药理学教学课件：Chapter 26 Gastrointestinal Drugs

Chapter26GastrointestinalDrugsDigestivesystemanddiseasesDigestivesystem:

includeesophago,stomach,bowel,liver,courage

andpancreas

etc.Diseasesofdigestivesystem

Commoninclinic,diseasesofisotropyand

functionalityinthisorgans.Antacids

anddrugsusedtotreatpepticulcerdisease

Digestants

LaxativesandantidiarrhealdrugsAntiemetic

drugsAdjuvantdrugusedinliverandgalldiseases--Gallstone-dissolutingdrug

andcholereticdrug

--Drugusedtotreathepaticcoma

ClassificationofdrugsindigestivesystemSection1

Antacids

anddrugusedtotreatpepticulcerdisease

PathogenesisofpepticulcerExcessivesecretionofgastricacidandpepsin(2)InfectionofHelicobacterPylori(幽门螺旋杆菌,HP)(3)Mucosalprotectiveeffectdecreasing

--

gastromucosalfluid(胃粘液)andHCO3—secretion

--prostaglandins(PGs)Drugsusedtotreatpepticulcerdisease1.Gastricacidantisecretorydrugs2.Antacids3.Mucosalprotectiveagents4.Anti-Hpagents1.

GastricacidantisecretorydrugsAcetylcholineHistaminePGE2andPGI2Gastrin

H+、K+-ATPaseGastricacidsecretionbyparietalcellsGastricacidsecretion--acomplexandcontinuousprocess,factorsasfollows：nerve（ACh）---M3-Rparacrine（histamine）---H2-RH+-K+-ATPaseendocrine（gastrin）---CCK2-R

ThereareAChandgastrinreceptorsinenterochromaffin-likecell(肠嗜铬样细胞,ECL).AChandgastrincannotonlystimulateparietalcellsdirectlybutalsoenhancehistaminereleaseandstimulategastricacidsecretionindirectly.----H2-RantagonistcaninhibitgastricacidsecretioninducednotonlybyhistaminebutalsoACh

andgastrin.parietalcells

Protonpumpinhibitors

Omeprazole(奥美拉唑),Lansoprazole(兰索拉唑),Rabeprazole(雷贝拉唑),Pantoprazole(泮托拉唑)，

Esomeprazole(埃索美拉唑).

(1)InhibitorsofH+/K+-ATPase--

InhibitorsofH+/K+-ATPaseorprotonpump,reducegastricacidsecretion

Omeprazole（奥美拉唑,洛赛克,losec）---Changetocompetentsulphonamide

(次磺酰胺)inacidenvironment.TheScombinewiththe–SHofH+/K+-ATPase，H+pumpwasinactivated，andthesecretionofgastricacidwasdecreased

--Increasegastricmucosalbloodflow--inhibitHPpepticulcer：Gastrelcosisandduodenalulcer.(superiortoH2-Rantagonists)Refluxesophagitis（gastroesophagealrefluxdisease,GERD胃食管反流病)Zollinger-Ellisonsyndrome卓-艾综合症----inducedbytumorofGastricAntrum（胃窦）Gcellwhichsecretegastrin;---Characteristic:Hypergastrinemia,generousgastricacidsecretion,multipleandrefractoryupperdigestivetractpepticulcer.

ClinicalusesClinicalusesUppergastrointestinalbleeding:pH7.0，easilystopbleedEradicateHP:combinedwithantibioticsClarithromycin克拉霉素，amoxicillin阿莫西林GastrinomaandgastrelcosisinducedbyNSAID.parietalcells

Mechanism:

blockH2-R→reducethesecretionofgastricacid→↓thevolumeofgastricacid&acidityClinicaluses:

①pepticulcer②zollinger-ellisonsyndrome(卓-艾综合征)③gastroesophagealreflux(胃食管反流)(2)H2-receptorantagonists

Adversereaction:

1)Antiandrogeniceffect:gynecomastia(男子女性型乳房),

impotency,galactorrhea

(溢乳)2)Inhibitliverinducedenzyme：inhibitorsofdrug-metabolizingenzymesInhibitcytochromeP450catalyzedoxidativedrugmetabolismpathway→reduceclearanceofotherdrugsCimetidine(西咪替丁;甲氰咪胍):

400mgbid4W→80%healingRanitidine(雷尼替丁)1)Antisecretiveeffectis10timesthatofCimetidine.2)Lesseffectonhepaticmicrosomalmetabolismsystem.3)LongerdurationandlessantiandrogeniceffectFamotidine(法莫替丁),Nizatidine(尼扎替丁):1)Antisecretiveeffectis30times

thatofCimetidine.2)Havenoeffect

onhepaticmicrosomalmetabolismsystem.Ebrotidine(乙溴替丁):1)↑Expressionofepidermalgrowthfactor(EGF，表皮生长因子)andplatelet-derivedgrowthfactor(PDGF，血小板衍生生长因子)→stimulateproliferationofepithelium2)increasemucussecretion

(2)M1-receptor

antagonistsBlock

M1-receptor

selectively，Inhibitgastricacidsecretion

UsedingastrelcosisandduodenalulcerPirenzepine(哌仑西平)Telenzepine

(替仑西平)BlockGastrinreceptor

InhibitH+pumpReducegastricacidsecretionProtectgastricmucosa

(4)G-receptor

antagonistsProglumide丙谷胺Similarstructurewithgastrin,combinecompetitivelyG-receptorwithgastrinGastrelcosisandduodenalulcerAcuteuppergastrointestinalhemorrhage

Clinicalusage2.Antacids

Weakbases

:Mg(OH)2,MgSiO3,Al(OH)3CaCO3,Ca(HCO3)2,NaHCO3Actions:

1)neutralizegastricacid→reducegastricacidity→reducepepticactivity2)injuryfromH+2.

AntacidsPepticulcerGastroxia(胃酸过多症)TherapeuticUsesCompoundpreparation(复方制剂）

isusedoften.

3.MucosalProtectiveAgents

Cellbarrier

GastricmucosalbarriercytomembranetightjunctionresistgastricacidandpepsinReconstructionandregenerationMucosalfluid-HCO3-GlucoproteinandbicarbonatePGs（PGE2、PGI2）

--StimulatePG-receptor,inhibitcAMPdependentcalciumchannel

andH+pump，reducethegastricacidsecretion；PGE2PGI2--Enhancethesecretionofmucosalfluidandbicarbonateby

stomachandduodenalsecretion

--Increasegastricmucosalbloodflow--Protectgastricmucosa--Stimulatereceptor,inhibitthesecretionofgastricacidandpepsin

causedbygastricacid,histamine,gastrin,andfood--Inhibitgastricbleeding,ulcerandnecrosis

causedbyacetylsalicylicacidetc.

Misoprostol米索前列醇

increasethesecretionofgastricmucosalfluidandHCO3—，regionalbloodflowClinicaluses--Gastrelcosisandduodenalulcer--GastrointestinalhemorrhageMechanismsofActionSucralfate

(硫糖铝)--formingcomplexgelwithmucus,createsaphysicalbarrierthatimpairsdiffusionofHClandpreventsdegradationofmucusbypepsin--adsorb

pepsinandcholalicacid，inhibitactivity--increasethe

secretionofgastricmucosalfluidand

HCO3—

GastrelcosisandduodenalulcerBismuthpotassiumcitrate(枸橼酸铋钾)Protectsgastricmucosa

IncresesPGEreleaseInhibitsHelicobacterpyloriInactivatepepsinMechanismofaction:

1)selectivebindingtoulcer,coatingitandprotectingitfromacidandpepsin.2)inhibitpepsinactivity3)stimulatemucousproduction4)increaseprostaglandinsynthesis.5)antimicrobialactivityagainstHpylori

Gastrelcosisandduodenalulcerwhencombinedwithantibiotics(metronidazole甲硝唑andtetracycline四环素),ulcerhealingratesofupto98%havebeenseen.clinicalusesColloidalBismuthSubcitrateranitidine枸橼酸铋钾雷尼替丁BismuthPotassiumCitrateranitidineDouble-acting4.Anti-HpagentsHelicobacterpylori(Hp)Agents-Metronidazole甲硝唑-Tetracycline四环素-Ampicillin氨苄西林-Amoxicillin阿莫西林2005年诺贝尔奖澳大利亚临床微生物学家RobinWarren和BarryMarshallSection2Digestants

Dilutehydrochloricacid

PepsinPancreatinDriedyeastBiofermin(乳酶生,lactasin)Compositionofdigestivejuice

AgentsthatenhanceitssecretionSection3

LaxativesandAntidiarrhealDrugs-Increasewater-Softfeces-Promoteenterokinesia-Helpdefecation

Bulklaxative

容积性泻药Contactcathartics

接触性泻药Emollientcathartics

润滑性泻药1.

LaxativesBulkLaxative

Magnesiumsulfate

-increasethebulk-increasecholecystokinin(胆囊素)secretion-cholagogueaction（利胆作用）口服后肠道很少吸收，在肠腔内形成高渗，增加肠容积而促进肠道推进性蠕动，产生泻下作用。Whatisthebulklaxative?SodiumsulfateClinicaluses:obstructivejaundicechroniccholecystitis（慢性胆囊炎）ContactcatharticsPhenolphthalein(酚酞)Anthraquinone(蒽醌)Castoroil(蓖麻油)与肠粘膜接触，改变肠粘膜的通透性，使电解质和水分向肠腔扩散，使肠腔水分增加，蠕动增强，引起泻下。WhatistheContactcatharticsEmollientcathartics

liquidparaffin（液体石蜡）Glycerin（甘油）2.AntidiarrhealDrugs-Diphenoxylate(地芬诺酯)-medicinalactivatedcharcoal

(活性炭)--absorption-Opiumpreparations-Albumintannate(鞣酸蛋白)--stypsis常见症状，可引起疼痛，对毒物的排出有一定保护作用。但严重的腹泻，可引起脱水和电解质紊乱，应适当给予止泻药以缓解症状。能使胃粘膜表面蛋白质凝固、沉淀，从而减轻刺激，降低炎性渗出物，发挥收敛、止泻作用。DiarrheaSection4Antiemetic

DrugsVestibularfunctionCTZ(chemoreceptortriggerzone)D2,H1,M1,5-HT3

Whydoseapersonvomite?Scopolamine东莨菪碱Benzhydramine苯海拉明Chlorpromazine氯丙嗪Dimenhydrinate乘晕宁Ondansetron

(昂丹司琼)

:usedinthepreventionofchemotherapy-inducedandpostoperativenauseaandvomiting1.5-HT3-Rinhibitor2.dopaminereceptorantagonists:Metoclopramide(甲氧氯普胺)

Mechanism

1)blockD2-receptorinCTZ2)blockgastrointestinalD-receptor→promotevermiculation肠蠕动

Clinicaluses:

1).Vomiting-Functionaldisorderofgastrointestinaltract-Radiotherapy,operationand

drugs

2)Gastrointestinaltract

hypotonia张力减退Adversereaction:

extrapyramidal(锥体束外的)symptoms,especiallydystonia（张力障碍）--blockDA-receptorofgastrointestinalmuscularlayer

nerveplexus,promotevermiculation（肠蠕动）--de pressthepostsynapse

cholinergicneurondepressanteffect，increaseAChrelease.--difficultlypenetrateBBB,havenoextrapyramidalsymptomsDomperidone（多潘立酮,吗丁啉）Gastrointestinalprokinetics

Nausea,vomiting-hemicrania偏头痛-craniocerebraltrauma颅脑损伤-radiationtherapy

GastrointestinaldyskinesiaClinicalUsesCisapride（西沙比利）

stimulate5-HT4-R,

promoteAChreleaseOthers1.

H1receptorblocker：Diphenhydramine苯海拉明，Dimenhydrinate乘晕宁2.Mreceptorblocker：

Scopolamine东莨菪碱3.D2

receptorblockerinCTZChlorpromazine氯丙嗪Section5

Gallstone-dissolutingdrug

andcholereticdrug

Ursodeoxycholicacid(熊去氧胆酸)1.

Lowerthecontentof

cholesterolinbile,

makecholesterol

dissolve

fromthe

surfaceofcalculus.2.

inhibittheabsorptionofcholesterolinintestinaltract3.

Usedin

cholesterolc