Pharmacology 18 - NSAIDs Flashcards
How widely used are NSAIDs in England?
- Widely prescribed (16 million annual prescriptions)
- 6% patients experienced possible adverse drug reactions
- Available over counter
What are the risks of NSAIDs?
Increased risk of GI and CVS deaths
What are NSAIDs used for?
- Relief of mild to moderate pain (toothache, headache, menstrual pain) ANALGESIC
- Reduction of fever (influenza) ANTIPYRETIC
- Reduction of inflammation (rheumatoid arthritis, osteoarthritis, soft tissue injuries, gout) ANTI-INFLAMMATORY
How do NSAIDs work?
- Inhibit prostaglandin and thromboxane synthesis
- Lipid mediators derived from arachidonic acid
- COX enzymes are inhibited (arachidonic acid to prostaglandin H2 which is later converted to thromboxane A2 and prostaglandins D2, F2a and E2)
- Widely distributed
- Receptor mediated
List the prostanoid receptors. Describe their qualities.
- DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1,IP2, TP
- Naming based on agonist potency
- Prostanoids have both G protein-dependent and -independent effects
- Physiological and pro-inflammatory
List the unwanted actions of PGE2
- Increased pain perception
- Increased body temperature
- Acute inflammatory response
- Immune response
- Tumorigenesis
- Inhibition of apoptosis
How does PGE2 increase pain?
- Lowers threshold for pain by sensitising nociceptors, both acutely and chronically
- cAMP mediated.
- Activates P2X3 nociceptors in the periphery.
- During inflammation, there is increased PGE2 production and increase in cAMP
- Also activates Epac (exchange pathway activated by cAMP) pathway to recruit more nociceptors
- May also affect neurones in the spine, or increase beta-endorphin in the spine
List the desirable physiological actions of PGE2
- Bronchodilation
- Renal salt and water homeostasis
- Gastroprotection
- Vasoregulation (can cause dilation and constriction depending on receptors activated)
Why should asthmatics not take NSAIDs?
- 10% asthma patients experience worsening symptoms with NSAIDs
- COX inhibition favors production of leukotrienes (bronchoconstrictors)
Compare actions of PGE2 and NSAIDs in kidney
- PGE2 increases renal blood flow
- COX-1 and COX-2 are distributed throughout the kidney
- NSAIDs can cause toxicity via constriction of afferent renal arteriole, reduction in GFR and renal artery flow
What is the role of PGE2 in gastric cytoprotection?
- Downregulates HCl secretion
- Stimulates mucus and bicarbonate secretion
- Therefore, blocking PGE2 can increase risk of ulceration
List the unwanted cardiovascular effects of NSAIDs
- Vasoconstriction
- Salt and water retention
- Reduced effect of antihypertensives
- Selective COX2 inhibitors have higher risk of cardiovascular disease (increase probability of atherosclerosis, heart failure, and BP)
Describe risk benefit of NSAID use
Analgesic use
- Usually occasional and low dose
- Relatively low risk of side effects
Anti-inflammatory use
- Often sustained use
- Higher doses
- Relatively high risk of side effects (older patients aren’t as good at metabolising drugs)
List the strategies to limit GI side effects of NSAIDs
- Topical application (muscle pain)
- Use COX2 inhibitors instead (although there is risk of CV events)
- Minimise NSAID use in patients with history of GI ulceration
- Treat H pylori if present
- If NSAID essential, administer with omeprazole or other proton pump inhibitor
- Minimise NSAID use in patients with other risk factors and reduce risk factors where possible (e.g. Alcohol consumption, anticoagulant or glucocorticoid steroid use)
List the newer NSAIDs being developed
- Duel COX and LOX inhibitors (however cause liver injury)
- Nitric oxide or hydrogen sulphide releasing NSAIDS (NO and H2S are protective to GI and CVS)
- May be safer
How does aspirin work?
- COX-1 selective
- Binds irreversibly to COX-1 by acetylating the active site
- Antiinflammatory, analgesic, anti-pyretic
- Reduces platelet aggregation
- Aspirin particularly causes ulcers
Describe effect of aspirin on platelet aggregation
- Inhibits thromboxane A2 production from platelets (made by COX-1 only, which platelets cannot replenish as they have no nucleus)
- Production of prostacyclin continues from endothelial cells as they can continue production via COX-1 and 2, and can produce new enzyme
- Prostacyclin decreases platelet aggregation while thromboxane A2 increases platelet aggegation
List the side effects of aspirin
- Gastric irritation and ulceration
- Bronchospasm in sensitive asthmatics
- Prolonged bleeding times
- Nephrotoxicity
- Reye’s syndrome seen in patient under 20
Why are side effects likely with aspirin?
Side effects likely with aspirin because it inhibits COX covalently, not because it is selective for COX-1
What is paracetamol?
- Is a widely used effective analgesic for mild-to-moderate pain which is available over the counter
- Has anti-pyretic action
- Has minimal anti-inflammatory effect
- Therefore it is not a NSAID
What is the mechanism of action of paracetamol?
- Mechanism not understood, probably central and peripheral
- May act via cannabinoid receptors
- May interact with endogenous opiods
- May interact with 5HT and adenosine receptors
What is the result of paracetamol overdose?
- Irreversible liver failure due to depletion of glutathione
- Gluthionine oxidises thiol groups of key hepatic enzymes, causing cell death
What is the antidote for paracetamol poisoning?
- Add compound with –SH groups if you catch the overdose early
- Usually intravenous acetyl cysteine
- Occasionally oral methionine
- Could be added to the formulation but increased cost
- Acetyl cysteine used in cases of attempted suicide and accidental poisoning
- If not administered early enough, liver failure may be unpreventable and only a liver transplant will save a life
How is PGE2 pyrogenic?
Stimulates hypothalamic neurones directly to initiate a rise in body temperature
What are the main causes of death from NSAIDs?
- 50% gastric ulcers/bleeding
- 50% cardiovascular (hypertension, MI, stroke)
Compare risk of COX2 and COX1 inhibitors
- COX 1 inhibitors have high GI risk
- COX 2 inhibitors have a high cardiovascular risk, therefore were less successful than hoped when manufactured to combat GI risk
How does reye’s syndrome occur?
- Viral infection and aspirin.
- Damage to mitochondria occurs leading to ammonia production, damage to astrocytes and therefore oedema in the brain
What is the legislation on paracetamol?
- No more than 2 packs per transaction, illegal to sell more than 100 paracetamol in one transaction
- Pack size restricted to 16 x 500mg per pack
- Now decline in deaths due to overdose and in registration for liver transplants
