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Drug absorption

  1. 1. Pharmacokinetics Dr. Jahid MBBS, M.phil (Pharmacology) Head of Pharmacology (MD-AUCMS)
  2. 2. Learning objectives  Learning objectives        Drug absorption and clinical implications (1 hour) Drug transport processes Discuss factors affecting drug absorption Define and describe the following pharmacokinetic parameters: bioavailability (absolute and relative), area under the curve Define and describe bioequivalence studies Describe the principle of first-pass effect Explain the physicochemical factors influencing the absorption of drugs across biological membranes
  3. 3.  Pharmacokinetics:  It is a branch of pharmacology which deals withabsorption body distribution metabolism and excretion drug
  4. 4. Drug absorption
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  6. 6.
  7. 7. Drug absorption  It is the process of drug transport from site of administration to systemic circulation by crossing biological membrane.  Why drugs should be transported? In order to reach its receptor and produces biological functions.
  8. 8. ABSORPTION OCCURS FOR THE FOLLOWING DRUG ADMINISTRATION SITE 1. oral 1. sublingual (will avoid 1st pass metabolism, breakdown in stomach and liver) 2. transdermal (e.g. contraceptive) (very slow absorption) 3. rectal (use when patient is vomiting) 4. intramuscular injection 5. subcutaneous injection (Slow absorption) 6. miscellaneous - inhalation, intranasal, eye, nose, ear drops
  9. 9. Drug absorption  If oral……from Stomach & Intestine to portal circulation  If Per-rectal……from Rectum to systemic circulation  If Intramuscular…..from muscles to systemic circulation…  No absorption is needed if given Intravenously.
  10. 10. Drug absorption So, for absorption, drug needs crossing of the cell membrane.
  11. 11. Drug absorption
  12. 12. Drug absorption  Cell membrane consists ofLipid bilayer with Interspersed protein (islands of protein)
  13. 13. Drug absorption • Lipid layers are mostly “tight junction”  Only lipid soluble substances can diffuse through it…..  Water soluble substances can’t cross through tight lipid layer…..
  14. 14. Drug absorption
  15. 15. Drug transport processes  Passive Transport Simple diffusion (99%)  Almost  Specialized transport • Active transport • Facilited diffusion • Endocytosis • Exocytosis all drugs are absorbed by simple diffusion with exception of a few.
  16. 16. Drug transport processes  Simple diffusion Movement of solute from high to low conc.  No carrier protein  No energy required.  Almost all drug follow this Process.
  17. 17. Drug transport processes  Simple diffusion occur by Here the ink is spreading by moving to lower ink solute concentration.  Eventually all the water will be evenly colored.
  18. 18. Practice: 1. Release of Adrenaline into synapse 2. Responsible for absorption of glucose from intestine 3. This process don’t require energy and carrier protein. 4. Vitamin B12 absorbed by this process.
  19. 19. Drug absorption Simple diffusion occurs in Passive aqueous diffusion Through aqueous channel For small molecules (150-200 MW)  Passive lipid diffusion  Only lipid soluble drugs can cross by this process.
  20. 20. Passive acqueous diffusion by-  Fick’s Law:  Rate = (C1 - C2) x (A x Permeability Coefficient) T  So this equation quantify Moves from high to low conc. C1: higher concentration area. C2: lower concentration.  Drug absorption is faster from organ with large surface area. A: diffusion surface area.  Moreover drug absorption PC: Permeability Coefficient better from organ with thin T: Thickness of the membrane membrane barrier (Lungs)
  21. 21. Lipid Diffusion • In the case of weak acids and weak bases the ability to move from aqueous to lipid or vice versa varies with the pH of the medium. • Henderson-Hasselbalch equation (can be use to predict the effect of pH change on ABSORPTION): Acid: pH = pKa + log [A-]/[HA] Base: pH = pKa + log [B]/ [HB+]
  22. 22. Drug absorption  Factors influencing drug absorption (Drug factors) or Physiochemical factors:  Lipid solubility of drug  Nature of the drug  pH of the media (Stomach & Intestine)  pKa of the drug  Molecular size of drug  Disintegration & dissolution of drug
  23. 23. Lipid solubility of drug  Drugs which are lipophilic easily cross membrane  Drugs which are lipophobic/hydrophilic have problem crossing membrane  This is a major source of variation in drug diffusion or absorption.
  24. 24. DEGREE OF IONIZATION (POLARITY)  Only a non-ionized (non polar) drugs diffuses across the membrane, hence this is an important factor .  Non polar drugs are lipid soluble.  Polar drugs are water soluble, they can’t absorb from biological membrane.
  25. 25. DEGREE OF IONIZATION (POLARITY)  Lipid soluble = Non-ionized molecules (NaCl)  Hydrophilic = Ionized molecules. (Na+, Cl- ). So, The more Lipid Soluble of drug------more absorption The more Water Soluble of drug-----less absorption
  26. 26. Drug absorption MEMBRANE Ionized Molecule (water soluble) CELL Non-Ionized Molecule (lipid soluble)
  27. 27. Effect of pH on Drug Absorption  Acidic drug better absorbed in acidic media.  Basic drug better absorbed in basic media. Acidic drugs (Aspirin) are better absorbed in stomach (in acidic media) and Basic drugs (Diazepum) are better absorbed in intestine (in alkaline media)
  28. 28. Continue………. Acidic drug better excreted in basic media. Basic drug better excreted in acidic media  Incase of acidic drug poisoning alkalization done to promote excretion of that drug. and  Incase of basic drug poisoning acidification done to promote excretion of that drug.
  29. 29. A. Diffusion of non-ionized form of a weak acid through lipid membrane
  30. 30. Continue………. B. Diffusion of non-ionized form of a weak base through lipid membrane.
  31. 31. Importance of environment pH & drug pKa  Degree of ionization (polarity) depends on the pKa of drug (and pH of body fluid).  pKa: value of drug pH when the concentration of ionized and non-ionized drug form is equal.  If pKa of a drug is equal to pH of the media, then… “50% of the drug are ionized & 50% are non-ionized”
  32. 32. Acidic Drug Acidic drugs – more NON ionized in acidic pH N pH 2 I N I pH 6 N I pH 8 What’s the pKa for this drug? = Non ionized molecules = Ionized molecules I pH 9
  33. 33. TRY THIS OUT Let’s consider the influence of pH on absorption of a weak acid (pKa = 3.4) between gastric juice (pH1.4) and plasma (pH7.4). The mucosa can be considered a simple lipid barrier.
  34. 34. Where Drug absorption more drug??? Acid: pH = pKa + log [A-]/[HA] Log [A-]/[HA] = (pH – pKa) [A-]/[HA] = 10 (pH –pKa) In plasma: [A-]/[HA] = 10 (7.4-3.4) = 104 =10,000 In gastric juice: [A-]/[HA] = 10 (1.4-3.4) = 10-2 = 0.01
  35. 35. MOLECULAR Drug absorption WEIGHT  Molecular weight: this is relatively constant for most drugs because molecular weights usually vary between about 100 and 500. Molecular size: The smaller in size-----more absorption
  36. 36. Drug absorption Disintegration & dissolution of drug Drug orally given GIT Disintegration (to form granules ) into small molecules Dissolution into the aqueous media Absorption
  37. 37. Drug absorption  Host factors or Biological factors)  Surface area  Motility of GIT  Presence of food (Drug binding)  Blood supply at the absorptive area  Destruction of drug in GIT
  38. 38. Drug absorption Surface area The more absorptive surface area, the more absorption Surface area of intestine is far greater than the SA of stomach, so more drug absorption takes place in Intestine Relative SA: Stomach 0.1 - 0.2 Small Intestine 100
  39. 39. Drug absorption Motility of GIT - Drugs are better absorbed in normal GIT movement Blood supply at the absorptive area - The more circulation - the more maintenance of concentration gradient - The more absorption
  40. 40. DRUG BINDING  Binding on Food  Increased hydrochlorothiazide, propranolol  Reduced Ampicillin, isoniazid, rifampicin, erythromycin, thyroxine Binding with other drug or compounds Tetracycline with Ca2+ Chloroquine with retina
  41. 41. Drug absorption  Destruction of drug in GIT In GIT, there are gastric HCl, enzymes etc. So, drugs may be destroyed in GIT before absorption Example: Benzyl penicillin is destroyed by gastric HCL Insulin is destroyed by proteolytic enzymes
  42. 42. Drug Bio-availability Bio: Blood ( Systemic circulation) Availability : How much available?
  43. 43. Drug absorption Simply….  Bioavailability is the percentage of administered drug available in the systemic circulation in respect of route of administration. If 100 mg of drug A is administered orally & 60 mg reaches in systemic circulationthen the oral bioavailability of drug A is 60%
  44. 44. Drug absorption Measurement of AUC
  45. 45. Drug absorption  Factors influencing oral bioavailability of drug:  Any route other than iv route  Incomplete absorption of drug Destruction of drug in GIT  1st pass hepatic metabolism Distribution of drug to other tissue.
  46. 46. Drug absorption  Formula for bioavailability of drug:  The systemic bioavailability of the drug F= f- (1-ER)  Here: f = extent of absorption Extraction Ratio (ER)= CLliver / Q Q=where Q is hepatic blood flow, normally about 90 L/h.
  47. 47.   Bioequivalence (BE): Definition Two preparations of a drugs are consider Bioequivalence when- there is absence of a significant difference in the rate and extent of bioavailability at the same molar dose under similar conditions in an appropriately designed study    Importances: Oral formulation of a drug from different company Or different batches from same company may contain same amount of drugs.
  48. 48. mL) Concentration (ng/ 90 80 70 60 Test/G eneric 50 Reference/B rand 40 30 20 10 0 0 5 10 15 Time (hours) 20 25 30
  49. 49. 1st pass hepatic metabolism  After oral administration….. Absorption from GIT Portal circulation Liver Systemic circulation
  50. 50. 1st pass hepatic metabolism Metabolism of drugs after absorption in the liver while passing through it before reaching systemic circulation…. This is known as 1st pass hepatic metabolism.
  51. 51. 1st pass hepatic metabolism Usually most drugs undergo to some extent of 1st pass hepatic metabolism  But if this 1st pass hepatic metabolism happens extensively for any drug, then the effect of that drug is not found by oral administration Example : Nitroglycerine (GTN)

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