Week 2 outline

1. Week 2 outline • Pharmacokinetics: • How drugs are handled by the body • Overview followed by details!!

4. Lets say you have a headache or a really really really bad reaction to poison ivy and you take some meds – This illustrates the basic processes in the branch of pharmacokinetics

5. pharmacokinetics....... • the route of administration - how a drug is taken into the body • absorption and distribution - factors affecting its absorption and how it gets distributed to the brain

6. 3. metabolism (detoxification or breakdown) how a drug is broken down or made into inactive forms 4. excretion – (elimination) • how the drug is eliminated

7. Knowing about pharmacokinetics tells us critical information about insight into the actions of a drug. Ex. benzodiazepenes ultra short acting, short acting, long acting

8. lorazepam (Ativan) and triazolam (Halcion) – pharmacokinetics • lorazepam – persists for at least 24 hr • triazolam – 6 – 8 hours • midazolam – 1 – 2 hrs

9. Drug Absorption • Absorption – the process by which a drug enters the bloodstream without being chemically altered or • The movement of a drug from its site of application into the blood

10. What are the routes of drug administration? • oral • injection • iv, im, sc, intrathecal, intraperitoneal

12. oral administration • most common, sometimes referred to as po • safe, self administered, economical BUT blood levels are often irregular (most complicated route of adm) • liquid more readily absorbed than solids

14. What are the qualities a drug needs to be absorbed orally? • soluble and stable in stomach (not destroyed by stomach enzymes more acidic) • enter intestine; penetrate lining of intestine, pass into bloodstream and reach site of action • absorption favored if the drug is nonionized and more lipophilic

15. What do orally administered drugs have to deal with? • chemicals in stomach must deal with: • stomach acids • digestive enzymes • first pass metabolism through liver • other items in stomach • ex. tetracycline

16. Advantages of oral administration • Convenient - can be self- administered, pain free, easy to take • Absorption - takes place along the whole length of the GI tract • Inexpensive - compared to most other parenteral routes

17. oral administration • disadvantages of oral administration: • vomiting/stomach distress • variability in dose • effect too slow for emergencies • unpleasant taste of some drugs • unable to use in unconscious patient • first pass metabolism

18. First-pass metabolism • First pass metabolism - term used for the hepatic metabolism of a drug when it is absorbed from the gut and delivered to the liver via the portal circulation. • The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally

19. first pass metabolism

20. oral administration • disadvantages of oral administration: • vomiting • stomach distress • variability in dose • first pass metabolism • ex. buspirone (BuSpar) – antianxiety drug • 5% reaches central circulation and is distributed to brain • metabolism can be blocked by drinking grapefruit juice (suppresses CYPp450 enzyme)

21. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression Hours J.Clin. Invest. 99:10, p.2545-53, 1997

22. Some additional interesting points regarding oral adm • Drugs that are destroyed by gastric juice or cause gastric irritation can be administered in a coating that prevents dissolution in acidic gastric contents (however may also preclude dissolution in intestines) • Controlled – Release Preps -

24. Factors that affect rate of absorption following PO route • GI motility- speed of gastric emptying affects rate of absorption • ex. migraine and analgesics vs metoclopramide • Malabsorptive States - • GI diseases, ex. Crohn’s disease can affect absorption

25. Factors that affect rate of absorption following PO route • Food - • iron, milk alters tetracycline • fats • first pass metabolism

26. Parenteral or Injection • chemicals delivered with a hypodermic needle; • most commonly - injected into vein, muscle or under the upper layers of skin, in rodents also intraperitoneal cavity • requirements for parenteral: • must be soluble in solution (so it can be injected)

27. B. Parenteral (Injection) • Intravenous • Intramuscular • Subcutaneous • Intracranial • Epidural • Intraperitoneal

29. Intramuscular • absorption more rapid than SC • less chance of irritation; • ways to speed up or slow down absorption • depot injections -

30. Intravenous • extremely rapid rate of absorption • adv: useful when you need rapid response or for irritating substances • Disadv: rapid rate of absorption

31. Absorption for parenteral route • contingent on blood flow SO • IV, intraperitoneal, IM, SC • increasing or decreasing blood flow affects drug absorption • Drugs leave bloodstream and are exchanged between blood capillaries and body tissues

32. What if a drug is injected in oil? • bolus or depot shots • related - drugs that accumulate in fat • ex. THC

33. Mucosal membranes • nasal, oral, buccal • medications include: nitroglycerine, fentanyl –(1998) , nicotine gum, lozenges, buprenorphine • cocaine – • snuff, cigars

34. Advantages and Disadvantages of Buccal • Advantages: • rapid absorption • avoid first-pass effect • Disadvantages: • inconvenient • small doses • unpleasant taste of some drugs

35. transdermal or transcutaneous • 1990’s – several medications incorporated into transdermal patches: • estrogen, nicotine, fentanyl, nitroglycerin, scopolamine • controlled slow release for extended periods of time

36. Rectal Administration • usually suppository form • for unconscious, vomiting or unable to swallow • disadv: not very well regulated dose; irritation (yikes)

37. Inhalation • not really used for psychotropics

38. Route for administration -Time until effect- • intravenous 30-60 seconds • inhalation 2-3 minutes • sublingual 3-5 minutes • intramuscular 10-20 minutes • subcutaneous 15-30 minutes • rectal 5-30 minutes • ingestion 30-90 minutes • transdermal (topical) variable (minutes to hours)

39. Drug Absorption • The rate at which a drug reaches it site of action depends on: • Absorption - involves the passage of the drug from its site of administration into the blood • Distribution - involves the delivery of the drug to the tissues

40. Drug Absorption • Factors which influence the rate of absorption • routes of administration • dosage forms • the physicochemical properties of the drug • protein binding • circulation at the site of absorption • concentration of the drug

41. Distribution • drugs are distributed throughout body by blood • very little at site of action at any one time • role of passive diffusion, concentration gradient

42. Absorption • Mostly a passive process - • from higher conc to lower (in blood)

43. Concentration Gradient Drug goes from higher concentration to lower concentration  [DRUG] receptors ≈ [DRUG] circulation

44. Absorption and Distribution • Mostly a passive process - • from higher conc to lower (in blood) • Binding to plasma proteins • results in a store of bound drug in plasma • examples - • 95-99% - chlorpromazine, diazepam, imipramine • 90 - 95% - valproate, propanolol, phenytoin

46. Factors that can play a role in reducing the amount of drug bound to proteins • Renal insufficiency • last trimester of pregnancy • drug interactions (other drugs that bind to proteins) • diseases

47. Additional issue for drugs to reach the CNS • Blood brain barrier- • layer of thickly packed epithelial cells and astrocytes that restrict access of many toxins/drugs to the brain

49. 3 Factors that affect how well a drug can cross the blood brain barrier (or placental barrier) • Lipid solubility – how soluble the drug is in fats • cell membranes are lipid bilayers • similar characteristics allow drugs to cross brain as to cross into cells

50. 3 Factors that affect how well a drug can cross the blood brain barrier • Lipid solubility • Size of molecule • Ionization – whether the degree has a charge (+ or -)