h. Save [S] figure. Are plasma levels of phenytoin in the therapeutic K. Return to main menu and select CHOOSE DRUG, select PHENYTOIN-LIVER CIRRHOSIS, select DOSAGE CHOICE and enter LD = 705 mg, MD = 196 mg, DI = 12 h and save [S] figure. Are plasma levels of phenytoin in the therapeutic Return to main menu and select DOSAGE CHOICE and enter LD = 705 mg, MD = 98 mg, DI = 12 h and save [S] figure. Are plasma levels of phenytoin in the therapeutic Explain why cirrhosis and aging lower the maintenance dose of phenytoin: They are associated with reduced clearance of phenytoin by the liver.
9 Dr. Ritter Pharmkin page 127 L. Return to main menu and select CHOOSE DRUG, select PHENYTOIN-DRUG INDUCTION, select DOSAGE CHOICE and enter LD = 705 mg, MD = 196 mg, DI = 12 h and save [S] figure. Are plasma levels of phenytoin in the therapeutic Return to main menu and select DOSAGE CHOICE and enter LD = 705 mg, MD = 392 mg, DI = 12 h and save [S] figure. Are plasma levels of phenytoin in the therapeutic Explain why induction of liver drug metabolism increases the maintenance dose of phenytoin. The induced state is associated with increased hepatic clearance of phenytoin. M. What effect does a change in serum creatinine from 1 to 3 have on the loading dose and maintenance dose of PHENYTOIN? Circle one: no effect a small effect a large effect Explain the rationale of your decision: Phenytoin isn't cleared by a renal mechanism. N. What does this indicate about the clearance of PHENYTOIN by the kidney? Circle one: no clearance little clearance large clearance O. What tissue do you think primarily clears PHENYTOIN? Circle one: Kidney Liver Lung G.I. P. Which of the following agents might increase the clearance of phenytoin? Circle ones: phenobarbital alcohol (chronic/acute) phenytoin rifampin smoking Q. Which of the following agents might reduce the clearance of phenytoin? Circle ones: cimetidine chloramphenicol alcohol (acute) disulfiram In summary, a number of factors (age, weight, drugs, smoking, liver disease, chronic alcohol intake, kidney disease, heart disease, etc) influence the dose of drug required to maintain plasma drug levels in the therapeutic range. Appropriate use of drugs is only possible when one understands that drug doses must be adjusted when you treat patients with different characteristics. Failure to understand basic pharmacokinetic concepts results in giving too much or too little drug to patients and both situations result in inappropriate drug therapy. The elderly patient is at increased risk of inappropriate drug therapy as a result of ageassociated changes in drug pharmacokinetics, pharmacodynamics and the high rate of use of prescription and over the counter drugs.
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