中医中药药理学外文版 (3).pdf

1PK-Absorption-How drug transport across membranes?PHARMACOLOGIC PRINCIPLES2How drug transport across membranes?1.Membrane2.Passive transport3.Active transport 3The membranes with poreare composed of lipids and proteins in a ratio of 70:1.The liquid-form double-deck of membranes is formed from lipid molecules;The special proteins inserted into the double-deck are receptors,enzymes,ion channels,carriersDrug transport across membranes1.MembranepharmacokineticsO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OATPaLipid diffusionbFiltrationcFacilitatedtransportdActivetransporteIon transportlipidsporecarrierion channelscarrierpermeation across membranespassive4Cell membranes56How drug transport across membranes?1.Membrane2.Passive transport3.Active transport 7A drug molecule moves froma side of membrane relativelyhigh concentration to anothersideoflowconcentrationwithout requiring energy,untilanequilibriumhasbeenachieved on both sides of themembrane.2.Passive transport across membranes(down hill)highlowequilibriumpharmacokineticspermeation across membranes.81)diffusion of unionized drugs(Simple diffusion,diffusion of unionized drugs)The most common and most important mode of drug transportpharmacokineticspermeation across membranesThree influence factors:partition coefficient:Solubility in an organic solventSolubility in an aqueous solution concentration gradientSurface area of the cell membrane9Nonionized formIonized form2)diffusion of drugs of weak electrolytesion trappingless polar molecules polar moleculespharmacokineticspH(pKa)pKa is pH when Ionized rate is 50%permeation across membranesmore lipid soluble less lipid solubleeasy permeation hard permeationk1k2Henderson-Hasselbalch equationThe degree of ionization of a drug:10k1H+A-k1H+BKaKa k2HAk2BH+ABpKapHlog pKapHlog HABH+A-BpHpKalog pHpKalog HABH+HA(weak acids)B(weak bases)k1k1HAH+A-BH+BH+k2k2pharmacokineticsLipid diffusionA-B10pHpKa10pHpKaHABH+11weak acidsweak bases pHA-pHBH+Degree of ionizationdegree of ionizationlipid solutionlipid solutionpermeationpermeationpharmacokineticsA-B10pH-pKa10pH-pKaHABH+Lipid diffusionNeither weak acids or weak bases are dissolved in same acid-base solution,the lipid solution,permeation;They are dissolved in opposite solution,the lipid solution,permeation.12pharmacokineticsLipid diffusionFor example,Bicarbonate(NaHCO3)is very effective for treatment of acute toxication from weak acid drugs(like barbiturates).why？13 Alkalization of gastric juice ionization permeation absorption Alkalization of blood plasma permeationacross blood-brain barriergastric juice blooddrugdrugblood Cerebrospinal fluid drugdrugpH pHA-A-pH pHA-A-Gastrolavage of NaHCO3Intravenous drop of NaHCO3pharmacokineticsLipid diffusion14 Alkalization of humor(extra-cellular fluid)ionization permeation Alkalization of urineionization permeation drug tubular reabsorption excretiondrugdrugdrug A-urinepH pH pHA-A-bloodcellpharmacokineticsLipid diffusion15*Water-soluble drugs with low molecular weight(Inc.some polar molecules)can diffuse through theaqueous pores of membrane.*Almost free drugs can be filtrated across largepores of capillaries from or to plasma.(like drugdistribution,glomerular filtration and absorptionfollowing im or sc injection)3)Filtration(Aqueous diffusion):pharmacokineticsSmall molecules(100-200 dalton)pass through aqueous pores without requiring energy driven by concentration gradient.filtration16Themovementofadrugacross the membrane could befacilitated by its special carrierand concentration gradient.Inthe carrier-mediated transport,the drug is released to anotherside of the membrane,and thecarrier then returns to originalside and state.4)Facilitated diffusion(Carrier-mediated transport)pharmacokineticsfacilitated transport17a.saturable process;b.special binding to the carrierc.cannot move against a concentrationgradient without energy.The properties of facilitatedtransport are as follows:pharmacokineticsfacilitated transport182.Active transport (up hill)A drug molecule moves from a sideof membrane relatively low to one ofhigh concentrationwithrequiringenergy and special carrier.pharmacokineticsa.saturable processb.special binding to the carrierc.transport against concentration gradientwith consuming energy.Active transport19For example:penicillin and probenecidAfter glomerular filtration,penicillin undergoes tubular secretion(an active transport),having a very short half-life(t1/2=2030 min);probenecid having the same active mechanism can competitively inhibit the tubular secretion of penicillin.The t1/2&effects of penicillin are prolonged.Glomerularfiltration(passive)penicillintubular Secretion(active)BloodtubuleExcretion of penicillinprobenecidcompetitively inhibitBloodtubulepharmacokineticsActive transportH2O absorptionTubule high osmosis 20How drug transport across membranes?1.Membrane2.Passive transport1)diffusion of unionized durgs2)diffusion of drugs of weak electrolytes3)Filtration(Aqueous diffusion)4)Facilitated diffusion3.Active transport Summary21Active and passive transport of drugs across biomembrane22The transport of drugs from bloodstream to various organs and tissues,or to different physical compartments of body.II.II.DistributionpharmacokineticspharmacokineticsDistribution231.CompartmentsAccording to perfusion rate of drugsto various organs and tissues,body canabstractly be divided into one,two ormore parts(one compartment model,two compartments model,three).pharmacokineticsDistribution24Drugs within the model are assumed to bedistributed just to the organs or tissues with highblood flow and rapid uniform(brain,heart,liver,kidneys,lungs,active muscle,).The C-T curvehave one phase:elimination.The distribution istoo rapid to be found in the C-T curve.。DistributionT1)One compartment modelKadrugKe25pharmacokineticsDistribution2)Two compartments model Drugs are not only distributed to the organs or tissues with rich blood perfusion(central compartment),but also to that with low blood flow(peripheral compartment:fat,skin,bone,resting muscle).The C-T curve have two phases:a.The distribution rate is known as the alpha half-life,t1/2.b.The elimination rate is known as the beta half-life,t1/2.26Vd is that drug in a plasma concentration shouldbesolvedinapparentvolumeofbodyfluidincluding the general circulation and the tissues.Vd is used for measuring distribution range,relatingtheamountinthebody(A)totheconcentration of drug(C)in blood.total amount of drug in body,A(mg)F.DVd(L)concentration of drug in plasma,C(mg/L)C2.Apparent volume of distribution(Vd)pharmacokineticsDistribution27Phase 1oxidation reduction hydrolysisdrug activityPhase 2conjugationtoxicity binding rate more polarexcretionInactivation Prodrugsactivation III.III.Biotransformationmainly in the liverhepatic microsomal mixed function oxidase systempharmacokineticsBiotransformationwith glycuronic acid 1.two phases28Drugsandtheirmetabolitesincirculation are excreted by kidneys,bile,milk,sweat and lungs.I.I.Excretion of drugspharmacokinetics29pharmacokinetics.Kinetics and rate process DifferentalequationKinetics modelKCdtdC=CPPPCCCCKCKdtdCCKCKKCdtdC12212112+=+=KineticsKdrug1 compartmentK12K21Kdrug2 compartment30pharmacokinetics1 compartmentExponentequationKteCC=0ttBeAeC+=Linear equationt2.303-logA)Be-log(C t 303.2KlogClogC.-0=tt303.2logBlogC=Semi-logarithmicequationKinetics2 compartmentsTCTCABTlogCTlogC31two-kinds of elimination kineticsFirst-order elimination kineticsMore quickly drug in plasma eliminates from body,higher concentration of the drug is,so it called fixed percentage elimination.fixed half time.If the concentrations unit is expressed by logarithm,the c-t curve is a beeline.Most of drugs used by clinical dosages are eliminated by first order kinetics.32The eliminated rate has no relationship with the drug concentration.The quantity of eliminated drugs in per unit of time are fixed.Having no fixed half life.If the concentration are expressed by numerical value,the C-t curve are a beeline.When drugs in the body are excessive to exceed the maxim eliminative ability,the kinetics of the drug in the body is according to zero order kinetics;while the concentration descends to the range which the body can eliminate,the kinetics will accord to first order kinetics.Characteristic of zero order kinetics33The half-life(t1/2)is the time required to decrease thedrug plasma concentration by one-half(50%)duringelimination.It is considered that drugs are almost(97%)eliminated after 5 t1/2.T1/2is relates to drug character(lipid-solubility,sizeof particle,molecular structure,drug interaction)andbody condition(function of kidneys and liver),butgenerally not relates to drug blood concentration andthe routes of administration(therapeutic dose).4)Half-life of drug(t1/2)pharmacokineticsElimination34Clearance（CLs）Another“constant”that describes drug elimination=volume of plasma“cleared”of drug per unit time(mL/min L/hr)35When given at a regular interval,a drug plasmaconcentration approximately could reach a plateauafter 5 t1/2.1)Level of Css relates to:*dose Css*interval shorten wave of Css intravenous drip smooth concentration curves.（the most effective and safe administration)2.Steady state concentration (Css)pharmacokineticsSteady state36T1/20 1 2 3 4 5n first-orderA.dose 100 100 100 100 100 100amount 50 75 87.5 93.5 96.9100B.dose 200 200 200 200 200 200amount 100 150 175 187.5 193.8 200C.dose 200 100 100 100 100 100amount 100100 100 100 100zero-orderdose 100 100 100 100 100 100amount 50 100 150 200 250Steady state concentrationpharmacokineticsSteady state37Thank you!