NSAIDS 2024 - Part II PDF

PROPIONIC ACID DERIVATIVES Drug Plasma t1⁄2 1. Ibuprofen 2 hr 2. Naproxen 3. Ketoprofen 4. Flurbiprofen 12–16 hr 2–3 hr 4–6 hr Dosage 400–600 mg (5-10 mg/kg) TDS 250 mg BD– TDS 50-100 mg BD–TDS 50 mg BD–QID Preparations BRUFEN NAPROSYN KETOFEN FLUROFEN Ibuprofen Ibuprofen was the first member of thi...

PROPIONIC ACID DERIVATIVES Drug Plasma t1⁄2 1. Ibuprofen 2 hr 2. Naproxen 3. Ketoprofen 4. Flurbiprofen 12–16 hr 2–3 hr 4–6 hr Dosage 400–600 mg (5-10 mg/kg) TDS 250 mg BD– TDS 50-100 mg BD–TDS 50 mg BD–QID Preparations BRUFEN NAPROSYN KETOFEN FLUROFEN Ibuprofen Ibuprofen was the first member of this class to be introduced in 1969 as a better tolerated alternative to aspirin. The antiinflammatory efficacy is rated somewhat lower than high dose of aspirin. Adverse effects: 1. Side effects are milder and their incidence is lower. 2. Gastric discomfort, nausea and vomiting. 3. CNS side effects include headache, dizziness, blurring of vision, tinnitus and depression. 4. Rashes, itching and other hypersensitivity phenomena are infrequent. However, these drugs can precipitate asthma in subjects sensitive to aspirin. 5. Fluid retention is less marked than that with phenylbutazone. 6. They are not to be prescribed to pregnant women and should be avoided in peptic ulcer patient. Ibuprofen Pharmacokinetics and interactions: o All propionic acid derivatives are well absorbed orally. o All propionic acid derivatives enter brain, synovial fluid and cross placenta. o They are largely metabolized in liver by hydroxylation and glucuronide conjugation and excreted in urine as well as bile. Uses: 1. Ibuprofen, available as an ‘over-the-counter’ drug, is used as a simple analgesic and antipyretic. 2. Used in rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders, especially where pain is more prominent than inflammation. 3. They are indicated in soft tissue injuries, tooth extraction, fractures, vasectomy, postpartum and postoperatively: suppress swelling and inflammation and are very popular in dentistry. FENAMATE (Anthranilic Acid Derivative) Mephenamic acid Ananalgesic, antipyretic and weaker antiinflammatory drug, which inhibits COX as well as antagonises certain actions of PGs. Mephenamic acid exerts peripheral as well as central analgesic action. Pharmacokinetics: o Oral absorption of mephenamic acid is slow but almost complete. o It is highly bound to plasma proteins—displacement interactions can occur; partly metabolized and excreted in urine as well as bile. Plasma t1⁄2 is 2–4 hours. Mephenamic acid Adverse effects: 1. Diarrhoea is the most important dose - related side effect. 2. Epigastric distress is complained, but gut bleeding is not significant. 3. Haemolytic anaemia is a rare but serious complication. Uses: 1. Mephenamic acid is indicated primarily as analgesic in muscle, joint and soft tissue pain where strong antiinflammatory action is not needed. 2. It may be used in dental pain, but has no distinct advantage. Dose: 250–500 mg TDS ENOLIC ACID DERIVATIVES Piroxicam It is a long-acting NSAID with potent antiinflammatory and good analgesic-antipyretic actions. It is a reversible inhibitor of COX and in addition, reduces leucocyte chemotaxis. Thus, it can inhibit inflammation in diverse ways. Pharmacokinetics: o Piroxicam is rapidly and completely absorbed: 99% plasma protein bound; largely metabolized in liver and excreted both in urine and bile. o Plasma t1⁄2 is long—nearly 2 days. Single daily administration is sufficient. Piroxicam Adverse effects: 1. Heart burn, nausea and anorexia, but it is better tolerated and less ulcerogenic than indomethacin; causes less faecal blood loss than aspirin. 2. Rashes and pruritus occur in < 1% patients. 3. Edema and reversible azotaemia have been observed. Uses: Piroxicam is suitable for use as long-term antiinflammatory drug in rheumatoid and osteoarthritis, ankylosing spondylitis, acute gout, as well as in dentistry, but is relatively more toxic. Dose: 20 mg BD for two days followed by 20 mg OD ACETIC ACID DERIVATIVES Ketorolac o This NSAID has potent analgesic and modest antiinflammatory activity. o In postoperative pain it has equalled the efficacy of morphine, but does not interact with opioid receptors and is free of opioid side effects. o Like other NSAIDs, it inhibits PG synthesis and relieves pain primarily by a peripheral mechanism. In short-lasting pain, it has compared favourably with aspirin. Pharmacokinetics: Ketorolac is rapidly absorbed after oral and i.m. administration. It is highly plasma protein bound and 60% excreted unchanged in urine. Major metabolic pathway is glucuronidation; plasma t1⁄2 is 5–7 hours. Ketorolac Adverse effects: Nausea, abdominal pain, dyspepsia, ulceration, loose stools, drowsiness, pain at injection site, rise in serum transaminase and fluid retention have been noted. Uses: Ketorolac is frequently used in postoperative, dental and acute musculoskeletal pain. Dose: 15–30 mg i.m. or i.v., can be repeated every 4–6 hours (max. 90 mg/day). Orally it is used in a dose of 10–20 mg 6 hourly for short-term management of moderate pain. PREFERENTIAL COX-2 INHIBITORS Nimesulide o This NSAID is a relatively weak inhibitor of PG synthesis and moderately COX-2 selective. o The analgesic, antipyretic and antiinflammatory activity of nimesulide has been rated comparable to other NSAIDs. Pharmacokinetics: Nimesulide is almost completely absorbed orally, 99% plasma protein bound, extensively metabolized and excreted mainly in urine with a t1⁄2 of 2–5 hours. Nimesulide Adverse effects: Gastrointestinal (epigastralgia, heart burn, nausea, loose motions), dermatological (rash, pruritus) and central (somnolence, dizziness). Gastric tolerability of nimesulide is claimed to be better, but ulcer complications may be as prevalent as with other NSAIDs. Recently, several instances of fulminant hepatic failure have been associated with nimesulide and it has been withdrawn in several countries. Uses: It has been used primarily for short-lasting painful inflammatory conditions like sports injuries, sinusitis, dental surgery, bursitis, low backache, dysmenorrhoea, postoperative pain, osteoarthritis and for fever. Dose: 100 mg BD Diclofenac sodium An analgesic - antipyretic antiinflammatory drug, similar in efficacy to naproxen. It inhibits PG synthesis and is somewhat COX-2 selective. Pharmacokinetics: Diclofenac is well absorbed orally, 99% protein bound, metabolized, and excreted both in urine and bile. The plasma t1⁄2 is ~ 2 hours. However, it has good tissue penetrability and action lasts 6–8 hours. Diclofenac sodium Adverse effects: Epigastric pain, nausea, headache, dizziness, rashes. Gastric ulceration and bleeding are less common. Some comparative trials have found its gastric toxicity to be similar to the selective COX-2 inhibitors celecoxib and etoricoxib. Uses: Diclofenac is among the most extensively used NSAIDs; employed in rheumatoid and osteoarthritis, ankylosing spondylitis, toothache, dysmenorrhoea, renal colic, post-traumatic and postoperative inflammatory conditions—affords quick relief of pain and wound edema. Dose: 50 mg TDS, then BD oral, 75 mg deep i.m. SELECTIVE COX-2 INHIBITORS (Coxibs) o Because of the theoretical advantage of inhibiting COX-2 without affecting COX- 1 function, some highly selective COX-2 inhibitors have been introduced over the past 2 decades. o They cause less gastric mucosal damage; occurrence of peptic ulcer and ulcer bleeds is clearly lower than with traditional NSAIDs. o The selective COX-2 inhibitors do not depress TXA2 production by platelets, because it is COX-1 dependent. o They do not inhibit platelet aggregation or prolong bleeding time, but reduce PGI2 production by vascular endothelium. SELECTIVE COX-2 INHIBITORS (Coxibs) The selective COX-2 inhibitors reduce endothelial PGI (antiaggregatory) production without affecting TXA-2 (proaggregatory) synthesis by platelets. This appears to exert prothrombotic influence and enhance cardiovascular risk. It has been concluded that selective COX- 2 inhibitors should be used in the lowest dose for the shortest period of time as per need. Moreover, they should be avoided in patients with history of ischaemic heart disease/hypertension/cardiac failure/ cerebrovascular disease, who are pre-disposed to CV events. Examples: Celecoxib, Etoricoxib and Parecoxib PARA-AMINO PHENOL DERIVATIVES Paracetamol (acetaminophen) It is the deethylated active metabolite of phenacetin, was also introduced in the last century but has come into common use only since 1950. Actions: o The central analgesic action of paracetamol is like that of aspirin, i.e. it raises pain threshold, but has weak peripheral antiinflammatory component. o Analgesic action of aspirin and paracetamol is additive. Paracetamol is a good and pyretic-Analgesics promptly acting antipyretic. tial. Platelet aggregation agen exposure remained oxib recipients, and serum not reduced. Though, coxib is better than that SAIDs, still abdominal nd mild diarrhoea are the Paracetamol (acetaminophen) Pharmacokinetics: o Paracetamol is well absorbed orally, only about 1/4th is protein bound in plasma and distribution in the body is quite uniform. o It is conjugated with glucuronic acid and sulfate and is excreted rapidly in urine. o Plasma t1⁄2 is 2–3 hours. o Effects after an oral dose last for 3–5 hours. Adverse effects: In isolated antipyretic doses paracetamol is safe and well tolerated. Nausea and rashes occur occasionally , leukopenia is rare. Paracetamol (acetaminophen) Uses: 1. Paracetamol is one of the most commonly used ‘over-the-counter’ analgesic for headache, musculoskeletal pain, toothache, etc. where antiinflammatory action is not required. 2. It is relatively ineffective when inflammation is prominent (as in rheumatoid arthritis). 3. It is one of the best drugs to be used as antipyretic. 4. Because it does not prolong bleeding time, risk of tooth extraction haemorrhage is not accentuated. 5. Paracetamol can be used in all age groups (infants to elderly), pregnant/lactating women, in presence of other disease states and in patients in whom aspirin is contraindicated. 6. It does not have significant drug interactions. Dose: Adults 325–650 mg, children 10–15 mg/kg, 3–4 times a day. Paracetamol (acetaminophen) Acute paracetamol poisoning It occurs specially in small children who have low hepatic glucuronide conjugating ability. If a large dose(>150mg/kg or >10g in an adult) is taken, serious toxicity can occur. Early manifestations are just nausea, vomiting, abdominal pain and liver tenderness with no impairment of consciousness. After 12–18 hours centrilobular hepatic necrosis occurs which may be accompanied by renal tubular necrosis and hypoglycaemia that may progress to coma. Fulminating hepatic failure and death are likely if the plasma levels are high. If the levels are lower— recovery with supportive treatment is the rule. Treatment: Apart from supportive measures, specific antidote is N-acetylcysteine infused i.v. or given orally. It is practically ineffective if started 12–16 hours or more after paracetamol ingestion. Analgesics/NSAIDs in dentistry Some guidelines are: 1. Mild-to-moderate pain with little inflammation—paracetamol or low-dose ibuprofen. 2. Postextraction or similar acute but short-lasting pain—ketorolac, a propionic acid derivative, diclofenac or nimesulide. 3. Gastric intolerance to conventional NSAIDs or predisposed patients— etoricoxib or paracetamol. 4. Patients with history of asthma or anaphylactoid reaction to aspirin/other NSAIDs— nimesulide, COX-2 inhibitor. Analgesics/NSAIDs in dentistry 5. Paediatric patients—only paracetamol, aspirin, ibuprofen and naproxen have been adequately evaluated in children— should be preferred in them. Due to risk of Reye’s syndrome, aspirin should be avoided unless viral infection can be ruled out. 6. Pregnancy—paracetamol is the safest; low - dose aspirin is probably the second best. 7. Hypertensive, diabetic, ischaemic heart disease, epileptic and other patients receiving long-term regular medication— possibility of drug interaction with NSAIDs should be considered and the physician consulted. 8. Patients with risk factors for cardiovascular diseases, stroke — avoid etoricoxib/ celecoxib; ibuprofen or low-dose aspirin may be used. Thank You