NSAIDs and Coxibs Flashcards
what are eicosanoids?
inflammatory mediators
how are eicosanoids made?
synthesised from membrane phospholipids via intermediate arachidonic acid
what are the main groups of eicosanoids?
prostaglandins
leukotrienes
thromboxanes
what are prostanoids?
prostaglandins and thromboxanes
what are the two classes of drugs for prostanoids?
non steroidal anti-inflammatory drugs (NSAIDS)
anti-inflammatory steroids (glucocorticoids)
what do steroidal anti-inflammatories do?
block the synthetic pathway
what do non-steroidal anti-inflammatories do?
block prostaglandin pathway
what is an example of a non-steroidal anti-inflammatory?
aspirin (NSAIDS)
what is an example of a steroidal anti-inflammatory?
predisolone
how are prostanoids synthesised?
- arachidonic acid is released from membrane phospholipids by phospholipase A2
- arachidonic acid has to fates
i) conversion to prostanoids (prostaglandins and thromboxanes) via COX pathway (cyclooxygenase)
ii) conversion to leukotrienes via 5-lipoxygenase pathway
what is the synthesis of prostanoids via the COX pathway?
- phospholipids -> arachidonic acid via phospholipase A2
- arachidonic acid -> PGH2 via COX
- PGH2 -> PGI2, PGE2, PGD2, PGF2alpha, TXA2
what are the 5 classes of prostanoids and what are their corresponding G-coupled receptors?
- Prostaglandin D2 (PGD2), DP G-coupled receptor
- Prostaglandin E2 (PGE2), EP G-coupled receptor
- Prostaglandin F2alpha (PGF2alpha), FP G-coupled receptor
- Prostaglandin i2 (PGI2), IP G-coupled receptor
- Thromboxane A2 (TXA2), TP G-coupled receptor
what produces PGI2?
vascular endothelium
what produces TXA2?
platelets
what produces PGE2?
macrophages
what produces PGD2?
mast cells
what is the action of PGI2?
vasodilation
inhibition of platelet aggregation
what is the action of PGE2?
vasodilation hyperalgesia fever bronchoconstriction mucus secretion
what is the action of PGD2?
vasodilation
inhibition of platelet aggregation
what is the action of PGF2alpha?
bronchoconstriction
what is the action of TXA2?
vasoconstriction
promotion of platelet aggregation
how are leukotrienes synthesised?
phospholipids —-PLA2—> arachidonic acid —5-lipoxygenase—> leukotrienes
what are the 4 kinds of leukotrienes?
LTB4
LTC4
LTD4
LTE4
what does LTB4 do?
chemotaxis - attracts neutrophils and eosinophils
what does LTC4, LTD4 and LTE4 do?
bronchoconstriction, increase vascular permeability, promote mucus secretion
what conditions are leukotrienes used to treat?
asthma
what kind of NSAID is aspirin?
salicylicates
what kind of NSAID is ibuprofen?
propionic acid
what are the clinical uses of NSAIDs?
diseases associated with pain and inflammation e.g. rheumatoid arthritis and musculoskeletal disorders
somatic pain e.g. headaches, toothache, menstrual pain
febrile conditions e.g. fever
what are the 3 main effects of NSAIDs?
anti-inflammatory
analgesic
antipyretic
how are the 3 main effects of NSAIDs produced?
by inhibiting the COX enzyme of prostaglandin synthesis pathway
how do NSAIDs produce an analgesic effect?
decrease PGs which decrease the sensitisation of nerve endings to BradyKinin and 5-HT
how do NSAIDs produce an anti-inflammatory effect?
decrease PGE2/PGI2 -> decrease vasodilation -> decrease oedema and redness
how do NSAIDs produce an antipyretic effect?
decreased PGE2 produced in response to IL-1 (inflammatory pyrogen) -> decreased elevation of hypothalamic set point for temperature control in fever
why doesn’t NSAIDs completely abolish inflammation - why does it only decrease it?
NSAIDs don’t inhibit other inflammatory mediators such as bradykinin or histamine
what synthesis do NSAIDs inhibit to for analgesic action?
inhibit synthesis of PGE2 and PGF2alpha in inflamed tissues
how does fever occur?
- infection
- leukocytes
- IL-1
- PGE2
- hypothalamus
- fever
how does aspirin cause antiplatelet action?
inhibition of TXA2 synthesis in platelets via inhibiting COX
inhibition of endothelial PGI2 synthesis
what are the gastrointestinal effects of aspirin?
nausea vomitting diarrhoea gastric damage: - irritation - bleeding - ulceration due to prostaglandin synthesis inhibition (prostaglandins protect mucosa)
PGE2 and PGI2 reduce acid secretion and promote mucus secretion
except gastrointestinal, what other adverse effects of aspirin are there?
hypersensitivity
renal insufficiency
- due to inhibition of vasodilatory PGE2 and PGI2
- problematic in elderly/renal patients
effects on the uterus
- delay labour by inhibiting PGE2 and PGF2alpha
Reye’s syndrome
- associated with aspirin treatment of childrens viral infections
- hepatitis with cerebral oedema
what new versions of COX have been discovered?
COX 1
COX 2
what are COX 1 and 2?
isoenzymes
when is COX 1 produced?
constitutive- always present
when is COX 2 produced?
inducible - by inflammatory stimuli
where is COX 1 found?
platelets, kidney, stomach, other tissues
where is COX 2 found?
most inflammatory cells
Adverse effects of NSAIDs are due to inhibition of which enzyme?
COX1
therapeutic effects of NSAIDs are due to inhibition of which enzyme?
COX2
name 2 COX-2 selective drugs
celecoxib (celebrex)
rofecoxib (vioxx)
how can COX1 and 2 inhibitors be designed to be selective from eachother?
structual differences between the substrate-binding channels of COX 1 and COX 2
what kind of adverse effects occur with coxibs?
serious cardiovascular
what do COX1s do in the endothelium?
constitutive
what do COX2s do in the endothelium?
induced by ischaemia and inflammation. generate mostly PGI2 and prevents aggregation
what do COX1s do in platelets?
constitutive. generate mostly TXA2 and promote aggregation
what do tNSAIDs inhibit?
COX-1 of platelet aggregation
COX-1 and COX-2 of PGI2 synthesis
what do coxibs inhibit?
COX-2 of PGI2 synthesis
what are celecoxib and etoricoxib used to treat?
both- licensed for the relief of pain in osteoarthritis and rheumatoid arthritis
celecoxib- relief of ankylosing spondylitis
etoricoxib - relief of pain from gout
what is a condition cause by an adverse effect of aspirin?
Reye’s syndrome
aspirin in children with viral infections
fulminating hepatitis with cerebral oedema
