1 ANALGESIC & ANTI INFLAMMATORY DRUGS ANALGESIC & ANTI INFLAMMATORY DRUGS

2 PAIN l Pain is always a subjective experience l Everyone learns the meaning of “pain” through experiences usually related to injuries in early life l As an unpleasant sensation it becomes an emotional experience l Pain is a significant stress physically, emotionally

3 TYPES TYPES l Somatic pain: caused by the activation of pain receptors in either the cutaneous (the body surface) or deeper tissues (musculoskeletal tissues). l Visceral pain: pain that is caused by activation of pain receptors from infiltration, compression, extension or stretching of the thoracic, abdominal or pelvic viscera (chest, stomach and pelvic areas). l Neuropathic pain: caused by injury to the nervous system either as a result of a tumor compressing nerves or the spinal cord, or cancer actually infiltrating into the nerves or spinal cord.

4 Various Descriptors of Pain l Mild l Moderate l Severe l Acute l Chronic l Malignant

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6 Treatment Non – opioid analgesics l Salicylates, NSAID’s, Cox 2 inhibitors Opioid analgesics – Morphine, Pethidine.. Both can be used in combined therapy.

7 l Most of the drugs used as analgesics have the property of anti inflammatory actions also. l Some of these drugs have anti-pyretic property also.

8 Anti-Inflammatory Drugs l Non steroidal Anti-inflammatory Drugs (NSAID’s) l Steroidal agents

9 ROLE OF PROSTAGLANDINS Cell Membrane (phospholipids) phospholipase A 2 Arachidonic acid cyclooxygenase aspirin, indomethacin (COX1 & COX2) Cyclic endoperoxides (PGG 2, PGH 2 ) prostacyclin prostaglandin thromboxane synthetase synthetase synthetase prostacyclin PGE 2 PGF 2  Thromboxane A 2 PDX, PGI 2 (vasodilator, (erythma (vasodilator (vasoconstriction antiaggregating) edema uterus contractor) platelet agregation) pain, fever)

10 NSAID’s ( Nonselective COX Inhibitors) l Salicylic acid derivatives: Aspirin, Diflunisal etc l Para-aminophenol derivatives: Acetaminophen l Indole and indene acetic acids: Indomethacin l Heteroaryl acetic acids: Tolmetin, Ketorolac l Propionic acids: Ibuprofen, Naproxen, Ketoprofen etc l Anthranilic acids (Fenamates): Mefenamic acid, Meclofenamate

11 NSAIDs Selective COX 2 Inhibitors l Rofecoxib (Vioxx) l Celecoxib (Celebrex) l Valdecoxib

12 Salicylates l Aspirin: prototype  Aspirin uniquely inactivates COX by irreversibly acetylating the enzyme. Uses  Pain (analgesic): moderate dose  Fever (anti pyretic): moderate dose  Anti inflammatory: high dose  Anti platelet: low dose

13  Therapeutic uses: Control of Rheumatoid Arthritis, Gout, Osteoarthritis, Ankylosing spondylitis and prophylaxis against platelet aggregation. & other pains.  Adverse effects: Gastrointestinal irritation, Peptic ulcer, Hypersensivity, ↑ bleeding time, renal dysfunction (chronic use), bronchospasm, hyperuricemia, hyperthermia at large doses (cause of death).  Reye syndrome: encephalopathy, fatty infiltration of the liver, kidney, spleen

14  Salicylism: due to toxic doses causes tinnitus, vertigo, ↓ hearing, confusion, hallucination, delirium, coma and death from respiratory failure  Treatment: no specific antidote  ↑ urinary Ph, gastric lavage +/- activated charcoal, dialysis

15 Salicylates (continued) l Diflunisal: difluorophenyl derivative of salicylic acid.  Diflunisal is more potent than aspirin in analgesic & anti-inflammatory actions. However, it is largely devoid of antipyretic effects.  Longer duration (half-life:8-12 hrs vs. 2.5 hrs for salicylates).  Fewer and less intense gastrointestinal and antiplatelet effects than does aspirin.

16 Indole and Indene Acetic Acids l Indomethacin:  Indomethacin is a potent reversible inhibitor of the COX.  The toxicity of indomethacin limits its use in the treatment of ankylosing spondylitis, gouthy arthritis and osteoarthritis.  SE: Thrombocytopenia, agranulocytosis Sulindac: an indene derivative  It must be reduced to sulfide metabolites to become active form of NSAID.  Sulindac has been used mainly for the treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.  SE: stevens-johnson syndrome, hematotoxicity

17 Phenyl Acetic Acid Derivatives l Diclofenac: phenyl acetic acid derivative  It is a COX inhibitor, and its potency is substantially greater than that of indomethacin.  Diclofenac sodium (Voltaren) is approved for the long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.  It can also be used for short-term treatment of acute musculoskeletal injury, acute painful shoulder, postoperative pain and Dysmenorrhea.  Toxic effects: gastrointestinal effects are the most common.

18 Propionic Acid Derivatives Propionic acid derivatives are used for the symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and acute gouty arthritis. l Ibuprofen: l Naproxen: The half-life of naproxen in plasma is about 14 hrs. l Ketoprofen: l Oxaprozin: It is unique among propionic acid derivatives because it can be administered once daily. l Fenoprofen l Flurbiprofen

19 Selective COX-2 inhibitors Celecoxib (celebrex): It has been approved for the treatment of osteoarthritis and rheumatoid arthritis. The recommended dose for treatment osteoarthritis is 200 mg per day as a single dose or as two 100-mg doses.

l Causes less GIT toxicity l Less antiplatelet action l Potential cardiotoxicity which resulted in its withdrawal from the market (rofecoxib) l SE: abdominal pain, diarrhea, dyspepsia l CI: pts allergic to aspirin, chronic renal insufficiency, severe heart disease, volume depletion and hepatic failure. 20

21 Others Acetaminophen l Inhibits mainly PG in CNS – antipyretic & analgesic ation l No anti inflammatory action l No anti platelet action l No effect on uric acid l Not known to cause Reye syndrome l Not bronchospastic

22 l Good for pt’s with aspirin SE. l Analgesic and antipyretic in viral infections in children l Conjugated in the liver to form sulfated metabolite l A portion is hydroxylated to form N- acetylbenzoiminoquinone a highly reactive and potentially dangerous metabolite that reacts with sulfhydryl groups. l At normal doses, it reacts with the sulfhydryl grp of glutathione, forming a nontoxic substance which is excreted in urine

23 SE: l Not much with normal doses, l High doses –N acetyl benzoiminoquinone reacts with sulfhydryl groups of hepatic proteins. l Can lead to hepatic necrosis and also renal tubular necrosis. l Anti dote – N - acetylcysteine

DISEASE MODIFYING ANTIRHEUMATIC DRUGS(DMARDS) l NSAIDS are commonly used for the initial management of RA, but require high doses which generally results in marked adverse effects l The NSAIDS decrease swelling and pain but have no effect on the progression of the joint damage l DMARDS slow disease progression, so used in combination with NSAIDS 24

25 DMARDS These drugs are relatively toxic, and they are reserved for patients with progressive disease, refractory cases or patients unable to tolerate standard medications.

26 l Gold compounds: Aurothioglucose, Gold sodium thiomalate, and auranofin  Mechanism: Gold compounds are taken up by macrophages and suppress phagocytosis and lysosomal enzyme activity.  USES; cannot repair existing damage, rather can only prevent further injury.  Toxicity: Lesions of the mucous membranes include dermatitis, nephrotoxicity, pharyngitis etc. Severe blood dyscrasias also may occur.

27 Miscellaneous agents for rheumatoid arthritis (continued) l Immunosuppressive agents, : Azathioprine, Methotrexate Of the cytotoxic immunosuppressant, only Azathioprine and low oral doses of methotrexate have been approved for treatment of RA. l Penicillamine: orally effective alternatives to gold in the treatment of patients with early, mild, and nonerosive disease. l It suppresses T-cell and circulating rheumatoid factor. Toxicities: various cutaneous lesions, blood dyscrasias etc. l Antimalarial agents: Hydroxychloroquine

Anticytokine therapies in RA IL-1 and TNF- α are proinflammatory cytokines involved in the pathogenesis of RA l Secreted by synovial macrophages, stimulates synovial cells to proliferate and synthesize collagenase, thereby degrading cartilage, stimulating bone resorption and proteoglycan synthesis 28

l Etanercept: recombinant form of TNF receptor that binds TNF l Infliximab, Adalimumab: a monoclonal antibody to tumor necrosis factor l Other uses: infliximab (crohn disease) l Anakinra: a IL-1 receptor antagonist l S.E: infections, reactions at injection sites 29

30 Gouty arthritis An acute attack of gout occurs as a result of an inflammatory reaction to crystals of sodium urate that are deposited in the joint tissue. The inflammatory response involves: l Local infiltration of granulocytes, which phagocytize the urate crystals.

31 l Tophaceous deposit: sodium urate deposits in and around joints in cartilage, bone, bursa and subcutaneous tissue. l Uric acid nephrolithiasis: formation of urate stone

CAUSES OF GOUT l Overproduction of uric acid l Under excretion of uric acid 32

Therapeutic goal of treatment l Interfering with uric acid synthesis l Increasing uric acid excretion l Inhibiting leukocyte entry into the affected joint l Administration of NSAIDs 33

Drugs for acute treatment of gout l Indomethacine: decrease the movement of granulocytes into the affected area l NSAIDs: to decrease pain and inflammation l Glucocorticoids l Aspirin is contraindicated because it competes with uric acid for organic acid secretion by the PCT 34

TREATMENT OF CHRONIC GOUT l Allopurinol: its metabolite, alloxanthine, is an inhibitor of xanthine oxidase, which is required to synthesize uric acid. l Adverse effects: GIT distress, peripheral neuropathy, rash and stone formation l It inhibits the metabolism of 6-MP 35

36 l Colchicine: it is largely effective only against gouty arthritis. - MOA: binds to tubulin causing its depolymerization which inhibits the migration of granulocytes into the inflamed area and a decreased metabolic and phagocytic activity of granulocytes - It also blocks cell division by binding to mitotic spindle - Side effects: nausea, vomiting, diarrhea, and abdominal pain. - Toxic effects: hemorrhagic gastroenteritis, extensive vascular damage, nephrotoxicity, and muscular depression.

37 Drugs used in the treatment of gout (continued) l Uricosuric drugs: sulfinpyrazone and probenecid These drugs, at higher doses, block proximal tubular reabsorption of urate, thus increasing urinary excretion of uric acid and lowering serum urate concentration. l It is ineffective if GFR is <50mL/min  Probenecid: - Liberal fluid intake should be maintained throughout therapy. - The uricosuric action of Probenecid is blunted by administration of salicylates