ABSORPTION OF

DRUGS

SUBMITTED BY

JASEEM.K

1ST YEAR M-PHARM

APSC , PARIYARAM

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.

STRUCTURE OF CELL MEMBRANE

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.

PASSIVE AND ACTIVE TRANSPORT

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

In endocytosis, there are two process

A) Phagocytosis

B) Pinocytosis

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.

FOR WEAK ACIDS

FOR WEAK BASE

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