Over View of NSAIDS By Somnath Mondal

Classification
1. i. COX 1 and 2 inhibitors: Analgesic and antiinflammatory

Salicylates: Aspirin and other salicylates. Acetic acid derivatives: Indomethacin, diclofenac, Ketorolac Propionic acid derivatives: Ibuprofen, Naproxen. Fenamic acid derivatives: Mefenamic acid, Enolic acid derivatives: Piroxicam

ii.

Analgesic but poor antiinflammatory Paraminophenol derivative: Paracetamol (Acetaminophen)

2.

COX-2 inhibitors: Celecoxib, etoricoxib, meloxicam(preferential COX2 inhiibitor) Dont affect platelets, efficacy equals to older NSAIDs; GIT safety improved but they may inc. hypertension, edema

Click to Mechanism of action of NSAID edit Master text styl

They inhibit cyclooxygenase and inhibit the formation of prostaglandins. There are two main types of cyclooxygnase (COX).

COX-1 constitutive, present in most tissues: GIT (cytoprotective), kidney (vasodilatation), platelets (controls platelet aggregation, PGI2 inhibits &TxA2 increases) involved in tissue homeostasis.

Second level Third level Fourth level Fifth level

COX-2 is induced in inflammatory cells by cytokines & endotoxins- produce prostanoids. It is constitutive in brain, kidney. Infection or immune reaction release IL-1 & TNF induction of COX-2 in inflammatory cells PG formation Role of PGs in inflammation: Vasodilatation: redness. Inc. capillary permeability: edema formation-swelling Infection/inflammation IL-1 release from macrophages inc. PGE2 in hypothalamus inc set point of hypothalamic temperature regulating centre increase heat production fever

NSAIDs
Mechanism of action They act by inhibition of cyclooxygenase responsible for the formation of prostaglandins. Most NSAIDs inhibit both COX1 and 2. Some NSAIDs are selective COX2 inhibitors. Aspirin irreversibly acetylates and blocks cyclooxygenase (COX 1& 2) Other NSAIDs are reversible inhibitors. Additional mechanisms: Inhibition of lipooxygenase by indomethacin & declofenac . Also inhibition of leucocyte migration & superoxide formation. Down regulation of IL-1 production Interference with calcium mediated intracellular events Decrease the sensitivity of vessels to bradykinin & histamine,

NSAIDs: shared properties to edit Master text styles Click

Most of the NSAIDs have three major types of effects: Antipyretic effect. Analgesic effect Anti-inflammatory effects

Second level Third level Fourth level Fifth level

Antipyretic action : Mechanism NSAIDs inhibit production of PGE2 in the hypothalamus . Rapidly reduce elevated body temperature in patients with fever, but no effect in normal person. It resets the hypothalamic thermostat to normal

NSAIDs- shared actions

Analgesia : Mechanism: Decreased PG formation dec sensitivity to nociceptive pain producing effect of bradykinin & histamine. A central subcortical action: Dec. PG, inc pain threshold even in the absence of inflammation Relieve inflammatory, tissue injury related connective tissue and integumental pain . Relatively ineffective in severe visceral and ischemic pain Effective in arthritis, bursitis, pain of muscular and vascular origin, toothache, dysmenorrhoea, pain of post partum hemorrhage and cancer metastases in bone,(all conditions associated with increased PGs synthesis). In combination with opioids, they decrease postoperative pain, and may reduce the requirement of opioids by as much as 1/3 rd. Indomethacin, diflunisal and naproxen are effective in pain not related to PG synthesis.

NSAIDs- shared actions

Antiinflammatory action : Mechanism Inhibition of synthesis of PG. Reduce COX-2 induced infl. or immune response. Reduce vasodilatation, edema & influx of leucocytes- reduce signs of infl but not the progression of disease in rheumatoid arthritis and rheumatic fever. Other actions: Inhibition of platelet function- all except COXII inhibitors and nonacetylated salicylates. Gastric & duodenal mucosal damage. Renal effects: Inh. of PG synthesis- acute renal failure in elderly, CHF, cirrhosis. Analgesic nephropathy on chronic use (chronic interstitial nephritis & papillary necrosis)

NSAIDs: other shared properties

Hepatotoxicity Reduction in incidence of colon cancer (50% reduction in 5 years of use) Prolongation of gestation and labor: dec. PG E & F- inhibit the initiation & progression of labor. Premature closure of ductus arteriosus in utero- adm. of NSAIDs to pregnant woman, dec. formation of PG to keep the ductus patent. Hypersensitivity reaction: urticaria, severe rhinitis & asthma in susceptible persons (e.g nasal polyps- pseudoallergic reaction)blocking of COX pathway diversion of arachidonic acid to lipooxygenase pathway formation of LTs- bronchospasm. Shared uses: rheumatoid arthritis and other arthritis, osteoarthritis, localised musculoskeletal syndromes (sprains, strain,), gout except aspirin

NSAIDs: Common unwanted 1. GI disturbances: Commonest- particularly in elderly patients. effects abdominal pain, diarrhoea sometimes constipation, nausea and vomiting. Dyspepsia,
Gastric damage, ulcer, which may be silent but carries a definite risk of serious haemorrhage and or perforation. Highest incidence of bleeding with piroxicam, less bleeding with diclofenac and naproxen, least risk with ibuprofen. 2. Skin reactions 2nd most common adverse effect particularly with mefenamic acid. Skin rashes all types, pruritus, urticaria, photosensitivity to severe fatal conditions. 3. Renal effects: Acute renal insufficiency : more with indomethacin. Retention of salt and water and edema formation in some (inh. of PG). Chronic analgesic use: can cause analgesic nephropathy (chronic nephritis and renal papillary necrosis). 4. 5. 6. 7. 8. CNS: headache, tinnitus, dizziness CVS: fluid retention, hypertension, edema, CHF Pulmonary: asthma Liver disorders: abnormal liver functions; overdose of paracetamol causes liver failure. Rare: Hematological: thrombocytopenia, neutropenia and even aplastic anemia- indomethacin

Commonly used NSAIDs: Aspirin and salicylates

The Salicylates. i. ii. Salicylic acid (keratolytic) & methylsalicylate (counterirritant) - used topically. Nonacetylated salicylates: magnesium choline salicylate, sodium salicylate and salicyl salicylate: are antiinflammatory, less analgesic, have no effect on platelets, preferred in patients with asthma, bleeding & renal dysfunction.Sodium salicylate: a salt of salicylic acid, has 2/3rd of the potency of aspirin , causes less GI irritation. Aspirin (acetyl salicylic acid)- ester of salicylic acid, relatively insoluble but Na+ & Ca++ salts are readily soluble, pKa 3.5. Rapidly converted in body to salicylic acid, which is responsible for most of its actions.

iii.

Pharmacological actions: aspirin

1. 2. 3. 4. Analgesia- small dose: central and peripheral Antipyretic action- small dose Antiinflammatory action- large dose Metabolic effects : seen only at antiinflammatory doses.

Uncoupling of oxidative phosphorylation increased cellular metabolism-increased CO2 production- inc resp. Inc utilisation of glucose, blood sugar may dec.esp.in diabetics. Hyperglycemia seen at toxic doses due to central sympathetic stimulation and release of adrenaline and corticosteroids.

5.

Effect on Respiration : dose dependent.

At antiinflammatory dose respirations are stimulated: direct stimulation of RC and also through peripheral effects, i.e, inc CO2 production, stimulate resp centre hyperventilation. Further inc. in salicylate conc.resp. depression.

Pharmacological actions: aspirin

6. i. Effect on Acid base and electrolyte balance: Occur at higher doses (antiinflammatory and higher doses: Initial respiratory stimulation washes away carbon dioxide respiratory alkalosis. This is compensated by inc. renal excretion of bicarbonate with loss of sodium, potassium and water- compensated respiratory alkalosis. ii. Still higher doses - respiratory depression retention of carbon dioxide respiratory acidosis. Metabolic acidosis develops due to:
dissociated salicylic acid metabolic acids (lactic, pyruvic, acetoacetic- which are produced in excess and sulfuric acid and phosphoric acid- not excreted due to depressed renal function, plasma bicarbonates are already low. Most children manifest this phase while in adults this is seen late.

Dehydration due to:

increased water loss in urine to accompany sodium, potassium and bicarbonate increased sweating and hyperventilation.

Pharmacological actions: aspirin

7. Effect on Urate excretion: Dose related; <2gm/d- urate retention and antagonism of all other uricosuric drugs. 2-5 gm/d- variable effects, often no change. >5 gm/d- increased urate excretion. Aspirin is not used in chronic gout as high doses are not tolerated well. 8.
i. n.

Effect on Blood: Platelet: In small doses (81-325mg)irreversibly acetylates and inhibits COX-1 & synthesis of TXA2 by platelets. Platelets have no capacity to synthesise protein, hence effect lasts for life of platelet (7-8D)

Interferes with platelet aggregation and bleeding time is prolonged. Effect lasts a week (turnover time of platelets). ii. Prothrombin time:

Long term use of large doses dec. synthesis of clotting factors in liver can be prevented by prophylactic vitamin K.

Pharmacological actions: aspirin

9. GIT:
Cause irritation of GI mucosa, produce epigastric distress, nausea and vomiting. Also stimulates CTZ. Aspirin (pKa 3.5) unionized and diffusible in the acid gastric juice but on entering the mucosal cell (pH 7), gets ionised, enhances gastric toxicity. Promote back diffusion of acid local necrosis of mucosal cells and capillaries acute ulcers, erosive gastritis, congestion and microscopic hemorrhages. Inc.in occult blood loss in stools- averages 5 ml with therapeutic doses. Haemetemesis -an idiosyncratic reaction.

Mechanism: All NSAIDs inhibit PG synthesis. PGs inhibit gastric acid secretion, inc.mucus production and act as cytoprotective for gastric mucosa. Thus aspirin enhances aggressive factors ulcerogenic.

Pharmacokinetics: Aspirin
Absorption From stomach and small intestine.. Distribution 80% bound to plasma proteins, enters brain, crosses placenta. Displacement interaction may occur Metabolism Rapidly deacetylated by esterases in the gut wall, liver, plasma and other tissues to release salicylic acid - the major circulating and active form. Both aspirin and salicylic acid are conjugated in liver to glycine (75%) salicyluric acid (major pathway- rate limiting); and glucuronic acid (15%). Little oxidised 1% genitisic acid. Metabolites are excreted by GF and TS. Normally 10%is excreted as free salicylic acid- but this can be increased by alkalinization of urine. Half life: dose dependent metabolism. Aspirin: 15-20 minutes, salicylic acid - 3-5 hours. At higher doses- 15 to 30 hours. Preparations: tablets: plain, buffered, soluble effervescent, enteric coated, sustained release

Adverse effects
i. GI effects:
Nausea, vomiting, epigastric distress, increased occult blood loss in stools. Profuse gastric hemorrhage- idiosyncratic response. Aspirin and all NSAIDs: gastric mucosal damage and peptic ulceration.

CNS effects with higher (Antiinflammatory) doses (3-6g/d): chronic moderate toxicity-salicylism: tinnitus, hearing difficulty, dizziness, headache, mental confusion. Hepatic toxicity: Aspirin- Reye's syndrome (a rare form of hepatic encephalopathy)- seen in children with viral (varicella,influenza) infection. Dose dependent- hepatotoxicity- more in patients with connective tissue diseases- inc transaminases Allergy or pseudoallergy and idiosyncrasy Rashes,urticaria, rhinitis, angioedema, asthma and shock- those who already suffer from urticaria, nasal polyps or asthma are more susceptible- pseudoallergic reaction.

Salicylate toxicity
Conc. ( g/ml) Effects Complications

Up to 10 Analgesic, antipyretic, antiplatelet 10-40 50 50-80 80-110 Mild intoxication Moderate Antiinflammatory, uricosuric

Gastric intolerance, bleeding, hypersensitivity reactions, impaired hemostasis

Tinnitus Central hyperventilation Fever, dehydration, acidosis metabolic

110-160 Severe >160 Lethal

Vasomotor collapse, coma, hypoprothrombinemia Renal and respiratory failure

Contraindications/cautions: aspirin
Contraindications:
Patients who are sensitive. Patients with hemophilia. Patients with peptic ulcer, bleeding tendencies Children suffering from chicken pox or influenza due to risk of Reye's syndrome. Patients with chronic liver disease - hepatic necrosis may occur.

Cautions:
Avoided in patients with diabetes, diminished cardiac reserve or frank CHF, and juvenile rheumatoid arthritis. Should be stopped one week prior to any surgery. Given during pregnancy- low birth babies. Taken at term: delayed and prolonged labor, greater postpartum blood loss and premature closure of ductus arteriosus. It should be avoided by nursing mothers. Bronchial asthma Gout

Uses: aspirin
To decrease incidence of TIA (transient ischemic attacks), unstable angina, coronary artery thrombosis & myocardial infarction and thrombosis after coronary bypass graft, in postmyocardial infarction and post stroke patients: low dose aspirin: 81 mg/d Reduces the risk of cancer of colon and possibly also rectal cancer. As analgesic: Nonvisceral pain of mild to moderate severity. E.g. effective in headache, myalgia, joint pain, toothache, neuralgia,and dysmenorrhoea. With opioids for cancer pain As antipyretic- It is effective in fever of any origin; dose is same as for analgesia Acute rheumatic fever: drug of first choice Rheumatoid arthritis: Large doses not tolerated, NSAIDs are often used. Osteoarthritis. Other uses of aspirin: Pregnancy associated hypertension and preeclampsia: PDA: for closure, indomethacin is preferred. Radiation sickness diarrhoea: PGs probably are involved, aspirin reduces stool volume.

Acetic acid derivatives

Indomethacin
Highly effective antiinflammatory drug, potent analgesic and antipyretic. Inhibits phospholipase A and C. Reduce neutrophil migration. Reduce T and B cell proliferation. Available as oral, epidural injection (for pain relief in postlaminectoly syndrome) ophthalmic preparation. Uses: Acute gout, ankylosing spondylitis. For closing patent ductus arteriosus. Rheumatoid arthritis, osteoarthritis, acute musculoskeletal disorders To relieve moderate to severe pain. Pain due to pericarditis, pleuritis Pain following minor operation. To reduce opioid requirement after major operation As tocolytic Diabetes insipidus Adverse reactions: GI upset Renal: Salt and water retention: reduce effectiveness of diuretic. Aggravation of preexisting renal disease. CNS: Frontal headache (very common)- due to cerebral edema, dizziness, ataxia, mental confusion, hallucination , depression, and psychosis. Leucopenia & other hypersensitivity reactions- cross reactivity with aspirin. Contraindication: Machinery operators, drivers, psychiatric patients, epileptics, kidney disease, pregnancy and in children & in patients with GI disease and infection.

Acetic acid derivatives

Diclofenac sodium Analgesic, antiinflammatory and antipyretic. Available for oral, rectal, IM and topical use (eye, skin). Available in combination with misoprostol, omeprazole to decrease GI bleeding Uses Moderate pain and inflammation due to rheumatoid and osteoarthritis, bursitis, ankylosing spondylitis. Renal colic. Dysmenorrhoea. Postoperative pain- affords quick relief of pain and wound edema. Adverse reactions: GI: epigastric distress, nausea, gastric ulceration and bleeding are infrequent. Renal toxicity: dec in renal blood flow and GFR Hepatic toxicity: inc. transaminases CNS: headache, dizziness Rashes.

Acetic acid derivatives

Ketorolac A NSAID with potent analgesic and modest antiinflammatory activity. In postoperative pain -efficacy equal to morphine. ADME- oral, IM, IV. Uses: For postoperative and acute musculoskeletal pain (IM). Orally it is used for short term management of moderate pain, Continuous use for more than 5 days is not recommended. GI and renal adverse effects limit its use. Adverse effects: GI: nausea, abdominal pain, dyspepsia, loose stools CNS: headache, dizziness, nervousness, Others: stomatitis, pruritus, pain at injection site, rise in serum transaminases and fluid retention . Caution In ulcer patients, in cardiac, renal & hepatic disease, in children, elderly and pregnant women.

Propionic acid derivatives

Ibuprofen, Naproxen, oxaprozin. Ibuprofen: available for oral, IV, topical use
ADME. The plasma t of ibuprofen is 2 hours, of naproxen is 12-16 hours Uses Simple analgesic and antipyretic. Particularly good for postsurgical dental pain- gel. Rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders, especially where pain is more prominent than inflammation. They are indicated in soft tissue injury, fracture, tooth extraction, postpartum and postoperatively to suppress inflammation and swelling. To close PDA- efficacy similar to indomethacin Adverse reactions. This gr is better tolerated than other NSAIDs and side effects are milder GI: less, many peptic ulcer patients are able to tolerate this gr. Gastric erosion and occult blood loss are rare. CNS: headache, dizziness, blurred vision, tinnitus, depression. Rashes- hypersensitivity reactions- asthma Fluid retention. Ibuprofen has been rated as the safest NSAID by the spontaneous ADR reporting system in U.K. Naproxen- in acute gout. It is also recommended for ankylosing spondylitis.

Fenamic acid (anthranilic) derivatives: mefenamic acid

An analgesic, antipyretic and antiinflammatory drug of low potency. Half life: 2-4 hours. Adverse reactions: Diarrhoea - most common dose related side effect. Hemolytic anemia- rare but serious. Epigastric distress. Skin rashes , dizziness and other CNS manifestations. Uses As analgesic in muscle, joint and soft tissue pain, where strong antiinflammatory action is not needed. Quite effective in dysmenorrhoea.

Enolic acid (oxicam) derivatives: Piroxicam, tenoxicam

Piroxicam. Half life 45 H. given once daily Inhibit Polymorphonuclear leucocyte migration Decreases oxygen radical production and inhibits lymphocyte function Adverse effects GI: heart burn, nausea and anorexia,causes less fecal loss of blood than aspirin. CNS: Rashes and pruritus Oedema and reversible azotemia. Uses Rheumatoid and osteoarthritis, ankylosing spondylitis, acute gout, musculoskeletal injuries, dentistry, episiotomy, dysmenorrhoea etc.

Drug

Some Properties of various groups of NSAIDs

T1/2 Anal Ant py An-infl Comments
3-5 + + + Fairly marked GIT upsets and hemorrhage. Tinnitus, Hypersensitivity reactions. Cheap and effective. A drug of first choice for mild analgesia. An encephalitis can be precipitated in children with viral infections. All have similar actions and side effects. Effective and better tolerated than most other NSAIDs. Naproxen more potent than aspirin. Ibuprofen is a drug of first choice for inflammatory joint disease because it has the lowest incidence of untoward effects. 13 2 + + + + + + + + + + ++ ++ One of the most potent inhibitor of cyclooxygenase in vitro. Clinically effective but high incidence of side effects. Headache, dizziness and GIT upsets common Moderate potency and GIT side effects. Moderate anti-inflammatory action. GIT upsets. Diarrhea likely. Hemolytic anemia has been reported Used for chronic inflammatory conditions. GI irritation tinnitus, rashes. Given once daily.

Salicylic acid Derivatives: Aspirin Propionic acid derivatives: Naproxen Ibuprofen

Indomethacin Diclofenac

2 2

Mefenamic acid Oxicams: Piroxicam Tenoxicam Paracetamol

+ + +

+ + +

+ ++ +

45 42-98 2-4 + + Safe and effective mild analgesic in therapeutic doses. Less analgesic efficacy in inflammatory conditions. Chronic use can cause kidney damage. Over dose causes serious hepatotoxicity.

Acetaminophen (paracetamol)
A metabolite of phenacetin. Central analgesic effect: Acts on COX-3 Antipyretic. It has no antiinflammatory activity. No effect on respiration, acid base balance; cellular metabolism. Gastric irritation is insignificant and mucosal erosion and bleeding occur rarely only in overdose. It doesn't alter platelet function or clotting factors. It is not uricosuric. ADME: Abs. well, 33% protein bound distributed in the body. Conjugated with glucuronic acid (60%) and sulphate (35%) and partly hydroxylated (NAPQI- epoxide which conjugates with glutathione to form mercapturate), rapidly excreted in urine. Plasma half life- 2-3 hours.

Acetaminophen
Adverse effects:

Click to edit Master text style Second level Rashes, nausea, and leucopenia is rare. Third level Analgesic nephropathy- chronic use- mainly phenacetin but others might also produce this condition. Fourth level Acute paracetamol poisoning- hepatotoxicity, renal Fifth level
toxicity Mechanism of toxicity N acetyl-benzoquinone-imine is a highly reactive metabolite detoxified by conjugation with glutathione. With large dose , hepatic glutathione is depleted and this metabolite oxidses SH containing enzymes and proteins and causes cellular damage ( and renal tubules) causing necrosis. In chronic alcoholics small dose ( 5-6 gram/day) taken for a few days may produce hepatotoxicity. Treatment: N-acetylcysteine. It is practically ineffective if started 16 hours or more after paracetamol ingestion. Uses: As analgesic , Antipyretic.

Differences bet aspirin and paracetamol Aspirin Paracetamol

Analgesic,antipyretic and antiinflammatory Antiplatelet aggregatory action Effect on uric acid excretion Analgesic and antipyretic No such effect No such effect

More prone to produce GI upset. C/I in Less GI side effects, no contraindicated in peptic ulcer patient peptic ulcer patients Produces metabolic effects No such effects Produces acid base disturbances in overdose Less so in acute toxicity Hypersensitivity reactions are common Significant drug interactions Less incidence of hypersensitivity reactions Not so

Acid base and electrolyte abnormailities inHepatotoxicity in acute overdosage acute overdosage

COXII inhibitors: coxibs

Celecoxib, Etoricoxib, meloxicam (preferentially selective)
Have analgesic, anti-inflammatory, antipyretic activity No effect on platelets: Reversible inhibition of COX-2. COX2 inh. Inhibits endothelial PGI2 and no effect on platelet TXA2- alteration of PGI2/TXA2 ratio inc. tendency for platelet aggregation No cardioprotective effects. Higher incidence of CV thrombotic events led to withdrawal of rofecoxib. COX-1 preserve PGE2 production in GIT Uses: used in patient with high risk of GI toxicity Acute gouty arthritis, acute musculoskeletal pain, ankylosing spondylitis osteoarthritis, rheumatoid arthritis. Primary familial adenomatous polyposis Dysmenorrhea Adverse reactions: Less GI upsets- bleeding and ulceration Rash- it is a sulfonamide derivative hence - allergic reactions-celecoxib. HTN and edema. Inc risk of thrombotic CV events. Renal toxicity Etoricoxib: 2nd generation, half life 22 hours given once daily. Monitor LFT

Meloxicam
Related to piroxicam Preferentially inhibits COX-2 over COX 1 at low dose. Has less GI symptoms than piroxicam and diclofenac Inhibits TXA2