pharmacokinetics principle for pharmacy student and dentistry students

1. Pharmacokinetics
BY
Dr. Abeer M.R. Hussein

2. -Pharmacokinetics (PK) deals with the
movement of a drug over time through the
body and study relationship between drug’s
action and its plasma concentration. It will
determine onset, intensity and duration of
drug action.
- Pharmacokinetics is the quantitative study
of drug absorption, distribution, metabolism
and excretion and their mathematical
relationship.

4. • Pharmacokinetic knowledge allows
dosage adjustment according to the body
size and composition, circulation, hepatic
and renal functions.
• Also, Pharmacokinetic parameters
including bioavailability, half-life, volume of
distribution and clearance will be used in
individualizing the doses in combination
with therapeutic drug monitoring (TDM)
system.

5. A-DRUG ABSORPTION

6. - It is defined by the transfer of a drug from
its site of administration to the blood stream.

7. Mechanisms of transport of drugs across
cell membranes:
1- Passive " lipid" diffusion:
- The driving force for passive absorption of
a drug is the concentration gradient across a
membrane separating two body
compartments; the drug moves from a
region of high concentration to one of lower
concentration. The vast majority of drugs
gain access to the body by this mechanism

8. • It is dependent on the lipid solubility of
drugs (Lipid-soluble drugs readily move
across most biologic membranes due to
their solubility in the membrane lipid
bilayers).
• Unionized drug is lipid soluble and
diffusible;
• ionization is pH and pKa -dependent.

9. Fick’s Law of Diffusion:
The passive flux of molecules down a concentration
gradient is given by Fick’s law:
Flux (molecules / unit of time) =
(C1 - C2) × Area × permeability coefficient
Thickness
-Where C1 is the higher concentration, C2 is the
lower concentration, area is the cross-sectional area of
the diffusion path, permeability coefficient is a
measure of the mobility of the drug molecules in the
medium of the diffusion path, and thickness is the
thickness (length) of the diffusion path.

10. 2- Facilitated diffusion:
- Other agents can enter the cell through
specialized transmembrane carrier proteins
(transporters) that facilitate the passage of
large molecules. These carrier proteins
undergo conformational changes allowing the
passage of drugs or endogenous molecules
into the interior of cells, moving them from an
area of high concentration to an area of low
concentration. This type of diffusion does not
require energy and can be saturated.

11. Examples for carriers or transporters:
i- ATP-binding cassette transporter family
(ABC). This family includes:
a) The P-glycoprotein or multidrug
resistance type 1 (MDR1) transporter found
in the brain, testes, and other tissues, and in
some drug-resistant neoplastic cells.

12. b) The multidrug resistance-associated
protein (MRP) transporters play important
roles in the excretion of some drugs or their
metabolites into urine and bile and in the
resistance of some tumours to
chemotherapeutic drugs.
ii- Non-ATP binding transporter. Some of
these (the solute carrier [SLC] family) are
particularly important in the uptake of
neurotransmitters

13. 3- Filtration or aqueous diffusion:
- It occurs with water soluble drugs, where
drugs pass through aqueous channels or
pores between the cells. These pores are
absent in the blood brain barrier (BBB) and
soluble drug can't cross BBB and placental
barrier.

14. 4- Active transport:
- Active transport
a) It is energy-dependent (energy is driven
by the hydrolysis of adenosine
triphosphate),
b) Capable of moving drugs against a
concentration gradient,
c) It needs carriers
d) It shows selectivity and saturation kinetics
for the carrier.

16. 5- Pinocytosis (endocytosis):
- It occurs with high molecular weight drugs
as iron, hormones and vit.B12. Endocytosis
involves engulfment of a drug molecule by
the cell membrane and transport into the cell
by pinching off the drug-filled vesicle. For
example, vitamin B is transported across the
gut wall by endocytosis.

17. Factors affecting drug absorption:
(a) Factors related to the drug:
- Lipid solubility, pH, ionization, pKa,
molecular weight, dosage form and
concentration of the drug are affecting drug
absorption.

18. • Among these factors is influence of pH of
the medium and the pKa of the weak
electrolytes will be discussed because
they greatly affecting ionization.
• Weak acidic drugs become less ionized
(less polar or lipophilic) in acidic medium,
while weak basic drugs become less
ionized (less polar or lipophilic) in basic or
alkaline medium.

19. • For drugs, a weak acid is best defined as a
neutral molecule that can reversibly dissociate
into an anion (a negatively charged molecule)
and a proton (a hydrogen ion). For example,
aspirin dissociates as follows:
•A weak base can be defined as a neutral
molecule that can form a cation (a positively
charged molecule) by combining with a proton.

20. • Note that the protonated form of a weak acid is
the neutral, more lipid-soluble form, whereas
the unprotonated form of a weak base is the
neutral form.
• The law of mass action requires that these
reactions move to the left in an acid
environment (low pH, excess protons
available) and to the right in an alkaline
environment.

21. • The Henderson-Hasselbalch equation relates
the ratio of protonated to unprotonated weak
acid or weak base to the molecule’s pKa and
the pH of the medium as follows:
• The pKa of a drug is defined as the pH at
which it is 50% ionized and 50% unionized.
Extent of ionization could be calculated using
Henderson-Hasselbalch equation:
PH= pKa + log (protonated)
( unprotonated)

22. - In acidic pH, acidic drugs will be more
non-ionized and hence can be absorbed
easily.
- -For example, aspirin (weak acid; pKa =
3.5) is mostly unionized in acidic pH of the
stomach, therefore it is well absorbed from
the gastric mucosa. Conversely, a weak
base like theophylline (pKa = 8.8) is well
absorbed from intestine (alkaline pH).

23. (b) Factors related to the patient:
- Route of administration
- Blood supply
- Healthy state
- GIT motility
- Presence of other drugs
- Presence of food

24. Transfer across special membranes:
1-Blood-brain barrier (BBB)
- It is formed from tight junctions of capillary
endothelial cells with the absence of
intercellular pores. Also, there is a special
arrangement of pericapillary glial cell.
- The drug molecule must traverse both cell
membranes to reach the cerebral neurons
.

25. • Unionized, highly lipid soluble drugs that
are poorly bound to plasma proteins are
able to cross the BBB.
• In case of inflammation of the meninges,
local permeability of the BBB increases
and some drugs could pass e.g., penicillin.
• Cerebral blood flow is the only limitation to
permeation to CNS by highly lipid soluble
drugs.

26. Figure (1-16): Structure of the blood brain barrier (BBB)

27. 2-Placental transfer of drugs
- Drugs can cross placental barrier by simple
diffusion, therefore, pregnant women should
receive no drugs unless highly indicated
because some drugs may cause
teratogenicity especially if given during the
period of organogenesis (first trimester).

28. -FDA put a classification for drugs according to the risk on pregnancy

30. THANK YOU