ABSORPTION OF DRUGS SUBMITTED BY JASEEM.K 1ST YEAR M-PHARM
TOPICS DEFINITION STRUCTURE OF GIT MECHANISM OF TRANSPORT FACTORS AFFECTING ABSORPTION -PHYSIO-CHEMICAL FACTORS
DEFINITION 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 ECHANISM OF DRUG ABSORPTION1. Passive diffusion2. Carrier- mediated transport: a) .Active diffusion b). Facilitated diffusion3. Pore Transport4. Ionic or Electrochemical diffusion5. Ion-pair transport6. Endocytosis
PASSIVE D IFFUSIONCharacters 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)/VhSink 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
P ORE T RANSPORT 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 onthe number & size of the pores, & given as follows: dc = N. R2. A . ∆C dt (η) (h)where, dc = rate of the absorption. dt N = number of pores R = radius of pores ∆C = concentration gradient η = viscosity of fluid in the pores
I ONIC OR E LECTROCHEMICAL 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
I ON 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 requiredlipophilicity as well as aqueous solubility for passivediffusion.This phenomenon is known as ion-pair transport.
E NDOCYTOSIS 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 processA) PhagocytosisB) Pinocytosis
P INOCYTOSIS This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients.
FACTORS AFFECTING DRUG ABSORPTION • PHYSIOLOGICAL FACTORPATIENT RELATED FACTORS • CLINICAL FACTOR •Physico-chemical factorsPHARMACEUTICAL FACTORS •Formulation factors
P HYSICO - 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
D RUG SOLUBILITY &D ISSOLUTION RATE Rate determining process in the absorption of orally administered drugs are :- 1.rate of dissolution 2.rate of drug permeation through the biomembraneHydrophobic-RDS- Dissolution Eg:- griseofulvin , spiranolactoneHydrophilic-RDS-permeation rate limited Eg: - cromolyn sodium or neomycin
P ARTICLE SIZE & EFFECTIVESURFACE 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 AMORPHISMPOLYMORPHISMWhen substance exists indifferent crystallineforms, 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 DRUGSalt 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
D RUG P K A , 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 , nitrazepam2.Bases in pKa range 5 to 11 is pH dependant –betterabsorbed from theRelatively alkaline conditions of the intestineEg:-chloroquine , imipramine3. Strong bases (pKa>11) ionized at entire pH range –poorly absorbedEg:-mecamylamine 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.
D RUG 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