git physiology Flashcards
what is the only route without an absorption step
IV
Factors affecting absorption will depend on:
– The physiology of the administration site(s)
– The membrane barriers present at those
site(s) that the drug needs to cross in order to
reach the systemic circulation.
why is the oral rout popular
– It is natural and convenient for the patient
– It is relatively easy to manufacture oral
dosage forms.
• Oral dosage forms do not need to be
sterilized
• They are compact
• They can be produced in large quantities
by automated machines.
why is the oral rout popular
– It is natural and convenient for the patient
– It is relatively easy to manufacture oral
dosage forms.
• Oral dosage forms do not need to be
sterilized
• They are compact
• They can be produced in large quantities
by automated machines.
what are the different rate limiting steps
1.For a drug which has a very poor aqueous
solubility the rate at which it dissolves in the
gastrointestinal fluids is often the slowest step
• The bioavailability of that drug is said to be
dissolution-rate limited.
2.for a drug that has a high aqueous
solubility its dissolution will be rapid and the
rate at which the drug crosses the gastrointestinal
membrane may be the rate-limiting step
(permeability limited).
4– The rate of release of the drug from the dosage
form This can be by design in the case of
controlled- release dosage forms)
5– The rate at which the stomach empties the drug
into the small intestine
6– The rate at which the drug is metabolized by
enzymes in the intestinal mucosal cells during its
passage through them into the mesenteric blood
vessels
7– The rate of metabolism of drug during its initial
passage through the liver, often termed the ‘firstpass’ effect.
what is the GIT
The gastrointestinal tract is a muscular tube
approximately 6 m in length with varying diameters.
• It stretches from the mouth to the anus and consists of
four main anatomical areas:
– The oesophagus,
– The stomach
– The small intestine
– The large intestine or colon.
• The luminal surface of the tube is not smooth but very
rough thereby increasing the surface area for
absorption.
what is the GIT
The gastrointestinal tract is a muscular tube
approximately 6 m in length with varying diameters.
• It stretches from the mouth to the anus and consists of
four main anatomical areas:
– The oesophagus,
– The stomach
– The small intestine
– The large intestine or colon.
• The luminal surface of the tube is not smooth but very
rough thereby increasing the surface area for
absorption.
what are the different layers in the gait tract
– The serosa: which is an outer layer of epithelium
and supporting connective tissue;
– The muscularis externa: which contains two layers
of smooth muscle tissue
–A thinner outer layer: longitudinal in
orientation
–A thicker inner layer: whose fibers are
oriented in a circular pattern.
• Contractions of these muscles provide the forces
for movement of gastrointestinal contents;
– The submucosa,: which is a connective tissue layer
• It contains some secretory tissue
• It is richly supplied with blood and lymphatic
vessels.
• A network of nerve cells, known as the
submucous plexus, is also located in this layer;
– The mucosa: which is essentially composed of
three layers
• The muscularis mucosa
• A layer of connective tissue known as the lamina
propria
• The epithelium.
The majority of the gastrointestinal epithelium is
covered by a layer of mucus.
– It has a large water component (~95%).
– Its other primary components are large
glycoproteins called mucins.
what is the mucins
A protein backbone approximately 800 amino
acids long and
• Oligosaccharide side chains that are typically up
to 18 residues in length.
– The mucus layer ranges in thickness from 5 m to
500 m along the length of the gastrointestinal tract
(with average values of around 80 m).
how is the mucus replaced (turned over)
Mucus is constantly being removed from the luminal
surface of the gastrointestinal tract through abrasion
and acidic and enzymatic breakdown and is
continually replaced from beneath.
• Turnover time has been estimated at 4-5 hours, but
this may well be an underestimate and is liable to
vary along the length of the tract.
what is the oesophagus
The oesophagus Links the oral cavity with the
stomach
– It is composed of a thick muscular layer
approximately 250 mm long and 20 mm in
diameter.
– It joins the stomach at the gastrooesophageal
junction (or cardiac orifice).
The oesophagus contains a well differentiated
squamous epithelium of non-proliferative cells.
• The last 20 mm of oesophagus is similar to the
gastric mucosa.
Epithelial cell function is mainly protective.
• Simple mucous glands secrete mucus into the
narrow lumen to lubricate food and protect the lower
part of the oesophagus from gastric acid.
• The pH of the oesophageal lumen is usually
between 5 and 6.
Materials are moved down the oesophagus by the act of
swallowing.
Peroral administration: via the mouth.
• At this point contact with the oral mucosa is usually
brief.
what happens after swallowing
a single peristaltic wave of contraction
passes down the length of the oesophagus at the rate of
20-60 mm per second, speeding up as it progresses.
– Its amplitude linked to the size of the material being
swallowed.
• When swallowing is repeated in quick succession
– The subsequent swallows interrupt the initial
peristaltic wave
– Only the final wave proceeds down the length of the
oesophagus to the gastrointestinal junction, carrying
material within the lumen with it.
Secondary peristaltic waves occur involuntarily
in response to any distension of the oesophagus
and serve to move sticky lumps of material or
refluxed material to the stomach.
• In the upright position the transit of materials
through the oesophagus is assisted by gravity.
• The oesophageal transit of dosage forms is
extremely rapid, usually of the order of 10—14
seconds.
what is the stomach function
– To act as a temporary reservoir for ingested food and
to deliver it to the duodenum at a controlled rate.
– To reduce ingested solids to a uniform creamy
consistency, known as chyme, by the action of acid
and enzymatic digestion.
– This enables better contact of the ingested
material with the mucous membrane of the
intestines and thereby facilitates absorption.
• Another, perhaps less obvious, function of the stomach
is its role in reducing the risk of noxious agents reaching
the intestine.
what is the anatomy of the stomach
• The stomach is the most dilated part of the
gastrointestinal tract .
• It is situated between the lower end of the
oesophagus and the small intestine.
• Its opening to the duodenum is controlled by the
pyloric sphincter.
• The stomach can be divided into four anatomical
regions
– The fundus
– The body
– The antrum
– The pylorus.
what is the anatomy of the stomach
• The stomach is the most dilated part of the
gastrointestinal tract .
• It is situated between the lower end of the
oesophagus and the small intestine.
• Its opening to the duodenum is controlled by the
pyloric sphincter.
• The stomach can be divided into four anatomical
regions
– The fundus
– The body
– The antrum
– The pylorus.
The stomach under fasting conditions usually
contains no more than 50 mL of fluid, which is
mostly gastric secretions.
what are the stomach secretions
- Acid secreted by the parietal cells: which
maintains the pH of the stomach between 1
and 3.5 in the fasted state - The hormone gastrin: which itself is a potent
stimulator of gastric acid production. The
release of gastrin is stimulated by peptides,
amino acids and distension of the stomach - Pepsins:
• Secreted by the peptic cells in the form of its
precursor pepsinogen.
• They are peptidases which break down
proteins to peptides at low pH.
• Above pH 5 pepsin is denatured; - Mucus:
• Secreted by the surface mucosal cells
• It lines the gastric mucosa
• It protects the gastric mucosa from
autodigestion by the pepsin-acid
combination.
• Very little drug absorption occurs in the stomach
owing to its small surface area compared to the
small intestine.
• The rate of gastric emptying can be a controlling
factor in the onset of drug absorption from the
major absorptive site, the small intestine.
what is the small intestine function
– Digestion: the process of enzymatic digestion, which
began in the stomach, is completed in the small
intestine.
– Absorption: the small intestine is the region where
most nutrients and other materials are absorbed.
what is the small intestine anatomy
The small intestine is the longest (4-5 m) and most
convoluted part of the gastrointestinal tract
– It extends from the pyloric sphincter of the stomach to
the ileocaecal junction where it joins the large
intestine
The small intestine is divided into
– The duodenum: 200-300 mm in length
– The jejunum: approximately 2 m in length
– The ileum: approximately 3 m in length.
• The wall of the small intestine has a rich network of
both blood and lymphatic vessels.
• The gastrointestinal circulation is the largest systemic
regional vasculature and nearly a third of the cardiac
output flows through the gastrointestinal viscera.
• The blood vessels of the small intestine receive blood
from the superior mesenteric artery via branched
arterioles.
The blood leaving the small intestine flows into the
hepatic portal vein, which carries it via the liver to
the systemic circulation.
• Drugs that are metabolized by the liver are
degraded before they reach the systemic circulation:
this is termed hepatic presystemic clearance, or
first-pass metabolism.
• The wall of the small intestine also contains lacteals:
which contain lymph and are part of the lymphatic
system.
The lymphatic system is important in the
absorption of fats from the gastrointestinal tract.
• In the ileum, there are areas of lymphoid tissue
close to the epithelial surface which are known as
Peyer’s patches.
• These cells play a key role in the immune
response as they transport macromolecules and
are involved in antigen uptake
what are the adaptations that increases the small intestine size
- Folds of Kerckring:
• These are submucosal folds which extend
circularly most of the way around the intestine
• The are particularly well developed in the
duodenum and jejunum.
• They are several millimetres in depth.
2.
Villi:
–
These have been described as finger-like
projections into the lumen
–
Approximately 0.5-1.5 mm in length and 0.1 mm in
diameter.
–
They are well supplied with blood vessels.: Each
villus contains an arteriole, a venule and a
blindending lymphatic vessel (lacteal).
3.
Microvilli:
–
~ 1 m in length and 0.1 m in width.
–
Approximately 600-1000 of these brush-like
structures cover each villus
–
The provide the largest increase in surface area.
what are the secretions that increase the small intestine ph
1– Brunner’s glands
• They are located in the duodenum
• They are responsible for the secretion of
bicarbonate which neutralizes the acid emptied
from the stomach.
2– Intestinal cells
• They are present throughout the small intestine.
• They secrete mucus and enzymes.
• The enzymes, hydrolases and proteases, continue
the digestive process
3• Pancreatic secretions:
– The pancreas is a large gland which secretes about
1-2 L of pancreatic juice per day into the small
intestine via a duct.
– The components of pancreatic juice are sodium
bicarbonate and enzymes.
– The enzymes consist of proteases, principally trypsin,
chymotrypsin and carboxypeptidases, which are
secreted as inactive precursors or zymogens and
converted to their active forms in the lumen by the
enzyme enterokinase.
– Lipase and amylase are both secreted in their active
forms.
– The bicarbonate component is largely regulated by
the pH of chyme delivered into the small intestine
from the stomach.
4-bile
what are the secretions that increase the small intestine ph
1– Brunner’s glands
• They are located in the duodenum
• They are responsible for the secretion of
bicarbonate which neutralizes the acid emptied
from the stomach.
2– Intestinal cells
• They are present throughout the small intestine.
• They secrete mucus and enzymes.
• The enzymes, hydrolases and proteases, continue
the digestive process
3• Pancreatic secretions:
– The pancreas is a large gland which secretes about
1-2 L of pancreatic juice per day into the small
intestine via a duct.
– The components of pancreatic juice are sodium
bicarbonate and enzymes.
– The enzymes consist of proteases, principally trypsin,
chymotrypsin and carboxypeptidases, which are
secreted as inactive precursors or zymogens and
converted to their active forms in the lumen by the
enzyme enterokinase.
– Lipase and amylase are both secreted in their active
forms.
– The bicarbonate component is largely regulated by
the pH of chyme delivered into the small intestine
from the stomach.
4-bile
what is the bile
Bile
– It is secreted by hepatocytes in the liver into bile
canaliculi,
– It get concentrated in the gallbladder and hepatic
biliary system by the removal of sodium ions,
chloride and water.
– It is delivered to the duodenum.
– Bile is a complex aqueous mixture of organic
solutes (bile acids, phospholipids, particularly
lecithin, cholesterol and bilirubin) and inorganic
compounds (plasma electrolytes; sodium and
potassium).
– Bile pigments, the most important of which is
bilirubin, are excreted in the feces.
– The enterohepatic recirculation: the bile acids are
absorbed by an active process in the terminal ileum
They are returned to the liver via the hepatic
portal vein and resecreted in the bile
what are the main functions of the bile
– Promoting the efficient absorption of dietary fat,
such as fatty acids and cholesterol, by aiding its
emulsification and micellar solubilization
– The provision of excretory pathways for
degradation products
what is the colon anatomy
• The colon is the final part of the gastrointestinal tract.
• It stretches from the ileocaecal junction to the anus and
makes up approximately the last 1.5 m of the 6 m of the
gastrointestinal tract.
• It is composed of
– The caecum: ~85 mm in length
– The ascending colon: -200 mm
– The hepatic flexure
– The transverse colon: usually greater than 450 mm
– The splenic flexure
– The descending colon: ~300 mm
– The sigmoid colon ~400 mm
– The rectum
The colon has no specialized villi.
how is the size of the colon increased
– The microvilli of the absorptive epithelial cells
– The presence of crypts
– The irregularly folded mucosae.
s
approximately 1/30th that of the small intestine
what are the functions of the colon
The main functions of the colon are:
– The absorption of sodium ions, chloride ions
and water from the lumen in exchange for
bicarbonate and potassium ions.
– Thus, the colon has a significant
homeostatic role in the body.
– The storage and compaction of feces
The colon is permanently colonized by an
extensive number (about 1012 cfu per gram of
contents) and variety of bacteria. what do they do?
• This large bacterial mass is capable of several
metabolic reactions including:
– Hydrolysis of fatty acid esters
– The reduction of inactive conjugated drugs to
their active form.
• The bacteria rely upon undigested polysaccharides
in the diet and the carbohydrate components of
secretions such as mucus for their carbon and
energy sources.
• They degrade the polysaccharides to produce shortchain fatty acids (acetic, proprionic and butyric
acids), the gases hydrogen, carbon dioxide and
methane
These fatty acids lower the luminal pH.
– The pH of the caecum is around 6-6.5.
– This increases to around 7-7.5 towards the
distal parts of the colon.
• Recently, there has been much interest in the
exploitation of the enzymes produced by these
bacteria with respect to targeted drug delivery to
this region of the gastrointestinal tract
what does the transit time in the oesophagus depends on
• Transit through the oesophagus is dependent
both upon the dosage form and posture and adhesion
• Transit of liquids has always been observed to
be rapid, and in general faster than that of
solids.
• Most dosage forms are taken in an upright
position.
In this case, they transit through the
oesophagus quickly usually in less than 15
seconds.
• Tablets/capsules taken in the supine position
(especially if taken without water) are liable to
lodge in the oesophagus.
• Adhesion to the oesophageal wall can occur as
a result of partial dehydration at the site of
contact and the formation of a gel between the
formulation and the oesophagus.
• The chances of adhesion will depend on the
shape, size and type of formulation.
what does the delay in reaching the stomach result in
delay a
drug’s onset of action or cause damage or irritation
to the oesophageal wall,
– Potassium chloride tablets.
– Bisphosphonates: alendronate (Fosamax®
),
risedronate (Actonel®
), and ibandronate
(Boniva®
).
– Tetracyclines : particularly doxycycline
– NSAIDs
– Iron
– Alprenolol
– Pinaverium
what is gastric emptying
Gastric residence time, gastric emptying time or gastric emptying rate: it is the time a dosage form
takes to traverse the stomach
what does the gastric emptying depend on
1• The dosage form
2• The fed/fasted state of the stomach.
– Normal gastric residence times usually range
between 5 minutes and 2 hours
– Much longer times (over 12 hours) have been
recorded, particularly for large single units.
what is the interdigestive myoelectric motor cycle
(IMMC) or migrating myoelectric complex (MMC)
the electrical activity of the stomach
4 phases in the fasted stage
– Phase I (the basal state): a relatively inactive period
of 40-60 minutes with only rare contractions occurring
– Phase II (the preburst state): characterized by
increasing frequency and strength of contractions
~ 30 – 45 minutes
– Phase III (the burst state): characterized by
strong contractions. Physiologically, this
phase serves to clear out the stomach of any
undigested material or saliva and thus,
contractions in this phase are called
(housekeeper waves) ~ 5 – 15 minutes
– Phase IV: a short transitional period between
the powerful activity of phase III and the
inactivity of phase I ~ 5 minutes
The cycle repeats itself every 2 hours until a
meal is ingested and the fed state or motility is
initiated.
what happens to the gastric motillity in the fed state
here gastric
emptying is delayed by the presence of food in the
stomach,
– After ingesting typical meal the motor activity
of the stomach starts to resemble phase II in the
fasted state
– Typically, last for 3 – 4 hours (depends on the
caloric value of the meal)
– The pyloric sphincter allows liquids and small
food particles to empty while other material is
retropulsed into the antrum of the stomach for
further size reduction before emptying
Thus, in the fed state: liquids, pellets and
disintegrated tablets will tend to empty
with food
• Large sustained or controlled release
dosage forms can be retained in the
stomach for long periods of time.
• In the fasted state: the stomach is less
discriminatory between dosage form types
what factors influence the gastric emptying
– The type of dosage form
– The presence of food
– The composition of the food
– The postural position
– The effect of drugs and disease state
give examples on drugs that effects the gastric emptying
• Metoclopramide: it is a drug that ↑ gastric emptying
rate ↑ the rate of absorption of paracetamol.
• Proprantheline: it is a drug that delays gastric
emptying it delays the absorption of
paracetamol
In general, food, particularly fatty foods, delays gastric
emptying and hence the absorption of drugs.
• Therefore, a drug will reach the small intestine most
rapidly if it is administered with water to a patient whose
stomach is empty
– Small intestinal transit has been found to be
relatively constant = ~ 3 hours.
– The small intestine does not discriminate
between solids and liquids, and hence
between dosage forms, or between the fed
and the fasted state
what is the small intestine resident tie important for
– Dosage forms that release their drug slowly
(e.g. controlled- sustained- prolonged-release
systems) as they pass along the length of the
gastrointestinal tract
– Enteric-coated dosage forms which release
drug only when they reach the small intestine
– Drugs that dissolve slowly in intestinal fluids
– Any drugs that are absorbed by intestinal
carrier-mediated transport systems.
what does the transit time in the colon depend on
• The type of dosage form
• Diet
• Eating pattern
• Disease state.
Contractile activity in the colon can be divided into
two main types:
- Propulsive contractions or mass movements:
which are associated with the aboral (away
from the mouth) movement of contents - Segmental or haustral contractions: which
serve to mix the luminal contents and result
in only small aboral movements
Segmental contractions: are brought about by
contraction of the circular muscle they are
the predominant contractions
•
Propulsive contractions: are due to
contractions of the longitudinal muscle
occur only 3-4 times daily in normal
individuals.
Accordingly Colonic transit is
characterized by short bursts of activity
followed by long periods of stasis.
• Colonic transit can vary from anything
between 2 and 48 hours.
• In most individuals, mouth-to-anus transit
times are longer than 24 hours.
what do we need For efficient absorption of drug to take
place:
– The drug needs to remain in solution.
– The drug should not become bound to food or
other material within the gastrointestinal tract.
– The drug needs to be chemically stable in
order to withstand the pH of the
gastrointestinal tract
– The drug must be resistant to enzymatic
degradation in the lumen.
– The drug then needs to diffuse across the
mucous layer, without binding to it, across the
unstirred water layer
The drug should cross the gastrointestinal
membrane (its main cellular barrier) no
efflux
– After passing through this cellular barrier, the
drug encounters the liver before it reaches the
systemic circulation.
what changes the ph in the stomach
Gastric fluid is highly acidic, normally exhibiting a pH
within the range 1-3.5 in healthy people in the fasted
state.
– Following the ingestion of a meal, the gastric juice is
buffered Typical gastric pH values following a meal
are in the range 3-7.
– Depending on meal size the gastric pH returns to
the lower fasted-state values within 2-3 hours.
• Thus, only a dosage form ingested with or soon
after a meal will encounter these higher pH values.
• Intestinal pH values are higher than gastric pH
values owing to the neutralization of the gastric
acid with bicarbonate ions secreted by the
pancreas into the small intestine.
• There is a gradual rise in pH along the length of
the small intestine from the duodenum to the
ileum.
• The pH drops again in the colon as the
bacterial enzymes, which are localized in the
colonic region, break down undigested
carbohydrates into short-chain fatty acids
– This lowers the pH in the colon to around 6.5.
• Intestinal pH values are higher than gastric pH
values owing to the neutralization of the gastric
acid with bicarbonate ions secreted by the
pancreas into the small intestine.
• There is a gradual rise in pH along the length of
the small intestine from the duodenum to the
ileum.
• The pH drops again in the colon as the
bacterial enzymes, which are localized in the
colonic region, break down undigested
carbohydrates into short-chain fatty acids
– This lowers the pH in the colon to around 6.5.
what does the ph influence
– The chemical stability of the drug in the lumen
– The drug dissolution
– The drug ionization and absorption
• Chemical degradation due to pH-dependent hydrolysis
can occur in the gastrointestinal tract.
– The result of this instability is incomplete
bioavailability as only a fraction of the administered
dose reaches the systemic circulation in the form of
intact drug.
Example of drugs that degrade rapidly in the stomach
and gastric pH.
– Penicillin G (benzylpenicillin)
– Erythromycin
– Proton pump inhibitors (e.g. omeprazole)
what is the luminal enzymes effect
– The primary enzyme found in gastric juice is pepsin.
– Lipases, amylases and proteases are secreted from
the pancreas into the small intestine in response to
ingestion of food.
– These enzymes are responsible for most of nutrient
digestion.
– Pepsins and the proteases are responsible for the
degradation of protein and peptide drugs in the
lumen.
– Other drugs that resemble nutrients, such as
nucleotides and fatty acids, may also be susceptible
to enzymatic degradation.
– The lipases may also affect the release of drugs from
fat/oil-containing dosage forms.
– Drugs that are esters can also be susceptible to
hydrolysis in the lume
what is the effect of bacterial enzymes
These enzymes have been utilized when designing
drugs or dosage forms to target the colon.
• Sulphasalazine, for example, is a prodrug of 5-
aminosalicylic acid linked via an azo bond to
sulphapyridine.
• The sulphapyridine moiety makes the drug too large
and hydrophilic to be absorbed in the upper
gastrointestinal tract
– And thus permits its transport intact to the colonic
region
• In the colon the bacterial diazoreductase enzymes
reduce the azo bond and release the active drug (5-
aminosalycylic acid) for local action in colonic
diseases such as inflammatory bowel disease
The prodrug reach the colon as such
because:
• There is no diazoreductase activity in the
upper parts of the GIT
• There is limited absorption of the prodrug in
the small intestine.
what is the influence of food
- Complexation of drugs with components in the diet
- Alteration of pH
- Alteration of gastric emptying
- Stimulation of gastrointestinal secretions
- Competition between food components and drugs
for specialized absorption mechanisms - Increased viscosity of gastrointestinal contents
- Food-induced changes in presystemic metabolism
- Food-induced changes in blood flow
give an example on a drug food interaction
Tetracycline: forms non-absorbable complexes with
calcium and iron
• Patients are advised to not take products containing
calcium or iron, such as milk, iron preparations or
indigestion remedies, at the same time of day as the
tetracycline.
what is the effects of stimulation of the GIT
– Gastrointestinal secretions (e.g. pepsin) produced
in response to food may result in the degradation
of drugs that are susceptible to enzymatic
metabolism.
– The ingestion of food, particularly fats, stimulates
the secretion of bile.
• Bile salts are surface active agents and can
increase the dissolution of poorly soluble drugs
thereby enhancing their absorption.
• However, bile salts have been shown to form
insoluble and hence non-absorbable
complexes with some drugs, such as
neomycin, kanamycin and nystatin.
what is • Competition between food components and drugs for
specialized absorption mechanisms
– It happens in the case of those drugs that have a
chemical structure similar to nutrients required by
the body for which specialized absorption
mechanisms exist
– There is a possibility of competitive inhibition of
drug absorption.
– Example of such drugs are:
• Peptide-like drugs: penicillins, cephalosporins,
angiotensin-converting enzyme inhibitors (ACE)
and renin inhibitors they rely on the peptide
transporters for their efficient absorption
• Nucleosides and their analogues for
antiviral and anticancer drugs
depend on the nucleoside transporters
for their uptake.
• L-dopa and -methyldopa: transported
by the carrier-mediated process for
amino acids.
Increased viscosity of gastrointestinal
contents
– The presence of food in the gastrointestinal
tract provides a viscous environment which
may result in a reduction in the rate of drug
dissolution.
– In addition, the rate of diffusion of a drug in
solution from the lumen to the absorbing
membrane lining the gastrointestinal tract may
be reduced by an increase in viscosity.
– Both of these effects tend to decrease the
bioavailability of drug.
Food-induced changes in presystemic metabolism
– Certain foods may increase the bioavailability of drugs
that are susceptible to presystemic intestinal metabolism
by interacting with the metabolic process.
– Example: Grapefruit juice is capable of inhibiting the
intestinal cytochrome P450 (CYP3A family)
• If it is taken with drugs that are susceptible to
CYP3A metabolism it is likely to result in their
increased bioavailability.
• Clinically relevant interactions exist between
grapefruit juice and the antihistamine terfenadine, the
immunosuppresant cyclosporin, the protease inhibitor
saquinavir and the calcium channel blocker
verapamil.
– Certain foods may increase the bioavailability of drugs
that are susceptible to presystemic intestinal metabolism
by interacting with the metabolic process.
– Example: Grapefruit juice is capable of inhibiting the
intestinal cytochrome P450 (CYP3A family)
• If it is taken with drugs that are susceptible to
CYP3A metabolism it is likely to result in their
increased bioavailability.
• Clinically relevant interactions exist between
grapefruit juice and the antihistamine terfenadine, the
immunosuppresant cyclosporin, the protease inhibitor
saquinavir and the calcium channel blocker
verapamil.
Blood flow to the gastrointestinal tract and liver increases
shortly after a meal thereby increasing the rate at which
drugs are presented to the liver.
– The metabolism of some drugs (e.g. propranolol,
hydralazine, dextropropoxyphene) is sensitive to their rate
of presentation to the liver:
• The faster the rate of presentation the larger the
fraction of drug that escapes first-pass metabolism.
• This is because the enzyme systems responsible for
their metabolism become saturated by the increased
rate of presentation of the drug to the site of
biotransformation.
• For this reason, the effects of food serve to increase
the bioavailability of some drugs that are susceptible to
first-pass metabolism.
what are the drug food interactions categories
– Reduced absorption
– Delayed absorption
– Increased absorption
– Accelerated absorption
– No effect on absorption
Disease state and physiological disorders
– Local diseases can cause alterations in gastric pH that
can affect the stability, dissolution and/or absorption of
the drug.
– Gastric surgery can cause drugs to exhibit differences in
bioavailability than that in normal individuals.
• Partial or total gastrectomy results in drugs reaching
the duodenum more rapidly than in normal
individuals.
• This increased rate of presentation to the small
intestine may result in an increased overall rate of
absorption of drugs that are primarily absorbed in the
small intestine.
• However, drugs that require a period of time in the
stomach to facilitate their dissolution may show
reduced bioavailability in such patients
The unstirred water layer
The unstirred water layer or aqueous boundary
layer is a more or less stagnant layer of water,
mucus and glycocalyx adjacent to the intestinal
wall.
– It is ~ 30-100 m in thickness.
– This layer can provide a diffusion barrier to drugs
(non-polar drugs).
– Some drugs are also capable of complexing with
mucus, thereby reducing their availability for
absorption
The gastrointestinal membrane
– It separates the lumen of the stomach and intestines from
the systemic circulation.
– It is the main cellular barrier to the absorption of drugs
from the gastrointestinal tract.
– This barrier has the characteristics of a semipermeable
membrane allowing the rapid transit of some materials
and impeding or preventing the passage of others.
– It is permeable to amino acids, sugars, fatty acids and
other nutrients.
– It is impermeable to plasma proteins.
– It can also be viewed as a semipermeable lipoidal sieve
• Allows the passage of lipid-soluble molecules across it
• Allows the passage of water and small hydrophilic
molecules (ions) through its aqueous por
Efflux of drugs from the intestine
– There are counter-transport efflux proteins
that expel specific drugs back into the lumen
of the gastrointestinal tract after they have
been absorbed.
– One of the key counter-transport proteins is
P-glycoprotein.
– P-glycoprotein is expressed at high levels on
the apical surface of columnar cells (brush
border membrane) in the jejunum.
– It is also present on the surface of many other
epithelia and endothelia in the body, and on
the surface of tumour cells.
P-glycoproteins were originally discovered because of
their ability to cause multidrug resistance in tumour
cells by preventing the intracellular accumulation of
many cytotoxic cancer drugs by pumping the drugs
back out of the tumours.
• Certain drugs with wide structural diversity are
susceptible to efflux from the intestine via Pglyocprotein.
• Usually, co-localized with the enzyme CYP3A4
More efficient presystemic metabolism may be
achieved as the drug is repeatedly absorbed
back into the enterocytes and thus exposed for
longer to the degradation enzymes
• Such efflux may have a detrimental effect on drug
bioavailability.
• These efflux proteins pump drugs out of cells in a
process that requires energy
– They can work against a concentration gradient
– They can be competitively inhibited by structural
analogues
– They can be inhibited by inhibitors of cell
metabolism
– It is a saturable process.
• Example of drugs that are susceptible to efflux by Pglycoprotein: Cyclosporine, Nifedipine, Verapamil,
Paclitaxel, Celiprolol, Digoxin
first pass metabo
It will result in a low bioavailability of those drugs
which are rapidly metabolized by the liver.
• The bioavailability of a susceptible drug may be
reduced to such an extent as
– To render the gastrointestinal route of
administration ineffective, or
– To necessitate an oral dose which is many times
larger than the intravenous dose
– For example: propranolol Although it is
well absorbed, only about 30% of an oral
dose is available to the systemic circulation
owing to the first-pass effect.
The bioavailability of sustained-release propranolol is
even less:
– As the drug is presented via the hepatic portal vein
more slowly than from an immediate-release
dosage form the liver is therefore capable of
extracting and metabolizing a larger portion.
• Other drugs which are susceptible to a large first-pass
effect are
– The cholesterol lowering agent atorvastatin
– The anesthetic lidocaine
– The tricyclic antidepressants imipramine
– The analgesics pentazocine, morphine, demerol
– Other: buprenorphine, diazepam, midazolam, and
cimetidine
