NSAIDs Flashcards
What does NSAIDs stand for?
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
What are the main actions of NSAIDs?
1) Anti-inflammatory
2) Analgesic
3) Anti-pyretic
What is the primary physiological action of NSAIDs?
Inhibit prostaglandin biosynthesis by direct action on cyclo-oxygenase enzymes
What are the mechanisms of action of NSAIDs?
All inhibit cyclo-oxygenase (COX) but do so by two main mechanisms:
1) An irreversible, time-dependent inhibition of the enzyme
2) A rapid, reversible competitive inhibition of the enzyme
Describe the irreversible, time-dependent inhibition of the enzyme mechanism of action of NSAIDs
• e.g. aspirin
– inactivates the enzyme
– aspirin acetylates the a-amino group of the terminal serine of the enzyme forming a covalent bond
– further synthesis of prostaglandins requires synthesis of new enzyme
Describe the rapid, reversible competitive inhibition of the enzyme mechanism of action of NSAIDs
• e.g. ibuprofen
– binds reversibly to the enzyme
– competes with natural substrate, Arachidonic Acid
What are prostaglandins?
A family of compounds generated in tissues from a precursor (arachidonic acid) by cyclo-oxygenase enzymes
What are some prostaglandins?
– PGE2 and PGF2a were the first ones isolated and structures determined
– Thromboxanes, prostaglandins & leukotrienes all products of arachidonic acid metabolism
What are cyclo-oxygense enzymes?
A group of enzymes consisting of two main enzymes
What are the two main cyclo-oxygenase enzymes?
COX-1
COX-2
Describe COX-1
– Constitutive
– Important in maintain
GIT integrity
Describe COX-2
– Inducible
– Involved in
inflammatory response
– Implicated in cancer development
What is the role of prostaglandins in inflammation?
Inflammation always accompanied by release of prostaglandins
What are the prostaglandins released in inflammation?
– Predominantly PGE2 but also PGI2
– PGD2 from mast cells
What do the prostaglandins released in inflammation do?
PGE2, PGI2 and PGD2
– Act as potent vasodilators
– Also synergise with other inflammatory mediators (e.g. histamine and bradykinin)
– Potentiate histamine and bradykinin actions on postcapillary venule permeability and pain sensory nerves
Describe the anti inflammatory action of prostaglandins
Prostaglandins are important mediators of inflammation
– Particularly vasodilation and resultant oedema – Less effect on cellular accumulation or migration
What is the impact of the role of prostaglandins in inflammation on the use of NSAIDs?
NSAIDs only effect aspects of inflammation in which prostaglandins play a significant part. NSAIDs can reduce many of the local signs and symptoms of inflammation:
– i.e. redness, heat, swelling, pain
What is body temperature regulated by?
The hypothalamus
How is a fever caused?
– Fever occurs when the hypothalamic thermostat “set point”
is raised
– Bacterial endotoxins cause release of factors (e.g.
interleukin 1) from macrophages
– Interleukin 1 causes generation of prostaglandins in the
hypothalamus (PGEs)
– Prostaglandins ↑ the thermostat “set point”
How do NSAIDs have an anti-pyretic effect?
NSAIDs act by preventing the formation of prostaglandins and prevent the rise in temperature
– No effect on normal body temperature
What causes pain in inflamed regions?
Inflamed regions painful due to histamine and bradykinin release
– activate nocioceptive afferent nerve terminals
– register a painful stimulus
Prostaglandins sensitise nocioceptive nerves to these compounds
How do NSAIDs have an analgesic effect?
By preventing prostaglandin production NSAIDs prevent sensitisation to pain-producing compounds
What is a famous example of salicylates
Also known as the aspirin family
Therefore: aspirin
Describe aspirin physiologically
– pro-drug (acetylsalicylic acid)
—-• can directly acetylate COX enzyme
– also metabolised to active compound (salicylic acid) by plasma and tissue esterases
– salicylates found in plasma within 30 mins
– peak plasma concentrations within 1-2 hr
What are the unwanted effects of salicylates?
Stomach
– bleeding, ulcers
Systemic
– tinnitus, dizziness, impaired hearing, nausea, vomiting, hypersensitivity
Metabolic changes
– acid/base balance affected
Haemostasis
– blood coagulation affected through and action on platelets
CNS effects
– stimulation initially, ultimately coma and respiratory depression
Renal
– insufficiency insusceptible patients and with chronic use and overdose
What are propionic acids?
– e.g. ibuprofen, naproxen
– not prodrugs
– well absorbed
– last for 4-6 hours
What are fenamates?
– e.g. mefenamic acid
Describe the physiological effects of paracetamol
Good analgesic and antipyretic activity Poor anti-inflammatory
Well tolerated in GIT
Weak COX inhibitor
– May be selective inhibitor of CNS-specific COX, COX-3
How is paracetamol given?
Given orally, well absorbed
– Peak plasma conc in 30-60 mins
– Half life in plasma 2-4 hr for therapeutic doses
What is another name for paracetamol?
acetaminophen
What is a benefit of paracetamol?
Fewer side effects than other NSAIDs (perhaps due to its selectivity for COX enzymes)
What is a major issue with paracetamol?
Major issue is hepatotoxicity due to overdose
– Normally inactivated in the liver by glucoronate
and sulphate conjugation
– When these enzymes saturated, toxic metabolites are formed
– Result can be hepatic necrosis
What are selective COX-2 inhibitors?
Coxibs
– e.g. celecoxib
– used for osteoarthritis and rheumatoid arthritis
– restricted for when traditional NSAIDs produce too severe GIT side effects
– cardiovascular risk needs to be assessed
What are the clinical uses of the analgesic properties of NSAIDs?
– headache – dysmennorhea – backache – bony metastases of cancers – postoperative pain
What NSAIDs should be used for short term analgesia?
– aspirin, paracetamol, ibuprofen
What NSAIDs should be used for longer lasting analgesia for chronic pain?
– naproxen, diclofenac
What are the clinical uses of the anti-inflammatory properties of NSAIDs?
– Both chronic or acute inflammatory conditions
– Dosage for chronic inflammatory disorders is high
– Therefore low incidence of side effects is important
—-• e.g.ibuprofen
– Coxibs sometimes used for osteoarthritis and rheumatoid arthritis
What are the clinical uses of the anti-pyretic properties of NSAIDs?
– To lower temperature
– Paracetamol preferred because it lacks GIT side effects
