Transcript PHARMACOKINETICS

PHARMACOKINETICS
Definition: quantitative study of
drug absorption, distribution,
metabolism, and excretion
(ADME), and their mathematical
relationship.
Disposition: term used to describe
the simultaneous effect of the
distribution and elimination
(processes subsequent to
absorption).
Absorption
Absorption: passage of drug through
body barriers.
 Transmembrane movement of drugs:
 Passive transfer:

– Simple diffusion
– Filtration

N.B.: Diffusion is most important
means. It is affected by: size of
molecule, conc. Gradient, surface
area, permeability coefficient. (FICK'S
Law).
N.B.: Permeability coeffiecient varies
according to the concentration of ionized
and nonionized form of the drug on both
sides of the membrane, determined by
pka of the drug.
Henderson Hasselbalch equation
pH=pka + log [nonprotonated species/
protonated species]
Specialized transport
– Active transport
1-1ry active transport
2- 2ndry active transport
(Cotransport,countertransport)
– Facilitated diffusion
– Pinocytosis and phagocytosis
Bioavailability:
percentage of drug
released from a
formulation that becomes
available for biological
effect.
Factors affecting bioavailability:
a)Factors affecting absorption from
GIT:
1-Drug
2-Formulation
3-Patients
4-Food.
 b) First pass effect: presystemic
elimination.It is the metabolism of
some drugs in a single passage
through the liver, gut walls, or lungs
before reaching the systemic
circulation.

Hepatic: e.g.:propranolol,
nitroglycerin,cortisone.
Pulmonary: isoprenaline,nicotine.
Intestinal: tyramine,morphine.
*Pulmonary Absorption
*Absorption from subcutaneous
tissues
*Methods for delaying absorption:
a.oral
b.parenteral.
Distribution
Passage of drug between blood and
tissues.
 Compartment concept:
 - one-compartment model
 -Two- compartment model
 Mathematically, apparent volume of
distribution (Vd): apparent volume
that would accommodate all drug in
the body if its conc. throughout the
body was the same as that in the
plasma (not real).

 N.B.:
small volume of
distribution is favored by low
lipid solubility, high degree of
plasma protein binding and
low level of tissue binding, &
vice-versa.

Vd = amount of drug in the body / plasma
concentration.
Importance:
-extent of tissue up-take
-calculation of loading dose
- dialysis

Factors affecting distribution of drugs:
1-Physicochemical properties
2-Size of the tissue and its blood flow.
3-Binding to plasma proteins: a- Albumin
b-α-1-acid glycoprotein
4-Binding to cell and tissue components

 Results
of binding to plasma
proteins:
1-drugs with higher affinity can
displace those with lower.
2-Reservoir
3-Prolongs t 1/2.
4-Determines Vd
5-may facilitate absorption
The bound portion is
inactive,nondiffusible, & cannot
be metabolized or excreted.
–BBB
–Placental barrier
Biotransformation"metabolism"
 Def.:
changes that occur to drug
after absorption until excretion.
 Consequences:
-abolishes activity
-promotes activity
-changes active to another active
form.
Types of reaction:
-Non-synthetic (phase-I): oxidation,
reduction, and hydrolysis.

-Synthetic (phase-II): adds a
constituent to the drug to form highly
polar rapidly eliminated
conjugates"Conjugation". These
include: glucoronic acid,Nacetylation,glycine and sulphuric acid
conjugation.

Factors affecting biotransformation:
species,age,sex, pathological
conditions,environmental factors.
Microsomal enzymes:
 SER of liver.
1-MFO, that requires cytochrome P-450,
NADPH,molecular oxygen
2-metabolize lipid soluble to water soluble
drugs
3-metabolize drugs as well s body as body
constituents
4-lack substrate specificity
5-not well developed in newborn.



Non-microsomal enzyme systems: e.g.peroxidases, oxidases,and dehydrogenases.
N.B.: Enzyme induction
Enzyme inhibition.
Drug Clearance



A measure of the body's ability to
eliminate drugs. It's defined as the
volume of a fluid from which all drug
is removed per unit time.
CLEARNCE (CL)= Rate of elimination /
Drug conc.
May involve: kidney, liver, lungs, and
other organs.
 Factors
affecting clearance:
– Blood flow
– binding to plasma proteins
– activity of the processes involving
blood removal(e.g.: hepatic
enzymes…etc).
 N.B.:
hepatic clearance depends
on: intrinsic activity of metabolic
enzymes and transport
processes, free fraction of drug
and total effective blood flow.


Elimination half-life: the time
required to reduce the plasma
concentration of drug to 1/2 the
initial conc.
t (1/2)=0.693 Vd / CL
Value of t (1/2):
-time required to attain Css.
-Determines dosage interval ( usually =
t 1/2)
-Index of drug elimination

 Firstorder
kinetics:
(non-saturable)
Clearance is directly proportional
to the conc. o the drug in the
plasma, i.e.; the rate of elimination
is exponentially related to the
amount of drug available. This
means that a constant fraction or
ratio of drug is eliminated per unit
time.
Characteristics:
 Constant
t1/2.
 AUC, Css and amount of drug
excreted unchanged in urine; all
are proportional to the dose.
 Composition of the drug
metabolites excreted is
independent of the dose.
Zero-order kinetics (non-linear):
Drug elimination occurs at a constant
rate of the amount of drug to be
eliminated. This means that a
constant amount of drug being
eliminated per unit time.

Characteristics:
1. Half-life increases with dose
2. AUC, Css and amount of drug
excreted unchanged in urine; all not
proportional to the dose.
3. Composition of the drug metabolites
excreted may vary
with the dose.


Saturable kinetics:
The elimination does not follow
first-order kinetics throughout the
dose range. Clearance will vary
depending on the achieved drug
concentration. Many ADME processes
occur via enzymes or carriermediated systems which for these
drugs become saturated in the
therapeutic range and results in
saturable non-linear elimination
kinetics. Modest changes in dose or
bioavailaility of these drugs may
produce unexpected toxicity.