NSAIDS Flashcards
what are the 3 main actions of NSAIDS?
what is the primary baseline action of NSAIDS?
in what 2 mechanisms do NSAIDS carry out this action?
1) Anti-inflammatory
2) Analgesic
3) Anti-pyretic
- All of these actions are related to the primary action of these drugs which is to inhibit prostaglandin biosynthesis by direct action on cyclo-oxygenase enzymes
- 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
Give an example of an NSAID which causes an irreversible, time-dependent inhibition of the enzyme and how it works? (mechanism 1)
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
Give an example of an NSAID which causes a rapid, reversible competitive inhibition of the enzyme? (mechanism 2)
e.g. ibuprofen
- binds reversibly to the enzyme
- competes with natural substrate, Arachidonic Acid
list some products of arachidonic acid metabolism
prostaglandins, thromboxanes, leukotrienes
what are the two main cyclo-oxygenase enzymes?
COX-1
- Constitutive (present in most body tissues)
- Important in maintain GIT integrity
COX-2
- Inducible (induced during an inflammatory response)
- Involved in inflammatory response
- Implicated in cancer development
prostaglondin biosynthetic pathway - remember where NSAIDS inhibit the pathway
when are prostaglandins released?
which prostaglandins are released?
what do these prostaglandins act as?
what two actions do they do?
- prostaglandins are always released and accompany the inflammatory response
- predominantly PGE2 are released as well as PGI2 and then PGD2 from mast cells
- they act as potent vasodilators
- they synergise (combine) with other inflammatory mediators (e.g histamine and bradykinin)
as well as potentiate (make more effective) histamine and bradykinin actions on postcapillary venule permeability and pain sensory nerves
in what two ways are prostaglandins important mediators of inflammation?
what do NSAIDS effect and reduce?
what are the signs and symptoms of inflammation which are reduced?
- Prostaglandins are important mediators of inflammation particularly causing vasodilation and resultant oedema (swelling), they cause a lesser effect on cellular accumulation or migration
- NSAIDS only effect aspects of inflammation in which prostaglandins play a significant part
- NSAIDS reduce many of the local signs and symptoms of inflammation
- signs and symptoms: redness, heat, swelling, pain
anti-pyretic effect:
what is body temperature regulated by?
what are the 4 steps of the anti-pyretic effect?
how do NSAIDS prevent this effect?
- 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 ↑ the thermostat “set point”
- NSAIDs act by preventing the formation of prostaglandins and prevent the rise in temperature and so there is no effect on normal body temperature
analgesic effect:
why are inflamed regions painful?
what do these two compounds do?
how do NSAIDS help prevent this and cause an anti-inflammatory response?
- inflamed regions are painful due to histamine and bradykinin release
- histamine and bradykinin: activate nocioceptive afferent nerve terminals and register a painful stimulis
- prostoglandins sensitise nocioceptive nerves to these compounds. So by preventing prostaglandin production, NSAIDS therefore prevent sensitisation to pain-producing compounds (histamine + bradykinin)
what is an example of salicylates?
what is a prodrug?
after how long are salicylates found within plasma?
after how long after intake are peak plasma concentrations of salicylates?
- aspirin is an example of salicylates
- a prodrug is pharmacologically inactive drug (acetylsalicyclic acid) which is metabolised into its active compound (salicylic acid) by plasma and tissue esterases
- salicylates are found in plasma within 30 minutes
- the peak plasma concentration within 1-2 hours
what are the 6 unwanted effects of salicylates?
effects: stomach, systemic, metabolic changes, haemostasis, CNS effects, renal
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 in susceptible patients and with chronic use and overdose
what are examples of propionic acids? and some characteristics?
what is an example of fenamates?
Propionic acids
e.g. ibuprofen, naproxen
- not prodrugs
- well absorbed
- last for 4-6 hours.
Fenamates
e.g. mefenamic acid
what is paracetamol also known as?
what two actions is paracetamol good at?
what action is paracetamol bad at?
where is paracetamol well tolerated?
what is it weak at?
how is it given?
when is the peak plasma concentration?
what is the half life in plasma for therapeutic doses?
- paracetamol is also known as acetaminophen
- paracetamol is a good analgesic and antipyretic activity
- paracetamol is a poor anti-inflammatory
- paracetamol is well tolerated in the gastrointestinal tract
- it is a weak COX inhibitor, it may be a selective inhibitor of CNS-specific COX called COX-3
- it is given orally, and well absorbed
- its peak plasma concentration is after 30-60 minutes
- for therapeutic doses, the half life in plasma in plasma is 2-4 hours
Paracetamol has fewer side effects than NSAIDS, perhaps due to its selectivity for COX enzymes
what is its major side effect issue?
what are the causes?
The major issue of paracetamol is hepatotoxicity due to overdose which can result in hepatic necrosis
- normally it is inactivated in the liver by glucoronate and sulphate conjugation
- when these enzymes are saturated, toxic metabolites are formed (resulting in hepatic necrosis)
