Pharmacology Flashcards
(55 cards)
What are the main actions of NSAIDs
- Anti-inflammatory
- Analgesic
- Anti-pyretic
What is the primary action of NSAIDs?
-Inhibit prostaglandin biosynthesis by direct action on cyclo-oxygenase enzymes
What are the two main mechanisms by which NSAIDs inhibit cyclo-oxygenase (COX)?
- An irreversible, time dependent inhibition of the enzyme
- A rapid, reversible competitive inhibition of the enzyme
Describe aspirin’s mechanism of action
- inactivates the enzyme
- aspirin acetylates the alpha-amino group of the terminal serine of the enzyme forming a covalent bond
- further synthesis of prostaglandins requires synthesis of new enzyme
Describe ibuprofen’s mechanism of action
- Binds reversibly to the enzyme
- Competes with natural substrate, arachidonic acid
What are prostaglandins?
- Called prostaglandins because it was believed that they originated from the prostate gland
- Family of compounds - PGE2 and PGF2a were the first ones isolated and structures determined
- Generated in tissues from a precursor (arachidonic acid) by cyclo-oxygenase enzymes - thromboxanes, prostaglandins and leukotrienes are all products of arachidonic acid metabolism
What are the two main types of cyclo-oxygenase?
COX-1:
- Constitutive -expressed normally and regularly in a wide range of tissues
- Important in maintaining GIT integrity
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
- Predominantly PGE2 but also PGI2
- PGD2 from mast cells
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
How does anti-inflammatory action work on prostaglandins?
Prostaglandins are important mediators of inflammation
- Particularly vasodilation and resultant oedema
- Less effect on cellular accumulation or migration
Therefore NSAIDs only affect 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 anti-pyretic effects do NSAIDs have?
Body temperature is regulated by the hypothalamus
- 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 increase the thermostat set point
Therefore NSAIDs act by preventing the formation of prostaglandins and prevent the rise in temperature - no effect on normal body temperature
Describe the analgesic effect of NSAIDs
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
Therefore by preventing prostaglandin production NSAIDs prevent sensitisation to pain-producing compounds
What family does aspirin belong to?
Salicylates
Give some details about aspirin
- pro drug (acetylsalicylic acid) - can directly acetylate COX enzyme
- Also metabolised to active compound (salicylic acid) by plasma and tissue esterases
- Salicylate found in plasma within 30 mins
- Peak plasma concentration within 1-2 hours
Give some details about aspirin
- pro drug (acetylsalicylic acid) - can directly acetylate COX enzyme
- Also metabolised to active compound (salicylic acid) by plasma and tissue esterases
- Salicylate found in plasma within 30 mins
- Peak plasma concentration within 1-2 hours
What are some unwanted effects of salicylates?
- Stomach: bleeding, ulcers
- Systematic: tinnitus, dizziness, impaired hearing, nausea, vomiting, hypersensitivity
- Metabolic changes: acid/base balance affected
- Haemostasis: blood coagulation affected through and action on platelets
- CNS effect: stimulation initially, ultimately coma and respiratory depression
- Renal: insufficiency in susceptible patients and with chronic use and overdose
Describe propionic acids and give some examples
- Not prodrugs
- Well absorbed
- Last for 4-6 hours
- e.g ibuprofen, naproxen
Describe propionic acids and give some examples
- Not prodrugs
- Well absorbed
- Last for 4-6 hours
- e.g ibuprofen, naproxen
What is an example of a fenamate?
Mefenamic acid
What are some features of paracetamol (acetaminophen)?
- 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
- Given orally, well absorbed - peak plasma conc in 30-60 mins - half life in plasma is 2-4 hours for therapeutic doses
Explain side effects of paracetamol
Fewer side effects than other NSAIDs (perhaps due to its selectivity for COX enzymes)
Major issue is hepatotoxicity due to overdose
- Normally inactivated in the liver by glucoronate and sulphate conjugation
- When these enzymes are saturated, toxic metabolites are formed
- Result can be hepatic necrosis
Describe coxibs and give an example
- Selective COX-2 inhibitor
- Used for osteoarthritis and rheumatoid arthritis
- Restricted for when traditional NSAIDs produce too severe GIT side effects
- Cardiovascular risk needs to be assessed
- e.g celecoxib
What clinical analgesic uses of NSAIDs are there?
- Headache
- Dysmennorhea
- Backache
- Bony metastases of cancers
- Postoperative pain
Which NSAIDs are used for short term analgesia?
Aspirin, paracetamol, ibuprofen
What longer lasting NSAIDs are used for chronic pain?
Naproxen, diclofenac
