Absorption

1. Factors Affecting Rate and Extent of Absorption of A Drug Dr. Hidayat H. Khan

2. Absorption Passage of Drugs from site of Administration to the Systemic Circulation One of the Pharmacokinetic Processes

3. Rate of drug absorption- passage of the drug from its site of administration into the circulation

4. Factors Affecting Rate and Extent of Absorption • Drug Related Factors Physicochemical Properties of the Drug • Patient Related Factors

5. Drug Related Factors • Lipid Solubility • Degree of Ionization • Concentration of Drug • Physical State • Molecular Size

6. Dosage Form Particle Size Disintegration Time (Rate of breakup) Dissolution Rate (Rate at which it goes into solution Formulation

7. Patient Based Factors • Route of Administration • pH of the Absorbing Surface • Surface Area of Absorption • Thickness of Diffusing Path • Vascularity of Absorbing Surface

8. Absorption from GIT • Presence of Food • Presence of Other Drugs • GIT Motility • Metabolism • GIT Disease • P-Glycoproteins

9. Lipid Solubility or Lipid Aqueous Partition Coefficient • Measure of how readily a drug enters the lipid medium from an aqueous medium. • Flux = (C1-C2) x Area x Permeability Co-efficient Thickness

10. Degree of Ionization • The extent to which a drug becomes ionized depends on the pH of the Medium and the pKa of the drug • Acidic drugs remain mostly unionized in the acidic medium (stomach)

11. Basic drugs remain mostly unionized in the alkaline medium (intestine) • Some drugs remain highly ionized a) Negatively charged : Heparin b) Positively charged: Tubocurarine & Suxamethonium

12. Some drugs do not ionize & remain in unionized form-for example digoxin and chloramphenicol

13. Effect of pH on the absorption of weak acids and weak bases -many drugs are weak acids or weak bases HA H+ + A- for weak acids the protonated form is nonionized HB+ H+ + B for weak bases the unprotonated form is nonionized i.e. the red form goes across biomembranes

14. Thus : HA and B are unionized HB+ and A- are ionized

15. Dissociation Constant and pKa The Ka is the dissociation constant and pKa is the negative logarithm of the dissociation constant of the weak electrolyte.

16. pKa is a measure of the strength of interaction of a compound with a proton The less the interaction the lower the pKa • Since acids have tendency to donate proton and thus have less interaction, they have lower pKa • Thus lower the pKa the stronger the acid

17. Henderson Hasselbalch Equation pH = pKa + log unprotonated Protonated For Acid pH = pKa + log A- (Ionized) HA (Non-ionized) For Base pH = pKa + log B (Non-ionized) BH+ (Ionized)

18. Example • If pH = pKa • pH = pKa + log ionized un- ionized pH – pKa = log ionized un- ionized thus 0 = log ionized un- ionized

19. Log ( ?) = 0 • Log (1) = 0 • Thus Ionized =1 Unionized Thus 50% of drug is ionized and 50% is unionized

20. Thus pKa is numerically equal to the pH at which the drug is 50 % ionized AND 50% unionized • If an acidic drug of pKa 3.5 (aspirin) is put in the medium of pH 3.5, 50% of the drug would be in the ionized form.

21. If the pH is increased by 1 unit then, 4.5 = 3.5 + log A- HA OR 4.5-3.5 = log A-/HA OR log A- = 1 HA OR A- = 10 HA

22. If the pH is decreased by 1 unit then, • 2.5 = 3.5 +log A-/HA OR 2.5-3.5 = log A- HA OR log A- = -1 HA OR A- = 1/10 HA

23. It means that 1 unit change in pH causes a 10 fold change in ionization • If an acidic drug such as Aspirin is put in a medium of 2.5 , then 90% of the drug will be in the protonated or unionized form

25. From the Henderson Hasselbalch equation: When pH is less than pKa, the Protonated forms HA (unionized form) and BH+ (ionized form) dominate And when pH is greater than pKa, deprotonated forms A- (ionized) and B (un-ionized) dominate

26. We can also conclude that an acidic drug will be MORE unionized in an ACIDIC medium and thus better absorbed And basic drug will be ionized in an acidic medium and will be less absorbed Because When pH is less than pKa, the Protonated forms HA (unionized form) and HB+ (ionized) dominate

27. Ion Trapping • The unionized form of acidic drugs that cross the surface membrane of gastric mucosal cell reverts to ionized form within the cell (pH 7) and thus slowly passes on to the ECF • Thus it become trapped in the cell. • “A weak electrolyte crossing a membrane to encounter a pH from which it cannot escape easily” • Other sites: Breast milk, aqueous humor, prostatic and vaginal secretions

28. Application • Acidic drugs are ionized more in alkaline urine, • Therefore do not diffuse back into the kidney tubules and are excreted faster • So if some person has taken excess acidic drug, we can make the urine alkaline to INCREASE the excretion of the acid

29. Other Drug Related Factors • Physical State • Concentration of Drug • Molecular Size • Dosage Form Particle Size Disintegration Time (Rate of breakup) Dissolution Rate (Rate at which it goes in sol.) Formulation- Use of diluents

30. Patient Based Factors • Route of Administration • pH of the Absorbing Surface • Surface Area of Absorption • Thickness of Diffusing Path • Vascularity of Absorbing Surface

31. Question • Aspirin is weak organic acid with a pKa of 3.5. What % of a given dose will be in the lipid soluble form at a stomach pH of 2.5? • About 1% • About 10% • About 50% • About 90%

32. Question • For Which of the following drugs will excretion be most significantly accelerated by acidification of the urine? Suppose Urine pH can be modified over range 5.5-7.5 • A) Weak acid with pKa of 5.5 • B) Weak acid with pKa of 3.5 • C) Weak base with pKa of 7.5 • D) Weak base with pKa of 6.5

33. Absorption from GIT • Presence of Food • GIT Motility • Presence of Other Drugs • Metabolism • GIT Disease • P-Glycoproteins

34. Presence of Food • Generally most drugs are absorbed better on an empty stomach • Presence of food dilutes the drug and retards absorption • Food delays gastric emptying • Certain drugs form poorly absorbed complexes with food constituents e.g. tetracyclines with calcium in milk

35. GIT Motility (GIT Transit time) • Increased GIT motility as seen in diarrhea and by certain drugs decreases GIT transit time and thus decreases absorption • Delayed gastric emptying decreases absorption and vice versa

36. Presence of Other Drugs • Formation of insoluble complexes e.g. Tetracyclines with Iron preparations and antacids, • Vitamin C and iron • Some drugs may alter GIT motility • Some drugs may cause mucosal damage • Alteration of gut flora by antibiotics may disrupt the enterohepatic recycling of oral contraceptives and digoxin

37. Enterohepatic Recycling • A number of drugs form conjugates with glucoronic acid in the liver and are excreted in the bile • These glucoronides are too polar (ionised) to be reabsorbed • They remain in the GIT where they are hydrolysed by enzymes and GIT bacteria to release the parent drug which is then reabsorbed

38. Entrohepatic cycling-

39. Metabolism/Destruction Rapid degradation (metabolism) of the drug in the GIT decreases absorption Penicillin G is destroyed by acid Insulin by peptidases and thus ineffective orally Enteric coating of some drugs can prevent this

40. GIT disease • Malabsorption : Tropical sprue, Ulcerative Colitis • Diarrhea • Obstruction in GIT tract including Intestinal Obstruction

41. P Glycoproteins • P-glycoproteins are type of special carriers present in the membrane of many cells. They are less selective and are specialized for expelling foreign molecules, • P-glycoprotein modulates the intestinal drug transport and functions to expel drugs from the intestinal mucosa into the lumen.

42. Methods To Delay Absorption • Decreasing Blood Flow : Addition of Adrenaline to a local anaesthetic • Use of relatively insoluble slow release form e.g. procaine penicillin • Subcutaneous Implants absorption prop. to surface area of implant e.g. steroids estrogens

43. Importance of Study • Bioavailability • Frequency of Administration • Clinical Efficacy • Toxicity • Drug Interactions