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Pharm Module 6.pdf

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Department
Pharmacology
Course
Pharmacology 2060A/B
Professor
Dr.Mike
Semester
Fall

Description
CLINICAL▯PHARMACOKINETICS▯–▯TIME▯COURSE▯OF▯DRUG▯ACTION▯ 6.1▯CLINICAL▯PHARMACOKINETICS▯ ▯ The▯underlying▯principle▯of▯clinical▯pharmacokinetics▯is▯that▯a▯relationship▯exists▯between▯the▯ effects▯of▯a▯drug▯and▯the▯concentration▯of▯drug▯in▯the▯body.▯ ▯ In▯clinical▯pharmacokinetics▯we▯try▯to▯provide:▯ ▯ 1) a▯quantitative▯relationship▯between▯drug▯dose▯and▯effect▯▯ 2) a▯framework▯to▯interpret▯measurements▯of ▯drug▯concentrations▯in▯biological▯fluids▯to▯benefit▯ patient▯drug▯therapy.▯ ▯ ▯ The▯most▯important▯parameters▯determining▯drug▯disposition▯in▯humans▯are:▯ ▯ 1) Clearance▯–▯the▯body’s▯efficiency▯in▯drug▯elimination.▯ 2) Volume▯of▯Distribution▯–▯the▯apparent▯space▯in▯the▯body▯available▯to▯contain▯the▯drug.▯ 3) Elimination▯Half▯Life▯(T )▯1/2▯measure▯of▯the▯rate▯of▯removal▯of▯the▯drug▯from▯the▯body.▯ 4) Bioavailability▯–▯the▯fraction▯of▯drug▯that▯reaches▯the▯systemic▯circulation.▯▯▯▯ ▯ 6.2▯PLASMA▯DRUG▯CONCENTRATIONS ▯ ▯ Measuring▯Drug▯Concentrations▯ ▯ ▯ Ideally▯drug▯concentrations▯would▯be▯measured▯from▯the▯site▯ of▯action.▯ ▯ In▯reality,▯this▯is▯not▯feasible.▯ ▯ Let’s▯take▯the▯example▯of▯drugs▯used▯to▯treat▯schizophrenia.▯ These▯drugs▯act▯in▯the▯brain.▯ ▯ Clearly▯ taking▯ a▯ sample▯ from▯ a▯ patients’▯ brain▯ to▯ measure▯ drug▯ concentrations▯ is ▯ invasive▯ and▯ would▯ likely▯ do▯ more▯ harm▯than▯good.▯▯ ▯ ▯ ▯ In▯reality▯drug▯concentrations▯are▯usually▯measured▯ in▯plasma.▯ ▯ Plasma▯ is▯ a▯ good▯ site▯ to▯ measure▯ drug▯ concentrations▯because:▯ ▯ 1) It▯is▯relatively▯non▯invasive▯ 2) For▯most▯drugs▯there▯is▯a▯good▯correlation▯between▯ plasma▯ concentration▯ and▯ therapeutic▯ and▯ toxic▯ drug▯effects.▯ Free▯vs.▯Total▯Plasma▯Drug▯Concentration▯ ▯ ▯ Recall▯that▯drugs▯in▯plasma▯exist▯as▯bound▯to▯plasma▯proteins▯or▯free.▯ ▯ It▯is▯only▯free▯drug▯that▯is▯able▯to▯elicit▯a▯pharmacological▯response.▯ ▯ In▯theory,▯measuring▯free▯drug▯concentration▯would▯be▯ideal▯to▯guide▯drug▯dosing.▯ ▯ In▯reality,▯measuring▯free▯drug▯concentration▯is▯difficult▯and▯tedious▯so▯total▯(free▯+▯protein▯ bound)▯concentration▯is▯usually▯measured.▯ ▯ For▯most▯drugs,▯measuring▯total▯plasma▯concentration▯provides▯enough▯information▯to▯guide▯ drug▯dosing.▯▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ 6.3▯DRUG▯CONCENTRATION▯TIME▯CURVES ▯ ▯ Oral▯Administration▯ ▯ ▯ When▯a▯drug▯is▯administered▯orally▯it▯must▯be▯absorbed▯into▯the▯blood.▯▯▯ ▯ At▯the▯beginning▯the▯rate▯of▯drug▯absorption▯is▯greater▯than▯the▯rate▯of▯drug▯elimination▯so▯ plasma▯drug▯concentrations▯increase.▯ ▯ At▯a▯later▯time▯the▯rate▯of▯absorption▯equals▯the▯rate▯of▯elimination. ▯▯ This▯is▯the▯peak▯of▯the▯ concentration▯time▯curve▯and▯is▯called▯the▯Cmax.▯ ▯ After▯ the▯ Cmax▯ the▯ rate▯ of▯ elimination▯ is▯ greater▯ than▯ the▯ rate▯ of▯ absorption▯ so▯ the▯ concentration▯begins▯to▯decline.▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ Characteristics▯of▯Plasma▯Concentration▯Time▯Curves▯ ▯ ▯ Plasma▯drug▯concentrations▯must▯be▯high▯enough▯to▯have▯a▯therapeutic▯effect▯but▯not▯so▯high▯as▯ to▯induce▯toxicity.▯ ▯ Minimum▯Effectice▯Concentration▯(MEC)▯ o The▯ minimum▯ concentration▯ required▯ to▯ have▯ a▯ therapeutic▯ effect.▯ Drug▯ concentrations▯ below▯ this▯level▯do▯not▯have▯a▯therapeutic▯ effect.▯▯ ▯ Duration▯ o Length▯ of▯ time▯ the▯ drug▯ concentration▯is▯above▯the▯MEC.▯▯ ▯ Toxic▯Concentration▯ o If▯ plasma▯ concentrations▯ are▯ too▯ high,▯toxic▯side▯effects▯will▯occur.▯ ▯ Therapeutic▯Range▯ o Drug▯ concentrations▯ above▯ the▯ MEC▯ but▯ below▯ toxic▯ concentrations.▯▯ The▯ goal▯ of▯ pharmacotherapy▯is▯to▯attain▯plasma▯concentrations▯in▯the▯therapeutic▯range▯▯ ▯ Therapeutic▯Range▯ ▯ ▯ The▯width▯of▯the▯therapeutic▯range▯is▯an▯index▯for▯how▯safely▯a▯drug▯can▯be▯used.▯▯▯ ▯ Drugs▯with▯a▯narrow▯therapeutic▯range▯are▯difficult▯to▯administer▯safely▯since▯there▯is▯only▯a▯ narrow▯window▯where▯the▯drug▯will▯be▯effective▯and▯not▯toxic.▯ ▯ Drugs▯with▯a ▯narrow▯therapeutic▯window▯often▯undergo▯therapeutic▯monitoring▯to▯ensure▯ that▯drug▯concentrations▯are▯within▯the▯target▯range.▯ ▯ **NOTE**▯Therapeutic▯Range▯may▯also▯be▯referred▯to▯as▯the▯therapeutic▯window.▯▯ ▯ Onset▯of▯Action▯ ▯ ▯ Drugs▯ given▯ orally▯ are▯ subject▯ to▯ a▯ lag▯ time▯before▯they▯reach▯the▯MEC.▯ ▯ The▯ lag▯ time▯ varies▯ between▯ different▯ drugs.▯ ▯ The▯rate▯and▯extent▯of▯absorption▯affect▯ the▯onset▯of▯action.▯ ▯ The▯ onset▯ of▯ action▯ determines▯ how▯ soon▯a▯drugs▯effect▯will▯occur.▯ ▯▯ Continuous▯ Intravenous▯Infusion▯ ▯ ▯ In▯ continuous▯ intravenous▯ infusion,▯ the▯ rate▯ of▯ drug▯ entry▯into▯the▯body▯is▯constant.▯ ▯ Using▯ intravenous▯ administration▯ there▯ is▯ no▯ drug▯ absorption▯ as▯ the▯ drug▯ directly▯ enters▯ the▯ systemic▯ circulation.▯▯ ▯ After▯initiation▯of▯the▯infusion,▯the▯plasma▯concentration▯ rises▯ until▯ the▯ rate▯ of▯ elimination▯ equals▯ the▯ infusion▯ rate.▯ ▯ When▯the▯rate▯of▯elimination▯equals▯the▯infusion▯rate▯the▯ plasma▯ drug▯ levels▯ do▯ not▯ change▯ over▯ time.▯▯ This▯ is▯ referred▯to▯as▯steady▯state.▯ ▯ When▯ the▯ infusion▯ is▯ stopped▯ plasma▯ drug▯ concentrat
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