PHARMACOKINETICS how the body affects the drug Listen to Audio absorption distribution biotransformation excretion compartment models elimination = biotransformation + excretion clearance measures the rate of elimination absorption -routes of absorption: oral, sublingual, rectal, inhalational, transdermal, subcutaneous, intramuscular, and intravenous -process which the drug leaves the site of administration and enters the blood circulation affected by: -physical properties of drug (solubility, pKa, and concentration) -physical properties of site of absorption (circulation, pH, surface area) distribution -major determinant of end-organ drug concentration affected by -organ perfusion of the drug -protein binding to the drug -lipid solubility of the drug -molecular size of the drug -tissue binding of the drug organ perfusion of the drug -highly perfused vessel rich groups (ex. brain) take up large amounts of drug compared with less perfused organs (ex.muscles) -amount of drug uptake from a highly perfused organ can large despite having a relative small mass (ex. brain vs muscle groups) protein binding of the drug -protein binding of the drug to plasma proteins prevents uptake of the drug by the organ despite the extent of perfusion to the organ -decreased protein binding of plasma proteins to a drug creates increased amount of free available drug for tissue uptake increased amount of free drug available for tissue uptake occurs when: -diminished plasma proteins (ex. hepatic failure: decreased synthetic function to manufacture plasma proteins) -protein binding sites occupied by other drugs (ex. competitive antagonist drugs) Albumin plasma protein generally binds to acidic drugs (ex. barbituates) Alpha1-acid glycoprotein (AAG) generally binds to basic drugs (ex. local anesthetics) Lipid solubility of the drug -lipid soluable, nonionized drugs pass freely through lipid membranes (basic constituents of cellular membranes) ex. lipid insoluable, ionized drug has limited uptake through the BBB therefore will have diminished or no effect on the CNS lipid soluable, nonionized drug passes freely through the BBB and therefore may have profound effects on the CNS Molecular size of the drug -may also influence the distribution of the drug Tissue binding of the drug -may also influence the distribution of the drug Redistribution -responsible for the termination of action for many anesthetic drugs once highly perfused organs of the vessel-rich group (ex.brain) become fully saturated during the initial distribution: -lesser perfused organs (ex.muscle groups, adipose tissue) continue drug uptake from the systemic circulation -plasma concentrations of the drug diminish in the systemic circulation from the slow continual uptake of less perfused organs -diminished plasma concentrations of drug in systemic circulation is no longer in equillibrium -therefore drugs from the highly perfused organ will redistribute into the plasma to maintain equillibrium -once the lesser perfused organs are saturated then there is less drug uptake from systemic circulation -plasma concentrations remain in equillibrium therefore diminished or no redistribution occurs lack of redistribution: -may prolong emergence since awakening is no longer dependant on redistribution but instead affected primarily by drug excretion ex. infusion or multiple doses of thiopental or fentanyl may have prolonged effects Volume of distribution (Vd) -apparent volume a drug would have to be distributed into to account for its plasma concentration Vd= dose of administered drug / plasma concentration of the drug Small Vd: relative confinement of drug within the intravascular space therefore high plasma concentration of drug causes: high protein binding, ionization ex. pancuronium Vd = 10L in average sized person Large Vd: high distribution of drug outside the intravascular space and therfore smaller plasma concentration of drug causes: high lipid solubility, high peripheral tissue binding ability ex. fentanyl Vd = 350 L in average sized person Biotransformation -metabolic alteration of a substance generally to inactivate and create a water soluable form for easy excretion via kidneys -primary organ of biotransformation is the liver Metabolic biotransformation has two phases: -phase I reaction: oxidation/reduction, hydrolysis: conversion of intial drug into a more polar molecule -phase II reaction: conjugation reaction which couples an endogenous subtrate creating a highly polar molecule polarized metabolic biotransformed molecule is then able to be eliminated via the kidneys Hepatic clearance -rate of drug elimination due to liver biotransformation -volume of plasma cleared of drug / time = ml/min -affected by: hepatic blood flow and hepatic extraction ratio hepatic extraction ratio: fraction of drug removed from the plasma by the liver high hepatic extraction ratio: effecient removal of drug from plasma by the liver clearance proportional to heptic blood flow low hepatic extraction ratio: ineffecient removal of drug from plasma by the liver clearance limited to hepatic enzyme capacity Excretion -primary organ of excretion is the kidneys -alterations in urine pH can alter renal excretion of drugs -kidneys are also capable of secretion of some drugs -altered pharacokinetics may occur with renal failure due to changes in protein binding, Vd, and rates of clearance -nonprotein bound drugs: freely cross from the systemic circulation into the glomerular filtrate -protein bound drugs: unable to cross glomerulus therefore unable to enter into filtrate -nonionized fraction of the nonprotein bound drug which entered into the glomerular filtrate becomes reabsorbed back into circulation -ionized fraction of the nonprotein bound drug which enetered into the glomerular filtrate is excreted via urine Renal clearance rate of elimination of a drug due to kidney excretion Compartment models -conceptual compartments to describe the distribution and elimination of drugs from the body central compartment: ex.plasma and vessel rich groups peripheral compartment: ex.less perfused groups (ex. muscles, fat tissue) Two Compartment model: -distribution phase (alpha phase): redistribution of drug from the central compartment to the peripheral compartment ex. redistribution of drug from the plasma or vessel-rich groups (ex.brain) to the lesser perfused groups (ex.muscles.fat tissue) -elimination phase (beta phase) : as redistribution slows, slow continual elimination of drug from the central compartment first order kinetics: constant fraction/percentage of drug distributed/metabolized per unit of time despite the plasma concentration zero order kinetics: constant amount of drug metabolized per unit of time regardless of plasma drug concentration