Salicylates - Analgesic-Antipyretics

ANALGESIC-ANTIPYRETICS

The analgesic -antipyretics of paramount importance are salicylates and paracetamol. Phenacetin is no more used today. Analgin has serious adverse effects but is still available in India. Nefopam is a new entrant.

Salicylates

These compounds are derivatives of salicylic acid and include acetyl salicylic acid, sodium salicylate, and methyl salicylate. Salicin, a naturally occurring salicylate is a constituent of several plants but is present in highest concentration in the willow tree (Salix alba vulgaris) (Fig 29.1), which grows near lakes and rivers in temperate climates and whose branches are used to make cricket bats and baskets. Other plants include Acacia (flower oil), Aspens, Birches, Calycanthus (leaves), Camellia (leaves), Chenopodium (leaves), Hyacinth, Marigold, Milkwort, Poplars, Spiraea, Teaberry, Tulips and Violets.

Salicylic acid (orthohydroxy benzoic acid) is so irritating that it can only be used as an external application. Hoffman, a chemist at Bayer Company first synthesised acetyl salicylic acid in the laboratory in 1897, and together with his chief pharmacologist Heinrich Dreser, he performed a number of pharmacological and toxicological tests to evaluate its therapeutic benefits and safety profile. The name “aspirin” was coined in 1899, and since then the drug has marched through time displaying a rare and astonishing staying power. In fact, in recent times aspirin has surprised the medical profession with newer and far more exciting applications (vide infra).

Examples

Acetaminosalol, Aloxiprin, Aluminium aspirin, Ammonium salicylate, Antipyrine salicylate, Aspirin, Benorylate, Bismuth subsalicylate, Bromosalicylic acid acetate, Calcium aminosal-icylate, Calcium carbaspirin, Carbamoylphenoxyacetic acid, Choline salicylate, Diethylamine salicylate, Ethyl salicylate, Fendosal, Glycol salicylate, Homomenthyl salicylate, Lithium salicylate, Magnesium salicylate, Menthyl salicylate, Octyl salicylate, Phenazone salicylate, Phenyl aminosalicylate, Phenyl salicylate, Physostigmine salicylate, Potassium aminosalicylate, Potassium salicylate, Salicylamide, Salicylic acid, Salsalate, Silver salicylate, Sodium aminosalicylate, Sodium salicylate, Sodium thiosalicylate, Thurfyl salicylate, Triethanolamine salicylate, Trolamine salicylate

Physical Appearance

Acetyl salicylic acid is an odourless, white, crystalline powder with an unpleasant saline taste. Sodium salicylate occurs as odourless, white scaly crystals with the same unpleasant saline taste. Methyl salicylate is a colourless liquid with aromatic odour and sweetish taste.

Salicylates for therapeutic use are available as tablets, capsules, powders, effervescent tablets and liquid preparations for ingestion; rectal suppositories; and as liniments, creams and lotions for topical application.

Uses

Sodium salicylate and acetyl salicylic acid:

·              Antipyretic.

·              Analgesic.

·              Treatment of rheumatoid arthritis.

·              Low-dose aspirin is used in the prophylaxis of cere-brovascular ischaemic events, angina pectoris, and is also recommended by some authorities for the preven-tion of colon cancer, and migraine. Accumulating data suggests that aspirin may prevent or protect against the development of colon and possibly other types of gastrointestinal cancers. Combination of warfarin with aspirin may improve efficacy in preventing ischaemic heart disease, but may ironically increase the chances of a haemorrhagic fatal stroke.

Sodium aminosalicylate:

·              It is used sometimes as a second-line drug in the management of tuberculosis.

Bismuth subsalicylate:

·              It is used to treat diarrhoea, and as prophylaxis for travellers diarrhoea.

New derivatives of salicylic acid:

·              Mesalamine (5-aminosalicylic acid) is used as a suppos-itory or rectal suspension enema for its local effects in the treatment of inflammatory bowel disease (proctosig-moiditis). Olsalazine (sodium azodisalicylate) is said to be effective in relieving manifestations of ulcerative colitis, and can be administered orally. Sulfasalazine (salicylazosulfapyridine) is also beneficial.

·              Diflunisal, a difluorophenyl derivative of salicylic acid is said to be much more potent than aspirin in the treat-ment of musculoskeletal sprains and osteoarthritis.

·              Benorylate (4-acetamidophenyl-o-acetylsalicylate) is an ester of aspirin and paracetamol. It causes less gastric irritation and bleeding. The usual therapeutic dose in adults is 4 gm/day. Toxicity can result if this is exceeded. Manifestations are a combination of those seen in aspirin and paracetamol poisoning with partic-ular tendency toward centrilobular hepatic necrosis.

Locally acting salicylates:

·              Salicylic acid is a keratolytic agent.

·              Methyl salicylate (oil of wintergreen, sweet birch oil,gautheria oil), is used for the local treatment of musculo-skeletal pain and inflammation. Commercial preparations are not less than 98% w/w. One ml of 98% methyl salicy-late is equivalent to 1.4 grams ASA in salicylate potency, and its action is the same as salicylates; or one teaspoonful of oil of wintergreen (5 ml) is equivalent to approximately 7000 mg of salicylate or 21.7 adult aspirin tablets.

·              Methyl salicylate is also used as a flavouring agent for candy.

·              Homomenthyl salicylate (homosalate) is a sunscreen agent found in many sunscreen products and contains 46% salicylic acid. Homosalate could be hydrolysed in vivo to free salicylic acid and homomenthol.

·              Trolamine salicylate cream (10 grams of cream contains 500 mg of salicylic acid) is used in the management of osteoarthritis.

·              Salicylates are often combined with antihistamines and decongestants, or caffeine in cold and allergy preparations. Several products contain combinations of paracetamol and salicylate, while others combine salicylate with opioids.

Toxicokinetics

Salicylates are rapidly absorbed from the stomach, and to a slightly lesser extent from the small intestine. Delayed absorption is seen in the following situations: enteric coated preparations, pylorospasm, pyloric stenosis, and bezoar formation. Therapeutic serum salicylate levels should not exceed 30 mg/100 ml. Salicylic acid and methyl salicylate are readily absorbed through intact skin. Salicylates distribute well into plasma; saliva; milk; and spinal, peritoneal and synovial fluid and into body tissues including kidney, liver, lung and heart.

Metabolism occurs chiefly in the liver, where salicylates are broken down into salicyluric acid, ether glucoronide, ester glucoronide, and gentisic acid. Excretion is mainly through urine.

The half-life of salicylates is 2 to 4 hours at therapeutic levels, but may increase to 20 hours at toxic levels. Plasma salicylate is 50 to 80% protein bound, especially to albumin, with salicylic acid being more highly bound than aspirin. As salicylate doses are increased, the proportion bound to plasma protein decreases, and the volume of distribution increases. There is also a decrease in protein binding from 90% at thera-peutic levels to less than 75% at toxic levels. The apparent volume of distribution increases from 0.2 L/kg to more than 0.3 L/kg. The half-life of plasma salicylate elimination increases with dose. The reported half-lives in adults range from 2.4 to 19 hours with doses of 0.25 gram, and about 10 to 20 grams of sodium salicylate, respectively. In poisoned children, the half-life ranged from 15 to 29 hours.

Sustained release preparations of aspirin contain aspirin released over a 12-hour or longer period of time. Prolonged absorption and persistently elevated salicylate levels may occur following overdose. Enteric-coated formulations are designed to dissolve in the alkaline medium of the small intestine, and are likely to cause bezoars and prolonged drug absorption.

Mode of Action

■■Salicylates stimulate the respiratory centre in the brainstem leading to hyperventilation and respiratory alkalosis. They also interfere with Krebs cycle, inhibit production of ATP, and increase lactate production, leading to ketosis and a wide anion-gap metabolic acidosis. In children, respira-tory alkalosis is quite transient, and metabolic acidosis is the predominant feature. Respiratory acidosis in salicylate overdose indicates grave prognosis and is seen in salicylate-induced pulmonary oedema, CNS depression from mixed overdose,* or severe fatigue due to prolonged hyperven-tilation.

■■  Salicylates are extremely irritating to the GI mucosa, and overdose often results in haemorrhagic gastritis. In the US, the FDA requires an alcohol warning on all over-the-counter pain relievers, which includes aspirin, other salicylates, paracetamol, ibuprofen, ketoprofen, and naproxen sodium, due to a potential drug interaction resulting in upper GI bleed or liver damage.

■■  Aspirin is commonly involved in allergic reactions, ranging in severity from urticaria or angioedema to acute anaphy-laxis.

Drug Interactions

■■  Salicylate and/or acetazolamide toxicity may occur in patients taking salicylates chronically when acetazolamide is added to drug regimen. The syndrome of effects reported are confusion, fatigue, hyperchloraemic metabolic acidosis, incontinence, lethargy, and somnolence shortly after the introduction of acetazolamide in patients chronically receiving aspirin.

■■  Effective October, 1998, the US FDA mandated that products containing aspirin or other salicylates display the following warning regarding chronic consumption of alcohol and salicylate use, “Alcohol warning: If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take this medication or other pain relievers/fever reducers. This medication may cause stomach bleeding”.

Clinical (Toxic) Features

Acute Poisoning:

·              Early—Nausea, vomiting, sweating, tinnitus (ringingor hissing), vertigo, and hyperventilation due to respi-ratory alkalosis. Irritability, confusion, disorientation, hyperactivity, slurred speech, agitation, combativeness, hallucinations, ataxia, and restlessness may be early findings in patients with severe toxicity.

·              Late—Deafness, hyperactivity, agitation, delirium,convulsions, hallucinations, hyperpyrexia. Coma is unusual.

·              Complications—Metabolic acidosis, pulmonaryoedema, rhabdomyolysis, cardiac depression, thrombo-cytopenic purpura. Gastrointestinal bleeding, perfora-tion and pancreatitis are less common complications. Salicylates must not be therapeutically administered to children under 15 years of age, especially if they are suffering from chicken pox or influenza. There is a serious risk of precipitating Reye’s syndrome which can be fatal (Table 29.1). 

The main features are acute onset of hepatic failure and encephalopathy. It prob-ably results from damage to mitochondria in liver cells. Patients with Reye’s syndrome generally have elevated serum ammonia levels, elevated LFT’s and an absent or low CSF salicylate level, while salicylate intoxicated patients have higher serum and CSF salicylate levels. Recovery is associated usually with permanent neuro-logical sequelae.

·              Respiratory alkalosis develops early in the course of intoxication and may be the only acid base distur-bance with mild salicylism. Respiratory alkalosis with compensatory metabolic acidosis develops in most adults with moderate intoxication. Metabolic acidosis with acidaemia and compensatory respiratory alkalosis develops in severe overdose and is associated with a higher rate of complications and death.

·              The three most common auditory alterations described by individuals after large doses of salicylates include tinnitus, loss of absolute acoustic sensitivity, and alterations of perceived sounds. Symptoms can occur gradually within the initial few days of therapy or within hours of an extremely large dose.

·              Dehydration and hypokalaemia are common. QT prolongation, U waves and flattened T waves have been described in several patients with hypokalaemia after acute salicylate overdose.

·              Significant toxicity has been reported after chronic topical use of creams and ointments containing salicy-lates. Salicylic acid found in topical wart removal products at concentrations up to 17% (w/w) can cause mucosal burns if ingested.

Chronic Poisoning (Salicylism):

·              This is characterised by slow onset of confusion, agita-tion, lethargy, disorientation, slurred speech, halluci-nations, convulsions, and coma. There may also be tinnitus, hearing loss, nausea, dyspnoea, tachycardia and fever.

·              Sometimes “salicylism” presents as pseudosepsissyndrome characterised by fever, leukocytosis, hypo-tension, and multi-organ system failure: ARDS, acute renal failure and coagulopathy (DIC).

·              Prolongation of PT and PTT, thrombocytopenia, hypofibrinogenaemia, elevation of fibrin degradation products, and red blood cell fragmentation has devel-oped in some patients with multiorgan system failure associated with chronic salicylate toxicity.

·              Chronic maternal ingestion is associated with an increased incidence of stillbirths, antepartum/post-partum bleeding, prolonged pregnancy/labour, and lower birth weight. The American Academy of Pediatrics recommends that salicylates should be used cautiously during breastfeeding; some studies also suggest that bismuth subsalicylates consumed during lactation can lead to problems.

Treatment

·              In patients with severe poisoning, examine the urine for calcium oxalate crystals. Also, monitor calcium and renal function (BUN, creatinine).

·              Local treatment with cold milk or ice cream as a demulcent is sufficient in most cases. Cold water or sucking on crushed ice will also relieve oral pain. Remove all visible evidence of plant debris from the oropharynx.

·              In severe cases, parenteral opioids, corticosteroids, IV fluids, and endotracheal intubation may be required. Tetany should be treated with intravenous calcium gluconate.

·              Ocular exposure to sap resulting in chemical conjuncti- vitis and corneal abrasions must be treated with copious irrigation, systemic analgesics, and expert ophthalmologic consultation.

Diagnosis

·              Monitor serum salicylate level, glucose and electrolytes every 2 hours until the salicylate level is consistently falling and acid base abnormalities are improving. Peak salicylate may be delayed 6 hours or more following ingestion of tablets, and more than 12 hours after ingestion of enteric coated or sustained release products. Obtain an arterial blood gas in symptomatic patients and follow until acid base abnormalities are improving.

·              Obtain a CBC, renal and hepatic function tests and INR or PT and PTT in patients with clinical evidence of moderate to severe toxicity.

·              In patients with pyloric stenosis, enteric coated aspirin has been shown to remain in the stomach for prolonged periods of time. This can be shown by instillation of contrast media into the stomach followed by an abdominal X-ray. This procedure should be considered in patients with serum salicylate levels that do not decline or continue to rise. Concretions of bismuth subsalicylate or enteric coated aspirin may be radiopaque on plain abdominal radiographs. 

Laboratory Findings:

·              Anion-gap acidosis.

·              Hypokalaemia (acidosis may mask it).

·              Hypocalcaemia.

·              Hypoglycaemia.

Bed-side Tests:

Ferric chloride test—

–– Add a few drops of 10% ferric chloride solution to 1 ml of urine. A purple colour indicates the presence of salicylates.

–– However it is not conclusive, since a positive result is also obtained in phenol, phenothiazines, phenyl-butazone, and oxyphenbutazone.

–– A method using ferric chloride on methanolic extract of haemolysed whole blood has been described. The minimum salicylate level this method can detect is 5 mg/100 ml.

Trinder’s test—

–– Reagent: Trinder’s reagent is used which is obtained by mixing 40 grams of mercuric chloride (dissolved in 850 ml of purified water), with 120 ml of aqueous HCl (1 mol/L) and 40 grams of hydrated ferric nitrate, followed by dilution to 1 litre with purified water.

––  Method: The test can be done on urine, stomach contents, or scene residue. Add 0.1 ml of Trinder’s reagent to 2 ml of sample and mix for 5 seconds.

A strong violet colour indicates the presence of salicylates. Mere darkening is not significant. If the sample to be tested is stomach contents or scene residue, it is better to first boil 1 ml of the sample with 1 ml of aqueous HCl (0.1 mol/L) for 10 minutes, cool, filter, and then neutralise with 1 ml of aqueous sodium hydoxide (0.1 mol/L).

Confirmatory test—

––  The only confirmatory test is to estimate the serum salicylate level. Unfortunately, the seriousness of poisoning correlates poorly with serum levels. Previously, the Done nomogram (first published in 1960) was highly recommended to correlate serum salicylate level with the degree of intoxica-tion at varying intervals after acute ingestion of aspirin. But there are severe limitations to its use and is now not generally considered to be reliable.

It has been shown to underestimate or overestimate toxicity after salicylate ingestion, and is of no use in evaluating toxicity after ingestion of enteric coated or sustained release products, or in patients with subacute or chronic salicylism. Studies have indicated that it has poor predictive value.

––  Whenever a serum salicylate level is obtained, it is essential to determine the concurrent arterial blood pH, since in the presence of acidaemia more salicylic acid leaves the blood and enters the CSF and other tissues, with consequent worsening of symptoms. Therefore, a falling serum salicylate level may be difficult to interpret as it can reflect either an increased tissue distribution with increased toxicity, or an increased clearance with decreased toxicity. A falling serum salicylate level accompanied by a falling or low blood pH should be presumed to reflect a serious or worsening situation, not a benign or improving one.

Treatment

·              Patients with major signs or symptoms (metabolic acidosis, dehydration, mental status changes, seizures, pulmonary oedema) should be admitted to the Intensive Care Unit regardless of serum salicylate level. Patients with minor symptoms only (i.e. nausea, tinnitus) following acute overdose may be managed in the emergency department with decontamination and alkaline diuresis if the salicy-late level is shown to be declining. Admission should be strongly considered regardless of the salicylate level or symptoms in infants, children less than 2, the elderly, in chronic overdose, or when the ingested tablets are enteric coated or sustained release.

·      Stomach wash may be beneficial upto 12 hours after ingestion, since toxic doses of salicylates often cause pylorospasm and delayed gastric emptying. Whole bowel irrigation might be useful in patients with bezoars, or patients who have ingested enteric coated or sustained release products.

·      Activated charcoal (AC): It is said to be very efficacious in the treatment of salicylate poisoning since each gram of AC can adsorb 550 mg of the drug. A 10:1 ratio of AC to salicylate ingested appears to result in maximum efficiency. The initial dose of AC can be combined with a cathartic to enhance elimination. Some investigators recommend multiple dosing of AC (i.e. MDAC), while others do not consider it to be more beneficial.

·      Urinary alkalinisation: This should not be confused with forced diuresis which was recommended in the past, wherethe accent was on increasing urinary flow rate in order to increase salicylate clearance. It carries with it the risk of fluid overload with attendant complications. Alkalinisation of both blood and urine can be achieved with intravenous sodium bicarbonate.* Acetazolamide must not be used since it produces a systemic metabolic acidosis.

·              Dose of NaHCO_{3 –}

–– For mild poisoning: 1 mEq/kg of NaHCO₃ is added to the first bottle of 5% dextrose. If alkalinisation (i.e. urinary pH between 7.5 and 8.5) is not achieved in a few hours, it can be repeated.

–– For severe poisoning: Additional bolus therapy of 50 to 100 mEq of NaHCO₃ over 1 to 2 hours may be necessary.

–– Monitor serum electrolytes and urine pH every 1 to 2 hours. Adjust potassium and bicarbonate administration as needed to maintain a urine pH of 7.5 to 8. It is important to correct hypokalaemia while alkalinising the urine. Alkalinisation should be stopped when serum salicylate level falls below 35 mg/100 ml.

Haemodialysis: It is very effective in salicylate poisoning and must always be considered in the presence of cardiac or renal failure, intractable acidosis, convulsions, severe fluid imbalance, or a serum salicylate level more than 100 mg/100 ml. Patients with evidence of cerebral oedema require immediate dialysis. Charcoal haemoperfusion produces better salicylate clearance than haemodialysis, but does not correct fluid and electrolyte balance like haemodialysis.

·      Supportive measures:

o     Correction of fluid and electrolyte imbalance (watchout for fluid overload!).

o     Correct dehydration with 0.9% saline 10 to 20 ml/kg/ hr over 1 to 2 hours until a good urine flow is obtained (at least 3 to 6 ml/kg/hr). In patients, in whom urinary alkalinisation is being considered, initial hydration may be with 10 to 20 ml/kg of D5W with 88 to 132 milliequivalents of bicarbonate added. Patients in shock may require more rapid fluid administration.

o     Hypoprothrombinaemia can be corrected by 2.5 to 5 mg of vitamin K IV every day.

o     Hyperpyrexia must be tackled by cooling measures (e.g. ice in the axilla and groin).

o     Correction of metabolic acidosis with NaHCO₃.

o     Correction of hypocalcaemia with calcium gluconate IV (5 to 10 ml in adults).

o     Correct hypokalaemia as needed. Patients undergoing forced or alkaline diuresis may require large amounts of potassium supplementation due to renal potassium wasting. Institute continuous cardiac monitoring in patients with hypokalaemia, and those requiring high doses of potassium.

o     Correction of hypoglycaemia with glucose IV (50 ml of 5% dextrose or 1 ml/kg).

o     Treatment of convulsions with benzodiazepines.

o     Mild cerebral oedema and elevated intracranial pres-sure (ICP) can be managed by head elevation and administration of mannitol; hyperventilation should be performed if there is evidence of impending herniation. Haemodialysis may be necessary.

o     Salicylates can interfere with coagulation mechanisms, therefore, patients with evidence of active bleeding or coagulation disorders require laboratory monitoring to include prothrombin time (PT) and INR. Give blood or blood products (fresh frozen plasma) if bleeding is excessive. Vitamin K may be beneficial in the presence of a prolonged PT or INR.

·      Treatment of Reye’s syndrome:

o     Admit the patient to an intensive care unit.

o     Raise the head-end of bed (400).

o     Mannitol IV (0.2 to 1.0 gm/kg).

o     Acute hyperventilation may be helpful.

o     Short acting barbiturates in resistant cases.

Autopsy Features

·      Petechiae in the skin (occasionally).

·      Erosions of gastric mucosa. Black, altered blood may lie in the stomach. Sometimes massed concretions of tablets are present.

·      Petechiae in various organs and serous membranes (parietal pleura, pericardium).

·              Pulmonary and cerebral oedema.

Forensic Issues

·              Most of the cases of overdose are suicidal in nature; a few may be accidental.

·              In some individuals, a small dose of aspirin can provoke a fatal hypersensitivity reaction. The patient is usually (curi- ously) a middle-aged female, and often has nasal polyps. Within minutes of ingestion there is an acute vasomotor rhinitis, angioneurotic oedema, and urticaria. Death results from laryngeal oedema, hypotension, or shock.

·              Salicylate poisoning can also result from extensive applica-tion of salicylate-containing ointments, keratolytic agents, or other agents containing methyl salicylate.