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Anatomic and Physiological

Consideration in Oral Drug


Absorption
Gastrointestinal Tract
• The GIT comprises of a number of components, their
primary function being secretion (Saliva enzymes,
pancreatic enzymes, mucus secretion), digestion and
absorption.
• Food constituents are mostly absorbed in the
proximal area (duodenum) of the small intestine.
• Absorption may be considered as the net result of
both lumen-to-blood and blood-to-lumen transport
movements.
Gastrointestinal Tract
• The mean length of the entire GIT is 450 cm. The
major functional components of the GIT are
stomach, small intestine (duodenum, jejunum and
ileum) and large intestine (colon).
Oral Cavity
• Saliva is the main secretion of the oral cavity, and it
has a pH of about 7. Saliva contains ptyalin (salivary
amylase), which digests starches. Mucin, a
glycoprotein that lubricates food, is also secreted and
may interact with drugs. About 1500 mL of saliva is
secreted per day.
Esophagus
• The esophagus connects the pharynx and the cardiac
orifice of the stomach.
• The pH of the fluids in the esophagus is between 5
and 6. The lower part of the esophagus ends with
the esophageal sphincter, which prevents acid reflux
from the stomach.
Stomach
• The fasting pH of the stomach is about 2 to 6. In the
presence of food, the stomach pH is about 1.5 to 2, due
to hydrochloric acid secreted by parietal cells.
• Basic drugs are solubilized rapidly in the presence of
stomach acid.
• Food and liquid are emptied by opening the pyloric
sphincter into the duodenum.
• Stomach emptying is influenced by the food content and
osmolality. Fatty acids and mono - and diglycerides delay
gastric emptying.
• High-density foods generally are emptied from the
stomach more slowly.
Duodenum
• A common duct from the pancreas and the gallbladder
enters into the duodenum.
• The duodenal pH is about 6 to 6.5, because of the
presence of bicarbonate that neutralizes the acidic chime
emptied from the stomach
• Trypsin, chymotrypsin, and carboxypeptidase are
involved in the hydrolysis of proteins into amino acids.
• Amylase is involved in the digestion of carbohydrates.
Pancreatic lipase secretion hydrolyzes fats into fatty acid.
• The duodenum is a site where many ester prodrugs are
hydrolyzed during absorption.
Jejunum
• The jejunum is the middle portion of the small
intestine, between the duodenum and the ileum.
• Digestion of protein and carbohydrates continues
after addition of pancreatic juice and bile in the
duodenum.
• This portion of the small intestine generally has
fewer contractions than the duodenum and is
preferred for in-vivo drug absorption studies.
Ileum
• The ileum is the terminal part of the small intestine.
This site has fewer contractions than the duodenum
and may be blocked off by catheters with an
inflatable balloon and perfused for drug absorption
studies.
• The pH is about 7, with the distal part as high as 8.
Due to the presence of bicarbonate secretion, acid
drugs will dissolve. Bile secretion helps to dissolve
fats and hydrophobic drugs.
Colon
• The colon lacks villi and has limited drug absorption
also, because of the more viscous and semisolid nature
of the lumen contents.
• The colon is lined with mucin that functions as
lubricant and protectant.
• The pH in this region is 5.5 to 7.
• A few drugs, such as theophylline and metoprolol, are
absorbed in this region.
• Drugs that are absorbed well in this region are good
candidates for an oral sustained-release dosage form
Rectum
• The rectum is about 15 cm long, ending at the
anus.
• In the absence of fecal material, the rectum has a
small amount of fluid (approximately 2 mL) with a
pH about 7.
• The rectum is perfused by the superior, middle,
and inferior hemorrhoidal veins.
• The inferior hemorrhoidal vein (closest to the anal
sphincter) and the middle hemorrhoidal vein feed
into the vena cava and back to the heart. Drug
absorption after rectal administration may be
variable, depending on the placement of the
suppository or drug solution within the rectum
Drug Absorption in GIT
• Drugs may be absorbed by passive diffusion from
all parts of the alimentary canal including
sublingual, buccal, GI, and rectal absorption.
• For most drugs, the optimum site for drug
absorption after oral administration is the upper
portion of the small intestine or duodenum region.
• In addition, the duodenal region is highly perfused
with a network of capillaries, which helps to
maintain a concentration gradient from the
intestinal lumen and plasma circulation.
Gastric Emptying
• The passage from stomach to the small intestine,
called as gastric emptying, can also be a rate-limiting
step in drug absorption because the major site of
drug absorption is intestine.
• Rapid gastric emptying is advisable where;
– A rapid onset of action is desired e.g. sedatives
– Dissolution of drug occurs in the intestine e.g. enteric
coated dosage forms
– The drugs are not stable in the gastric fluids e.g. penicillin
G and erythromycin
– The drug is best absorbed from the distal part of the small
intestine e.g. vitamin B12
• Delay in gastric emptying is recommended
particular where;
– The food promotes drug dissolution and absorption
e.g. griseofulvin
– Disintegration and dissolution of dosage form is
promoted gastric fluids
– The drugs dissolve slowly e.g. griseofulvin
– The drugs irritate the gastric mucosa e.g. aspirin,
phenylbutazone and nitrofurantoin
– The drugs are absorbed from the proximal part of the
small intestine and prolonged drug-absorption site
contact is desired eg; vitamin B2 and vitamin C
Factors Influencing Gastric Emptying

1. Volume of meal
2. Composition of meal
3. Physical state and viscosity of meal
4. Temperature of the meal
5. Gastrointestinal pH
6. Electrolytes and osmotic pressure
7. Body posture
8. Emotional state
9. Exercise
10. Disease state
11. Drugs
Intestinal Transit
Small intestine transit time about 3 to 4 hours.
Thus a drug may take about 4 to 8 hours to pass
through the stomach and small intestine during
the fasting state. During the fed state, SITT may
take 8 to 12 hours. Delayed transit is desirable for:
– Drugs that dissolve or release slowly from their
dosage form (sustained release products)
– Drugs that dissolve only in the intestine (enteric
coated formulations)
– Drugs absorbed from specific sites in the intestine
(several B vitamins)
Gastrointestinal pH
• The GI pH generally increases gradually as one move
down the stomach to the colon and rectum as shown
in figure below. GI fluid pH influence drug absorption
in several ways as disintegration, dissolution,
absorption and stability.
Disease States
• Drug absorption may be affected by any disease that
causes changes in (1) intestinal blood flow, (2)
gastrointestinal motility, (3) changes in stomach
emptying time, (4) gastric pH that affects drug
solubility, (5) intestinal pH that affects the extent of
ionization, (6) the permeability of the gut wall, (7)
bile secretion, (8) digestive enzyme secretion, or (9)
alteration of normal GI flora.
Blood Flow to the GIT.
• The high perfusion rate of GIT ensures that once the
drug has crossed the membrane, it is rapidly removed
from the absorption site thus maintaining the sink
conditions and concentration gradient for continued
drug absorption.
• 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 (28% of cardiac output) more than the lymph
flow, most drugs reach the systemic circulation via
blood whereas only a few drugs, especially low
molecular weight, and lipid soluble compounds are
removed by lymphatic system.
Gastrointestinal Contents
A. Food-drug interactions
• Presence of food may either delay, reduce, increase or
may not affect drug absorption.
• 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 gastric emptying, affecting drugs unstable in the
stomach e.g. penicillins,
• Formation of a poorly soluble, unabsorbable complex
e.g. tetracycline-calcium
• 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:
– Increased time for dissolution of a poorly soluble drug
– Enhanced solubility due to GI secretions like bile
– Prolonged residence time and absorption site contact of
the drug e.g. water-soluble vitamins
– Increased lymphatic absorption e.g. acitretin
B. Fluid volume
• Administration of a drug with large fluid volume
results in better dissolution, rapid gastric emptying
and enhanced absorption.
• For example, erythromycin is better absorbed when
taken with a glass of water under fasting condition
than when taken with meals.
C. Interaction of drug with normal GI constituents
• The GIT contains a number of normal constituents such as
mucin, bile salts and enzymes which influence drug
absorption
• Mucin, a protective mucopolysaccharide that lines the Gl
mucosa, interacts with streptomycin and certain
quaternary ammonium compounds and retards their
absorption.
• It also acts as a barrier to diffusion of drugs. The bile salts
aid solubilization and absorption of lipid soluble drugs like
griseofulvin and vitamins A, D, E and K on one hand and on
the other, decreases absorption of neomycin and
kanamycin by forming water insoluble complexes.
D. Drug-Drug interactions in the GIT
– Physicochemical of drug-drug interactions
• Adsorption
• Complexation
• pH change
– Physiological drug-drug interactions
• Decrease GI transit
• Increased gastric emptying
• Altered GI metabolism
Decreased absorption, and First-
pass/presystemic metabolism.
• Before a drug reaches blood circulation, it has to pass
for the first time through organs of elimination namely
the GIT and the liver.
• The loss of drug through biotransformation by such
eliminating organs during its passage to systemic
circulation is called as first-pass or presystemic
metabolism.
• The diminished drug concentration or rarely, complete
absence of the drug in plasma after oral administration
is indicative of first-pass effects.
• The 4 primary systems which affect presystemic
metabolism of a drug are;
– Lumenal enzymes
– Gut wall enzymes/mucosal enzymes,
– Bacterial enzymes, and
– Hepatic enzymes.
Absorption of Drugs From Non Per Oral
Route Bioavailability
Parenteral routes
Intravenous Complete (100%) systemic
bolus (IV) drug absorption Rate of bioavailability
considered instantaneous
Intravenous Complete (100%) systemic
infusion (IV inf) drug absorption
Rate of drug absorption controlled
by infusion pump
Intramuscular Rapid from aqueous solution
injection (IM)
Slow absorption from non-aqueous
(oil) solutions
Subcutaneous Prompt from aqueous solution
injection (SC) Slow absorption from repository
formulations
Enteral routes
Buccal or Rapid absorption from
sublingual (SL) lipid-soluble drugs
Oral (PO) Absorption may vary Generally
slower absorption rate compared
to IV bolus or IM injection
Rectal (PR) Absorption may vary from
suppository
More reliable absorption
from enema (solution)
Other routes
Transdermal Slow absorption, rate may vary
Increased absorption with
occlusive dressing
Inhalation Rapid absorption Total dose
absorbed is variable
Intraocular The barrier for penetration is the cornea
administration Viscosity imparters increase bioavailability
Oily solution, ointments and gels sustained drug
action
Vaginal administration Intended for locally treatment
Systemic delivery of contraceptive without the
disadvantage of first-pass metabolism