NONSTEROIDAL ANTIINFLAMMATORY DRUGS

Transcription

1 Analgesics are drugs that relieve pain without significantly altering consciousness. They relieve pain without affecting its cause. Analgesics Opioid (Narcotic analgesics) Non-opioid (Nonsteroidal antiinflammatory drugs) NONSTEROIDAL ANTIINFLAMMATORY DRUGS Classification 1. Nonselective cyclooxygenase (COX) inhibitors a. Salicylates: b. Propionic acid derivatives: Ibuprofen, ketoprofen, naproxen, flurbiprofen. c. Acetic acid derivatives: Diclofenac, aceclofenac. d. Fenamic acid derivatives: Mefenamic acid. e. Pyrrolo pyrrole derivatives: Ketorolac, etodolac. f. Oxicam derivatives: Piroxicam, tenoxicam. g. Indole derivatives: Indomethacin. 2. Preferential COX-2 inhibitors: Nimesulide, meloxicam, nabumetone. 3. Highly selective COX-2 inhibitors: Etoricoxib, parecoxib, lumiracoxib. 4. Analgesic antipyretics with poor antiinflammatory effect: Paracetamol, nefopam. 1

2 Mechanism of action COX is the enzyme responsible for the biosynthesis of various prostaglandins. There are two wellrecognized isoforms of COX: COX-1 and COX-2. COX-1 is constitutive, found in most tissues such as blood vessels, stomach and kidney. PGs have important role in many tissues (Fig. 7.2, p. 201). COX-2 is induced during inflammation by cytokines and endotoxins, and is responsible for the production of prostanoid mediators of inflammation. and most of the nonsteroidal antiinflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2 isoforms, thereby decrease prostaglandin and thromboxane synthesis. The antiinflammatory effect of NSAIDs is mainly due to inhibition of COX-2. causes irreversible inhibition of COX. Rest of the NSAIDs cause reversible inhibition of the enzyme. Pharmacological actions of aspirin and other NSAIDs (acetylsalicylic acid) is the prototype drug. The other nonselective NSAIDs vary mainly in their potency, analgesic, antiinflammatory effects and duration of action. 1. Analgesic effect: NSAIDs are mainly used for relieving musculoskeletal pain, dysmenorrhoea and pain associated with inflammation or tissue damage. Analgesic effect is mainly due to peripheral inhibition of PG production. They also increase pain threshold by acting at subcortical site. These drugs relieve pain without causing sedation, tolerance or drug dependence. 2. Antipyretic effect: The thermoregulatory centre is situated in the hypothalamus. Fever occurs when there is a disturbance in hypothalamic thermostat. NSAIDs reset the hypothalamic thermostat and reduce the elevated body temperature during fever. They promote heat loss by causing cutaneous vasodilatation and sweating. They do not affect normal body temperature. The antipyretic effect is mainly due to inhibition of PGs in the hypothalamus. 3. Antiinflammatory effect: Antiinflammatory effect is seen at high doses (aspirin: 4 6 g/day in divided doses). These drugs produce only symptomatic relief. They suppress signs and symptoms of inflammation such as pain, tenderness, swelling, vasodilatation and leukocyte infiltration but do not affect the progression of underlying disease. The antiinflammatory action of NSAIDs is mainly due to inhibition of PG synthesis at the site of injury. They also affect other mediators of inflammation (bradykinin, histamine, serotonin, etc.), thus inhibit granulocyte adherence to the damaged vasculature. NSAIDs also cause modulation of T-cell function, stabilization of lysosomal membrane and inhibition of chemotaxis. 4. Antiplatelet (antithrombotic) effect: in low doses ( mg/day) irreversibly inhibits platelet TXA 2 synthesis and produces antiplatelet effect, which lasts for 8 10 days, i.e. the life-time of platelets. in high doses (2 3 g/day) inhibits both PGI 2 and TXA 2 synthesis; hence beneficial effect of PGI 2 is lost. should be withdrawn 1 week prior to elective surgery because of the risk of bleeding. (2 3 g/day) PGI 2 (PGI 2 causes vasodilatation and inhibits platelet aggregation) TXA 2 (TXA 2 causes vasoconstriction and promotes platelet aggregation) Low-dose aspirin ( mg) 2

3 5. Acid base and electrolyte balance: In therapeutic doses, salicylates cause respiratory alkalosis, which is compensated by excretion of alkaline urine (compensated respiratory alkalosis). In toxic doses, the respiratory centre is depressed and can lead to respiratory acidosis. Later, there is uncompensated metabolic acidosis. 6. Gastrointestinal tract (GIT): irritates the gastric mucosa and produces nausea, vomiting and dyspepsia. The salicylic acid formed from aspirin also contributes to these effects. also stimulates chemoreceptor trigger zone (CTZ) and produces vomiting (Fig. 7.4). Inhibits PGs in the gastric mucosa Increase in HCl production Loss of protective action Gastric irritation, peptic ulcer Acidic ph of stomach Acute ulcers Erosive gastritis Haemorrhage Exists in unionized form Enters the mucosal cell ph 7.1 Ionized and becomes indiffusible PGs CTZ HCl Salicylic acid Fig. 7.4 Action of aspirin on stomach and CTZ., Stimulation;, inhibition; PGs, prostaglandins. 7. Cardiovascular system (CVS): Prolonged use of aspirin and other NSAIDs causes sodium and water retention. They may precipitate congestive cardiac failure (CCF) in patients with low cardiac reserve. They may also decrease the effect of antihypertensive drugs. 8. Urate excretion: Salicylates, in therapeutic doses, inhibit urate secretion into the renal tubules and increase plasma urate levels. In high doses, salicylates inhibit the reabsorption of uric acid in renal tubules and produce uricosuric effect. Pharmacokinetics Salicylates are rapidly absorbed from the upper GI tract. They are highly bound to plasma proteins but the binding is saturable. Salicylates are well distributed throughout the tissues and body fluids; metabolized in liver by glycine and glucuronide conjugation. In low doses, elimination follows first-order kinetics and with high doses as the metabolizing enzymes get saturated, it switches over to zero-order 3

4 kinetics. After this, an increase in salicylate dosage increases its plasma concentration disproportionately and severe toxicity can occur. Alkalinization of urine increases the rate of excretion of salicylates. Dosage regimen for aspirin Analgesic dose: 2 3 g/day in divided doses. Antiinflammatory dose: 4 6 g/day in divided doses. Antiplatelet dose: mg/day (low-dose aspirin). Adverse effects 1. GIT: Nausea, vomiting, dyspepsia, epigastric pain, acute gastritis, ulceration and GI bleeding. Ulcerogenic effect is the major drawback of NSAIDs, which is prevented/minimized by taking: a. NSAIDs after food. b. proton pump inhibitors/h 2 -blockers/misoprostol with NSAIDs. c. buffered aspirin (preparation of aspirin with antacid). d. selective COX-2 inhibitors. 2. Hypersensitivity: It is relatively more common with aspirin. The manifestations are skin rashes, urticaria, rhinitis, bronchospasm, angioneurotic oedema and rarely anaphylactoid reaction. Bronchospasm (aspirin-induced asthma) is due to increased production of leukotrienes. Incidence of hypersensitivity is high in patients with asthma, nasal polyps, recurrent rhinitis or urticaria. Therefore, aspirin should be avoided in such patients. 3. In people with G6PD deficiency, administration of salicylates may cause haemolytic anaemia. 4. Prolonged use of salicylates interferes with action of vitamin K in the liver decreased synthesis of clotting factors (hypoprothrombinaemia) predisposes to bleeding (can be treated by administration of vitamin K). 5. Reye s syndrome: Use of salicylates in children with viral infection may cause hepatic damage with fatty infiltration and encephalopathy Reye s syndrome. Hence, salicylates are contraindicated in children with viral infection. 6. Pregnancy: These drugs inhibit PG synthesis, thereby delay onset of labour and increase chances of postpartum haemorrhage. In the newborn, inhibition of PG synthesis results in premature closure of the ductus arteriosus. 7. Analgesic nephropathy: Slowly progressive renal failure may occur on chronic use of high doses of NSAIDs. Renal failure is usually reversible on stoppage of therapy but rarely, NSAIDs may cause irreversible renal damage. Salicylism Salicylate intoxication may be mild or severe. The mild form is called salicylism. The symptoms include headache, tinnitus, vertigo, confusion, nausea, vomiting, diarrhoea, sweating, hyperpnoea, electrolyte imbalance, etc. These symptoms are reversible on stoppage of therapy. Acute Salicylate Poisoning Manifestations are vomiting, dehydration, acid base and electrolyte imbalance, hyperpnoea, restlessness, confusion, coma, convulsions, cardiovascular collapse, pulmonary oedema, hyperpyrexia and death. 4

5 Treatment There is no specific antidote for salicylate poisoning. Treatment is symptomatic. Hospitalization. Gastric lavage followed by administration of activated charcoal (activated charcoal adsorbs the toxic material physical antagonism). Maintain fluid and electrolyte balance. Correct acid base disturbances. Intravenous sodium bicarbonate to treat metabolic acidosis. It also alkalinizes the urine and enhances renal excretion of salicylates (since salicylates exist in ionized form in alkaline ph). External cooling. Haemodialysis in severe cases. Vitamin K 1 and blood transfusion, if there is bleeding. Clinical uses of NSAIDs (For basis and explanation, see under pharmacological actions) 1. As analgesic: In painful conditions like toothache, headache, backache, bodyache, muscle pain, temporomandibular and other joint pain, bursitis, neuralgias, dysmenorrhoea, etc. 2. As antipyretic: To reduce elevated body temperature in fever paracetamol is preferred because: a. Gastrointestinal symptoms are rare. b. It does not cause Reye s syndrome in children. 3. Rheumatoid arthritis: NSAIDs are the first group of drugs to be used. They have analgesic and antiinflammatory effects and can produce only symptomatic relief, but they do not alter the progression of disease. 4. Acute rheumatic fever: is the preferred drug. It reduces fever, relieves swelling and joint pain, but does not affect the normal course of the disease. 5. Osteoarthritis: In mild cases, paracetamol is used. In severe cases of osteoarthritis, other NSAIDs are more effective than paracetamol. Topical agents like methyl salicylate, diclofenac gel, capsaicin cream, etc. can also be used. 6. Thromboembolic disorders: The antiplatelet effect of low-dose aspirin is made use of in the prophylactic treatment of various thromboembolic disorders, such as: a. Transient ischaemic attacks (TIA) b. Myocardial infarction (MI) (i) to reduce incidence of recurrent MI (ii) to decrease mortality in post-mi patients 7. Other uses: a. Medical closure of patent ductus arteriosus (indomethacin is preferred). b. Colon and rectal cancer: Regular use of aspirin is reported to reduce the risk of cancer. c. is reported to reduce the risk and retard the onset of Alzheimer s disease. d. To control radiation-induced diarrhoea. e. To control pruritus and flushing associated with the use of nicotinic acid. per se is rarely used at present because of the following disadvantages 1. It has a short duration of action, requires large doses and frequent administration. 2. Gastric irritation and ulcerogenic effect are the main drawbacks of NSAIDs. The incidence is high with aspirin. 3. Salicylates should be avoided in children with viral infection. 4. NSAIDs may precipitate bronchospasm in patients with bronchial asthma (aspirin-induced asthma). 5

6 Other NSAIDs (Table 7.3) They have similar mechanism of action, pharmacological actions, therapeutic uses and adverse effects. They vary mainly in their potency, duration of action, analgesic and antiinflammatory effects. Table 7.3 NSAIDs and Their Important Features Drug Route and Formulations with Oral Dose 1. Ibuprofen Oral and topical gel Dose: mg TDS 2. Diclofenac Oral, i.m., rectal, topical, gel and ophthalmic preparation (eye drops) Dose: 50 mg BD or 100 mg sustained-release preparation OD 3. Indomethacin Note: It has extra mechanism extra uses extra side effects Oral, eyedrops and suppository Dose: 50 mg TDS 4. Piroxicam Oral, i.m. and topical gel Dose: 20 mg OD 5. Ketorolac Oral, i.m., i.v., ophthalmic preparation and transdermal patch Dose: mg QID 6. Mefenamic acid Oral Dose: mg TID Other Points It has moderate antiin ammatory effect It is better-tolerated than aspirin It can be used in children (does not cause Reye s syndrome) It has potent antiin ammatory effect It gets concentrated in synovial uid, hence preferred in in ammatory conditions of joint (arthritis) Incidence of hepatotoxicity is more Combination of diclofenac with misoprostol (PGE 1 analogue) available, which reduces GI irritation and peptic ulcer It is a nonselective COX inhibitor It has potent antiin ammatory effect It inhibits migration of neutrophils to in amed area It is very effective in ankylosing spondylitis, acute gout and psoriatic arthritis It has prominent GI side effects CNS side effects are severe headache, confusion, hallucinations, etc. It is contraindicated in epileptics, psychiatric patients and drivers It has potent antiin ammatory effect It is long-acting Increased incidence of peptic ulcer and bleeding It has potent analgesic effect and ef cacy is almost equal to morphine. It relieves pain without causing respiratory depression, hypotension and drug dependence It is used in renal colic, postoperative and metastatic cancer pain It has analgesic, antipyretic and weak antiin ammatory effect It is used in dysmenorrhoea, osteoarthritis, rheumatoid arthritis 6

7 Selective COX-2 Inhibitors ( Coxibs ) Some of the COX-2 inhibitors are parecoxib, etoricoxib, lumiracoxib, etc. Parecoxib is a prodrug of valdecoxib and is administered parenterally; etoricoxib is given by enteral route (Table 7.4). Selective COX-2 inhibitors (coxibs) Etoricoxib Parecoxib Toxic to Gastric friendly GI irritation and peptic ulcer are rare Kidney Inhibit COX-2 Na +, H 2 O retention Oedema Heart Higher incidence of cardiovascular thrombotic events. They mainly inhibit PGI 2 ; TXA 2 is anaffected. This may be responsible for increased risk of cardiovascular events. Table 7.4 Differences Between Nonselective COX and Selective COX-2 Inhibitors Nonselective COX Inhibitors Analgesic effect + Antipyretic effect + Antiin ammatory effect + Antiplatelet effect + GI side effects are marked + + Renal toxicity + (sodium and water retention) +: present; ++: effect is more. Selective COX-2 Inhibitors Analgesic effect + Antipyretic effect + Antiin ammatory effect + No antiplatelet effect GI side effects are less (less ulcerogenic potential) Renal toxicity + Paracetamol Paracetamol is effective by oral and parenteral routes. It is well absorbed, widely distributed all over the body, metabolized in liver by sulphate and glucuronide conjugation. The metabolites are excreted in urine (Table 7.5). 7

8 Table 7.5 Differences Between and Paracetamol Paracetamol 1. It is a salicylate derivative 1. It is a para-aminophenol derivative 2. It has analgesic, antipyretic and potent antiin ammatory effects 3. It causes GI irritation (nausea, vomiting, peptic ulcer and bleeding) 4. In large doses, it produces acid base and electrolyte imbalance 2. It has potent antipyretic and analgesic effects with poor antiin ammatory activity 3. It usually does not produce gastric irritation 4. It does not produce acid base and electrolyte imbalance 5. It has antiplatelet action 5. It has no antiplatelet action 6. It has no speci c antidote 6. N-acetylcysteine is the antidote 7. It is contraindicated in peptic ulcer, people with bleeding tendency, bronchial asthma and in children with viral infection 7. Paracetamol is the preferred analgesic and antipyretic in patients having peptic ulcer, bronchial asthma and in children Uses 1. As antipyretic: To reduce body temperature during fever. 2. As analgesic: To relieve headache, toothache, myalgia, dysmenorrhoea, etc. 3. It is the preferred analgesic and antipyretic in patients with peptic ulcer, haemophilia, bronchial asthma and children. Adverse effects 1. Side effects are rare, occasionally causes skin rashes and nausea. 2. Hepatotoxicity: with acute overdose or chronic use. 3. Nephrotoxicity is commonly seen on chronic use. Acute paracetamol poisoning Acute overdosage mainly causes hepatotoxicity symptoms are nausea, vomiting, diarrhoea, abdominal pain, hypoglycaemia, hypotension, hypoprothrombinaemia, coma, etc. Death is usually due to hepatic necrosis. Mechanism of toxicity and treatment (Fig. 7.5) The toxic metabolite of paracetamol is detoxified by conjugation with glutathione and gets eliminated. High doses of paracetamol cause depletion of glutathione levels. In the absence of glutathione, toxic metabolite binds covalently with proteins in the liver and kidney and causes necrosis. Alcoholics and premature infants are more prone to hepatotoxicity. N-acetylcysteine or oral methionine replenishes the glutathione stores of liver and protects the liver cells. Activated charcoal is administered to decrease the absorption of paracetamol from the gut. Charcoal haemoperfusion is effective in severe liver failure. Haemodialysis may be required in cases with acute renal failure. 8

9 Liver Paracetamol s toxic metabolite NAPQI binds to Proteins Glutathione Depletion of glutathione Renal tubular necrosis Proteins Hepatic necrosis Intravenous or oral N-acetylcysteine Or Oral methionine replenishes Glutathione stores Fig. 7.5 Mechanism of paracetamol toxicity and its treatment. NAPQI, N-acetyl-p-benzo-quinoneimine. Key Points for Dentists NSAIDs should be taken after food. NSAIDs should be avoided in patients with peptic ulcer as it may aggravate the condition. Preferred analgesics for patients with peptic ulcer are paracetamol and selective COX-2 inhibitors. Patients on aspirin should inform the doctor if surgery/dental procedure is planned. Educate patient about adverse effects and drug interactions of aspirin. Advise patient to report signs of bleeding, if any. The preferred analgesic in patients with chronic renal failure is paracetamol. 9