Para-Amino Phenol Derivatives

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Chapter: Essential pharmacology : Nonsteroidal Anti-inflammatory Drugs And Antipyreticanalgesics

Phenacetin introduced in 1887 was extensively used as analgesicantipyretic, but is now banned because it was implicated in analgesic abuse nephropathy.


PARA-AMINO PHENOL DERIVATIVES

 

Phenacetin introduced in 1887 was extensively used as analgesicantipyretic, but is now banned because it was implicated in analgesic abuse nephropathy.

 

Paracetamol (acetaminophen) the de-ethylated active metabolite of phenacetin, was also introduced in the last century but has come into common use only since 1950.

 

Actions

 

The central analgesic action of paracetamol is like aspirin, i.e. it raises pain threshold, but has weak peripheral anti-inflammatory component. Analgesic action of aspirin and paracetamol is additive. Paracetamol is a good and promptly acting antipyretic.

 

Paracetamol has negligible anti-inflammatory action. It is a poor inhibitor of PG synthesis in peripheral tissues, but more active on COX in the brain. One explanation offered for the discrepancy between its analgesic-antipyretic and anti-inflammatory actions is its inability to inhibit COX in the presence of peroxides which are generated at sites of inflammation, but are not present in the brain. The ability of paracetamol to inhibit COX3 (an isoenzyme so far located in dog brain) could also account for its analgesic antipyretic action.

 

In contrast to aspirin, paracetamol does not stimulate respiration or affect acidbase balance; does not increase cellular metabolism. It has no effect on CVS. Gastric irritation is insignificant— mucosal erosion and bleeding occur rarely only in overdose. It does not affect platelet function or clotting factors and is not uricosuric.

 

Pharmacokinetics

 

Paracetamol is well absorbed orally, only about 1/4th is protein bound in plasma and it is uniformly distributed in the body. Metabolism occurs mainly by conjugation with glucuronic acid and sulfate: conjugates are excreted rapidly in urine. Plasma t½ is 2–3 hours. 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.

 

Analgesic nephropathy occurs after years of heavy ingestion of analgesics; such individuals probably have some personality defect. Pathological lesions are papillary necrosis, tubular atrophy followed by renal fibrosis. Urine concentrating ability is lost and the kidneys shrink. Because phenacetin was first implicated, it went into disrepute, though other analgesics are also liable to produce similar effects.

 

Acute paracetamol poisoning It occurs especially in small children who have low hepatic glucuronide conjugating ability. If a large dose (> 150 mg/kg or > 10 g in an adult) is taken, serious toxicity can occur. Fatality is common with > 250 mg/kg.

 

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. Jaundice starts after 2 days. Further course depends on the dose taken. Fulminating hepatic failure and death are likely if the plasma levels are above the line joining 200 μg/ml at 4 hours and 30 μg/ml at 15 hours. If the levels are lower —recovery with supportive treatment is the rule.

 

Mechanism Of Toxicity

 

N-acetylpbenzoquinoneimine (NABQI) is a highly reactive arylating minor metabolite of paracetamol which is detoxified by conjugation with glutathione. When a very large dose of paracetamol is taken, glucuronidation capacity is saturated, more of the minor metabolite is formed—hepatic glutathione is depleted and this metabolite binds covalently to proteins in liver cells (and renal tubules) causing necrosis. Toxicity thus shows a threshold effect manifesting only when glutathione is depleted to a critical point.

 

In chronic alcoholics even 5–6 g/day taken for a few days can result in hepatotoxicity because alcoholism induces CYP2E1 that metabolises paracetamol to NABQI.

 

Paracetamol is not recommended in premature infants (< 2 kg) for fear of hepatotoxicity.

 

Treatment

 

If the patient is brought early, vomiting should be induced or gastric lavage done. Activated charcoal is given orally or through the tube to prevent further absorption. Other supportive measures, as needed, should be taken.

 

Specific: N-acetylcysteine (MUCOMIX, ANTIFEN 200 mg/ml inj in 2, 5 ml amps) 150 mg/kg should be infused i.v. over 15 min, followed by the same dose i.v. over the next 20 hours. Alternatively, 75 mg/kg may be given orally every 4–6 hours for 2–3 days. It replenishes the glutathione stores of liver and prevents binding of the toxic metabolite to other cellular constituents.

 

Ingestion treatment interval is critical; earlier the better. It is practically ineffective if started 16 hours or more after paracetamol ingestion.

 

Uses

 

Paracetamol is one of the most commonly used ‘overthecounter’ analgesic for headache, mild migraine, musculoskeletal pain, dysmenorrhoea, etc. but is relatively ineffective when inflammation is prominent. Paracetamol is recommended as first choice analgesic for osteoarthritis by many professional bodies. It is one of the best drugs to be used as antipyretic, especially in children (no risk of Reye’s syndrome).

 

Dose to dose it is equally efficacious as aspirin for noninflammatory conditions. It is much safer than aspirin in terms of gastric irritation, ulceration and bleeding (can be given to ulcer patients), does not prolong bleeding time. Hypersensitivity reactions are rare; no metabolic effects or acidbase disturbances; 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. It does not have significant drug interactions. Thus, it may be preferred over aspirin for most minor conditions.

 

Dose: 0.5–1g TDS; infants 50 mg; children 1–3 years 80– 160 mg, 4–8 years 240–320 mg, 9–12 years 300–600 mg. CROCIN 0.5, 1.0 g tabs; METACIN, PARACIN 500 mg tab, 125 mg/5 ml syrup, 150 mg/ml paed. drops, ULTRAGIN, PYRIGESIC, CALPOL 500 mg tab, 125 mg/ 5 ml syrup, NEOMOL, FEVASTIN, FEBRINIL 300 mg/2 ml inj., CROCIN PAIN RELIEF: 650 mg + Caffeine 50 mg tab.

 

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