They have action similar to aspirin and their main therapeutic effects are: an anti-inflammatory effect an analgesic effect

an antipyretic effect

gastric irritation, which may range from simple discomfort to ulcer formation an effect on renal blood flow in the compromised kidney a tendency to prolong bleeding through inhibition of platelet function controversially, it is argued that they may also all-but especially COX-2 selective drugsincrease the likelihood of thrombotic events such as myocardial infarction by inhibiting prostaglandin (PG) I2 synthesis.

COX converts arachdonic acid into prostaglandins and related compounds e.g. prostacyclin (PGI2) and thromboxane A2. COX 1 is found in all tissues where they do housekeeping chores- protecting gastric mucosa, renal function and promoting platelet aggregation. COX 2 is found in site of tissue injury where it mediates inflammation and contributes to perception of pain.

Inhibition of COX 1 leads to protection against myocardial infarction. However it also leads gastric erosion and ulceration, bleeding tendencies, renal impairment. Inhibition of COX 2 leads to suppression of inflammation, alleviation of pain and reduction of fever.

Inhibits cyclo-oxygenase (prostaglandin synthase) that is responsible for conversion of arachidonic acid to cyclic endoperoxides 2 isoforms of enzyme - COX-1: constitutive, present in platelets, stomach and kidney. Responsible for gastric cytoprotection, platelet aggregation , renal blood flow autoregulation and the initiation of parturition. -COX-2 inducible by cytokines & endotoxins at sites of inflammation e.g., joints

An anti-inflammatory action: the decrease in prostaglandin E2 and prostacyclin reduces vasodilatation and, indirectly, oedema. Accumulation of inflammatory cells is not reduced. An analgesic effect: decreased prostaglandin generation means less sensitization of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine. Relief of headache is probably a result of decreased prostaglandin-mediated vasodilatation.

An antipyretic effect: interleukin-1 releases prostaglandins in the central nervous system, where they elevate the hypothalamic set point for temperature control, thus causing fever. NSAIDs prevent this. Examples: aspirin, ibuprofen, naproxen, indomethacin, piroxicam and paracetamol. Newer agents with more selective inhibition of COX-2 (and thus fewer adverse effects on the gastrointestinal tract) include celecoxib and etoricoxib.

From inhibition of COX-1 are : Dyspepsia, nausea and vomiting. Gastric damage may occur in chronic users, with risk of haemorrhage. The cause is suppression of gastroprotective prostaglandins in the gastric mucosa. Skin reactions. Mechanism unknown. Reversible renal insufficiency. Seen in individuals with compromised renal function when the compensatory PE2-mediated vasodilatation is inhibited. 'Analgesic-associated nephropathy'. long-continued high doses of NSAIDs (e.g. paracetamol) . Liver disorders, bone marrow depression. Bronchospasm. Seen in 'aspirin-sensitive' asthmatics

Aspirin is a derivative of salicyclic acid It is a non selective inhibitor of cyclooxygenase. It inhibits Prostaglandin synthase which is formed at the site of an injury. It is an irreversible inhibitor of COX, hence the duration of action is dependent on how fast tissues can synthesise COX. This inhibits the production of prostaglandins which produce fever and swelling as well as transmitting pain signals to the brain.

Absorbed rapidly and completely following oral administration. Has a very short half life since it is converted to salicylic acid upon metabolism (an active metabolite). Salicylic acid is extensively bound to albumin. It excreted via the kidney. Its excretion is highly dependent on urinary pH- more if alkaline.

Analgesic - central and peripheral action Antipyretic - act in hypothalamus to lower the set point of temperature control elevated by fever, also causes sweating Anti-inflammatory - inhibition of peripheral prostaglandin synthesis Respiratory stimulation -direct action on respiratory centre, indirectly by CO2 production Dose: 325-1000mgs 4 hrly

Suppression of inflammation Analgesia : inhibiting PG synthesis Reduction of fever: lowers the set point in the hypothalamus by inhibiting COX2 Dysmenorrhea: Suppression of platelet aggregation

Ingestion of > 10 g can cause moderate/severe poisoning in an adult Clinical features - salicylism: tremor, tinnitus, hyperventilation, nausea, vomiting, sweating Management- mainly supportive

Heart burn, nausea and gastric distress Bleeding Renal impairment Salicylism Reyes syndrome: encephalopathy and fatty liver degeneration in children.

Equivalent analgesic efficacy to aspirin. No useful anti-inflammatory action. Used for mild to moderate pain, but aspirin is preferred if due to inflammatory process. Dose: 325-650mgs every 3-4 hrs and to not exceed 4g/d.

rare in therapeutic usage occasional skin rash and allergy Overdose can result in fulminant hepatic necrosis and liver failure

Ingestion of >10g of paracetamol may be fatal May be lower in chronic alcoholics or subjects with underlying liver disease. Clinical features In severe poisoning up to 24 hours -none or nausea and vomiting > 24 hours - nausea and vomiting, right upper quadrant pain, jaundice, encephalopathy

Blood for paracetamol at 4 hours post ingestion Check treatment curve for N-acetylcysteine infusion ( if in doubt of severe poisoning, dont delay) Check prothrombin time and plasma creatinine, pH Acute renal (due to acute tubular necrosis) and hepatic failure and occur at 36-72 hours after ingestion Indications for referral to liver unit are - rapid development of Grade 2 encephalopathy - PTT >45 secs at 48 hours or >50 secs at 72 hours - rising plasma creatinine - Arterial pH <7.3 more than 24 hours after ingestion

Same potency as ASA . Works by inhibiting COX. Better tolerated (fewer side effects) Used for mild to moderate pain. Especially good in dysmenorrhea because it causes inhibition of PG in the uterine muscle. Dose: 200-800mgs tid-qid to not exceed 3200mgs/day. (400mgs qid). Half life: 2-4hrs.

More potent than ASA but inferior at doses tolerated by rheumatoid arthritis patients. Quite toxic. Dose: PO 25mds bid or tid up to a total of 150200mgs/day.

Used for RA, osteoathritis and ankylosing spondylitis. It is a PG synthetase inhibitor. Dose: PO 100-200mg/day bd or qid

Adverse effects of NSAIDS are theorized to be due to inhibition of COX-1 (ex. GI complications via decreased PGE2 and potentially altered blood flow) In some instances cytoprotectives e.g., misoprostol (PGE2 analogue) may be taken with NSAIDS to reduce GI effects. Selective COX-2 inhibitors were developed e.g., Celecoxib (Celebrex); rofecoxib, valdecoxib.

Osteoarthritis, rheumatoid arthritis, acute pain (200mg BD), primary dysmenorrhea. May increase the anticoagulant effect of warfarin leading to risk of bleeding.