NIMESULIDE
Therapeutic Indications
Efficacy of NIMESULlUE is demonstrated clinically in a large variety of conditions associated with pain and inflammation Some of these conditions are rheumatoid arthritis, osteoarthritis, degenerative arthritis conditions, musculo -skeletal injuries, low back pain, dysmenorrhoea .and other gynaecological disorders,dental surgeiy, postoperative pain, cancer pain, ear, nose and throat inflammation and urogenital tract
disorders. In all these conditions nimesulide in a dose of 200 mg/day was found to be as effective as or more effective as usual therapeutic does of Piroxicam. Naproxen, lbuprofen, Phenylprenazone,Ketoptofen Seriatiopeptidase, Mefenamic acid, etc.
In (children significantly faster reduction of fever and signs and symptoms (cough, dyspnoea, asthma,hyperaemia, dysphagia, oedema and pharyngeal pain) of respiratory tract infection occurred with nimesutide administered as grannies, suspension or suppositories. With postoperative or musculoskeletal pain in children nimesulide given orally or rectally showed equal efficacy as dipyrone,Ketoprofen and paracetamol
contraindications
Hypersensitivity
Active peptic ulcer
Moderate to severe hepatic impairement
caution should be exercised in
Patients with compromised renal function (particularly elderly)
Congestive cardiac failure
Cirrhosis
Those who are volume-or-salt-depleted - Pregnancy and lactation (since adequate data about its use not available).
Dosage and Administration
Adults
Oral dose -100 mg BD (Tablet),
Rectal dose -200 mg BD (Suppositories)
Children
Suspension or Granules 5 mg/kg/day in 2 to 3 divided dose.
Adverse Reactions
Nimesulide has a good tolerability profile. Analysis of data for an Italian post-marketing survey in which 22938 patients had taken nimesulide therapy for 1 to 3 weeks, the overall incidence of side effects reported was 8.2% (1887 patients). Only in 2.2 % (498 patients) of patients the adverse effects were severe enough that it necessitated drug withdrawal.
Gastrointestinal Disturbances Incidence
Epigastric Pain 4 1 %
Heart Bum 3.1%
Nausea 0.8 %
Diarrhoea 0.3%
Vomiting 0.2 %
Dermatological Reactions
Rash0.1%
Pruritus 0.I %
CNS effects
doses. It is effective in reducing pain and inflammation associated with osteoarthritis. Cancer,thrombophlebitis, oral surgery and dysmenorrhoea in adults, reducing pain associated with general surge in adults and children, and pain, fever and inflammation in RTIs, ENT diseases and traumatic injury in adult and children. The clinical trial and post marketing surveillance studies have confirmed that it is well tolerate by children, adults and the elderly.
CHEMISTRY AND STRUCTURE ACTIVITY RELATIONSHIP
Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) which is weakly acidic (pKa~6.5). It differ from the other NSAIDs in that its chemical structure does not contain a carboxyl group but instead it has sulfanilamide moiety as ths acidic group.
Nimesulide is a weak inhibitor of prostaglandin synthesis and it exerts its effects through a variety of mechanisms.interfere with production/action of mediators other than prostaglandins such as enzyme toxic oxygen derivatives, cytokines, platelet-activating factor (PAF) and histamine.
Mechanism of Action
Nimesuiide unlike other NSAIDs is a relatively weak or selective inhibitor of prostaglandin synthesis.In addition it exerts its pharmacological effects through a number of other complex mechanisms Viz.
i) Inhibition of superoxide anion generation by activated neurophils without influencing their phagocytic
'~otactic responsiveness.
ii)scavenging of hypochlorous acid and hydroxyl ions generated during the phagocytic process.
iii) Inhibition of histamine release from human basophils and tissue mast cells.
iv) Inhibition of platelet activating factor (PAF) synthesis in stimulated human neutrophils.
v) Inhibition of the synthesis of metaloproteinase thus preventing the breakdown ofosteoarthritic huma
cartilage.
vi) Inhibition of bradykinin and tumour necrosis factor-alpha (TNF-alpha) which is responsible for th
release of hyperalgesic cytokinase.
With the help of a number of animal models the anti-inflammatory, analgesic and antipyretic effects NIMESULIDE have been demonstrated which have been later confirmed in numerous clinical trials. Using standard animal models of inflammation such as Carrageenin-induced rat paw oedema and inflammation
UV-light induced erythema in guinea pigs and adjuvant arthritis in rats, therapeutic efficacy of Nimesulide found to be as good as or superior to indomethacin, diclofenac, piroxicam and ibuprofen. In acetic acid
writhing test for analgesia in rats, NIMESULIDE demonstrated simitar efficacy as ibuprofen but less than indomethacin With yeast-induced fever in rats Nimesulide has shown greater antipyretic potency than indomethacin, ibuprofen, aspirin and paracetamol.
ABSORPTION, DISTRIBUTION, FATE AND EXCRETION
The absorption of NIMESULIDE after oral administration is rapid and almost complete. Mean peak plasm concentrations (Cmax) of 1.98 to 9.85 ml/L are achieved after an oral dose of 50-200 mg given to healthy
adult volunteers. This is achieved in 1.67 to 3.17 hrs (tmax). For the granule (saches) or suspensio formulations corresponding values after 100 to 200 mg dose are 4.11 to 5.60 mg/L (Cmax) in 1.22 to 2.0 hrs (tmax) which was generally shorter as compared to tablet form. After rectal administration of Nimesulid
100 to 200 mg a lower Cmax (2.14 to 2.32 mg/L) and a longer tmax (3-4.58 hrs) were obtained. Thus bioavailabitity of Nimesulide after rectal administration relative to oral administration is 54-65%. If the oral dose of 160 mg nimesulide is given with food the Cmax is 21% lower than that under fasting conditions, by
both the tmax and AUC (Area under the plasma concentration time curve) were not significantly modified by tood intake Thus food does not significantly alter the rate and extent of bioavaliability of NIMESULIDE.
NIMESULIDE is extensively bound (99%) to human plasma proteins has an apparent volume of distribution of 0,19-0.351./kg after oral administration. Drug is principally distriouted in the extracellular fluid compartment. In female reproductive tissues the concentration of NIMESULIDE 2-3 hrs after a single oral
dose of 100 mg are 33-50% of those in plasma. When given 100 mg BD orally for 7 days the mean nimesulide plasma and synovial fluid concentrations obtained are 5.48 and 2.39 mg/L at 3hrs and 2.57 and
38 mg/L at 12 hrs following the last dose. Thus concentrations reached in synovial fluid are 44% after 1 hrs. and it remains longer in the synovial fluid than inplasma After an oral dose, nimesulide is extensively metabolised in the liver to its major metabolite 4-OH nimesulide which.also has significant anti-inflammatory activity. Only 1-3% of the dose is excreted unchanged in the urine. Of the metabolites 70% are excreted in the urine and 20% in the faeces.
Peak concentrations of 4-OH NIMESULIDE (both conjugated and unconjugated) ranged for 0.84 to 3.0.mg/L and were attained within 2.61 to 5.33 he i s. The eliminatt n half-life of 4-OH Nimesulide ranges from 2.89 to 4.78 hrs. and is generally similar or slightly higher than that of the parent compound which is 1.56 to 4.95 hrs.Clearance of NIME8UUDE depends mainly on renal and hepatic mechanisms. In elderly,patients, in children and in patients with moderate renal impairment there is insignificant change in the pharmacokinetics of NIMESULIDE and its 4-OH nimesulide. In case of patients with moderate of severs hepatic insufficiency there is risk of drug accumulation and hence nimesulide should not be recommended in such a situation. Not much data is available regarding the crossing of nimesulide across placenta or its excretion in human milk. Therefore, it should be best avoided in pregnant and lactating mothers.
references
Ward A, Brogden RN. Nimesulide: a preliminary review of its pharmacological properties and therapeutic
efficacy in inflammation and pain states. Drugs. 1988:36: 732-53.
i-asticci MB. et al. Nimesulide thrombocytopenic purpura, and human immunodeficiency virus (HIV
ction.Ann. Intern. Med. 1990: 112: 233-4.