Absorption of Drugs

Drug absorption is defined as the process of movement of unchanged drug the
site of administration to systemic circulation. Absorption can also be defined
as the process of the movement of unchanged drug from the site of administration
to the site of measurement ie plasma.

Routs of Drug Administration

The Enteral Route:

Include per oral ie gastrointestinal , sublingual / buccal and rectal routs.
The GI rout is most common for administration of majority of drugs.

The parentral Route

Includes all routes of administration through or under one or more layers
ofskin. While no absorption is required when the drug is administered iv, it is
necessary for exravascular parentral routes like the subcutaneous and intramuscular
routes.

The Topical Route

Includes skin, eyes or other specific membranes. THe intranasal, inhalation,
intravaginal and transdermal routes may be considered enteral or topical
according to different definitions.

MECHANISM OF DRUG ABSORPTION

Passive diffusion

Pore transport

Facilitated Diffusion

Active transport

Ionic or electrochemical diffusion

Ion-pair transport

Endocytocis

Passive diffusion or Nonionic Diffusion

More than 90% of drugs follow this process . Here the
driving force is concentration or electrochemical gradient.

It is defined as the difference in the drug concentration on the either side
of the membrane. Drug movement is a result of the kinetic energy of the
molecule.

Explanation By

Fick's
first law of diffusion

Explanations of Passive diffusion on the Basis of Ficks Law

The drug moves down the concentration gradient indicating downhill
transport

The rate of drug transfer is directly proportional to the concentration
gradient between GI fluids and the blood compartment

Greater the area and lesser the thickness of the membrane, faster the
diffusion thus, more rapid is the rate of drug absorptioin from the
intestine than from the stomach'

Equilibrium is attached when the concentration on either side of the
membrane becomes equal

Drugs which can exist in both ionised and unionised forms approach
equilibrium primarily by the transfer of unionised species; the rate of
transfer of unionised species is 3 to 4 times the rate for ionised drugs.

Greater the membrane partition coefficient of the drug, faster the
absorption: since the membrane is lipoidal in nature a lipophilic drug
diffuses at a faster rate by solubilising in the lipid layer of the
membrane

The drug diffuses rapidly when the vol of GI fluid is low: conversly,
dilution of GI fluids decreases the drug concentration in this fluids (C_GIT)
and the lower concentration gradient (C_GIT- C). This phenomena
is however made use of in treating cases of oral overdose or poisening.

Passive diffusion is a energy independent and non saturable but dependent
to a lesser extend on the square root of the molecular size of the drug the
molecular w.ts of most drugs lie bw 100-400 daltons which can be effectively
absorbed passively

Pore Transport or convective Transport or Bulk flow or Filtration

The process is important in the absorption of low mol wt (less than 100) low
mol size (smaller than the diameter of the pore). And generally water soluble
drugs through narrow, aqueous filled channels or pores in the membrane
structure.( Ex: Urea Water Sugars) Chain like or linear compounds of mol wt upto
400 daltons can be absorbed by filtration. The driving force is
constituted by the Hydrostatic pressure or the osmotic differncess across the
membranes due to which bulk flow of water along with small solid molecules occurs
through aqueous chanels.

Water flux that promotes such a transport is called as solvent drag.

Facilitated Diffusion

It is a carrier mediated transport system that operate down the concentration
gradient( Down hill transport) But its a faster process than the passive
diffusion. The driving force is conc gradient hence a passive processsince no
energy expenditure is involved.

The process is not inhibited by metabolic poisons that interfere with energy
production. Facilitated diffusion is of limited importance in the
absorption of drugs.

Ex: Entry of glucose to Rbc. Intestinal absorption of VIt B1 & B2

Absorption of Vit B12 in intestine, An intrinsic factor (IF), a glycoprotien
produced by the gastric parietal cells forms a complex with vith B12 which is
then transported across the intestinal membrane by a carrier system.

Active transport

Comparison with Facilitated diffusion

The drug is transported from a region of lower to one of higher
concentration ie against the concentration gradient or uphill transport.
with out any regard for equilibrium

Since the process is uphill, energy is required in the work done by the
carrier

As the process requires expenditure of energy it can be inhibited by
metabolic poisons that interfere with energy production like fluorids,
cyanade and dinitrophenol and lack of Oxygen, etc.

Ex : Absorption of Na, Ca, K, Fe, Glucose certain amino acids and vit like
niacin pyridoxin and ascorbic acid. Drugs having structural similarity to such
agents are absorbed actively, particularly the agents use full in cancer
chemotherapy.

Ex : absorption of 5 fluro Uracil and 5 Bromo uracil via the pyramidine
transport system absorption of Methyl dopa L dopa via L amino acid transport
system.

Enalapril via small peptide carrier system

Ionic or electrochemical diffusion

The rate of permiation of the drugs follow the order

unionicedmolecule>anions>cations

The permeation of the ionised drugs, particularly the cationic
drugs, depended on the potential difference of the electrical gradient as the
driving force across the membrane. A cationic charge is repelled due to the
positive charge on the out side of the membrane.

Ion-pair transport

Mechanism of absorption explains the absorption of the quaternary ammonium
compounds and sulfonic acids, which ionise under all pH conditions, is ion pair
transport.

Endocytocis

Minor transport mechanism which involves the engulfing extracellular
materials within a segment of the cell membrane to form a saccule or a vesicle (
hence also called as corpuscular or vesicular transport) which is then
pinched-of intracellularly

Includes 2 type process

Phagocytosis (cell eating) : adsorptive uptake of solid particulate

^{Pinocytosis (cell drinking)
: uptake of fluid solute.}

Factors Influencing GI Absorption of a Drug from its Dosage
form

PHARMACEUTIC FACTORS
- Physicochemical Properties of Drug Substances
  - Drug solubility and dissolution rate
  - Particle size and effective surface area
  - Polymorphism and amorphism
  - Pseudopolimorphism ( Hydrates and solvates)
  - Salt form of the drug
  - pKa of the drug and pH
  - Drug stability
- Dosage Form Characteristics and pharmacologic
  Ingredients
  - Disintegration time (tablets and capsules)
  - Dissolution time
  - Manufacturing Variables
  - Pharmaceutic Ingredients
  - Nature and type of dosage form
  - Product age and storage condition

PATIENT RELATED FACTORS
- Age
- Gastric emptying time
- Intestinal transit time
- Gastro intestinal pH
- Disease states
- Blood Flow to the GIT
- Gastrointestinal contents
  - Other Drugs
  - Food
  - Fluids
  - Other Normal GI contents
- Presystemic Metabolism
  - Luminal Enzymes
  - Gut wall enzymes
  - Bacterial Enzymes
  - Hepatic Enzymes

Rahul Soman

Saturday, May 30, 2009

Tuesday, January 15, 2008