Absorption of drug

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  • Absorption of drug

    1. 1. ABSORPTION OF DRUGS SUBMITTED BY JASEEM.K 1ST YEAR M-PHARM
    2. 2. TOPICS DEFINITION STRUCTURE OF GIT MECHANISM OF TRANSPORT FACTORS AFFECTING ABSORPTION -PHYSIO-CHEMICAL FACTORS
    3. 3. 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.
    4. 4. STRUCTURE OF CELL MEMBRANE
    5. 5. 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
    6. 6. 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.
    7. 7. 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
    8. 8. Active Absorption  Relatively unusual.  Occurs against concentration gradient.  Requires carrier and energy.  Specific  Saturable.  Iron ,K , Na , Ca  Uptake of levodopa by brain.
    9. 9. PASSIVE AND ACTIVE TRANSPORT
    10. 10. FACILITATAED DIFFUSION Occurs along the concentration gradient Require carriers Saturable Stucture specific No energy required Mixed order kinetics monosaccharides , amino acids , vitamins
    11. 11. 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.
    12. 12. 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
    13. 13. 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.
    14. 14.  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
    15. 15. 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.
    16. 16. 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
    17. 17. In endocytosis, there are two processA) PhagocytosisB) Pinocytosis
    18. 18. P INOCYTOSIS This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients.
    19. 19. FACTORS AFFECTING DRUG ABSORPTION • PHYSIOLOGICAL FACTORPATIENT RELATED FACTORS • CLINICAL FACTOR •Physico-chemical factorsPHARMACEUTICAL FACTORS •Formulation factors
    20. 20. 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
    21. 21. 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
    22. 22. 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
    23. 23.  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
    24. 24. D) POLYMORPHISM AND AMORPHISMPOLYMORPHISMWhen substance exists indifferent crystallineforms, it is polymorphism. Plot of Cp Vs Time for three formulations of Chloramphenicol Palmitate
    25. 25. 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.
    26. 26. 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
    27. 27. 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.
    28. 28. FOR WEAK ACIDSFOR WEAK BASE
    29. 29. 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
    30. 30. 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
    31. 31. 1)pH-partition Hypothesis Simplest principle: Unionised Higher Drug: Absorption Ionised Low Drug: Absorption
    32. 32. • Weak Acid pKa>8 High Pentobarbital & aspirin • Weak Base pKa<5Absorption (Theophylline, caffeine, codeine) Low • Strong Acid(Disodium cromoglyate)absorption • Strong Base(Guanethidine)
    33. 33. 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.
    34. 34. 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
    35. 35. 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

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