Download - Absorption of drug
TOPICS
DEFINITION
STRUCTURE OF GIT
MECHANISM OF TRANSPORT
FACTORS AFFECTING ABSORPTION
-PHYSIO-CHEMICAL FACTORS
DEFINIT ION
It is defined as the process of movement of unchanged drug from the site of administration to the systemic circulation.
There always present a correlation between plasma concentration of a drug & the therapeutic response & thus, absorption can also be defined as the process of movement of unchanged drug from the site of administration to the site of measurement. i.e., plasma.
M E C H A N I S M O F D R U G A B S O R P T I O N
1. Passive diffusion
2. Carrier- mediated transport:
a) .Active diffusion
b). Facilitated diffusion
3. Pore Transport
4. Ionic or Electrochemical diffusion
5. Ion-pair transport
6. Endocytosis
PASSIVE DIFFUSION
Characters common.
Occurs along concentration gradient. Non selective
Not saturable
Requires no energy
No carrier is needed
Depends on lipid solubility.
Depends on pka of drug - pH of medium.
Expressed by Fick’s first law of diffusion - “The drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained & the rate of diffusion is directly proportional to the concentration gradient across the membrane”.
dq/dt = D A Ko/w (Cgit – Cplm)/Vh
Sink condition
dQ/dt =P CGIT
Active Absorption
Relatively unusual.
Occurs against concentration gradient.
Requires carrier and energy.
Specific
Saturable.
Iron ,K , Na , Ca
Uptake of levodopa by brain.
FACILITATAED DIFFUSION
Occurs along the concentration gradient
Require carriers
Saturable
Stucture specific
No energy required
Mixed order kinetics
monosaccharides , amino acids , vitamins
PORE TRANSPORT
Also known as convective transport, bulk flow or filtration.
Important in the absorption of low mol. Wt. (less than 100). Low molecular size (smaller than the diameter of the pore) & generally water-soluble drugs e.g. urea, water & sugars
The driving force for the passage of the drugs is the hydrostatic or the osmotic pressure difference across the membrane.
Rate of absorption via pore Transport depends on the number & size of the pores, & given as follows:
dc = N. R2. A . ∆Cdt (η) (h)
where, dc = rate of the absorption.
dtN = number of poresR = radius of pores∆C = concentration gradientη = viscosity of fluid in the pores
IONIC OR ELECTROCHEMICAL DIFFUSION
Charge on membrane influences the permeation of drugs.
Molecular forms of solutes are unaffected by the membrane charge & permeate faster than ionic forms.
The permeation of anions & cations is also influenced by pH.
Once inside the membrane, the cations are attached to negatively charged intracellular membrane, thus giving rise to an electrical gradient.
If the same drug is moving from a higher to lower concentration, i.e., moving down the electrical gradient , the phenomenon is known as electrochemical diffusion
Thus, at a given pH, the rate of permeation may be as follows:
Unionized molecule > anions > cations
ION PAIR TRANSPORT It is another mechanism to explain the
absorption of such drugs which ionize at all pH condition.
Quaternary ammonium compounds, sulfonic acid
Although they have low o/w partition coefficient values, they will penetrate the membrane by forming reversible neutral complexes with endogenous ions. e.g. mucin of GIT.
Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion.
This phenomenon is known as ion-pair transport.
ENDOCYTOSIS
It involves 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 off intracellularly
Fats , starch , oil soluble vitamins
Insulin
Absorbed into lymphatic circulation –bypassing first pass hepatic metabolism
PINOCYTOSIS
This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients.
FACTORS AFFECTING DRUG ABSORPTION
PATIENT RELATED FACTORS
• PHYSIOLOGICAL FACTOR• CLINICAL FACTOR
PHARMACEUTICAL FACTORS
• Physico-chemical factors
• Formulation factors
PHYSICO -CHEMICAL FACTORS
Drug solubility and dissolution rate.
Particle size & effective surface area.
Polymorphism & amorphism.
Pseudopolymorphism
Salt form of the drug
Lipophilicity of the drug
pKa of the drug & Ph
Drug stability
DRUG SOLUBILITY & DISSOLUTION RATE
Rate determining process in the absorption of orally administered drugs are :-
1.rate of dissolution
2.rate of drug permeation through the biomembrane
Hydrophobic-RDS- Dissolution
Eg:- griseofulvin , spiranolactone
Hydrophilic-RDS-permeation rate limited
Eg: - cromolyn sodium or neomycin
PARTICLE SIZE &EFFECTIVE SURFACE AREA
Particle s size and surface area of a solid drugs are inversely related to each other
Smaller particle size-> greater surface area->rapid dissolution
Micronization –grater surface area-rapid dissolution
hydrophilic drugs-follows
Eg:-griseofulvin, spiranolactone
Hydrophobic drugs-micronization-decrease in effective surface area-fall in dissolution rate
Causes
Adsorption of air to surafce
Particle reaggregation
Surface charge
Eg:- aspirin , phenacetin
In that case add-surfactants –tween 80
hydrophilic diluents-PEG ,PVP
DEXTROSE
D) POLYMORPHISM AND AMORPHISM
POLYMORPHISM
When substance exists in different crystalline forms, it is polymorphism.
Plot of Cp Vs Time for three formulations of Chloramphenicol Palmitate
AMORPHISM
These drugs can exist with no internal crystal structure.
Such drug represents the highest energy state and can be considered as super cooled liquids and thus have greater solubility. E.g. Novobiocin.
Thus, the order of Dissolution & hence Absorption for different solid dosage forms is amorphous > meta-stable > stable.
F) SALT FORM OF THE DRUG
Salt of weak acid and weak bases have much higher aqueous solubility than the free acid or base.
Therefore, if the drug can be given as a salt, the solubility can be increased and the dissolution thus can be improved. Fig 1. It shows the dissolution
Profile of various salts
DRUG PKA, LIPOPHILICITY & G I PH
According to pH PARTITION THEORY, the process of absorption of drug compounds of molecular weight greater than 100 Daltons transported across the biomembrane by passive diffusion depend upon the following factor
Dissociation constant of the drug i.e., pKa of the drug
Lipid solubility of the unionized drug i.e., Ko/w
pH at the absorption site
The amount of drug that exist in unionized form is a function of dissociation constant(pKa) of the drug and pH of the fluid at the absorption site.
PREDICTION BASED ON THEORY
FOR WEAK ACIDS
1.very weak acids(pKa>8)– unionized at all ph—absorption is rapid—indipendantof GI ph
Eg:-phenytoin , ethosuximide
2.acids in the pKa range 2.5 to 7.5 largely affected by ph change—absorption ph dependant—better absorbed from acidic conditions of stomach (ph<pKa)where they largely exist in unionized form
Eg:-aspirin , ibuprofen
3.strong acids (pKa<2.5) ionized at entire ph range of GIT ---remain poorly absorbed
Eg:-cromolyn sodium
For basic drugs1.Very weak bases(pKa<5) unionized at all pH values ---absorption is rapid and pH indipendantEg:-diazepam , nitrazepam
2.Bases in pKa range 5 to 11 is pH dependant –better absorbed from the Relatively alkaline conditions of the intestine Eg:-chloroquine , imipramine
3. Strong bases (pKa>11) ionized at entire pH range –poorly absorbedEg:-mecamylamine guanethidine
1)pH-partition Hypothesis
Unionised
Drug:
Higher Absorption
Simplest principle:
Ionised Drug:
Low Absorption
High Absorption
• Weak Acid pKa>8 Pentobarbital & aspirin
• Weak Base pKa<5 (Theophylline, caffeine, codeine)
Low absorption
• Strong Acid(Disodium cromoglyate)
• Strong Base(Guanethidine)
LIPOPHILICITY
Only unionized drug having sufficient lipid solubility is absorbed into systemic circulation.
So drug should have sufficient aqueous solubility to dissolve in the fluids at the absorption site and lipid solubility high enough to facilitate the partitioning of the drug in lipoidal membrane and into systemic circulation.
DRUG STABILITY
Two major stability problems are
1.degradation of the drug into inactive form
2.interaction with one or more component either of the dosage form or those present in the GIT to form a complex that is poorly soluble
REFERENCES
Brahmankar D.M;Jaiswal Sunil.B; “Biopharmaceutics and Pharmacokinetics–A Treatise, second edition 2009.
A Mechanistic Approach to Understanding the Factors Affecting Drug Absorption: A Review of Fundamentals Marilyn N. Martinez, PhD, and Gordon L. Amidon
overview of factors affecting oral drug absorption BY Nai –Ning Song, Shao u zhang