SALICYLATES - Aspirin (prototype)

  

SALICYLATES

Aspirin (prototype)

Aspirin is acetylsalicylic acid. It is rapidly converted in the body to salicylic acid which is responsible for most of the actions. Other actions are the result of acetylation of certain macromolecules including COX. It is one of the oldest analgesic-antiinflammatory drugs and is still frequently used.

 

PHARMACOKINETICS

Aspirin is absorbed from the stomach and small intestines. Its poor water solubility is the limiting factor in absorption: microfining the drug-particles and inclusion of an alkali (solubility is more at higher pH) enhances absorption. However, higher pH also favours ionization, thus decreasing the diffusible form.

Aspirin is rapidly deacetylated in the gut wall, liver, plasma and other tissues to release salicylic acid which is the major circulating and active form. It is ~80% bound to plasma proteins and has a volume of distribution ~0.17 L/kg. Entry into brain is slow, but aspirin freely crosses placenta. Both aspirin and salicylic acid are conjugated in liver with glycine to form salicyluric acid (major pathway). They are also conjugated with glucuronic acid. Few other minor metabolites are also produced. The metabolites are excreted by glomerular filtration and tubular secretion. Normally, only 1/10th is excreted as free salicylic acid, but this can be increased by alkalinization.

The plasma t½ of aspirin as such is 15–20 min, but taken together with that of released salicylic acid, it is 3–5 hours. However, metabolic processes get saturated over the therapeutic range; t½ of antiinflammatory doses may be  8–12 hours while that during poisoning may be as high as 30 hours. Thus, elimination is dose dependent.

 

ADVERSE EFFECTS

(a) Side effects that occur at analgesic dose (0.3–1.5 g/day) are nausea, vomiting, epigastric distress, increased occult blood loss in stools. The most important adverse effect of aspirin is gastric mucosal damage and peptic ulceration.

(b) Hypersensitivity and idiosyncrasy Though infrequent, these can be serious. Reactions include rashes, fixed drug eruption, urticaria, rhinorrhoea, angioedema, asthma and anaphylactoid reaction. Profuse gastric bleeding occurs in rare instances.

(c) Antiinflammatory doses (3–5 g/day) produce the syndrome called salicylism—dizzi-ness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental con-fusion, hyperventilation and electrolyte imbalance. The dose has to be titrated to one which is just below that producing these symptoms; tinnitus is a good guide.

Aspirin therapy in children with rheumatoid arthritis has been found to raise serum transami-nases, indicating liver damage. Most cases are asymptomatic but it is potentially dangerous. An association has been noted between salicylate

 

therapy and ‘Reye’s syndrome’, a rare form of hepatic encephalopathy seen in children having viral (varicella, influenza) infection.

In adults also, long-term therapy with high dose aspirin can cause insidious onset hepatic injury. Salt and water retention occurs in a dose related manner.

(d) Acute salicylate poisoning It is more common in children. Fatal dose in adults is estimated to be 15–30 g, but is considerably lower in chil-dren. Serious toxicity is seen at serum salicylate levels > 50 mg/dl.

Manifestations are:

Vomiting, dehydration, electrolyte imbalance, acidotic breathing, hyper/hypoglycaemia, petechial haemorrhages, restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory failure + cardiovascular collapse.

Treatment is symptomatic and supportive. Most important is external cooling and i.v. fluid with Na+, K+, HCO3¯ and glucose: according to need determined by repeated monitoring. Gastric lavage to remove unabsorbed drug; alkaline diuresis or haemodialysis to remove absorbed drug is indicated in severe cases. Blood transfusion and vit K should be given if bleeding occurs.

Precautions and contraindications

• Aspirin is contraindicated in patients who are sensitive to it and in peptic ulcer, bleeding tendencies, in children suffering from chicken pox or influenza. Due to risk of Reye’s syndrome pediatric formulations of aspirin are prohibited in India and the UK.

• Cautious use in chronic liver disease: cases of hepatic necrosis have been reported.

• It should be avoided in diabetics, in those with low cardiac reserve or frank CHF and in juvenile rheumatoid arthritis.

• Aspirin should be stopped 1 week before elective surgery.

• Given chronically during pregnancy it may be responsible for low birth weight babies. Delayed or prolonged labour, greater postpartum blood loss and premature closure of ductus arteriosus are possible if aspirin is taken at or near term.

• It should be avoided by breastfeeding mothers.

• Avoid high doses in G-6PD deficient individuals—haemolysis can occur.