Gastrointestinal

Absorption
• A drug injected intravascularly (intravenously and/or intra-arterially)
directly enters the systemic circulation and exerts its pharmacologic
effects.
• However, majority of drugs are administered extravascularly,
generally orally.
• If intended to act systemically, such drugs can exert their
pharmacologic actions only when they come into blood circulation
from their site of application, and for this, absorption is an important
prerequisite step.
Definition:
• The process of movement of unchanged drug from the site of administration
to systemic circulation.
• The effectiveness of drug can only be accessed by its concentration at the site
of action.
• however it is difficult to measure the drug concentration at such a site.
• Instead the concentration can be more correctly measured in plasma
• There always exist a correlation between the plasma concentration of a drug
& the therapeutic response
• absorption can also be defined as the process of movement of unchanged
drug from the site of administration to the site of measurement. i.e., plasma
• This definition takes into account the loss of drug that occurs after oral
administration due to presystemic metabolism or first-pass effect.
• Not only the magnitude of drug that comes into the systemic circula-tion
but also the rate at which it is absorbed is important. This is clear from
Figure.
• A drug that is completely but slowly absorbed may fail to show
therapeutic response as the plasma concentration for desired effect is
never achieved.
• On the contrary a rapidly absorbed drug attains the therapeutic level
easily to elicit pharmacologic effect. Thus, both the rate and the extent
of drug absorption are important
• Such an absorption pattern has several advantages:
1. Lesser susceptibility of the drug to degradation or interaction due to
rapid absorption
2. Higher blood levels and rapid onset of action
3. More uniform, greater and reproducible therapeutic response
• Drugs that have to enter the systemic circulation to exert the effect can
be administered by three major routes
1. The Enteral Route includes per oral i.e GI, buccal, sublingual, and rectal
route.
2. The Parenteral Route includes all routes of administration through or
under one or more layers of Skin while no absorpotion is required when
the drug is administered i.v, it is necessary for extravascular parenteral
routes like the subcutanous and the intramuscular routes.
3. The Topical Route includes skin eyes or other specific membranes The
intranasal, inhalation, vaginal and transdermal route may be considered
enteral or topical.
• The oral route is the most common for systemically acting drugs
therefore more emphasis will be given to GI absorption of drugs.
• moreover it covers all the aspects of variability observed in drug
absorption.
Cell membrane
• Also called the plasma membrane, plasmalemma or phospholipid
bilayer.
• The plasma membrane is a flexible yet sturdy barrier that surrounds &
contains the cytoplasm of a cell.
• Thin barrier = 8nm thick
• Controls traffic in and out of cell
• Selectively permeable
Cell membrane mainly consists of:
1. Lipid bilayer-
-phospholipid
-Cholesterol
-Glycolipids.

2. Proteins-
-Integral membrane proteins
-Lipid anchored proteins
-Peripheral Proteins
• For a drug to be absorbed and distributed into organs and tissues and
eliminated from the body, it must pass through one or more biological
membranes/barriers at various locations.
• Such a movement of drug across the membrane is called as drug
transport.
Factors affecting drug
absorption
• Patient related factors
• Physicochemical factors
• Formulation factors
Patient related factors
1. GI Motility and emptying
2. Blood flow through GIT
3. Influence of food
4. Intestinal transit time
5. Pre-systemic metabolism by various enzymes
6. Age
7. Clinical factors
GI Motility and emptying
• Gastric emptying:
• apart from the dissolution of drug and its permeation through the bio membrane, the
passage from stomach to small intestine, called as gastric emptying,
• can also be a rate limiting step in absorption because the major site of drug absorption is
intestine.
• rapid gastric emptying is advisable where:
1. Rapid onset of drug is desired eg: sedatives
2. Drug not stable in gastric fluids eg: pencillin G
3. Dissolution occuring in intestine eg: enteric coated forms
4. Drug is absorbed from distal part of small intestine
• Generally rapid gastric emptying increases the bioavailibilty of drug
• It is faster in case of solution and suspension than solid dosage form.
Delay in gastric emptying is recommended in particular where:
• Food promotes drug dissolution and absorption eg: griseofulvin.
• The drugs dissolve slowly.
• Disintegration and dissolution of dosage form is promoted by gastric
fluids.
Gastric emptying is first order process. Several parameters used to
quantify are:
• Gastric emptying rate: speed at which stomach contents empties into
intestine.
• Gastric emptying time: time required for gastric contents to empty
into small intestine
• Gastric emptying t1/2 : time taken for half of the stomach contents
to empty
Factors influencing gastric
emptying
• Volume of meal: larger the bulk of meals, longer the gastric emptying
time. Since gastric emptying is first order, a plot of volume of contents
remaining in stomach vs time yields a straight line.
• Composition of meal:
carbohydrates > proteins> fats Delayed gastric emptying with fatty
meal, is beneficial for the absorption of poorly soluble drugs like
griseofulvin.
• Physical state and viscosity of meal:
Liquid meals take less than hour to empty whereas a solid meal may take as
long as 6 to 7 hours.
• Temperature:
High or low temperature of injested fluid reduces the gastric emptying.
• Gastro intestinal ph:
Retarded at low stomach ph and promoted at high ph.
Electrolytes and osmotic ph:
water, isotonic solutions and of low salt concentration empty rapidly whereas
high electrolyte conentration decreases gastric emptying.
• Drugs that retard gastric emptying include
• Poorly soluble antacids: aluminium hydroxide
• Anticholinergics: atropine
• Narcotic analgesics: morphine
• Tricyclic anti depressents: imipramine
• Disease state: like gastroenteritis, gastric ulcer, pyloric stenosis retard
gastric emptying rate.
Gastro intestinal pH
• The GI ph generally increases as one moves down the stomach to the
colon and rectum.GI ph influence absorption in several ways.
• Disintegration: the disintegration of some dosage forms is ph
dependent. with Enteric coated formulations coat dissolves only in
intestine followed by disintegration.
• Dissolution:
• weakly acidic drugs: dissolve rapidly in alkaline ph of intestine
• Weakly basic drugs: dissolve in acidic ph of stomach
• Absorption : Depending upon the drug pKa and whether its an acidic
or a basic drug, the GI pH influences drug absorption by determining
the amount of drug that would exist in the unionized form at the site
of absorption.
• Stability : GI pH also influences the chemical stability of drugs. The
acidic stomach pH is known to affect degradation of penicillin G and
erythromycin. This can be overcome by preparing prodrugs of such
drugs that do not degrade or dissolve in acidic pH erythromycin
estolate.
Intestinal transit
• Since small intestine is the major site for absorption of most drugs,
long intestinal transit time is desirable for complete drug absorption.
• The residence time depends upon the intestinal motility or contrac-
tions.
• The mixing movement of the intestine that occurs due to peristaltic
contractions promote drug absorption, firstly, by increasing the drug-
intestinal membrane contact, and secondly, by enhancing drug
dissolution especially of poorly soluble drugs, through induced
agitation.
Delayed transit time is desirable for:
• Drugs that dissolve or release slowly from their dosage form.
• Drugs that dissolve only in intestine (enteric coated tablets)
• Drugs absorbed from specific sites in the intestine e.g several b
vitamins.
• Anticholinergic drugs: retard gastric and intestinal transit promote
absorption of poorly soluble drugs eg:propantheline
• Laxatives promote the rate of intestinal transit.
Pre systemic metabolism
• For a drug administration orally, the 2 main reasons for its decreased
bioavailability are:
• Decreased absorption and
• First pass metabolism
• The loss of drug through biotransformation by such eliminating organs
during its passage to systemic circulations called as first pass or presystemic
metabolism.
• The 4 primary systems which effect presystemic metabolism of a drug are:
a. Luminal enzymes c. Bacterial enzymes
b. Gut wall enzymes d. Hepatic enzymes
Luminal enzymes:
• These are present in gut fluids and include enzymes from intestinal
and pancreatic secretions.
• latter contain hydrolases which hydrolyse ester drugs like
chloramphenicol palmitate into active chloramphenicol, and
peptidases which split amide linkages and inactivate proteins.
• One approach to effect oral absorption of peptides is to deliver them
to colon which lack peptidases.
Gut wall enzymes :
• Also called as mucosal enzymes, they are present in stomach,
intestine and colon.
• Alcohol dehydrogenase (ADH) is an enzyme of stomach mucosa that
inactivates ethanol.
• Intestinal mucosa contains both phase I and phase II (predominant)
enzymes.
• The colonic mucosa also contain both phase I and phase II enzymes.
However, it is only the enzymes of the proximal small intestine that
are most active.
Bacterial enzymes :
• The GI microflora is 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 for example sulfasalazine, a drug used in ulcerative
colitis, is hydrolyzed to sulfapyridine and S-amino salicylic acid by the
microbial enzymes of the colon.
• An important role of intestinal microflora is that in enterohepatic
cycling. Their enzymes hydrolyze the conjugates of drugs actively
secreted
Hepatic enzymes:
• several drugs undergo first pass hepatic metabolism, the highly
extracted ones being
• Lidocaine
• Morphine
• propranolol
• isoprenaline
• nitroglycerine
• alprenolol
• Diltiazem etc.
Blood flow through GIT
• GIT is extensively supplied by blood capillary network and the
lymphatic system. The absorbed drug can thus be taken up by the
blood or the lymph.
• Since the blood flow rate to the GIT is 500 to 1000 times more than
the lymph flow, most drugs reach the systemic circulation via blood
whereas only a few drugs, especially low molecular weight, lipid
soluble compounds are removed by lymphatic system.
• For drugs that have high permeation rates, e.g. highly lipid soluble
drugs or drugs absorbed through pores, the GI perfusion rate could be
rate limiting step in the absorption.
• Blood flow is also important for actively absorbed drugs since oxygen
and energy is required for transportation.
• Food influences blood flow to the GIT. The perfusion rate increases
after meals and persists for few hours but drug absorption is not
influenced significantly.
Influence of food
Food can affect absorption by Altering,
• Stomach pH
• Affect Gastric emptying
• Forms complex with the drug.
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 decreased drug absorption by the food could be due to
one or more of the several mechanisms:
(a) Delayed gastric emptying, affecting drugs unstable in the stomach
e.g. penicillins, or preventing the transit of enteric coated tablets into
the intestine
(b) Formation of a poorly soluble, unabsorbable complex e.g. tetracy-
cline-calcium
(c) Increased viscosity due to food thereby preventing drug dissolution
and/or diffusion towards the absorption site
• Increased drug absorption following a meal could be due to one or
more of the under mentioned reasons:
(a) Increased time for dissolution of a 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
(d) Increased lymphatic absorption
Age
• In children & Infants Gastric pH is high, intestinal surface and blood
flow is low resulting in altered absorption.
• while in Elderly patient there is altered gastric emptying, decrease
intestinal surface area, decrease gastric blood flow & higher incidence
of achlorhydria and bacterial overgrowth in small intestine which
result in altered absorption.
CLINICAL FACTORS

• A) DISEASES
• B) SURGERY
• C) INFECTIONS
• D) INTERACTIONS
Gastric diseases
ACHLORHYDRIA:
i) Achlorhydria affects Aspirin absorption by increasing gastric emptying time &
increasing stomach pH.
ii) Intestinal diseases like celiac disease, chron’s disease.
iii) Cardio-vascular diseases
Several changes associated with congestive cardiac failure influence the bio-
availability of the drug, edema of the intestine, decreases blood flow to GIT, etc.
iv) Hepatic diseases
Disorders such as hepatic cirrhosis influence bio-availability mainly of drugs
that undergo considerable first-pass hepatic metabolism e.g. Propranolol
INTERACIONS
i) Food-Drug Interactions
Presence of food may either delay,reduce,increase or may not affect drug
absorption.
ii) Drug-Drug Interactions
PHSICO-CHEMICAL Adsorption, Complexation E.g. Antacids, Heavy Metals
PHYSIOLOGICAL Decrease GI transit, Increase Gastric emptying E.g. Metoclopramide
iii) Drug-GI contents interactions
Interaction with mucin, enzymes and bile salts influence drug absorption.
E.g. Bile salts Increase absorption of –Vitamins (Solution)
Decrease absorption of –Neomycin and Kanamycin (Insoluble complex)
PHARMACEUTICAL FACTORS

• Formulation factors
• Physicochemical factors
FORMULATION FACTORS
A)DISINTEGRATION TIME (Tablets/Capsules)
B)MANUFACTURING VARIABLES
C)PHARMACEUTIC INGREDIENTS (Excipients, Adjuvants)
D)NATURE AND TYPE OF DOSAGE FORM
E)PRODUCT AGE AND STORAGE CONDITIONS
DISINTEGRATION TIME

• Rapid disintegration is important to have a rapid absorption

• In-vivo disintegration gives no means of guarantee of drug bio-
availability, because if the disintegrated drug particles do not dissolve,
then the dissolution is not possible.
• However, if a solid dosage form does not conform to the DT, it
presents bioavailability problems because the subsequent process of
dissolution will be much slower and absorption may be insufficient.
• Coated tablets, especially sugar coated ones have long DT. Rapid
disintegration is thus important in the therapeutic success of a solid
dosage form.
• DT of a tablet is directly related to the amount of binder present and
the compression force (hardness) of a tablet.
• A harder tablet with large amount of binder has a long DT.
• Disintegration can be aided by incorporating disintegrants in suitable
amounts during formulation.
• After disintegration of a solid dosage form into granules, the granules
must deaggregate into fine particles as dissolution from such tiny
particles is faster than that from granules.
• Now D.T of tablet is directly proportional to amount of binder,
Compression force.
Manufacturing/Processing
Variables
• Drug dissolution is the single most important factor in the absorption
of drugs, especially from the most widely used conventional solid
dosage forms, tablets and capsules. The dosage form related factors
that influence dissolution and hence absorption of a drug from such
formulations are
• Excipients (formulation ingredients apart from the active principles)
• Manufacturing processes
• Several manufacturing processes influence drug dissolution from solid
dosage forms.
• Processes of such importance in the manufacture of tablets
1. Method of granulation, and
2. Compression force: The processing factor of importance in the
manufacture of capsules that can influence its dissolution is the
intensity of packing of capsule contents.
• Method of granulation:
Wet granulation yields a tablet that dissolves faster than those made by
other granulating methods. But wet granulation has several limitations
like formation of crystal bridge or chemical degradation.
• Other superior recent method named APOC (agglomerative phase of
communition) that involves grinding of drug till spontaneous
agglomeration and granules are prepared with higher surface area. So
tablet made up of this granules have higher dissolution rate.
• Compression force: Higher compression force yields a tablet with
greater hardness and reduced wettability & hence have a long D.T.
• but on other hand higher compression force cause crushing of drug
particles into smaller ones with higher effective surface area which
results in increase in dissolution.
• effect of compression force on dissolution is difficult to predict so it
should be thoroughly studied on each formulation.
Nature and type of dosage form

• Drug formulations are designed to provide an attractive, stable, and

convenient method to use products.
• Conventional dosage forms may be broadly characterized in order of
decreasing dissolution rate as solutions, solid solutions, suspensions,
capsules and tablets, coated capsules and tablets, and controlled
release formulations.
• Solutions: Aqueous solutions, syrups, elixirs, and emulsions do not
present a dissolution problem and generally result in fast and often
complete absorption as compared to solid dosage forms. Due to their
generally good systemic availability, solutions are frequently used as
bioavailability standards against which other dosage forms are
compared.
Suspensions:
• A drug in a suspension is in solid form, but is finely divided and has a large
surface area. Drug particles can diffuse readily between the stomach and
small intestine so that absorption is relatively insensitive to stomach
emptying rate.
• Adjusting the dose to a patient’s needs is easier with solutions and
suspensions than with solid dosage forms. Liquid dosage forms, therefore,
have several practical advantages besides simple dissolution rate.
• However, they also have some disadvantages, including greater bulk,
difficulty in handling, and perhaps reduced stability.
Capsules and tablets:

• These formulations differ from each other in that material in capsules is less
impacted than in compressed tablets. Once a capsule dissolves, the contents
generally disperse quickly.
• Tablets generally disintegrate in stages, first into granules and then into
primary particles. As particle size decreases, dissolution rate increases due
to of increased surface area.
• Powders and granules are popularly administered in hard gelatin capsules
whereas viscous fluids and oils in soft elastic shells. Factors of importance in
case of hard gelatin capsules include drug particle size, density,
polymorphism, intensity of packing and influence of diluents and excipients.
• Powders: Though powders are superior to tablets and capsules, they
are not in use nowadays due to handling and palatability problems.
Major factors to be considered in the absorption of a drug from
powders are particle size, polymorphism, wettability, etc.
• Hydrophilic diluents like lactose improve wettability, deaggregation
and dispersion of poorly aqueous soluble drugs whereas inhibitory
effect is observed with hydrophobic lubricants like magnesium
stearate.
• Soft elastic capsules as such dissolve faster than hard gelatin capsules
and tablets and show better drug availability from oily solutions,
emulsions or suspensions of medicaments (especially hydrophobic
drugs).
• poorly soluble drugs can be dissolved in PEG or other suitable solvent
with the aid of surfactants and encapsulated without difficulty.
• Soft gels are thus of particular use where the drug dose is low, drug is
lipophilic or when oily or lipid based medicaments are to be
administered.
• A problem with soft gels is the high water content of the shell (above
20%). This moisture migrates into the shell content and crystallization
of drug occurs during the drying stage resulting in altered drug
dissolution characteristics.
• As a general rule, the bio- availability of a drug from various dosage
forms decrease in the following order:
• Solutions > Emulsions> Suspensions > Capsules >Tablets > Coated
Tablets > Enteric coated Tablets > Sustained Release Products.
Nature and type of dosage form
Pharmaceutical ingredients /
Excipients
• More the no. of excepients in dosage form, more complex it is &
greater the potential for absorption and Bioavailability problems.
• Changing an excipient from calcium sulfate to lactose and increasing
the proportion of magnesium silicate, increases the activity of oral
phenytoin.
• Absorption of tetracycline from capsules is reduced by calcium
phosphate due to complexation.
• Vehicle: Rate of absorption depends on its miscibility with biological
fluid. Miscible vehicles (aq. or water miscible vehicle) rapid absorption
e.g. propylene glycol.
• Diluents: Hydrophilic diluents form the hydrophilic coat around
hydrophobic drug particles thus promotes dissolution and absorption
of poorly soluble hydrophobic drug.
• Binders & granulating agent : Hydrophilic binders imparts hydrophilic
properties to granule surface, better dissolution of poorly wettable
drug e.g. starch, gelatin, PVP. More amount of binder increases
hardness of tablet decrease dissolution & disintegration rate.
 Disintegrants
• Mostly hydrophilic in nature.
• Decrease in amount of disintegrants significantly lowers B.A.
Lubricants :
• Commonly hydrophobic in nature
• therefore inhibits penetration of water into tablet and thus dissolution and disintegration.
Suspending agents/viscosity agent :
• Stabilize the solid drug particles and thus affect drug absorption.
• Macromolecular gum forms unabsorbable complex with drug e.g. Na CMC.
• Viscosity imparters act as a mechanical barrier to diffusion of drug from its dosage form
and retard GI transit of drug.
Surfactants :
• May enhance or retards drug absorption by interacting with drug or
membrane or both.
• Surfactants have been considered as absorption enhancers
• Polyoxyethylene ethers have been shown to enhance gastric or rectal
absorption of lincomycin, penicillin, cephalosporins, and fosfomycin in
rats and rabbits.
• However, in humans, oral polyoxyethylene resulted in poor and
variable insulin absorption.
Colourants:
• Even a low concentration of water soluble dye can have an inhibitory
effect on dissolution rate of several crystalline drugs.
• The dye molecules get absorbed onto the crystal faces and inhibit the
drug dissolution e.g: Brilliant blue retards dissolution of sulfathiazole.
Product age and storage
conditions :
• number of changes, especially in the physicochemical properties of a
drug in dosage form, can result due to aging and alterations in storage
conditions which can adversely affect bioavailability.
• With solution dosage form, precipitation of drug due to altered
solubility, especially due to conversion of metastable into poorly
soluble, stable polymorph can occur during the shelf-life of the
product.
• Changes in particle size distribution have been observed with a
number of suspension dosage forms resulting in decreased rate of
drug dissolution and absorption. Incase of solid dosage forms,
especially tablets, disintegration and dissolution rates are greatly
affected due to aging and storage conditions.
• An increase in these parameters of tablets has been attributed to
excipients that harden on storage (e.g. PVP, acacia, etc.) while the
decrease is mainly due to softening/crumbling of the binder during
storage (e.g. CMC).
• Changes that occur during the shelf-life of a dosage form are affected
mainly by large variations in temperature and humidity. In one of the
studies conducted on prednisone tablets containing lactose as the
filler, high temperature and high humidity resulted in harder tablets
that disintegrated and dissolved slowly.