Pharmacokinetics Drug molecules interact with target sites to affect the nervous system –The drug must be absorbed into the bloodstream and then carried to the target site(s) Pharmacokinetics is the study of drug absorption, distribution, metabolism and elimination –Absorption depends on the route of administration –Drug distribution depends on how soluble the drug molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin) –Drug elimination is accomplished by excretion into urine and/or by inactivation by enzymes in the liver

Pharmacokinetics

Routes of Administration Alimentary 消化道 :Oral, Rectal, sublingual Adventages and disadvantages(029109) Parenterally 胃肠外的 : Intravenous, Intramuscular, Subcutaneous Adventages and disadvantages(029110) Inhalation: Absorption through mucous membranes Topical:

Routes of Administration

Drug Delivery Systems Tablets Injections (Syringe) Cigarettes Beverages 饮料 Patches 斑 Suppositories 栓剂 Candy Gum 口香糖 Implants 埋植剂 Gas Creams 乳剂 Others?

Membranes Types of Membranes: Cell Membranes: This barrier is permeable to many drug molecules but not to others, depending on their lipid solubility. Small pores, permit small molecules such as alcohol and water to pass through. Walls of Capillaries: Pores between the cells are larger than most drug molecules, allowing them to pass freely, without lipid solubility being a factor. Blood/Brain Barrier: This barrier provides a protective environment for the brain. Speed of transport across this barrier is limited by the lipid solubility of the psychoactive 影响精神行为的 molecule. Placental Barrier: This barrier separates two distinct human beings but is very permeable to lipid soluble drugs.

absorption Passive diffusion (029106) pH affects (acidic or basic) drug absorption (029107) Active transport (029108)

Drug Distribution Factors affecting drug distribution (029111) Two types of distribution interactions are most common: Protein Binding / Displacement and Cellular Distribution Interactions. Once absorbed, medications are distributed via the circulatory system as both free drug and plasma protein bound drug. Only the free or unbound fraction of the medication is active. Any change in percentage of bound or free drug can alter its availability to receptor sites.

Metabolism (biotransformation) Metabolism often results in inactivation of the drug. Some drugs which were activated by metabolism are called prodrugs. Biochemical reactions involved in drug metabolism: oxidation (liver P450 system); reduction; hydrolysis; conjugation. Two Phases of Drug Metabolism Phase I Biotransformation: Alters chemical structure of the medications. Phase II Conjugation: Results in the addition of a hydrophilic moiety onto a drug or its metabolite enhancing the ability of the kidney to filter the drug into the urine

Liver P450 system Liver enzymes inactivate some drug molecules –First pass effect (induces enzyme activity) –First pass effect(029109) P450 activity is genetically determined: –Some persons lack such activity  leads to higher drug plasma levels (adverse actions) –Some persons have high levels  leads to lower plasma levels (and reduced drug action) Other drugs can interact with the P450 systems –Either induce activity (apparent tolerance) – Inactivate an enzyme system

P450 Interactions The P450 system can be induced, as well as inhibited, by a variety of compounds. Induction of the P450 system can lead to pharmacokinetic tolerance and increased capacity to metabolize a drug. Inhibition of the P450 system results in elevated plasma levels and prolonged half-lives for drugs usually metabolized by the P450 system. –

Drug-Hepatic Interactions Enzyme SubstrateInhibitorInducer –1A2 Clozapine, haloperidolCimetidineTobacco smoke –2B6 Bupropion Thiotepa Phenobarbital –2C19 CitalopramFluoxetinePrednisone –2C9 FluoxetineParoxetineSecobarbital –2D6 Most ADs, APsCPZ, ranitidineDexamethasone –2E1 Gas anestheticsDisulfiramEthanol – 3A4,5,7 AlprazolamGrapefruit juiceGlucocorticoid –

Elimination (Excretion) The half-life (t 1/2 ) Routes of elimination Kidney Biliary tract and the feces Others: expired air, sweat, saliva, tears

Bioavailability (029118) Factors that influence bioavailabity