Nsai10

Non-steroidal Anti-inflammatory Drugs

Dr Alex Dodoo Ph.D. MPSGH, MRPharmSCentre for Tropical Clinical Tropical Pharmacology &

Therapeutics, UGMSAccra, GHANA

[email protected] OR [email protected]

Non-Steroidal Anti-Inflammatory Drugs

18th July 2008

Outline

NSAIDs Indications Mechanism(s) of Action Non-specific Cox or Cox-2 Side-effects Selection


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


18th July 2008

NSAIDs Types

Salicylates (Salicylic acid derivatives)

Aspirin

Diflusinal

Sodium Salicylate

Acetic Acid derivatives Indometacin

Sulindac

Etodolac

Diclofenac


18th July 2008

NSAIDs Types

Propionic Acid Derivatives

Ibuprofen

Naproxen

Ketoprofen

Flurbiprofen

Enolic Acids Piroxicam

Phenylbutazone

Non-acidic compounds Nabumetone


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


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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


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


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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)


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


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!!!


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


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


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)


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


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


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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


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


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?


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


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


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


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)


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

Nsai10

Travel

azapropazone cox

costeffectiveness of

nonselective cox

nonselective ibuprofen

inflammation inhibition

action of nsaids

nsaids bnf

effects of nsaids celecoxib