Multi-Compartment Models PDF

Most common model Body tissues two broad categories: Group of tissues which equilibrate instantaneously are supposed to reside in central compartment Sampled compartment ( though such sampling is not always necessary). iver, Highly perfused tissues : lungs, kidney etc. TWO COMPARTMENT OPEN MODEL...

Most common model Body tissues two broad categories: Group of tissues which equilibrate instantaneously are supposed to reside in central compartment Sampled compartment ( though such sampling is not always necessary). iver, Highly perfused tissues : lungs, kidney etc. TWO COMPARTMENT OPEN MODEL Contains slowly equilibrating tissues Central Compartment: Drug requires some length of time for equilibration. Peripheral or Tissue Compartment: This model assumes Drug eliminated from central compartment. Part of an organ in the central compartment Rest in the tissue compartment. Possible to have: Determining factor for classification Rate of equilibration. Categorization of two compartment model Depending upon the compartment from which the drug is eliminated Two compartment model with elimination from central compartment Two compartment model with elimination from peripheral compartment Two compartment model with elimination from both the compartments. Types of Two compartment model Other: After an intravenous injection Are: Decline in plasma conc. : Biexponential Distribution Two disposition processes Elimination Distribution into more slowly perfused tissues. Rapid decline due to Initial rapid decline in the central compartment Graph: distribution phase of the curve. pseudo-distribution equilibrium achieved between two compartments State of equilibrium between central compartment After sometime: and more poorly perfused tissue compartment. loss of drug from central compartment appears to be single first-order process After this equilibrium is established: overall processes of elimination of drug from the body. It is due to: The second, slower rate process elimination phase. Two compartment model assumes: t = 0 there is no drug in the tissue compartment. Two compartment kinetics The tissue drug level will eventually peak Tissue drug level curve after a single intravenous dose of drug shown in fig. start to decline as conc. gradient between two compartment narrows total amount of drug remaining in the body at any time. Theoretical tissue conc. together with the blood conc.,IDEA OF : This information would not be available without using: pharmacokinetic models. Distribution Phase Elimination phase Samples of blood removed from central compartment analyzed for presence of drug: Distribution phase may take minutes or hours may be missed entirely if blood is sampled too late after administration of the drug. K12 and K21 : first order rate constants Depict drug transfer between central and peripheral compartments. Rate of Drug change in tissues: In the model depicted above 1. Notes: 2. 3. Single compartment pharmacokinetic calculations relatively simple. PHARMACOKINETIC PARAMETERS Situations HAVING two, and occasionally more than two compartments drug distribution, elimination and pharmacologic effect. smaller, rapidly equilibrating volume, usually made up of plasma or blood and First compartment those organs or tissues that have high blood flow Initial Volume of Distribution (volume : Vi) are in rapid equilibrium with the blood or plasma drug conc. Equilibrates over a somewhat longer period. Second compartment This volume referred to as V t or tissue volume of distribution. Half life for distribution phase alpha half life Half life for drug elimination ! Notes Multi-Compartment Models beta half life. Sum of Vi and Vt : apparent volume of distribution (V). Drugs are assumed to enter into and be eliminated from Vi. Any drug that distributes into tissue compartment (Vt ) must re- equilibrate into Vi before it can be eliminated. Some time required for a drug to distribute into: Effects of a Two – Compartment Model on the loading dose and plasma conc.( C ): Since Vt have slowly equilibriating (tissue components) Vt: Rapidly administered loading dose calculated on the basis of V ( Vi+ Vt) Can effect certain body parts negatively Must be given slowly Loading dose? Affect heart, even tho no relation If fast? higher than predicted Result in an initial C Why ? initial volume of distribution (Vi) is always smaller than V total Whether target organ behaves as though it were located in Vi or Vt. Consequences of an inaccurate prediction depend on: Examples: Lidocaine, Phenobarbital, procainamide, and theophylline exert therapeutic and toxic effects on target organs when loading doses are calculated based on the: In these instances that behave as though they are located in Vi. total volume of distribution, conc. of drug delivered to the target organs could be: much higher than expected produce toxicity if loading dose is: not administered appropriately. First calculating loading dose based on the total volume of distribution ( V ), Then administering the loading dose at a rate slow enough to allow for drug distribution into Vt. 1st approach: This approach is common in clinical practice, principle of two-compartment modeling with Guidelines for rates of drug administration are often based on: ( toxic or therapeutic) responding as though they were located in Vi. Receptors for clinical response To administer loading dose in sufficiently small individual bolus doses such that C in Vi does not exceed some predetermined critical conc. with the end-organ being located in Vi. Problem can be circumvented by: Its cardiac effects parallel the plasma conc. Potassium is a good example of a drug that follows this principle of two-compartment modeling In addition, there is slow equilibrium between plasma and tissue potassium concs. Potassium is primarily an intracellular electrolyte When potassium is given intravenously: rate of administration must be carefully controlled serious cardiac toxicity and death will occur if patient experiences excessive plasma (Vi) concs. Concept of two compartment modeling also important in evaluating the offset of drug effect. Rapid achievement of a therapeutic response 2nd approach: Followed quickly by loss of therapeutic response For drugs with end organ for clinical response located in Vi: drug being distributed into larger volume of distribution may be the result of: rather than drug being eliminated from the body. e.g. digoxin, lithium high C, which may be observed before distribution occurs, is not dangerous. will not reflect the tissue conc. at equilibrium. However plasma concs that are obtained before distribution is complete These plasma samples cannot be used to predict therapeutic or toxic potential of these drugs. Clinicians usually wait for 1-3 hours after an intravenous bolus dose of digoxin before evaluating the effect so that the full therapeutic or toxic effects of a dose can be observed. Digoxin to distribute to site of action (myocardium) When the drug’s target organ is in second or tissue compartment, Vt: Slow drug distribution into the tissue compartment can pose problems in accurate interpretation of drug conc. when a drug is given by intravenous route. This delay allows: Generally not a problem when a drug is given orally. Rate of absorption is usually slower than the rate of distribution from Vi to Vt. Digoxin and lithium are exceptions to this rule. several hours required for complete absorption and distribution. Plasma samples obtained less than 6 hours after an oral dose Digoxin oral dose of lithium less than 12 lithium hours : questionable value. These drugs given orally: Receptors in end-organs behave as though they are located in more slowly equilibrating tissue compartment For these two drugs: Plasma concs obtained during the distribution phase ( before equilibrium with the deep tissue compartment is complete) Pharmacologic response will be much less than the plasma concs would indicate. Only when attached to receptors Alpha phase for most drugs represents distribution of drug from Vi into Vt Relatively little drug eliminated during distribution phase. Drugs that behave in this way are generally referred to as: non- significant two compartment drugs. If patient not harmed by initially elevated drug conc. in alpha phase and no drug samples are taken in alpha phase, Drug can be successfully modeled as one-compartment drug Then: DRUGS WITH SIGNIFICANT AND NON- SIGNIFICANT TWO COMPARTMENT MODELING: Non-significant means: (i.e only the elimination or beta phase is considered). Increased drug plasma concs during the alpha phase can be clinically significant serious toxicity Why? For some drugs, If end organ behaves as though it lies within the: These drugs considered to exhibit “nonsignificant ” two compartment modeling only after: Plasma samples obtained for pharmacokinetic modeling only during: Drugs with “ significant ” two compartment modeling: alpha phase or distribution has been completed. beta or elimination phase. Those eliminated to significant extent during initial alpha phase. alpha phase cannot be thought of simply as distribution, Methotrexate Example: Why? Significant elimination occurs as well. lithium & lidocaine. Drugs that border on having significant two compartment modeling: When a one-compartment model is used for drugs that exhibit significant drug elimination in the alpha phase, Actual trough concs will be lower than those predicted by one- compartment model. Two-compartment computer models are available for therapeutic drug monitoring. initial volume of distribution (Vi) If care taken to avoid obtaining samples in distribution phase, Very similar pharmacokinetic interpretations are usually arrived at using simpler one-compartment model. Vt. will be increased,