Pharmacokinetic, Pharmacodynamic and Clinical .ภาควิà¸à¸²à¹€à¸ à¸à¸±à¸à¸§à¸´à¸—ยา ... Pharmacokinetic process

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  • Pharmacokinetic, Pharmacodynamicand Clinical Application

    ..

  • Pharmacology

    Pharmacokinetic :

    Pharmacodynamic :

  • Metabolism & Elimination

    Drug concentration in systemic circulation

    Dose of drug

    administered

    Drug concentration at site of action

    AbsorptionDistribution

    Drug in tissues

    Drug metabolized

    and excreted

    PKs

    Pharmacological effect

    EfficacyToxicity

    Clinical responsePDs

    Relationship between Pharmacokinetics and Pharmacodynamics

  • Pharmacokinetic

    the rate and manner in which drugs are absorbed, distributed,

    metabolized and eliminated within and from the body

    What the body does to the drug

  • Dosage regimen Effects

    PHARMACOKINETICS PHARMACODYNAMICS

    PlasmaConcen-tration

    Sitesof

    action

  • Pharmacokinetic = A D M E

    A

    D

    M

    E

  • Pharmacokinetic process

    Absorption- For local effect

    * Application to skin* Application to mucous membranes

    # nose, throat, mouth, eye, genitourinary tract* Oral administration (limited)

    # cathartics, antacids or drugs used to treat parasiticor bacterial infections of gastrointestinal tract

    * Various techniques for administering local anesthetics or agents useful in pulmonary diseases

  • Pharmacokinetic process

    Absorption- For systemic effect

    * Sublingual administration* Oral administration* Rectal administration* Inhalation* Subcutaneous administration* Intramuscular administration* Intravenous administration* Intrathecal (injection into spinal subarachnoid space)

  • Pharmacokinetic process

    Absorption from GI tract

    FIGURE :Drug concentration-time curve following a single oral dose showing the maximum systemic exposure (Cmax) and the time of its occurrence (tmax). The concentration could represent drug in whole blood, plasma, or serum.

    Area under the curve (AUC)

  • Pharmacokinetic processDistribution

    - Occurs when drugs reach the systemic circulation

    - 2 phases: initial phase, distribution phase

  • Pharmacokinetic processDistribution

    - Plasma drug concentration depends on

    * Dose taken

    * Distribution of drug after absorption

  • Pharmacokinetic processDistribution

    - Special barrier to distribution

    * Blood-brain barrier ---> permeable only lipid-soluble drugs

    or low molecular weight

    - Redistribution

    * Lipid-soluble drugs redistribute into fat tissues

    * Resulting in longer duration than the first dose

    * Amiodarone ---> deposit in adipocytes ---> long half-life

  • Pharmacokinetic processDistribution

    - Plasma protein binding

    * Competition (drug-drug interaction)

    # high plasma protein binding

    * Hypoproteinemia (hypoalbuminemia)

    # transient increase ratio of free form : bound form drug

    # transient increase therapeutic effect & adverse effect

    of drugs

  • Pharmacokinetic processDistribution

    - Plasma protein binding

    FIGURE 4-19. The percent of drug in plasma unbound varies widely among drugs.

    Flurbiprofen

  • Pharmacokinetic processConditions in which the plasma concentration of the

    two major plasma proteins to which drugs bind are altered

    Plasma protein Condition Change in concentrationof plasma protein

    Albumin Hepatic cirrhosis DecreaseBurn DecreaseNephrotic syndrome DecreaseEnd-stage renal disease DecreasePregnancy Decrease

    1-Acid glycoprotein Myocardial infarction IncreaseSurgery IncreaseCrohns disease IncreaseTrauma IncreaseRheumatoid arthritis Increase

  • Pharmacokinetic processDistribution

    - Volume of distribution (Vd)

    * Calculate loading dose

    # an initial higher dose of a drug that may be given at the

    beginning of a course of treatment before dropping

    down to a lower maintenance dose

    * Needed to rapidly achieve a therapeutic response

    * Ex: phenytoin loading dose

    Loading dose = Vd x Cp

  • Pharmacokinetic processDistribution

    - Volume of distribution (Vd)

    FIGURE 4-17. The apparent volume into which drugs distribute varies widely.

  • Pharmacokinetic processBiotransformation (Metabolism)

    - Termination of activities

    - Generation of active compounds

    - Transform into more water-soluble

    - Liver is the major site

    - Phase I & Phase II reactions

  • Pharmacokinetic processBiotransformation (Metabolism)

    - Phase I reactions

    * Oxidation

    * Reduction

    * Hydrolysis

  • Pharmacokinetic processBiotransformation (Metabolism)

    - Microsomal enzymes

    Cytochrome P450 mixed function oxidase (CYP450)

    * Major enzyme systems involved in phase I reactions

    * CYP450 superfamily

    CYP3A4

    CYP2D6

    CYP2C9

    CYP2C19CYP1A2

    CYP3A4Family

    SubfamilyGene product

  • Pharmacokinetic processBiotransformation (Metabolism)

    - Enzyme inducers

    * Induced enzyme synthesis that use in biotransformation

    of substrate drugs (clinically significant effect ~ 2 weeks)

    * Decrease therapeutic effects of substrate drugs

    * Ex: rifampicin, carbamazepine, phenytoin, phenobarbital,

    griseofulvin

  • Pharmacokinetic processBiotransformation (Metabolism)

    - Enzyme inhibitors

    * Inhibit enzyme activity that use in biotransformation

    of substrate drugs (clinically significant immediate effect)

    * Increase therapeutic & adverse effects of substrate drugs

    * Ex: cimetidine, erythromycin, azole antifungals, amiodarone,

    fibrates, protease inhibitors

  • Pharmacokinetic processBiotransformation (Metabolism)

    - Phase II reactions

    * Conjugation with endogenous compounds

    # glucuronidation

    # acetylation

    # sulfation

    # methylation

  • Pharmacokinetic processBiotransformation (Metabolism)

    - Factors affecting biotransformation

    * Genetics

    * Other drugs

    * Environmental pollutants

    * Disease

    * Age

  • Pharmacokinetic processExcretion

    - Kidney is most important

    * Glomerular filtration

    * Passive tubular reabsorption

    * Active tubular secretionFIGURE 5-13. Schematic representation of the functional unit of the kidney, the nephron. Drug enters the kidney via the renal artery and leaves partly in the exiting renal vein and partly in urine. Urinary excretion (4) is the net effect of glomerular filtration of unbound drug (1) and tubular secretion (2), processes adding drug into the proximal part of the lumen of the tubule, and tubular reabsorption of drug from the lumen and collecting tubule back into the perfusing blood (3).

  • Concn

    Time (h)

    0 1 2 4

    C0

    C = C0e-kt

    Dose t1/2

    10

    8

    6

    4

    2

  • Pharmacokinetic processExcretion

    - Elimination kinetics

    * First-order kinetics

    * Zero-order kinetics

  • Pharmacokinetic processExcretion

    - Elimination kinetics

    * First-order kinetics

    # Type of elimination for most drugs

    # Rate of elimination is directly proportional to plasma level

    # Exponential decay versus time

    Time (h)

    Plas

    ma

    conc

    entra

    tion

  • Pharmacokinetic processExcretion

    - Elimination kinetics

    * Zero-order kinetics

    # Constant rate of elimination

    # Independent of plasma concentration

    # Saturation kinetics (saturated metabolizing enzymes)

    # Narrow therapeutic index ---> high toxicity

    # Phenytoin, theophylline, ethanol

    Time (h)

    Plas

    ma

    conc

    entra

    tion

  • Pharmacokinetic processExcretion

    - Biliary excretion

    * Enterohepatic circulation

    - Other routes: feces, milk, saliva

    FIGURE 2-10. Drugs sometimes are excreted from the liver into the bile and stored in the gall bladder. On emptying the gall bladder, particularly when induced by food, drug passes into the lumen of the small intestine, where it may be absorbed into a mesenteric vein draining the small intestine and colon, and conveyed by blood back to the liver via the portal vein. The drug has then completed a cycle, the enterohepatic cycle, as shown in color.

  • PHARMACODYNAMICS

  • Definition

    study of the biochemical and physiological effects of drugs and their mechanisms of action

    how drugs affect the body

    the interaction of drugs with receptors

    the consequences of this interaction

    What the drug does to the body

  • Metabolism & Elimination

    Drug concentration in systemic circulation

    Dose of drug

    administered

    Drug concentration at site of action

    AbsorptionDistribution

    Drug in tissues

    Drug metabolized

    and excreted

    PKs

    Pharmacological effect

    EfficacyToxicity

    Clinical responsePDs

    Relationship between Pharmacokinetics and Pharmacodynamics

  • Targets for drug binding

    Protein structure :-

    receptors (physiological receptor of endogenous ligands :-hormones, growth factors, neurotransmitters and autacoids)

    enzymes (e.g., DHFR* , AChE*)

    ion channels (Na+ K+-ATPase)

    carrier molecules (Na-K-2Cl cotransporter, proton pump)

    secreted glycoproteins

    cytoskeleton (tubulin)

    Non-protein :-

    nucleic acid for chemotherapeutic drug

    DHFR* = Dihydrofolate reductase, AChE* =Acetylecholinesterase

  • Drug-Receptor Interaction

    Drugs that bind to receptors