OA Drugs

Question 1

Tylenol

Answer 1

• Acetaminophen
• Analgesics and antipyretic
• NO ANTIINFLAMMATORY
• MoA: Not sure!
• Absorption: well absorbed orally, peaks at 30-60 mins
• Metabolism: hepatic, half life 2-3 hours
• E: Urine

Question 2

Tylenol MoA Options

Answer 2

-Weak, non-selective COX inhibitor, blocks production of prostaglandins

OR

• Analgesia - activates serotonergic inhibitory pathways, nociceptive systems
• Antipyesis - inhibition of hypothalamic, heat-regulating center

Question 3

NSAIDs

Answer 3

• Analgesic, antipyretic, AND anti-inflammatory
• MoA: dose-dependent inhibition of COX-1 (low dose) and COX-2 (high dose) to reduce prostaglandin synthesis. Antiinflammatory effects result from inhibiting chemical mediators that drive neutrophil and macrophage influ
• Absorption: rapid oral administration
• Metabolism: hydrolyzed in liver to salicyclic acid, half life depends on drug (naproxen is longest)
• Excretion: Urine

Question 4

NSAID Comparisons

Answer 4

• Some evidence that NSAIDs are more effective

- NSAIDs equally effective to COX-2 inhibitors

Question 5

NSAID AE

Answer 5

• GI: nausea, pain, heartburn in 10-60%
• Serious complications: peptic ulcers, GI bleed, perforations, CV complications
• Increased risk in those with prior peptic ulcers, anticoagulant use, antiplatelet therapy, multiple NSAID use or combo with ASA
• Add Misoprostol or PPI to possibly reduce these risks

Question 6

Topical NSAIDs

Answer 6

• Recommended in those >75 yo
• Enhanced drug delivery to affected tissues
• Reduced incidence of systemic AE
• EX: Diclofenac (Cataflam) accumulates in synovial fluid, half life: 1-2 hours

Question 7

Topical Capsaicin

Answer 7

• MoA: activates TRPV1 ligand-gated cation channels to deplete substance P from neuron with repeated exposure to inhibit transmission of pain impulses
• Initial applications result in stinging and burning that subsides with continued use
• Max efficacy after 2-4 weeks
• Studies have shown pain reduction in knees and hands with OA when applied 4x daily

Question 8

COX-2 Selective Inhibitor

Answer 8

• CeleBREX (Celecoxib)
• Analgesic, antipyretic, anti-inflammatory
• MoA: inhibits prostaglandin synthesis by inhibiting COX-2
• Preferred over NSAIDs in those with history of GI bleed or peptic ulcer disease
• Is a sulfonamide - allergic reaction including rash/skin irritation may occur
• A: Oral absorption, peaks at ~3 hours
• M: hydrolyzed in liver by CYP2C9, half life ~11 hours (fluconazole can double its levels from inhibiting CYP2C9)

Question 9

COX-2 Inhibitor CI

Answer 9

• Renal insufficiency
• Coronary artery bypass graft surgery
• NSAIDs and COX-2 inhibitors may decrease effects of ACE inhibitors and some diuretics

Question 10

Glucosamine

Answer 10

• Prepared from shells or crabs and other crustaceans
• Substrate for production of articular cartilage
• Produces glycosaminoglycans
• Symptom improvement usually reported at 4-8 weeks compared with 2 weeks with NSAIDs
• 1500 mg/day compared with ibuprofen and piroxicam 20 mg/day was found effective in improving symptoms

Question 11

Chondroitin Sulfate

Answer 11

• Prepared from bovine or porcine cartilage sources
• Mucopolysaccharide used in synthesis of cartilage
• 1200 mg/day compared with diclofenac 150 mg/day as effective in decreasing pain over 3 months
• Responds later than NSAIDs

Question 12

Glucosamine + Chondroitin

Answer 12

• Used in GAIT trial
• Found to slightly reduce pain more than the agents alone, but not significantly (only 1-2%)
• AE were mild and evenly distributed between the combined and monotherapy agents

Question 13

Intra-articular Injection Options

Answer 13

• Corticosteroids
• Hyaluronic acid
• Increased bioavailability
• Reduced systemic exposure
• Fewer AE

Question 14

Corticosteroids

Answer 14

• Triamcinolone or methylprednisolone
• MoA: binds to GR and regulates glucocorticoid response element regulated genes which inhibits most inflammatory cytokines and pain receptors
• Short-term improvement of symptoms in knee (1-6 weeks)
• Some studies indicate injections every 3 months over 2 years to be safe
• Limit injections to 3-4x/year, more frequent could lead to cartilage damage
• Oral CS NOT recommended in OA

Question 15

Hyaluronic Acid

Answer 15

• MoA: Hyaluronate is believed to act as a viscosupplement following intra-articular injection, replacing or supplementing this endogenous ECM component
• Naturally accuring glycosaminoglycan
• Acts as a viscous lubricant
• Mixed clinical trails but may reduce NSAID need

Question 16

Ultram

Answer 16

• Tramadol
• Analgesic
• MoA: Binds to mu opiate receptors in CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain
• Also inhibits reuptake of NE and 5HT which are involved in descending inhibitory pain pathway responsible for pain relief
• A: rapid and almost complete absorption orally
• M: hepatic metabolism via demethylation by CYP3A4 and CYP 2D6
• E: Urine

Question 17

Tramadol Adjustments

Answer 17

• 7% have reduced CYP2D6 (poor metabolizers)
• Dose-adjustment needed with cirrhosis, renal insufficiency, >75 yo
• CI: MAO inhibitors, SSRIs, TCAs, other opioids (seizures and serotonin syndrome)

Question 18

Tramadol Mechanism of Toxicity

Answer 18

• Binds to opioid receptors in CNS and causes CNS depression
• Causes bradycardia, hypotension, and pupil constriction
• Opioid-induced respiratory depression occurs from inhibiting mu receptors in the medulla
• Serotonin syndrome is also a possibility

Question 19

Duloxetine

Answer 19

• Antidepressant
• MoA: 5HT/NE reuptake inhibitor
• A: well absorbed orally, peak ~ 6 hours, food decreases absorption
• M: hepatic metabolism via CYP1A2 and CYP2D6, half life ~12 hours
• E: Urine