1. Asmah Nasser, M.D.
Pharmacokinetics

2. Pharmacokinetics
Pharmacokinetics is the quantitative study of drug movement in, through and out of the body

3. What Happens After Drug Administration?
Absorption
Distribution
Metabolism
Elimination /Excretion

4. Important factors to know…
Factors affecting absorption
Concept of ionization , pKa and pH
Henderson –Hassel Balch equation
Bioavailability , Bioequivalence , AUC
Distribution , volume of distribution (Vd), redistribution
Plasma protein binding

5. Important factors to know…
Metabolism (biotransformation) , CYP 450 etc
Excretion
First and zero order kinetics of elimination
Plasma Half life
Clearance
Steady state ,loading and maintenance dose
Therapeutic drug monitoring
Pharmacokinetic calculations

6. Absorption
After a drug is administered, how does it reaches site of action?
Absorption… is the transfer of a drug from its site of administration to the blood stream. In order to reach their site of action, a drug has to pass through several membranes

7. Transport
A. Passive diffusion: Concentration gradient across membrane is the driving force for movement of drug molecule across the membrane
Small size, water soluble drug molecule penetrate through aqueous channels or paracellular spaces …Filtration …few drugs does this
Lipid soluble drugs readily pass through membrane by dissolving in membrane ….many drugs does this
B. Active Transport:
Movement occurs against the concentration gradient and needs energy like ATP

8. Factors that affects absorption
The particle size – Smaller is better
concentration gradient
Surface area and vascularity of that area
Lipid solubility / Water solubility
Nature of the drug…acidic or basic
Ionized or non ionized
The pH levels on either side of cell membrane
pKa of the drug

9. Lipid/Water solubility
Once in solution, drugs exist as a mixture of two interchangeable forms
1. Water-soluble is the ionized or electrically charged form…Cannot cross membrane
2. Lipid-soluble is the non ionized, or uncharged form….Can cross membrane

10. Concept of ionization…continued
• We know most of the drugs are either weak acid or a weak base and when dissolved in body fluids, some or all of a drugs molecules become ionized/unionized
HA H A-
BH+
B + H+

11. Concept of ionization…continued
What percentage is ionized /unionized determined by following factors :
1.Whether the drug was an acid or a base.
2. Whether it is dissolved in an acid or base medium (Eg: Stomach or intestine ?) i.e pH of the medium.
3. And also the pKa of the drug.

12. Role of pH in ionization of a Weak base
As pH increases, a weak base will become more and more unionized, lipid soluble and better absorbed
As pH decreases, a weak base will become more and more ionized, lipid insoluble, and will not be absorbed. Also becomes more water soluble and better excreted.

13. Role of pH in ionization of a Weak base
100%
75%
50%
% of Unionized form
25% 0% 1 14
pH of the medium

14. Role of pH on ionization of a Weak Acid
As pH increases, a weak acid will become more and more ionized , lipid insoluble and will not be absorbed. Also becomes more water soluble and better excreted .
As pH decreases, a weak acid will become more and more unionized , lipid soluble and better absorbed .

15. Role of pH in ionization of a Weak acid
100%
75%
50%
% of Unionized form
25% 0% 1 14
pH of the medium

16. Question Aspirin is an acidic drug.
In the stomach, is it mostly in the ionized or unionized form?

17. Moral of the story...
Acidic drugs are Absorbed best in Acidic environments
Basic drugs are Best absorbed in Basic environments

18. So... To  absorption of an basic drug… acidify the environment
To  absorption of an acidic drug…
alkalanize the environment...
This concept is very important in treatment of a drug poisoning

19. pKa
pKa is equivalent to the pH at which 50% drug is ionized and 50% is unionized….Remember this point
pKa Is the negative logarithm of acidic disassociation constant of the weak electrolyte …not necessary to know

20. 100%
75%
% of Unionized form
50%
25% 0% 1 14
pH of the medium
pKa

21. Henderson-Hasselbalch equation
The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson-Hasselbalch equation
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:

22. Henderson-Hasselbalch equation
pH = pKa + log (Unprotonated form)
(Protonated form)
For a weak acid, if pH – pKa is low it will be more non-ionized and better absorbed
For a weak base if pH – pKa value is high it will be more non-ionized and better absorbed

23. pH-pKa -2 -1 +1 +2 99 90 50 10 01 Weak acid: %nonionized+1 +2
Weak acid: %nonionized 99 90 50 10 01
Weak base: %nonionized

24. Question
1. The pKa of acetylsalicylic acid is 3.5. What percentage of the drug is in an absorbable form in the stomach at pH of 1.5? A. 0.1% B. 1% C. 10% D. 90% E. 99

25. Question
The greater proportion of the dose of a drug administered orally will be absorbed in the small intestine. However, on the assumption that passive transport of the nonionized form of a drug determines its rate of absorption, which of the following compounds will be absorbed to the least extent in the stomach?
a. Ampicillin (pKa = 2.5)
b. Aspirin (pKa = 3.0)
c. Warfarin (pKa = 5.0)
d. Phenobarbital (pKa = 7.4)
e. Propranolol (pKa = 9.4)

26. Summary
A drug molecule carrying an electrical charge is said to be Ionized
Lipid-soluble is the non ionized, or uncharged form….Can cross membrane
Percentage of ionized drug depends on :
1.Whether the drug was an acid or a base
2. Whether it is dissolved in an acid or base medium (Stomach or intestine ?) i.e pH
3. And also the pKa of the drug
As pH increases, a weak base will become more and more unionized ,lipid soluble and better absorbed
As pH decreases, a weak acid will become more and more unionized ,lipid soluble and better absorbed

27. Summary
pKa is equivalent to the pH at which 50% drug is ionized and 50% is unionized
For a weak acid if pH –pKa is low it will be more nonionized and better absorbed
For a weak base if pH –pKa value is high it will be more nonionized and better absorbed