Lec 38- NSAID Flashcards
Mechanism of action
-Tissue injury
-Phospholipids
-Arachidonic acid (also form leukotrienes)
1) COX-1 this enzyme: protects gastric mucosa and aids platelet aggregation
+It is inhibited by NSAIDs and aspirin
2)COX-2 this enzyme: recruiter inflammatory cells; sensitises skin pain receptors; regulates hypothalamic temperature control
+Induced by: Cytokines and growth factors
+Inhibited by: COX-2 inhibiters; NSAIDS: aspirin
trends in prescribing of NSAIDS in England
- Decrease in diclofenac
- Ibuprofen is the same
- Increase in naproxen
- Meloxicam, celecoxib, etoricoxib, etodolac and other are in low numbers and are staying constant
Prostaglandins (PG) biosynthesis mechanism of action
COX1
-Stimuli
-Stomach, kidney, intestine, platelets
-PGE2; TXA2 (block platelet aggregation); PGI2
-Physiological funcitons
COX2
-Stimuli
-Inflammatory sites (macrophages, synovicytes)
NB COX 2 does have some constitutive function in kidney and CNS
-Inflammatory PG ; Proteases; O2
-Radical
NSAID competitive inhibitor for COX enzyme so blocking its action
-Anti-pyrexic effect is done by blocking IL-1
NSAID properties
- Functionally acid c (pKa 3-6)- inflamed sites are acidic pH 6-6.5
- Absorption occurs throughout the GI tract but particularly in the stomach (acidic environment)
- 2 or more aromatic groups (except aspirin)- lipophilic pass through membranes
- Pharmacokinetic drugs must accumulate at inflammatory site-paracetamol is ineffective as anti-inflammatory agent but is an analgesic
Aspirin pharmacology
- Irreversible inactivation of COX enzyme e.g. acetylation of the active site of the enzyme
- Antiplatelet: TXA2 enhances platelet aggregation, while PGI2 decreases it. Aspirin (75mg) in low doses irreversibly block (where as most NSAID is reversible) the formation of TXA2 in platelets without markedly affecting TXA2 production in endothelial cells of blood vessels
- The effects of aspirin persists for a period of 3-7 days which is the life cycle of platelets
- Decrease of TXA2 will decrease platelet aggregation
- Only NSAID with anti-thrombotic properties
Anti-inflammatory effects
- Most commonly used NSAIDs block COX1 and 2
- Anti-inflammatory effects due to inhibition of COX2
- Inhibition of COX enzyme therefore main effects on pain via bradykinin (BK)
- Vasodilation (by reducing the synthesis of vasodilator PGs)
- Oedema (by an indirect action: the vas adulation facilities and potentiates the action of mediators such as histamine)
- Ibuprofen in the short term. for chronic conditions, drugs which interfere with the disease process (e.g. DMARDs or Cytotoxics may be given)-NSAIDS NOT LONG TERM SOLUTION
Analgesia effects
- PGs sensitise nerve endings to BK
- Inhibition of PGE synthesis by NSAIDs prevents nerve ending sensitisation
- NSAIDS effective in modulating inflammatory pain-RA, toothache
- Relieve headache by inhibiting PG mediated vasodilation in vasculature
- NSAIDs in spinal column can inhibit pain
- Aspirin, paracetamol, ibuprofen for short term analgesia; piroxicam for chronic inflammatory pain
Antipyretic effects
- IL-1 endogenous pyrogen released from macrophages
- IL-1 stimulates PGE production in the hypothalamus
- PGE disturbs hypothalamic thermostat= FEVER
- NSAIDs inhibit production of PGE= anti-pyretic
- Paracetamol preferred-lower GI side effect profile and without risk of Reyes syndrome in children
Several classes of NSAID in their potency, duration of action and elimination
- Aspirin (100x more potent for COX1) cheap and effective. Can cause Reyes syndrome in children. Anti-thrombotic effect (NB give 75mg because its lowest dose= less side effects)
- Propionic acids- ibuprofen- effective and better tolerated than most NSAIDs. half life= 1-4 hours
- Phenylacetic acids- diclofenac
- Fenamic acids- mefenamic acid for menstrual pain
- Heterocyclic acetic acids- indomethacin- one of the most potent NSAIDs in vitro: RA
- Pyrazolones- phenylbutazone- v.potent and toxic used for ankylosing spondylitis
Side effects
- Gastric bleeds- inhibit GI COX and decrease in platelet aggregation (Risk 1.3% to 1.6%% hospitalisation)
- Reversible renal insufficiency- PGE2 and PGI2 maintain renal blood supply= lack of compensatory vasodilation in response to angiotensin II
- Skin reactions- Urticaria
- In 3-5% asthmatics, aspirin can cause asthma to worsen, often in the form of a severe and sudden attack
- COPD may be exacerbated by NSAIDs as arachidonic is dinverted away from the PG synthesis pathway towards the LT synthesis
- Leading cause of admission to hospital in HF patients-due to interference with ACEI/diuretics
GI adverse effects: In details (risk factors)
Risk factors include
- Age over 65
- History of GI bleed or ulcers
- Concurrent use of drugs that increase the risk of GI adverse events
- Heavy smoking or alcohol use
- Prolonged NSAID use
- Particular NSAID and high dose
- Serious co-morbities
chance of GI bleed due to NSAID in any one year
16-45: 1:2100
- 45-64: 1:646
- 65-74= 1:570
- > 75= 1:110
Chance of death due to NSAID bleed, risk in any one year
- 16-45= 1:12,353
- 45-64= 1:3800
- 65-74= 1:3353
- > 75= 1:647 (Bandolier NSAIDs and adverse effects)
Catergories of COX inhibitors
- COX1 specific= Low dose aspirin
- COX non-specific= all current NSAIDs
- COX2 preferential= some anti-inflammatory or analgesic activities that inhibit COX2, but no significant inhibition of COX1
- COX2 specific= causes no clinically significant inhibition of COX1 even at max dose
Efficacy of NSAIDs
- 60% of patients respond to any NSAID
- Those who don’t respond to one may respond to another
- Pain relief starts from the first dose, with full analgesic effects obtained within a week
- Anti-inflammatory effects may not be achieved for up to 3 weeks
