Tuesday, January 15, 2008

Absorption of Drugs

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




  1. Passive diffusion




  2. Pore transport




  3. Facilitated Diffusion




  4. Active transport




  5. Ionic or electrochemical diffusion




  6. Ion-pair transport




  7. 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



  1. The drug moves down the concentration gradient indicating downhill
    transport

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

  3. 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'

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

  5. 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.

  6. 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 

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

  8. 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



  1. 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

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

  3. 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



  1. Phagocytosis (cell eating) : adsorptive uptake of solid particulate

  2. 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







 


 

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