pharmacology药理学浙江大学教学信息化平台.pptx
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1、KineticsKineticsModelsModelsParameterParameters s第1页/共81页2.Transport of Drug in the BodyMechanisms of drug permeation across cell Mechanisms of drug permeation across cell membranemembraneA.aqueous channels in the intercellular junctionsB.B.lipid lipid cell cell membranemembranes s C.C.carriers carr
2、iers(transporters)(transporters)(into or out of(into or out of cells)cells)D.D.endocytosisendocytosis exocytosisexocytosis 第2页/共81页 2.1 Transmembrane Transport of Drugs2.1 Transmembrane Transport of Drugs(1)Non-carrier Transport(1)Non-carrier Transport Simple diffusionSimple diffusion(简单扩散简单扩散简单扩散简单
3、扩散/单纯扩散单纯扩散单纯扩散单纯扩散)FiltrationFiltration(滤过滤过滤过滤过)第3页/共81页(2)Carrier-mediated Transport(2)Carrier-mediated Transport a.Active transporta.Active transport Characteristics of active transportCharacteristics of active transport Involving specific carrier(Involving specific carrier(transportertransporte
4、r)Energy-dependent Energy-dependent Saturability Saturability Competition at same carrier Competition at same carrier Moving Moving against against concentration concentration gradient gradient(up-hill)(up-hill)第4页/共81页b.Facilitated diffusion(易化扩散易化扩散易化扩散易化扩散)(transporter-mediated diffusiontransport
5、er-mediated diffusion)Involving specific carriers(Involving specific carriers(transportertransporter)Energy-independent Energy-independent Saturability Saturability Competition with other drugs Competition with other drugs Concentration gradient(down-hill)Concentration gradient(down-hill)(3)Endocyto
6、sis/exocytosis(入入入入胞胞胞胞/出出出出胞胞胞胞)第5页/共81页Another classificationPassive transportSimple diffusionSimple diffusion(简单扩散简单扩散简单扩散简单扩散/单纯扩散单纯扩散单纯扩散单纯扩散)FiltrationFiltration(滤过滤过滤过滤过)Facilitated diffusionFacilitated diffusion(易化扩散易化扩散易化扩散易化扩散)Active transportActive transport(Active transport(主动转运主动转运主动转运主
7、动转运)Pinocytosis/exocytosisPinocytosis/exocytosis(入入入入胞胞胞胞/出出出出胞胞胞胞)第6页/共81页A.Simple diffusionMost drugs are weak acids or bases.Their diffusion passing through cell membrane depends the lipid-soluble state(un-ionized form)第7页/共81页 Determinants of simple diffusionDeterminants of simple diffusion For
8、most drugs of small molecules(usually are weak acids or weak For most drugs of small molecules(usually are weak acids or weak bases):bases):Lipid-soluble or un-ionized formsLipid-soluble or un-ionized forms pKa pKa of the drug andof the drug and pHpH of the body fluidof the body fluid TheThe pKapKa
9、is the pH at which the is the pH at which the concentrations of the ionized and un-concentrations of the ionized and un-ionized forms are equal.ionized forms are equal.第8页/共81页 Henderson-Hasselbalch equationHenderson-Hasselbalch equation Weak acid drugs:Weak acid drugs:p pH-H-p pKa=log(AKa=log(A-/HA
10、)/HA)p pKa-Ka-p pH=log(HA/AH=log(HA/A-)Weak base drugs:Weak base drugs:p pKa-Ka-p pH=log(BHH=log(BH+/B)/B)p pH-H-p pKa=log(B/BHKa=log(B/BH+)第9页/共81页 pHpKaun-ionized un-ionized formformlipid-lipid-solublesolubleSimple Simple diffusiondiffusionWeak acidsWeak basesAnd/orAnd/orAnd/orAnd/orAnd/orAnd/orAn
11、d/orAnd/or第10页/共81页Three types of functional membrane proteins.B.Carrier(transporter)-mediated transport第11页/共81页Models of transmembrane transport across the lipid bilayerModels of transmembrane transport across the lipid bilayer第12页/共81页 2.2 Free and Bound Forms2.2 Free and Bound Forms Plasma prote
12、in bindingPlasma protein binding Tissue/organ affinity Tissue/organ affinity第13页/共81页3.Fate of the drug in the body Absorption Distribution Metabolism(Biotransformation)(Biotransformation)Excretion ADMEADME第14页/共81页3.1 AbsorptionAbsorption Absorption is is the the transfer transfer of of a a drug dr
13、ug from from its its site of administration to the blood stream.site of administration to the blood stream.Gastrointestinal tract Parenteral injection -i.m.,s.c.Inhalation Transdermal 第15页/共81页(1)Gastrointestinal tractRoute:OralOral Sublingual Sublingual Rectal RectalAbsorption sites:Oral Oral Gastr
14、icGastric Intestinal Intestinal Rectal Rectal第16页/共81页Factors influencing absorption:blood flow to the absorption siteblood flow to the absorption site total total surface surface area area available available for for absorptionabsorption contact time at the absorption surface contact time at the ab
15、sorption surface physic-chemical properties of the drug physic-chemical properties of the drug first-pass eliminationfirst-pass elimination第17页/共81页(2)Parenteral injection intramuscular injection(i.m.)intramuscular injection(i.m.)subcutaneous injection(s.c.)subcutaneous injection(s.c.)DeterminantsDe
16、terminants Local blood flow;Solubility of the drug Local blood flow;Solubility of the drug (3)Others Inhalation;Intranasal;Inhalation;Intranasal;Transdermal;Topical Transdermal;Topical第18页/共81页3.2 DistributionDrug Drug distribution distribution is is the the process process by by which which a a dru
17、g drug reversibly reversibly leaves leaves the the blood blood stream stream and and enters enters the the interstitium interstitium(extracellular(extracellular fluid)and/or the cells of the tissues.fluid)and/or the cells of the tissues.Blood flow-dependent phase of distribution Blood flow-dependent
18、 phase of distribution Selective distribution Selective distribution Tissue-plasma Tissue-plasma balance:balance:importance importance of of measuring measuring plasma plasma concentrationconcentration第19页/共81页(1)Binding of drug to plasma proteins Bound drug:can not distribute/inactive temporallycan
19、 not distribute/inactive temporallyreversible reversible(storage(storage form)form)/percentage percentage of of bindingbindingplasma protein capacityplasma protein capacitycompetitive displacementcompetitive displacement 第20页/共81页 (2)(2)Physic-chemical Physic-chemical properties properties of of the
20、 the drugdrug (3)Blood flow and re-distribution (3)Blood flow and re-distribution (4)Affinity to organs or tissues (4)Affinity to organs or tissues (5)Barriers (5)Barriers Blood-brain barrier(BBB)Blood-brain barrier(BBB)Placental barrier Placental barrier Blood-eye barrier Blood-eye barrier 第21页/共81
21、页 Blood-brain barrier(BBB)Blood-brain barrier(BBB)Able to pass throughAble to pass through Unable to pass throughUnable to pass through Small molecules Small molecules Large moleculesLarge molecules Lipid-solubleLipid-soluble Water-solubleWater-soluble Transporter-mediation Transporter-mediation Amo
22、unt of drug passing through BBBAmount of drug passing through BBB Increases Increases when when inflammation inflammation oror larger larger doses doses usedused第22页/共81页Placental barrier:More permeable Drugs for pregnant women:Drugs for pregnant women:A,BA,B relatively safe relatively safeC C-cauti
23、on-cautionD,D,X X-toxic-toxic第23页/共81页3.3 Metabolism(biotransformation)Drug Drug metabolism metabolism is is the the process process transforming transforming lipophilic lipophilic drug drug into into more more hydrophilic hydrophilic metabolites,metabolites,which which is is essential essential for
24、 for the the elimination elimination of of these these compounds from the body and termination of their biological activitycompounds from the body and termination of their biological activity.(1)Metabolism sites(1)Metabolism sites Liver:Liver:for most of the drugsfor most of the drugs Other organs/t
25、issuesOther organs/tissues:intestine,kidney,intestine,kidney,lung,plasma,lung,plasma,etcetc.第24页/共81页 (2)Phases of metabolism(2)Phases of metabolism Phase Phase I:I:Oxidation,Oxidation,reduction,reduction,hydrolysishydrolysis most drugs are inactivatedmost drugs are inactivated few(few(prodrugsprodr
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