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Non-steroidal Anti-inflammatory Drugs
Dr Alex Dodoo Ph.D. MPSGH, MRPharmSCentre for Tropical Clinical Tropical Pharmacology &
Therapeutics, UGMSAccra, GHANA
alexooo@yahoo.com OR anododoo@ug.edu.gh
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Outline
NSAIDs Indications Mechanism(s) of Action Non-specific Cox or Cox-2 Side-effects Selection
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
NSAIDs
Non-steroidal anti-inflammatory drugs Compare with opoid analgesics (usually
required for moderate to severe pain; narcotic; usually addictive) e.g. morphine; codeine
Compare with paracetamol which has very little or no anti-inflammatory activity
Most are organic ACIDS
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
NSAIDs Types
Salicylates (Salicylic acid derivatives)
Aspirin
Diflusinal
Sodium Salicylate
Acetic Acid derivatives Indometacin
Sulindac
Etodolac
Diclofenac
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
NSAIDs Types
Propionic Acid Derivatives
Ibuprofen
Naproxen
Ketoprofen
Flurbiprofen
Enolic Acids Piroxicam
Phenylbutazone
Non-acidic compounds Nabumetone
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Indications
Pain and inflammation in rheumatic diseases Musculoskeletal disorders Post-operative analgesia Acute Gout Migraine Dysmenorrhoea Fever and pain in children (including post-immunization pyrexia) Pyrexia Dental pain Less well-defined conditions of back pain and soft-tissue disorders
Patients NOT responsive to one NSAID may well respond to another – need to tailor treatment to the individual patient. Full analgesic effect may take up to three weeks
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Mechanism(s) of Action
Inhibition of prostaglandin synthesis Inhibition of Cox-1 Inhibition of Cox-2
Cox-2 is induced 10-80 fold in inflammation Inhibition of Cox-2 is the main mechanism for the anti-
pyretic, analgesic and anti-inflammatory actions Inhibition of Cox-1 leads to side effects Most NSAIDS are non-selective but there are
“selective” Cox-2 inhibitors
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Non-selective Cox or Cox-2?
Non-selective Ibuprofen, Diclofenac, Indometacin, naproxen,
Piroxicam, ketoprofen, azapropazone Cox-2
Newer Provides protection against gastrointestinal side
effects of NSAIDS Celecoxib, RofecoxibRofecoxib, Etoricoxib, Lumiracoxib,
Parecoxib, ValdecoxibValdecoxib
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Nonselective Cox or Cox-2?
Action of NSAIDs due to inhibition of Cox-2 Side effects usually due to inhibition of Cox-1 Extensive experience with Non-selective Cox
Inhibitors Cox-2 expensive Evidence for cost-effectiveness of Cox-2
(see www.npc.co.uk)
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
CSM Advice on NSAIDS (BNF 53) All NSAIDs are associated with serious
gastrointestinal toxicity Relative risk higher in the elderly Among 7 non-selective NSAIDs, Ibuprofen has the
lowest side effect profile with Azapropazone having the highest side effect profile
Piroxicam, ketoprofen, indometacin, naproxen and diclofenac intermediate
Selective Cox-2 inhibitors have lower risk of serious upper GI side effects than non-selective NSAIDS
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
CSM Advice on NSAIDS (BNF 53) Ibuprofen generally preferred; start at lowest
recommended dose Not to use more than ONE NSAID at a time All NSAIDs (including Cox-2 inhibitors) contraindicated in
patients with ACTIVE peptic ulceration Non-selective NSAIDs contraindicated in patients with
peptic ulceration Combination of a NSAID with low dose aspirin may
increase GI side effects Any degree of worsening of asthma may be related to the
ingestion of NSAID!!!
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
NSAIDS and Cardiovascular events:CSM Advise on selective Cox-2 inhibitors
In the light of emerging concerns abut CV safety, Cox-2 inhibitors should be used in preference to non-selective NSAIDS ONLY when specifically indicated (i.e. for patients who are at particularly high risk of developing gastro duodenal ulcer, perforation or bleeding and after an assessment of CV risk.
CHM advised (October 2006) that the lowest effective dose of NSAID or Cox-2 inhibitor should be prescribed for the shortest period of time to control symptoms and that the need for long-term treatment should be reviewed periodically
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Examples
Ibuprofen Lowest incidence of side effects Lowest (?) potency Maximum daily dose 2.4g Useful alternative to aspirin in children under 12 (16 years!) –
Reye’s syndrome Sustained-Release preparations e.g. Brufen Retard Various oral preparations Combination products with paracetamol (e.g. Parafen), codeine
(Nurofen Plus; Codafen Continus) Topical preparations e.g. Ibugel, Ibuleve, Proflex Useful in dysmenorrhoea, dentistry Not strong enough in acute gout
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Examples
Diclofenac Moderate potency Useful in acute gout Moderate side effects (compared to ibuprofen) Maximum daily dose (by ANY route) is 150mg!!! Tablets, Suppositories, Gels, Injections Sustained Release Products Combination of strengths? E.g. Voltarol Retard 100mg +
Voltarol ec 50mg; Naklofen-Duo 75 mg (dual release 25mg immediate release and 50mg m/r)
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Examples
Aspirin Avoid in under 12 (under 16s) because of Reye’s syndrome Useful in juvenile arthritis Irreversible inhibitor of platelet aggregation Low dose aspirin for prevention of cardiovascular events and
DVT? Combination of low dose aspirin and NSAID not recommended Dose 300-900mg every 4 to 6 hours Present in several OTC products – watch out for accidental over
dosage (e.g. Alka Seltzer, Anadin etc) Combination products – with paracetamol, caffeine, codeine etc No topical preparation
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Side-Effects
Most notorious side effect adverse gastrointestinal events including gastric or intestinal
ulceration 2 mechanisms responsible for GI side effects
Local erosion of orally administered agents (THEREFORE they are to be taken with or after meals)
Inhibition of biosynthesis of cytoprotective prostaglandins PGI2 and PGE2 Hence NSAIDs still do cause GI side effects despite the ROUTE of
administration Administration of cytoprotectants e.g. misoprostol [AVOID IN PRE-
MENOPAUSAL WOMEN] for GI protection May be given with proton pump inhibitors e.g. omeprazole,
esomeprazole, rabeprazole, lansoprazole for GI protection
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Side Effects
Others include: Nephrotoxicity - possible interactions with ACE
Inhibitors Renal failure may be provoked by NSAIDs especially in
patients with pre-existing renal impairment Hypersensitivity reactions including rashes,
urticaria, brochoconstriction Anaphylaxis (rare) Hepatotoxicity
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Caution/Contraindication
Avoid ALL NSAIDs in patients with active peptic ulceration
Caution in those with peptic ulceration (risk/benefit)
Asthma – any worsening of asthma should be investigated
Pregnancy; Breastfeeding ; allergic conditions
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Selection
Which NSAID Combination of optimum strength with least side effects
Which Route Oral; rectal; Parenteral reserved for inpatient use Topical for musculoskeletal pain etc
Wash hands thoroughly after use Which Patient
Caution in elderly; those requiring chronic care; those with allergies
Fixed Dose Combination products? Combination with other analgesics?
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Selection
Chronic or acute pain? Gastroprotection? Cox-2 inhibitors
Benefits only few patients hence should be given ONLY when benefits are clear
Avoid concomitant use of aspirin as benefit of Cox-2 inhibition is lost
Side effects? (low GI side effects but other side effects notably serious cardiotoxicity exist!): Rofecoxib and Valdecoxib withdrawn due to association with excess cardiac-related mortality following long-term use
Use in patients with cancer Use post-operatively
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Other Drugs for Inflammation Gout
NSAIDs for acute gout Aspirin usually contraindicated as it inhibits
excretion of uric acid, even at low doses Allopurinol Colchicine
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Other drugs for pain and inflammation Disease Modifying Anti-rheumatic Drugs
(DMARDs) antimalarials (chloroquine; hydroxychloroquine) Penicillamine Sulfasalazine Immunosuppresants e.g. azathioprine,
cyclophosphamide, methotrexate Gold compounds
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Other drugs for pain and inflammation Tricyclic antidepressants, e.g. amitriptyline
especially for neuropathic pain Benzodiazepines Baclofen (a skeletal muscle relaxant) Anticonvulsants, typically Carbamazepine in
trigeminal neuralgia; phenytoin and gabapentin have also been tried. Pregabalin is licensed for trigeminal neuralgia
Transcutaneous electrical nerve stimulation (TENS)
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
Rubefacients and topical antirheumatics Rubefacients act by counter-irritation. Topical NSAIDs provide slight relief of pain in
muscoloskeletal conditions Examples include:
Ibuprofen Piroxicam Ketoprofen Felbinac Diclofenac
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