14. NSAIDs Flashcards
Obligatory to know NSAIDs substances (8):
- acetylsalicylic acid
- carprofen
- flunixin meglumine
- meloxicam
- metamizole sodium
- firocoxib
- robenacoxib
- mavacoxib
Other important NSAID (not bold from drug list):
- sodium salicylate
- sulfasalazine
- mesalazine
- olsalazine
- ketoprofen
- vedaprofen
- tolfenamic acid
- phenylbutazone
- piroxicam
- paracetamol
- nimesulide
- deracoxib
- cimicoxib
Mechanism of action of NSAIDs
The main mechanism of action of NSAIDs is the inhibition of the enzyme cyclooxygenase (COX). Cyclooxygenase is required to convert arachidonic acid into thromboxanes (TX) (platelet adhesion), prostaglandins (PGE, PGF) (vasodilation, increase the temperature set-point in the hypothalamus and a role in anti-nociception) and prostacyclins (PGI). The therapeutic effects of NSAIDs are attributed to the lack of these eicosanoids (eico - 20 in greek, arachidonic acid has 20 carbon atoms)
There are two cyclooxygenase isoenzymes, COX-1 and COX-2.
COX-1 gets constitutively expressed in the body, and it plays a role in maintaining gastrointestinal mucosa lining, kidney function, and platelet aggregation.
COX-2 is not constitutively expressed in the body; and instead, it inducibly expresses during an inflammatory response.
COX-3 is present in CNS, mainly in hypothalamus and thalamus leading to fever and increased pain perception (inhibition of COX-3 will not have antiiflammatory effect =› not NSAIDs but minor analgesics)
For what enzymes arachidonic acid is a substrate?
⋆ Lipoxigenase (→ leukotriens, lipoxins)
⋆ Cyclooxigenase (→ prostaglandins, prostacyclins, thromboxins)
⋆ Epoxigenase
Cyclooxigenase (COX) products
⋆ prostaglandins (PGF, PGE)
⋆ prostacyclins (PGI)
⋆ thromboxins (TX)
Localization of COX-1
Stomach, kidney, platelets.
Constitutive enzyme (constantly present in the body)
Role of PGE (produced by COX-1) in protecting gastric wall
⋆ ↓ HCl secretion
⋆ ↑ mucuous secretion
⋆ ↑ blood perfusion of stomach wall -> better regeneration
Effect of PGE on the kidney.
What happens in case of COX-1 inhibition?
Dilation of vessels. ↑RBF
If COX-1 is inhibited -› PGE is not produced -› vasoconstriction and kidney damage
Role of TX
providing normal aggregation of platelets
Result of COX-1 inhibition:
⋆ gastric ulceration (no PGE effect on GIT)
⋆ kidney damage (no PGE effect on kidneys)
⋆ bleeding (no thromboxins effect)
Localization of COX-2
⋆ Macrophages, fibroblasts.
⋆ Produced at the site of inflammation. Primar inflammatory enzyme.
⋆ Inductive drug (is produced when iflammation is present)
Which COX enzyme is the target when we apply NSAIDs?
COX-2
COX-3
present in CNS, mainly brain, mainly hypothalamus and thalamus → fever, pain sensation
inhibition of COX-3 will not have antiiflammatory effect =› not NSAIDs but minor analgesics
inhibitors of COX-3
⋆ Paracetamol (acetaminophen)
⋆ Metamizole
Very good antipyretic (antifever) and analgesic effect WITHOUT antiiflammatory effect → NOT NSAID, but MINOR ANALGESICS
What are 3 groups of NSAIDs? (COX2/COX1)
⋆ classical NSAIDs: < 1 (ketoprofen, aspirin)
⋆ more selective COX-2 inhibitors: 1-20 (meloxicam, carprofen)
⋆ coxibs: > 20
Pharmacological effect of NSAIDs
⋆ ANTIINFLAMMATORY
⋆ ANALGESIC
⋆ ANTIPYRETIC (anti fever)
⋆ platelet aggregation inhibition (aspirin)
⋆ antiendotoxin (meloxicam, flunixin)
⋆ spasmolytic (flunixin, metamizole)
⋆ antineoplastic (piroxicam)
NSAIDs with antiendotoxin effect
⋆ meloxicam
⋆ flunixin (very often used in horses)
Gr- bacteria
NSAIDs with spasmolytic effect
⋆ flunixin (very often used in horses)
⋆ metamizole (COX-3)
GI tract, urinary tract, genital tract
NSAIDs with antineoplastic effect
⋆ piroxicam
prostate and urinary bladder tumors
Pharmacokinetics of NSAIDs. Absorption
- weak acids -› 2 forms in the body: inionised and ionised. In stomach juice non-ionised form will be overproduced -› quick absorption already from stomach.
- weak acids -› irritant for the stomach, so it’s better to give WITH food.
Exceptions in NSAIDs regarding giving it with food
- Ketoprofen: food decreases absorption
- carprofen and meloxicam: don’t care, can be given both way
- mavacoxib: empty stomach - 20% absorption, full stomach - 80% absorption! Always mavacoxib with food
Pharmacokinetics of NSAIDs. Distribution
⋆ extensive albumin binding (check for hypoalbuminaemia). Do not combine with other drugs with high albumin binding (will compete for albumin -› increase of toxicity)
⋆ loading dose
⋆ can’t go through blood-milk barrier (0 WP for milk) (blood-milk barrier can be penetrated only by free form of the drug)
Why should we check patient for hypoalbuminaemia before administration of NSAIDs?
extensive albumin binding → in case of hypoalbuminaemia lots of free drug → toxicity↑ → blood sample first, if hypoalbuminaemia, then decrease the dose of NSAID
Also not to combine with other drugs with high albumin binding (will compete for albumin -› increase of toxicity)
Why loading dose and maintenance dose needed?
To saturate all of the albumin first, then decrease the dose (maintenance dose) so there is no free drug
Pharmacokinetics of NSAIDs. Metabolism
Mostly glucuronic acid conjugation
Glucoronic acid is absent in cats!!!
Why cats are sensitive for NSAIDs?
Cats don’t have glucoronic acid -> drug is not conjugated -> half-life↑↑↑ -> slower elimination
Ususally in cats doses are lower or drugs are given less frequently. No drug is authorised (officially) for cat for more than 1 week!!! Meloxicam is good long-term variant due to publications
Pharmacokinetics of NSAIDs. Excretion
ecxreted mainly via urine
2 main side effects of NSAIDs:
⋆ GI ulceration - stomach and duodenal ulcers
⋆ Kidney damage
Explain GI ulceration side effect of NSAIDs
- local irritation by weak acids -› weak acids fall into “ion trap” of the cells of the stomach -› intracellular damage
- decrease of PGE level (most importantly)
For treating of this proton pump inhibitors will be used (e.g. omeprazole).
Explain kidney damage side effect. When should we especially careful?
⋆ vasoconstriction
⋆ ↓perfusion of kidney
⋆ CAREFUL:
1. preexistal renal disease
2. dehydrated animals (perfusion is decreased, rehydrate first!)
3. during anaesthesia (perfusion is decreaed, NSAIDs are used as POST operative analgesia usually)
Other side effects of NSAIDs:
⋆ Hepatotoxicity (paracetamol, carprofen)
⋆ Platelet aggregation inhibition
⋆ Methaemoglobinaemia
⋆ Proteoglycan synthesis inhibition (cartilage damage)
⋆ Fetal damage (teratogenicity)
⋆ Placenta retention (48+36 hours)
Why paracetamol can be hepatotoxic?
metabolised in very active NAPQI →
⋆ damage of liver in human and dog
⋆ IN CATS oxidises Fe2+ → Fe3+ => METHAEMOGLOBINAEMIA
NEVER PARACETAMOL TO CATS
In which dog breed which NSAIDs drug can cause idiosencratic (individual) hepatotoxic reactions.
Carprofen. Retrievers
NSAIDs that cause platelet aggregation inhibition
⋆ aspirin
⋆ flunixin
⋆ ketoprofen
⋆ tolfenamic acid
NOT RECOMMENDED AFTER SURGERY
Drugs that can cause proteoglycan synthesis inhibition (cartilage damage)
⋆ aspirin
⋆ ketoprofen
⋆ (ibuprofen, naproxen) - human drugs
bad because NSAIDs are often given to arthritis patients
Which NSAID can be used during pregnancy?
Metamizol (COX-3)
Which NSAID does not cause placenta retention and can be used during parturation ?
Meloxicam
NSAIDs are not recommended 48h before and 36h after parturition
Aspirin (acetylsalycilic acid)
⋆ rarely used (farm animals: swine, poultry)
⋆ is safe short-term for dogs
Na salycilate
- more COX-2 selective than aspirin
- only in farm animals
Sulfasalazine, mesalazine
- only in dogs in humans
- chronic colitis tratment (Crohn’s desease)
- applied orally, act locally in large intestine -› very safe
Ketoprofen
⋆ old drug
⋆ platelets! -> not after surgery or in bleeding animals
⋆ very safe short-term (short half-life in cats), maybe the best antipyretic in cats
⋆ cartilage damage
Vedaprofen
- for horses only
- oral paste
- COX-2 selective
- similar to carprofen
Carprofen
⋆ VERY OFTEN USED
⋆ very safe COX-2 selective for all species
⋆ can be given life-long
⋆ hepatotoxic idiosyncratic reaction in retrievers
⋆ long action in cattle (4-5 days, WP for meat - 1 month)
How carprofen is applied?
- p.o./ s.c./ i.v. (4.4 -› 2.2 mg/kg - dog dose)
Flunixin meglumine
⋆ thrombocyta-aggregation inhibition (bleeding)
⋆ antiendotoxic
⋆ spasmolytic (often in horses)
⋆ in cattle half-life is very short -> flunixin-containing pour-on
Tolfenamic acid
- bleeding time increases
- short-term safe drug in cats (very short half-life)
Phenylbutazone
- sometimes in horses
- mainly as an ointment
- kinda outdated
Piroxicam
- human drug
- is not considered safe
- in vet medicine is used in oncology, not as antiinflammatory, not as painkiller
Meloxicam
⋆ VERY OFTEN USED
⋆ COX-2 mainly
⋆ safe in all species (and in humans too)
⋆ loading dose needed (0.2 -› 0.1 mg/kg dose on dog)
⋆ antiendotoxin
⋆ injection and oral application
Paracetamol
- COX-3 - minor analgesic
- NEVER IN CATS
- idiosyncratic reaction in humans
Metamizole sodium
⋆ mainly COX-3 inhibitor - minor analgesic
⋆ very safe (no affect on stomach, nor kidney)
⋆ in cats nervous system affected (excitation, salivation), not to use in cats
⋆ mainly in dogs and rodents
Coxibs
⋆ Firocoxib (+horse)
⋆ Robenacoxib (+the only coxib for cats)
⋆ Mavacoxib (with food, long half-life)
⋆ Deracoxib
⋆ Cimicoxib
Deracoxib
- authorised for dogs
- similar to meloxicam but much safer
Firocoxib
- highly selective COX-2
- dogs and horses orally
- one of best NSAIDs
Robenacoxib
- only coxib licensed for cats
- only coxib by injection
Cimicoxib
- tablets for dogs
Mavacoxib
- only for dogs. tablets
- very long half-life in dogs (5-7 days)
- 3-4 weeks duration of action
- give with food !!! (20% vs 80% bioavailability)
- convinient for owner, very effective, very safe
