临床药理学课件：Geriatrics Pediatrics

2023/12/81Geriatrics&Pediatrics2023/12/82Geriatrics已达1.78亿20102013年，我国60岁以上老年人口突破2亿，到2050年左右，老年人口将达到全国人口的三分之一，“银发潮”将对我国的经济、社会、政治、文化发展产生深远的影响。

中国成为全球唯一老年人口超过1亿国家。

我国60岁以上老人20082013已达1.50亿达到2亿2023/12/84PharmacotherapyfortheelderlyYoungelders:age65-74.Old-old:85yearsandolder.2023/12/85Theaimsofpharmacotherapyingeriatrics:CureorpalliatediseaseEnhancehealth-relatedqualityoflifePhysicalfunction,psychologicalfunction,socialfunction,andoverallhealth.2023/12/86Overviewoftheproblem-mismedication1.Elderlycompriseonly17%ofpopulation,but39%ofallhospitalizationfor,and51%ofdeathsfromdrugreaction.2.Theypurchase25%ofalldrugprescription.3.Theytakeanaverageof3-6prescriptiondrugs,andanother3OTCproducts.4.60%ofADEswerepreventablewithoutcompromiseoftheefficacy.5.TheaverageadditionallengthofstayinhospitalsassociatedwithanADEwas2.2days,atanaverageincreaseincostofUSD$3244.2023/12/872023/12/88WarningTheelderlypatientisatriskofenteringaviciouscycleinwhichthepatientismorelikelytoreceivedrugs,morelikelytodevelopadversedrugreactions,andpotentiallymorelikelytoreceiveevenmoredrugstotreattheunrecognizedadversedrugeffect.2023/12/89ADRFrequencybyDrugUsefortheelderlyNumberofMedications0-56-1011-1516-20Theelderlycannottakemorethanfivekindsofdrugatthesametime0-5kinds:4%;6-10:10%;11-15:25%;16-20:54%2023/12/810Toptencausesofdeathinelderly1.Heartdisease2.Cancer3.Cerebrovasculardisease4.Chronicobstructivepulmonarydisease5.Pneumonia/influenza6.Diabetesmellitus7.Accidents/adverseeffects8.Alzheimer’sdisease9.Kidneydisease10.Septicemia2023/12/811PhysiologicalchangewithagingThereisaprogressivefunctionaldeclineinorgansystemswithadvancingage.Thesephysiologicalchangesmaycausereductionsinfunctionalreservecapacityandthehomeostasisofthebody,thusmakinganeldermoresusceptibletodecompensationinastressfulsituation.Thecardiovascular,musculoskeletalandCNSmaybemostaffected.2023/12/812Pharmacokinetics&pharmacodynamicsanumberofphysiologicalchangesineldercouldpotentiallyaffectpharmacokineticsandpharmacodynamics.Problem:limitedinformationfordrugscommonlyusedintheelderly.ImprovebyFDAinfuture?“Guidelinesforthestudyofdrugslikelytobeusedintheelderly”2023/12/813AtrophyofgastricmucosaGastrointestinalperistalsisisslowThegastrointestinalbloodsupplyreductionTheeffectofPhysiologicaldeteriorationofthedigestiveorgansfortheelderlyondrugabsorptionEffectsongastrointestinalabsorptionofdrugs,easytocausegastrointestinaldysfunction2023/12/814Alteredpharmacokinetics-absorptionOral–gastrointestinalabsorption:1.Atrophyofgastricmucosa---Thereductionofgastricacidsecretion---pHincreaseinthegastrointestinaltract2.Gastrointestinalperistalsisisslow---Delayedgastricemptyingtime---Prolongthetimeofdrugabsorption3.Thegastrointestinalandhepaticbloodsupplyreduction---Plasmaproteinbindingrateisdeclined---blooddrugconcentrationincreased4.hepaticbloodsupplyreduction---Decreasedfirst-passeffectandincreasedbioavailability(e.g.,propranolol&morphine).2023/12/815Alteredpharmacokinetics-distributionThechangesofbodycompositioninelderly:Increasedfatmass,theproportionofmuscleandwaterreductionDecreasedvolumeofdistributionandincreasedconcentrationofwater-solubledrugs.Increasedvolumeofdistributionandincreasedhalf-lifeforfat-solubledrugs.Decreasedserumalbuminandincreasedfreefractionofaciddrugs.Increasedalpha-1acidglycoproteinanddecreasedfreefractionofbasicdrugs.2023/12/816Alteredpharmacokinetics-metabolismTheliveristhemajororganfordrugmetabolism,phaseI(Redoxhydrolysisreaction)andphaseII(conjugationreaction).1.Age-relateddecreasesinphaseImetabolismareduetoreducedlivervolume,andreducedhepaticenzymaticactivityP450activitydecreased---increasedt1/2

fordiazepam,piroxicam,theophylline,andquinidine.2.PhaseIImetabolismisrelativelyunaffectedbyage.ActivityofGlucuronicacidcombinedenzymeunchanged3.Age-relateddecreasesinliverbloodflowcansignificantlydecreasethemetabolismofhighhepaticextractionratiodrugs(imipramine,lidocaine,morphine,andpropranolol).2023/12/817Alteredpharmacokinetics-eliminationDecreasedclearanceandincreasedhalf-lifeofrenaleliminateddrugs,includingacetazolamide,amantadine,aminoglycosides,atenolol,captopril,cimatidine,digoxin,lithium,andvancomycin.2023/12/818AlteredpharmacodynamicsMoresensitivetomanydrugspossiblemechanisms:1.Changesinreceptornumbers2.ChangesinreceptoraffinityMoresensitivetobenzodiazepine;greateranalgesicresponsetonarcotics;enhancedanticoagulantstowarfarinandheparin;Butdecreasedsensitivitytobetaagonistsandantagonists.2023/12/819ClinicalgeriatricsChallenges:1.Commonproblemsseeninelderly-performbasicactivitiesofdailyliving.2.Multiplecoexistingchronicillnesses.3.Diagnosis-50%ofolderpatientspresentwithatypicalsymptoms.2023/12/820Atypicaldiseasepresentationintheelderly

1.Acutemyocardialinfarction-only50%presentwithchestpain.2.Gastrointestinalbleeding:non-specificsymptoms(mentalstatuschanges,syncope).3.Congestiveheart

failure-nodyspnea,butwithhypoxiasymptoms.4.Urinarytractinfection-nodysurina,fever,andflankpain,butwithincontinence,confusion,abdominalpain.5.Upperrespiratoryinfection-nofever,chillsandcough,butwithlethargy,confusion,andanorexia.2023/12/8212023/12/822Drug-relatedproblemsintheelderlyTwonegativeoutcomes:1.Therapeuticfailure19%ofdrugrelatedhospitaladmissionswereinadequatedrugtherapy.2.AdversedrugeffectsMorecommon.2023/12/823Riskfactorsofdrug-relatedproblems

InappropriateprescribingInappropriateprescribingisdefinedasprescribingofmedicationsoutsidetheboundsofacceptedstandards,orasthosedrugswhoseuseshouldbeavoided,becausetheriskoutweighsthebenefit.¾medicationsfortheelderlyareinappropriatelyprescribed.50%ADRscausinghospitaladmissionsinelderlypatientswereduetoinappropriateprescribingofdrugswithcontraindicationsorinteractions.2023/12/824Riskfactorsofdrug-relatedproblems

UnderuseNecessarydrugsomittedbylackofphysicianprescribing.UnderuseofdrugforHypertension,cancerchemotherapy,depression,andmyocardialinfarction.Especially,depressionintheelderlyisanillnessthatisunderdiagnosedandundertreated.2023/12/825Riskfactorsofdrug-relatedproblems

MedicationcomplianceMedicationnoncomplianceiscommonproblemintheelderly.Theprevalenceisreportedtorangefrom40%to70%.Thosepatientsmaybecompliantwithupto75%ofmedications.SomemedicationnoncompliancemayberelatedtoADRs.2023/12/826OptimalpharmacotherapyfortheelderlyPrinciplesofpharmacotherapy:1.Considerwhetherdrugtherapyisabsolutelynecessary.2.Streamlinethenumberofmedicinesneededtotreatcommonproblems.3.Adjustdosesand/ordosageintervalsformedications.4.Establishreasonabletherapeuticendpointsandmonitorforthesedesiredoutcomes.5.MonitorADRs.6.Encouragecompliance.7.Regularlyreviewforlong-termmedications.2023/12/827Pediatrics2023/12/828DefinitionsPediatricpatients:<18-yearsold.Premature:Newborninfantsbornbefore37weeksofgestationalage.Neonates:1day-1month.Infants:1month-1year.Earlychildhood:1-3yearsold,alsoknownastheageofthenurseryPreschoolage:3yearsoldto7,6yearsofageSchoolage:6,7yearsoldto11,12yearsofageAdolescents:12–18years.2023/12/829ProblemsofmarketeddrugsusedinpediatricpatientsOnly¼ofthedrugsapprovedbyFDAhaveindicationsspecificforuseinthepediatricpopulations.Dataonthepharmacokinetics,pharmacodynamics,efficacy,andsafetyofdrugsininfantsandchildrenarescarce.“Wearenotlittleadults!”30新生儿(neonate，newborn)离开母体结扎脐带～出生后28d内从宫内到宫外，首次独立面对外界生存环境，需完成一系列适应性生理变化。新生儿阶段是人类自身比较特殊时期，药物治疗也表现特殊性。2023/12/831PhysiologicalcharacteristicsintheneonateReducedgastricacidsecretionGastricemptydelayedUnderdevelopedepidermalbarrierIncreasedskinhydrationLowerplasmaproteinconcentrationLowerbindingcapacityofproteinHepaticoxidativemetabolismandglucuronideconjugationaredeficientReducedglomerularfiltrationrateRenaltubularfunctionareimmature2023/12/832Physiologicalcharacteristicsintheneonate2023/12/833Disasters1.Graybabysyndrome---chloramphenicolLackofG6PD---chloramphenicolaccumulation--toxicitydoes100-300mg/kg/d,serumconcentration75-100microg/mlvomiting,diarrhea,respiratorydistress,hypotension,shock.2023/12/8342.Kernicterus---sulfonamidesDisplacebilirubinfromprotein-bindingsitesintheblood---hyperbilirubinemia---passthroughblood-brainbarrier---depositioninthebrain---braindamagesClinicalmanefestation:Sleepiness,suckingreflexweakenedandhypotoniaDisasters2023/12/835Absorption-Gastrointestinaltract1.pH-dependentpassivediffusionFull-terminfants–6-8atbirth,1-3within24hrs.Prematureinfants–highergastricpH–immatureacidsecretion.2.GastricemptyingPrematureinfants–slower3.gastricsmallcapacity,cardiacrelaxation,pronetoexcessivemilkorvomiting4.swallowingabilityispoor,asyrupagentcanbeused,insteadoftablets2023/12/8362023/12/837Absorption-skinPercutaneousabsorptionissubstantiallyincreasedinnewborninfants–

underdevelopedepidermalbarrierandincreasedskinhydration.Toxiceffects–hexachlorophenesoapsandpowders,salicylicacidointment,andrubbingalcohol.Theophylline–prematureinfants-topicalapplication-apnea2023/12/838Absorption–routeofadministrationintravenousdruguse:fastabsorption,drugefficacyismorereliableskinormucosatothemedicine:delicateskinandmucousmembranes,richbloodvessels,absorbquickly,soitisnotsuitableforlong-termorlargeareaofskintothemedicinespecialrouteofadministration:Breastfeeding:ifnecessaryumbilicalcordbloodvessels:caution2023/12/839DistributionPhysiologicalcharacteristicsPrematureneonateinfantchildadultTotalbodywater8570706560(%ofweight)Fat(%ofweight)1151515202023/12/840DistributionPrematureneonateinfantchildadultTotalbodywater8570706560(%ofweight)Fat(%ofweight)115151520影响因素药物分布特点1体液成分及体脂：体液量大(80%)，细胞外液占45%，脂肪含量低水溶性药物：Vd↑Cmax↓、t1/2↑、细胞内药物浓度高(内/外＜成人)脂溶性药物：游离↑，脑部↑2血浆蛋白结合率：蛋白合成少、亲和力低、胆红素竞争结合游离药物↑药物敏感性↑核黄疸：水杨酸类、磺胺类、安定→置换胆红素→核黄疸3血脑屏障：功能不完善，通透性高药物易入中枢：1.有助于细菌性脑膜炎的治疗；2.全麻药、镇静催眠剂、吗啡等可造成中枢损害41年龄越小肝药酶越不成熟经肝代谢药物t1/2

↑↑葡萄糖醛酸转移酶缺乏葡萄糖醛酸结合力差灰婴综合症胆汁不易排出

经胆汁排泄药物易蓄积氯霉素药物不良反应（茶碱、地西泮、苯巴比妥）Metabolism2023/12/842MetabolismDrugmetabolismissubstantiallyslowerininfantscomparedwitholderchildrenandadults.Thematurationofvariouspathwaysofmetabolismwithinaprematureinfantaredifferent.Chloramphenicol–decreasedmetabolismofdrugbyG6PD----graybabysyndrome.43肾有效血流量仅成人20%-40%新生儿肾清除率低下

经肾排泄原型药物清除减慢→t1/2

↑

青霉素G、氨基糖苷类、磺胺类、地高辛等新生儿肾小球滤过率仅成人25%-40%肾小管排泄能力仅成人20%-30%Elimination2023/12/844EliminationTheprocessesofglomerularfiltration,tubularsecretion,andtubularreabsorptiondeterminetheefficiencyofrenalexcretion.Theseprocessesmaytakeseveralweekstooneyearafterbirthtodevelopfully.药物通过乳汁排泄小分子、蛋白结合率低、脂溶性强的有机碱类药物易进入乳汁哺乳期禁用药物抗甲状腺药丙硫氧嘧啶抗凝血药苯茚二酮吗啡氯丙嗪碳酸锂氨基甙类四环素等Drugefficacyandtoxicity神经系统血脑屏障通透性高，阿片类药物极易出现呼吸中枢抑制，如吗啡。血液系统G6PD缺乏症，易发生高铁血红蛋白血症，并导致溶血现象禁用新生霉素、磺胺、水溶性维生素K等药物骨骼系统四环素Tetracycline

-牙齿变黄，影响牙齿和骨骼生长肾上腺皮质激素，如地塞米松、强的松引起生长发育迟缓、骨质疏松而骨折维生素A不足者：减慢骨骺软骨细胞的成熟过量：影响软骨发育，对软骨细胞造成不可逆损伤其他系统可引起新生儿高胆红素或核黄疸的药物磺胺类、甲氧苄啶、水杨酸类、维生素K3等可引起新生儿高铁血红蛋白血症的药物磺胺类、对氨基水杨酸、非那西汀等2023/12/848TheprincipleofrationaldruguseinpediatricsChoosetherightmedicineCalculatetheappropriatedoseChoosetherightRouteofadministrationUseappropriatedosageformIndividualizeddosingandmonitoring2023/12/849抗生素氨基糖苷类--肾和听力障碍氯霉素--灰婴综合征喹诺酮类--颅压升高、骨骼发育障碍四环素--牙釉质发育不良解热镇痛抗炎药物对乙酰氨基酚：3岁以下幼儿因肝肾功能发育不完善，应避免使用。布洛芬：6m以下小儿慎用；布洛芬混悬液为FDA推荐的婴幼儿退热药；吲哚美辛：在幼儿体内代谢缓慢，半衰期长达18-28h，对幼儿血小板抑制作用较强，可产生严重全身毒性反应，如肾毒性、出血性肠炎、坏死性小肠结肠炎等，因此14岁以下儿童禁用。（一）药物选择镇咳、祛痰药：婴幼儿呼吸道狭窄，炎症时粘膜肿胀，渗出物多，可以祛痰消炎为主，选用支气管扩张药和祛痰剂，不宜使用中枢镇咳药。止泻剂：选用微生态制剂或粘膜保护剂，不建议使用止泻药，疗效不明显且不良反应多激素：大剂量或长期使用可致免疫功能低下52（二）确定剂量按体重计算按体表面积计算——最为科学按年龄折算2023/12/853OptimaldosageDose=(patient’sbodysurface/adul