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KATZUNG CHAPTER 3

PHARMACOKINETICS & PHARMACODYNAMICS



CLEARANCE
o Measure of the ability of the body to eliminate the
drug
o Has an additive character
o 2 major sites of elimination: KIDNEYS and LIVER
o CL = rate of elimination / concentration

A) Capacity limited elimination/ Mixed order/
Saturable/ Dose or Concentration dependent/ Non
linear/ Michaelis Menten Elimination
o Phenytoin, Ethanol, Aspirin
o Clearance is dependent on concentration of
drug that is achieved
o Rate of elimination = Vmax x C/ Km + C
o Vmax = maximum elimination capacity
o Km = Drug concentration where rate of
elimination is 50% of Vmax
o If dosing rate exceed elimination capacity,
steady state cant be achieved
B) Flow dependent elimination
o Rate of drug delivery to organ of
elimination determines elimination of drug
o Called HIGH EXTRACTION DRUGS almost
completely extracted from blood by organs
VOLUME OF DISTRIBUTION
o Measure of apparent space in the body available to
contain the drug
o V = amount of drug in the body / concentration of
drug in blood or plasma
o V = conc. In extravascular tissues than in
vascular component not homogeneously
distributed
o Drugs retained in vascular component = V
HALF LIFE
o The time required to change the amount of drug in
the body by during elimination or in a constant
infusion
o T1/2 = 0.7 x Volume of distribution/ clearance
o Indicated the time required to attain 50% of steady
state or to decay 50% from steady state after a
change in the rate of drug administration
DRUG ACCUMULATION
o Inversely proportional to fraction of dose lost in
each dosing interval
o Fraction lost = 1 minus fraction remaining just
before next dose
o Peak concentrations after intermittent doses at
steady state = peak concentration after the first
dose multiplied by the accumulation factor

BIOAVAILABILITY
o Fraction of unchanged drug reaching systemic
circulation following administration by any route
o AUC is proportional to extent of bioavailability if
elimination is first order
SITE BIOAV % REMARKS
Intravenous 100 Most rapid onset
Intramuscular 75 to 100 Large volumes
Subcutaneous 75 to 100 Smaller volumes
Oral 5 to 100 Most convenient;
significant first
pass
Rectal 30 to 100 Less first pass
than PO
Inhalation 5 to 100 Very rapid onset
Transdermal 80 to 100 Very slow
absorption;
prolonged
duration of
action
A) Extent of Absorption
If too hydrophilic, drug cant cross lipid cell
membrane
If too lipophilic, drug isnt soluble enough to cross
water adjacent to cell
Inhibition of P-glycoprotein and gut wall
metabolism = absorption of drug
B) First Pass Elimination
Reduction in bioavailability when drug enters gut
wall portal blood liver systemic
circulation
Extraction ratio (ER) = CL liver / Q
Q = hepatic blood flow 90L/h in a 70kg person
Systemic bioavailability of drug (F) = f x (1-ER)
f = extent of absorption
C) Rate of Absorption
Determined by site of administration and drug
formulation
D) Zero Order Drug Absorption
Rate is independent of the amount of drug
remaining in the gut which is determined by rate
of gastric emptying or controlled release drug
formulation
E) First Order Drug Absorption
When dose is dissolved in the gastrointestinal
fluids, the rate of absorption is proportional to
gastrointestinal concentration
EXTRACTION RATIOS AND FIRST PASS EFFECT
o Systemic clearance is not affected by bioavailability
but can affect extent of availability cause it
determines extraction ratio
o Drugs with extraction ratios show marked
variations in bioavailability between subjects due
to differences in hepatic function and blood flow
ALTERNATIVE ROUTES OF ADMINISTRATION AND
FIRST PASS EFFECT
o Hepatic first pass avoided by sublingual tablets/
transdermal preparations/ rectal suppositories