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Module 2.pdf

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

Description
PHARMACOKINETICS▯–▯ABSORPTION▯ 2.1▯INTRODUCTION▯ Pharmacokinetics▯ ▯ Is▯defined▯the▯study▯of▯drug▯movement▯in▯the▯body.▯▯ ▯ Is▯what▯the▯body▯does▯to▯the▯drug.▯ ▯ Pharmacokinetics▯is▯composed▯of▯four▯basic▯processes:▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ Absorption ▯ ▯ ▯ Drug▯absorption▯is▯the▯movement▯of▯the▯drug▯from▯the▯site▯of▯administration▯into▯the▯blood.▯▯ ▯ The▯rate▯of▯absorption▯determines▯how▯quickly▯the▯drug▯effect▯will▯occur.▯ ▯ The▯amount▯of▯drug▯absorption▯determines▯how▯intense▯the▯effect▯of▯the▯drug▯will▯be.▯▯ ▯ 2.2▯FACTORS▯AFFECTING▯ ABSORPTION▯ ▯ 1) Rate▯of▯Dissolution▯ 2) Surface▯Area▯ 3) Blood▯Flow▯ 4) Lipid▯Solubility▯ 5) pH▯Partitioning▯ 6) Activity▯of▯Drug▯Transport▯Proteins▯▯ ▯ 1) Rate▯of▯Dissolution ▯ ▯ ▯ Dissolution▯means▯dissolving▯in▯solution.▯ ▯ Drugs▯must▯dissolve▯before▯they▯can▯be▯absorbed.▯▯▯ ▯ Drugs▯with▯a▯fast▯rate▯of▯dissolution▯will▯have▯a▯faster▯ onset▯of▯action▯than▯drugs▯with▯slow▯dissolution.▯▯▯ ▯ The▯ example▯ to▯ the▯ right▯ shows▯ drugs▯ placed▯ in▯ a▯ liquid.▯▯ Over▯ time▯ dissolution ▯ occurs▯ and▯ the▯ drug▯ molecules▯are▯dissolved▯in▯the▯liquid.▯▯The▯same▯thing▯happens▯when▯we▯swallow▯a▯medication,▯ the▯tablet▯undergoes▯disintegration▯and▯the▯medication▯dissolves▯in▯our▯stomach▯contents.▯ ▯ 2) Surface▯Area ▯ ▯ ▯ Surface▯area▯is▯a▯major▯determinant▯of▯drug▯ absorption.▯ ▯ The▯larger▯ the▯surface▯area,▯the▯faster▯drug▯ absorption▯is.▯ ▯ Which▯has▯the▯greater▯surface,▯the▯stomach▯ or▯the▯small▯intestine?▯▯ ▯ While▯the▯stomach▯has▯folds▯called▯rugae,▯the▯ intestine▯ has▯ thousands▯ of▯ finger▯ like▯ projections▯called ▯villi.▯▯ The▯villi▯that▯line▯the▯ intestine▯make▯the▯surface▯area▯very▯large.▯ ▯ 3) Blood▯Flow ▯ ▯ ▯ Drug▯absorption▯is▯fastest▯in▯areas▯with▯high▯blood▯flow.▯▯▯ ▯ Areas▯with▯a▯high▯blood▯flow▯maintain▯a▯concentration▯gradient▯which▯drives▯absorption.▯ ▯ Areas▯with▯low▯blood▯flow▯do▯not▯maintain▯as▯great▯of▯a▯concentration▯gradient.▯ ▯ Exercise▯increases▯blood▯flow▯and▯can▯increase▯drug▯absorption.▯ ▯ Blood▯flow▯is▯decreased▯in▯heart▯failure,▯severe▯hypotension,▯hypothermia▯and▯circulatory▯shock.▯▯ ▯ 4) Lipid▯Solubility▯ ▯ ▯ Drugs▯ with▯ high▯ lipid▯ solubility▯ (i.e.▯ lipophilic▯ drugs)▯ are▯ absorbed▯more▯rapidly▯than▯water▯soluble▯(i.e.▯hydrophilic)▯ drugs.▯ ▯ Lipophilic▯ drugs▯ are▯ able▯ to▯ cross▯ the▯ cell▯ membrane▯ whereas▯hydrophilic▯drugs▯can’t.▯▯ ▯ ▯ ▯ 5) pH▯Partitioning▯ ▯ ▯ Drug▯ absorption▯ is▯ greater▯ when▯ there’s▯ a▯ difference▯ between▯the▯pH▯at▯the▯site▯of▯administration▯and▯the▯blood▯ such▯that▯the▯drug▯is▯ionized▯in▯the▯blood.▯▯ ▯ Remember▯ the▯ effect▯ of▯ pH▯ dependent▯ ionization▯ from▯ Module▯1!▯▯ 6) Activity▯of▯Drug▯Transport▯Proteins▯▯ ▯ ▯ The▯ rate▯ and▯ extent▯ of▯ drug▯ absorption▯ can▯ be▯ significantly▯impacted▯by▯drug▯transporters.▯ ▯ Uptake▯ drug▯ transporters▯ increase▯ the▯ absorption▯ of▯ drugs.▯ ▯ Efflux▯ drug▯ transporters▯ decrease▯ the▯ absorption▯ of▯ drugs.▯▯ ▯ ▯ ▯ ▯ ▯ 2.3▯ROUTES▯OF▯ADMINISTRATION ▯ ▯ ▯ There▯are▯8▯major▯routes▯of▯drug▯administration▯summarized▯below.▯ ▯ 1) Oral▯(PO▯=▯per▯os▯which▯is▯latin▯for▯by▯mouth)▯ 2) Sublingual▯ 3) Transdermal▯▯ 4) Rectal▯ 5) Intravenous▯(IV)▯ 6) Subcutaneous▯(SubQ▯or▯SC)▯ 7) Intramuscular▯(IM)▯ 8) Pulmonary▯▯ ▯ ▯ Routes▯of▯administration▯are▯often▯referred ▯to▯as▯enteral▯or▯parenteral.▯ ▯ Enteral▯–▯Routes▯of▯administration▯that▯involve▯the▯gastrointestinal▯tract.▯ ▯ Parenteral▯–▯Routes▯of▯administration▯that▯do▯not▯involve▯the▯gastrointestinal▯tract.▯▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ 1) Oral▯Absorption▯ ▯ Intestine▯vs▯Stomach▯ ▯ ▯ Earlier▯ we▯ discussed▯ the▯ impact▯ of▯ surface▯area▯on▯drug▯absorption▯and▯ determined▯ that▯ the▯ intestine▯ has▯ a▯ much▯ larger▯ surface▯ area▯ than▯ the▯ stomach,▯ therefore▯ drug▯ absorption▯ would▯be▯greater▯in▯the▯intestine▯than▯ the▯stomach.▯ ▯ What▯ about▯ drugs▯ that▯ are▯ weak▯ acids,▯ wouldn’t▯ they▯ be▯ better ▯ absorbed▯in▯the▯stomach?▯ ▯ Based▯on▯the▯pH▯effects▯weakly▯acidic▯ drugs▯ should▯ be▯ better▯ absorbed▯ in▯ the▯ acidic▯ environment▯ of▯ the▯ stomach▯ because▯ they▯ would▯ unionized.▯ ▯ However,▯ the▯ surface▯ area▯ of▯ the▯ stomach▯is▯small▯and▯the▯stomach▯is▯ covered▯with▯a▯thick▯layer▯of▯mucous.▯ ▯ Therefore▯the▯rate▯of▯drug▯absorption▯in▯the▯intestine▯will▯be▯greater▯than▯the▯stomach,▯even▯if▯ the▯drug▯is▯ionized!▯▯ ▯ The▯bottom▯line▯is▯for▯most▯drugs,▯oral▯absorption▯is▯greatest▯in▯the▯intestine.▯▯ Pharmaceutical▯Phase▯ ▯ ▯ The▯ pharmaceutical▯ phase▯ occurs▯ after▯ the▯ patient▯swallows▯a▯tablet.▯ ▯ It▯ involves▯ the▯ disintegration▯ of▯ the▯ tablet▯ and▯the▯dissolution▯of▯the▯drug.▯ ▯ If▯the▯drug▯does▯not▯completely▯disintegrate▯ or▯ does▯ not▯ go▯ into▯ solution,▯ absorption▯ is▯ reduced.▯▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ Gastric▯Emptying▯ ▯ ▯ Gastric▯ emptying▯ is▯ quite▯ simply▯ the▯ movement▯ of▯ the▯ stomach▯ contents▯into▯the▯intestine.▯▯▯ ▯ Since▯the▯rate▯of▯drug▯absorption▯is▯greater▯in▯the▯intestine,▯things▯that▯ increase▯gastric▯emptying▯also▯increase▯the▯rate▯of▯drug▯absorption.▯▯ ▯ ▯ Factors▯Affecting▯Gastric▯Emptying ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ Enteric▯Coating ▯ ▯ ▯ Drugs▯with▯enteric▯coating▯are▯covered▯with▯a▯special▯coating▯that▯ prevents▯their▯dissolution▯in▯the▯acidic▯environment▯of▯the▯stomach.▯▯▯ ▯ Once▯the▯drug▯passes▯into▯the▯more▯alkaline▯duodenum,▯the▯enteric▯ coating▯dissolves.▯▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ ▯ Bioavailability▯ ▯ ▯ Bioavailability▯is▯the▯fraction▯of▯a▯dose▯of▯drug▯that▯reaches▯the▯systemic▯circulation▯unchanged.▯ ▯ Bioavailability▯can▯be▯influenced▯by:▯ 1) Drug▯formulation▯ 2) Route▯of▯Administration▯ 3) Degree▯of▯Metabolism▯▯ ▯ ▯
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