Overview - ABSORPTION

							ADME/T(ox)
   Absorption
   Distribution
   Metabolism
   Excretion
   Toxicology
Overview - ABSORPTION
Some drugs work outside the body (barrier creams,
  some laxatives) but most must:
 enter the body:

ENTERAL (entering the intestine) - oral, sublingual (under the
  tongue), rectal
PARENTERAL - intravenous, subcutaneous,
  intramuscular
 be transported by the blood to the target organ but
  note local delivery (asthma)
 cross lipid barriers / cell walls: gut wall, capillary wall,
  cell wall, blood brain barrier
              ---- and reach the cellular target
Oral Administration
    Oral Administration
   Advantages                     Disadvantages
       Generally the safest           Absorption may be variable
        route                          Gastric irritation may cause
                                        vomiting
       Economical
                                       Not useful if patient is
       Convenient for owner            vomiting
       No need for sterile            Requires cooperation of
        equipment                       patient
       Systemic distribution          Drug may be destroyed by
                                        gastric acidity, gut flora,
                                        mucosal enzymes, liver
                                        enzymes
                                       Onset of effect is slow
                                       Drug dilution
Factors affecting oral
absorption
   Disintegration of dosage form
   Dissolution of particles
   Chemical stability of drug
   Stability of drug to enzymes
   Motility and mixing in GI tract
   Presence and type of food
   Passage across GI tract wall
   Blood flow to GI tract
   Gastric emptying time
Intravenous Injection
        Intravenous Injection
   Advantages                              Disadvantages
       Extremely rapid                         Most dangerous route
       Initial absorption step is by-          Drug must be in aqueous
        passed                                   solution
       Drug levels are more                    Must be performed slowly
        accurately controlled
                                                Once injected, drug cannot
       Good for irritant drugs                  be removed
       Suitable for large volumes
Bioavailability
   the proportion of the drug in a dosage form available
    to the body

i.v injection gives 100% bioavailability.
Says nothing about effectiveness.
Overview - DISTRIBUTION
The body is a container in which a drug is distributed -
  but the body is not homogeneous
  plasma; extracellular fluid; intracellular fluid; +
  special areas (fetus, brain)

 ----- affects concentration at site of action/elimination
Drug Distribution Factors
   Blood Flow
    The rate at which a drug reaches different organs and tissues will
    depend on the blood flow to those regions. Equilibration is rapidly
    achieved with heart, lungs, liver, kidneys and brain where blood flow is
    high. Skin, bone, and fat equilibrate much more slowly.
   Lipid Solubility
    Lipid solubility will affect the ability of the drug to bind to plasma
    proteins and to cross lipid membrane barriers. Very high lipid solubility
    can result in a drug initially partitioning preferentially into highly
    vascular lipid-rich areas. Subsequently these drugs slowly redistribute
    into body fat where they may remain for long periods of time.
Drug Distribution Factors
   Capillary Permeability
    The capillaries in liver are extremely permeable, while those at
    the blood-brain barrier lie at the other extreme. Molecular size is
    the major factor affecting the permeability of water-soluble
    drugs across capillaries.
Overview - METABOLISM
   Drug molecules are processed by enzymes evolved to
    cope with natural compounds
   Drug may have actions increased or decreased or
    changed
   Individual variation genetically determined
   May be several routes of metabolism
   May not be what terminates drug action
   May take place anywhere BUT liver is prime site
   Not constant - can be changed by other drugs; basic
    of many drug-drug interactions
     … metabolism is what the body does to the drug
Sites of biotransformation
   where ever appropriate enzymes occur; plasma,
    kidney, lung, gut wall and

                       LIVER

   the liver is ideally placed to intercept natural ingested
    toxins (bypassed by injections etc) and has a major
    role in biotransformation
Factors affecting
biotransformation
   age (reduced in aged patients &
    children)
   sex (women more sensitive to ethanol)
   species (phenylbutazone 3h rabbit, 6h
    horse, 8h monkey, 18h mouse, 36h
    man); route of biotransformation can
    also change
   Race, clinical or physiological condition
Biotransformation of Drugs
   Phase I
       Usually convert the parent drug to a more polar metabolite
        by introducing or unmasking a functional group (-OH, -NH2,
        -SH). Often these metabolites are inactive, although in some
        instances activity is only modified. If Phase I metabolites are
        sufficiently polar, they may be readily excreted.
   Phase II
       Parent drugs or their Phase I metabolites that contain
        suitable chemical groups often undergo coupling or
        conjugation reactions with an endogenous substance
        (glutathione, glucouronic acid, and sulfuric acid) to yield
        drug conjugates. In general, conjugates are polar molecules
        that are readily excreted and often inactive
Overview - EXCRETION
   Urine is the main but NOT the only route.
   Glomerular (kidney) filtration allows drugs <25K
    MW to pass into urine; reduced by plasma
    protein binding; only a portion of plasma is
    filtered.
   Tubular secretion active carrier process for
    cations and for anions; inhibited by
    probenicid.
   Passive re-absorption of lipid soluble drugs
    back into the body across the tubule cells.
Special aspects of excretion
   lactating women in milk
   little excreted in feces unless poor
    formulation or diarrhea
   volatile agents (general anesthetics) via lungs