Pharm 17 - NSAIDS Flashcards
Use of NSAIDS are associated with deaths involving which systems?
GI and CVS
Which 3 properties of NSAIDS make them widely used?
- Analgesic
- Anti-pyretic
- Anti-inflammatory
Where is arachidonic acid derived from?
Phospholipid membranes
What reaction does COX-1/2 mediate
Conversion of Arachidonic acid into prostaglandin H2
NSAIDS inhibit what?
COX-1/2 - prevents Prostaglandin and Thromboxane A2 synthesis
Prostanoid receptors have 2 actions,
- Physiological
- Pro-inflammatory (pathological)
There are 10 known prostanoid receptors
PGE2 has 2 downstream mechanisms
- Ca mobilisation/immobilisation
2. cAMP increase/decrease
Which 4 receptors does PGE2 have?
EP1, EP2, EP3, EP4
What are 6 unwanted actions of PGE2
- Increased pain perception
- Increased body temperature
- Acute inflammatory response
- Immune responses
- Tumorigenesis
- Inhibition of apoptosis
Why may PGE2 analogues lower pain threshold
- PG receptors are stimulated
2. Peripheral PG receptor stimulation sensitises the nociceptors
Why might stimulation of PG receptors cause pain?
- cAMP mediated
- P2X3 nociceptors activated
- Inflammation causes Epac pathway to be activated and more PGE2 to be produced
- More activation of P2X3 nociceptors
What other reasons for pain may there be via PG receptor activation?
- EP1 /EP4 receptor activation (periphery and spine)
- Endocannabinoids (neuromodulators in thalamus, spine and periphery)
- Decreased beta-endorphins in the spine
What do NSAIDS do in the spine
Increase beta-endorphin in the spine
How does PGE2 have a pyrogenic effect?
PGE2 stimulates hypothalamic neurones - stimulates rise in temp
PGE2 role in inflammation is extremely complex
y=Y
What are desirable physiological actions of pGE2 and other prostanoids
- Bronchodilation
- Renal salt and water homeostasis
- Gastroprotection
- Vasoregulation
Why should asthmatic patients avoid taking NSAIDS?
Because COX inhibition favours leukotriene production - leukotrienes = bronchoconstrictors
How can NSAIDS cause renal toxicity
PGE2 (& other prostaglandins) increase renal blood flow.
NSAIDS:
- Constrict afferent arteriole
- Reduce renal artery flow
- Reduce GFR
What gastroprotective features does PGE2 have?
- Downregulates HCl secretion
2. PGE2 stimulates mucus and bicarbonate secretion
What gastric complication do NSAIDS increase the likelihood of?
Gastric ulceration
What is the coxib family?
NSAIDS that selectively reversibly inhibit COX-2
e.g. Celecoxib (caused fewer ulcers than normal NSAIDS)
Ibuprofen selectively inhibits which isoforms of COX?
Both - i.e. COX 1 and 2
What are the unwanted CVS effects of NSAIDS
- Vasoconstriction
- Salt and water retention
- Reduced effect of antihypertensives
can cause:
- Hypertension
- Stroke
- MI
Selective COX-2 inhibitors have what problem?
Pose higher risk of CVS disease than conventional NSAIDS
Which prostaglandin causes vasodilation and decreases platelet aggregation
PGI2
COX-1 selective NSAIDS increase what risk?
COX-2 selective NSAIDS increase what risk?
COX -1 = gastric
COX -2 = CVS
How can GI side effects be reduced?
- Topical application
- Minimise use in GI ulceration patients
- Treat H pylori if present
- Coadminister with omeprazole or PPI
- Minimise NSAID use in patients with other RFs e.g. alcohol consumption / anticoagulant/glucocorticoid use
Aspirin is selective for which COX enzyme?
COX-1
How does aspirin bind to COX enzymes?
ASPIRIN BINDS IRREVERSIBLY BINDS TO COX ENZYMES
Aspirin also reduces platelet aggregation. How
- COX-1 permanently inhibited (due to covalent bonding) which suppresses TxA2 production by platelets (TXA2 increases platelet aggregation)
- Aspirin has low capacity to inhibit COX-2.
- PGI2 is synthesised by both COX-1 and COX-2 in endothelial cells
- Therefore, there is still PGI2 synthesis as COX-2 works
- PGI2 decreases platelet aggregation.
Platelets have no nucleus, so more platelets must be regenerated for TXA2 and platelet aggregation to occur (when aspirin is administered).
Y
Endothelial cells that produce PGI2 have a nucleus so can produce COX1/2.
Aspirin can cause gastric irritation, bronchospasm, excess bleeding, nephrotoxicity. These side effects are likely not because aspirin is selective for COX-1, but because they:
Inhibit COX covalently (i.e. irreversibly)
Why is paracetamol not an NSAID
It has minimal anti-inflammatory effect
but it does have a anti-pyretic action
Overdosing on paracetamol may cause?
Liver failure
How can overdosing on paracetamol cause liver failure
- Glutathione used to metabolise a toxic metabolite of paracetamol into an inactive reduced form
- Depleted glutathione = toxic metabolite oxidises thiol groups
- Thiol groups are crucial in key hepatic enzymes - hepatotoxicity results and cell death occurs
Paracetamol depletes glutathione
What is the antidote for paracetamol poisoning
- Add compound with -SH groups (often IV acetylcysteine)
2. (Occasionally oral methionine)
