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VMED 5223 NSAIDs EXAM WITH 1 00 % VERIFIED SOLUTIONS!!
Non-steroidal anti-inflammatory drugs (NSAIDs) What drugs are: Non-narcotic and provide the following activities: vAnalgesic vAnti-inflammatory vAnti-pyretic
Based on a specific enzyme and eicosanoid metabolites affected How are NSAIDs classified?
Pain & inflammation from osteoarthritis, surgery and trauma Why do we use NSAIDs?
- No sedation
- More rapid recovery after anesthesia
- Where greater analgesia is required, can be combined with other analgesics (opioid) - Combination dosing: Requires smaller dose of the narcotic agent.
Advantages of NSAIDs over other narcotic analgesics?
Prostaglandins & leukotrienes What inflammatory compounds cause hyperalgesia = pain response to stimuli that do not normally induce pain (In other words, lowers the pain threshold)?
nociceptive Prostaglandins and leukotrienes help magnify ________________ transmission to the spinal cord and act a local mediators of inflammation
- COX-1/COX-2 (nonselective) NSAIDs
- COX-2 Selective NSAIDs
- Lipoxygenase (LOX) NSAIDs Pathway where arachidonic acid is freed from cell membranes - Types of NSAIDs that affect these enzymes?
- Initially, membrane damage signals an increase in phospholipase A2 (PLA2) activity.
- PLA2 cleaves arachidonic acid from the damaged membrane.
- COX catalyzes first two steps in conversion of arachidonic acid to PGH2.
- PGH2 is then converted to the individual prostaglandin/thromboxane metabolites by other enzymes.
- Oddly, COX1 and COX2 activities produce differing metabolites = enzyme localization.
Describe the cyclooxygenase pathway?
COX-2, COX-
Binding pocket in COX-2 enzyme is wider - Substitution of a Valine for an Isoleucine in COX-1 creates a change in protein confirmation to make the binding pocket more narrow.
COX-_____inhibitors act by blocking the binding pocket
◦Exception: Aspirin acetylates the binding pocket = irreversible inhibition
larger COX-2 inhibitors are structurally __________ than nonselective inhibitors
narrow Nonselective COX inhibitors are conformationally more __________
- Naproxen
- Carprofen, S more active
- Ketoprofen, S more active
**For some NSAIDs, R enantiomer has some activity. What are NSAIDs of the 2-proprionic acid class (which enantiomer has more activity, usually sold in racemic mixtures)?
greater Common misconception: COX-2 inhibitors exhibit ___________ inhibition of COX-2 = Actually, they inhibit COX-2 at high levels while either not inhibiting COX-1 or inhibiting COX-1 at low levels.
EC50 COX-
EC50 COX-
Large number
Small number
Greater COX-
selectivity
How does increasing the IC50 ratio of COX-1/COX-2 impact the COX-2 selectivity?***
Not memorization = just know how to compare
- Peak analgesia occurs at 80% COX-2 inhibition
- GI side effects occurs at 10-20% COX-1 inhibition
Other considerations:
A selective inhibitor, preferential for COX-
- Would you not have GI ulcers? = You would think so but data has come out that ucleration still occurred Based on this curve, how would you describe the selectivity of firocoxib?
Clotting issues = so far except for unusal circumstances, don't develop
- May be contraindications in heart patients What complication of NSAID use in humans is still uncer investigation in dogs/cats?
GI, renal and hepatic toxicities
- Varies with non-selective/selective classification What side effect profiles are of most concern with NSAIDs?
- Enzyme specificity
- Pharmacokinetics -Metabolism Species/breed variant factors that can impact safety considerations with NSAID use?
- Cats are deficient in the liver enzyme glucuronyl transferase
- Many NSAIDs are metabolized through glucuronidation, albeit to differing degrees.
- Glucuronidation is a major route of elimination for acetaminophen and aspirin.
- More toxic metabolites are made instead due to lack of glucuronide
What are some NSAIDs like asprin and acetaminophen harmful to cats?
NSAID recommendations in cats NSAID recommendations in cats
- Co-administration of corticosteroids
- Dehydration
- Hypovolemic shock
- Disruption of normal blood flow in gut What factors can precipitate gastric ulceration from NSAID use?
- Reduced renal blood flow due to prostaglandin inhibition leads to reduced filtration.
- Significant renal toxicity can occur if the animal is volume depleted, sodium depleted or for systemic hypotension.
- In cases of shock, production of PGI2 is stimulated by vasoconstrictive substances = Blocking prostaglandins at this point could result in renal failure.
- NSAIDs should not be administered in a patient with shock.
What are mechanisms through which NSAIDs can cause renal toxicity?
◦Uncommon in dogs receiving NSAIDs.
Carprofen What NSAID:
◦ COX-2 selective inhibitor, but effects may be due to PLA2 inhibition also (2 hit mechanism)***
◦ Acute and chronic pain
◦ Osteoarthritis
◦ Perioperative analgesia
- Comparable to opioids in dogs and cats
- May be longer lasting than some drugs.
Administered every 12 or 24h in dogs. Single dose but not repeated dosing in cats.
- Labs may exhibit idiosyncratic hepatotoxicity.
- Extended half-life in cats makes chronic administration problematic. Dosing carprofen in dogs v.s. cats?
Meloxicam What NSAID:
◦ Preferential COX-2 inhibitor.
◦ Soft-tissue or musculoskeletal pain, including osteoarthritis in dogs. ◦ Perioperative pain for orthopedic or soft tissue surgeries.
◦ Can use for short term (1 day) treatment of cats.
◦ Half life is 24h - once daily dosing.
- Can get even longer if administered for > 45 d.
Firocoxib What NSAID: ◦ Preferential COX-2 inhibitor.
◦ Soft-tissue or musculoskeletal pain, including osteoarthritis in dogs.
◦ Perioperative pain for orthopedic or soft tissue surgeries.
◦ Can use for short term (1 day) treatment of cats. ◦ Half life is 24h - once daily dosing.
- Can get even longer if administered for > 45 d.
Robenacoxib What NSAID:
◦ Preferential COX-2 inhibitor. Appears to be relatively selective for COX-2 in dogs and cats.
◦ Approved for use in cats (US, up to 3 d).
Librela What is a monoclonal antibody against NGF (inflammatory mediator), degenerative myelitis may be a possible side effect?
Dogs
- Meloxicam
- Carprofen
- Firocoxib
- Grapiprant
Cats
Common NSAIDs used in clinics for dogs and cats?
Say you pick - D 100 mL bottle
14 kg * 2.2 lb/kg = 30.8 lb
Loading dose = 30.8 lb * 0.1 mg/lb = 3.08 mg/ (1.5mg/ml) = 2.05 mL
Maintenance dose = 30.8 lb * 0.05 mg/lb = 1.54 mg/ (1.5 mg/ml) = 1.025 mL
(100 mL - 2.05 mL)/1.025 mL = 98 days supply for $112. Noah is a 12 y.o., 14 kg male neutered pointer with lung carcinoma, now presenting for hind limb weakness due to arthritis. To improve his quality of life, he was started on meloxicam. Meloxicam is normally dosed initially at 0.1 mg/lb, with subsequent days at 0.05 mg/lb. Which of these options makes the most sense for dosing this animal?
A. 15 mg tablet B. 7.5 mg tablet C. 0.5 mg/mL liquid (15 mL bottle) D. 1.5 mg/mL liquid (10, 32, and 100 mL bottles)
Additional note on pricing: 15 mg tablet - $0.11 each 0.5 mg/mL liquid (15 mL) - $39. 7.5 mg - $0.07 each 1.5 mg/mL liquid (100 mL) - $112. 1.5 mg/mL liquid (32 mL) - $58. 1.5 mg/mL liquid (10 mL) - $37.
