Analgesia Flashcards
Definition of Pain
unpleasant sensory and emotional experience associated with actual or potential tissue damage.
pain experience: consequence of tissue damage, also effective component–>emotional experience of pain.
Physiological pain vs. pathological pain
Physiological: pain proportional to intensity of noxious stimuli–>protects against further injury
Pathological: pain greater than apparent noxious stimuli–>detrimental
Pain pathway
nociceptor: generates an AP (transduction)
afferent fibre: conducts AP to CNS (tranmission)
Spinal cord: processing at level of dorsal horn (modulation)
Brain: conscious experience of pain.
Inhibitory influences of pain pathway
Descending inhibitory neurons (arising in mid-brain) reduce transmission at level of dorsal horn–> decreased tranmission of pain
Sensitisation
may be peripheral or central–> touching a wound/burn becomes painful
Peripheral: inflammatory meditaors (e.g. prostaglandins) increase nociceptor activation at area of tissue damage– lower threshold, therefore more likely to generate AP
Central: repetitive nociceptive input enhances tranmission at level of dorsal horn (NMDA receptor=key mediator in sensitization)– In very severe injury, barage of APs at dorsal horn and subsequent tranmission is enhanced.
Analgesia
absence of pain or a reduction in intensity of pain perceived
drugs: LAs, opioids, NSAIDs, alpha 2 agonists, ketamine, Nitrous oxide
Sites of drug action
- nociceptor- e.g. NSAIDs reduce production of inflammatory mediators- normalize the threshold of nociceptors
- afferent fibre- e.g. local anaesthetics inhibit tranmission of AP in afferent fibre
- dorsal horn e.g. opioids and alpha 2 agonists modulate neurotranmission at 1st synapse between afferent fibres and ascending neuron.
- sensory cortex e.g. central conscious perception of pain e.g. opioids–>emotional aspect of pain
Pre-emptive analgesia
administration of analgesic drugs prior to occurence of tissue damage
- prevents or limits central sensitisation
- post-op pain easier to control–> this is difficult to prove
Preventive analgesia
administration of analgesic drugs throughout peri-operative period
to prevent or limit development of sensitization induced by pre-, intra- or post-operative noxious stimulation
Multimodal analgesia
use of combo of drugs that act a different points in the nociceptive pathway
- more effective analgesia- often means we can use lower doses of individual drugs
- fewer adverse effects
Adjunctive analgesics
drugs not normally used to alleviate pain. increasingly used to manage chronic pain
i.e. NMDA receptor antagonists e.g. amantidine, ketamine
anticonvulsants e.g. gabapentin
tricylic antidepressants e.g. amitryptiline
Local Anaesthetics
widely used in large animals; alternative to GA
used increasingly in small animals (multimodal analgesia)
LA- topical use
to desensitize mucous membranes (oral, ocular, nasal, etc)
to desensitize intact skin (EMLA cream)
LA- local infiltration
i.e. into the edges of a wound
to desensitize dermal and subcutaneous tissues for mino surgery
example: field blocks for flank laparotomies
LA- instillation into a cavity or wound
intrapleural anaesthesia: thoracic cavity, esp. if drain in place
intra-articular anaesthesia- joint
wound soaker catheters: finely fenestrated–>when you inject LA, goes along the length of the wound
LA- IV regional anaesthesia (Bier’s block)
useful in large animals
IV administration of lidocaine distal to a tourniquet
-desensitize distal limb e.g. digit amputation
LA- Peripheral nerve blocks
used diagnostically and therapeutically
-paravertebral, intercostal, brachial plexus, dental nerve blocks, etc
LA- epidural (extradural) block
to desensitize perineum, hindlimb and caudal abdomen
large animals: before 1st coccygeal (more distal than small animals)
small animals: lumbosacral junction
LA- systemic administration
IV infusion of lidocaine in very painful patients
NB: LIDOCAINE INFUSIONS CAN NOT BE GIVEN IN CATS
Physiology of LAs
RMP is -60 to -90 mV due to higher Na+ in ECF and higher K+ in ICF
Excitable cells generate an AP in response to membrane depolarisation. Voltage-gated Na+ channels open
Repolarisation involves: inactivation of Na+ channels and delayed opening of voltage-activated K+ channels
Na+/K+ pump
**LAs act by blocking Na+ channels–> prevents initation/conduction of APs **
Mechanism of LA action
LAs are weak bases. BH+ <–> B + H+
pH of environment; the charged form is active in LAs. Charged form is too big to fit into the channel.
LAs can access channel by passing through (uncharged) membrane and can diffuse into channel from there. LA must pick up an H+ from somewhere to become activated.
LAs and Na+ channels
Channels exist in 3 states: open, inactivated and closed
open and inactivated channels have a higher affinity for LA
Use dependence: LAs bind more readily to Na+ channels in an activated state, thus the onset of neuronal blocks is faster in neurons that are rapidly firing.
The hydrophilic pathway (i.e. drug has to go allw the way through the membrane and into the channel from inside the cell)–> more opportunity for drug to get into the channel. Hydrophillic pathway is use-dependent
The hydrophic pathway: drug goes INTO (not through) membrane and in membrane, goes direct to channel– non-use dependent.
Susceptibility to LAs
all nerve fibres are sensitive, howevere small myelinated and small unmyelinated fibres are more/most susceptible.
LA blocks pain impulses better than touch impulses
Selectively block pain pathways at lower doses–> doesn’t effect movement
LA Pharmacokinetics- Chemical structure
Lipophilic aromatic group attached to hydrophilic amine side chain by either ester (C-O) or amide (NH) link
Structure affects metabolism
LAs are generally ampiphillic- water soluble to diffuse to site of action and fat soluble to pass through membranes.
LA Pharmacokinetics- Physical properties
weak bases; largely ionized at physiological pH
Ionization increases as pH decreases. Inflamed tissues may be resistant. pH at inflammation tends to be acidic–> LAs get charged and have a decreased ability to pass through membranes (uncharged form goes through membrane).
pH dependence
Speed of onset related to degree of ionisation
Duration of action related to protein-binding (more protein-binding, the longer the duration)
Potency is related to lipid solubility
Other drugs may be aded:
Bicarb: influence pH; increase pH, speed up onset of activity
Adrenaline: localized vasoconstriction, decreased blood flow, decrease chance of LA getting carried away–> means of prolonging persistence?
Local Anaesthetic Pharmacokinetics- Elimination
Ester-linked drugs: rapidly hydrolyzed by non-specific cholinesterase (metabolic enzymes present in plasma): short half life
Amide-linked drugs: metabolized in liver; longer half life
Adverse effects of LA
Harmful effects most likely seen following OD or accidental IV administration
Toxic dose of LA often defined as dose to induce seizure
CNS effects: initial stimulation (muscle twitching), leading to convulsions; later depression and death
CVS: myocardial contractility and HR fall–> overall CV depression; peripheral vasodilation–>decrease in BP
Miscellaneous: allergic rxns rare/unpredictable (ester>amide)
methemoglobinaemia? uncommon side effect. oxidize iron from Fe2+ to Fe3+; interferes with ability to transport O2–> seen with prilocaine
Lidocaine- Clinical use
used in all types of LA technique; effective antidysrrhythmic drug (tx for ventricular dysrrhythmia) and GIT pro-kinetic (colic)
Lidocaine/lignocaine HCL: licensed in dogs, cats and horses. Licensed preparation contains adrenaline.
Adrenaline preparation prolongs persistence. CANNOT give adrenaline prep IV.
Chemical structure: amide-linked; stable and predictable half life
Rapid onset (25% unionized at pH 7.4) (high compared to other LAs)
Duration: 1-2 hours (70% protein bound)
Metabolised in liver
Adverse affects: CNS toxicity and seizures
Bupivacaine
used mostly in small animals for therapeutic nerve blocks and epidurals (NOT IV)
Bupivacaine HCL: no vet license- longer duration, v. practical for post-op use
Amide linked
Slow onset: 15% unionized at pH 7.4
Long duration: 4-8 hours (95% protein bound)
Metabolized in liver (glucoronide conjugation)
Adverse effects: CV toxicity (that’s why we don’t give IV) and bradycardia (persistent and hard to tx; decrease in CO)
L-isomer is less cardiotoxic but generally comes in racemic mixture
Mepivicaine
used for infiltration, nerve blocks, intra-articular and epidural anaesthesia in horses
Mepivicaine HCL: licensed in horses
Amide- linked; hepatically metabolized
Rapid onset (39% unionized at pH 7.4)
Duration 90-180 minutes ( 77% protein bound)
Adverse effects: CNS toxicity
Procaine
used for peripheral nerve blocks and infiltration
Procaine HCL: licensed in cats, dogs, cattle, horses- preparation contains adrenaline
Ester-linked: only commonly used ester-linked LA
Slow onset (3% unionized at pH 7.4)
Short duration 45-60 min (6% protein bound)
Hydrolyzed by plasma cholinesterase enzymes (short half life)–metabolite PABA antagonizes sulphonamide antimicrobials
Adverse effects: CNS toxicity and seizures
-hypersensitivity–> ester-linked has slightly higher incidence of allergic side fx
Other LAs
Cocaine: 1st used medically (1880s)
Ropivacaine: preferentially effects nociceptive fibres, available as L-isomer only, reported to cause less motor blockade
Proxymetacaine: ophthalmic LA
EMLA cream: eutetic mixture of lidocaine and prilocaine
Opioid Analgesia
opioid: relates to any substance (endogenous or synthetic) that produces morphine-like effects that can be blocked by naloxone
opiate: restricted to synthetic morphine-like drugs with non-peptide structure
opium: extract of poppy seed juice: contains many alkaloids (codeine, pamparin) related to morphine
Many peptides with opioid activity
3 families: enkephalins, endorphins, dymorphins
under normal conditions: low, weak, tonic activity
under stress: can be upregulated
Opioid receptors
1) mu (OP3)- most clinically relevant; also responsible for side effects
2) kappa (OP2)- in spinal cord–> sedative/dysphoric effects
3) delta (OP1)- peripherally important, but minor role in analgesia
Opioid agonists, partial agonists, antagonists
Agonists: morphine, pethidine, methadone, fentanyl, alfentanyl, lopeamid, codeine, dextropropoxyphene, etorphine
partial agonists: buprenorphine, butorphanol, nalbuphine
antagonists: naloxone, diprenorphine
Mechanism of opioid action
Bind to opioid receptors in brain, spinal cord, periphery
All opioid receptors are G-coupled protein receptors
GCPR: 1) inhibit adenylate cyclase–> decrease cAMP
2) promote opening of K+ channels–> hyperpolarization, decreased neuronal excitability
3) inhibit opening of voltage-gated Ca2+ channels- if pre-synaptic, decrease in NT release (inhibitory)
these three actions aren’t interdependent
differential distribution of receptors resulting in varied response
CNS effects of opioids
1) Analgesia: central and peripheral sites; acute and chronic pain; reduce affective (emotional) pain component
2) euphoria: powerful sense of contentment and well-being; diminished if animal is already in pain
3) respiratory depression (not accompanied by effect on CVS): decreased sensitivity of resp. centre to PCO2–> increased arterial PCO2–>altereted RR and then altered tidal volume
Effects can occur at therapeutic doses but unlikely to cause any problems
4) depression of cough reflex- unclear mechanism
5) nausea/vomiting (defecation)- up to 40% of patients– via chemoceptor trigger zone; usually transient; more likely in absence of pain
6) pupillary constriction: pin-point pupils= diagnostic feature of OD (NB: in cat–>mydraisis, in dog–>miosis)–most other causes of coma cause dilation.
GIT effects of opioids
1) increased tone, decreased motility–>constipation is side effect. Opioid receptors in myenteric plexus–>decreased release of ACh, inhibit peristalsis
2) constriction of biliary sphincter and increased tone of anal sphincter– increases amount of water absorbed
NB: delayed gastric emptying can lead to delayed oral drug absorption if given in combo with opioids.
Other effects of opioids
1) Histamine releasing from mast cells (morphine and pethidine); not receptor-mediated, as naloxone doesn’t antagonize. Urticaria/itching, bronchoconstriction, hypotension
2) CVS (large doses- could be related to histamine release): hypotension and bradycardia
3) smooth muscle (other than bronchi and GIT): little effect except spasm of uterus/bladder (implications in using in pregnant animals) and straub tail reaction: tail stiffens and raises
4) immunosuppression?
5) body temp: small effects, species variation
6) tolerance: increase in dose required to provoke a given pharmacological effect. Dependence: clear cut abstinence syndrome.
Tolerance involves upregulation of adenylate cyclase– extends to most effects except gut motility and pupil constriction.
Pharmacokinetics of Opioids
oral absorption is variable
considerable 1st metabolism (process whereby oral drug is absorbed through portal vein to liver before going systemic)
33% plasma protein bound (morphine)
half-life 3-6 hours–> varies significantly depending on agent
Hepatic metabolism: usually conjugation by glucuronide; demethylation: pethidine; hydrolysis: diamorphine–>morphine (can undergo enterohepatic recycling)
Excreted in urine or bile
Nasal or buccal route with very lipid soluble drugs
Side effects: mainly respiratory depression, nausea/emesis, constipation
Clinical use of opioids in vet med
** relief of moderate to severe pain
to provide sedation
to reduce GA dose required
to treat diarrhea
to control coughing
Contraindications to opioid use: a) existing hypoventilation (with exceptions e.g. fracture ribs where pain is inhibiting adequate respiration)
i. e. myasthenia gravis is contraindicated
b) head injuries/brain tumor: many opioids increase intra-cranial pressure (due to increase in PCO2)
Considerations when choosing an opioid
1) efficacy
2) adverse effects
3) licensing
4) controlled drug legislation
5) route of admin
6) potency
7) cost
Analgesic efficacy of opioids
what level of analgesia do we need?
for moderate/severe pain–> highly efficacious i.e. full agonist
mu agonists are more efficacious than kappa agonists
full agonists are more efficacious than partial agonists
Adverse effects of opioids
side effects common to all opioids; usually dose-dependent
less significant in partial vs. full agonists
some differences between individual drugs i.e. morphine can cause vomiting; pethidine can cause histamine release
opoids occasionally selected for their efficacy in producing a side effect: loperamide=antidiarrheal, butorphanol=antitussive
Opioid licensing and controlled drugs
If no license, apply cascade
Licensed full agonists: methadone, pethidine, fentanyl
Licensed partial agonists: buprenorphine, butorphanol
Schedule 2: full agonists: morphine, methadone, pethidine, fentanyl, etorphine
Schedule 3: buprenorphine
Not controlled: butorphanol, tramadol
Route of Administration of opioids
differences between drug can affect choice
not all can be given IV: e.g. pethidine (causes histamine release)
few have sufficient bioavailability to be effective orally except tramadol; codeine+paracetamol
Novel routes of admin: transmucosal- buprenorphine absorbed buccally in cats (100% bioavailable)
Transdermal- fentanyl patch, “spot-on” soution
Potency of opioids
amount of drug equired to produce a given effect. Etorphine is HIGHLY potent- have anatagonist on hand just in case. Accidental self-admin is hazardous. Useful in remote administration i.e. dart gun.
Relative analgesic potencies
buprenoprhine: 10-20
butorphanol: 4-7
etorphine: at least 1000
fentanyl: 80-100
methadone: 1
morphine: 1
pethidine: 0.1
When to use opioid antagonists
to treat resp depression (OD)
to treat excitement/dysphoria (high doses)- horses box walk with v. high doses of opioids
to reverse fx of opioid analgesics in puppies delivered by C-section
Emergency 1st aid in event of accidental injection
Clinical Pharmacology of Methadone
analgesic for moderate/severe acute pain-widely used for surgical/trauma analgesia. Full agonist, v. efficacious
Methadone HCl- schedule 2
licensed for use in dogs and cats
mu selective agonist (some kappa and delta activity)
-NMDA receptor antagonist- may help normalize pain pathway
Administer IM, iV or SC; variable duration (2-6 hours)
Initial dose has short effect but more extended duration with repeated dose–> perhaps some degree of accumulation
side effects: less sedation than morphine; no vomiting
Fentanyl
injectable solution; CD2- full agonist
Analgesic for severe acute pain, including intra-op “rescue analgesia” (if animal is undergoing surgery and its reacting noxiously, can bump up fentanyl) and post-op analgesia
Recently licensed for IV admin in dogs, also hypnorm (fentanyl+fluanisone)- neuroleptanalgesic combo licensed in small furries.
Potent, pure, mu selective, full agonist
rapid onset (1 minute IV) and short duration (5-20 minutes)–> rescue analgesia
Significant side effects: bradycardia (hypotension with high dose)–> not terrible because of fast onset and short duration means we can titrate to effect
respiratory depression (esp. if anaesthetized): fentanyl can stop breathing; need to have ventilation/means to aid in respiration
Transdermal preparation of fentanyl
analgesic for post-op/chronic pain
1) Self-adhesive transdermal patch: can be quite useful in cancer pain mgmt.
- no vet license
- delay in onset to reach therapeutic levels (~24 hours in dogs, 12 hours in horses, 6 hours in cats)
- variable absorption; perhaps d/t application problems
2) transdermal spot-on solution
- available after online traning
- licensed in dogs (onset ~4 hours, duration ~4 days). Apply 2-4 hours pre-op, analgesia up to 4 days.
very concentration solution, therefore administer v. carefully (don’t get on your own skin)
Buprenoprhine
analgesic for mild/moderate pain; partial agonist
CD3: licensed in dogs, cats, horses
potent mu selective partial agonist.
High affinity for receptor- difficult to displace; difficult to reverse with antagonist (not a huge issue b/c it has decreased side fx b/c it’s a partial agonist)
Administer IV, IM or SC
oral trans-mucosal route in cats
slow onset- up to 45 minutes
long duration- up to 12 hours (6–8 hours clinically)
side fx: mild sedation
NB: if surgery is more invasive/extensive, but you’ve already given buprenoprhine-> hard to top up with morphine because it doesn’t have as high affinity for mu to knock off buprenorphine.
Butorphanol
mixed: partial kappa agonist; mu antagonist
analgesic for mild pain (unreliable); but effective sedative and antitussive
Butorphanol tartate: licensed in horses, dogs and cats
Admin IV, IM, SC or orally
short duration: up to 2 hours after injection
Side fx: dysphoria with high doses
NB: mu receptor most important for mammal analgesia; kappa most important for bird/reptile analgesia
NSAIDs- understanding of mechanism
Cyclooxygenase (COX) is enzyme responsible for catalyzing the production of prostaglandins and thromboxanes from arachidonic acid
NSAIDs inhibit COX, thereby decreasing PGs and thromboxane
Inflammation is a response to invasion of a pathogen or tissue damage. Results in the release of pro-inflammatory mediators; redness, heat, and swelling, loss of function; pain and hyperalgesia (sensitization), where normally non-noxious stimuli becomes painful.
Peripheral sensitization
if we can inhibit production of inflammatory mediators, we can damp down sensitization pathway.
Tissue damage–> products from damaged cells and inflammatory mediators–> inflammatory soup
Inflammatory soup–>decrease firing threshold, increase firing rate, silent nociceptors–> hypersensitization
nb: NSAIDs act on both peripheral and central sensitization
COX pathway
Cell membrane phospholipids–>arachidonic acid by action of phospholipases (nb: steroids inhibit phospholipases)
Arachidonic acid can go through lipoxygenase pathway to form leukotrienes, etc. or through cyclooxyengase pathway to form prostaglandins and thromboxanes.
If we block COX pathway, more arachidonic acid goes to lipoxygenase pathway.
Other roles of PGs: IR, GIT, CV, Kidney, lungs, repro, brain and spinal cord–>side effects d/t NSAID effects on PG production
Cyclooxygenase
COX: enzyme which converts arachidonic acid to PG precursor PGH2
NSAIDs are: anti-inflammatories; GIT toxic and antithrombotic
COX-1
responsible for physiological activities of PGs i.e controlled pathways where PGs are doing beneficial things in the body.
COX-1 is constitutively expressed in most tissues; involved in normal homeostasis; many physio functions, especially maintaining GIT mucosa (PGs increase Q to GIT and allow for mucus production); upregulated under stress conditions.
COX-2
induced under inflammatory conditions; responsible for pathological PGs that produce pain and increased temperature.
COX-2 drugs have a better GI safety profile, but CV and renal side effects.
COX-1 and COX-2 don’t have as clear-cut roles as we thought- have both physiological and pathological roles.
COX-2 is constitutively expressd in many tissue, including kidney, testicular and ovarian cells and in CNS
also induced in response to inflammatory stimuli
maintain renal Q, nerve function and bone metabolism
Traditional NSAIDs vs. Cox specific
Traditional: block channel to prevent arachidonic acid from getting to binding site
COX-2 specific: blocks channel in COX-2 but too bulky to fit into COX-1
NB: aspirin has irreversible inhibition–> cell has to produce a new enzyme to get back to normal after aspirin use
COX-3: expressed predominantly in CNS–>inducible enzyme linked to analgesic and antipyretic activity
Non-selective cox inhibitors are most commonly used
Preferential cox-2 inhibitors: meloxicam, diclofenac
Specific cox-2 inhibitors: rofecoxib, celecoxib, firocoxib
Effects of NSAIDs
Analgesic: central and peripheral
Anti-pyretic
Anti-inflammatory
Anti-thrombotic
Anti-endotoxic
Analgesic effects of NSAIDs
1) peripheral action: NSAIDs decrease PG production at site of inflammation–>reduce sensitization of nociceptive nerve endings to inflammatory mediators
2) central action: NSAIDs block PG release and neuronal excitation–> decreased central sensitization
Antipyretic effects of NSAIDs
Hypothalamus regulates normal body temperature- ensures balance between heat loss and heat production
inflammation–> IL-1 (endogenous pyrogen)–> Increased PGE2 synthesis (by COX-2/COX-3)–> act on thermoregulation centre in hypothalamus to increase body temp–>fever
increased [PGE2] found in CSF during infection. Decreased production of PGE2 to prevent increased temp–> no effect on normal body temp.
Anti-inflammatory effects of NSAIDs
NSAIDs inhibit COX induction and release of PG at site of inflammation. Decrease vasodilator PGs leads to decreased oedema
decreased immune response prevents peripheral sensitization
Antithrombotic effects of NSAIDs
NSAIDs inhibit synthesis of thromboxanes (TXA2) which inhibits platelet aggregation.
This action is more effective at lower doses.
Platelets produce TXA2–> stimulate aggregation; low dose NSAID, TXA2 inhibited, anti-thrombotic action
Endothelial cells produce PGI2 to protect endothelium from RBCs sticking–>facilitate blood flow
At high doses of NSAID, PGI2 is inhibited–> pro-thrombotic effect.
Anti-endotoxic effects of NSAIDs
endotoxins are LPS generated by gram negative bacteria. endotoxins damage WBCs and vascular endothelium, thus releasing vasoactive mediators.
NSAIDs prevent generation of vasoactive mediators during endotoxemia
Flunixin has endotoxic shock prevention as part of its license.
Pharmacokinetics of NSAIDs
most well absorbed following oral admin; parenteral formulations also available
Relatively small Vd- extracellular fluid
Highly plasma protein bound (>99%)–>good penetration into acute inflammatory exudate–>drug is carried right where you need it! Acid will pick up H+ ions and allow for good penetration.
Metabolism: generally by conjugation and renal elimination of metabolites (some biliary elimination). **Marked interspecies variability **
Adverse effects of NSAIDs
often due to chronic drug use
dyspepsia, nausea and vomiting
GI ulceration
renal/hepatic toxicity
injury to articular cartilage
precipitate asthma
GIT adverse effects of NSAIDs
PGI2 and PGE2 in gut protect gastric mucosa by inhibiting gastric secretion and inducing blood flow/vasodilation
COX-1 is primary isoform responsible for gastric mucosal PG production. COX-2 is absent in normal gastric mucosa BUT induced rapidly in response to injury/gastric erosions.
GIT ulceration: inhibition of COX-1, decrease in PG causes ulceration.
Mucosal ischemia–>impairment of mucous barrier, mucosa exposed to acid
All species susceptible
NSAIDs should be given with food to protect gastric mucosa; contact area of tablet results in high localized concentration of drug increasing potential for ulcer formation
Renal toxicity of NSAIDs
PGE2 and PGI2 synthsized in renal medulla and glomerulus respectively
Involved in renal Q and excretion of salt and water via vasodilatory actions
Inhibition of PGs result in impaired renal blood flow
in healthy, well-hydrated animals, decreased renal PGs are of little consequence.
Significant renal toxicity can occur in dogs and cats if they’re volume depleted. Use extreme caution when considering using in animals at risk of dehydration
Hepatotoxicity of NSAIDs
relatively uncommon in animals; some idiosyncratic reports i.e hepatotoxicity in dogs getting carprofen, old horses getting phenylbutazone
Cartilage damage effect of NSAIDs
chronic NSAID therapy may worsen cartilage degeneration in animals with osteoarthritis–> particularly aspirin, ibuprofen and naproxen
more seen with COX-1 selectivity
Asthma and NSAIDs
shunting of arachidonic acid to lipoxyenase pathway with COX-inhibition–> production of leukotrienes–potential to cause bronchospasm
Clinical use of NSAIDs in vet med
1) management of pain: acute (trauma or surgical) and chronic (osteoarthritis, cancer, dental)
2) management of inflammatory disorders: inflammatory arthritis, lupus and ophthalmological disorders e.g. keratitis or uveitis
3) management of endotoxemia in large animals: equine colic, bovine toxic mastitis
4) management of pro-thrombotic states: i.e. saddle thrombus d/t feline hypertrophic cardiomyopathy
5) managment of some tumors- some dependent on COX-2 activity. Piroxicam has been used to treat transitional cell carcinoma of the bladder.
Contraindications of NSAID use
- acute/chronic renal insufficiency: NSAIDs decrease renal perfusion
- hepatic insufficiency- most NSAIDs hepatically metabolized
- gastric ulceration or other GI disorder
- coagulopathies (factor deficiencies, von willebrand’s, thrombocytopenia)
- severe or poorly controlled asthma
- breeding/pregnant/lactating animals: potentially teratogenic; PGs have role in ovulation, implantation and parturition
- hypovolemic animals: congestive HF, hypotensive/shock
- animals being treated with corticosteroids
Considerations of choosing NSAIDs
1) efficacy
2) adverse effects/safety
3) licensing
4) ease of admin
5) cost
Efficacy of NSAIDs
no NSAID is consistently more effective than another wrt analgesia
COX-2 selectivity doesn’t appear to influence analgesic efficacy
nb: individual differences in patients
differences in efficacy wrt to other actions are recognized:
- aspirin is most effective antithrombotic
- paracetamol is better anti-pyretic than anti-inflammatory
Adverse effects/safety of NSAIDs
generally have narrow safety margins and accurate dosing is required. All NSAIDs can potentially induce GIT signs +/- ulceration
renal and hepatic injury
COX-2 selectivity can be used to predict GIT safety. Described by COX1:COX2 ratio. Concentration that inhibits 50% of COX-1 activity divided by concentration that inhibits 50% of COX-2 activity. A COX1:COX2 ratio greater than 1 indicates COX-2 selectivity (ie. very high number for cox-1 and very low number for cox-2)
we want drug that doesn’t really inhibit cox-1, but DOES inhibit cox-2.
RIsk of GIT toxicity decreases with increasing COX-2 selectivity. COX-2 selectivity doesn’t reduce other forms of toxicity. No evidence of lesser renal effects.
May get delayed wound healing. May be increased risk of myocardial infarction and stroke–> reflects shifting from thromboxane production toward pro-thrombotic state
Licensing of NSAIDs
Species considerations: difference in pharmacokinetics e.g. aspirin half life in dogs is 8.5 hours and 37.5 hours in cats
Differences in toxicity: ibuprofen widely used in people, very toxic in dogs
Differences in Cox-2 selectivity: carprofen is non-selective in sheep; cox-2 preferential in dogs
Intended duration of TX: some NSAIDs licensed for long-term use i.e. meloxicam, firocoxib
Perioperative use: some NSAIDs licensed for peri-op use i.e carprofen, meloxicam, robenacoxib
NB: anaesthesia decrease renal perfusion
Individual NSAIDs
phenylbutazone and flunixin: non-selective, primarily use in large animals
Carprofen and meloxicam: used in small and large animals
Firocoxib and robenacoxib: COX-2 specific
Newer NSAIDs
COXIBS: most, but not all, are COX-2 specific. Those that are specific have improved GIT tolerance but caution re: overall safety profile
Firocoxib: specific cox-2 inhibitor, very high cox1:cox2
available as a chewable tablet, paste and injectable
licensed in dogs and horses
Robenacoxib
specific cox-2 inhibitor
as tablet or injectable
authorized for peri-op use in dogs and cats
Cimicoxib
highly selective cox-2 inhibition–> available as chewable tablet for dogs
Mavacoxib
very long duration
preferential cox-2 inhibitor; authorized for long-term management of osteoarthritis in dogs; chewable tablet
Repeated after 2 weeks and thereafter monthly (max 7 tablets per tx cycle)- then have a month off before re-starting
maintains a much more consistent plasma concentration of the drug–>better control of chronic pain
BUT concern is if animal develops side effects after day 1–> drug still in system for the whole month–> need to manage these problems.
Paracetamol (acetaminophen)
Not typical NSAID
Licensed in combo with codeine for dogs
Poor anti-inflammatory but v. effective analgesic and anti-pyretic
Mechanism: central cox-inhibition (cox-3?)- not peripheral COX inhibition– less likely to get renal, GI side fx
Metabolised by 3 pathways: *glucuronidation (most important), sulfation and oxidation
Paracetamol side effects/toxicity
Hepatic toxicity: phase I metabolite of oxidation NABQ is normally conjugated with hepatic glutathione (glutathione deactivates NABQ and inactivates it)
In OD: glutathione is overwhelmed and NABQ binds to hepatocytes inducing heptatic necrosis–> severe hepatic damage
In cats: DO NOT USE- Limited glucuronidation d/t v. little glucuronidase enzyme, so increased oxidation and increased NABQ. Signs include facial oedema, methemoglobinemia, hemolytic anemia, icterus
