Drugs » Anti-pyretics & analgesic

Anti-pyretics & analgesic

Non steroidal Anti Inflammatory Drugs, Antipyretic and Analgesics

All drugs grouped in this class have analgesic, antipyretic and anti-inflammatory actions, albeit in different proportions. Taking morphine as the gold standard in analgesia, these are weaker analgesics (except for inflammatory pain); do not depress CNS; do not produce physical dependence and have no abuse liability. These are also called non-narcotic, non-opioid analgesics. They act primarily on peripheral pain mechanism but also in CNS to raise pain threshold.

Classification

1. Nonselective COX inhibitors (conventional NSAIDs)
   1. Salicylates: Aspirin, Difunisal.
   2. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone (currently banned in India and most countries for their bone marrow suppression action).
   3. Indole derivatives: Indomethacin, Sulindac.
   4. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen
   5. Anthranilic acid derivative: Mephenamic acid.
   6. Aryl-acetic acid derivatives: Diclofenac
   7. Oxicam derivatives: Piroxicam, Tenoxicam
   8. Pyrrolo-pyrrole derivatives: Ketorolac
2. Preferential COX - 2 inhibitors
   Nimesulide, Meloxicam, Nabumetone
3. Selective COX - 2 inhibitors
   Celecoxib, Rofecoxib, Valdecoxib.
4. Analgesic - antipyretics with poor anti- inflammatory action.
   1. Para-aminophenol derivatives : Paracetamol (Acetaminophen)
   2. Pyrazolone derivatives : Metamizol (Dypyrone), Propiphenazone.
   3. Benzoxazocine derivative : Nefopam

Mechanism of action

Aspirin and NSAIDs block Prostaglandins generation. PGs, prostacyclin (PGI₂) and thromboxane A₂ (TXA₂) are produced from arachidonic acid by the enzyme cyclo-oxygenase which exists in a constitutive (COX-1) and an inducible (COX-2) isoforms; the former serves physiological 'house keeping' functions, while The latter, normally present in minute quantities, is induced by cytokines and other Signal molecules at the site of inflammation. Most NSAIDs inhibit COX-1 and COX-2 non - selectively, but now some selective COX-2 inhibitors have been produced.

Aspirin inhibits COX irreversibly by acetylating one of its serine residues, return of COX activity depends on synthesis of fresh enzyme. Other NSAIDs are competitive and reversible inhibitors of COX, return of activity depends on their dissociation from the enzyme which in turn depends on the pharmacokinetics of the compound.

Analgesia

NSAIDs do not affect the tenderness induced by direct application of PGs, but block the pain sensitizing mechanism induced by bradykinin, TNFα, interleukins (ILs) and other algesic substances. They are therefore more effective against inflammation associated pain.

Antipyresis

NSAIDs reduce body temperature in fever, but do not cause hypothermia in normothermic individuals. Fever during infection is produced through the generation of pyrogen, ILs, TNF, interferons which induce PG production in Hypothalamus - raise its temperature set point. NSAIDs block the action of pyrogens but not that of PGE₂ injected into the hypothalamus. The isoform present at this site appears to be COX-2.

Antiinflammatory action

The most important mechanism of anti-inflammatory action of NSAIDs is considered to be inhibition of PG synthesis at the site of injury. The anti-inflammatory potency of different compounds roughly corresponds with their potency to inhibit COX. PGs are only one of the mediators of inflammation, inhibition of COX does not depress the production of other mediators like LTs. PAF, cytokines etc. Inflammation is the result of concerted participation of a large number of vasoactive, chemotactic and proliferative factors at different stages, and there are many targets for anti-inflammatory action.

Antiplatelet aggregation

NSAIDs inhibit synthesis of both proaggregatory (TXA₂) and anti-aggregatory (PGI₂) prostanoids, but effect on platelet TXA₂ predominates. Therapeutic doses of most NSAIDs inhibit platelet aggregation: bleeding time is prolonged. Small doses are enough to exert antithrombotic effect for several days.

Adverse effects shared by NSAIDs

1. GI - mucosal damage, gastric irritation, erosions, peptic ulceration, gastric bleeding/ perforation, oesophagitis.
2. Blood - bleeding, thrombocytopenia, haemolytic anaemia, agranulocytosis.
3. Limitation of renal blood flow - Na+ and water retention, chronic renal failure, Interstitial nephritis and papillary necrosis.
4. Delay/ prolongation of labour.
5. Asthma and anaphylactoid reactions in susceptible individual, nasal polyposis, Skin rashes, pruritus and angio-oedema.
6. Hepatic - raised transaminases.
7. CNS: headache, mental confusion, behavioural disturbances, seizure precipitation.

Contraindications

NSAIDs hypersensitivity: because of potential cross-sensitivity to other NSAIDs. These agents should not be given to patients in whom aspirin, iodides or other NSAIDs have induced symptoms of asthma, rhinitis, urticaria, nasal polyps, angio-oedema, bronchospasm and other symptoms of allergic or anaphylactoid reactions, active peptic ulceration.

Special Precautions

• Allergic disorders
• Renal/ cardiac or hepatic impairment.