Salicylates - Aspirin

SALICYLATES

Aspirin (prototype)

Aspirin is acetyl salicylic 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 macro-molecules including COX. It is one of the oldest analgesic anti-inflammatory drugs and is still widely used.

Pharmacological Actions

1. Analgesic, Antipyretic, Anti-Inflammatory Actions

Aspirin is a weaker analgesic than morphine type drugs: aspirin 600 mg ~ codeine 6 mg. However, it effectively relieves inflammatory, tissue injury related, connective tissue and integumental pain, but is relatively ineffective in severe visceral and ischaemic pain. The analgesic action is mainly due to obtunding of peripheral pain receptors and prevention of PG-mediated sensitization of nerve endings. A central subcortical action raising threshold to pain perception also contributes, but the morphinelike action on psychic processing or reaction component of the pain is missing. No sedation, subjective effects, tolerance or physical dependence is produced.

Aspirin resets the hypothalamic thermostat and rapidly reduces fever by promoting heat loss (sweating, cutaneous vasodilatation), but does not decrease heat production.

Anti-inflammatory action is exerted at high doses (3–6 g/day or 100 mg/kg/ day). Signs of inflammation like pain, tenderness, swelling, vasodilatation and leucocyte infiltration are suppressed. In addition to COX inhibition, quenching of free radicals may contribute to its anti-inflammatory action.

2. Metabolic Effects

These are significant only at anti-inflammatory doses. Cellular metabolism is increased, especially in skeletal muscles, due to uncoupling of oxidative phosphorylation → increased heat production. There is increased utilization of glucose → blood sugar may decrease (especially in diabetics) and liver glycogen is depleted. However, hyperglycaemia is often seen at toxic doses: this is due to central sympathetic stimulation → release of Adr and corticosteroids. Chronic use of large doses cause negative N₂ balance by increased conversion of protein to carbohydrate. Plasma free fatty acid and cholesterol levels are reduced.

3. Respiration

The effects are dose dependent. At anti-inflammatory doses, respiration is stimulated by peripheral (increased CO₂ production) and central (increased sensitivity of respiratory centre to CO₂) actions. Hyperventilation is prominent in salicylate poisoning. Further rise in salicylate level causes respiratory depression; death is due to respiratory failure.

4. Acidbase And Electrolyte Balance

Anti-inflammatory doses produce significant changes in the acidbase and electrolyte composition of body fluids. Initially, respiratory stimulation predominates and tends to wash out CO₂ despite increased production → respiratory alkalosis, which is compensated by increased renal excretion of HCO¯ (with accompanying Na+, K+ and water). Most adults treated with 4–5 g/day of aspirin stay in a state of compensated respiratory alkalosis.

Still higher doses cause respiratory depression with CO₂ retention, while excess CO₂ production continues → respiratory acidosis. To this are added dissociated salicylic acid as well as metabolic acids (lactic, pyruvic, acetoacetic) which are produced in excess + metabolically derived sulfuric and phosphoric acid which are retained due to depression of renal function. All these combine to cause uncompensated metabolic acidosis since plasma HCO₃¯ is already low. Most children manifest this phase during salicylate poisoning; while in adults it is seen in late stages of poisoning only.

Dehydration occurs in poisoning due to increased water loss in urine (to accompany Na+, K+ and HCO¯) increased sweating and hyperventilation.

5. CVS

Aspirin has no direct effect in therapeutic doses. Larger doses increase cardiac output to meet increased peripheral O₂ demand and cause direct vasodilatation. Toxic doses depress vasomotor centre: BP may fall. Because of increased cardiac work as well as Na+ and water retention, CHF may be precipitated in patients with low cardiac reserve.

6.    GIT

Aspirin and released salicylic acid irritate gastric mucosa → cause epigastric distress, nausea and vomiting. It also stimulates CTZ: vomiting has a central component as well at higher doses.

Aspirin (pKa 3.5) remains unionized and diffusible in the acid gastric juice, but on entering the mucosal cell (pH 7.1) it ionizes and becomes indiffusible. This ‘ion trapping’ in the gastric mucosal cell enhances gastric toxicity. Further, aspirin pCh. No. coming in contact with gastric mucosa promotes local back diffusion of acid → focal necrosis of mucosal cells and capillaries → acute ulcers, erosive gastritis, congestion and microscopic haemorrhages. The occult blood loss in stools is increased by even a single tablet of aspirin; averages 5 ml/day at anti-inflammatory doses. Haematemesis occurs occasionally: may be an idiosyncratic reaction.

Soluble aspirin tablets containing calcium carbonate + citric acid and other buffered preparations are less liable to cause gastric ulceration.

7.   Urate excretion

Doserelated effect is seen: < 2 g/day—urate retention and antagonism of all other uricosuric drugs.

2–5 g/day—variable effects, often no change. > 5 g/day—increased urate excretion.

Aspirin is not suitable for use in chronic gout.

8.   Blood

Aspirin, even in small doses, irreversibly inhibits TXA₂ synthesis by platelets. Thus, it interferes with platelet aggregation and bleeding time is prolonged to nearly twice the normal value. This effect lasts for about a week (turnover time of platelets).

Longterm intake of large dose decreases synthesis of clotting factors in liver and predisposes to bleeding; can be prevented by prophylactic vit K therapy.

Pharmacokinetics

Aspirin is absorbed from the stomach and small intestines. Its poor water solubility is the limiting factor in absorption: microfining the drugpCh. No.s 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. It slowly enters brain but freely crosses placenta. Both aspirin and salicylic acid are conjugated in liver with glycine → salicyluric acid (major pathway); and with glucuronic acid. Few other minor metabolites are also produced. The metabolites are excreted by glomerular filtration as well as 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 anti-inflammatory doses may be 8–12 hours while that during poisoning may be up to 30 hours. Thus, elimination is dose dependent.

Adverse Effects

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.

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.

Anti-Inflammatory Doses (3–5 g/day) produce the syndrome called salicylism—dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion, 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 transaminases, indicating liver damage. Most cases are asymptomatic but it is potentially dangerous. An association between salicylate therapy and ‘Reye’s syndrome’, a rare form of hepatic encephalopathy seen in children having viral (varicella, influenza) infection has been noted.

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

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+, HCO¯ and glucose: according to need determined by repeated monitoring. Gastric lavage to remove unabsorbed drug; forced 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.

·        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 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 G6PD deficient individuals—haemolysis can occur.

Interactions

Aspirin displaces warfarin, naproxen, sulfonylureas, phenytoin and methotrexate from

binding sites on plasma proteins: toxicity of these drugs may occur. Its antiplatelet action increases the risk of bleeding in patients on oral anticoagulants.

It inhibits tubular secretion of uric acid (at analgesic doses) and antagonizes uricosuric action of probenecid. Tubular secretion of methotrexate is also interfered.

Aspirin blunts diuretic action of furosemide and thiazides and reduces K+ conserving action of spironolactone. Competition between canrenone (active metabolite of spironolactone) and aspirin for active transport in proximal tubules has been demonstrated.

Aspirin reduces protein bound iodine levels by displacement of thyroxine; but hypothyroidism does not occur.

USES

1. As Analgesic

For headache (including mild migraine), backache, myalgia, joint pain, pulled muscle, toothache, neuralgias and dysmenorrhoea; it is effective in low doses (0.3–0.6 g 6–8 hourly). Analgesic effect is maximal at ~ 1000 mg (single dose).

2. As Antipyretic

It is effective in fever of any origin; dose is same as for analgesia. However, paracetamol, being safer, is generally preferred. Antipyretics are not useful in fever due to heat stroke; only external cooling lowers body temperature.

3. Acute Rheumatic Fever

Aspirin is the first drug to be used in all cases; other drugs are added or substituted only when it fails or in severe cases (corticosteroids act faster). In a dose of 4–5 g or 75–100 mg/kg/day (in divided portions producing steady state serum salicylate concentration 15–30 mg/dl) it brings about marked symptomatic relief in 1–3 days. Dose reduction may be started after 4–7 days and maintenance doses (50 mg/kg/day) are continued for 2–3 weeks or till signs of active disease (raised ESR) persist. Withdrawal should be gradual over the next 2 weeks.

Granulomatous lesions, nodules, cardiac complications, valvular defects, chorea and duration of disease are not altered by salicylate therapy.

4. Rheumatoid Arthritis

Aspirin in a dose of 3–5 g/day is effective in most cases; produces relief of pain, swelling and morning stiffness, but progress of the disease process is not affected. Since large doses of aspirin are poorly tolerated for long periods it is rarely used now; other NSAIDs are preferred.

5. Osteoarthritis

It affords symptomatic relief only; may be used on ‘as and when required’ basis, but paracetamol is the first choice analgesic for most cases.

6. Post-Myocardial Infarction And Poststroke Patients

By inhibiting platelet aggregation aspirin lowers the incidence of reinfarction. TXA₂ synthesis in platelets is inhibited at low doses. It has been argued that high doses can reverse the beneficial effects by concurrently inhibiting PGI₂ (antiaggregatory and vasodilatory) synthesis in vessel wall. Large studies have demonstrated that aspirin 60–100 mg/day reduces the incidence of myocardial infarction (MI): it is now routinely prescribed to postinfarct patients; many recommend it for primary prophylaxis as well. ‘New onset’ or ‘sudden worsening’ angina is associated with high infarction rate. This can be reduced to half by 100–150 mg aspirin per day for 12 weeks.

Aspirin reduces ‘transient ischaemic attacks’ and lowers incidence of stroke in such patients. But the risk of stroke in postMI patients is not reduced.

7. Other less well established uses of aspirin are:

       i.            Pregnancyinduced hypertension and preeclampsia: imbalance between TXA₂ and PGI₂ is believed to be involved: aspirin 80–100 mg/day benefits many cases by selectively suppressing TXA₂ production.

     ii.            Patent ductus arteriosus: aspirin can bring about closure and avoid surgery.

  iii.            Familial colonic polyposis: aspirin and other NSAIDs suppress polyp formation and afford symptomatic relief in this rare disorder.

   iv.            Prevention of colon cancer: incidence of colon cancer among regular aspirin users is much lower. Colonic tumours express large quantities of COX2. However, the rofecoxib trial (APPROVE) was prematurely terminated and the drug withdrawn due to increased incidence of cardiovascular events. The Adenoma Prevention with Celecoxib (APC) trial has also been terminated due to 2.5 fold increase in risk of major fatal/nonfatal cardiovascular events.

     v.            To prevent flushing attending nicotinic acid ingestion, which is due to PGD₂ release in the skin.

ASPIRIN 350 mg tab, COLSPRIN 100, 325, 650 mg tabs,

ECOSPRIN 75, 150, 325 mg tabs, DISPRIN 350 mg tab,

LOPRIN 75, 162.5 mg tabs.

An injectable preparation has been made available recently; BIOSPIRIN: Lysine acetylsalicylate 900 mg + glycine 100 mg/vial for dissolving in 5 ml water and i.v. injection.

Other salicylates (salicylamide, benorylate, diflunisal) are seldom if ever used.