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1. Absorption of Drugs

2. DRUG:
• A drug
intravascularly
is injected
(iv or ia)
directly enters into systemic
circulation.
• Majority of drugs are
administered extravascularly
(generally orally).
• Such drugs can exert the
pharmacological action only
when they come into systemic
circulation from their site of
administration .
• Thus, absorption is an important
prerequisite step

3. Definition of Absorption
• The process of movement of unchanged drug from the site
of administration to systemic circulation
• The effectiveness of a drug can only be assessed by its
concentration at the site of action.
• It is difficult to measure the drug concentration at such
site.
• Instead, the concentration can be measured more correctly
in plasma
• As there always a correlation between the plasma
concentration of a drug & therapeutic response

4. Cell Membrane
Structure & Physiology

5. CELL MEMBRANE
• Cell membrane separates living cell from nonliving
surroundings
• thin barrier = 8nm thick
• Controls traffic in & out of the cell
• selectively permeable
• allows some substances to cross more easily than others
• hydrophobic vs hydrophilic
• Made of phospholipids, proteins & other macromolecules

6. • Proteins determine membrane’s specific
functions
– cell membrane & organelle membranes
each have unique collections of proteins
• Membrane proteins:
– peripheral proteins
• loosely bound to surface of membrane
• cell surface identity marker (antigens)
– integral proteins
• penetrate lipid bilayer, usually across whole
membrane
• transmembrane protein transport proteins
– channels, permeases (pumps)

7. Physiological factors affecting oral
absorption (outline)
• Passage of drugs
across membranes
1.Active transport
2.Facilitated diffusion
3.Passive diffusion
4.Pinocytosis
5.Pore transport
6.Ion pair formation
• Main factors
affecting oral
absorption
• Physiological factors
• Physical-chemical
factors
• Formulation factors

8. MECHANISMS OF
DRUG ABSORPTION

9. I. Passive Diffusion
 Diffusion
 Movement from high 
low concentration
• Major process for absorption
of more than 90% of drugs
• Non ionic diffusion
• Driving force – concentration
or electrochemical gradient
• Difference in the drug
concentration on either side
of the membrane
• Drug movement is a result of
kinetic energy of molecules

11. Mathematically(Fick’s First law of
diffusion)
.................I
dQ/dt = rate of drug diffusion (amount/time)
D = diffusion coefficient of the drug
A= surface area of the absorbing membrane for drug diffusion
Km/w = partition coefficient of drug between the lipoidal membrane &
the aqueous GI fluids
(CGIT – C) = difference in the concentration of drug in the GI fluids &
the plasma (Concentration Gradient)
h = thickness of the membrane

12. Characteristics of Passive diffusion:
Energy independent
Greater the area & lesser the thickness of the membrane, faster
the diffusion
The process rapid over for short distances
Concentration equal on both the sides of the membrane -
Equilibrium is attained
Greater the PC of the drug faster the absorption

13. But this is not the case……
The passively absorbed drug enters blood, rapidly swept away
& distributed into a larger volume of body fluids
Hence,
The concentration of drug at absorption site CGIT is maintained
greater than the concentration in the plasma. Such a condition is
called as sink condition for drug absorption.

14. Under usual absorption conditions,
D, A, Km/w & h are constants, the term DAKm/w /h can be replaced by
a combined constant P called as permeability coefficient
Permeability - ease with which a drug can permeate or diffuse
through a membrane.
Due to sink conditions, the C is very small in comparison to CGIT.

15. ……………..II
Equation II is an expression for a first order process.
Thus, passive diffusion follows first order kinetics.

16. II. PORE TRANSPORT
• It is also called as convective transport, bulk flow or filtration.
• Mechanism – through the protein channel present in the cell
membrane.
• Drug permeation through pore transport – renal excretion, removal
of drug from CSF & entry of drug into the liver

17. The driving force – hydrostatic or osmotic pressure differences across
the membrane. Thus, bulk flow of water along with the small solid
molecules through aqueous channels. Water flux that promotes such a
transport is called as solvent drag
The process is important in the absorption of low molecular weight
(<100D), low molecular size (smaller than the diameter of the pore)
& generally water soluble drugs through narrow, aqueous filled
channels or pores e.g. urea, water & sugars.
Chain like or linear compounds (upto 400D)- filtration

18. III. ION-PAIR TRANSPORT
Responsible for absorption of compounds which ionizes at all
pH values. e.g. quaternary ammonium, sulphonic acids
Ionized moieties forms neutral complexes with endogenous ions
which have both the required lipophilicity & aqueous solubility
for passive diffusion.
E.g. Propranolol, a basic drug that forms an ion pair with oleic
acid & is absorbed by this mechanism

19. CARRIER MEDIATED Transport
• Involves a carrier
which reversibly
binds to the solute
molecules and forms
a solute-carrier
complex.
• This molecule
transverse across the
membrane to the
other side and
dissociates, yielding
the solute molecule.
• The carrier then
returns to the original
site to accept a new
molecule.
• There are two type of
carrier mediated
transport system
1) Facilitated
diffusion
2) Active transport

20. FACILITATED DIFFUSION
• Facilitated diffusion is a
form of carrier transport
that does not require
the expenditure of
cellular energy.
• Carriers are numerous in
number & are found
dissolved in cell
membrane .
• The driving force is
concentration
gradient, particles move
from a region of high
conc to low conc.

21. Contd…
• The transport is aided
by integral
membrane proteins.
• Facilitated diffusion
mediates the
absorption of some
simple sugars,
steroids, amino acids
and pyrimidines from
the small intestine
and their subsequent
transfer across cell
membranes.

22. ACTIVE TRANSPORT
• Requires energy, which
is provided by hydrolysis
of ATP for transportation.
• More commonly,
metabolic energy is
provided by the active
transport of Na+, or is
dependent on the
electrochemical gradient
produced by the sodium
pump, Na+/K+ ATPase
(secondary active
transport).

23. This transport requires energy in the form of ATP

24. PRIMARY ACTIVE TRANSPORT
• Direct ATP requirement
• The process transfers only one ion or molecule & only in
one direction. Hence, called as UNIPORT
• E.g. absorption of glucose
• ABC (ATP binding Cassette) transporters

25. Secondary active transport
• No direct requirement of ATP
• The energy required in transporting an ion aids transport
of another ion or molecule (co-transport or coupled
transport) either in the same direction or opposite
direction.
• 2 types:
• Symport (co-transport)
• Antiport (counter transport)

26. symport
antiport
A
TP A
TP
ANTIPORT ANDSYMPORT

27. ENDOCYTOSIS
• It is a process in which
cell absorbs molecules
by engulfing them.
• Also termed as
vesicular transport.
• It occurs by 3
mechanisms:
Phagocytosis
Pinocytosis
Transcytosis

28. PHAGOCYTOSIS

29. TRANSCYTOSIS
• It is the process
through which various
macromolecules are
transferred across the
cell membrane.
• They are captured in
vesicles, on one side
of the cell and the
endocytic vesicle is
transferred from one
extracellular
compartment to
another.
• Generally used for the
transfer of IgA and
insulin.

30. PINOCYTOSIS
• It is a form of endocytosis in
which small particles are
brought to the cell, forming
an invagination.
• These small particles are
suspended in small vesicles.
• It requires energy in the form
of ATP
.
• It works as phagocytosis, the
only difference being, it is
non specific in the
substances it transports.
• This process is important in
the absorption of oil soluble
vitamins & in the uptake of
nutrients

31. FACTORS AFFECTING RATE OF
ABSORPTION

32. DRUG SOLUBILITY AND
DISSOLUTION RATE
• MAXIMUM ABSORBABLE DOSE (MAD)
• Ka = intrinsic absorption rate constant
• SGI = the solubility of the drug in the GI fluid
• VGI = the volume of the GI fluid
• tr = residence time of the drug in the GI

33. CLAS
S
SOLUBILIT
Y
PERMIABILIT
Y
ABSORPTION
PATTERN
RATE
LIMITING
STEP
EXAMPLE
1 HIGH HIGH WELL
ABSORBED
GASTRIC
EMPTYING
DILTIAZEM
2 LOW HIGH VARIABLE DISSOLUTI
ON
NIFEDEPINE
3 HIGH LOW VARIABLE PERMIATIO
N
INSULIN
4 LOW LOW POORLY
ABSORBED
CASE BY
CASE
TAXOL

34. PARTICLE SIZE AND SURFACE AREA
• Particle size 1/surface area
• Absolute surface area
• Effective surface area
• Larger the surface area higher the dissolution rate
• Decrease in particle size can be accomplished by micronisation.

35. • hydrophobic drugs
- The hydrophobic surface of the drug adsorbs
air onto their surface which inhibits their
wettability
- The particles re-aggregate to form larger
particles due to their high surface free energy.
- Electrically induced agglomeration owing to
surface charges prevents intimate contact of the
drug with the dissolution medium.

36. REMEDIES
the
• -Use of surfactant as wetting
agent
 Decreases
interfacial tension
 Displaces the
adsorbed air with the
solvent
2. Adding hydrophilic diluents
which coat the surface
of hydrophobic drug particles &
render them
hydrophilic. E.g. PEG, PVP
•
•
•
•
• Particle size reduction &
subsequent increase in the
surface area & dissolution rate
is not advisable for-
• - When the drugs are
unstable & degrade in the
solution form e.g.
penicillins, erythromycin.
- When drugs produce
undesirabe effects (gastric
irritation caused by
nitrofurantoin).
- When a sustained effect is
desired.

37. Polymorphism and Amorphism
• A substance exists in more than one crystalline form, the
different forms are designated as polymorphs & the
phenomenon as polymorphism.
• Enantiotropic polymorph: sulphur
• Monotropic polymorph: glyceryl stearate

38. • Depending on their relative stability, one of the several
polymorphic forms will be physically more stable than the others.
• Stable polymorphs
- lowest energy state
- highest MP
- least aqueous solubility
• Metastable polymorphs
- higher energy state
- low MP
- high aqueous solubility

39. Chloramphenicol Palmitate - A, B & C.
• E.g. Riboflavin has 5 polymorphs- I, II, III, IV & V
• Only 10% of the pharmaceuticals are present in metastable
forms.
• Aging of dosage forms containing metastable forms usually
result in formation of less soluble, stable polymorph.
• E.g. More
converts to
soluble crystalline form II of cortisone acetate
less soluble form V in aqueous suspension
resulting in caking of solid.

40. • Amorphism:
• Amorphous forms: having no internal crystal structure
• The highest energy state
• Have greater aqueous solubility than the crystalline forms
because the energy required to transfer a molecule from
crystal lattice is greater than that required for non-crystalline
(amorphous) solid.
• E.g. the amorphous form of novobiocin is 10 times more
soluble than the crystalline form.

41. Salt form of drug
• Most drugs are either weak acids or weak bases.
• Solubilization technique – salt formation of drugs
• Weakly acidic drugs- strong base salt
• Weakly basic drugs- strong acidic salt

43. Drug pKa & GI pH
• The pH partition theory – the process of drug absorption from the GIT & its
distribution across GI membrane.
• Many drugs are either Was or WBs
• The drugs primarily transported
diffusion, is governed by –
across the biomembrane by passive
1. The dissociation constant
2. The lipid solubility of the unionised drugs
3. The pH at absorption site
• Drug pKa & GI pH
• Unionised form of drug = Function of dissociation constant of the drug &
pH of fluid at the absorption site

44. Drug Lipophilicity
Lipophilicity & Drug Absorption:
Ideally a drug should have
• Sufficient aqueous solubility
absorption site
to dissolve in the fluids at
• Sufficient lipid solubility to facilitate the partitioning of the drug
in lipoidal membrane
• A perfect hydrophilic-lipophilic balance should be there in the
structure of the drug for optimum bioavailability.

45. Drug Permeability
• Three major drug properties which affects drug permeability –
1. Lipophilicity
2. Polarity of the drug
3. Molecular size of the drug

46. Drug Stability
• A drug for oral use may destabilize either during its
shelf life or in the GIT
• Reasons:
• Degradation of the drug into inactive form
• Interaction with one or more different component either
of the dosage form or present in the GIT to form
complex which is poorly absorbable or is unabsorbable

47. FORMULATION
FACTORS

48. DISINTEGRATION TIME
• Is of particular importance in case of solid dosage forms
like tablets and capsules
• Rapid disintegration-important in the therapeutic success
of solid dosage form
• Sugar coated tablets have long DT
• DT is directly related to the amount of binder present and
the compression force of a tablet
• After disintegration-granules deaggregate into tiny
particles-dissolution faster

49. MANUFACTURING VARIABLES
Method of granulation:
• Wet granulation was thought to be the most conventional
technique
• Direct compressed tablets dissolve faster
• Agglomerative phase of communition-superior product

50. Compression force:
• Higher compression force-
increased density and
hardness-decreased
porosity and penetrability-
reduced wetability -inturn
decreased DR
• Also causes
deformation,crushing-
increased effective surface
area-increased DR
• Intensity of packing of
capsule contents:
• Tightly filled capsules-
diffusion of GI fluids-high
pressure-rapid bursting
and dissolution of contents
• Opposite also possible-
• poor drug release due
to decreased pore size
and poor penetrability of
GI fluids

51. DOSAGE FORMS
• Different Types
• Solution
• Suspension
• Tablets
• Capsules
• Coated Tablets
• Enteric Coated Tablet
• Powders

52. ORDER OF ABSORPTION
• Solutions>Emulsions>Suspensions>Capsules> Tablets>
Coated Tablets>Enteric Coated Tablet>Sustain Release
Tablet
• Mechanism
• Factors

53. PRODUCTAGE ANDSTORAGE CONDITIONS
Aging and alteration in storage condition change the physiochemical
properties of a drug ---adversely affect Bioavailability
During storage
• Metastable form
• Change in particle size
stable form
• T
ablet harden
soften
Eg
Prednisone tablet containing lactose as a filler ,high temp& high
humidity resulted in harder tablet that disintegrated and dissolve
slowly

54. PATIENT RELATED
FACTORS

55. GI PH
i) disintegration: some dosage forms is Ph sensitive , with
enteric coating the coat dissolves only in in intestine.
ii) Dissolution: A large no. of drugs whose solubility is affected
by pH are weak acidic and weak basic drugs.
A. drugs dissolve rapidly in the alkaline medium whereas
B. drugs dissolve in acidic medium.
iii) Absorption : Depending on drug pKa and whether it is acidic
or basic , absorption depends on the amount of unionised
form at site of absorption.
iv) Stability: GI pH affects chemical stability of drug.
Eg. Acidic pH of stomach degrades Penicillin G and
erythromycin. Hence they are administered as prodrugs
namely carindacillin and erythromycin estolate.

56. Blood flow through GIT
-GIT extensively supplied by blood capillary network .
Therefore it helps in maintaining the sink condition for continued drug absorption.
DRUG
(A) For highly lipid soluble drug
(B) For lipophilic drug
(C)For polar drugs
BLOOD FLOW EFFECT
More
Intermediate
No effect

57. GASTROINTESTINAL CONTENTS
I) Food
Influence of food on drug absorption.
Delayed Decreased Increased Unaffected
Aspirin Penicillins Griseofluvins Methyldopa
Paracetamol Erythromycin Diazapam Propylthiouracil
Diclofenac Tetracyclines
Delayed or decreased drug absorption could be due to
a)Delayed gastric emptying
b) Formation of poorly soluble , unabsorbable complex.
c) Increased viscosity due to food therby preventing drug dissolution.
Increased drug absorption could be due to:
a) Increased time for dissolution of a poorly soluble drug.
b) Enhanced solubility due to GI secretions.
c) Prolonged residence time Eg. Vitamins.

58. II. Fluid volume
Large food volume results in better dissolution and enhanced drug absorption
Eg. Erythromycin is better absorbed when taken with a glass of water under fasting
condition.
III.Interaction with normal GI constituents.
-mucin , a protective mucopolysaccharide that lines GI mucosa interacts with
streptomycin
and certain quaternary ammonium copmpounds and retards their absoprtion
-Bile salts aid to solubilisation of drugs like Vitamin A,D,E and K
-Enzymes.
IV)Drug-drug interaction in the GIT:
They can be physicochemical.
V) Physicochemical D-D interaction can be due to :
a) Adsorption : Antidiarrhoeal preparation contain adsorbant like kaolin-pectin
retard absorption of co-administerd drugs like promazine and lincomycin.
b) complexation: formation of unabsorpable complexes.Eg. Tetracyclines
c)pH change

59. • In infants – incomplete development of biological system - the
gastric pH is high & intestinal surface area & blood flow to GIT is
less – results in altered absorption pattern
• Elderly patients – impaired biological system like altered gastric
emptying, decreased intestinal surface area, decreased blood
flow to GIT, higher incidence of achlorhydria & bacterial
overgrowth in small intestine.

60. INTESTINALTRANSIT
Defined as, the residence time of drug in small intestine.
Delayed intestinal transit is desirable for:
1. Sustained release dosage forms.
2. Drug that only release in intestine ie ,enteric coated
formulations,
3. Drugs absorbed from specific sites in intestine, eg;
several B vitamins .
4. Drugs which penetrate intestinal mucosa very slowly
5. Drugs with minimal absorption from colon.

61. DISEASE STATE
Several disease state may influence the rate and extent
of drug absorption.
Three major classes of disease may influence
bioavailability of drug.
• GI diseases
• CVS diseases
• HEPATIC diseases

62. GI DISEASES
A. GI Infections
1. Celiac diseases:(characterized by destruction of villi
and microvilli) abnormalities associated with this
disease are increased gastric emptying rate and GI
permeability, altered intestinal drug metabolism.
2. Crohn’s disease: altered gut transit time and decreased
gut surface area and intestinal transit rate.
B. GI surgery: Gastrectomy may cause drug dumping in
intestine, osmotic diarrhoea and reduce intestinal
transit time.

63. CVS DISEASES:
In CVS diseases blood flow to GIT
decrease causing decreased drug absorption.
HEPATIC DISEASES:
Disorders like hepatic cirrhosis
influences bioavailability of drugs
which under goes first pass
metabolism.