General pharmacology

1. General pharmacology (Pharmacokinetics; drug administration and absorption, distribution and biovailbility Revision) Dr.IshfaqBukhari Pharmacology Department

2. What is Pharmacology? • From the Greek pharmakon (drug), and legein (to speak or discuss) • Broadly defined as the study of how chemical agents affect living processes. • e.g Hormones, Neurotransmitters and drugs

3. Some Pharmacology Definitions and Areas of Study • Pharmacokinetics • Study the fate of drugs once ingested. It covers , How the body absorbs, distributes, • metabolizes, and excretes drugs (what the body does to a drug?) • Pharmacodynamics • Study the mechanisms by which drugs work ,Also study endogenous agents (what the drug does to the body?)

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

5. Routes of drug administration

6. Routes of drug administration

7. Oral administration

8. 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.

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).

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

12. Small intestine • The small intestine, with its large surface area and high blood perfusion rate, has a greater capacity for absorption than the stomach. • Conditions that shorten intestinal transit time (e.g., diarrhea) decrease intestinal drug absorption and vice versa

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

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

15. Sublingual

16. Rectal administration

17. 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)

19. Intravenous administration

21. 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

22. Inhalation

23. Nebulizer Atomizer

24. 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)

25. 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.

26. 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

27. 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).

29. 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.

31. Simple diffusion Low conc High conc

32. 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.

33. 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 medium, on the contrary basic are more lipid soluble and more diffusible in a relatively alkaline medium

34. 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)

35. 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.

36. 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

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

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

43. Mechanisms of drug absorption

44. Factors modifying drug absorption • GENERAL FACTORS • lipid solubility • Degree of ionization • Drug solubility (aqueous sol better than oily,susp,sol) • Dosage forms (depending on particle size and disintegration) • Concentration of drugs • Circulation at site of absorption • Area of absorbing surface (small intestine has large surface area) • Route of administration.

45. Bioavailability • Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action • I.V. provides 100% bioavailability. • Oral usually has less than I.V.

46. By the end of the lectures, students should be able to define the following: • Major body fluid compartments • Concept of compartments. • Apparent volume of distribution (vd). • Plasma protein binding. • Tissue binding.

47. Bioavailability • Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action (therapeutic effect) • Bioavailability (F) = AUC (oral) X 100 AUC (I.V.)

48. Bioavailability • I.V. provides 100% bioavailability i.e. F= 1. • Subcutaneous, intramuscular, oral, rectal, and other extra vascular routes of administration require that the drug be absorbed first, which can reduce bioavailability.

50. Absolute bioavailability • The bioavailability of a drug after administration by any route is compared to its intravenous standard formulation.