ANATOMICAL AND PHYSIOLOGICAL FACTORS AFFECTING DRUG ABSORPTION

Gastrointestinal tract:
Gastrointestinal tract GIT comprises of number of compartments, there primary functions are:
 Secretion
 Digestion
 Absorption
The mean length of GIT is 450cm. The major functional components of the GIT are stomach
small intestine (duodenum, jejunum, and ileum) large intestine (colon). These grossly differ from
each other in terms of anatomy, function, secretions, pH
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. Very little drug dissolution occurs in the
esophagus.
Stomach:
The stomach is a bag like structure having smooth mucosa and thus small surface area. The
surface area for absorption of drugs is relatively small in the stomach due to the absence of
macrovilli & microvilli. The stomach is not principal region for drug absorption because: 1) The
total mucosal region is small 2) More secreting cells than absorptive cells. 3) Gastric residence
time is limited
Small Intestine:
The small intestine, comprising of duodenum, jejunum and ileum has a unique surface structure
making it ideally for digestion and absorption. All types of drugs are predominantly absorbed
through the small intestine; the transit time of a dosage form is the major determinant of extent
of absorption. It is a major site for absorption of most drugs due to its characteristics:
1) Large surface area: Due to folds in intestinal mucosa kerckings result In 3 fold increase
of surface area. Surface of folds possesses finger like projections called as villi (Increases
surface area 30times). The surface of villi protrudes several microvilli (Increases surface
area 600 times)
2) Great length of small intestine: It is more than 200 square meters
3) Greater Blood Flow: The blood flow to small intestine is 6 to 10 times that of stomach.
4) Favorable p H range: pH range is 5 to 7.5 favorable for drugs to remain unionized.
5) Slow Peristaltic Movement: Prolongs the residence time of drug in intestine.
6) High permeability: The intestinal epithelium is dominated by absorptive cells.
Duodenum:
The duodenum, into which the stomach opens, is about 25 cm long, C-shaped and begins at the
pyloric sphincter. 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. Trypsin, chymotrypsin, and carboxy peptidase 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.
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. The pH is about 7, with the distal part as high as 8.
Large intestine:
Drug absorption in this region is insignificant as its length and mucosal surface area is very
small. Only a few drugs are absorbed in this region. The major function of large intestine is
absorption of water and electrolytes. The Longer residence time (6 to 1 2hrs) and colonic transit
of large intestine is important for absorption of poorly soluble drugs and sustained release drugs.
Colon:
The colon lacks villi and has limited drug absorption also, because of the more viscous and
semisolid nature of the lumen contents. Colon is lined with mucin that functions as lubricant and
protectant. The pH in this region is 5.5 to 7 .0. A few drugs, such as Theophyllin e 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. 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. The colon contains both aerobic
and anaerobic microorganisms that may metabolize some drugs. For example: L-dopa and
lactulose are metabolized by enteric bacteria.
Rectum:
Rectum The rectum is about 15 cm long, ending at the anus. In the absence of faecal 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 haemorrhoidal veins. The superior haemorrhoidal
vein joins the mesenteric circulation, which feeds into the hepatic portal vein and then to the
liver. The inferior haemorrhoidal vein and the middle haemorrhoidal vein feed into the vena cava
and back to the heart. Drug absorption after rectal administration may be variable, depending
upon the placement of the suppository (or) Drug solution within the rectum.
Gastrointestinal Motility
GI motility tends to move the drug through the alimentary canal, so the drug may not stay at the
absorption site. The transit time of the drug in the GI tract depends on the physiochemical and
pharmacologic properties of the drug, the type of dosage form, and various physiologic factors.
Physiologic movement of the drug within the GI tract depends on whether the alimentary canal
contains recently ingested food (digestive or fed state) or is in the fasted or interdigestive state.
During the fasted or interdigestive state, alternating cycles of activity known as the migrating
motor complex (MMC) act as a propulsive movement that empties the upper GI tract to the
cecum.
Characteristics of the Motility Patterns in the Fasted Dog
Phase Duration Characteristics
Fasted
I 30–60 min Quiescence.
II 20–40 min Irregular contractions.
Medium amplitude but can be as high as phase III.
Bile secretion begins.
Onset of gastric discharge occurs
Onset of particle and mucus discharge may occur
III 5–15 min Regular contractions (4–5 cont. /min) high amplitude.
Mucus discharge continues.
Particle discharge continues.
IV 0–5 min Irregular contractions.
Medium descending amplitude.
Sometimes absent.
Fed State
One phase As long as food is Regular, frequent contractions.
only present in the stomach
Amplitude is lower than phase III.
4–5 Contractions/min.
Physiological & Pathological Characacteristics of Patient
1. Age:
In infants GI pH is high and intestinal surface and blood flow to GIT is low as compared to
adults resulting in poor drug absorption. In elderly people, alteration in drug absorption is
because of alteration in gastric emptying, incidents of achlorhydria and bacterial over growth in
small intestine.
2. Gastric emptying:
Defined, as passage of contents of stomach into the intestine. Rapid gastric emptying is advisable
where:
 Rapid onset action is required, eg; sedatives.
 Dissolution of drug occurs in intestine. eg; Enteric coated tablets.
 Drug is unstable in gastric fluids.
 Drug is best absorbed from distal part of small intestine, eg: vitamin B.
Gastric residence time of various dosage forms
Factors affecting GI emptying:
a) Volume of meal: The larger the starting volume, the greater the initial rate of emptying,
after this initial period, the larger the original volume, the slower the rate of emptying.
b) Composition of meal: The rate of gastric emptying for various food materials is in the
following order carbohydrates>proteins>fats.
c) Physical state: Liquid meal takes less time as compared to solid meals.
d) Temperature of the meal: High or low temperature of the ingested fluid (in comparison
to body temperature) reduces the gastric emptying rate.
e) Body Posture: Gastric emptying is favoured while standing and by lying on the right
side since normal curvature of the stomach provides a downhill path. Whereas lying on
the left side or in supine position retards it.
f) Exercise: Vigorous physical training retards gastric empting.
g) Emotional state: Stress and anxiety promotes GI motility, where as depression retards it.
h) Drugs: That retards gastric emptying are Antacids, Anti Cholinergic, Narcotic analgesics
and tricyclic antidepressants. Metaclopramide, Domperidone and Cisapride stimulate
gastric emptying.
i) Electrolyte and Osmotic Pressure: Water, isotonic solutions and solutions of low salt
concentration empty stomach rapidly. Whereas higher electrolyte concentration decreases
gastric emptying rate.
j) Viscosity: Rate of emptying is greater for less viscous solutions.
k) Disease States: Disease like gastroenteritis, gastric & duodenal ulcer, pyloric stenosis
and diabetes retard gastric emptying while hyperthyroidism promotes it.
l) Bile salts: Rate of emptying is reduced.

3. Intestinal transit:
Defined as, the residence time of drug in small intestine. As small intestine is major site for
absorption of most drugs long intestinal transit time is desirable for drug absorption. The
residence time mainly depends on the intestinal motility or contractions.
Intestinal residence time of various dosage forms:

Delayed intestinal transit is desirable for:

1. Sustained release dosage forms eg; cholrothiazide.
2. Drug that only release in intestine ie., enteric coated formulations.
3. Drugs absorbed from specific sites in intestine, eg; several B vitamins.
4. When the drug penetrate the intestinal mucosa very slowly eg; Acyclovir.
5. When absorption of drug from the colon is minimal.
Transit time for contents from different regions of intestine

Intestinal transit is influenced by several factors like food, drugs and diseases. Food decreased
digestive secretions and pregnancy retards intestinal transit whereas diarrhea promotes it. Drugs
like metoclopramide that promote gastric emptying and intestinal transit enhances absorption of
rapidly soluble drugs.

4. Influence of Drug pka and GI pH On Drug Absorption

Depending upon drug pKa whether it is an acidic or basic drug the GI pH influences drug
absorption.
5. Blood Flow to GIT:
GIT is extensively supplied by a network of blood capillaries and lymphatic vessels (splanchnic
Circulation), about 28% of cardiac output is supplied to GIT portion. Most drugs reach the
systemic circulation via mesenteric blood flow after absorption through small intestine. Any
factor which affects blood flow to GIT may also affect 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. Reason: as perfusion rate increases after meal and persist for
few hours.
6. Disease state:
Several disease states may influence the rate and extent of drug absorption. Three major classes
of disease may influence bioavailability of drug.
a) Gastric diseases:
Achlorhydria: The influence of achlorhydria (decreased gastric acid secretion and increases
stomach pH) on gastric emptying and drug absorption, especially that of acidic drugs (decreased
absorption e.g. aspirin, Ketoconazole) has been studied.
Celiac disease: characterized by destruction or atrophy of villi and microvilli of small intestine.
Patients with celiac disease generally have an increased rate of stomach emptying and increased
permeability of the small intestine. Cephalexin absorption appears to be increased in celiac
disease.
Crohn’s disease: (a type of inflammatory bowel disease). The disease is accompanied by regions
of thickening of the bowel wall, overgrowth of anaerobic bacteria, and sometimes obstruction
and deterioration of the bowel. For example, higher plasma propranolol concentration has been
observed in patients with Crohn's disease after oral administration of propranolol.
G I surgery: Gastrectomy may cause drug dumping in intestine, osmotic diarrhea and reduce
intestinal transit time.
b) Hepatic diseases:
Disorders such as hepatic cirrhosis influence bio-availability mainly of drugs that undergo
considerable first-pass hepatic metabolism. e.g. propranolol In such cases enhanced
bioavailability is also observed.
 c) Cardio-vascular diseases:
In CVS diseases blood flow to GIT decrease, causes decreased drug absorption. Several changes
associated with congestive cardiac failure influence bio-availability of a drug viz., Edema of the
intestine, decreased blood flow to the GIT and Gastric emptying rate and altered GI pH,
Secretions and Microbial flora. For example, furosemide (Lasix), a commonly used loop diuretic,
has erratic and reduced oral absorption in patients with CHF.
7. Gastro intestinal contents:
a. Food- drug interaction: In general presence of food in GIT delays, reduces, increases
or may not affect absorption. Digested foods contain amino acids, fatty acids and many other
nutrients that may affect intestinal pH and solubility. Generally drugs are better absorbed under
fasting conditions and presence of food retards or prevent it.
Some effects of food on the bioavailability of a drug from a drug product include:

 Delay in gastric emptying

 Stimulation of bile flow

 A change in the pH of the GI tract

 An increase in splanchnic blood flow

 A change in luminal metabolism of the drug substance

 Physical or chemical interaction of the meal with the drug product or drug
substance

Examples of Delayed or decreased drug absorption due to food:

e.g., ampicillin, aspirin, L-dopa
Examples of Increased drug absorption following a meal:
Example: propranolol, chloramphenicol, lithium carbonate.
b. Interaction of drug with normal GI contents: GIT contains number of normal
constituents such as mucin, bile salts and enzymes, which influence the drug absorption. E.g;
Inhibitory action of bile on GI motility. The surface active bile salts may enhance the dissolution
rate of poorly soluble drugs and thereby promote intestinal absorption grisofulvin. Various
enzymes and other proteins in the gastrointestinal tract are capable of interacting with drugs in a
number of possible ways. i.e., pancreatin and trypsin deacylates N-acetyl sulfisoxazole.
Proteinaceous materials have been shown to reduce the activity of aluminium antacids by a
complex interaction
c. Fluid volume: administration of drug with large fluid volume results in Better
dissolution Rapid gastric emptying Enhanced absorption. E.g; erythromycin is better absorbed
with glass of water under fasting condition than with meal;
d. Drug-Drug interaction in the GIT:
Adsorption: e.g. Anti diarrheal preparations contains adsorbents like kaolin, prevents absorption
of many drugs co-administered with them.
Complexation: e.g. Penicillin derivative with ca- gluconate.
pH changes: Basic drugs changes gastric pH e.g. Tetracycline with antacids.
e. Altered GI metabolism: Antibiotics inhibit bacterial metabolism of the drugs. e.g.:
Erythromycin enhances efficacy of digoxin by this mechanism. Coadminitration of antibiotics
with oral contraceptives like (Ethinylestradiol) decreases the efficacy of oral contraceptives by
decreasing enterohepatic cycling of steroid conjugates.
8. First pass metabolism:
The loss of drug through biotransformation in gut wall before reaching systemic circulation or by
eliminating organs (liver) during its passage to systemic circulation is known as first pass
metabolism. It is a process that reduces the availability of orally administered drugs. Four types
of enzymes are responsible for First pass metabolism.
1. Luminal enzymes: are present in gut fluids and include enzymes from intestinal and
pancreatic secretions. Pancreatic secretions contain hydrolases, peptidases.
Chloramphenicol palmitate hydrolyses into active chloramphenicol. Peptidases inactivate
protein /polpeptide drugs
2. Gut wall enzymes: also called mucosal enzymes are present in wall of GIT. Stomach
mucosa contains Alcohol dehydrogenase (inactivates ethanol), Intestinal mucosa contain
both phase 1 and phase 2 enzymes and Colonic mucosa also contain both phase 1 and
phase 2 enzymes
3. Bacterial enzymes: (microflora) present in stomach, small intestine and is rich in colon.
Colonic microbes render drug more active or toxic on biotransformation. Intestinal micro
flora has important role in the enterohepatic cycling.
4. Hepatic enzymes: Several drug undergo first-pass hepatic metabolism by hepatic
enzymes. Highly extracted ones are Isoprenaline, Nitroglycerin, Morphine, Dilitiazem,
Lidocaine and Nifedipine.