Flashcards in NSAIDs 1 - Understanding the clinical pharmacology of NSAIDs and its relevance to clinical practice Deck (54):
How do NSAIDs reduce inflammation?
inhibit production of prostaglandins released by damaged tissue through inhibition of COX enzyme
Clinical indications - NSAIDs
- control pain in non-infectious/ non-allergenic inflammatory disorders (DJD, peri and post-op)
- Decrease platelet aggregation (thromboembolus, heartworm disease)
- Ophthalmology (rx of keratitis, scleritis, don't inhibit corneal re-epithelialisation, intra-ocular sx as may minimise post-op increase protein content of AH).
- Some immunological diseases (SLE and RA, anti-inflammatory, may stimulate T suppressor cells in their action against T helper cells and auto-Ab producing BCs)
- endotoxic shock (LA only) but must be administered prior or immediately after onset of endotoxaemia with other supporive tx.
COX1 - actions
- produces prostaglandins important in physiological modulation of normal function:
- gut mucosal barrier
- intra-renal perfusion when renal BF decreased
What is COX-2 activated and released by?
- tissue damage
- bacterial lipopolysaccharide
- growth factors
- inflammation where PGE2 predominates
- important physiological functions (expressed constitutively in kidney macular densa to maintain renal perfusion by dilating afferent arteriole when vasoconstriction stimulated)
What is the COX1: COX2 ratio?
- ratio of effect varies with different drugs (why some are more ulcerogenic than others and other toxicity profiles)
- recent evidence shows the relative COX2 preference of a drug is influenced by the assay chosen, tissue type and species
What is the gold standard assay for COX profile of a drug?
whole blood assay
Outline carprofen specificity
- Dog = COX2 preferential (or non-selective)
- Horse = non-selective
- Cat = COX2 preferential (but significantly longer half-life than dog, daily dosing --> GIT disorder)
- Man = COX1 preferential
What is a non-specific COX inhibitor?
one with no meaningful or clinical differences in COX1 or 2 inhibition
COX2 inhibition - clinical benefits
- fever (some)
- Alzheimer's disease (this is an inflammatory process associated with COX2 increased expression, epidemiological studies suggest delayed expression and/or slow progression with NSAID use).
- Some cancers (colon, pancrease, lung, TCC, melanoma)
3 types of NSAID
- preferential (at least 2x greater inhibition of COX2 than -1 but usually 10-40)
- selective (>100 times selective for COX2)
Mechanisms of COX action
- inhibition of COX isoforms
- other actions at molecular levels peripherally and centrally (varies with drug)
- Many contribute to pharmacological, toxocological and therapeutic properties (5LO inhibition, prostaglandin-R blockade, scavenging free radicals, anti-bradykinin properties, inhibition of enzyme release or action, inhibition of cytokine release, inhibition of NFkB)
Pharmacodynamics - COX
usually expressed as IC50 values
Assay methods - COX assay
- cell based
- tumour cell lines
- whole blood (gold standard)
How is COX1 inhibitory activity detected?
inhibition of clot-induced thromboxane B2 production
How is COX2 inhibitory activity detected?
inhibition of LPS induced PGE2 production
What may influence safety of NSAIDs?
- degree of acidity of the pro-drug (direct gastric mucosal damage)
- plasma half life
- degree of enterohepatic recycling
Therapeutic aim - NSAIDs
- >80% inhibition of COX2 (for p art though not all of 24hr)
- COX1 inhibition should be
Examples - non-selective COX inhibitors
- tolfenamic acid
Outline preferential COX-2 inhibitors
- 2 to 40 x more selective for COX2
- analgesic and anti-inflam. at doses that inhibit COX2 but not COX1
- some COX1 inhibition at elevated or therapeutic dosages
- includes drugs classes as coxibs
Examples - preferential inhibitors of COX2 (dog, cat)
- Cimicoxib (probably)
- Deracoxib (USA and Australia)
Examples - UK selective inhibitors of COX2
Example - dual inhibitor (COX and LOX)
= TEPOXALIN (inhibit LOX for a short period during day, non-selective inhibitor of COX1 and COX2
Which human NSAIDs are toxic to pets?
- piroxicam (only use for TCC in veterinary)
- mefanamic acid
- paracetamol/acetaminophen (toxic to cats only)
Effects of feline paracetamol ingestion
- facial and paw oedema
Pharmacokinetics - NSAIDs
- well absorbed from stomach and SI
- well absorbed after SC or IM injection
- topical administration can result in measurable drug levels in tissues and synovial fluids comparable to that observed after oral administration
- oromucosal delivery can achieve effective systemic levels (revitcam)
- weak acids so readily penetrate inflamed tissue
- highly protein bound (accumulation of drug in protein-rich inflammatory exudate)
- duration of effect of NSAIDs may exceed apparent systemic half life
Outline NSAID metabolism
- excreted at various rates depending on metabolic pathway and extend of enterohepatic circulation
- elimination half life varies considerably b/w drug and species
- toxicity and pharmacokinetic data on one species can NEVER be transposed to another species
Describe aspirin in dogs and cats
- used in both
- prolonged half life in cats (thus same dose but q72hours not BID)
Outline carprofen in dogs and cats
- used in both
- T(1/2) is 20 hours (Cat) vs 8 hours (dog)
- only licensed for once only use in cats
Outline meloxicam in dogs and cats
- used in both
- 21 vs 24 hrs half life (similar but different doses)
3 main NSAID side effect (systems)
What is prostaglandin role in GIT?
PGI2 and PGE2 maintain integrity of protective barrier that prevents gastric mucosa from damage by gastric acid by:
- inhibit gastric acid secretion
- maintain mucosal BF
- involved in secretion and composition of healthy mucous
- act as intercellular messengers to stimulate mucous cell tunrover and migration
- COX1 is source of 'good' PGs
Main mechanism that GIT ulceration occurs d/t NSAIDs
COX1 inhibition however both COX1 and 2 need to be inhibtied to generate mucosal injury in the absence of pre-existing injury
Which gut cells express COX2? 4
- endothelial cells
Can COX2 inhibition retard ulcer healing?
some studies suggest yes
- safety of COX2 inhibition in presence of inflammation needs to be demonstrated
When is it good to avoid NSAIDs?
patients with confirmed, presumed or potential GIT inflammation including pancreatitis
How else can NSAIDs cause GIT damage?
- relative rate of gastric absorption
- systemic availability of drug via circulation to mucosa
- direct damage to gastric mucosa
- degree of enterohepatic recycling
What increases ulcerogenic potential of NSAIDs?
- concurrent corticosteroids
- hypovolaemic shock
- disruption of normal GIT BF
Are COX presence in renal tissue?
IHC staining of normal renal tissue shows both COX1 and 2 thus COX2 has physiological role in normal kidney:
- when renal perfusion is reduced, renal PGs maintain renal BF via vasodilatory actions (COX1 and 2)
- natriuresis (COX2)
Outline COX2 species differences
- expression markedly increased in volume-depleted rats and dogs, not monkeys (thus preferential or selective COX2 inhibitors may not be as renally safe as thought in dogs vs primates).
T/F: in a healthy, well-hydrate animal, reduced renal PG production is of little consequence
When can significant renal toxicity result d/t NSAIDs?
If the animal is:
- volume depleted
- avidly retaining Na (CHF or hepatic cirrhosis)
- has pre-existing renal insufficiency
T/F: recent study showed cats with CKD on meloxicam for DJD had longer survival than those not on meloxicam
Which NSAIDs are safest for kidney?
Preferential (carprofen, meloxicam) and to a greater extent selective (firoxib, robenacoxib, mavocoxib, cimicoxib) COX2 inhibitors have less risk of renal toxicity when renal perfusion is reduced than non-selective NSAIDs (aspirin, PBZ, ketoprofen, tepoxalin).
T/F: no NSAID is completely renally safe when renal perfusion is reduced or may be reduced
Normal effects - thromboxane - 2
- potent vasoconstrictor
- activates platelet activation
Effects of thromboxane inhibition
Can lead to increased risk of bleeding thus use any NSAID with care in breeds with high prevalence of vonWillibrands disease. (although usually only significant with older NSAIDs)
Metabolism of NSAIDs - location
Extensive hepatic metabolism so care with hepatic disease
Advice for NSAIDs with liver dz
- critically review if NSAIDs really necessary
- if essential, increase dose interval rather than decreasing dose
When to be careful when using ACEI+NSAID?
if renal perfusion reduced --> advise owner to stop NSAID immediately if on this combination and becomes unwell
What premeds shoudl you be careful with when using NSAIDs?
- alpha 2 agonists
- avoid high dose ACP as predmed
Effects of an NSAID + diuretic combination
COX2 inhibition may attenuate effect of diuretic
Contraindications - NSAIDs (selective as well as non-selective)
- evidence/ suspicion GIT inflammation
- GIT BF reduce or may be reduced (shock, dehydration, reduced CO)
- renal BF reduced or may be reduced
- pathological Na retention present (nephrotic syndrome, cardiac failure, cirrhotic hepatic disease)
- renal dysfunction (except old cats with DJD)
- hepatic disease * if necessary use with increased dose interval to compensate for decreased rate of metabolism*
What is essential for all patients on NSAIDs?
- good peripheral circulation
- good renal function
- normal sodium/water balance
- ideally not have liver dz (if essential increase dosing interval)
- not have or have potential GIT pathology