General pharmacology ( Pharmacokinetics; drug and administration and absorption)

1. General pharmacology (Pharmacokinetics; drug and administration and absorption) Prof. Hanan Hagar Dr.IshfaqBukhari Pharmacology Department

2. Pharmacokinetics (Drug absorption) The student should be able to • Discuss the different routes of drug administration • Identify the advantages and disadvantages of various routes of drug administration • Know the various mechanisms of drug absorption • List different factors affecting drug absorption • Define bioavailability

3. Recommended books • Lippincott’s illustrated reviews (Pharmacology) by Howland and Mycek • Basic and Clinical Pharmacology by by Katzung

4. PHARMACOKINETICS: • Pharmacokinetics:It is the study of what the body does to the drug i.e ADME • ABSORPTION • DISTRIBUTION • METABOLISM • EXCRETION of the drug Note: Pharmacodynamic is what the drug does to our body

5. Routes of drug administration • Enteral via gastrointestinal tract (GIT)( Oral and Rectal ) • Sublingual • Parenteral administration = injections. • Topical application • Inhalation

6. Oral administration

7. Factors affecting absorption from GIT • GIT motility changed by drug / diseases • Presence of food • Blood flow/surface area • GIT juices • pH of GIT fluids • Chemical/drug interactions • dosage form of a drug Most of the drug is absorbed with in 1-3 hours,mostly it occurs in small intestine ,rate of absorption depends on lipid solubility ,ionization and pH.

8. Factors affecting absorption from GIT • Drugs administered in aqueous solution are absorbed faster & completely than tablet or suspension forms. • Drugs such as the tetracyclines, which are highly ionized, can complex with Ca++ ions in membranes, food, or milk, leading to a reduction in their rate of absorption. • Factors that accelerate gastric emptying time, permitting drugs to reach the large absorptive surface of the small intestine sooner, will increase drug absorption unless the drug is slow to dissolve.

9. First pass Metabolism Metabolism of drug in the gut wall or portal circulation before reaching systemic circulation • So the amount reaching system circulation is less than the amount absorbed Where ? • Liver • Gut wall • Gut Lumen Results ? Low bioavailability. Short duration of action of drugs (t ½).

10. First pass Metabolism

12. First pass effect

13. Stomach pH • The low pH of the gastric contents (pH 1–2) may influence absorption of drugs because it can affect the degree of drug ionization. e.g, the weak base diazepam (pKa 3.3) will be highly Ioninized in the gastric juice, and absorption will be slow. • weak acid drug, acetaminophen (pKa 9.5) will exist mainly in its unionized form and can more readily diffuse from the stomach into the systemic circulation.

14. Small intestine • The small intestine, with its large surface area and high blood perfusion rate, has a greater capacity for absorption than does the stomach. • Conditions that shorten intestinal transit time (e.g., diarrhea) decrease intestinal drug absorption, while increases in transit time will enhance absorption by permitting drugs to remain in contact with the intestinal mucosa longer.

15. Oral Dosage Forms (oral formulations) • Tablets (enteric coated tablets) • Capsules (hard and soft gelatin capsules) • Syrup • Suspension • Emulsion

16. Spansule Tablets Soft- gelatin capsule Hard- gelatin capsule

17. Sublingual

18. Rectal administration

19. Parenteral administration Intradermal (I.D.) (into skin) Subcutaneous (S.C.) (under skin) Intramuscular (I.M.) (into muscles) Intravenous (I.V.) (into veins) Intra-arterial (I.A.) (into arteries) Intrathecal (I.T.) (cerebrospinal fluids ) Intraperitoneal (I.P.) (peritoneal cavity) Intra - articular (Synovial fluids)

21. Intravenous administration

22. Single use Repeated use Ampoule Vial

24. Topical application • Drugs are mainly applied topically to produce local effects. They are applied to • Skin (percutaneous) e.g. allergy test, topical antibacterial and steroids prep and local anesthesia • Mucous membrane of respiratory tract (Inhalation) e.g. asthma • Eye drops e.g. conjunctivitis • Ear drops e.g. otitis externa • Intranasal, e.g. decongestant nasal spray

25. Inhalation

26. Nebulizer Atomizer

27. Transdermal patch a medicated adhesive patch applied to skin to provide systemic effect (prolonged drug action) e.g. the nicotine patches (quit smoking) Scopolamine (vestibular depressant)

28. Drug absorption Is the passage of drug from its site of administration to its site of action through various cell membranes. • Except for intravenous administration, all routes of drug administration require that the drug be transported from the site of administration into the systemic circulation.

29. Drug absorption Is the passage of drug from its site of administration to its site of action through cell membranes. Cell membrane Sites of Administration Sites of action

30. Absorption & distribution Elimination Sites of Administration

31. Mechanisms of drug absorption • The transport of drugs across membranes occurs through one or more of the following processes: • Simple diffusion = passive diffusion. • Active transport. • Facilitated diffusion. • Pinocytosis (Endocytosis).

32. Cell membrane

34. Simple or passive diffusion • water soluble drug(ionized or polar) is readily absorbed via diffusion through aqueous channels or pores in cell membrane. • Lipid soluble drug(nonionized or non polar) is readily absorbed via diffusion through lipid cell membrane itself.

35. Simple diffusion

36. Simple diffusion Low conc High conc

37. Simple 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.

38. Simple diffusion Drugs exist in two forms ionized (water soluble) nonionized forms (lipid soluble) in equilibrium. Drug ionized form + nonionized form • Only nonionized form is absorbable. • Nonionized / ionized fraction is determined by pH and pKa As general basic drugs are more ionized and less diffusible in a relatively acidic(less than the pka) medium, on the contrary basic are more lipid soluble and more diffusible in a relatively alkaline medium

39. PKa of the drug (Dissociation or ionization constant): pH at which half of the substance is ionized & half is unionized. • The lower the pKa value (pKa < 6) of the acidic drug the stronger the acid e.g aspirin (Pka= 3.0 ), • The higher the pKa value (pKa >8) of a basic drug, the stronger the base e.g propranolol ( pKa= 9.4)

40. PKa of the drug (Dissociation or ionization constant): pH at which half of the substance is ionized & half is unionized. pH of the medium Affects ionization of drugs. • Weak acids  best absorbed in stomach. • Weak bases  best absorbed in intestine.

42. Which one of the following drugs will be best absorbed in stomach (pH=3)? Aspirin pka=3.0 warfarin pka=5.0 Arrange the following drugs in ascending order from least to greatest in rate of absorption in small intestine (pH=7.8)? Propranolol pka= 9.4 Aspirin pka=3.0 warfarin pka=5.0

43. Active Transport • Relatively unusual. • Occurs against concentration gradient. • Requires carrier and energy. • Specific • Saturable. • eg. • Sugar, amino acids and Iron absorption. • Uptake of levodopa by brain.

45. Carrier-mediated Facilitated Diffusion • Occurs along concentration gradient. • Requires carriers • Selective. • Saturable. • No energy is required.

49. Phagocytosis (Endocytosis & Exocytosis) Endocytosis: uptake of membrane-bound particles. Exocytosis: expulsion of membrane-bound particles. Phagocytosis occurs for high molecular weight Drugs or highly lipid insoluble drugs.

50. (Exocytosis) (Endocytosis) OUT IN IN OUT