DRUG ABSORPTION

Introduction

 A drug may be defined as a therapeutic

substance intended to affect the structure or
function of the body in order to restore
abnormal function to normal.
 For a drug to produce a therapeutic
effect, it must reach to its target and it
must accumulate at that site to reach to
the minimum concentration required to
produce the required effect.
 The effects of drugs depend upon the
ability of the drug to reach the site of
action.
 This ability is influenced by a
number of phenomena like translocation
and disposition.
 Translocation of Drug
Molecules

 For a drug to reach its site of action in

the body, it must cross numerous
biological membranes, including the
cellular membranes.
 These membranes include the
gastrointestinal mucosa (if given orally)
or lung mucosa (if inhaled), the lymphatic
or capillary wall, and the cell wall.
 There are 4 ways by which small
molecules cross cell membranes:

1. By diffusion through the membrane lipid

2. By diffusion through aqueous pores

3. By combination with a carrier molecule

4. By pinocytosis
 Drugs in general pass through cells
rather than in between them.

 Plasma membranes thus represent

 
the common barrier.

 Most drugs cross membranes by

passive diffusion.
Diffusion through lipid

 The drug molecule penetrates

membranes by passive diffusion along its
concentration gradient by virtue of its
solubility in the lipid bilayer.
 Such transfer is directly proportional to
the magnitude of the concentration
gradient and the Lipid: Water partition
coefficient of the drug.
 The greater the partition coefficient of
the drug, the higher is the concentration
of the drug in the membrane and the
faster is its diffusion.
pH and ionization

 Most drugs are weak acids or weak bases

that are present in solution as both the
ionized and non-ionized form.
 Non-ionized molecules are usually lipid
soluble and can diffuse across cell
membranes
 In contrast, ionized molecules are usually
unable to penetrate the lipid membrane
because of their low lipid solubility.
 The ratio of ionized to unionized species
depends on the pKa of the drug and the
pH of the membrane environment, and
can be calculated from the
Henderson-Hasselbalch equation.
Base
BH +
B+H +

Acid
AH A +H
- +
 The acid (low pH) nature of the stomach
generally results in a higher degree of
ionization for weak bases than for weak
acids.

i.e. Weak acids will be more unionized and

thereby absorbed more readily.
 In the small intestine, the pH is about
5.0-8.0 and the reverse situation holds true.
 When there is relative “acidity” of distal
tubular urine, there is tendency to increase
the ionization of weak bases thereby
hastening their renal elimination whereas
weak acids passively diffuse
(in the unionized form) back into the
circulation.
 “Alkalinization” of urine (for example

with NaHCO3) would tend to reverse this

situation whereas further “acidification”

(for example with NH4Cl) would amplify

these mechanisms.
 In a similar manner, certain physiologic
secretions will tend to concentrate certain
ions.

For example, breast milk (pH 6.7)

is slightly acidic and tends to concentrate
weak bases.
 Thus the pain-relieving narcotic
meperidine, which is a weak base, when
given during labor and delivery will be
present in breast milk
 Summary
Drug is weak acid:
AH A- + H+
Acidic environment: protonated,
non-ionized, lipid-soluble

Basic environment: un-protonated, ionized,

water-soluble
 Drug is weak base:
BH+ B + H+
 
Acidic environment: protonated, ionized,
water-soluble

Basic environment: un-protonated,

non-ionized, lipid-soluble
 Drug absorption

 Absorption is the passage of a drug from

its site of administration into the plasma
(circulation).
The main routes of drug administration are:
Enteral: oral, sublingual, rectal

Parenteral: intravascular (intravenous),

intramuscular, subcutaneous

Other: inhalation, intranasal, intrathecal,

topical, transdermal
Oral
1. Easy, practical and reliable way

2. Drug is first dissolved in GI fluids,

absorbed through epithelial lining of the
GI tract, and enters into blood vessels.

 little absorption in the large intestine

3. Most of the drug is absorbed in the small
intestine. Why?
 small intestine has a much larger surface
area for absorption (∼200 m2) as compared
to the stomach (∼1-3 m2).
 drug spends more time in the small
intestine (∼4 hrs) than the stomach
(∼0.5-1 hrs).
4. Solubility of the drug in the GI tract

5. Time in the GI tract. Any pathological

condition that changes that either increase
or decrease the passage time of the drug
in the GI tract will change the quantity of
absorption.
6. Food in the stomach can decrease
absorption.

 Food may cause changes in transit time,

increase release of fluids into the stomach,
interactions between drug and food particles.
 If food causes problems with
a certain drug, it should be taken 2 hrs
after food intake and 1 hr before the next
food intake.
7. Drugs may be metabolized by enzymes of
GI mucosa or enter the hepatic portal
circulation and undergo metabolism by liver
enzymes which may result in their
inactivation.
Sublingual

 Good absorption through capillary bed

under tongue

 Drugs are easily self administered

 Because the stomach is bypassed,
acid-lability and gut-permeability is not
important
 Drugs are absorbed from the mouth
straight into the systemic circulation
without entering the portal system and
so escape first-pass metabolism by the liver.
Rectal

 Useful for unconscious or vomiting

patients and small children

 Absorption is unreliable
Intravenous
 Rapid onset of action because the drug is
injected directly into the bloodstream
 Useful in emergencies and in patients
that are unconscious

 The drug avoids the GI tract and

first-pass metabolism by the liver
Intramuscular

 Drug passes through capillary walls to

enter the blood stream.
 Rate of absorption depends on
formulation (oil-based preparations are
absorbed slowly, aqueous preparations are
absorbed rapidly).
Subcutaneous
 Drug is injected beneath the skin and
permeates capillary walls to enter blood
stream.

 Absorption from the site of injection is

dependent on local blood flow.
Inhalation
 Inhalation provides the rapid delivery
of a drug across the large surface area of
the mucous membranes of the respiratory
tract and pulmonary epithelium, producing
an effect almost as rapidly as by
intravenous injection.
 This route of administration is used for
drugs that are gasses (for example some
anesthetics) or those that can be dispersed
in an aerosol (for example some
asthma drugs).
 The route is particularly effective and
convenient for patients with respiratory
complaints (for example asthma or chronic
obstructive pulmonary disease) as drug is
delivered directly to the site of action and
systemic side effects are minimized.
Topical
 Useful for local delivery of drugs,
particularly those which have toxic effects
if administered systemically

 Used for most dermatologic and

ophthalmologic preparations
For example, clotrimazole is applied as a
cream to the skin in the treatment of
dermatophytosis, and atropine is instilled
directly into the eye to dilate the pupil and
permit measurement of refractive errors.
First-Pass Effect
 Since drugs are absorbed from the
gastrointestinal tract into the portal
circulation, some drugs may be extensively
metabolized in the liver or in the intestinal
mucosa before reaching the systemic
circulation.
 This “first-pass effect” can substantially
decrease the amount of active drug reaching
the systemic circulation and thus, its
bioavailability.
Example:
Lidocaine is a drug with a first-pass effect
that is so great that oral administration
is not practical.
 In the case of propranolol, a significant
portion of the orally administered dose is
metabolized through a first-pass effect;
 therefore, a much larger oral dose is
required to achieve the same therapeutic
response as that obtained from a dose
administered intravenously.
Gastric emptying

 The rate of drug absorption after an

oral dose can be altered by altering the rate
of gastric emptying.
 Ingestion of a solid dosage form with a
glass of cold water will accelerate gastric
emptying.
 This will expose the drug to the upper
intestine with a higher pH and a much
larger surface area (better absorption).

 Some drugs can also increase gastric

emptying.
 Conversely, ingestion of a drug with a
fatty meal or an acidic drink will slow
gastric emptying.

 Drugs with anti-cholinergic effects can

also slow gastric emptying.
 SUMMARY

 When a drug is to be administered to a

patient to achieve a therapeutic blood level
Consideration must be given to:
 Route of administration
(as determined by chemical nature of the
drug and/or the clinical circumstances)

 Desired time of onset of action

(as determined by the route of
administration and the dose)
 Since most drugs are given orally, the
factors which can alter absorption
characteristics must be also considered

i.e., dissolution rate, dosage form, changes

in pH of GI tract and transit time
as a result of :
 The clinical state of the patient

 Presence of other drugs or substances that

interfere with absorption (breakdown or
binding of drug, formation of insoluble
compounds)

 Individual differences of absorption rates