The Compartment Model and Definitions
From pEx
Pharmacokinetics  the study of absorption, distribution, metabolism and excretion of injected and inhaled drugs and their metabolites  what the body does to the drug
 Determines the concentration of drug at its sites of action and the intensity of the drug's effects with time
 Also determines variability in drug responses between patients
The Compartment Model
 The body can be simplified to be thought of as a number of compartments representing theoretical spaces
 A twocompartment model can be used to illustrate pharmacokinetics:
 Drug is introduced by IV injection directly into the central compartment
 The drug subsequently distributes to the peripheral compartment, before returning to the central compartment where clearance from the body occurs from
 The central compartment includes intravascular fluid and highly perfused tissues such as lungs/heart/brain/kidneys  into which uptake of the drug is rapid
 These tissues recieve 75% of the cardiac output, but represent only 10% of the body mass
 Compartments are considered in terms of calculated volume, not actual anatomical volume
 Large calculated volume for the peripheral compartment suggests extensive uptake of drug by the tissues making up the peripheral compartment
 Rate of drug transfer (rate constant = K) may decrease with aging, causing higher plasma concentrations of drugs such as thiopental in elderly patients
 Residual drug in the peripheral compartment will diminish the effect of distributive processes in the reduction of the plasma concentration and lead to exaggerated repeat dose effects
 Degree of cumulative drug effect can be calculated knowing the drug's dosing interval and elimination halftime
 The two compartment model doesn't always hold:
 Doesn't work with rapid IV injection of drugs which attain maximum effect in <2 minutes
 Doesn't hold with drugs which don't depend on nonorgan clearance mechanisms eg. atracurium and cisatracuruim which are eliminated by Hoffman elimination/ester hydrolysis
 Elimination halftime is based on drug disposition in a single compartment model is of limited value in multicompartmental models
Plasma Concentration Curves

 A graphic plot of the logarithm of the decrease in the plasma concentration of a drug versus time after a rapid IV bolus characterises the:
 Alpha  distribution of a drug  begins immediately after IV injection, reflects the drugs distribution from the circulation to peripheral tissues
 Beta  elimination of a drug  occurs after the initial distribution phase  a more gradual decline in the drug's plasma concentration as the drug is cleared by the renal and hepatic clearance mechanisms
 Logarithms are used because they allow a large range of plasma concentrations to be plotted after the IV injection of a drug, especially in 1st order kinetics which occur in most drugs
 The traditional concept holds that a drug's effect parallels plasma concentration  however with cisatracurium, plasma concentration is already decreasing while the pharmacologic effect is still increasing  can consider this as a third compartment linked to plasma by a rate constant  this is called effect compartment modeling
Elimination HalfTime
 The time necessary for the plasma concentration of a drug to decrease to 50% during the elimination phase
 The term most often used to characterize a drug's pharmacokinetic behavior
 Directly proportional to volume of distribution Vd, and inversely proportional to clearance
 About 5 elimination halftimes are required for nearly total (96.9%) elimination of drug from the body
 Drug accumulation is predictable if dosing intervals are less than 5 elimination halftimes
 Less useful in multicompartmental models
 Rate constant K (/min) = 1 / Time constant (min)
 Halflife = 0.693 x Time constant
Elimination HalfLife
 The time necessary to eliminate 50% of the drug from the body after its rapid IV injection
 Clearance  the volume of plasma cleared of drug by renal excretion and/or metabolism in the liver or other organs
 First Order Kinetics  the rate of change of drug concentration by any process is directly proportional to the drug concentration remaining to undertake that process. Remember first order kinetics is an assumption of a linear model not a one compartment model
 Zero Order Kinetics  rate of elimination of a drug is constant regardless of Cp (i.e. constant amount of drug eliminated per unit time). Cp decreases linearly with time. A drug normally displaying first order kinetics can display zero order kinetics at high doses due to saturation of clearance pathways
 Volume of Distribution  also known as apparent volume of distribution, is a pharmacological, theoretical volume that a drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma = total amount of drug in body / drug blood plasma concentration
 Bioavailability  the fraction of an administered dose of unchanged drug that reaches the systemic circulation  by definition IV bioavailability is 100%
 Area Under the Plasma Drug ConcentrationTime Curve (AUC)  reflects the actual body exposure to drug after administration of a dose of the drug and is expressed in mg*h/L
 Extraction Ratio  rate of plasma drug removal by an organ of elimination, divided by the rate at which it is presented to this organ  E = (C_{A}  C_{V}) / C_{A}