Principles IV

Principles IV

1. Biotransformation

   • Influences...
     • route of administration
     • Dose
     • Effectiveness
     • Toxicity, safety
     • Duration of effect
   • Purpose
     • Drug Detoxification
       • change activity
     • Prepare Drug for Excretion
       • Make drug easier to absorb
         • make larger
         • add more charges
         • make more water soluble
   • Sites
     • Liver
       • SER
       • Cytoplasm
       • Microsomal Drug Metabolizing System
         • Both Phase 1 and 2
         • Undergoes Induction and Inhibition
       • Mixed Function Oxidase System
         • NADPH
         • Cytochrome P450 reductase
           • low ratio of reductase to P450
         • Cytochrome P450
           • low specificity
           • Large genetic variation
           • Catalyzes reductions and oxidations
           • Will want to use different P450 systems when giving multiple drugs
             • competition with inhibition
               • potential toxicities
             • Induction
               • decrease effectiveness for a given dose
         • Mg 2+
         • Phospholipid
         • O2
         • Usually lipid soluble drugs
         • Influenced by disease factors, age and sex
     • Anywhere else in the body
       • Non-microsomal System
         • Usually Phase 1
         • Can only be Inhibited
   • Phases
     • Phase 1
       • Oxidation, Reduction, Hydrolysis
       • Expose or Add Functional Groups
     • Phase 2
       • Biosynthetic
       • Conjugation
         • resulting molecule
           • larger, charged, water soluble, inactive
           • Want to remove the molecule
     • Changes from Lipophilic to Hydrophilic
   • Phenotypes of Metabolic Activity
     • Poor
       • Potential Toxicity
     • Intermediate
     • Extensive
     • Ultrarapid
       • potential no effect
       • high first pass metabolism

2. Drug Excretion

   • Renal Excretion
     • Primary Route of elimination of drug or metabolites
     • Entry to the Nephron
       • Glomerular Filtration
         • only free drug molecules
         • depends on
           • GFR
           • free drug concentration
       • Active Tubular Secretion
         • one system for acids, one for bases
         • Inhibition
           • Competitive, will sustain drug levels
         • Saturation
           • Occurs at therapeutic doses or overdoses
             • Zero Order
     • Reabsorption in Nephron
       • Passive
         • lipid soluble drugs
         • reverse concentration gradient occurs in Loop of Henle
       • Active
         • Works for some drugs
     • Enhancing
       • Forced diuresis
       • change pH of urine
         • "pH trapping"
         • Raise urine pH from 5.5 to around 8
   • Excretion Formula
     • Amount of Drug Excreted = (Amount entering Tubule) - (amount reabsorbed)
   • Biliary Excretion
     • Enter Bile by...
       • secretion (active transport)
       • Passive Diffusion
     • Reabsorption through passive diffusion
       • May start Enterohepatic cycling
   • Alternate Routes
     • Lung
     • Sweat
     • Saliva
     • Tears
     • Breastmilk

3. Elimination

   • Decrease [D_plasma}
     • Redistribution
     • Biotransformation
     • Excretion
   • Clearance
     • volume of plasma that is cleared of drug per unit time
     • Clearance Total = Clearance Metabolic + Clearance Renal
       • Liver Disease
         • decreased metabolic clearance
       • Renal Disease
         • reduced renal clearance
     • Factors
       • body surface area
       • protein binding
       • cardiac output
       • renal function
       • hepatic function
       • blood flow to systemic organs