Pharmacology - NSAIDs vs GCS Flashcards
What is the mechanism of NSAID activity?
Can you administer NSAIDs with systemic GCS?
No, never administer NSAIDs with systemic GCS concurrently. They reduce the production and alter the composition of gastric mucous.
What is the analesic ladder?
- Provides guidance for treating pain
- Mild pain - Mild analgesia, SSRIs
- Moderate pain - non opiod analgesics, NSAIDS or weak opiods
- Severe pain - strong opiods, nerve blocks
What is mavacoxib (Trococil)?
- NSAID
- Dogs only
- DO NOT give to dogs <12 months or <5kg
- DOSE: 1 tab per month taken with food - less than or equal to seven consecutive doses
What adverse effects are seen with NSAIDs?
- Gastric ulceration especially when the animal has low blood pressure, hypovolaemic or dehydrated
- Reduction in renal blood flow
- Reduced platelet function – tendency to bleed
- Occasional liver dysfunction
- Occasional idiosyncratic reactions
How can gastric ulceration be prevented?
- Select your patient wisely (not dehydrated, clinically normal, good liver and kidney function)
- Do not co‐administer with systemic glucocorticosteroids
- Consider the dosage to be used
- Increase stomach pH with a proton pump inhibitor such as omeprazole or a histamine2 (H2) receptor inhibitor e.g. cimetidine
- Or administer a PGE2 analogue such as misoprostol (Cytotec®)
How is gastric ulceration treated?
- Sucralfate (Carafate) is a drug that is administered orally & covers the ulcer. In the acid environment of the stomach the polymerised product forms a viscous paste. Administered prior to the H2 antagonists or proton pump inhibitors
- Increase stomach pH with a proton pump inhibitor such as omeprazole or a histamine2 (H2) receptor inhibitor e.g. cimetidine
- Supportive treatment: IV fluids, nil by mouth, antibacterial, analgesics
What are the contraindications of NSAIDs?
- Bleeding disorders or anticoagulation drugs – heparin, glycosaminoglycans, clopidogrel
- Severe kidney dysfunction (current recommendations – can be used with mild / stable chronic kidney disease in
- older cats*)
- Liver disease
- Gastrointestinal ulceration
- Chronic inappetance
- Dehydration
- Prolonged general anaesthesia as can result in hypotension
- Concurrent treatment with systemic glucocorticosteroids
Can paracetamol be used in dogs and cats?
- Can be used in dogs only, toxic to cats
- Good in head trauma for dogs, particularly when NSAIDs are contraindicated
- We use it at 10 mg/kg q 8h IV (or 15 mg/kg PO) as part of multimodal analgesia.
- If there is any concern about liver dysfunction, we won’t use it.
- Doesnt appear to induce liver toxicity in dogs
What is the mechanism of paracetamol in the CNS?
- Thought to act through inhibition of a subclass of COX enzyme isoforms in the central nervous system
- May enhance endocannabinoid transmission ‐ may simulate cannabinoid receptors
- Reported to have effects on the descending inhibitory pain pathway. Opioids also stimulate this pathway
- Descending inhibition pathway - thalamus to the dorsal horn and inhibits the pain amplification at the dorsal horn
What is the difference in hepatic metabolism between NSAID and paracetamol?
- NSAID - undergoes phase I metabolism by CYP2C, +/- a variable degree of phase II metabolism
- Paracetamol - undergoes phase I metabolism by CYP2E. There is also some degree of phase II glucuronidation
Is aspirin used in veterinary medicine?
- No longer used in veterinary medicine
- Used to be used to inhibit platelet aggregation to minimise thrombo-emboli formation (feline cardiomyopathy and pulmonary endarteritis associated with heartworm disease)
- We now use clopidogrel in place of aspirin.
- May result in severe bleeding in horses
- gastric ulceration
What are EP-4 Receptor antagonists and how do they work?
- PGE2 binds to one of four receptors (EP1‐EP4)
- EP4 receptors are widely distributed in the body – when activated signal to nerves, heart tissue, blood vessels, bone, gut, renal function, female reproductive function
- Inflammation up‐regulates the EP4 receptors
- Pain, redness and swelling – up‐regulates the EP4 receptors
- In animal models of osteoarthritis (OA) – the EP4 receptors in nerves and bones are upregulated
- Blocking these EP 4 receptors are thought to reduce pain/redness/swelling associated with OA
- They are a new anti-infalmmatory class ‘pripants’
- PRA = Prostaglandin receoptor antagonist
- By blocking this receptor, PG2α constitutive/homeostatic functions are maintained while blocking inflammation and pain at EP‐4 receptor
Are EP-4 Receptor antagonists safe?
- Safety profile – administered at high doses (35mg/day) for 9 months to dogs and found to have low grade adverse reactions
What is an example of an EP-4 receptor antagonist?
grapirant (galliprant)
Are there any alternatives to NSAIDs?
- Low dose NSAIDs + adjunctive agents /analgesics
- Oral tramadol; other drugs such as SSRIs and tricyclic antidepressants,
- NMDA receptor antagonists
- Gabapentenoids - potentially have analgesic activity when combined with another analgesic
Alternatives for Musculoskeletal inflammation:
- PRA
- Glucocorticosteroids good for welling but not for analgesic action
- Weight control
- Physical therapy
- Stem cell therapy?
- Paracetamol – DOGS ONLY
- Joint inflammation – chondroprotective agents
Why would it be necessary to find an NSAID alternative?
- GIT disease
- Blood clotting issues – use selective COX 2 inhibitor
- Liver disease or serious kidney disease
Mechanisms of action: NSAIDs vs GCS
NSAIDs - Mechanism of anti-inflammatory action: inhibit the enzyme cyclooxygenase to reduce production of prostaglandins. Some PGs responsible for redness, swelling, pain
GCS - Stabilise phospholipase which prevents cell membranes from leaking; Inhibits white blood cell chemotaxis
Differences in administration: NSAIDs vs GCS
NSAIDs - Usually administered orally, not for acute emergencies. Effects commence within 30 mins
GCS - Some injectable, water soluble GCS can exert anti-inflammatory effects in minutes
Immunosuppressive effects: NSAIDs vs GCS
NSAID - Not considered immunosuppressive drugs
GCS - Major immunosuppressive actions – inhibits actions of macrophages, T lymphocytes, cytokines etc
Analgesic properties: NSAIDs vs GCS
NSAIDs - Inhibition of PGE2 results in mild to moderate analgesia
GCS - Not considered to have significant analgesic properties
Adverse effects: NSAIDs vs GCS
NSAIDs: Some adverse effects – reducing gastric mucous, is a significant adverse effect
GCS: Many potentially adverse effects such as immunosuppression, but reduces gastric mucous production
