PHARMACOKINETICS

1. PHARMACOKINETICS

2. WHAT THE BODY DOES TO THE DRUG

3. XENOBIOTIC • A compound to which the body is exposed that is foreign to the body. • Includes drugs, industrial and environmental chemicals

4. Pharmacodynamics – concentration – effect Graded response Quantal response • Pharmacokinetics – dose - concentration

5. Routes of drug administration

6. Routes of Administration

7. PHARMACOKINETICS • ABSORPTION • DISTRIBUTION • METABOLISM • EXCRETION

8. ABSORPTION • Describes the rate and extent to which a drug leaves its site of administration

9. Pharmacokinetics Absorption –the process by which the drug moves into the body from external source

10. Drug Absorption Orally Rectually(drug embedded in a suppository, which is placed in the rectum) Parenterally (given in liquid form by injection with a needle and syringe) Inhaled –thru the lungs as gases, as vapors, or as particulars carried in smoke or in an aerosol Absorbed through the skin Absorbed through mucous membranes (from snorting or sniffing the drug, with the drug depositing on the oral or nasal mucosa)

11. Drug Absorption -caveats Orally Drug must be soluble and stable in stomach fluid (not destroyed by gastric acids), enter the intestine, penetrate the lining of the stomach or intestine, and pass into the blood stream.

12. Drug Absorption -disadvantages • May occasionally lead to vomiting and stomach distress. • How much of the drug will be absorbed into the bloodstream cannot always be accurately predicted because of the genetic differences between people and because differences in the manufacture of the drugs. • The acid in the stomach destroys some drugs.

13. Drug Absorption -caveats Rectually Rarely used unless patient is vomiting, unconscious, or unable to swallow

14. Drug Absorption -disadvantages Rectually Often irregular, unpredictable, and incomplete Many drugs irritate the membranes that line the rectum.

15. Drug Absorption Parenterally Intravenous –directly into a vein Intramuscular –directly into muscle Subcutaneous –just under the skin

16. Drug Absorption Parenterally Often produces a more prompt response than does oral administration because absorption is faster. Permits a more accurate dose because the unpredictable processes of absorption are bypassed.

17. Drug Absorption -disadvantages Parenterally Leaves little time to respond to an unexpected drug reaction or accidental overdose. Requires the use of sterile techniques. Once a drug is administers by injection, it cannot be recalled. Drugs that cannot become completely soluble before injection, cannot be injected intravenuously.

18. Drug Absorption Inhaled Lung tissues have a large surface area with large blood flow, allowing for rapid absorption of drugs. Relatively quick route to the brain.* *May even have a faster onset of effect than drugs administered intravenously.

19. Drug Absorption Absorbed through the skin Provides continuous, controlled release of a drug from a reservoir through a semipermeable membrane. Potentially minimizes side effects associated with rapid rises and falls in plasma concentration of the drug contained in the patch.

20. CHARACTERISTICS OF A DRUG FAVORING ABSORPTION • Low molecular size • Nonpolar • Uncharged • High lipid solubility

22. MECHANISMS OF SOLUTE TRANSPORT ACROSS MEMBRANES • Passive diffusion • Facilitated diffusion • Active transport • Endocytosis

23. Passive Diffusion • Concentration gradient • Lipid-water partition coefficient • Area, Thickness and Permeability of the membrane • Ionic, pH, charge gradient*

24. Ionic Transport • pH gradient • Drug’s acid dissociation constant (pKa)

25. pKa – pH value at which one half of the drug is present in ionic form pKa = pH + log (HA) (A-)

26. Henderson-Hasselbalch equation • Calculates the ratio of non-ionized to ionized drug at each ph • pH = log [A-] + pka (Acid) [HA] or = log [B] + pKa (Base) [BH+] Ka = dissociation constant A = molar concentration of the acidic anion HA = molar concentration of the undissociated acid B = molar concentration of the basic anion HB = molar concentration of the undisscociated base

29. 1. Ionised drugs do not easily cross lipid barriers such as the gut, placenta and blood brain 2. Acidic drugs are well absorbed in the acidic medium of the stomach, basic drugs in the alkaline medium of the small bowel

30. Un-ionized Ionized Pharmacologic effect Active Inactive Solubility Lipids Water Cross lipid barriers Yes No (gastrointestinal tract, blood-brain barrier, placenta) Hepatic metabolism Yes No Renal excretion No Yes

31. Drugs and ionisation: Practise Acidic drugs (such as aspirin) will be ionised in an alkaline urine and thus cannot be reabsorbed across the renal tubular membrane (alkaline diuresis) pH trap (ion trapping) is significant for some drugs, especially local anaesthetics in labor

33. Factors Affecting GI Absorption • Gastric Emptying Time • Intestinal Motility • Food • Formulation Factors “First Pass Effect”

34. PK Definitions Cmax: Maximum concentration – may relate to some side effects 10000 AUC: Area under the curve (filled area) = overall drug exposure 3000 1000 Plasma Concentration Cmin: minimum or trough concentrations: may relate with efficacy of HIV drugs 100 0 2 4 6 8 10 12 Time Postdose (hr) http://www.thebody.com/content/art875.html

35. Drug Levels & Resistance

36. Quantity of drug in systemic circulation Quantity of drug administered BIOAVAILABILITY

37. Bioavailability

38. Bioavailability

39. Bioavailability

40. Measuring bioavailability I.v. dose Log Concentration Bioavailability = AUC I.v. AUC oral/ AUC i.v. Oral dose AUC oral time

41. Bioavailability (f) f = dose(IV) x AUC (PO)/dose(PO) x AUC (IV)

43. DISTRIBUTION Delivery of drug from systemic circulation to tissues

44. Pharmacokinetics Distribution –the drug is distributed throughout the body (including fetus)

45. Distribution • The movement of drug from the blood to and from the tissues

46. Drug Distribution 4 Body Membranes that Affect Drug Distribution 1. Cell membranes 2. Walls of the capillary vessels in the circulatory system 3. Brain-blood barrier 4. Placental barrier

47. Drug Distribution 1st Body Membrane that Affects Drug Distribution Cell membranes Permeable to small lipid (fatty) molecules

48. Drug Distribution 2nd Body Membrane that Affects Drug Distribution Walls of the capillary vessels in the circulatory system Does not depend on lipid solubility Only drugs that do not bind to plasma proteins pass through capillary pores.

49. Drug Distribution 3rd Body Membrane that Affects Drug Distribution Brain-blood barrier The rate of passage of a drug into the brain is determined by two factors: (1) the size of the drug molecule and (2) its lipid (fat) solubility.

50. Drug Distribution 4th Body Membrane that Affects Drug Distribution Placental barrier Oxygen and nutrients travel from the mother’s blood to that of the fetus, while carbon dioxide and other waste products travel from the blood of the fetus to the mother’s blood. Fat-soluble substances (including all psychoactive drugs) diffuse rapidly and without limitation.