Pharmacology

1. Pharmacology Introduction & Pharmacokinetic Principles Sean Burfeind, ATC, LAT, OTC

2. Objectives Define drug; differentiate between names Explain difference between generic name & drug Explain drug classification FDA role in development and recall Apply drug concepts Explain how drug chemical structure determines biological effects Primary mechanisms which drugs cross membranes, & metabolize Discuss drug excretion by kidneys

3. Drug • Chemical used to treat or prevent disease • Shown to be effective • All have a chemical name • Generic name is nonproprietary name • Proprietary name = brand name = trade name • How do we get a generic drug? • Differences between generic & trade name products

4. Differences Trade-Name Drug Generic-Name Drug Can have multiple trade names Names shorter & easier to pronounce Refers to entire product May include more than one active ingredient Only one generic name Refers to one chemical entity Less expensive Not all drugs marked as generic drugs Can be marketed by multiple companies Must obtain FDA approval Must be bioequivalent to trade name drug

5. Classification of Drugs • Nonprescription (OTC) • Lower amount of drug/dose unit compared with prescription • Contain multiple active ingredients • Prescription • Greater potential for adverse effects than OTC • Used for limited time period • Medical supervision mandated • Controlled (Schedule) • Abuse potential • More restrictive requirements regarding distribution, storage, and record keeping

6. Classification of Controlled Substances • Schedule I • High abuse potential; not accepted for medical use in US; may be used for research • Schedule II • High abuse potential; Accepted medical use in US • Schedule III • Lower abuse than II; Accepted medical use in US • Schedule IV • Lower abuse than III; accepted medical use • Schedule V • Lowest potential abuse; contain smaller quantities; some nonprescription in some states

7. FDA – New Drug Development • Responsible for review and approval of all new drugs before available to public • Demonstrate safety and effectiveness in clinical trials before use • Testing Procedures for new drug • Preclinical testing (3-6 years) • Phase I (1-2 years) • Phase II (2-3 years) • Phase III ( 3-4 years) • Phase IV (1.5-2.5 years)

8. FDA – Drug Recalls • Class I • Reasonable possibility that serious threat to health of consumer; need for additional labeling or color code on birth control error • Class II • Use of or exposure to produce may cause temporary health problem that is reversible; contamination in certain lots of medication • Class III • Use of or exposure to is not likely to cause health hazard; when certain batches of medicine have traces of iron; mislabel of drug packaging www.fda.gov

9. Drug Information Sources • Physician’s Desk Referene (PDR) • Chemical properties of drug; pharmacology and clinical data; precautions; adverse effects; indications/dosages; routes for administration • The Pharmacological Basis of Therapeutics • Goodman & Gilman • Drug Facts and Comparisons • US Pharmacopeia/National Formulary (USP/NF) • Standards for purity, strength, quality, and analysis of drug • USP on label if meets standards • Handbook of Nonprescription Drugs www.usada.org www.fda.gov/Drugs/default.htm www.ncaa.org/health-safety

10. Pharmacokinetics Study of impact of the body on a drug Primary focus on rate and extent to which the drug is absorbed into blood stream, distributed through body, metabolized and excreted Processes affect magnitude & duration of biological responses

11. Action • Site of Action • To have effect drug must reach site of action(molecular site where drug produces biological effect) • Usually receptor on or in cell or enzyme in cell • Onset of Action • Time it takes for drug to cause response • Minimum effective concentration • Duration of Action • Time between onset and termination • Half Life • Time for drug amount in blood to be reduced by ½ (%) Clearance rate: measure of efficiency of metabolism and excretion

12. Bioavailability & Bioequivalence • To be bioavailable, drug must reach blood • 2 components: amount of drug absorbed & rate of absorption • Diminished if: • First pass effect: • Bioequivalence – refers to comparison of amount and rate of drug entering circulation • Generic product

13. Chemical Structure • Determines chemical binding forces • Determines biological effects, rate of absorption, excretion and metabolism • Small changes have large biological effects • Determines size and chemical shape of each molecule • Solubility – determines how quickly drug dissolved in GI tract • Water vs. lipid

14. Absorption • Oral • Depends on rate of solubility; lipid solubility; stability with other GI contents • Must be in a solution • Once dissolved in intestinal tract must be passed to blood • Small intestines mostly; passive diffusion mostly • Liquid best • With food usually slows absorption; will reduce peak blood concentration • Good with NSAIDS • May delay intentionally for longer duration of effect

15. Administration & Absorption • Sublingual or Buccal • Under tongue or against cheek; rich blood supply facilitates absorption; potent drugs; protect from first pass • Rectal • Unconscious, vomiting, or too young; suppository; absorbed by hemorrhoidal veins; less absorption • Parenteral • IV, IM, subcutaneous; most rapid effect; need skill to administer • No absorption with IV – best for emergency • IM more rapid than subcu; drug must cross membrane in both

16. Administration & Absorption (cont) • Topical • Surface application for systemic or local effect • Rate of absorption depends on surface area and lipid solubility • If skin moist or blood flow increased permeability increased • Systemic effect = transdermal delivery • Inhalation • Need good technique • Fast onset

17. Pharmacology Drugs for Treating Inflammation

18. Objectives Describe and explain inflammatory process Explain how common chemical mediators affect inflammatory process Explain difference between COX1 & COX2 Explain how NSAIDS work Explain how corticosteroids work

19. Inflammatory Process • Normal and necessary process • If excessive may need to intervene • Chemical mediators released • Mast cells and basophils • Histamine • Serotonin • Thromboxanes* • Leukotrienes* • Prostaglandins* • Bradykinin

20. Arachidonic Acid Metabolites • COX pathway • TX, PG, and PGI2 • COX 1 • All tissues; relatively stable rate; maintain normal function of eicosanoid • COX 2 • Brain; female reproductive; blood vessel walls; kidneys • Induced in response to inflammation

21. NSAIDS Most frequently prescribed & OTC Aspirin is prototype Major mechanism to decrease PG production by inhibiting COX Little to no effect on LT pathway Selective COX2 NSAIDS Bextra; Vioxx

22. Therapeutic Use of NSAIDS • Tx both acute & chronic • 1-2 weeks typical • No guidelines to determine which is best for pathology • Principal use: pain & inflammation • Does the use of NSAIDS reduce healing time? • Analgesic & antipyretic • Fever = COX 2 response in brain

23. Therapeutic Uses of NSAIDS • If inhibit COX 1 = antiplatelet activity • Anticoauglant effect • COX 1 ----TXA2; stimulate platelet aggregation • COX 2 ----PGI2; inhibits platelet aggregation • Platelet aggregation – blood coagulation factors---thromboembolism --- MI • Low Dose Aspirin treatment • Increased risk of stroke/heart attack with selective COX 2 inhibitors

24. Dose/Pharmokinetics of NSAIDS Absorbed rapidly; oral preparations Enteric-coated – delayed absorption Liver metabolism to clear Pain 400mg 4x; inflammation 600mg 4x

25. Adverse Effects of NSAIDS • 16k die & > 100k hospitalized from use • Common sx • GI irritation, heartburn, nausea, upper GI bleeding, ulcers • Risk greater in >60 years • COX 2 selective lower incidence GI, but maybe not with Upper GI • New labeling on all NSAIDs (not aspirin) • Hypersensitivity • Renal toxicity

26. NSAIDS Drug Interactions Can enhance effect of anticoagulants Diminish effects of antihypertensive drugs Systemic corticosteroid or alcohol may cause peptic ulcers Need to monitor and educate patient

27. Corticosteroids • Adrenal cortex produces 2 types • Glucocorticoids (cortisol) • Glucose metabolism • Mineralocorticoids (alderstone) • Mineral balance, urinary reactions Na&K • Therapeutic use – potency of anti-inflammatory • Examples: hydrocortisone, dexamethasone, prednisone

28. Therapeutic Use of Corticosteroids • Suppress immune and acts as anti-inflammatory • Broader anti-inflammatory effect than NSAID • Inhibit activity of phospholipase • PG & LT • Reduce swelling & pain • Inhibit phagocytes & lymphocytes • Treat: RA, Gout, lupus, bronchial asthma, IBD, tendonitis, bursitis, ocular; allergy

29. Dose/Pharmokinetics of Corticosteroids Variable depending on disorder Initiate at low dose for as short as possible Trial and error – need to monitor Inhalation, topical, injection (local), oral (systemic)

30. Adverse Effects of Corticosteroids • Alters normal regulation of corticosteroid production • Adrenal cortex uses feedback loop based on amount in blood (HPA axis) • Need to be careful about taking off too quickly Hypothalamus CRH Anterior Pituitary ACTH Adrenal Gland Cortisol Inhibition Drug Interactions

31. Pharmacology Drugs for Treating PaiN

32. Objectives Explain how NSAIDS also have analgesic effect Explain pharmokinetics for acetaminophen & opioid drug Signs & symptoms for adverse reaction Identify common drug interactions Therapeutic advantages for different drugs Mechanics of actions Concept of agonist vs. antagonist Difference between drug addiction & physical dependence

33. Foundations • Terminology • Analgesic • Acetominophen • Opiates • Morphine, Codeine • Opioids • Oxycodone, Demerol • Narcotic analgesic • Narcotic

34. Nonsteroidal Anti-Inflammatory Drugs NSAID COX Inhibitor Inhibits PG Decreases Pain

35. Acetaminophen • Analgesic and antipyretic efficacy • Inhibits COX in brain not periphery • No blood clotting issues, GI • Peaks in blood ~ 1 hr post; t1/2 = 2hr • 325-1000mg; 4-6hr; adult – 24hrs<4000mg • Ceiling effect for analgesia (650-1300mg) • Allergic skin reaction; overdose common • 90% metabolized in liver, small amt toxic • >7.5g adult and 150mg/kg kids Careful with liver disease & Alcohol consumption

36. Opioid Analgesics • Combine with opioid receptors in CNS and PNS • 3 sites: mu(μ,MOR), kappa(κ,KOR), delta(δ,DOR) • Brain produces natural analgesics (endogenous opioids) • β-endorphins, enkephalins, dynorphins • Most clinically effective result from μ interaction • Addiction potential; schedule II mostly • Dependence potential

37. Opioid Analgesics • Withdrawal symptoms include • Duration & intensity depends on duration of action • Morphine • Relieve moderate to severe pain; anxiety & stress • Causes constipation & Sedative properties • Use to treat diarrhea

38. Opioid Analgesics • Other effects (adverse): respiratory depression, miosis, urinary retention, orthostatic hypotension, nausea, vomiting • Available by oral, rectal, or parenteral • Peaks 1.5 hrs post • Adult parenteral dose morphine = 10mg; oral = 20-60mg • Watch with CNS depressants Demerol Methadone Codeine Oxycodone Ultram

39. Caffeine Enhances analgesic properties Creates shorter onset & longer duration Stimulant drowsiness & fatigue alertness; 50-200mg Physical dependence; withdrawal symptoms

40. Local Anesthetics Topical preparations to alleviate pain Inhibit nerve impulse transmission Diminished hot, cold and touch Quick acting Can use parenterally Topically to treat pain or itching Lidocaine Ethyl Chloride Cocaine

41. Summary Defined drug; differentiate between names Explained difference between generic name & drug Primary mechanisms which drugs cross membranes, & metabolize Discussed drug excretion by kidneys Described and explained inflammatory process Explained difference between COX1 & COX2 Explained how NSAIDS work Explained how NSAIDS also have analgesic effect Explained pharmokinetics for acetaminophen & opioid drug

42. References Houglum JE, Harrelson GL. Principles of Pharmacology for Athletic Trainers. SLACK Incorporated; 2010. Golan DE, Tashjian AH, Armstrong EJ. Principles of Pharmacology, The Pathophysiologic Basis of Drug Therapy. Lippincott Williams & Wilkins; 2011. CicconeCD. Pharmacology in Rehabilitation. Philadelphia, PA. F.A. Davis Company; 2007. GladsonB. Pharmacology for Physical Therapists. St. Louis, MO: Saunders Elsevier; 2006. Harris Interactive, Inc. Attitudes and Beliefs About the Use of Over-the-Counter Medications: A Dose of Reality. KatzungBG, ed. 2009. Basic & Clinical Pharmacology. New York, NY. The McGraw-Hill Companies, Inc; 2009. Koester MC, Dunn WR, Kuhn JE, Spindler KP. The efficacy of subacromialcorticosteroid injection in the treatment of rotator cuff disease: A systematic review. J Am AcadOrthop Surg. 2007;15(1):3-11.

43. Questions?

44. Pharmacology Drugs for Treating Infections

45. Objectives Explain differences between infections caused by bacteria, fungi or virus Explain mechanism of action of or antimicrobial, antifungal, and antiviral meds Describe process that causes microorganism to become resistant to drug Superinfections resulting from antibiotics Role of antibiotics in UR & LR infections Differentiate between categories of antibiotics Discuss superficial vs. systemic fungal Role of ATC in care of patients on antibiotics

46. Terminology Antimicrobial…. Antibiotic…. Antibacterial… Fungal… Viral…

47. Antibiotic Categories • Chemical structure, mechanism of action • Bactericidal – kill bacteria • Bacteriostatic – slow growth • Spectrum (based on gram stain +/-) • Narrow • Broad

48. Antimicrobial Resistance • Microorganism response to drug • Sensitive vs. Resistant vs. Susceptible • Resistance promoted by overuse of antibiotics; diminish competition of resistant strains • Change in genetic makeup causes resistance • Enzyme inactivates drug • Altered structure of binding site • Altered entry mechanism

49. Superinfections Develop during treatment of initial infection When antibiotic kills normal flora in GI Mostly caused by broad spectrum antimicrobials & long duration treatment

50. Selection of Dose Regimen • Need to consider microorganism, site of infection, and patient • Effectiveness in fighting organism most important • Based on symptoms before lab results • Infection site might limit • Dose and duration depend on • Site of infection • Immune defense of patient