Sports Medicine Pharmacology

1. ESSENTIAL Sports Medicine Pharmacology Andrew R. Morgan, MD, FACEP

2. How is education supposed to make me feel smarter? Besides, every time I learn something new, it pushes some old stuff out of my brain. Remember when I took that home winemaking course and I forgot how to drive? -Homer Simpson

3. Context • Specialists • Consequence of activity: • Acute Injury • Overuse • Pathophysiology • Inflammation • Pain • Pharmacology • Analgesics • Steroids

4. Objectives • Survey NSAID and steroid pharmacology to equip you with: • Conversant knowledge on these drugs expected of a specialist • Pearls for success on the CAQ • Influence your practice

5. Acute Inflammation

6. Question Following an injury, the activation of inflammatory cells, especially macrophages, results in upregulation of which COX enzyme isoform leading to an increase in prostaglandins and thromboxanes? (A) COX 1 (B) COX 2 (C) COX 3 (D) COX 4

7. Overview of Inflammation Injury (trauma, necrosis, infection) ProliferationFibroblasts connective tissue matrix  collagen   Maturation & Remodelling(Under ideal conditions  Healing) Clotting (fibrin & platelets)  hemostasis Microbes, foreign bodies, & debris phagocytized by local macrophages Vascular changes (5HT, histamine, LTs, PGs, C’, NO): - Vasodilation upstream - Vasoconstriction downstream - Increased endothelial permeability Bacteria, local phagocytes, injured tissues, platelets, & endothelial cells  inflammatory mediators Leukocytes, macrophages, PMNs (LT, C’): Arrive  activate  adhere to endothelium  extravasate  chemotaxis to injury site  immune response Fluid impinges nerves / PG / Substance P / Histamine / Bradykinin  PAIN Plasma influx  EDEMA, WARMTH, REDNESS IL, PG, TNF  systemic circulation  malaise, fever

8. Hallmarks of Inflammation Mechanism Mediator Clinical Sign hyperemia, vasodilatation Rubor PGs, NO Tumor extravasation histamine, C3a, C5a, bradykinin, LTs hyperemia, vasodilatation Calor PGs, NO PGs, bradykinin, Substance P Dolor PNS/CNS PGs, IL-1, IL-6, TNF-α CNS Fever Tissue Damage PMN’s, free radicals Multiple

9. Arachidonic Acid Metabolites and Inflammation

10. Overview of NSAIDs • Among most commonly prescribed medications • Pharmacologically distinct from steroids • Primary effects • Anti-inflammatory • Antipyretic • Analgesic • Multi-route: PO, IM, IV, AAA

11. Question All of the following are sub-classes of NSAIDs EXCEPT (A) acetic acids (B) formic acids (C) propionic acids (D) enolic acids (E) fenamic acids

12. NSAID Classes

14. NSAID Selectivity

16. Question Aspirin is unique among NSAIDs because it (A) Irreversibly inhibits its target enzyme (B) Reduces recurrence of crystalline arthritides (C) Reduces fever (D) Exclusively inhibits the COX-1 enzyme

17. NSAID Actions

18. NSAID Indications • Muscle strain and soreness • May ↓ pain and short-term recovery time • Long-term effect? • Tendinopathy • ↓ pain • Detrimental to healing overall? • Sprains • ↓ pain and may ↓ RTP interval • Fractures • Likely inhibits new bone growth

19. NSAID Side Effects • GI • Inhibits PGI2: protects gastric mucosa • COX-2: Lower risk but not NO risk • ACC/AHA/ACG Guidelines for GI prophy: • Age >65 • History of PUD • On NSAID therapy • Concurrent use of corticosteroid, or anti-coagulant • Risk impacted by dose and therapy duration • Why not PPI for everyone?

20. NSAID Side Effects • Cardiovascular • May increase risk of thromboembolic stroke (COX-2) • ENT • ASA causes polyps in hypersensitive patients • Renal • Inhibits PGE2: regulates renal blood flow • Acute interstitial nephritis

21. NSAIDs Side Effects • Hepatic • P450 metabolized—check interactions • Pulmonary • Shifts prostaglandin synthesis in favor of LT production → bronchospasm • Hematologic • Inhibits thromboxane A2 production, preventing platelet aggregation • ASA special case

22. NSAIDs Topicals Limited availability in US Fewer adverse systemic effects Decrease drug-drug interactions Effective analgesia in a variety of MSK conditions Journal club . . .

23. “Efficacy and Safety of Diclofenac 2.32% Gel in Acute Ankle Sprain” MSSE 44:9, September 2012. Adults Acute grade I-II ankle sprains RANDOMIZED DDEA 2.32% BID DDEA 2.32% TID PLACEBO Pain on Movement Pain at rest Ankle joint function Pressure pain threshold Swelling Assessment of benefit No difference between BID and TID dosing, both superior to placebo

25. Trolaminesalicylate Methyl salicylate

27. Sprix (ketoralac)

28. NSAID Pearls Good for analgesia in most clinical scenarios Consider PPI or H2 blocker in patients with risk factors Try different NSAID classes Lowest dose, shortest duration Give topicals a try Educate your patients on OTCs Just use acetaminophen

29. Other Analgesics Opioids Other opioidμ-agonist Acetaminophen

30. Opioids • μ,κ, δ-receptors • Chronic use/abuse up-regulates cAMP • Reversal agent: naloxone • Antagonist at all 3 types of receptor • Short half-life • Relative potency

31. Oxycodone 5 mg po = Hydrocodone 7.5 mg po = Morphine 2.5 mg IV

32. Non-Opioidμ-Agonist Ultram (Tramadol) μ-receptor agonist, blocks 5HT, norepi uptake Partially reversed by naloxone Drug-drug interactions: anti-depressants/anti-psychotics Adverse effects/toxicity: seizures Non-scheduled

33. Acetaminophen • Tylenol, paracetamol • Blocks COX-1, COX-2 AND COX-3 • Analgesic • Antipyretic • Max recommended dosages: • Adults 1 g/dose (4 g/day) • Children 15 mg/kg/dose • Antidote in toxicity?

34. Question Pharmacologic effects of exogenous glucocorticoids include (A) Increased muscle mass (B) Hypoglycemia (C) Inhibition of leukotriene synthesis (D) Improved wound healing (E) Increased excretion of salt and water

35. Steroids • Cholesterol containing compounds with widespread effects • Occur endogenously and produced synthetically • Androgens • Mineralocorticoids • Glucocorticoids • Delivery

36. Atrophy Hyperglycemia Osteoporosis Gastric ulcers Diuresis Hematologic Immunologic Neuro/psych Anti-inflammatory

37. Arachidonic Acid Metabolites and Inflammation

38. Steroids: MSK Indications • Temporary analgesic • No clear long-term benefit • Controversial Osteoarthritis Tendinopathy Bursitis Neuropathy Spinal cord injury

39. Steroids: Relative Potency

40. Steroid Pearls Steroids are not benign Steroid tapers are dogma Hydrocortisone 1 mg = Cortisol 1 mg Prednisone and Triamcinolone Topicals?

41. Final Test A 43-year-old female presents to your clinic for intermittent left knee pain for the past two years. Pain episodes last for about 5 days mainly with excessive physical activities such as climbing stairs 4 to 5 times a day. Currently she has no pain. Other than Acetaminophen which moderately relieves the pain, she has not tried any other treatment. Her past medical history is significant for diabetic nephropathy. Physical examination revealed an obese female with mild left knee posteromedial joint line tenderness. What would be the best management option for her at this point? (A) 10-day course of oral steroids (B) Referral for an MRI (C) Topical Diclofenac as needed (D) Oral Ibuprofen as needed (E) Intra-articular steroid injection

42. Final Review Motrin and Naproxen are what subclass of NSAID? What prescription strength topical NSAID is available in the US? What is the relative potency of triamcinolone compared to hydrocortisone? What risk factors make a patient susceptible to NSAID-related GI complications? In the synthesis of arachadonic acid and its metabolites, steroids primarily act at what enzyme? What is the best caption for picture?