8th lecture - NSAIDs Flashcards
Nonsteroidal anti-inflammatory drugs have what effects (3)
Antipyretic effect
Anti-inflammatory effect
Analgesic effect
mechanism of action of NSAIDs
they block the formation of prostaglandins from arachidonic acid.
Prostaglandins play a key role in the generation of the inflammatory response.
The function of PG as an inflammation mediator is important from the point of view of the mechanism of action of NSAIDs.
Their biosynthesis is significantly increased in inflamed tissue and they contribute to the development of the cardinal signs of acute inflammation.
Prostaglandins are what type of substance
They are autacoids/tissue hormones that are also referred to as eicosanoids (20 carbons and are unsaturated fatty acids, synthesised in all cells of the body.
Prostaglandins play a key role in the generation of the inflammatory response.
How do prostaglandins affect the reproductive organs?
regulation of the function of reproductive organs (contractions of the uterus, motility of the ovarian tubes, the process of fertilization, occurrence of smooth muscle contractions)
Which prostaglandin is the most important in the context of veterinary med?
PGF2α from the standpoint of the reproductive function.
Prostaglandins are involved in pain perception at what level
the spinal level
Name the endogenous pyrogen leading to upward resetting of the temperature regulating center in the hypothalamus.
PGE2
The endogenous pyrogen PGE2 does not directly stimulate
nociceptors, but increases intensity and duration of the afferent discharge caused by histamine and bradykinin.
The endogenous pyrogen PGE2 does not directly stimulate nociceptors, but increases intensity and duration of the afferent discharge caused by (2)
histamine and bradykinin.
allodynia is defined as
“pain due to a stimulus that does not normally provoke pain.”
so when tissues are damaged, stimuli that are not normally painful, become painful
Analgesic action of NSAIDs is via the inhibition of
PG synthesis.
Arachidonic acid is what type of substance
20-carbon unsaturated fatty acid.
An estrified component of cell membrane phospholipid, which is released in tissue damage following activation of phospholipase A2.
Prostaglandins (PGs) are formed by the enzymatic activity of?
COX-1 and COX-2
Prostaglandins (PGs) formed by the enzymatic activity of COX-1 are primarily involved in the regulation of homeostatic functions throughout the body,
whereas PGs formed by COX-2 primarily mediate pain and inflammation.
prostaglandin synthase isoforms
COX1 and COX2
Name 5 classic Mediators of inflammation and pain
bradykinin
histamine
leukotrienes
prostaglandins
serotonin
Histamine main inflammatory effect
Dilation of capillaries, increase in permeability
Serotonin main inflammatory effect
Increase in permeability of capillaries
Bradykinin and leukotrienes main inflammatory effect
Increases the permeability of small veins, induces swelling and pain
Prostaglandins main inflammatory effect
Dilation of blood vessels, increase in permeability, bronchoconstriction
the eicosanoids family includes what main player
inflammatory mediator prostaglandin!
COX1 stands for
cyclooxygenase 1
COX1 mediates (5)
prostaglandin synthesis in many tissues,
it is involved in maintaining tissue homeostasis (mucous membrane of the gastrointestinal tract),
blood clotting,
regulation of vascular homeostasis, coordination of the actions of circulating hormones – „houskeeping“ functions.
Inhibition of COX1 is associated with the toxic effects of NSAIDs. Why?
blocking COX-1 mediated production of prostaglandins in the stomach by aspirin and other non-selective NSAIDs (e.g. ibuprofen, naproxen) is expected to increase the incidence of peptic ulcers (and associated symptoms including bleeding & pain)
So since COX-1’s primary role is to protect the stomach and intestines and contribute to blood clotting, using drugs that inhibit cyclooxygenase can lead to unwanted side effects like ulcers.
COX2 stands for
cyclooxygenase 2
is an enzyme, present in brain, kidney, ovary, uterus, ciliary body.
COX2 mediates
COX2 produces both pro- (in the early stages of inflammatory response) and anti-inflammatory (in the resolution face of inflammation) PGs at the sites of inflammation.
Why might we favor COX2 inhibitors?
COX-2 enzymes make prostaglandins that are mainly involved in inflammation.
COX-2 inhibitors don’t block COX-1 enzymes which are important for gut mucosal integrity.
This means that your stomach and intestinal lining protection and your body’s blood clotting ability are not severely affected when using selective COX2 inhibitors.
Mechanism of action of NSAIDs is at what enzymatic level
Suppression of the prostaglandin (most important inflammation mediators) synthesis on the cyclooxygenase level.
But They can also impact other inflammation mediators like They depress neutrophil functions and They suppress immune response of the organism.
Salicylate class of NSAIDs includes? (4)
Salicylic acid
Sodium salicylate
Acetylsalicylic acid, also known as aspirin (classical representative of NSAIDs)
Salicylamide
Derivatives of phenylacetic acid, class of NSAIDs includes? (1)
Diclofenac
Derivatives of phenylpropanoic acid, class of NSAIDs includes? (3)
Naproxen
Ketoprofen
Ibuprofen
Derivatives of anthranilic acid, class of NSAIDs includes? (3)
Mefenamic acid
Flufenamic acid
Tolfenamic acid
class of NSAIDs called Pyrazolones includes? (3)
Phenylbutazone, also known as butadion
Metamizole, also known as Analgin
Suxibuzone
class of NSAIDs that are Derivatives of indole include? (2)
Indometacin
Acemetacin
class of NSAIDs that are Oxicams include? (2)
Piroxicam
meloxicam
class of NSAIDs that are Derivatives of nicotinic acid include? (1)
Flunixin meglumine
Why is paracetamol not classified as a classic NSAID?
Paracetamol has similar analgesic and antipyretic properties to NSAIDs;
however, its classification is controversial, since unlike NSAIDs, it has little anti-inflammatory activity and is an inhibitor of the COX-3 isoenzyme, a centrally-located variant of COX-1 in dogs.
Some have suggested that paracetamol should be classified as an
atypical NSAID.
What is responsible for the antipyretic effects of paracetamol?
The inhibition of cerebral COX is responsible for the antipyretic effects of paracetamol, which is considered the drug of choice in human patients with gastritis, renal disease or with platelet aggregation problems, where the administration of NSAIDs is contraindicated.
In which species is paracetamol an effective analgesic and antipyretic
in dogs.
3 examples of COX2 inhibitors and the species they are indicated for
Firocoxib (Previcox) - for horses and dogs
Robenacoxib (Onsior) - for cats and dogs
Mavacoxib for dogs
side effects of NSAIDs may appear when
since NSAIDs are lipid soluble and bind to serum albumin (making the free fraction small) - in the case of a lower than normal amount of serum albumin there will be more of free fraction and side effects may occur.
The proportion of free fraction in the plasma is greater in young animals and old animals and the dose should be lower. They are eliminated at a slower rate from the inflamed tissue.
so hypoproteinemia
NSAID metabolism occurs where
in the liver, glucuronide conjugation occurs through glucuronyl transferase.
They are more toxic to cats (there is no enzyme glycuronyltransferace )!
NSAIDs are eliminated through
the kidneys
Pharmacodynamics of NSAIDs
In the event of inflammation, they reduce exudation, swelling, phagocytosis. This is particularly the case in the event of non-infectious inflammatory diseases.
The analgesic effect is best in case of somatic pains of endogenous origin (rheumatic pain, myocarditis, joint pain).
NSAID effect on blood
NSAIDs also suppress the coagulation of blood (especially aspirin) – antithrombotic effect.
Complete inhibition of COX2 (for long time) might cause side effects such as>
abortion, fetal abnormalities, delayed bone and soft tissue healing, nephrotoxicity, cardivascular effects.
Side effects of NSAIDs
More frequently occurring side effects are the following: (3)
Vomiting, diarrhoea,
depression of the central nervous system, ulcers in the stomach and the duodenum.
Aspirin – derivative of phenol.
And cats
Cats lack glucuronyl transferase therefore the duration of action of aspirin is long, the risk of side effects is thus high.
Describe the GI toxicity of NSAIDs
Occurrence of ulcers and bleeding in the gastrointestinal tract .
NSAIDs prevent the formation of COX1-mediated PGI2 and PGE2 in the epithelial layer of gastric mucous membrane, which are necessary for the creation of new epithelial cells of the mucous membrane and for the production of mucus.
Therefore, the enzymes and gastric acid in the stomach make the protective mucous epithelium thinner and cause ulcers, which are also facilitated by the acidic pH of the drugs.
NSAIDs cause irritation in the stomach, that can lead to persistent emesis.
The irritation can occur after parenteral as well as oral administration.
What type of NSAID causes less toxic effects to the GI tract?
Selective COX-2 inhibitors because COX-1 is needed for GI mucosal integrity.
Describe the cardiovascular effects of NSAIDs
„Cardiovascular events“ such as myocardial infarction, thrombosis, strokes, sudden death caused by COX2 inhibitors are reported in humans.
Rofecoxib withdrawn from the market.
In animals, most of studies do not confirm the risk for cardiovascular toxic effects.
How do NSAIDs contribute to anticoagulation?
NSAIDs inhibit the synthesis of prostaglandins.
Prostaglandins are required for platelet aggregation.
Prostaglandin (thromboxane) synthesis is mediated by COX-1 so when COX-1 is inhibited by NSAIDs, coagulation time is always prolonged.
Aspirin is the most specific COX1 inhibitor, the acetyl group inhibits the cyclo-oxygenase in platelets irreveribly.
What drug is the most specific COX1 inhibitor
Aspirin
Describe the renal effects of NSAIDs
PG-s regulate glomereular filtration, renin release and tubular sodium reabsorption („renoprotective action“).
COX1 inhibitors can cause sodium retension (leading to edema), reduced glomerular filtration, systemic hypertension.
Nephrotoxic effects do not generally occur.
Describe the hepatotoxic effects of NSAIDs
Liver toxicity is generally rare in animals.
Carprofen hepatotoxicosis has been reported in dogs.
Paracetamol toxicity has been reported in dogs and of course cats.
It can cause methemoglobinemia, hepatic necrosis, stomach ulcers.
Clinical Use of NSAIDs (5-6)
Preoperative (and postoperative) administration
Treatment of trauma
Musculoskeletal conditions
Colic in horse
Cancer (relief of pain and antineoplastic action)
To reduce body temperature
Antihemostatic actions of aspirin
NSAIDs can be used in case of any
inflammatory reaction (also respiratory disease, infections, together with antibiotics)
Mastitis, metritis, endotoxemia etc. (e.g. caused by E. coli)
Grapiprant is
a non-steroidal, non-cyclooxygenase inhibiting anti-inflammatory drug in the piprant class.
Trade name Galliprant.
Grapiprant is a selective antagonist of the EP4 receptor, a key prostaglandin E2 receptor that predominantly mediates prostaglandin E2‐elicited nociception.
The specific effects of the binding of prostaglandin E2 to the EP4 receptor include
vasodilation, increased vascular permeability, angiogenesis and production of pro‐inflammatory mediators.
drug Grapiprant is a selective antagonist of the EP4 receptor so inhibit th eabove deleterious effects.
Grapiprant indication for use
For the treatment of pain associated with mild to moderate osteoarthritis in dogs.
Do not use in pregnant, lactating or breeding animals as the safety of grapiprant has not been established during pregnancy and lactation or in dogs used for breeding.
Gabapentin was first discovered as anticonvulsant, but is now used in case of
neuropathic pain in humans and in animals.
Librela active ingrediant and indication for use.
Bedinvetmab
Active ingredient: canine monoclonal antibody expressed through recombinant techniques in Chinese hamster ovarian (CHO) cells.
Indication: For the alleviation of pain associated with osteoarthritis in dogs.
Bedinvetmab is a canine monoclonal antibody (mAb) targeting what exactly
Nerve Growth Factor (NGF). The inhibition of NGF mediated cell signalling has been demonstrated to provide relief from pain associated with osteoarthritis.
Solensia active ingrediant and indication for use.
Frunevetmab („Solensia“) – similar action to bedinvetmab for dogs, is a mAb targeting nerve growth factor that mediates pain signalling.
for the alleviation of pain associated with osteoarthritis in cats.
