drug absorption- mechanism of drug absorptionand factors affecting absorption

1. DRUG ABSORPTION FROM THE
GIT
Presented By
Sujitha Mary
M Pharm
St Joseph College Of Pharmacy
1

2. CONTENT:
• Introduction
• Systemic Event During Administration to Absorbtion of
drug
• Mechanism of Drug Absorption
• Factors Affecting Drug Absorption
• Factors Affecting Dissolution Rate
2

3. INTRODUCTION:
• Absorption process is developed in the biological system
for getting required organic and inorganic chemical into
the systemic circulation to maintain life.
• Absorpton is process of movement of unchanged drug
from the site of administration to the systemic circulation.
• There is always exist a correlation between the plasma
concentration of drug and the therapeutics response
3

4. 4

5. SYSTEMIC EVENT S OF DURING
ADMINISTRATION TOABSORPTION OF DRUG:
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6. MECHANISM OF DRUG ABSORPTION:
1.Passive Diffusion
2. Carrier –mediated transport
a)Active diffusion
b)Facilitated diffusion
3. Pore transport
4. Ionic or Electrochemical diffusion
5. Vesicular transport
6

7. 1.PASSIVE DIFFUSION
• Is the process by which molecule spontaneously diffuse from a
region of higher conc to a region of lower conc .
• No external energy is expamded.
• If the two side have the same drug conc forward moving drug
molecule are balanced by molecule moving back, resulting in no
net transfer of drug.
• When one side is higher in drug conc , at any given time , the
number of forward moving drug molecule will be higher than the
number of backward moving molecule ; the net result will be
transfer of molecule to the alternate site.
• The tendency of molecule to move in all direction is natural ,
because milecule passess kinetic energy & constatly collide with
one another in space.
7

8. • According to Ficks law of diffusion:
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9. 9

10. 3. PORE TRANSPORT
• Very small molecule ( such as urea , water & sugar ) are
able to cross the cell membrane rapidly , as if the
membrane contained channels or pore.
• A certain type of protein called as a transport protein
may form an open channel across the lipid membrane of
cell.
• Small molecule including drug move through the
channel by diffusion more rapidly than at other part of the
membrane.
10

11. 2. CARRIER –MEDIATED TRANSPORT
a) Active diffusion :
• A few lipid insoluble drug that resemble natural physiologic
metabolite are absorbed from GIT by this process. Active
transport is charaterised by the transport of drug against a conc
gradient .i.e. from region of low drug conc to region of high conc.
• Is an energy consuming system.
• Process require a carrier that bind the drug to form carrier-drug
complex that shuttles the drug across the membrane & then
dissocite the drug on the other side of membrane.
• The rate of drug absorbtion increase with drug conc until the
carrier molecule are completely saturated . At higher drug conc ,
the rate of drug absorption remain constatnt or zero order.
11

12. b)Facilitated diffusion :
• Differeing from active transport in that the drug move
along a conc gradient.
• This system does not require energy input
12

13. 4. IONIC OR ELECTROCHEMICALDIFFUSION
• Strong electrolyte drug are highly ionized or charged
molecule , such as quaternary nitrogen compound with
extreme pKa values.
• Strong electrolyte drug maintain their charge at all
physiologic pH values and penetrate membrane poorly.
• When the ionized drug is linked up with an oppositely
charged ion , an ion oair is formed in which the overall
charge of the pair is neutral.
• This neutral drug complex diffuses more easily across the
membrane.
• E.g. the formation of ion pair to facilitate drug absortion
has been demonstrated for propranolol , a basic drug that
form an ion pair with oleic acid and quinine , which form ion
pair with hexylsalicylate.
13

14. 5. VESICULAR TRANSPORT
• Is the process of engulfing particle or dissolved material by
the cell. Pinocytosis & phagocytosis are form of vesicular
transport that differ by the type of material ingested.
• Pinocytosis refer to the engulfment of small solute or fluid
& phagocytosis refer to the engulfment of larger particle or
macro molecule , generally by macrophages.
• Endocytosis & exocytosis are the processes of moving
specific macrophages into & out of cell
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15. 15

16. FACTORSAFFECTING DRUGABSORPTION
A) Physicochemical Factors :
1.Drug Solubility & Dissolution Rate
2.Particle Size & Effective Surface Area
3.Polymorphism & amorphism
4.Pseudopolymorphism
5.Salt form of the drug
6.Lipophilicity of drug
7.pH – partition hypothesis
8.Drug Stability
B) Pharmaceutical Factors:
1.Disintegration time
2.Dissolution time
3.Manufacturing variable
4.Pharmaceuticle Ingredient
5.Nature & type of dosage form
6.Product age & storage condition
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17. C) Patient Related Factor:
1.Route of Administration
2.Gasteric emptying time
3.Intestinal transit time
4.Disease State
5.Blood Flow Through the GIT
6.GI Content
a) food –drug interaction
b)fluids
c)other normal GI content
7.Presystemic metabolism by
a)Luminal enzyme
b)Gut-wall enzyme
c)Bacterial enzyme
d)Hepatic enzyme
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18. A) PHYSICOCHEMICAL FACTORS :
1) Drug Solubility & Dissolution Rate:
• The rate determining steps in absorption of orally
administered drugs are: a)Rate of dissolution b)Rate of
drug permeation through the biomembrane.
• Dissolution is rate determining step for hydrophobic &
poorly aqueous soluble drugs. E.g.Griesiofulvin &
Spironolactone.
• Permeation is the rate determining step for hydrophilic &
high aqueous soluble drugs. E.g.Cromolyn sodium OR
Neomycin.
• Prerequisite for the absorption of a drug is that it must be
present in aqueous solution & this is depend on rugs
aqueous solubility & its dissolution rate
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19. 19

20. 2.Particle Size & Effective SurfaceArea :
• Particles size plays a major role in drug absprption.
• Dissolution rate of solid particles is proportional to surface area.
• Smaller particle size , greater surface area then higher will be
dissolution rate , because dissolution is thought to take place at
the surface area of the solute(drug).
• Particle size redution has been used to increase the absorption of
a large number of poorly soluble drugs..
• E.g.Bishydroxycoumarin,digoxin .
• Two types of surface area
1) Absolute surface area
2)Effective surface area
• To increase the effective surface area,we have o reduce the size
of paticle up to 0.1 micron. So these can be achieved by
“Micronisation process”. 20

21. • But in these case one most important thing to be keep in
mind that which type of drug is micronised it is : a)
Hydrophilic b)Hydrophobic
a)HYDROPHILIC DRUGS :
• In hydrophilic drugs the small particles have higher energy
than the bulk of the solid resulting in an incresed interaction
with the solvent.
E.g. 1.Griesiofulvin – dose reduced to half due to
micronisation.
2.Digoxin – the bioavailability was found to be 100% in
micronized tablets.
• After micronisation it was found that the absorption
efficiency was highly increased.
b)HYDROPHOBIC DRUGS:
• In this micronisation techniqies result in decreased
effective surface area & thus fall in dissolution rate.
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22. • Reason for these :
1.The hydrophobic surface of the drugs adsorbed air on to
their surface which inhiits their wettability.
2.The particles reaggregates to form large particles due to
their surface free energy , which either float on the
surface on the bottom of the dissolution medium.
• Such hydrophobic drugs can be converted to their
effective surface area
a) use of surfactant as a wetting agent .
b) b)add hydropilic diluent like PEG , PVP, dextrose etc
22

23. 3.Polymorphism & amorphism:
• Depending upo the internal structure , a sloid can exist either in a
crystalline or amorphus form. When a substance exist in more
than one crystalline form,the different forms are designated as
polymorphs ,and the phenomenon as polymorphism.
• Polymorphs are of two types :
1.Enantiotropic polymorph is the one which can be reversibly
changed into another form by altering the temp or pressure. E.g.
Sulfur.
2.Monotropic polymorph is the one which is unstable at all the temp
& pressure. E.g. glyceryl strarates.
• The polymorphs differ from each other with respect to their
physical properties such as solubility , melting point, density,
hardness and compression characteristics . Thus , these change
in physical properties and hence the absorption.
23

24. AMORPHISM
• some drugs can exist in amorphous form (i.e.having no
internal crystal struture). Such drugs represent the
highest energy states.
• They have greater aqueous solubility than the crystalline
form because a energy required to transfer a molecule
from the crystal lattice is greater than that required for
non-crystalline
24

25. 4.Pseudopolymorphism:
• When the solvent molecules are entrapped in the
crystalline structure of thr polymorph, iot is known as
pseudo-polymorphism.
• SOLVATES: the stoichiometrics type of adducts where
the solvent molecles are incorporated in the crystal
lattice of the solid are called as the solvates , and the
trapped solvent as solvent of crystallization .
• HYDRATES:when the solvent in association with the
drugs is water , the solvates in known as a hydrates.
• Hydrate are pseudo-polymorphs where hydrates are less
soluble and solvent are more soluble and thus affect the
absorption accordingly 25

26. 5.Salt form of the drug:
• While considering the salt form of drug , ph of the diffusion
layer on important not the ph of the bulk of the solution .
• Example of salt of weak acid : It increases the ph of the
diffusion layer , which promotes the solubility the dissolution of
a weak acid and absorption is bound to be rapid.
• ther approach to enhance the dissolution ad absorption rate of
certain drugs is the formation of in-situ salt formation i.e.
increasing in ph of microenvironment of drug by incorporates of
a buffering agent.E.g. Aspirin.
• But sometimes more soluble salt form of drug may result in
poor absorption. E.g.sodium salt of phenobarbitone , its tablet
swells and did not get disintegrates , thus dissolved slowly and
result in poor absorption
26

27. 7.pH – partition hypothesis:
• The theory states that for drug compounds of molecular
weigt more than 100, which are primarily transported
across the biomembrane by passive diffusion , the
process of absorption is governed by,
1.the dissociation constant pka pf the drug.
2.the lipid solubility of the un-ionized drug.
3.the ph at the absorption site.
A) Drug pKa and GI pH:
• Amount of drug thst exit in un-ionised form and ionized
form is function of pKa of drug & pH of the fluid at the
absorption site and it can be determined by Handerson –
Hasselbatch eq :
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28. 28

29. • if there is a membrane barrier that separate the aqueous
solution of different pH such as the GIT and the plasma ,
then the theoretical ratio R of drug conc on either side of
thr membrane can be given by following eq
29

30. B ) Lipophilicity and drug absorption :
• The lipid solubility of thr drug is determined form its oil /
water partition coefficient ( ko/w) value , whereby the
increase in this value indicate the increase in percentage
drug absorbed .
30

31. 8.Drug Stability
• A drug for oral use may destabilize either during its shelf
life or in the GIT.
• Two major stability problems resulting in poor
bioavailability of an orally administered drug are
degradation of the drug into inactive form and interaction
with one or more different component either of thr doage
form or those present in the GIT to form a comp0lex that
is poorly soluble or is unabsorbable.
31

32. B) PHARMACEUTICAL
FACTORS:
1)Disintegration time :
• Rapid disintegration is important to have a rapid
absorption so lower disintegration time is required.
• Disintegration time of tablet is directly proportional to
amount of binder & compression force.
• In vitro disintegration test gives no means of a guarantee
of drugs bioavailability bacause if the disintegrated drug
particles do not dissolve then absorption is not possible.
• E.g.Coated Tablet :they have long disintegration time.
Fast dispersible tablet have short disintegration time
32

33. 2)Dissolution time:
• Dissolution is a process in which a solid substance
solubilises in a given solvent i.e. mass transfer from the
solid surface to the liquid phase.
• Dissolution time is also an important factor which affect
the drug absorption.
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34. 3)Manufactuing varibles:
• Several manufacturing processes influence drug
dissolution from solid dosage forms.
• E.g.For tablet its
-method of granulation
-compression force
34

35. 4)Pharmaceutical ingredients:
• more the number of exicipent in the dosage form, more
complex its is & greater the potential for absorption and
bioavailability problems.
a)Vehicles:
• Rate of absorption – depend on its miscibility with biological
fluid.
• Miscible vehicles causes rapid absorption e.g.propylene glycol.
• Immiscible vechicle – Absorption depend on its partitioning
from oil phase to aqueous body fluid.
b)Diluent:
• Hydrophilic diluent – impact Absorption
• Hydrophobic diluent – Retards Absorption
• Also , there is a drug diluent interaction , forming insoluble
complex and retards the absorption . 35

36. c)Binder & granulating agent :
• Hydrophillic binder – impact hydrophilic proporties to the
granules surface – gives better dissolution proporties .
E.g.Starch, Gelatin.
• More amount of binder increase the hardness of the
tablet and retard the absorption rate.
d)Disintegrants:
• Mostly hydrophilic in nature,
• Decrease in amount of disintegrant – significantly lowers
bioavailability.
e)Suspending agent :
• Stabilized the solid drug particles and thus affect drug
absorption.
• Macromolecular gum forms un-absorbable complex with
drug
36

37. f)Colorants:
• Even low conc of water soluble dye can have an
inhibitory effect on dissolution rate.
• The dye molecules get absorbed onto the crystal faces
and inhibit the drugs dissolution.
• E.g. Brilliant blue retards dissolution of sulfathiazole.
g)Complexing agent:
• Complex formation has been used to alter the
physicochemicals & biopharmaceutical proporties of a
drug.
• E.g. 1.Enhanced dissolution through formation of a
soluble complex. 2.Enhanced lipophilicity for better
membrane permeability. 37

38. C) PATIENT RELATED FACTOR:
1)Gastric emptying time:
• The process by which food leaves the stomach and enters
the duodenum.
• Rapid gastric emptying is required when the drug is best
absorbed from distal part of the small intestine.
• Delayed gastric emptying is required when drugs are
absorbed from proxinal part of the small intestine and
prolonged drug absorption site contact is desired.
• Gastric emptying is a first order process.
• Gastric emptying rate : is the speed at which the
stomach content empty into the intestine.
• Gastric emptying time : is the time required for the
gastric content to the Small Intestine.
38

39. 2)Intestinal transit time:
• Major site of absorption of most of drugs.
• The mixing movement of the intestine that occurs due to
peristaltic conctraction promotes drugs absorption.,firstly ,
by increasing the drug intestinal membrane contact and
secondly by enhancing drug dissolution of especially of
poorly soluble drug through induced agitation.
• Delayed intestinal transit is desirable for 1.Drugs that
dissolve or release slowly from their dosage form. 2.Drugs
that dissolve only in intestine 3.drug absorbed from
specific sites in the intestine.
• Intestinal transit time is influenced by various factors such
as food , diseases and drug.
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40. 3)Disease states:
a)Gastric disease: they may not hve adequate production of
acid in the stomach , stomach acid is essential for
solubilizing insoluble free bases.
• Many weak-base drugs that cannot form soluble salt &
remain undissolved therefore unabsorbed . Salt forms of
these drugs cannot be prepared because the free base
readily precipitats out.
• E.g. Dapsone, Itraconazole.
b)Cardio-vascular diseases: decreased blood flow to the GIT
and gastric emptying rate and altered GI pH, secreation
and microbial flora
40

41. 4)Blood flow through the GIT:
• maintain the conc gradient across the epithelial
membrane.
• GIT os extensively supplied by blood capillary network.
• Blood flow is imp for actively absorption of drugs.
• Absorption of polar molecules doesn’t depend on the
blood flow but lipid soluble molecules highy depend on
the blood flow.
41

42. 5) Presystemic metabolism:
The loss of drug through bio-transformation by such eliminating
organ during the passage to systemic circulation is called as
first-pass or pre-systemic metabolism.
A)Lumenal Enzymes: the primary enzyme found in gastric juice
is pepsin . Lipases , amylases and proteses are secreted from
the pancreas into the small intestine in response to ingestion of
food. Pepsins and the proteases are responsible for the
degradation of protein and peptide drugs in the lumen.
B)Gut wall enzymes: these also called mucosal enzymes , they
are present in stomach , intestine and colon. Alcohol
dehydroginase (ADH) is an enzyme of stomach mucosa that
inactivates ethanol.
C)Bacterial enzymes: which are localized within the colonic
region of the GIT , also secrete enzymes which are capable of
a range of reactions.
D)Hepatic enzymes: several drugs undergo first –pass hepatic
metabolism the highly extracted ones being Isoprenaline ,
propanolol , diltiazem. 42