Pharmacokinetic Principles of Two-Compartment Modeling 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). Central Compartment: iver, Highly perfused tissues : lungs, kidney etc. Con...

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