Analgesia

Question 1

Definition of Pain

Answer 1

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.

Question 2

Physiological pain vs. pathological pain

Answer 2

Physiological: pain proportional to intensity of noxious stimuli–>protects against further injury

Pathological: pain greater than apparent noxious stimuli–>detrimental

Question 3

Pain pathway

Answer 3

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.

Question 4

Inhibitory influences of pain pathway

Answer 4

Descending inhibitory neurons (arising in mid-brain) reduce transmission at level of dorsal horn–> decreased tranmission of pain

Question 5

Sensitisation

Answer 5

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.

Question 6

Analgesia

Answer 6

absence of pain or a reduction in intensity of pain perceived

drugs: LAs, opioids, NSAIDs, alpha 2 agonists, ketamine, Nitrous oxide

Question 7

Sites of drug action

Answer 7

1. nociceptor- e.g. NSAIDs reduce production of inflammatory mediators- normalize the threshold of nociceptors
2. afferent fibre- e.g. local anaesthetics inhibit tranmission of AP in afferent fibre
3. dorsal horn e.g. opioids and alpha 2 agonists modulate neurotranmission at 1st synapse between afferent fibres and ascending neuron.
4. sensory cortex e.g. central conscious perception of pain e.g. opioids–>emotional aspect of pain

Question 8

Pre-emptive analgesia

Answer 8

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

Question 9

Preventive analgesia

Answer 9

administration of analgesic drugs throughout peri-operative period

to prevent or limit development of sensitization induced by pre-, intra- or post-operative noxious stimulation

Question 10

Multimodal analgesia

Answer 10

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

Question 11

Adjunctive analgesics

Answer 11

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

Question 12

Local Anaesthetics

Answer 12

widely used in large animals; alternative to GA

used increasingly in small animals (multimodal analgesia)

Question 13

LA- topical use

Answer 13

to desensitize mucous membranes (oral, ocular, nasal, etc)

to desensitize intact skin (EMLA cream)

Question 14

LA- local infiltration

Answer 14

i.e. into the edges of a wound

to desensitize dermal and subcutaneous tissues for mino surgery

example: field blocks for flank laparotomies

Question 15

LA- instillation into a cavity or wound

Answer 15

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

Question 16

LA- IV regional anaesthesia (Bier’s block)

Answer 16

useful in large animals

IV administration of lidocaine distal to a tourniquet

-desensitize distal limb e.g. digit amputation

Question 17

LA- Peripheral nerve blocks

Answer 17

used diagnostically and therapeutically

-paravertebral, intercostal, brachial plexus, dental nerve blocks, etc

Question 18

LA- epidural (extradural) block

Answer 18

to desensitize perineum, hindlimb and caudal abdomen

large animals: before 1st coccygeal (more distal than small animals)

small animals: lumbosacral junction

Question 19

LA- systemic administration

Answer 19

IV infusion of lidocaine in very painful patients

NB: LIDOCAINE INFUSIONS CAN NOT BE GIVEN IN CATS

Question 20

Physiology of LAs

Answer 20

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 **

Question 21

Mechanism of LA action

Answer 21

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.

Question 22

LAs and Na+ channels

Answer 22

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.

Question 23

Susceptibility to LAs

Answer 23

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

Question 24

LA Pharmacokinetics- Chemical structure

Answer 24

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.

Question 25

LA Pharmacokinetics- Physical properties

Answer 25

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?

Question 26

Local Anaesthetic Pharmacokinetics- Elimination

Answer 26

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

Question 27

Adverse effects of LA

Answer 27

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

Question 28

Lidocaine- Clinical use

Answer 28

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

Question 29

Bupivacaine

Answer 29

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

Question 30

Mepivicaine

Answer 30

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

Question 31

Procaine

Answer 31

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

Question 32

Other LAs

Answer 32

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

Question 33

Opioid Analgesia

Answer 33

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

Question 34

Opioid receptors

Answer 34

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

Question 35

Opioid agonists, partial agonists, antagonists

Answer 35

Agonists: morphine, pethidine, methadone, fentanyl, alfentanyl, lopeamid, codeine, dextropropoxyphene, etorphine

partial agonists: buprenorphine, butorphanol, nalbuphine

antagonists: naloxone, diprenorphine

Question 36

Mechanism of opioid action

Answer 36

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

Question 37

CNS effects of opioids

Answer 37

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.

Question 38

GIT effects of opioids

Answer 38

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.

Question 39

Other effects of opioids

Answer 39

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.

Question 40

Pharmacokinetics of Opioids

Answer 40

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

Question 41

Clinical use of opioids in vet med

Answer 41

** 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)

Question 42

Considerations when choosing an opioid

Answer 42

1) efficacy
2) adverse effects
3) licensing
4) controlled drug legislation
5) route of admin
6) potency
7) cost

Question 43

Analgesic efficacy of opioids

Answer 43

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

Question 44

Adverse effects of opioids

Answer 44

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

Question 45

Opioid licensing and controlled drugs

Answer 45

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

Question 46

Route of Administration of opioids

Answer 46

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

Question 47

Potency of opioids

Answer 47

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

Question 48

When to use opioid antagonists

Answer 48

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

Question 49

Clinical Pharmacology of Methadone

Answer 49

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

Question 50

Fentanyl

Answer 50

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

Question 51

Transdermal preparation of fentanyl

Answer 51

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)

Question 52

Buprenoprhine

Answer 52

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.

Question 53

Butorphanol

Answer 53

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

Question 54

NSAIDs- understanding of mechanism

Answer 54

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.

Question 55

Peripheral sensitization

Answer 55

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

Question 56

COX pathway

Answer 56

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

Question 57

Cyclooxygenase

Answer 57

COX: enzyme which converts arachidonic acid to PG precursor PGH2

NSAIDs are: anti-inflammatories; GIT toxic and antithrombotic

Question 58

COX-1

Answer 58

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.

Question 59

COX-2

Answer 59

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

Question 60

Traditional NSAIDs vs. Cox specific

Answer 60

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

Question 61

Effects of NSAIDs

Answer 61

Analgesic: central and peripheral

Anti-pyretic

Anti-inflammatory

Anti-thrombotic

Anti-endotoxic

Question 62

Analgesic effects of NSAIDs

Answer 62

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

Question 63

Antipyretic effects of NSAIDs

Answer 63

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.

Question 64

Anti-inflammatory effects of NSAIDs

Answer 64

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

Question 65

Antithrombotic effects of NSAIDs

Answer 65

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.

Question 66

Anti-endotoxic effects of NSAIDs

Answer 66

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.

Question 67

Pharmacokinetics of NSAIDs

Answer 67

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 **

Question 68

Adverse effects of NSAIDs

Answer 68

often due to chronic drug use

dyspepsia, nausea and vomiting

GI ulceration

renal/hepatic toxicity

injury to articular cartilage

precipitate asthma

Question 69

GIT adverse effects of NSAIDs

Answer 69

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

Question 70

Renal toxicity of NSAIDs

Answer 70

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

Question 71

Hepatotoxicity of NSAIDs

Answer 71

relatively uncommon in animals; some idiosyncratic reports i.e hepatotoxicity in dogs getting carprofen, old horses getting phenylbutazone

Question 72

Cartilage damage effect of NSAIDs

Answer 72

chronic NSAID therapy may worsen cartilage degeneration in animals with osteoarthritis–> particularly aspirin, ibuprofen and naproxen

more seen with COX-1 selectivity

Question 73

Asthma and NSAIDs

Answer 73

shunting of arachidonic acid to lipoxyenase pathway with COX-inhibition–> production of leukotrienes–potential to cause bronchospasm

Question 74

Clinical use of NSAIDs in vet med

Answer 74

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.

Question 75

Contraindications of NSAID use

Answer 75

• 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

Question 76

Considerations of choosing NSAIDs

Answer 76

1) efficacy
2) adverse effects/safety
3) licensing
4) ease of admin
5) cost

Question 77

Efficacy of NSAIDs

Answer 77

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

Question 78

Adverse effects/safety of NSAIDs

Answer 78

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

Question 79

Licensing of NSAIDs

Answer 79

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

Question 80

Individual NSAIDs

Answer 80

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

Question 81

Newer NSAIDs

Answer 81

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

Question 82

Robenacoxib

Answer 82

specific cox-2 inhibitor

as tablet or injectable

authorized for peri-op use in dogs and cats

Question 83

Cimicoxib

Answer 83

highly selective cox-2 inhibition–> available as chewable tablet for dogs

Question 84

Mavacoxib

Answer 84

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.

Question 85

Paracetamol (acetaminophen)

Answer 85

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

Question 86

Paracetamol side effects/toxicity

Answer 86

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