Absorption of Drugs

DRUG:
A drug is injected
Thus, absorption is an important
intravascularly (iv or ia) prerequisite step
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 .
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
Cell Membrane
Structure & Physiology
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

 Proteins determine membranes 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)
 Physiological factors affecting oral
absorption (outline)
Passage of drugs Main factors
across membranes affecting oral
1.Active transport absorption
2.Facilitated diffusion
Physiological factors
3.Passive diffusion
4.Pinocytosis Physical-chemical
5.Pore transport factors
6.Ion pair formation
Formulation factors
MECHANISMS OF
DRUG ABSORPTION
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
Mathematically(Ficks 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
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
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.
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.

 ..II

Equation II is an expression for a first order process.

Thus, passive diffusion follows first order kinetics.

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
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

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

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

ATP ATP

antiport symport
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
PHAGOCYTOSIS
TRANSCYTOSIS
It is the process Generally used for the
through which various transfer of IgA and
macromolecules are insulin.
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.
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
FACTORS AFFECTING RATE OF
ABSORPTION
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

CLAS SOLUBILIT PERMIABILIT ABSORPTION RATE EXAMPLE
S Y Y PATTERN LIMITING
STEP
HIGH HIGH WELL GASTRIC DILTIAZEM
1 ABSORBED EMPTYING
LOW HIGH VARIABLE DISSOLUTI NIFEDEPINE
2 ON
HIGH LOW VARIABLE PERMIATIO INSULIN
3 N
LOW LOW POORLY CASE BY TAXOL
4 ABSORBED CASE
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.
 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.
REMEDIES
-Use of surfactant as wetting
agent Particle size reduction &
subsequent increase in the
Decreases the surface area & dissolution rate
is not advisable for-
interfacial tension - When the drugs are
unstable & degrade in the
Displaces the solution form e.g.
penicillins, erythromycin.
adsorbed air with the - When drugs produce
undesirabe effects (gastric
solvent irritation caused by
nitrofurantoin).
2. Adding hydrophilic diluents
which coat the surface - When a sustained effect is
desired.
of hydrophobic drug particles &
render them
hydrophilic. E.g. PEG, PVP
 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

 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
 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 soluble crystalline form II of cortisone acetate

converts to less soluble form V in aqueous suspension
resulting in caking of solid.
 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.
 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
 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 across the biomembrane by passive

diffusion, is governed by

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

 Drug Lipophilicity
Lipophilicity & Drug Absorption:

Ideally a drug should have

Sufficient aqueous solubility to dissolve in the fluids at

absorption site

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.
 Drug Permeability
Three major drug properties which affects drug permeability

1. Lipophilicity

2. Polarity of the drug

3. Molecular size of the drug

 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
FORMULATION
FACTORS
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
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

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
DOSAGE FORMS
Different Types
Solution
Suspension
Tablets
Capsules
Coated Tablets
Enteric Coated Tablet
Powders
ORDER OF ABSORPTION
Solutions>Emulsions>Suspensions>Capsules> Tablets>
Coated Tablets>Enteric Coated Tablet>Sustain Release
Tablet

Mechanism

Factors
Product age and storage conditions
Aging and alteration in storage condition change the physiochemical
properties of a drug ---adversely affect Bioavailability

During storage
Metastable form stable form
Change in particle size
Tablet harden
soften
Eg
Prednisone tablet containing lactose as a filler ,high temp& high
humidity resulted in harder tablet that disintegrated and dissolve
slowly
PATIENT RELATED
FACTORS
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.
W.A drugs dissolve rapidly in the alkaline medium whereas
W.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.
Blood flow through GIT
-GIT extensively supplied by blood capillary network .
Therefore it helps in maintaining the sink condition for continued drug absorption.

DRUG BLOOD FLOW EFFECT

(A) For highly lipid soluble drug More
(B) For lipophilic drug Intermediate
(C) For polar drugs No effect
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.
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
 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.

INTESTINAL TRANSIT

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.
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
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. Crohns 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.
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.