Pharmacology of Absorption for 3rd year Medical Students.ppt

Pharmacology of Absorption

1. Factors Affecting Rate and Extent of
Absorption of A Drug
Dr. Hidayat H. Khan

2. Absorption

Passage of Drugs from site of
Administration to the Systemic
Circulation
One of the Pharmacokinetic
Processes

3. Rate of drug absorption- passage of the drug from its site of
administration into the circulation

4. Factors Affecting Rate and Extent
of Absorption
A.Drug Related Factors
Physicochemical Properties of the
Drug
B.Patient Related Factors

5. Drug Related Factors
Lipid Solubility
Degree of Ionization
Concentration of Drug
Physical State
Molecular Size

6. Dosage Form
Particle Size
Disintegration Time (Rate of
breakup)
Dissolution Rate (Rate at which it
goes into solution
Formulation

7. Patient Based Factors
Route of Administration
pH of the Absorbing Surface
Surface Area of Absorption
Thickness of Diffusing Path
Vascularity of Absorbing Surface

8. Absorption from GIT
Presence of Food
Presence of Other Drugs
GIT Motility
Metabolism
GIT Disease
P-Glycoproteins

9. Lipid Solubility or Lipid Aqueous
Partition Coefficient
Measure of how readily a drug enters the
lipid medium from an aqueous medium.
Flux = (C1-C2) x
Area x Permeability Co-efficient
Thickness

10. Degree of Ionization
The extent to which a drug
becomes ionized depends on the
pH of the Medium and the pKa of
the drug
Acidic drugs remain mostly
unionized in the acidic medium
(stomach)

11. Basic drugs remain mostly
unionized in the alkaline medium
(intestine)
Some drugs remain highly ionized
a) Negatively charged : Heparin
b) Positively charged: Tubocurarine
& Suxamethonium

12. Some drugs do not ionize & remain in
unionized form-for example digoxin and
chloramphenicol

13. Effect of pH on the absorption of weak acids and
weak bases
-many drugs are weak acids or weak bases

HA H
+
+ A
-
for weak acids the
protonated form is
nonionized
HB
+
H
+
+ B for weak bases the
unprotonated form
is nonionized
i.e. the red form goes across biomembranes

14. Thus :
HA and B are unionized
HB+ and A- are ionized

15. Dissociation Constant and pKa
The Ka is the dissociation constant and pKa
is the negative logarithm of the
dissociation constant of the weak
electrolyte.

16. pKa is a measure of the strength of
interaction of a compound with a proton
The less the interaction the lower the pKa
Since acids have tendency to donate
proton and thus have less interaction,
they have lower pKa
Thus lower the pKa the stronger the acid

17. Henderson Hasselbalch Equation
pH = pKa + log unprotonated
Protonated
For Acid
pH = pKa + log A- (Ionized)
HA (Non-ionized)
For Base
pH = pKa + log B (Non-ionized)
BH+ (Ionized)

18. Example
If pH = pKa
pH = pKa + log ionized
un- ionized
pH – pKa = log ionized
un- ionized
thus 0 = log ionized
un- ionized

19. Log ( ?) = 0
Log (1) = 0
Thus Ionized =1
Unionized
Thus 50% of drug is ionized and 50% is
unionized

20. Thus pKa is numerically equal to the pH
at which the drug is 50 % ionized AND
50% unionized
If an acidic drug of pKa 3.5 (aspirin) is put
in the medium of pH 3.5, 50% of the drug
would be in the ionized form.

21. If the pH is increased by 1 unit then,
4.5 = 3.5 + log A-
HA
OR 4.5-3.5 = log A-/HA
OR log A- = 1
HA
OR A- = 10
HA

22. If the pH is decreased by 1 unit then,
2.5 = 3.5 +log A-/HA
OR 2.5-3.5 = log A-
HA
OR log A- = -1
HA
OR A- = 1/10
HA

23. It means that 1 unit change in pH causes
a 10 fold change in ionization
If an acidic drug such as Aspirin is put in
a medium of 2.5 , then 90% of the drug
will be in the protonated or unionized
form

25. From the Henderson Hasselbalch equation:
When pH is less than pKa,
the Protonated forms HA (unionized form)
and BH+ (ionized form) dominate
And when pH is greater than pKa,
deprotonated forms A- (ionized) and B (un-
ionized) dominate

26. We can also conclude that an acidic drug
will be MORE unionized in an ACIDIC
medium and thus better absorbed
And basic drug will be ionized in an acidic
medium and will be less absorbed
Because When pH is less than pKa, the
Protonated forms HA (unionized form)
and HB+ (ionized) dominate

27. Ion Trapping
The unionized form of acidic drugs that cross
the surface membrane of gastric mucosal cell
reverts to ionized form within the cell (pH 7) and
thus slowly passes on to the ECF
Thus it become trapped in the cell.
“A weak electrolyte crossing a membrane to
encounter a pH from which it cannot escape
easily”
Other sites: Breast milk, aqueous humor,
prostatic and vaginal secretions

28. Application
Acidic drugs are ionized more in
alkaline urine,
Therefore do not diffuse back into the
kidney tubules and are excreted faster
So if some person has taken excess
acidic drug, we can make the urine
alkaline to INCREASE the excretion of
the acid

29. Other Drug Related Factors
Physical State
Concentration of Drug
Molecular Size
Dosage Form
Particle Size
Disintegration Time (Rate of breakup)
Dissolution Rate (Rate at which it goes in sol.)
Formulation- Use of diluents

30. Patient Based Factors
Route of Administration
pH of the Absorbing Surface
Surface Area of Absorption
Thickness of Diffusing Path
Vascularity of Absorbing Surface

31. Question
Aspirin is weak organic acid with a pKa of
3.5. What % of a given dose will be in the
lipid soluble form at a stomach pH of 2.5?
a)About 1%
b)About 10%
c)About 50%
d)About 90%

32. Question
For Which of the following drugs will
excretion be most significantly accelerated
by acidification of the urine? Suppose Urine
pH can be modified over range 5.5-7.5
A) Weak acid with pKa of 5.5
B) Weak acid with pKa of 3.5
C) Weak base with pKa of 7.5
D) Weak base with pKa of 6.5

33. Absorption from GIT
Presence of Food
GIT Motility
Presence of Other Drugs
Metabolism
GIT Disease
P-Glycoproteins

34. Presence of Food
Generally most drugs are absorbed better
on an empty stomach
Presence of food dilutes the drug and
retards absorption
Food delays gastric emptying
Certain drugs form poorly absorbed
complexes with food constituents e.g.
tetracyclines with calcium in milk

35. GIT Motility (GIT Transit time)
Increased GIT motility as seen in diarrhea
and by certain drugs decreases GIT
transit time and thus decreases
absorption
Delayed gastric emptying decreases
absorption and vice versa

36. Presence of Other Drugs
Formation of insoluble complexes e.g.
Tetracyclines with Iron preparations and
antacids,
Vitamin C and iron
Some drugs may alter GIT motility
Some drugs may cause mucosal damage
Alteration of gut flora by antibiotics may disrupt
the enterohepatic recycling of oral
contraceptives and digoxin

37. Enterohepatic Recycling
A number of drugs form conjugates with
glucoronic acid in the liver and are
excreted in the bile
These glucoronides are too polar
(ionised) to be reabsorbed
They remain in the GIT where they are
hydrolysed by enzymes and GIT bacteria
to release the parent drug which is then
reabsorbed

38. Entrohepatic cycling-

39. Metabolism/Destruction
Rapid degradation (metabolism) of the drug
in the GIT decreases absorption
Penicillin G is destroyed by acid
Insulin by peptidases and thus ineffective
orally
Enteric coating of some drugs can prevent
this

40. GIT disease
Malabsorption : Tropical sprue, Ulcerative
Colitis
Diarrhea
Obstruction in GIT tract including
Intestinal Obstruction

41. P Glycoproteins
P-glycoproteins are type of special carriers
present in the membrane of many cells.
They are less selective and are specialized
for expelling foreign molecules,
P-glycoprotein modulates the intestinal drug
transport and functions to expel drugs from
the intestinal mucosa into the lumen.

42. Methods To Delay Absorption
Decreasing Blood Flow : Addition of
Adrenaline to a local anaesthetic
Use of relatively insoluble slow release form
e.g. procaine penicillin
Subcutaneous Implants
absorption prop. to surface area of
implant e.g. steroids estrogens

43. Importance of Study
Bioavailability
Frequency of Administration
Clinical Efficacy
Toxicity
Drug Interactions