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DESCRIPTIONPharmacokinetic concepts and principles in humans in order to design individualized dosage regimens which optimize the therapeutic response of a medication while minimizing the chance of an adverse drug reaction.
- 1. Clinical Pharmacokinetics and problem solvingDr Manukumar Shetty Department of Pharmacology UCMS & GTB Hospital Delhi
2. overview INTRODUCTION PHARMACOKINETICS PARAMETERS Linear/non-linear PK Pharmacokinetics models Clearance Vd Half-life Bioavailability DRUG DOSING IN Renal & hepatic disease Dialysis Heart failure Obesity -Time: .min 3. Definition Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient. Enhancing efficacy and decreasing toxicity of a patient's drug therapy. Plasma drug concentrations are affected by the rate at which drug is administered, the volume in which it distributes, and its clearance. 4. When medications are given on a continuous basis(theophylline i.v 50mg/hr, oral 300mg/6hr), serum concentrations increase until the rate of drug administration equals the elimination rate. Steady-state serum or blood concentrations are used to assess patient response and compute new dosage regimens. 5. Linear/non-linear pharmacokinetics When doses are increased for most drugs, steady-state concentrations increase in a proportional fashion leading to linear pharmacokinetics . When steady-state concentrations change in a disproportionate fashion after the dose is altered, drug is said to follow nonlinear pharmacokinetics. 6. Steady-state concentrations increase more than expected after a dosage increase, the most likely explanation is that the processes removing the drug from the body have become saturated. When steady-state concentrations increase less than expected after a dosage increase, there are two typical explanations Saturable plasma protein binding site- valproic acid & disopyramide Carbamazepine increase their own rate of metabolism autoinduction Drugs that exhibit nonlinear pharmacokinetics are oftentimes very difficult to dose correctly. Drugs that follow linear pharmacokinetics is more straightforward and relatively easy 7. Problem no 1 Two new antibiotics are marketed by a pharmaceutical manufacture. Reading the package insert, you find the following information CURACILLIN STEADY-STATE CONCENTRATIONS (mg/L)BETTERMYCIN STEADY-STATE CONCENTRATIONS (mg/L)000100152525037.562.5500751901000150510Dose What type of pharmacokinetics do each of these drugs follow? 8. Volume of distribution(Vd) Fluid volume that would be required to contain all of the drug in the body at the same concentration measured in the blood or plasma: Volume of distribution is an important pharmacokinetic parameter because it determines the loading dose=Css V d. How the drug binds in the blood or serum compared to the binding in tissues is also an important determinate of the Vd for a drug. A drug's Vd therefore reflects the extent to which it is present in extra vascular tissues and not in the plasma,. 9. Problem no - 02 If 3 g of a drug are added and distributed throughout a tank and the resulting concentration is 0.15 g/L, calculate the volume of the tank. A. 10 L B. 20 L C. 30 L D. 200 L3/0.15= 20L 10. Problem no - 03 If 100 mg of drug X is administered intravenously and the plasma concentration is determined to be 5 mg/L just after the dose is given, calculate volume of distribution A B C D20L 25L 50L 500LA 20L 11. Problem no 4 A physician wants to administer an anesthetic agent at a rate of 2 mg/hr by IV infusion. The elimination rate constant is 0.1 hr 1, and the volume of distribution (one compartment) is 10 L. What loading dose should be recommended if the drug level to reach 2 g/mL immediately? 12. Given, infusion rate =2mg/hr elimination rate = 0.1 hr 1 volume of distribution =10L Required concentration = 2 g/mLLoading dose = Vd X Css = 1000mL X 2 g/mL = 2000 g = 20mg Here we can calculate LD using infusion rate and elimination rate as well . 13. Pharmacokinetics models A basic type of model used in pharmacokinetics is the compartmental model. Compartmental models are categorized by the number of compartments needed to describe the drug's behavior in the body. There are one- compartment, two-compartment, and multicompartment models. The compartments do not represent a specific tissue or fluid but may represent a group of similar tissues or fluids. These models can be used to predict the time course of drug concentrations in the body 14. The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment. This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues. 15. Drugs which exhibit a slow equilibration with peripheral tissues, are best described with a two compartment model. 16. The solid line shows the serum concentration/time graph for a drug that follows one-compartment model pharmacokinetics. The dashed line represents the serum concentration/time plot for a drug that follows two- compartment model pharmacokinetics after an intravenous bolus is given. 17. Plasma concentration-time curve fallowing i.v administration of a drug (500mg) to a 70kg pt V= dose/Cp = 500/16= 31.3L Cl=kV= 90mL/mim V= dose/Cp =500/31= 16.1L Cl=kV= 84mL/mim 18. Importance of two-compartment models For many drugs, multicompartment kinetics may be observed for significant periods of time. Failure to consider the distribution phase can lead to significant errors in estimates of clearance and in predictions of the appropriate dosage. Also, the difference between the "central" distribution volume is important in deciding a loading dose strategy. 19. Clearance The definition of clearance is the volume of serum or blood completely cleared of the drug per unit time. Clearance is the most important pharmacokinetic parameter because it determines the maintenance dose=Cl.Css. Theophylline clearance for a patient,3 L/h and the desired steady-state theophylline serum concentration, 10 g/mL, the theophylline maintenance dose to achieve this concentration would be 30 mg/h. The liver is most often the organ responsible for drug metabolism while kidney is responsible for drug elimination. 20. Clearance(2) The drug clearance for an organ is equal to the product of the blood flow to the organ and the extraction ratio of the drug. extraction ratio (ER) : The ability of an organ to remove or extract the drug from the blood or serumER = (Cin Cout)/Cin How the pharmacokinetics of a drug will change during a drug interaction or if a patient develops hepatic, renal, or cardiac failure. 21. Clearance(3) Hepatic clearance hepatic clearance (ClH) for a drug is product of liver blood flow and the hepatic extraction ratio (ERH) .ClH = LBF Clint ERH- intrinsic ability of the enzyme to metabolize a drug (intrinsic clearance) hepatic clearance is very sensitive to changes in liver blood flow due to congestive heart failure or liver disease 22. Hepatic clearance high hepatic extraction ratios(ER>70%) Capacity to metabolize drug is very large, hepatic clearance is mainly a function of liver blood flow. ClH, does not change much when protein binding displacement or enzyme induction or inhibition occurs due to drug interactions. lidocaine, morphine, and most TCA. low hepatic extraction ratio (ER