GASTROINTESTINAL
ABSORPTION
Syllabus: Different factors affecting GIT
absorption. Physical, Chemical, Dietary and Dosage form factors.
Questions:
1.
Write the dosage form factors affecting drug absorption
from GIT. How binding agent affect the GIT absorption. 1998(S) [16]
2.
Describe the physiology of the different parts of the
GIT. Discuss the role of pH on the GIT absorption of drugs. 1998 8
+ 8 = [16]
3.
Discuss the physiochemical factors affecting drug
absorption from gut and significance of pH-partition hypothesis. 1997 [16]
4.
Describe the physico-chemical factors affecting drug
absorption from GIT. 1996 [16]
FACTORS INFLUENCING GASTROINTESTINAL ABSORPTION OF A DRUG
FROM ITS DOSAGE FORM
A. PHARMACEUTICAL FACTORS
This
includes factors relating to the physicochemical properties of the drug, and
dosage form characteristics and pharmaceutical ingredients.
1. Physicochemical
properties of drug substances:
(i)
Drug solubility and dissolution rate
(ii)
Particle size and effective surface area
(iii) Polymorphism
and amorphism
(iv) Pseudopolymorphism
(hydrates / solvates)
(v)
Salt form of the drug
(vi) Lipophilicity
of the drug – (pH partition hypothesis)
(vii)pKa of the drug and pH – (pH partition hypothesis)
(viii)Drug stability
2. Dosage
characteristics and pharmaceutical ingredients
(i)
Disintegration time (tablets / capsules)
(ii)
Dissolution time
(iii) Manufacturing
variables
(iv) Pharmaceutical
ingredients (excipients / adjutants)
(v)
Nature and type of dosage form
(vi) Product
age and storage conditions
B. PATIENT RELATED FACTORS
These
includes factors relating to the anatomic, physiologic and pathologic
characteristics of the patient.
(i)
Age
(ii)
Gastric emptying time
(iii) Intestinal
transit time
(iv) Gastrointestinal
pH
(v)
Disease states
(vi) Blood
flow through the GIT
(vii)Gastrointestinal contents
a)
Other drugs b) Food c) Fluids d) Other normal GI contents
(viii)Pre-systemic metabolism by
a)
Luminal enzymes b) Gut
wall enzymes c) Bacterial enzymes d) Hepatic enzymes
A. PHARMACEUTICAL FACTORS
1. Drug solubility
and dissolution rate
Orally
administered solid dosage form are first disintegrated or deaggregated, then
the solid particles are dissolved; drugs in solution then permeate across
biomembrane to be absorbed in the body.
Two critical processes in the absorption of orally
administered drugs are:
1. Rate of
dissolution, and
2. Rate of
drug permeation through the biomembrane (i.e. gastrointestinal membrane)
·
For poorly water-soluble drugs rate of
dissolution is the rate determining step hence the absorption is called to be dissolution
rate limited. e.g. griseofulvin, spironolactone.
·
For highly water-soluble drugs dissolution is
rapid so the rate determining step is permeation hence, the absorption is
called to be permeation rate limited. e.g., cromlyn sodium, neomycin
sulfate etc.
2. Particle size and
effective surface area of the drug particles.
From Noyes-Whitney’s equation of dissolution:
where, D = diffusion coefficient or diffusivity
of the drug molecule
A = surface area of the dissolving solid
exposed to the dissolution medium
KO/W = water/oil partition coefficient of the
drug
V = volume of dissolution medium
h = thickness of the stagnant layer
Cs – CB
= concentration gradient of the diffusing drug molecule.
From this equation it can be concluded that the greater the
surface area, A, faster the distribution.
When the particle size of a certain mass of a drug is
reduced the surface area is increased, hence, if particle size is reduced
dissolution rate increases.
Two types of surface area can be defined:
1.
Absolute surface area: Which is the total area
of solid surface of any particle, and
2.
Effective surface area: Which is the area of
solid surface exposed to the dissolution medium.
e.g. Micronization
of poorly water soluble drugs like griseofulvin, chloramphenicol and several salts of tetracycline results in superior dissolution rates.
However, size reduction has some limitation. In case of
hydrophobic drugs like aspirin, phenacetin and phenobarbital micronization
actually results in a decrease in effective surface area due to the following
reasons.
(i)
The hydrophobic surface of the drugs absorb air onto
their surface which inhibit their wettability, such powders float on the
dissolution medium.
(ii)
The particle reaggregate to form larger particles due
to their high surface free energy.
(iii) Extreme
particle size reduction may impart surface charges that may prevent wetting;
moreover electrically induced agglomeration may prevent intimate contact of the
drug with the dissolution medium.
3. Polymorphism and
amorphism
Depending
on the internal structure, a solid can exist either in a crystalline or
amorphous form.
·
When, a substance exists in more than one
crystalline form, the different forms are designated as polymorphs and
the phenomenon as polymorphism.
N.B. Various polymorphs
can be prepared by crystallizing the drug from different solvents under diverse
conditions. Depending on their relative stability, one of the several
polymorphic forms will be physically more stable than the others. Such a stable
polymorph represents the lowest energy state, has highest melting point and
least aqueous solubility. The remaining polymorphs are called metastable
forms which represents higher energy state, the metastable forms have a
thermodynamic tendency to convert to the stable form. A metastable form cannot
be called unstable because if it is kept dry, it will remain stable for years.
·
So the metastable forms have higher aqueous
solubility and hence higher bioavailability than the stable polymorphs.
e.g.
Chloramphenicol palmitate has three polymorphs A, B and C. The B -form shows
best bioavailability and A form is virtually inactive biologically.
e.g. Polymorphic form-III of riboflavin is 20 times more
water soluble than the form-I.
·
Due to aging of dosage forms containing
metastable forms of the drug results in the formation of less soluble, stable
polymorph.
e.g. more
soluble crystalline form-III of cortisone acetate converts to less soluble
form-V in an aqueous suspension resulting in caking of solid.
Amorphous form (i.e. having no internal structure)
Such drugs
represents the highest energy state and can be considered as supercooled
liquids. They have greater aqueous solubility than their crystalline form.
e.g. the amorphous form of the novobiocin is 10 times more
soluble than the crystalline form.
Thus the order for dissolution of different solid forms of
drug is amorphous > metastable > stable.
4. Pseudopolymorphism
(Hydrates / Solvates)
During
crystallization process the solvent molecules may be incorporated into the
crystal lattice of the solid in stoichiometric
proportion – these type of crystals are called solvates; and the trapped
solvent molecules as solvent of crystallization.
The
solvates again can remain in different polymorphic states, called as pseudopolymorphs.
The phenomenon is called as pesudopolymorphism.
When the
solvent with the drug is water, the solvate is known as hydrate.
Effect of absorption:
·
Generally, the anhydrous form of a drug
has greater solubility than the hydrates. This is because the hydrates are
already in equilibrium with water and therefore have less demand for water.
e.g. anhydrous
form of theophyline and ampicillin have higher aqueous solubilities, dissolve
at faster rate and show better bioavailability in comparison to their
monohydrates and trihydrate forms respectively.
·
On the other hand nonaqueous solvates have
greater aqueous solubility than the nonsolvates.
e.g. n-pentanol solvate of fludricortisone and succinyl
sulfathiazole and the chloroform solvates of griseofulvin are more water
soluble than their non-solvate forms.
5. Salt form of the
drug
Most drugs
are either weak acids or weak bases. One of the easiest approach to enhance the
solubility and dissolution rate of such drugs is to convert them into their
salt forms.
·
Weak acid HA is more soluble in basic pH and
weak base B is more soluble in acidic pH by the formation of salt.
·
Some time in-situ
salt formation can be utilized, e.g. certain drugs like aspirin and penicillin
are prepared as buffered alkaline tablets. When the tablets are put into water
the pH of the microenvironment of the drug is increased which promotes the
dissolution rate. So buffered aspirin tablets have two advantages
(i)
the gastric irritation and ulcerogenic tendency of the
drug is greatly reduced and,
(ii)
in dry form the hydrolytic stability is better.
(iii) bioavailability
is increased by increasing the dissolution.
·
Size of counter ion
Smaller the
size of the counter ion (of the salt form of a drug) greater the solubility of
the salt. e.g. bioavailability of novobiocin from its sodium salt, calcium salt
and free acid forms are in the following ratio:
Novobiocin
Na Novobiocin Ca Novobiocin free acid
50 20 1
·
Ionic strength of the counter ion
When the
counter ion is very large in size and/or has poor ionic strength (as in the
case of ester form of the drugs), the solubility may be much lower than the
free drug itself.
e.g. pamoates, stearates and palmitates of weak bases having
poor aqueous solubility:
prolong the
duration of action – e.g.
steroidal salts
overcome bad
taste – e.g.
chloramphenicol
overcome
GI-instability –
e.g. erythromycin estolate
decrease the side effects, local or systemic.
6. pKa of the drug
and pH
·
Drug pKa and lipophilicity and GI pH (pH
partition theory)
The pH
partition theory (Brodie et.al.) states that for drug compounds of molecular
weight greater than 100, which are primarily transported across the biomembrane
by passive diffusion:
The process
of absorption is governed by
1.
dissociation constant (Ka) of the drug
2.
lipid solubility of the unionized drug (Ko/w)
3.
the pH at the absorption site
The above statement of the hypothesis was based on the
assumptions that:
1.
The GIT is simple lipoidal barrier to the transport of
drug.
2.
Larger the fraction of unionized drug, faster the
absorption.
3.
Greater the lipophilicity (Ko/w) of the
unionized drug, better the absorption.
Handerson-Hasselbach equation
The amount
of drug that exists in unionized form is a function of dissolution constant
(pKa) of the drug and pH of the fluid at the absorption site.
Handerson-Hasselbach
equation
|
for weak acid:
 |
 |
 |
 |
|
Drugs
|
pKa
|
pH at the site of
absorption
|
|
Very weak bases
Theophyline
Caffeine
Oxazepam
Diazepam
|
(pKa < 5.0)
0.7
0.8
1.7
3.7
|
Unionized at all pH values: absorbed along the entire
length of GIT.
|
|
Moderately weak
bases
Reserpine
Heroin
Codeine
Amitriptyline
|
(5 < pKa < 11)
6.6
7.8
8.2
9.4
|
Ionized at gastric pH, relatively unionized at intestinal
pH better absorbed from intestine.
|
|
Stronger base
Mecamylamine
Guanethidine
|
(pKa > 11.0)
11.2
11.7
|
Ionized at all pH values: poorly absorbed form GIT.
|
It is the
pKa of the drug that determines the degree of ionization at a particular pH and
that only the unionized drug, if sufficiently lipid soluble, is absorbed into
the systemic circulation.
Ideally,
for optimum absorption, a drug should have sufficient aqueous solubility to
dissolve in the fluids at the absorption site and lipid solubility (Ko/w)
in the lipoidal biomembrane and into the systemic circulation. In other words,
a perfect hydrophilic-lipophilic balance (HLB) should be there in the structure
of the drug for optimum bioavailability.
DOSAGE FORM FACTORS AFFECTING DRUG ABSORPTION
1. Disintegration
time
Disintegration
time (DT) is of particular importance in case of solid dosage forms like
tablets and capsules. After disintegration of a solid dosage form into
granules, the granules must deaggregate into finer particles and then
dissolution takes place. If DT is long the bioavailability will be less. Rapid
disintegration is thus important in the therapeutic success of a solid dosage
form.
DT
increases with increase in the amount of binder and hardness of a tablet.
Disintegration
can be aided by incorporating disintegrants in suitable amounts during
formulation.
2. Manufacturing / process variables
Dissolution from a solid dosage
form depends on:
(A) excipients and (B)
manufacturing process.
(A) Excipients
A
drug is rarely administered in its original form. All dosage forms contains a
number of suitable excipients (non-drug components of a formulation).
(a) Vehicle
Vehicle
or solvent system that carries a drug is the major component of liquid orals
and parenterals. The three categories of vehicles generally used are:
(i) aqueous
vehicles e.g. water, syrup etc.
(ii) nonaqueous
but water miscible e.g. propylene glycol, glycerol, sorbitol.
(iii) nonaqueous
and water immiscible vehicle e.g. vegetable oils.
Bioavailability
of a drug from vehicle depends, to a large extent, on its miscibility with
biological fluids.
·
Aqueous and water miscible vehicles are rapidly
miscible with body fluids (e.g. G.I.-fluid, tissue fluid, blood etc.) and drugs
are rapidly absorbed from them.
·
Propylene glycol, glycerol etc. are used as co-solvent
to increase the solubility of a drug in water. Sometimes solubilisers, such as
Tween 80 are used to promote solubility of a drug in aqueous vehicle.
·
In case of water immiscible vehicles, the rate
of drug absorption depends upon its partitioning from the oil phase to the
aqueous body fluids, which could be a rate limiting step.
b) Diluents (Fillers)
Diluents
are commonly added to tablet (and capsules) formulations.
·
Hydrophilic powders used as diluent are starch,
lactose, microcrystalline cellulose etc. These hydrophilic powders forms a
coating over the hydrophobic drugs particles (e.g. spironolactone and
triamterene) and rendering them hydrophilic.
·
Inorganic diluents like dicalcium phosphate
(DCP) forms divalent calcium-tetracycline complex which is poorly soluble in
water and thus unabsorbable.
c) Binders and
granulating agents
These
materials are used to hold powders together to form granules or promote
cohesive compacts for directly compressible materials and ensure that the
tablet remains intact after compression.
·
Large amount of binders increase hardness and
thus decrease disintegration / dissolution rates of tablets.
·
Non-aqueous binders like ethyl cellulose also
retard dissolution.
d) Disintegrants
These
agents overcome the cohesive strength of tablet and break them up on contact
with water.
·
Almost all the disintegrants are hydrophilic in
nature.
·
A decrease in the amount of disintegrant can
significantly lower the bioavailability.
e) Lubricants
These
agents are added to tablet formulations to aid flow granules, to reduce
interparticular friction and to reduce sticking or adhesion of particles to
dies and punches.
·
The commonly used lubricants are hydrophobic
in nature (several metallic stearates and waxes). They reduce the wettability
of particle surface, penetration of water into tablet.
·
The best alternative is to use soluble
lubricants like sodium lauryl sulphate and carbowax which promotes drug
dissolution.
f) Suspending agents
/Viscosity building agents
Agents like
vegetable gums (acacia, tragacanth etc.), semisynthyetic gums (carboxy methyl
cellulose, methyl cellulose) and synthetic gums which reduces the sedimentation
rate of a suspension
·
The macromolecular gums often form unabsorbable
complex with amphetamine.
·
An increase in viscosity by these agents acts as
a mechanical barrier to the diffusion of drug from the dosage form into the
bulk of GI fluids.
h) Surfactants
Surfactants
are widely used in formulations as wetting agents, solubilizers, emulsifiers,
etc.
Surfactants increase the absorption of a drug by the
following ways:
1.
Promotion of wetting (through increase in effective
surface area) and dissolution of drugs e.g. Tween80 with phenacetin.
2.
Better membrane contact of the drug for absorption
3.
Enhanced membrane permeability of the drug .
Decreased absorption of drug in the presence of surfactants
has been suggested to be due to :
1.
Formation of unabsorbable drug-micelle complex at
surfactant concentrations above critical micelle concentration.
2.
Laxative action induced by a large surfactant
concentration.
i) Complexing agents
Several examples where complexation has been used to enhance
drug bioavailability are:
- Enhanced dissolution through formation of a soluble complex
e.g. ergotamine-caffeine complex
hydroquinone-digoxin complex.
- Enhanced lipophilicity for better membrane permeability e.g. caffeine-PABA complex (PABA = para amino benzoic acid) and
- Enhanced membrane permeability e.g. enhanced GI absorption (normally not absorbed from the GIT) in presence of EDTA (ethylene diamine tetraacetic acid) which chelates Ca++ and Mg++ ions of the membrane.
Disadvantages of complexation:-
1.
complexation may produce poorly absorbable drugs
complexes e.g. tetracycline with divalent and trivalent cations e.g..
tetracycline with divalent and trivalent cations like calcium (milk, antacids),
iron (hematinics), magnesium (antacids) and aluminium (antacids).
2.
large molecular size of drug-protein cannot diffuse
through the cell membrane.
j) Colorants
Even a very
low concentration of water-soluble dye can have an inhibitory effect on
dissolution rate of several
·
crystalline drugs. The dye molecules get
adsorbed onto the crystal faces and inhibit drug dissolution – e.g. brilliant
blue retards dissolution of sulphathiazole.
·
Dyes have also been found to inhibit micellar
solubilizaion effect of bile acids which may impair the absorption of
hydrophobic drugs like steroids.
(B) Manufacturing
process
(i) method of granulation and
(ii) Compression force
(iii) Intensity of packing of
capsules
i) Method of
granulation
The wet granulation
process is the most conventional technique of manufacturing tablet granules.
The limitation of this method include –
(i)
formation of crystal bridge due to the presence of
solvent,
(ii)
the liquid may act as medium or affecting chemical
reactions such as hydrolysis, and
(iii) the
drying step may harm the thermolabile drugs.
Wet granulation includes greater number of steps than dry
granulation or direct compression which can adversely affect the dissolution.
ii) Compression force
The
compression force employed in tableting process influence density, porosity,
hardness, disintegration time and dissolution of tablets.
The curve
obtained by plotting compression force versus rate of dissolution can take one
of the 4 possible shapes shown in the figures:
A. Higher compression force ®
density and hardness of tablet
¯ porosity, hence
penetrability of the solvent into the tablet
¯
wettability by forming a firmer and more effective sealing layer by the
lubricant
B. Higher compression force
® causes deformation, crushing or fracture of
drug particles into smaller ones or, convert a spherical granules into a disc
shaped particle with large increase in effective surface area
® in dissolution rate
C and D are combination of both the causes of A and B.
In short, the influence of compression force on the
dissolution is difficult to predict.
(iii) Intensity of
packing of capsule contents
Packing
density in case of capsule can either inhibit or promote dissolution.
·
Diffusion of GI fluids into the tightly filled
capsules creates a high pressure within the capsule results in rapid bursting
and dissolution of contents.
·
In some cases capsules with tight packing
® pore size of the compact
mass is decreased
® poor penetrability of GI
- fluid
® poor rate of drug release
NATURE AND TYPES OF DOSAGE FORM
Cause of events that occur following oral administration of
various dosage forms:
As a general rule, the bioavailability of a drug from
various dosage forms decreases in the following order:
Solution > Emulsions > Suspensions > Capsules >
Tablets > Coated tablets > Enteric coated tablets > Sustained release
tablets.
Thus,
absorption of a drug from solution is fastest with least potential for
bioavailability problems whereas absorption from sustained release product is
lowest with greatest bioavailability.
PATIENT RELATED FACTORS AFFECTING DRUG ABSORPTION
Physiology of GIT
·
The major components of the GIT are stomach,
small intestine (duodenum, jejunum and ileum) and large intestine (colon) which
differ from each other in terms of anatomy, function, secretions and pH.
·
The mean length of the entire GIT is 450 cm.
·
The entire inner surface of GIT from stomach to
large intestine is lined by a thin layer of muco-polysaccharides (mucous
membrane) which normally acts as a barrier to bacteria, cells or food
particles.
|
1. Mouth
|
pH 6 – 8
|
small surface area
|
lipophilic, neutral and basic drugs are absorbed directly
|
|
2. Stomach
|
pH 1 – 3
|
not too large a surface area
|
lipophilic, neutral and acidic drugs absorbed but lesser
than that from intestine
|
|
3. Small intestine
|
pH 5 – 7.5
|
very large surface area
|
major site for absorption of all types of drugs
(lipophilic, neutral, acidic or basic)
|
|
4. Large intestine
|
pH7.9–8.0
|
small surface area
|
all types of drugs are absorbed but to a lesser extent
|
|
5. Rectum
|
pH 7.5–8.0
|
much smaller surface area
|
all types of drugs are absorbed, about half of the
absorbed drug goes directly into the systemic circulation and the other half
to the liver
|
Stomach
The stomach is a bag like structure having a smooth mucosa
and thus small surface area. Its acidic pH, due to its secretion of HCl, favors
absorption of weakly acidic drugs like aspirin.
Small intestine
Fig. Components of
intestinal epithelium
The folds
in intestinal mucosa, called as fold of
Kerckring result in 3 fold increase in surface area. The surface of this
folds possess finger like projections as villi
which increases the surface area by 30 times.
·
From the surface of villi protrude several
microvilli resulting in 600 times increase in the surface area. All these
combined to impart a large surface area of more than 200 sq.m.
·
The blood flow is 6 – 10 times more than
stomach.
·
pH range is 5 to 7.5 which is more favorable for
most drugs to remain unionized.
·
The peristaltic
movement of intestine is slow, transit time is long, and penetrability
is high. All this factors make intestine the best site for absorption of most
drugs.
Large intestine
Its length
and mucosal surface area is very small (villi and microvilli are absent) compared
to small intestine and thus absorption of drug from this region is very small.
However,
because of the long residence time (6 to 12 hrs), colonic transit may be
important in the absorption of some poorly soluble drugs and sustained release
dosage forms.
PATIENT RELATED
FACTORS
1. Age
In infants gastric: pH is high
intestinal
surface is small
blood
flow is less.
In elderly persons: altered gastric emptying
decreased
intestinal surface area
decreased
GI blood flow
achlorhydria
bacterial
overgrowth in small intestine.
In both of these age drug absorption is impaired.
2. Gastric
emptying
Passage of
gastric content from stomach to small intestine is called gastric emptying.
·
Rapid gastric emptying is required where:
(i)
a rapid onset of action is required e.g. sedatives.
(ii)
dissolution of drug occurs in the intestine e.g.
enteric coated dosage forms.
(iii) the
drugs are not stable in gastric fluid e.g. penicillin-G and erythromycin.
(iv) the
drug is best absorbed from the distal part of the small intestine e.g. vitamin
B12.
·
Delay in gastric emptying is required where:
(i)
the food promotes drug dissolution and absorption e.g.
griseofulvin
(ii)
disintegration and dissolution of dosage form is
promoted by gastric fluid
(iii) the
drugs are absorbed from the proximal part of the small intestine e.g. vitamin B2
and vitamin C.
·
Gastric emptying is a first order rate process. Several parameters are used to quantify
gastric emptying:
(i)
Gastric emptying
rate is the rate at which the stomach content empty into the intestine.
(ii)
Gastric emptying
time is the time required for the gastric content to empty completely into
the small intestine.
(iii) Gastric emptying t1/2 is the
time taken for half the stomach contents to empty.
N.B. In vivo gastric emptying can be studied by using
radio-opaque contrast materials (e.g. BaSO4) or tagging the drug with a
radio-isotope and scanning the stomach at regular intervals of time.
·
Factors influencing gastric emptying rate:-
1. Volume of meal:
Larger the
volume of meal longer the gastric emptying time.
2. Composition of meal
The rate of
gastric emptying for various food materials is in the following order:
carbohydrates
> protein > fats
3. Physical state and viscosity of meal
Liquid
meals take less than an hour to empty solid meals take as long as 6 – 7 hours
to empty.
Viscous
material empty at a slow rate in comparison to less viscous materials.
4. Temperature of the meal
High or low
temperature of the ingested fluid (compared to body temperature) reduce gastric
emptying rate.
5. Gastrointestinal pH
Gastric
emptying is retarded at low stomach pH and
is promoted at higher or alkaline pH.
6. Electrolyte and osmotic pressure
Water, isotonic, and solutions of
low salt concentration empty the stomach rapidly whereas higher electrolyte
concentration decreases gastric emptying rate.
7. Body posture
Gastric emptying is favoured while
standing and while lying on the right side; while lying on the left side or in
supine position retards it.
8. Emotional state
Stress and anxiety promote gastric
motility whereas depression retards it.
9. Exercise
Vigorous physical exercise retards
gastric emptying.
10 Disease states
Diseases like gastroenteritis,
gastric ulcer, pyloric stenosis, diabetes and hypothyroidism retard gastric
emptying.
11. Drugs
Drugs that retard gastric emptying includes
(i) poorly soluble antacids e.g.
aluminium hydroxide,
(ii) anticholinergics e.g.
atropine, propantheline
(iii) narcotic analgesics e.g.
morphine and
(iv) tricyclic antidepressants e.g.
imipramine, amytriptyline.
Drug that stimulate gastric emptying are:
(i) metoclopramide
(ii) domperidone
(iii) cisapride
3. Effect of GI pH
on drug absorption
GI fluid pH influence drug absorption in several ways:
1. Disintegration
The
disintegration of some dosage forms is pH sensitive. With enteric coated
formulations, the coat dissolves only in the intestinal pH, followed by
disintegration of the tablet.
2. Dissolution
A large number
of drugs are either weakly acidic or weakly basic whose solubility is greatly
affected by pH. A pH that favours the
formation of salt of the drug enhances the dissolution rate. e.g. Weakly acidic
drugs dissolve rapidly in the alkaline pH of the intestine whereas basic drugs
dissolves in the acidic pH of the stomach.
3. Absorption
Depending upon
the pKa of the drug and the pH of the GI fluid some amount of the drug remain
in ionized state and some in unionized state. The unionized form will be
absorbed through GIT quickly than the ionized form.
4. Stability
GI pH influences
the chemical stability of drugs. e.g. The acidic stomach pH is known to affect
degradation of Penicillin-G and erythromycin.
4. Effect of GI
content
A number of
GI contents can influence drug absorption.
1. Food-drug interaction
Presence of food may either delay, reduce, increase or may
not affect drug absorption.
|
Delayed
|
Decreased
|
Increased
|
Unaffected
|
|
Aspirin
Paracetamol
Diclofenac
|
Penicillins
Erythromycin
Ethanol
Tetracyclines
Levodopa, Iron
|
Griseofulvin
Diazepam
|
Methyldopa
Sulfasomidine
|
As a
general rule, drugs are better absorbed under fasting conditions and
presence of food retards or prevents it.
Food does
not significantly influence absorption of a drug taken half an hour or more
before meals and two hours or more after meals.
·
Delayed or decrease drug absorption by food can
be due to one or more of the following reasons:
(a)
Delayed gastric emptying, affecting the drugs unstable
in the stomach e.g. penicillin, erythromycin.
(b)
Preventing the transit of enteric tablets into the
intestine which may be as long as 6 – 8 hrs.
(c)
Formation of poorly soluble, unabsorbable complex e.g.
tetracycline-calcium complex.
(d)
Increased viscosity due to food thereby preventing drug
dissolution and/or diffusion towards the absorption site.
·
Increased drug absorption following a meal can
be due to the following reasons:
(a)
Increased time for dissolution of poorly soluble drug.
(b)
Enhanced solubility due to GI secretions like bile.
(c)
Prolonged residence time and absorption site contact of
the drug e.g. water-soluble vitamins.
·
Types of
meal
(i)
Meals high in fat aid solubilisation of poorly aqueous
soluble drugs like griseofulvin.
(ii)
Food high in proteins increases oral availability of
propranolol because
a) such a meal promotes blood flow
to the GIT helping in drug absorption.
b) increases
hepatic blood flow due to which the drug can bypass first-pass hepatic
metabolism (propranolol is a drug with
high hepatic metabolism)
5. Drug-drug
interaction
Drug-drug interactions can be either physicochemical or
physiological.
(a) Physicochemical drug-drug interactions can be due
to –
Adsorption: Antidiarrheal preparations containing adsorbents like attapulgite or kaolin-pectin retard / inhibit absorption of promazine and lincomycin
when co-administered with them.
Complexation: Antacids containing heavy metals such as aluminium, calcium, iron,
magnesium or zinc retard absorption of tetracyclines due to the formation of
unabsorbable complexes.
pH change: Basic drugs dissolve in gastric pH. Co-administration of
sodium bicarbonate with tetracycline results in evaluation of stomach pH and
hence decreases dissolution rate or cause precipitation of drug.
(b) Physiologic drug-drug interaction can be due to
following reasons:
Decreased GI transit: Anticholinergic drugs such as
propantheline retard GI motility and promote absorption of drugs like ranitidine
and digoxin.
Increased gastric emptying: Metoclopramide promotes GI motility and
enhances absorption of tetracycline, pivampicillin and levodopa.
Altered GI metabolism: Antibiotics inhibit bacterial
metabolism of drugs e.g. erythromycin enhances efficacy of digoxin by this
mechanism.
6. Presystemic
metabolism / First pass effects
The loss of
drug through biotransformation by GIT and liver during the passage to systemic
circulation in called First pass or presystemic metabolism.
The 4 primary systems which affect presystemic metabolism of
drugs are:
1.
Lumenal enzymes
2.
Gut wall enzymes /mucosal enzymes
3.
Bacterial enzymes, and
4.
Hepatic enzymes
1. Lumenal enzymes
These are
enzymes present in the gut fluids and include enzymes from intestinal and
pancreatic secretions.
·
Pancreatic enzymes contains hydrolases which hydrolyze ester drugs like chloramphenicol palmitate into active chloramphenicol.
·
Peptidases
split amide ( –CONH) linkages and inactivate protein / polypeptide drugs. Thus
one of the approaches is to deliver them to colon which lacks peptidases.
2. Gut-wall enzymes (also called mucosal enzymes)
They are
present in stomach, intestine and colon.
·
Stomach mucosa contains alcohol dehydrogenase (ADH) inactivates ethanol.
3. Bacterial enzymes
The GI
microorganisms are scantily present in stomach and small intestine and is rich
in colon. Hence, most orally administered drugs remain unaffected by them.
·
The colonic microbes generally render a drug
more active or toxic on biotransformation:
e.g.
sulfasalazine (used in ulcerative colitis) is hydrolyzed to sulfapyridine and
5-amino salicylic acid by the microbial enzymes of the colon.
·
Digoxin, oral contraceptive drugs are absorbed
in the upper intestine; exerted through bile as glucuronide conjugates. This
conjugates of drugs are hydrolyzed by microbial enzymes. The free drugs are
reabsorbed into the systemic circulation.
4. Hepatic enzymes
e.g.
isoprenaline, propranolol, alprenolol, pentoxyfylline, nitroglycerin,
diltiazem, nifedipine, lidocaine, morphine etc.