NSAIDS Non steroidal anti-inflammatory drugs Dr Soe Aung Myint

OBJECTIVES Common MOA of NSAIDs- analgesic, antipyretic and anti inflammatory actions Properties of individual NSAIDs Therapeutic efficacy, uses, untoward effects, and contraindication Treatment of paracetamol overdosage

CLASSIFICATION 1. Para-aminophenol derivative paracetamol(acetaminophen) 2. Salicylic acid derivatives: aspirin (acetylsalicylic acid), diflunisal methylsalicylic acid (only for topical use) 3. Acetic acid derivatives: indomethacin, sulindac, tolmetin, diclofenac, ketorolac, etodolac** 4. Fenamic acid derivatives: mefenamic acid, flufenamic, meclofenamic 5. Propionic acid derivatives: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, oxaprozin 6. Enolic acid derivatives (Oxicams) piroxicam, tenoxicam, meloxicam** 7. Non acidic drug: Nabumetone, celecoxib**, aceclofenac [**= COX-2 Selectivity]

CLASSIFICATION BASED ON COX SELECTIVITY Non COX selective NSAIDS – Aspirin, indomethacin, diclofenac, piroxicam, ibuprofen, naproxen, mefenamic acid Preferential COX2 inhibitors – Nimesulide, meloxicam, nabumetone, aceclofenac Highly selective COX2 inhibitors ( COXIB ) – 1 st generation : celecoxib, rofecoxib (withdrawn in US) – 2 nd generation : valdecoxib (withdrawn in US), parecoxib, etoricoxib, Lumiracoxib (analog of diclofenac)

Mechanism of Action NSAIDs inhibit prostaglandin synthesis by inhibiting both COX- 1 and COX-2 COX-1 is non-inducible and present in platelet, stomach and kidney COX-2 is induced by cytokines and endotoxins at site of inflammation COX-2 is also attributable for generation of renal vasodilatory PGE 2 and PGI 2, formation of PGI 2 by platelet endothelial cell (which normally inhibit TXA 2 )

SALICYLATES Aspirin: prototype of NSAIDs ( From Willow bark) WILLOW TREE WILLOW BARKWILLOW TREE

Pharmacological Actions Analgesia - relieve pain of mild to moderate intensity from somatic origin, (especially pain arising from inflammation and post-op pain) Anti-inflammatory action - by inhibiting PGE 2, I 2 and F 2α synthesis Antipyretic - lower the elevated temperature rapidly and effectively

Antiplatelet effect – inhibit platelet aggregation and adhesion due to reduced production of TXA 2 (with low dose), prevent thrombosis and prolong BT – avoided in patients with severe hepatic damage, hypoprothrombinaemia, vitamin K deficiency or haemophilia because inhibition of platelet haemostasis can result in haemorrhage

GI irritation due to – back diffusion of acid causes injury to mucosa and submucosal capillaries resulting in necrosis and bleeding – inhibition of protective prostaglandin synthesis (PGE 2 & PGI 2 ) causes increased acid secretion and decreased mucous production.

Effect of uric acid excretion - Therapeutic dose (1-2 g/day)- ↓ urate excretion and ↑ plasma urate concentration. Closure of ductus arteriosus in fetus (indomethacin can be used) Effect on renal haemodynamic - Salt and water retention and oedema due to inhibition of renal vasodilator PGE 2 and PGI 2 synthesis

Effects on CNS - Toxic dose cause stimulation of CNS followed by depression. Confusion, dizziness, tinnitus, convulsion and coma. Stimulate respiration with therapeutic dose produces hyperventilation (respiratory alkalosis). Metabolic effects - high dose  hyperglycaemia & glycosuria, negative nitrogen balance, decreased lipogenesis. Local effect: - irritating to skin & mucosa and destroy epithelial cells (keratolytic action)

Therapeutic Uses 1. Systemic administration – Non-specific relief of certain types of pain eg. Headache, arthralgia, myalgia, neuralgia and dysmenorrhoea (dose: 300 mg tds or qid) – to reduce inflammation e.g. acute rheumatic fever, RA – to reduce fever (dose: not less than 3.5 g/day, high dose)

– prophylaxis of thrombo-embolic diseases e.g. CHD, DVT (dose: mg/day for long-term prophylaxis, antiplatelet effect, mg/day for acute myocardial infarction, unstable angina and acute ischaemic stroke) – for the closure of patent ductus arteriosus (indomethacin is more useful)

2. Local application (Uses) – topical application for muscle and joint pain (analgesic), warts, corn, fungus infection, eczematous dermatitis (keratolytic) – oral for ulcerative colitis (sulphasalazine = aminosalicylic acid + sulfapyridine)

Adverse Effects Nausea and vomiting (due to stimulation of CTZ & gastric irritation) GIT - heart burn, epigastric distress, vomiting, erosive gastritis, exacerbation of PU, gastrointestinal haemorrhage. increased bleeding tendency in blood disorders interfere with uricosuric agents

Salt and water retention and oedema allergic or hypersensitivity reactions (rhinitis, urticaria, angioneurotic oedema, asthma, shock) analgesic nephropathy in long-termed use premature closure of ductus arteriosus in fetus High dose produces toxic effect on CNS, consisting stimulation followed by depression. Confusion, dizziness, tinnitus, hearing difficulty, delirium, psychosis, stupor and coma may occur

Salicylism – characterized by tinnitus, vertigo, decreased hearing, N, V occurs with over dosage Reye’s syndrome – characterized by hepatic encephalopathy following an acute viral illness in children

Contraindications Children nursing mothers pregnant women

PARACETAMOL efficacy is equal to that of aspirin in analgesic and antipyretic action but in therapeutic doses has no significant anti-inflammatory action less effect on platelets, on BT and on GI irritation used to control pain or fever as substitute for aspirin in cases with PU, prolong BT and allergy or in cases less than 12 years of age

Pharmacokinetics Detoxified substances Glutathione Toxic metabolites well absorbed from GIT. Metabolized in liver. Hepatic glutathione is limited If amount of paracetamol metabolite is greater than the glutathione available, then the metabolite is able to oxidized thiol (SH Group) in hepatic proteins leads to hepatic necrosis Paracetamol

Treatment of Poisoning – N-acetylcysteine, methionine (precursors for the synthesis of glutathione) – activated charcoal (to reduce absorption) Dose: 0.5 – 1 g qid (maximum 4 g/day) (taken more than 10 g in one dose = over dose)

Adverse Effects few, rarely cause skin rash and allergy Well tolerated by the stomach Long-term daily use may predispose to chronic renal failure

Uses mild to moderate pain to relieve fever (can be used in patients with peptic ulcer, bleeding disorder, and children and pregnancy)

INDOMETHACIN, SULINDAC AND ETODOLAC are methylated indole derivatives more potent than aspirin in analgesic and anti-inflammatory actions

Therapeutic Uses to relieve pain and inflammation in ankylosing spondylitis, osteoarthritis, acute gout as antipyretic when fever is refractory to other agents eg. in Hodgkin’s disease closure of PDA (IV)

Side Effects common – Anorexia, nausea, abdominal pain – severe frontal headache, dizziness, vertigo, psychosis, skin rash, leucopoenia – It should not be used in pregnant women and children, persons with renal impairment, cardiac failure or mental disorder

KETOROLAC mainly as an analgesic, not as an anti-inflammatory as effective as morphine for post-surgical & cancer pain, with fewer side effects ( short-term, not more than 2 days) may also be given IM, IV side effects – haemorrhage, GI irritation, fluid retention, allergic reaction (no tolerance dependence, respiratory depression)

PHENYLBUTAZONE discontinued use

MEFENAMIC ACID Analgesic, antipyretic and anti-inflammatory properties. Used for mild to moderate pain where inflammation is not marked eg, muscular or dental pain, headache, dysmenorrhoea, and menorrhagia Side Effects: – diarrhoea, peptic ulcer, haemolytic anaemias – in elderly patient: renal failure

PROPIONIC ACID used in mild rheumatoid disease and musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis Also used as analgesics for acute tendonitis, bursitis & for primary dysmenorrhoea Naproxen is most potent among this group Naproxen and Ibuprofen can be given BD. Low incidence of GI side effect seen with ibuprofen low dose

DICLOFENAC SODIUM analgesic, antipyretic and anti-inflammatory agent Potency is substantially greater than indomethacin, naproxen and several other agents inhibits COX non-selectively Is rapidly and completely absorbed after oral administration First pass effect present (only 50% available). PPB 99%. Accumulates in synovial fluid thus having longer action in joints

Therapeutic Uses used for moderate pain and inflammation in RA, musculoskeletal disorders, OA, ankylosing spondylitis, dysmenorrhoea, renal colic, post- operative pain and after cataract extraction It can be given orally, parenterally, rectally and topically (t 1/2 - 2hr)

Side Effects GI and CNS are common Other side effects are skin rash, allergic reaction, fluid retention, oedema and impaired renal function

PIROXICAM antipyretic analgesic with marked anti-inflammatory action. T 1/ hr (Tenoxicam 72 hr, single daily dose) GI and CNS side effects are commonest completely absorbed from GIT Used in musculoskeletal disorders, RA and gout

NAMBUMETONE non-acidic and is largely metabolized to an active metabolite, an acid and a potent inhibitor of PG synthesis. Once daily is effective. Side effect: dyspepsia, diarrhoea and rash

SELECTIVE COX-2 INHIBITORS (MELOXICAM) used to treat osteoarthritis and rheumatoid arthritis. Dose 7.5 – 15 mg once a day

CELECOXIB (Furanone derivative) PA - Analgesic, antipyretic and anti-inflammatory action MOA - It is a potent selective COX 2 inhibitor. It exhibits above actions by inhibiting PG synthesis PK – readily absorbed after PO and is highly bound to plasma protein – Metabolized in liver and most of the drug is excreted as metabolites in urine – Dosage should be reduced by at least 50% in patients with moderate hepatic impairment – Half-life is 11 hours, so it is usually given once or twice daily

Uses - osteoarthritis, rheumatoid arthritis Dose: mg daily 1-2 divided doses Side Effects - hypertension and oedema, selective COX-2 inhibitors depress PGI 2 formation by endothelial cells → thrombosis (increased incidence with rofecoxib, celecoxib, valdecoxib) Contraindications - cardiovascular or cerebrovascular diseases

DRUGS FOR RHEUMATOID ARTHRITIS AND DEGENERATIVEJOINT DISEASES

Aim – to decrease inflammation, thereby decreasing the pain and slowing the joint destruction

Drugs 1. NSAIDs 2. Gold salts: accumulates in lysosomes, decreases the migration and phagocytic activity of macrophages (side effect: cutaneous reactions, albuminuria, haematuria, thrombocytopenia) 3. Penicillamine 4. Hydroxychloroquine 5. Corticosteroids 6. Immunosuppressive agents (azathioprine, methotrexate, cyclosporin)

Aspirin: a. can produce encephalopathy in children with measles b. decrease platelet aggregation with sub-analgesic dose c. can relieve pain of visceral origin d. dose dependent effect on uric acid excretion e. potentiate uricosuric action of probenecid Y Y N Y N

Paracetamol: a. is equivalent to aspirin in analgesic property b. has potent anti-inflammatory activity c. has severe GI irritation d. can be given safely to children e. is toxic to liver in overdose Y N N Y Y