Introduction:
The systemic absorption of a
drug is dependent on:
(1)
the physicochemical properties of the drug,
(2)
the nature of the drug product, and
(3)
the anatomy and physiology of the
drug absorption site.
Route of Drug Administration:
Drugs may be
given by parenteral, enteral, inhalation, transdermal (percutaneous), or
intranasal route for systemic
absorption. Each route of drug administration has certain advantages and
disadvantages. The systemic
availability and onset of drug action are affected by blood flow to
the administration site, the physicochemical characteristics of
the drug and the drug product, and by any pathophysiologic condition
at the absorption site.
Common Routes of Drug Administration: (Just for Understanding)
1.
Parenteral Routes:
a)
Intravenous bolus (IV):
Bioavailability:
·
Complete (100%) systemic
drug absorption.
·
Rate of bioavailability considered instantaneous.
Advantages:
·
Drug is given for immediate effect.
Disadvantages:
·
Increased chance
for adverse reaction.
·
Possible anaphylaxis.
b)
Intravenous infusion
(IV inf):
Bioavailability:
·
Complete (100%) systemic
drug absorption.
·
Rate of drug absorption controlled by infusion rate.
Advantages:
·
Plasma drug levels
more precisely controlled.
·
May inject large
fluid volumes.
·
May use
drugs with poor lipid solubility and/or irritating drugs.
Disadvantages:
·
Requires skill in insertion of infusion set.
·
Tissue damage at site of injection (infiltration, necrosis, or sterile
abscess).
c)
Intramuscular injection (IM):
Bioavailability:
·
Rapid from
aqueous solution.
·
Slow absorption from nonaqueous (oil) solutions.
Advantages:
·
Easier to
inject than intravenous injection.
·
Larger volumes may be
used compared to subcutaneous solutions.
Disadvantages:
·
Irritating drugs may be very painful.
·
Different rates of absorption depending
on muscle group injected and blood flow.
d)
Subcutaneous injection
(SC):
Bioavailability:
·
Prompt from
aqueous solution.
·
Slow absorption from repository formulations.
Advantages:
·
Generally, used for insulin injection.
Disadvantages:
·
Rate of drug absorption depends
on blood flow and injection
volume.
2.
Enternal:
Buccal or sublingual (SL):
Bioavailability:
·
Rapid absorption from lipid-soluble drugs.
Advantages:
·
No "first-pass" effects.
Disadvantages:
·
Some drugs may be swallowed.
·
Not for most drugs or drugs with high doses.
Oral (PO):
Bioavailability:
·
Absorption may vary.
·
Generally, slower absorption rate compared to IV bolus or IM injection.
Advantages:
·
Safest and easiest route of drug administration.
·
May use immediate-release and modified-release drug products.
Disadvantages:
·
Some drugs may have erratic absorption, be
unstable in the gastointestinal tract, or be
metabolized by liver prior to systemic
absorption.
Rectal (PR):
Bioavailability:
·
Absorption may vary from suppository.
·
More reliable
absorption from enema (solution).
Advantages:
·
Useful when patient
cannot swallow medication.
·
Used for local
and systemic effects.
Disadvantages:
·
Absorption may
be erratic.
·
Suppository may migrate
to different position.
·
Some patient discomfort.
Others:
- Transdermal (slow absorption, may irritate)
- Intranasal/Inhalation (rapid absorption)
Many drugs are
not administered orally because of drug instability in the gastrointestinal
tract or drug degradation by the digestive
enzymes in the intestine.
For example, erythropoietin and human
growth hormone (somatrophin) are administered
intramuscularly, and insulin is administered subcutaneously or
intramuscularly, because of the potential for degradation of these drugs in the stomach
or intestine.
Biotechnology
products are often too labile to be administered orally and therefore are
usually given parenterally. Drug absorption after subcutaneous injection is slower
than intravenous injection.
|
Cholestyramine exerts its
local action in GIT and
it has no systemic absorption. |
|
Mesalamine and Basalazide have local activity in GIT but significant amount is absorbed systemically. |
Physiological factors
(for absorption through
GIT)
These factors include:
·
Membrane physiology
·
Passage of drug molecules across
membrane
·
GIT physiology
NATURE OF CELL MEMBRANES:
Many drugs
administered by extravascular routes are intended for local effect. Other drugs
are designed to be absorbed from
the site of administration into the systemic circulation. For systemic drug absorption, the drug must cross cellular
membranes. After oral administration, drug molecules must cross the intestinal epithelium by going either through or between the
epithelial cells to reach the systemic
circulation. The permeability of a drug at the absorption site into the
systemic circulation is intimately
related to the molecular structure of the drug and to the physical and
biochemical properties of the cell
membranes. Once in the plasma, the drug may have to cross biological membranes
to reach the site of action.
Therefore, biological membranes potentially pose a significant barrier to drug delivery.
Transcellular absorption: is the process
of drug movement
across a cell.
Paracellular drug absorption: Some polar molecules may not be able to traverse
the cell membrane but, instead, go through gaps or tight
junctions between cells, a process known as paracellular drug absorption.
Some drugs are probably
absorbed by a mixed
mechanism involving one or more processes.
Functionally, cell membranes are semipermeable partitions that act as selective barriers
to the passage of
molecules. Water, some selected small molecules, and lipid-soluble molecules
pass through such membranes, whereas
highly charged molecules and large molecules, such as proteins and protein- bound drugs,
do not.
The
transmembrane movement of drugs is influenced by the composition and structure
of the plasma membranes. Cell
membranes are generally thin, approximately 70 to 100 A in thickness. Cell
membranes are composed primarily of
phospholipids in the form of a bilayer interdispersed with carbohydrates and protein
groups.
Two Theories:
1)
The lipid bilayer or unit membrane theory, , considers
the plasma membrane to be composed of two
layers of phospholipid between two surface layers of proteins, with the
hydrophilic "head" groups
of the phospholipids facing the protein layers and the hydrophobic
"tail" groups of the phospholipids aligned in the interior.
2)
The fluid mosaic model, explains the transcellular
diffusion of polar molecules. According to this model, the cell membrane consists of globular proteins
embedded in a dynamic fluid, lipid bilayer
matrix. Two types of pores of about
10 nm and 50 to 70 nm were inferred to be present in membranes based on capillary membrane transport studies.
These small pores provide a channel
through which water, ions, and dissolved solutes such as urea may move across
the membrane.
PASSAGE OF DRUGS
ACROSS CELL MEMBRANES:
Passive Diffusion:
Theoretically, a
lipophilic drug may pass through the cell or go around it. If the drug has a
low molecular weight and is lipophilic, the lipid cell membrane
is not a barrier to drug diffusion and absorption.
“Passive diffusion is the
process by which molecules spontaneously diffuse from a region of higher concentration to a region of lower
concentration. This process is passive because no external energy is expended”
When one side is
higher in drug concentration, at any given time, the number of forward-moving
drug molecules will be higher than
the number of backward-moving molecules; the net result will be a transfer
of molecules to the alternate
side. The rate of
transfer is called flux.
Example:
Molecules in
solution diffuse randomly in all directions. As molecules diffuse from left to
right and vice versa (small
arrows), a net diffusion from the high-concentration side to the
low-concentration side results. This
results in a net flux (J ) to the right side. Flux is measured in mass per unit
area (e.g. mg/cm2).
Passive diffusion is the major absorption process
for most drugs.
Fick’s Law of Diffusion:
According to
Fick's law of diffusion, drug molecules diffuse from a region of high drug
concentration to a region of low drug concentration.
Where,
dQ /dt = rate of diffusion, D = diffusion
coefficient,
K = lipid water partition coefficient of drug in the biologic membrane
that controls drug permeation, A =
surface area of membrane;
h = membrane thickness, and CGI -
Cp = difference between the concentrations of drug in the gastrointestinal tract and in the plasma.
Given Fick's law of diffusion, several other factors can be seen to influence
the rate of passive diffusion of drugs.
·
Because the drug distributes rapidly into a
large volume after entering the blood, the concentration of drug in the blood initially will be quite low with respect to the concentration at
the site of drug absorption. If the drug is given orally, then CGl
> Cp and a large concentration
gradient is maintained, thus driving drug molecules into the plasma from
the gastrointestinal tract.
·
The degree of lipid solubility of the drug
influences the rate of drug absorption. Drugs that are more lipid soluble
have a larger value of K .
·
The surface area, A , of the membrane also
influences the rate of absorption. Drugs may be absorbed from most areas of the gastrointestinal tract. However,
the duodenal area of the small intestine
shows the most rapid drug absorption, due to such anatomic features as villi
and microvilli, which provide a large
surface area. These villi are less abundant in other areas of the gastrointestinal tract.
·
The thickness of the hypothetical model
membrane, h , is a constant for any particular
absorption site. In the brain, the capillaries are densely lined with
glial cells, so a drug diffuses slowly
into the brain as if a thick lipid membrane existed. Drugs usually diffuse very
rapidly through capillary plasma
membranes in the vascular compartments, in contrast to diffusion through plasma membranes of capillaries in
the brain. However, in certain disease states such as meningitis these membranes may be disrupted or become
more permeable to drug diffusion.
·
The diffusion coefficient, D , is a constant for
each drug and is defined as the amount of a drug that diffuses across a membrane of a given unit area per unit
time when the concentration gradient is unity. The dimensions of D are
area per unit time for example, cm2 /sec.
Because D , A , K , and h are constants
under usual conditions for absorption, a combined constant P or permeability
coefficient may be defined.
The drug concentration in the plasma,
C p , is extremely small
compared to the drug concentration in the
gastrointestinal tract, C GI . If C p is negligible and P is substituted into
Equation 13.1, the following relationship for Fick's law is obtained:
Equation 13.3 is an expression for
a first-order process. Moreover, because of the large concentration gradient between C GI and C p , the rate
of drug absorption is usually more rapid than the rate of drug elimination.
Many drugs have both lipophilic and
hydrophilic chemical substituents. Those drugs that are more lipid soluble tend to traverse cell
membranes more easily than less lipid-soluble or more water- soluble
molecules. For drugs that act as weak electrolytes, such as weak acids and bases, the extent of
ionization influences the rate of drug. The
ionized species of the drug contains a charge and is more water
soluble than the non-ionized species
of the drug, which is more
lipid soluble.
Concept:
The ionized
species of the drug contains a charge and is more water soluble than the
nonionized species of the drug,
which is more lipid soluble. The extent of ionization of a weak electrolyte
will depend on both the pKa of the
drug and the pH of the medium
in which the drug is dissolved.
Henderson and
Hasselbalch used the following expressions pertaining to weak acids and weak
bases to describe the relationship between pKa and pH:
For Weak Acids:
For Weak Base:
Example:
Q. Find %ionization of Salicylic Acid in Stomach and Blood?
Carrier-Mediated Transport:
Theoretically, a
lipophilic drug may pass through the cell or go around it. If the drug has a
low molecular weight and is
lipophilic, the lipid cell membrane is not a barrier to drug diffusion and
absorption. In the intestine, drugs
and other molecules can go through the intestinal epithelial cells by either
diffusion or a carrier-mediated
mechanism. Numerous specialized carrier-mediated transport systems are present
in the body, especially in the
intestine for the absorption of ions
and nutrients required
by the body.
ACTIVE TRANSPORT:
Active transport
is a carrier-mediated transmembrane process that plays an important role in the gastrointestinal absorption and in renal and biliary secretion of many
drugs and metabolites.
E.g. A few lipid-insoluble drugs that
resemble natural physiologic metabolites (such as 5-fluorouracil) are absorbed from the gastrointestinal tract by this process.
“Active transport is
characterized by the transport of drug against a concentration gradient that
is, from regions of low drug
concentrations to regions of high concentrations. Therefore, this is an energy-consuming system.”
In addition, active transport is a specialized process requiring a
carrier that binds the drug to form a carrier
drug complex that shuttles the drug across the membrane and then dissociates
the drug on the other side of
the membrane.
The carrier molecule may be
highly selective for the drug
molecule.
Above figure
shows Comparison of the rates of drug absorption of a drug absorbed by passive
diffusion (line A ) and a drug absorbed
by a carrier- mediated
system (line B ).
FACILITATED DIFFUSION:
Facilitated
diffusion is also a carrier-mediated transport system, differing from active
transport in that the drug moves
along a concentration gradient (ie, moves from a region of high drug
concentration to a region of low
drug concentration). Therefore, this system does not require energy input.
However, because this system is carrier
mediated, it is saturable and structurally selective for the drug and shows
competition
kinetics for drugs of similar structure. In terms of drug absorption,
facilitated diffusion seems to play
a very minor role.
CARRIER-MEDIATED INTESTINAL TRANSPORT:
Various
carrier-mediated systems (transporters) are present at the intestinal brush
border and basolateral membrane for
the absorption of specific ions and nutrients essential for the body (). Many drugs are absorbed by these carriers
because of the structural similarity to natural substrates E.g. transmembrane protein, P- glycoprotein (Pgp),
has been identified in the
intestine.
Other
transporters are also present in the intestines. For example, many oral
cephalosporins are absorbed through
the amino acid transporter.
Ø Influx transporters
Influx
transporters enhance absorption. In particular, more than 400 membrane
transporters in two major super families
·
ATP-binding cassette (ABC)
·
Solute carrier (SLC)
Have been annotated in the human genome
Among these
influx (absorptive) transporter are the intestinal oligopeptide transporter, or
di-/tripeptide transporter,
proton/peptide cotransporter (PepT1) localized on the brush border membrane has potential
for enhancing intestinal absorption of peptide drugs.
For
example, amino acid transporter transports methyldopa and oligopetide
transporter transport
cefadroxil, cefixime and ceftibuten.
Ø Efflux transporters
Efflux
transporters cause the drug outflow. Many of the efflux transporters in GI
tract are membrane proteins located
strategically in membranes to protect the body from influx of undesirable
substrates. A common example is MDR1 multidrug-resistance
associated protein or P-gp which
is also named ABCB1 (example of
ATP-binding cassette (ABC)subfamily. P-gp
has been identified in the intestine and
reduces apparent intestinal epithelial cell permeability from lumen to
blood for various lipophilic or cytotoxic drugs.
The expression
of P-gp is triggered by disease or other conditions, contributing to efflux and
variability of plasma drug concentrations after administered dose.
Efflux transporters move drug molecules back into the gut lumen and reduce systemic drug absorption.
Vesicular Transport:
Vesicular transport is the process of engulfing particles
or dissolved materials
by the cell.
Pinocytosis and
phagocytosis are forms of vesicular transport that differ by the type of
material ingested.
Pinocytosis refers to the engulfment of
small solutes or fluid, whereas phagocytosis
refers to the engulfment of larger particles or macromolecules, generally by macrophages.
Endocytosis and exocytosis are the
processes of moving specific macromolecules into and out of a cell, respectively.
An example of exocytosis is
the transport of a protein such as insulin from insulin-producing cells of the pancreas into the extracellular space.
The insulin molecules are first packaged into intracellular vesicles, which
then fuse with the plasma membrane to release the insulin outside
the cell.
Transcytosis is the process by which
various macromolecules are transported across the interior of a cell. The vesicle fuses with the plasma
membrane to release the encapsulated material to another side of the cell. It is proposed process for
the absorption of orally administered sabin polio vaccine and various
large proteins.
Pore (Convective) Transport:
Very small
molecules (such as urea, water, and sugars) are able to cross cell membranes
rapidly, as if the membrane
contained channels or pores. Although such pores have never been directly
observed by microscopy, the model of
drug permeation through aqueous pores is used to explain renal excretion of drugs and the uptake of drugs into the liver.
A certain type
of protein called a transport protein may form an open channel across the lipid membrane of the cell.
Ion-Pair Formation:
Strong
electrolyte drugs maintain their charge at all physiologic pH values and
penetrate membranes poorly. When the
ionized drug is linked up with an oppositely charged ion, an ion pair is formed
in which the overall charge of the
pair is neutral. This neutral drug complex diffuses more easily across the membrane.
For example, the formation of ion pairs
to facilitate drug absorption has been demonstrated for propranolol, a basic
drug that forms an ion pair with oleic acid,
and quinine, which forms ion pair with
hexylsalicylate.
Ion pairing may transiently alter distribution, reduce high plasma free drug concentration, and reduce renal toxicity.
An interesting
application of ion pairs is the complexation of amphotericin B and DSPG (disteroylphosphatidylglycerol) in some
amphotericin B/liposome products.
ORAL DRUG ABSORPTION:
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.
Anatomic and Physiologic Considerations: (Mainly focus the pH)
The drug given
by the enteral route for systemic absorption may be affected by the anatomy, physiologic functions, content of the
alimentary canal. The total transit time including
gastric, small intestine and colonic
emptying ranges from 0.4 to 5 days.
While the small intestine transit time ranges from 3 to 4 hours.
Duodenum is the major site for passive drug absorption due to both its anatomy, which creates a high surface area and high
blood flow. High surface area of duodenum is due to presence of valve-like folds in the mucous membrane on which are
small projections known as “villi”. These villi contain even smaller
projections known as “microvilli”
forming a brush border. Duodenal region is highly
perfused with a network of capillaries.
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 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.
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. Stomach
emptying is influenced by the food content and osmolality. High-density foods generally
are emptied from the stomach more slowly.
In the antral
part of the stomach, a process of breaking down large food particles described
as antral milling.
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. 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.
JEJUNUM:
This portion of
the small intestine generally has fewer contractions than the duodenum and is
preferred for in-vivo
drug absorption studies.
ILEUM:
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.
COLON:
The pH in this
region is 5.5 to 7. Drugs that are absorbed well in this region are good
candidates for an oral
sustained-release dosage form. 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:
In the absence
of fecal material, the rectum has a small amount of fluid (approximately 2 mL)
with a pH about 7. Drug absorption
after rectal administration may be variable, depending on the placement of the suppository or drug
solution within the rectum.
|
pH |
|
|
Oral cavity |
7 |
|
Esophagus |
5-6 |
|
Stomach |
2-6(fasting) 1.5-2(fed) |
|
Duodenum |
6-6.5 |
|
Ileum |
7-8 |
|
Colon |
5.5-7 |
|
rectum |
7 |
Drug Absorption in the Gastrointestinal Tract:
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. The unique anatomy of the duodenum provides an immense surface area for the drug to diffuse
passively. The large surface area of the duodenum is due to the presence
of valvelike folds in the mucous membrane on which are small
projections known as villi .
These villi
contain even smaller projections known as microvilli, forming a brush border.
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.
·
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 GI tract depends on the physiochemical and pharmacological properties of the drug,
the type of dosage form, and various physiological factors. Movement of the drug depends
on whether the canal is in fed or fasted state.
ü
During the fasted
state altering cycles of activity known as the ‘migrating motor complex (MMC)’
act as propulsive movement that empties the upper GI tract to cecum.
Irregular contractions followed by
regular contractions with high amplitude (housekeeper
waves) push any residual contents distally or farther
down the alimentary canal.
ü
In fed
state, the MMC is replaced by regular contractions, which have the effect
of mixing intestinal contents and advancing intestinal stream towards the colon in short segments.
Characteristics of the Motility Patterns:
Fasted Stage:
|
Phase |
Duration |
Characteristics |
|
1 |
30-60 min |
Quiescence. |
|
2 |
20-40 min |
·
Irregular contractions. ·
Medium amplitude but can
be as high as phase
III. ·
Bile secretion begins. ·
Onset of gastric discharge of administered
fluid of small volume usually occurs before that
of particle discharge. ·
Onset of
particle and mucus discharge may occur during the latter part of phase II. |
|
3 |
5-15 min |
·
Regular contractions (4-5
contractions/min) with high
amplitude. ·
Mucus discharge continues. ·
Particle discharge continues. |
|
4 |
0-5 min |
·
Irregular contractions. ·
Medium descending amplitude. ·
Sometimes absent. |
Fed Stage:
|
One phase only |
As long as
food is present in the stomach |
Regular,
frequent contractions. Amplitude is lower than phase III.
4–5
Contractions/min. |
·
Gastric emptying
time
A swallowed
drug rapidly reaches the stomach and stomach empties its contents into the small intestine.
Because the duodenum has the greatest capacity for the absorption of drugs from
the GI tract, a delay in gastric
emptying time for the drug to reach the duodenum will slow the rate and
possibly the extent of drug absorption.
If gastric
emptying is unstable/delayed:
Some drugs, such
as penicillin, are unstable in acid and decompose if stomach emptying is
delayed. Other drugs, such as aspirin, may irritate
the gastric mucosa during prolonged
contact.
A number of factors affect
the gastric emptying
time. Some factors affect
gastric emptying time includes
consumption of meals high in fat, cold beverages, and anti-cholinergic drugs.
Liquids and
small particles are not retained in the stomach. Large particles, including
tablets and capsules, are delayed
from emptying for to 3 to 6 hours by
the presence of food. Indigestible solids empty
very slowly, during the indigestive phase the stomach is less motile but
periodically empties its content due to housekeeper wave contractions
|
Meal |
Stomach emptying time (50%) |
|
10oz of liquid soft
drink |
30 min. |
|
Scrambled egg |
154 min. |
|
Radio opaque marker |
3 to 4 hours |
Factors
Influencing Gastric Emptying: (Taken
from 5th edition. May use few
examples from table below if there is a note on Gastric
Emptying in Exam)
|
Factore |
Influence
on Gastric Emptying |
|
Volume |
The larger the starting volume, the greater
the initial rate of emptying. |
|
Type of meal |
Triglycerides: Reduction in rate of
emptying Carbohydrates: Reduction in rate of emptying Amino
acids: Reduction in rate of emptying Osmotic
pressure: Reduction in rate of emptying Acids:
Reduction in rate of emptying dependent upon concentration and
molecular weight of the
acid Anticholinergics: Reduction in rate
of emptying Narcotic analgesics: Reduction in rate of emptying Metoclopramide:
Reduction in rate of emptying Ethanol: Reduction in rate of emptying |
|
Miscellaneous |
|
|
Body position |
Rate of emptying is reduced in a
patient lying on left side. |
|
Viscosity |
Rate of emptying is greater for less viscous solutions. |
|
Emotional states |
Aggressive or stressful emotional states increase stomach contractions and emptying rate |
|
Bile salts |
Rate of emptying is reduced. |
|
Disease
states |
Rate of emptying is reduced in some diabetics and in patients with local pyloric |
|
lesions |
|
|
Exercise |
Vigorous exercise reduces emptying rate. |
|
Gastric
surgery |
Gastric emptying difficulties can be a serious problem
after surgery. |
·
Intestinal motility
Normal
peristaltic movements mix the contents of the duodenum, bringing the drug
particles into intimate contact with
the intestinal mucosal cells. The drug must have a sufficient time (residence time) at the absorption site for optimum absorption. In case of
high motility in the intestinal tract, as in
diarrhea, the drug has a very brief residence time and less opportunity for adequate absorption.
The average
normal small intestine transit time (SITT) was about 7 hours according to early studies while newer studies show that SITT to be 3 to 4 hours. Thus a drug may take about 4-8
hours to pass through stomach and
small intestine during the fasting state. During the fed state, SITT may
take 8 to 12 hours. For modified-release -dosage form the drug slowly
release over an extended period of time, the
dosage form must stay within
certain segment of the intestine so that the drug is absorbed before loss of dosage form in
feces.
Perfusion of the Gastrointestinal tract
The blood flow
to the GIT is important in carrying absorbed drug to the systemic circulation.
A large network of capillaries and
lymphatic vessels perfuse the duodenal region and peritoneum. The role of the lymphatic circulation in drug
absorption is well established. Drugs are absorbed through the lacteal or lymphatic vessels under the microvilli.
Absorption of drugs through the lymphatic system bypasses the first- pass effect due to liver
metabolism, because drug absorption through the hepatic-portal vein is avoided. The lymphatics are important in
absorption of dietary lipids and responsible for absorption of some lipophilic drugs.
Effect of food on gastrointestinal drug absorption:
The presence of
food in the GI tract can affect the bioavailability of the drug from an oral
drug product. Some effects of food on bioavailability of a drug are:
·
Delay in gastric
emptying
·
Stimulation of bile flow
·
A change in 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
Food effects on bioavailability are generally greatest
when drug taken shortly after meal.
§
Absorption of antibiotics (penicillin, tetracycline) and hydrophilic drugs is decreased with food
§
Lipid-soluble
drugs (griseofulvin, metazalone) are better absorbed with food having high
fat content
§
Bile increase the solubility of fat-soluble
drugs through micelle
formation
§
For basic
drugs with limited aqueous solubility, the presence of food in stomach
stimulates HCL secretion, causing
more rapid dissolution and better absorption. And absorption of these drugs is reduced when gastric acid secretion is reduced
§ Most drugs should be taken with full glass of water to ensure
that drug will wash down
§
Some drugs like erythromycin, iron salts, aspirin and NSAIDs are irritating to GI
mucosa so taken with food to reduce
absorption but retained efficacy
of drugs
§
The GI transit time for enteric-coated and
non-disintegrated drug products may also be affected by the presence
of food
§
Food can affect the integrity of the dosage
form, causing alteration in release rate of the drug for example theophylline
bioavailability from theo-24
controlled-release tablet is rapid when given in fed because of dosage form failure
known as dose-dumping
§
Absorption of cefpodoxime proxetil
is enhanced with food or if taken closely
after fatty meal
§ Alendronate
sodium must be taken at one-half hour before the first food or beverages.
§ Famotidine
and cimetidine are taken
before meals to curb excessive acid production.
§ Ticlopidine
(antiplatelet) has enhanced
absorption after a meal.
Effects
of disease states
on drug absorption
Drug absorption may be affected
by any disease that cause changes in
1.
Intestinal blood flow
2. Gastrointestinal motility
3. Changes in stomach emptying
time
4. Drug 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
9. Alteration of normal GIT flora
·
Patients on tricyclic
antidepressants (imipramine) and antipsychotic
drugs (phenothiazine) with anticholinergic drugs have reduced GI
motility or even intestinal abstruction and delay in drug absorption.
·
Achlorhydric patients have inadequate acid in stomach which is essential for
solubilizing insoluble free bases.
And itraconazole, dapsone and ketoconazole may be less well absorbed
in achlorhydria. Omeprazole render stomach achlorhydria affecting absorption
·
HIV-AIDS
patients are prone to diarrhea and achlohydria which affect
absorption
·
CHF patient have edema, reduced
blood flow and slow intestinal motility which results in decreased absorption
·
Crohn’s disease inflammation of intestine have unpredictable drug absorption
·
Celiac disease effecting proximal
small intestine which increase its permeability and absorption of drug like cephalexin is increased
·
Other intestinal conditions that may affect
drug absorption include corrective surgery involving
peptic ulcer, antrectomy with gastroduodenostomy and selective vagotomy.
Drugs that affect
absorption of other drugs
·
Anticholinergic
drugs (propantheline bromide) reduce acid secretion and may also slow
stomach emptying and motility
of small intestine
·
Tricyclic antidepressants and phenothizines cause slow slower peristalsis in GIT
·
Metoclopramide
stimulate stomach contraction and intestinal peristalsis thus reducing the effective time of absorption. For example Digoxin absorption is reduced by metoclopramide and increased by anticholinergic drugs
·
Antacids should
not be given cimetidine. Antacids may
complex with drugs like tetracycline, ciprofloxacin and indinavir
resulting in decreased absorption
·
Proton
pump inhibitors decrease gastric acid thereby raising gastric pH affecting
bioavailability of ketoconazole and
enteric-coated drug products
in which high pH may dissolve
coating
·
Cholestyramine
binds warfarin, thyroxine, and loperamide thereby reducing absorption
of these drugs
Nutrients
that interfere with drug
absorption
Many nutrients
substantially interfere with the absorption or metabolism of drugs in the body.
Oral drug-nutrient interactions are
often drug specific and can result in either an increase or decrease in drug absorption.
·
Absorption of water-soluble vitamin such as B-12
and folic acid are aided by
special absorption mechanism
·
Absorption of calcium in duodenum is an active process facilitated by vitamin D
·
Grapefruit
juice often increases bioavailability by increase in plasma levels of drugs
that are substrates for cytochrome P-450 (CYP)3A4. Grapefruit
juice can also block drug efflux by blocking P-gp for some drugs.
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