Transcript 4_The Stomach

Oral drug absorption
Dr Mohammad Issa Saleh
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Oral drug absorption
• The oral route of administration is the most
common and popular route of drug dosing
• The oral dosage form must be designed to
account for extreme pH ranges, the
presence or absence of food, degradative
enzymes, varying drug permeability in the
different regions of the intestine, and
motility of the gastrointestinal tract
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Anatomic and Physiologic
Considerations
• Drugs administered orally pass through various parts of
the enteral canal, including the oral cavity, esophagus,
and various parts of the gastrointestinal tract
• Residues eventually exit the body
• The total transit time, including gastric emptying, small
intestinal transit, and colonic transit, ranges from 0.4 to 5
days
• The most important site for drug absorption is the small
intestine. Small intestine transit time (SITT) ranges from
3 to 4 hours for most healthy subjects
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Anatomic and Physiologic
Considerations
• If absorption is not completed by the time a drug leaves
the small intestine, absorption may be erratic or
incomplete
• The small intestine is normally filled with digestive juices
and liquids, keeping the lumen contents fluid
• In contrast, the fluid in the colon is reabsorbed, and the
lumenal content in the colon is either semisolid or solid,
making further drug dissolution erratic and difficult
• The lack of the solubilizing effect of the chyme and
digestive fluid contributes to a less favorable
environment for drug absorption in the colon
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Oral drug absorption
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Oral Cavity
Esophagus
Stomach
Small intestine:
– Duodenum
– Jejunum
– Ileum
• Colon
• Rectum
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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
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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
• Tablets or capsules may lodge in this area, causing local
irritation
• Very little drug dissolution occurs in the esophagus
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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
• Gastrin is released from G cells, mainly in the antral
mucosa and also in the duodenum
• Gastrin release is regulated by stomach distention
(swelling) and the presence of peptides and amino acids
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Stomach
• Hydrochloric acid is produced by the parietal
cells in response to histamine, gastrin or
acetylcholine stimulation
• Basic drugs are solubilized rapidly in the
presence of stomach acid
• Mixing is intense and pressurized in the antral
part of the stomach, a process of breaking down
large food particles described as antral milling.
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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
chyme emptied from the stomach
• The pH is optimum for enzymatic digestion of protein
and peptide food
• Pancreatic juice containing enzymes is secreted into the
duodenum from the bile duct
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Duodenum
• 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 complex fluid medium in the duodenum helps to
dissolve many drugs with limited aqueous solubility.
• The duodenum is a site where many ester prodrugs are
hydrolyzed during absorption
• The presence of proteolytic enzymes also makes many
protein drugs unstable in the duodenum, preventing
adequate absorption.
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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
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Ileum
• The ileum is the terminal part of the small intestine
• This site has fewer contractions than the duodenum
• 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
• The ileocecal valve separates the small intestine from
the colon
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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
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Colon
• The colon contains both aerobic and anaerobic
microorganisms that may metabolize some drugs
• For example, L-dopa and lactulose are metabolized by
enteric bacteria
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Rectum
• The rectum is about 15 cm long
• 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
• The superior hemorrhoidal vein joins the mesenteric
circulation, which feeds into the hepatic portal vein and
then to the liver
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Rectum
• Drug absorption after rectal administration may be
variable, depending on the placement of the suppository
or drug solution within the rectum
• A portion of the drug dose may be absorbed via the
lower hemorrhoidal veins, from which the drug feeds
directly into the systemic circulation; some drugs may be
absorbed via the superior hemorrhoidal vein, which
feeds into the mesenteric veins to the hepatic portal vein
to the liver, and be metabolized before systemic
absorption
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Physiologic Factors Affecting
Oral Bioavailability
• The rate and extent of drug absorption
from the stomach depends to a great
extent on the pH of the gastric contents
and the pKa of the drug
• The pH and pKa relationship regulates the
degree of dissolution and ionization of a
drug that is administered in solid form
• This relationship also controls the extent to
which a drug precipitates out of solution
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Physiologic Factors Affecting
Oral Bioavailability
• The pH of the stomach contents is strongly
acidic and typically ranges between 1 and
3 for fasted and fed states, respectively;
Many drugs are prone to chemical
degradation in the highly acidic gastric
environment
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Physiologic Factors Affecting
Oral Bioavailability
• Absorption from the stomach is also
impaired by the thick layer of mucus on
the gastric lining, which rends to slow the
passage of drug across the membranc
• As a result, drug absorption from the
stomach is generally low
• Most drugs are absorbed more quickly and
effectively from the small intestine than
from the stomach
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Physiologic Factors Affecting
Oral Bioavailability
• The small intestine serves as a primary
absorption site for drugs because of its
extraordinarily large surface area and
favorable membrane permeability
• Consequently, intestinal transit time
significantly affects drug absorption,
particularly of drugs that exhibit poor
dissolution or are absorbed by active
transport
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Physiologic Factors Affecting
Oral Bioavailability
• The surface area available for absorption
in the small intestine is greatly multiplied
by the presence of fingerlike projections
called villi and microvilli
• Also, the pH range in the small intestine is
much wider than that in the stomach
• The pH in the proximal portion of the small
intestine is roughly 5, whereas in the distal
region it is roughly 7 to 8
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Three mechanisms for increasing surface area of the
small intestine. The increase in surface area is due to
folds of Kerkring, villi, and microvilli
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Physiologic Factors Affecting
Oral Bioavailability
• This wider pH range makes the
environment favorable for absorption of a
larger number of drugs
• Thee large intestine, which includes the
colon and rectum, is a major site for water
resorption and production of feces
• The large intestine has a much smaller
surface area than the small intestine and
is not a favorable site for drug absorption.
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Physiologic Factors Affecting
Oral Bioavailability
• A drug's stability is a function of the
surrounding pH
• Many drugs are unstable in the
environment of the stomach and will
degrade when exposed to an acidic pH
• A drug may undergo degradation in the
GIT or biotransformation in the intestinal
mucosa or in the liver before reaching the
systemic circulation
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Physiologic Factors Affecting
Oral Bioavailability
• In addition, enzymes such as pepsin,
chymotrypsin, and trypsin are also present
in the GIT
• These enzymes are responsible for the
degradation and breakdown of proteins
and peprides
• Cytochrome P-450 3A4, which is
expressed in the intestinal mucosa, is a
member of the crochrome P-450 oxidase
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system
Physiologic Factors Affecting
Oral Bioavailability
• Cytochrome P-450 3A4 is responsible for
the biotransformation of a number of
drugs, including cyclosporin, midazolam,
and tacrolimus, during absorption across
the intestinal mucosa
• Another major factor that limits drug
absorption is the efflux drug transporter Pglycoprotein
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Physiologic Factors Affecting
Oral Bioavailability
• This glycoprotein is localized in the apical
membrane of the epithelial cells in the
intestinal mucosa
• Drugs that are absorbed from the GIT are
transported to the liver via the hepatic
portal vein
• These drugs may undergo some
metabolism by the enzymes that are
present in the liver
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Physiologic Factors Affecting
Oral Bioavailability
• This metabolism of a drug in the liver
before the drug reaches the systemic
circulation is referred to as first-pass
hepatic metabolism
• In some instances virtually the entire
amount of a drug is metabolized and
inactivated by this first-pass metabolism
(cg, nitroglycerin)
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First-pass hepatic metabolism
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•Not
included
Informal HW
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Informal HW
• In the previous figure, the major site of drug
absorption is the stomach (true or false)
• Explain the association between Cmax and
gastric emptying rate
• Explain the association between Tmax and
gastric emptying rate
• A shorter gastric emptying half life implies a
faster gastric emptying rate (true of false)
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