Transcript Overview - ABSORPTION

ADME/T(ox)
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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
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Advantages
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Generally the safest
route
Economical
Convenient for owner
No need for sterile
equipment
Systemic distribution
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Disadvantages
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Absorption may be variable
Gastric irritation may cause
vomiting
Not useful if patient is
vomiting
Requires cooperation of
patient
Drug may be destroyed by
gastric acidity, gut flora,
mucosal enzymes, liver
enzymes
Onset of effect is slow
Drug dilution
Factors affecting oral
absorption
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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
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Advantages
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Extremely rapid
Initial absorption step is bypassed
Drug levels are more
accurately controlled
Good for irritant drugs
Suitable for large volumes
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Disadvantages
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Most dangerous route
Drug must be in aqueous
solution
Must be performed slowly
Once injected, drug cannot
be removed
Bioavailability
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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
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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.
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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
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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
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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
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where ever appropriate enzymes occur; plasma,
kidney, lung, gut wall and
LIVER
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the liver is ideally placed to intercept natural ingested
toxins (bypassed by injections etc) and has a major
role in biotransformation
Factors affecting
biotransformation
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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
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Phase I
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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
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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
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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
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lactating women in milk
little excreted in feces unless poor formulation
or diarrhea
volatile agents (general anesthetics) via lungs