NSAIDS #2 Flashcards
How are NSAIDs classified?
- Inhibitors of Prostanoids (PGs, TXA2)
- Miscellaneous Anti-Inflammatory Drugs
NSAIDs: Mechanisms of Action
NSAIDs: Adverse Effects
High doses
Long exposure
▪ Vomiting
▪ Diarrhea
**▪ GI ulceration, hemorrhage, and perforation
▪ Hepatotoxicity
▪ Renal toxicity
▪ Cardiovascular and blood toxicity
▪ CNS depression
▪ Circulatory disturbances
▪ Drug-drug interaction
NSAIDs that are used most commonly in humans can cause poisoning in small animals are?
Aspirin
Acetaminophen
Ibuprofen
Indomethacin
Naproxen
Pneumonic: IIAN
List the Desirable Features of NSAIDs
▪ Deactivate/desensitize _________ (_____)
▪ Attenuate ___________ response
▪ Synergistic with _______
▪ No ___________ or __________
▪ No ____________ depression
▪ Minimal ?
▪ ____ duration of action
▪ No ________ side effects
nociceptors, pain, inflammatory, opioids, addiction, dependence, respiratory, nausea/vomiting, Long, cognitive
COX-1 mediates ?
physiological responses (GI protection, platelet aggregation)
COX-2 is expressed by cells involved in ____________ (e.g.?) is responsible for
the synthesis of _____ and _____
inflammation, macrophages, monocytes, PGs, TXA2
Selective inhibition of COX-2 might have ?
better therapeutic responses
Selectivity of COX2 versus COX1 is often expressed as the?
COX1/COX2 inhibitory ratio
Write the inhibitory effect ratio.
If ratio is > _____, the drug is more specific for COX-2.
The inhibitory effect (IC50) = COX-1/COX-2;
COX-1/COX-2 >1, the drug is more specific for COX-2
COX-1 _______
COX-1 ______ ( _____ selective)
COX-2 _____
COX-2 _______
COX-2 ________ (______ selectivity)
selective, sparing, Non, specific, selective, preferential, limited
Potential benefits in inhibiting LOX pathway:
▪ Higher GI safety
▪ Greater analgesic efficacy
List the examples of Dual inhibitors:
Benoxaprofen
Ketoprofen
Licofelone
Corticosteroids (adverse effects)
Tepoxalin (Zubrin) is approved in Europe and USA
in animals (osteoarthritis in dogs)
List the NSAIDs that fall under the category of the following:
- Selective COX-1 inhibitor
- Non-selective COX inhibitors
- Selective COX-2 Inhibitors
- Dual Inhibitors - COX/LOX
See below
Selective COX-1 Inhibitors
Low-dose Aspirin
Non-selective COX Inhibitors
FAKIN
- Naproxen (AleveR)
- Ibuprofen (MotrinR, AdvilR)
- Ketoprofen ((AnafenR)
- Aspirin
- Flunixin meglumine
Selective-COX-2 Inhibitors
Dual Inhibitors COX / LOX
Tepoxalin
Adverse effects of NSAIDs
NS –> Aspirin - Dogs
Aspirin is not USDA –registered for dogs, but some forms are marketed
for dogs as if there were FDA approval. There is an approved combination
with methylprednisolone (Cortaba tablets)
COX-2 Inh for dogs?
Pneumonic:
Christine Eats Many Penises
______________ is Registered for dogs but not actively marketed
Phenylbutazone
Carprofen (________) Available as an ____________ and ____ (COX-___ sparing in dogs)
Rimadyl, injectable, oral, 1
Meloxicam (_______) is Registered for cats also as a ___ dose, available as an _____ and __
Metacam, single, injectable, oral
The NS Ketoprofen (Anafen) is registered for ?
cats only
Deracoxib (_________) is (COX-__ ______, first veterinary drug in this group)
Deramaxx, 2, specific
_________ _______ (Arquel) is _______ but not marketed
Meclofenamic acid, registered
__________ ____ (Tolfedine) is registered in ______ only, available as an ______ and ___
Tolfenamic acid, Canada, injectable, oral
Aspirin is a NSAID used to reduce?
Pain
Fever
Inflammation
Platelet aggregation
Aspirin: (low doses) prevents?
heart attacks and strokes.
Salicylic acid from _____ ____ have been used for ____ relief since ancient times
willow, bark, pain
Modification of Salicylic acid to ______ ________ ______ (____) = Aspirin
Acetyl Salicylic Acid (ASA)
Use of aspirin for pain and prevention of myocardial infarction
▪ Understanding the molecular mechanism of aspirin
Aspirin MOA
Aspirin irreversible inhibits COX-1 resulting in
decreased PG synthesis
decrease TXA2 expression
Effects of Aspirin
Analgesic
Antipyretic
Anticoagulant: platelet aggregation reducer
Anti-inflammatory: PGs expression reducer
Asprin PK:
Absorption from the _____ and ___ intestine
Bound to _____ (70-90%)
_____ t1/2 in cats (~30 hrs); in dogs (~ 8 hrs); in horses (~ 5 hrs)
_____ are sensitive to aspirin toxicity _____ are sensitive to GI effects (bleeding)
stomach, upper, albumin, Long, Cats, Dogs
______ are sensitive to aspirin toxicity
Cats
_____ are sensitive to GI effects (bleeding)
Dogs
Adverse effects of Asprin:
▪ GI distress: ?
▪ Paradoxical-_______ (body T above ______ F (____ C)
▪ _____ventilation, respiratory _____ (_____ depression)
▪ Metabolic ______
▪ ___________
▪ Pulmonary ______ (______)
▪ If chronic use —– _________ during surgery
▪ In dogs with _____, long-term use may result in aggravation of joint disease
▪ Drug-drug interaction (_______)
vomiting, anorexia, GI ulceration, diarrhea
hyperpyrexia, 106.70, 41.50, Hyper, acidosis, CNS, acidosis, Dehydration, edema, sheep, bleeding, OA, Warfarin
Treatment of aspirin-toxicity:
▪ Induce ______ in the case of ____ toxicity
▪ Increase _____ of the drug: gastric lavage followed by administration of activated _____
▪ Increase _____ excretion of aspirin by administrating an ______ agent
▪ Initiate IV ___ therapy to address _____ and metabolic ______
emesis, acute, removal, charcoal, urinary, alkalinizing, fluid, dehydration, acidosis
Aspirin
Contraindications: Patients with _____ GI ______; _______ disorders, _____, or _____ insufficiency
active, bleeds, bleeding, asthma, renal
Flunixin meglumie AKA?
Banamine
Flunixin: A _____-_________ COX inhibitor with potent __________ and ______-___________ effects
non-selective, analgesic, anti-inflammatory
MOA of Flunixin meglumine
MOA: Shows greater COX-2 inhibitory effects than COX-1 in _________-.
In _________-, it appears to exhibit preferential COX-1 inhibitory effect
MOA: Shows greater COX-2 inhibitory effects than COX-1 in horses.
In dogs, it appears to exhibit preferential COX-1 inhibitory effect
Uses of Flunixin meglumine
Uses:
▪ For the treatment of ____, ______, and _______ pain
▪ Exceptional property: it alleviates ________ pain related to colic
▪ In horses: effective in producing the _________ duration of ________ analgesia (~ ___ hrs)
▪ In cattle: for the control of _________ associated with respiratory disease, _________ and _______ (____ approved by FDA)
Uses:
▪ For the treatment of acute, visceral, and surgical pain
▪ Exceptional property: it alleviates visceral pain related to colic
▪ In horses: effective in producing the longest duration of postoperative analgesia (~ 13 hrs)
▪ In cattle: for the control of pyrexia associated with respiratory disease,
endotoxemia and mastitis (not approved by FDA)
PK for Flunixin meglumine
PK:
▪ Administered via what routes:
▪ IV: a plasma t1/2 of 2-4 hrs (______); 3-6 hrs (____); 4hrs (____);1-1.5 hrs (____)
▪ IV: Duration of action is ___-____ hrs
▪ _____ excretion
IV, IM, horses, cattle, dogs, cats, 24-36, Renal
Adverse Effects - Flunixin Meglumine
Adverse effects:
▪ _________ with IM administration
▪ Overdose in horses: ulcers on the ?, _____ depression, _______ (rare)
▪ In dogs: _____ failure and ___ damage
Adverse effects:
▪ Myonecrosis with IM
▪ Overdose in horses: ulcers on the tongue, gingiva, lips, and stomach
CNS depression, anorexia (rare)
▪ In dogs: renal failure and GI damage
Ketoprofen: A ____-_______ COX inhibitor with ___-_________ and _______ effects
non-selective, anti-inflammatory, analgesic
Ketoprofen MOA
MOA: Inhibition of COX-1 and COX-2 and LOX-pathway ( LTB4 synthesis)
List the uses of Ketoprofen
Uses: In horses:
▪ Acute and chronic ___________ disorders
PK:
▪ Admin routes?
▪ Excellent bioavailability of ___-___%
▪ _____ elimination t1/2 of ~ 1 hr (horses); 1.5 hrs (dogs and cats)
▪ _____ excretion
Uses: In horses:
▪ Acute and chronic musculoskeletal disorders
PK:
▪ IV, IM, SC or PO
▪ Excellent bioavailability of 80-100%
▪ Short elimination t1/2 of ~ 1 hr (horses); 1.5 hrs (dogs and cats)
▪ Renal excretion
Adverse effects of Ketoprofen?
Adverse effects:
▪ Safer profile compared to _____ or _________
▪ PO: GI injury including ______ and ______
▪ Caution in animals with ________ disorders (decreased platelet _______)
▪ Caution in animals with compromised _____ function
flunixin, phenylbutazone, ulceration, bleeding, hemostatic, aggregation, renal
Phenylbutazone: The _____ and _____ profile in addition to its _____
makes it the most commonly used NSAID in the ____
safety, efficacy, affordability, horse
Phenylbutazone MOA
Preferential COX-___ inhibitor in both ____ and ___
MOA: Preferential COX-2 inhibitor in both horses and dogs
Phenylbutazone Uses
Uses:
▪ Osteoarthritis
▪ Various forms of lameness
▪ Rheumatism
▪ Other painful conditions of the limbs
▪ Nonspecific inflammation in other conditions
Phenylbutazone PK
PK:
▪ After IV administration, t1/2 is ____-_____ hrs in the dog and horse
▪ Long duration of action (___-___ hrs)
▪ ______ metabolite (___________)
▪ High ______ binding
▪ Elimination via ____ excretion (25%)
PK:
▪ After IV administration, t1/2 is 2,5 – 6 hrs in the dog and horse
▪ Long duration of action (24 -72 hrs)
▪ Active metabolite (oxyphenylbutazone)
▪ High albumin binding
▪ Elimination via renal excretion (25%)
Adverse effects of Phenylbutazone
▪ GI distress: ?
▪ Renal papillary _______
▪ ________ (hypovolemic shock, ulcer-mediated sepsis)
Adverse effects:
▪ GI distress: erosions, ulcers, anorexia, colic, diarrhea
▪ Renal papillary necrosis
▪ Death (hypovolemic shock, ulcer-mediated sepsis
Contraindications of Phenylbutazone
Contraindications: Patients with serious cardiac, renal, hepatic injury, or hematologic disorder
Carprofen: preferential COX-___ inhibitor with _____ and ____-_____ effects
2, analgesic, anti-inflammatory
Carprofen MOA
Potency of carprofen for canine COX-___ is more than ______- fold greater relative to canine COX-___
MOA: Potency of carprofen for canine COX-2 is more than 100- fold greater relative to canine COX-1
Carprofen Uses
1. _____-term and _____-term pain management
2. ______________ disorders
Uses: Short-term and long-term pain management
▪ Musculoskeletal disorders
Carprofen PK
▪ Administrated via ?
▪ PO: the Tmax is short or long?
▪ Highly bound to _______ (99%)
▪ ______ metabolism
▪ Eliminated in the _____ and ______
▪ Elimination t1/2 in cats: ?
in dogs: ?
PK:
▪ PO, IV or SC
▪ PO: the Tmax is 1-3 hrs (dogs) SHORT
▪ Highly bound to albumin (99%)
▪ Liver metabolism
▪ Eliminated in the feces/urine
▪ Elimination t1/2 in cats: ~ 20 hrs LONG
in dogs: ~ 5-7 hrs MIDDLE GROUND?
Carofen adverse effects
▪ Lower frequency of GI ______ and ______
▪ ___________, __________, __________
▪ Caution in patients with _____ or ____ dysfunction
Adverse effects:
▪ Lower frequency of GI ulceration and hemorrhage
▪ Diarrhea, anorexia, vomiting
▪ Caution in patients with hepatic or renal dysfunction
Carprofen contraindications
Contraindications: Patients with hemostatic disorders; pregnant, lactating, or breeding bitches
Meloxicam aka?
Metacam
Meloxicam: A preferential COX-______ inhibitor with __________ and ____-________ effects
2, analgesic, anti-inflammatory
Meloxicam MOA
MOA: COX2/COX1 selectivity ratio of ~ 10
Meloxicam Uses
Uses: For treatment of chronic ____ and ________
▪ _______________
▪ ______-operative ______ pain
Uses: For treatment of chronic pain and inflammation
▪ Osteoarthritis
▪ Post-operative somatic pain
Meloxicam PK
▪ PO: ______ absorption, Tmax ~ ___ hrs
▪ _______ bound to albumin (97%)
▪ The plasma t1/2 is ______-specific: 12-24 hrs (____); 15 hrs (____); 3 hr (_______)
▪ ______ metabolism
▪ Elimination in the ____
PK:
▪ PO: good absorption, Tmax ~ 8 hrs
▪ Highly bound tp labumin (97%)
▪ The plasma t1/2 is species-specific: 12-24 hrs (dogs); 15 hrs (cats); 3 hr (horses)
▪ Liver metabolism
▪ Elimination in the feces
Meloxicam Adverse effects
___________ safe NSAID in dogs and cats
▪ ___ distress
▪ _________
▪ _______
^ all of the above are ____ and _____
Adverse effects:
Relatively safe NSAID in dogs and cats
▪ GI distress
▪ Anemia
▪ lethargy
Rare and transient
Repeated use of Meloxicam in cats can evoke ______ ______ failure and _____
Caution: Repeated use in cats can evoke acute renal failure and death
Meloxicam contraindications
Contraindications: Not recommended in pregnant, lactating or in young animals (< 4 months)
Meloxicam is FDA-approved in ______.
cats
Etodolac: A preferential COX-____ inhibitor with ______ and ____-________ effects
2, analgesic, anti-inflammatory
Etodolac MOA
?
Etodolac AKA
EtoGesic
Etodolac Uses
▪ _____________ in dogs
▪ Other conditions
▪ Osteoarthritis in dogs
▪ Other conditions
Etodolac PK
▪ PO: ______ absorption and a _____
onset of action (30-60 min)
▪ Is the half life long or short?
▪ ____ excretion
▪ PO: Rapid absorption and a rapid
onset of action (30-60 min)
▪ Long plasma t1/2 : 10-14 hrs
▪ Bile excretion
Etodolac Adverse effects:
____ distress
______ depression
______totoxicity
_______toxicity
May induce ________________ _____ in dogs (monitor ____ production)
GI distress , CNS depression, hepatotoxicity, nephrotoxicity
May induce keratoconjunctivitis sicca in dogs (monitor tear production)
Etodolac caution
Caution: In patients with hematological, renal, or hepatic impairment
Tepoxalin: _____ inhibitor: _____-_______ COX inhibitor plus potent inhibitory effect on _____
Dual, non-selective, LOX
Tepoxalin AKA
Zubrin
Tepoxalin MOA
MOA: inhibition of COX-__, COX-___, and ___-LOX
reduction of the production of ____ mediators of pain, fever, and inflammation
MOA: inhibition of COX-1, COX-2, and 5-LOX
reduction of the production of PG mediators of pain, fever, and inflammatio
Tepoxalin uses
▪ __________ in dogs
▪ _______ conditions in dogs
▪ ____- operative pain control
▪ Osteoarthritis in dogs
▪ Allergic conditions in dogs
▪ Postoperative pain control
Tepoxalin PK
▪ Readily absorbed after _____
▪ _______ metabolized, one ____ metabolite, Both are highly bound to ______
▪ T1/2: __ hrs and __ hrs, respectively
▪ Elimination in the ______
▪ Readily absorbed after PO
▪ Rapidly metabolized, one active metabolite
▪ Both are highly bound to albumin
▪ T1/2: 2 hrs and 13 hrs, respectively
▪ Elimination in the feces
Tepoxalin Adverse effects
▪ GI distress: vomiting, anorexia, diarrhea, ulceration
▪ CNS depression
▪ Hepatotoxicity
▪ Nephrotoxicity
Deracoxib (DeramaxxR) Uses
▪ Osteoarthritis
▪ Post-operative pain and inflammation
Deracoxib PK
▪ PO:
▪ _____ protein bound
▪ _____ excretion
▪ 20% may be excreted in the _____
▪ PO:
▪ Highly protein bound
▪ Bile excretion
▪ 20% may be excreted in the urine
Deracoxib adverse effects
GI distress
Firocoxib is also called ?
PrevicoxR, Equioxx
Firocoxib uses?
Osteoarthritis
Firocoxib PK
▪ The bioavailability: ~ 80% in _______
~ 40% in ___
▪ ______ protein bound
▪ _______ metabolism
▪ _____ excretion
▪ The bioavailability: ~ 80% in horses
~ 40% in dogs
▪ Highly protein bound
▪ Hepatic metabolism
▪ Fecal excretion
Firocoxib adverse effects
▪ Diarrhea, mouth ulcers
▪ Excitation (rare)
^ horses
▪ Vacuolization in the brain
(high doses)
^ dogs
Drugs that are rarely used in Veterinary Medicine
Non-selective COX Inhibitors:
Aspirin
Acetaminophen (TylenolR) ( particularly unsafe in cats)
(paracetamol)
Ibuprofen (Motrin, Advil)
Naproxen (Aleve) (used in horses to treat myositis, lameness)
Indomethacin
Dimethyl sulfoxide (DMSO): a solvent for many _____, ____ and _____ compounds. It is clear, _____ to ____-yellow liquid, highly _______.
aromatic, organic, inorganic, colorless, straw, hygroscopic
Dimethyl sulfoxide (DMSO) effects
▪ Anti-inflammatory: inhibits PG synthesis and traps free radicals
▪ Analgesic
▪ Skin penetrating
▪ Diuretic
▪ Anticholinesterase
▪ Weak antibacterial
▪ Weak antifungal
Dimethyl sulfoxide (DMSO) PK
▪ Well absorbed after _______ application
▪ _________ & ______ distribution
▪ Primarily _____ excretion
▪ Well absorbed after topical application
▪ Extensive & rapid distribution
▪ Primarily renal excretion
Dimethyl sulfoxide (DMSO) Uses
▪ _____ swelling (_________ trauma)
▪ Cerebral _____ & ______ (spinal cord trauma)
▪ _________ (urethral ________ in the cat)
▪ Superficial _____
▪ Skin _____
▪ Transient ______ conditions
▪ Edema of limbs resulting from _____
▪ _____ and _______ of mammary glands in the nursing bitch
▪ Severe __________ resulting from the extravascular injection of irritating drugs or lick granuloma
▪ Acute swelling (musculoskeletal trauma)
▪ Cerebral edema & paralysis (spinal cord trauma)
▪ Cystitis (urethral obstruction in the cat)
▪ Superficial burns
▪ Skin grafts
▪ Transient ischemic conditions
▪ Edema of limbs resulting from fractures
▪ Swelling and engorgement of mammary glands in the nursing bitch
▪ Severe inflammation resulting from the extravascular injection of irritating drugs or lick granuloma
Dimethyl sulfoxide (DMSO) adverse effects
When used as labeled, it is _____
▪ Transient _____ effects
▪ High doses, long use —- ______
▪ IV: _______ and ________
▪ _____ and ____ damages, pulmonary ____
▪ CNS: _______, _________, ________
When used as labeled, it is safe
▪ Transient local effects
▪ High doses, long use —- myopia
▪ IV: hemolysis and hemoglobinuria
▪ Hepatic and renal damages, pulmonary edema
▪ CNS: sedation, coma, seizures
OA is a degenerative joint disease that affects the dog’s spine and lower limbs leading
to stiffness and excruciating pain in the joint
Synovial lining is a membrane surrounding each joint, SF
(synovial fluid) helps ensure smoot and easy body movement
Hyaluronic acid (HA) is a natural lubricant of the joints, part of
SF.
Polysulfated glycosaminoglycan :
Disease-modifying osteoarthritis drugs (DMOADs)
(AdequanR) (PSGAG)
PSGAG MOA
▪ PSGAG modulates clinical signs of ______ by indirectly promoting ______________ effect via different mechanism
▪ Improves joint articular function by having effects on _________ _____
▪ Anti-inflammatory: inhibition of _____ biosynthesis, ________ migration & ________ levels
▪ PSGAG modulates clinical signs of OA by indirectly promoting chondroprotective effect
via different mechanism
▪ Improves joint articular function by having effects on synovial fluid
▪ Anti-inflammatory: inhibition of PGE2 biosynthesis, leukocyte migration & interleukin levels
PSGAG Uses
▪ To treat traumatic joint dysfunction (horses)
▪ To treat OA and prevent hip dysplasia (dogs)
PSGAG PK
route: Intra-articularly (IA) or IM
▪ No information is available
PSGAG Adverse Effects
When used as labeled, it is safe
Associated with drug administration, i.e. / septic arthritis
Polysulfated glycosaminoglycan (PSGAG)
Hyaluronate sodium (HS)
MOA?
A cushioning effect: reducing cell ________
Lubricating effect on the _______ ___ tissue
A scavenging effect: removes ____-derived free radicals
A cushioning effect: reducing cell migration
Lubricating effect on the articular soft tissue
A scavenging effect: removes O2-derived free radicals
Hyaluronate sodium Uses?
Uses: To treat _______ that is associated with OA in dogs and horses
PK: No information is available in _____
Adverse effects: Transient ____ effects: ?
Uses: To treat synovitis that is associated with OA in dogs and horses
PK: No information is available in animals
Adverse effects: Transient local effects: swelling, heat
Hyaluronate sodium PK
PK: No information is available in animals
Hyaluronate sodium Adverse effects
Adverse effects: Transient local effects: swelling, heat
Guidelines for the safe use of NSAIDs
▪ Individualized dosage based on the drug’s ________, ____ of the animal, and _________ of action
▪ Screen patients for underlying ______ and _______ dysfunction by performing ________ diagnostic procedures
▪ Monitor the _________ status of patients. __________ animals should not be places on NSAIDs before the hydration status is improved
▪ An adequate ______ ______ period should be allowed prior administrating a new NSAID
▪ Administer the _______ possible effective dose for the ______ period to minimize risk of injury
▪ Concurrent use of __________ and _______ should be avoided due to increased risk of GI complications
Guidelines for the safe use of NSAIDs
▪ Individualized dosage based on the drug’s efficacy, age of the animal, and duration of action
▪ Screen patients for underlying renal and hepatic dysfunction by performing routine diagnostic
procedures
▪ Monitor the hydration status of patients. Hypovolemic animals should not be places on NSAIDs
before the hydration status is improved
▪ An adequate wash out period should be allowed prior administrating a new NSAID
▪ Administer the lowest possible effective dose for the shortest period to minimize risk of injury
▪ Concurrent use of glucocorticoids and NSAIDs should be avoided due to increased risk of
GI complications
