Pharmacokinetics: General Principles-Lecture I, slide 1
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Absorption
Fick's Law
Routes of
Administration
First-Pass Effect
Pulmonary
Effects
Pharmacokinetics
Volume
of distribution
Clearance
Renal clearance: clearance of
unchanged drug and metabolites
Other Factors Affecting
Renal Clearance
Factors Affecting Hepatic
Clearance
Capacity-Limited Elimination
Half-life
Drug Accumulation
Bioavailablity
Extent of Absorption
First-Pass Elimination
Rate of Aborption
Placental
Transfer
Redistribution
Drug-Plasma
Protein Binding
Renal Clearance
Drug
Metabolism
Introduction
Phase
I and Phase II Reaction Overview:
Phase
I characteristics
Phase
II characteristics
Conjugates
Principal
organs for biotransformation
Sequence
I
Sequence
II
Bioavailability
Microsomal
Mixed Function Oxidase System and Phase I Reactions
The
Reaction
flavoprotein--NADPH
cytochrome P450 reductase
Cytochrome
P450: -- terminal oxidase
P450 Enzyme Induction
P450 Enzyme Inhibition
Human
Cytochrome P450
Phase II Reactions
Toxicities
Individual
Variation in Drug Responses
Genetic
Factors in Biotransformation
Effects
of Age on Drug Responses
Drug-Drug
Interactions
Pharmacokinetics
and some IV Anesthetics Agents
Barbiturates
Thiopental
Benzodiazepines
Ketamine
and Etomidate
Propofol
Opioids
Membrane
Bilayer Structure
Absorption
Principles:
I. Aqueous diffusion
Within large aqueous components
(e.g.,interstitial space, cytosol)
Across epithelial
membrane tight junctions
Across endothelial
blood vessel lining
through aqueous
pores: allows diffusion of
molecules with molecular weights
up to 20,000 -- 30,000.
Driving force: drug
concentration gradient (described by Fick's Law ).
The driving force represents a
tendency for molecules to move in the direction of
higher concentration to lower concentration in accord
with random molecular motion. A traditional way of
thinking about this is to imagine a fluid-filled
container which is two sections divided by an
imaginary plane. The solution on one side is
more concentrated in terms of some dissolved substance
that is the solution on the other side of the boundary
plane.
Recall that the molecules move
randomly, suggesting that sometimes a molecule
initially in the "low concentration" section
can move to the "high concentration"
section. However, on balance. It is more
likely that based on probability molecules will tend
to move from the higher concentrations side to the
lower concentrations side. Suppose that
initially there are 2,000 molecules on side A and
1,000 molecules on side B. After a while we look again
and find that there now are 1750 molecules on side A
and 1250 molecules on side B-- a new ratio is been
established, but the process continues until the ratio
is approximately 1:1.
Fick's Law
Fick's Law describes passive
movement molecules down its concentration
gradient.
Flux (J)
(molecules per unit
time) = (C1 -
C2) · (Area ·Permeability coefficient) / Thickness
where C1
is the higher concentration and C2
is the lower concentration
area = area across which diffusion
occurs
permeability coefficient: drug
mobility in the diffusion path
for lipid diffusion,
lipid: aqueous partition coefficient --
major determinant of drug mobility
partition
coefficient reflects how easily
the drug enters the lipid phase
from the aqueous medium.
thickness: length of the diffusion
path
Katzung, B. G. Basic
Principles-Introduction , in Basic and Clinical
Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998,
p 5.
Plasma protein-bound drugs
cannot permeate through aqueous pores
Charged drugs will
be influenced by electric field
potentials {membrane potentials,
important in renal, trans-tubular
transport}
above to
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