Poisoning by specific drugs clinical features and management Paracetamol (Acetaminophen) to Warfarin

Poisoning by specific drugs clinical features and management - Paracetamol (Acetominophen) to Warfarin - technical

Paracetamol (acetaminophen)

Mechanisms of toxicity

The toxicity of paracetamol is related to its metabolism (Figure 1). In therapeutic doses, 60 to 90% is metabolized by conjugation to form paracetamol glucuronide and sulphate. A much smaller amount (5–10%) is oxidized by mixed function oxidase enzymes to form a highly reactive compound (N-acetyl-p-benzoquinoneimine, NAPQI), which is then immediately conjugated with glutathione and subsequently excreted as cysteine and mercapturate conjugates. Only 1 to 4% of a therapeutic dose of the drug is excreted unchanged in urine.

In overdose, larger amounts of paracetamol are metabolized by oxidation because of saturation of the sulphate conjugation pathway. As a result, liver glutathione stores become depleted so that the liver is unable to deactivate the toxic metabolite. NAPQI is believed to have two separate but complementary effects. Firstly, it reacts with glutathione, thereby depleting the cell of its normal defence against oxidizing damage. Secondly, it is a potent oxidizing as well as arylating agent; it inactivates key sulphydryl groups in certain enzymes, particularly those controlling calcium homeostasis.

Paracetamol-induced renal damage probably results from a mechanism similar to that which is responsible for hepatotoxicity, i.e. by formation of NAPQI, although in the kidney this is generated by prostaglandin endoperoxide synthetase rather than by cytochrome P450-dependent mixed function oxidases.

paracetamol metabolism

Above: Figure 1 Paracetamol metabolism

Risk factors

As would be expected from the mechanism of toxicity, the severity of paracetamol poisoning is dose-related. An absorbed dose of 15 g (200 mg/kg) or more is potentially serious in most patients. There is, however, some variation in individual susceptibility to paracetamol-induced hepatotoxicity and patients with pre-existing liver disease; those with a high alcohol intake and poor nutrition; those receiving enzyme-inducing drugs; and those suffering from anorexia nervosa or acute starvation should be considered to be at greater risk. Individuals with HIV-related disease also appear to be more susceptible to paracetamol-induced hepatic damage. The mechanisms involved in all these cases have not been elucidated fully, though poor nutrition (and therefore glutathione depletion) plays a major role in some cases.

Clinical features

The features of paracetamol poisoning are summarized in Table 1. Following the ingestion of an overdose of paracetamol, patients usually remain asymptomatic for the first 24 h, or at most develop anorexia, nausea, and vomiting. Liver damage is not usually detectable by routine liver function tests until at least 18 h after ingestion of the drug, and hepatic tenderness and abdominal pain are seldom exhibited before the second day. Liver damage reaches a peak as assessed by plasma alanine or aspartate aminotransferase (ALT, AST) activity or prothrombin time (international normalized ratio, INR), 72 to 96 h after ingestion. More often there is prolongation of the prothrombin time and a marked rise in aminotransferase activity (activities of several thousand are not uncommon) without the development of fulminant hepatic failure. Renal failure due to acute tubular necrosis develops in about 25% of patients with severe hepatic damage and in a few without evidence of serious disturbance of liver function. Other features, including hypoglycaemia and hyperglycaemia, cardiac arrhythmias, pancreatitis, gastrointestinal haemorrhage, and cerebral oedema may all occur with hepatic failure due to any cause and are not direct consequences of paracetamol toxicity.

Paracetamol can cause metabolic acidosis at two distinct periods after overdosage. Transient hyperlactataemia is frequently found within the first 15 h in all but minor overdoses and appears to be due to inhibition of mitochondrial respiration at the level of ubiquinone and increased lactate production. It is rarely of clinical consequence, although in very severe paracetamol poisoning (plasma paracetamol concentration >500 mg/litre at 4 h after ingestion) the acidosis may be associated with coma. The second phase of hyperlactataemia and acidosis occurs in those patients who present late and go on to develop hepatic damage; in this instance decreased hepatic lactate clearance appears to be the major cause, compounded by poor peripheral perfusion and increased lactate production.

Hypophosphataemia is a recognized complication of acute liver failure, including that due to paracetamol, and may contribute to morbidity and mortality by inducing mental confusion, irritability, coma, and abnormalities of platelet, white cell, and erythrocyte functions. Phosphaturia appears to be the principal cause of hypophosphataemia in paracetamol poisoning; it may occur in the absence of fulminant hepatic failure and indicates paracetamol-induced renal tubular damage; it is a useful prognostic sign.

Prediction of liver damage

In the early stages following ingestion of a paracetamol overdose, most patients have few symptoms and no physical signs. There is thus a need for some form of assessment which estimates the risk of liver damage at a time when the liver function tests are still normal. Details of the dose ingested may be used but, in many cases, the history is unreliable and, even when the dose is known for certain, it does not take account of early vomiting and individual variation in response to the drug. However, a single measurement of the plasma paracetamol concentration is an accurate predictor of liver damage provided that it is taken not earlier than 4 h after ingestion of the overdose. Information gained from several studies has enabled the production of a graph which may be used for prediction of liver damage and which serves as a guide to the need for specific treatment. In patients who have taken several overdoses of paracetamol over a short period of time, the plasma paracetamol concentration will be meaningless in relation to the treatment graph. Such patients should be considered at risk and treated. Patients who regularly consume alcohol in excess of currently recommended limits (particularly those who are malnourished); those who regularly take enzyme-inducing drugs (e.g. carbamazepine, phenytoin, phenobarbital, primidone, and rifampicin); and those with conditions causing glutathione depletion (e.g. malnutrition and HIV infection) may be at risk of liver damage from lower plasma paracetamol concentrations than others. The plasma paracetamol concentration for such patients should be considered in relation to the ‘high risk’ treatment line.

Table 1 Clinical, biochemical, and haematological features of untreated paracetamol poisoning (>200 mg/kg)
Day 1 Day 2 Day 3
Asymptomatic May become asymptomatic (in severe untreated poisoning)
Nausea Vomiting Jaundice → liver failure → hepatic encephalopathy
Vomiting Hepatic tenderness ± generalized abdominal tenderness Back pain + renal angle tenderness → renal failure
Abdominal pain Occasionally, mild jaundice Cardiac arrhythmias →Chloralose is marketed for amate cardiac arrest
Anorexia   Disseminated intravascular coagulation
Biochemical abnormalities Haematological abnormalities
Bilirubin ↑ Platelets ↓
Blood sugar ↓ Clotting factors II ↓ V ↓ VII ↓
Creatinine ↑  
Lactate ↑  
Phosphate ↓  
Amylase ↑  
Potassium ↑  

Sixty per cent of patients whose plasma paracetamol concentration falls above the line drawn between 200 mg/litre (1.32 mmol/litre) at 4 h and 50 mg/litre (0.33 mmol/litre) at 12 h after the ingestion of the overdose are likely to sustain liver damage (ALT or AST >1000 iu/litre) unless specific protective treatment is given.

Prognostic factors

The overall mortality of paracetamol poisoning in untreated patients is only of the order of 5%. The prothrombin time is usually the first liver function test to become abnormal, and for this reason it is of particular value in assessing the prognosis of an individual patient. The more rapid the increase in prothrombin time, the worse the prognosis of the patient. A prothrombin time of more than 20 s at 24 h after ingestion indicates that significant hepatic damage has been sustained, and a peak prothrombin time of more than 180 s is associated with a chance of survival of less than 8%.

Acid–base disturbances are also a good guide to prognosis. Systemic acidosis developing more than 24 h after overdose indicates a poor prognosis; patients with a blood pH below 7.30 at this time have only a 15% chance of survival. In addition, a rise in the serum creatinine concentration is associated with poor survival; patients with a serum creatinine concentration above 300 µmol/litre have only a 23% chance of survival.

A study of prognostic indicators in paracetamol-induced fulminant hepatic failure treated conventionally compared the sensitivity (percentage of patients who died with a positive test), predictive accuracy (percentage of patients whose outcome was predicted accurately), positive predictive value (percentage of patients with a positive test who died), and specificity (percentage of survivors with a negative test) of measurement of factors V and VIII with conventional tests. (factor V is vitamin K-dependent and levels fall in liver failure; levels of factor VIII rise in patients with liver failure.) An admission pH below 7.30 with a serum creatinine concentration above 300 µmol/litre and a prothrombin time above 100 s in patients with grade III–IV encephalopathy has a sensitivity, predictive accuracy, positive prediction value, and specificity of 91, 86, 83, and 91, respectively. However, a factor VIII/V ratio above 30 had comparable values of 91, 95, 100, and 100.


Parenteral fluid replacement should be given for the first 1 or 2 days after overdose if nausea persists or vomiting occurs.

Patients who have taken staggered overdoses should be treated with an antidote irrespective of the plasma paracetamol concentrations. They can be discharged after antidotal treatment, provided they are asymptomatic and the INR, plasma creatinine concentration, and ALT activity are normal.

Patients who present 15 h or more after ingestion tend to be more severely poisoned and at greater risk of developing serious liver damage and should receive antidotal treatment as the plasma concentration alone may not be an accurate guide of severity, as it may be non-detectable at the time of late presentation. The INR, venous pH, plasma creatinine concentration, and liver function tests are helpful in determining prognosis.


Acetylcysteine acts by replenishing cellular glutathione stores and may also repair oxidation damage caused by NAPQI either directly or, more probably, through the generation of cysteine and/or glutathione. It may also act as a source of sulphate and so ‘unsaturate’ sulphate conjugation.

The most widely utilized regimen worldwide is a 20.25-h protocol (Bullet list 1). Provided that acetylcysteine is administered within 8 to 10 h of overdose, the development of hepatic damage is prevented; thereafter, the protective effects decline rapidly. Some 10 to 15% of patients treated with intravenous acetylcysteine (20.25-h regimen) develop rash, angio-oedema, hypotension, and bronchospasm. These reactions, which are due to the initial bolus, are seldom serious and no fatalities have been reported. Antihistamines such as chlorpheniramine or terfenadine may be given if such anaphylactoid reactions do occur, but discontinuing the infusion temporarily is all that is usually required.

Bullet list 1: Dosing regimen for acetylcysteine

Acetylcysteine (intravenous 20.25–21 h regimens)

  • 150 mg/kg over 15 min (is sometimes given over 60 min), then 50 mg/kg over the next 4 h and 100 mg/kg over the next 16 hrs
  • Total dose, 300 mg/kg over 20.25 h (or 21 h)

Management of severe liver damage

A 10% glucose solution should be administered to prevent the onset of hypoglycaemia. If fulminant hepatic failure supervenes, the use of a continued intravenous N-acetylcysteine (the 16-h infusion is continued until recovery or death) will reduce morbidity and mortality. In one prospective study, the survival rate in 25 patients with paracetamol-induced fulminant hepatic failure was 20%, with an incidence of cerebral oedema and of hypotension requiring inotropic support of 68 and 80%, respectively. With N-acetylcysteine, the comparable figures in 25 matched patients were 48% (survival rate), 40% (cerebral oedema), and 48% (hypotension).

A proton pump inhibitor will reduce the risk of gastrointestinal bleeding from ‘stress’ ulceration/erosion. There is no evidence that fresh frozen plasma prevents gastrointestinal haemorrhage in patients with severe coagulation abnormalities (prothrombin time >100 s). If acute renal failure supervenes, then this should be managed conventionally.

Liver transplantation has been performed successfully in patients with paracetamol-induced fulminant hepatic failure.


Despite the introduction of child-resistant packaging, the ingestion of aspirin by children still occurs, iatrogenic overdose is not uncommon, and aspirin remains the drug of choice for many adults who want to poison themselves. Salicylate poisoning may also result from percutaneous absorption of salicylic acid (used in keratolytic agents), and ingestion of methyl salicylate (‘oil of wintergreen’).

Mechanisms of toxicity

In therapeutic doses, aspirin is absorbed rapidly from the stomach and small intestine, but in overdose, absorption may occur more slowly, and plasma salicylate concentrations may continue to rise for up to 24 h. The pharmacokinetics of elimination of aspirin are important determinants of salicylate toxicity. Biotransformation to both salicyluric acid and salicylphenolic glucuronide is saturable with the following clinical consequences: (1) the time needed to eliminate a given fraction of a dose increases with increasing dose; (2) the steady state plasma concentration of salicylate, particularly that of the pharmacologically active non-protein-bound fraction, increases more than proportionately with increasing dose; and (3) renal excretion of salicylic acid becomes increasingly important, a pathway, which is extremely sensitive to changes in urinary pH.

When ingested in overdose, salicylates directly stimulate the respiratory centre to produce both increased depth and rate of respiration, thereby causing a respiratory alkalosis. At least part of this effect is due to local uncoupling of oxidative phosphorylation within the brainstem. In an attempt to compensate, bicarbonate, accompanied by sodium, potassium, and water, is excreted in the urine resulting in dehydration and hypokalaemia. More importantly, the loss of bicarbonate diminishes the buffering capacity of the body and allows an acidosis to develop more easily. Very high salicylate concentrations in the brain depress the respiratory centre and may further contribute to the development of acidaemia.

Simultaneously, a variable degree of metabolic acidosis develops, not only because of the presence of salicylic acid itself, but also because of interference with carbohydrate, lipid, protein, and amino acid metabolism by salicylate ions. Inhibition of citric acid cycle enzymes causes an increase in circulating lactic and pyruvic acids. Salicylates stimulate fat metabolism and cause increased production of the ketone bodies, β-hydroxybutyric acid, acetoacetic acid, and acetone. Dehydration and lack of food intake, because of vomiting, further contribute to the development of ketosis. Protein catabolism is accelerated and synthesis diminished. Aminotransferases (responsible for the interconversion of amino acids) are inhibited. Increased circulating blood concentrations of amino acids result, together with aminoaciduria; inhibition of active tubular reabsorption of amino acids also contributes. Aminoaciduria increases the solute load on the kidneys and, thereby, increases water loss from the body.

A primary toxic effect of salicylates in overdose is uncoupling of oxidative phosphorylation. ATP-dependent reactions are inhibited and oxygen utilization and CO2 production increased. Energy normally used for the conversion of inorganic phosphate to ATP is dissipated as heat. Hyperpyrexia and sweating result, causing further dehydration. Fluid loss is enhanced because salicylates stimulate the chemoreceptor trigger zone and induce nausea and vomiting and, thereby, diminish oral fluid intake. If dehydration is sufficiently marked, low cardiac output and oliguria will aggravate the metabolic acidosis already present which, if severe, can itself diminish cardiac output.

Glucose metabolism also suffers as a result of uncoupled oxidative phosphorylation because of increased tissue glycolysis and peripheral demand for glucose (Fig. 9.1.4). This is seen principally in skeletal muscle and may cause hypoglycaemia. The brain appears to be particularly sensitive to this effect and neuroglycopenia can occur in the presence of a normal blood sugar level when the rate of utilization exceeds the rate at which glucose can be supplied from the blood. Increased metabolism and peripheral demand for glucose activates hypothalamic centres resulting in increased adrenocortical stimulation and release of adrenaline. Increased glucose 6-phosphatase activity and hepatic glycogenolysis contribute to the hyperglycaemia, which is sometimes seen following ingestion of large amounts of salicylate. Increased circulating adrenocorticosteroids exacerbates fluid and electrolyte imbalance.

Although this is rarely a practical problem, salicylate intoxication may be accompanied by hypoprothrombinaemia due to a warfarin-like action of salicylates on the physiologically important vitamin K epoxide cycle. Vitamin K is converted to vitamin K 2,3-epoxide and then reconverted to vitamin K by a liver membrane reductase enzyme, which is competitively inhibited by warfarin and salicylates.

Clinical features and assessment of severity of salicylate intoxication

The dose of salicylate ingested and the age of the patient (see below) are the principal determinants of the severity of an overdose. The plasma salicylate concentration should be determined on admission, but it is important to repeat it 2 h later to ensure that the concentration is not rising. If the concentration has risen, the level should be repeated after a further 2 h. Generally speaking, plasma salicylate concentrations that lie between 300–500 mg/litre some 6 h after ingestion of an overdose are associated with only mild toxicity, concentrations between 500 and 700 mg/litre are associated with moderate toxicity, and concentrations in excess of 700 mg/litre confirm severe poisoning.

Salicylate poisoning of any severity is associated with sweating, vomiting, epigastric pain, tinnitus, and deafness (Bullet list 2).

Bullet list 2 Clinical features of salicylate poisoning

  • Nausea, vomiting, and epigastric discomfort
  • Irritability, tremor, tinnitus, deafness, blurring of vision
  • Hyperpyrexia, sweating, dehydration
  • Tachypnoea and hyperpnoea
  • Noncardiogenic pulmonary oedema
  • Acute renal failure
  • Mixed respiratory alkalosis and metabolic acidosis (except in children who usually develop metabolic acidosis alone)
  • Hypokalaemia, hypernatraemia, or hyponatraemia
  • Hyperglycaemia or hypoglycaemia
  • Hypoprothrombinaemia (rare)
  • Confusion, delirium, stupor, and coma (in severe cases)

Young children quickly develop metabolic acidosis following the ingestion of aspirin in overdose, but by the age of 12 years the usual adult picture of a combined dominant respiratory alkalosis and mild metabolic acidosis is seen. To some extent, the presence of an alkalaemia protects against serious salicylate toxicity because salicylate remains ionized and unable to penetrate cell membranes easily. Development of acidaemia allows salicylates to penetrate tissues more readily and leads, in particular, to central nervous system toxicity characterized by excitement, tremor, delirium, convulsions, and stupor and coma. Very high plasma salicylate concentrations cause paralysis of the respiratory centre and cardiovascular collapse due to vasomotor depression.

Pulmonary oedema is seen occasionally in salicylate poisoning, and although this is often due to fluid overload as a result of treatment, it may be noncardiac and occur in the presence of hypovolaemia. In these circumstances, the pulmonary oedema fluid has the same protein and electrolyte composition as plasma, suggesting increased pulmonary vascular permeability.

Although aspirin overdose may be complicated by inhibition of platelet aggregation and hypoprothrombinaemia, gastric erosions and gastrointestinal bleeding are rare following acute salicylate overdose.

Oliguria is sometimes seen in patients following the ingestion of salicylates in overdose. The most common cause is dehydration but, rarely, acute renal failure or inappropriate secretion of antidiuretic hormone may occur.

Although the urinary pH may be alkaline in the early stages of salicylate overdose, it soon becomes acid. Measurement of arterial blood gases, pH, and standard bicarbonate may show a respiratory alkalosis in the early stages of salicylate intoxication accompanied by the development of a metabolic acidosis. The plasma potassium concentration is often low; rarely, the blood sugar may be high.


The plasma salicylate concentration should be re-measured 2 to 3 h after the first measurement. Dehydration, electrolyte imbalance and, most importantly, metabolic acidosis should be corrected.

The role of multiple-dose activated charcoal in increasing salicylate elimination is controversial, and it cannot be recommended on current evidence. As the relationship between renal clearance of salicylates and urine pH is logarithmic, urine alkalinization should be undertaken in patients with a plasma salicylate concentration greater than 500 mg/litre, particularly if an acidosis is present. The therapeutic aim is to make the urine alkaline (ideally, pH 7.5–8.5), and in adults this may be achieved by administration of sodium bicarbonate, 225 mmol (225 ml of 8.4%); further doses of bicarbonate are given as required. Hypokalaemia should be corrected before administration of sodium bicarbonate, because this lowers the serum potassium concentration further. In patients with severe poisoning (plasma salicylate concentration >700 mg/litre or >5.1 mmol/litre), haemodialysis should be considered, particularly when severe acid–base abnormalities are present.

Pulmonary oedema occasionally complicates salicylate toxicity. Fluid overload should be excluded as far as possible but, if increased pulmonary vascular permeability is suspected, measurement of the pulmonary artery wedge pressure may be needed both for confirmation of the diagnosis and to monitor subsequent fluid administration. Positive end expiratory pressure ventilation appears to be beneficial.


Poisoning may complicate therapeutic use as well as being the result of deliberate self-poisoning. If a sustained-released formulation has been ingested, peak plasma concentrations of the drug are frequently not attained until 6 to 12 h after overdose and the onset of toxic features is correspondingly delayed.

Clinical features

Symptoms include nausea, vomiting, and hyperventilation, haematemesis, abdominal pain, diarrhoea, sinus tachycardia, supraventricular and ventricular arrhythmias, hypotension, restlessness, irritability, headache, hyperreflexia, tremors, and convulsions. Hypokalaemia probably results from Na+-K+-ATPase activation. A mixed respiratory alkalosis and metabolic acidosis is common. Most symptomatic patients have plasma theophylline concentrations in excess of 25 mg/litre. Convulsions are seen more commonly when concentrations are greater than 50 mg/litre.


MDAC (e.g. 50 g 4-hourly) enhances the systemic elimination of theophylline. Intractable vomiting may be alleviated by ondansetron, 8 mg intravenously in an adult. Gastrointestinal haemorrhage may require blood transfusion and the administration of a proton pump inhibitor intravenously. Tachyarrhythmias may be induced by the rapid flux of potassium across cell membranes and early correction of hypokalaemia may prevent their development. The plasma potassium concentration should therefore be measured on admission and at hourly intervals thereafter while the patient is symptomatic. Potassium supplements will be needed in almost all cases and doses of up to 60 mmol/h may be required at the outset in severe cases. Non-selective β-adrenoceptor blocking drugs, such as propranolol, may also be useful in the treatment of tachyarrhythmias secondary to hypokalaemia. Convulsions should be treated with diazepam 10 to 20 mg intravenously in an adult.


Clinical features

Only a small percentage of patients who ingest large amounts of thyroid hormones develop features of toxicity. Symptoms develop within a few hours with tri-iodothyronine (T3) and after 3 to 6 days with thyroxine (T4). They tend to resolve in about the same time as they take to develop. Sinus tachycardia, tremor, anxiety, irritability, insomnia, hyperactivity, sweating, diarrhoea and fever, are most common. Atrial fibrillation and convulsions have also been reported. Myocardial necrosis may occur rarely.


Serum T4 and T3 concentrations should be measured in blood taken 6 to 12 h after ingestion (this need not be measured as an emergency) since a normal result precludes the possibility of delayed toxicity and allows the patient to be discharged. Those with high T4 concentrations should be reviewed for evidence of toxicity on the fourth or fifth day after ingestion. Patients who develop toxicity should be given propranolol for 5 days.


Warfarin toxicity is more likely to occur in the setting of therapeutic anticoagulation (as a result of a drug interaction), than as a consequence of acute overdose.

Clinical features

Epistaxis, gingival bleeding, spontaneous bruising, haematomas, haematuria, bilateral flank pain, rectal bleeding, and haemorrhage into any organ. Spontaneous haemoperitoneum has been reported. Severe blood loss may result in hypovolaemic shock, coma, and death.


If major bleeding occurs, give vitamin K1 10 mg by slow intravenous injection together with prothrombin complex concentrate 50 units/kg or fresh frozen plasma 15 ml/kg. If the INR is 8.0 or more and there is no active bleeding, and the intention is to continue anticoagulation, discontinue warfarin (restart when the INR ≤ 5.0), give phytomenadione 0.5 mg by slow intravenous injection and repeat the dose if the INR is 8.0 or more 24 h later.

If the INR is 6.0 to 8.0, and there is no active bleeding or only minor bleeding, warfarin should be discontinued and restarted when the INR less than or equal to 5.0.

If the INR is 4.0 or less, there is no active bleeding, and continued anticoagulation is unnecessary, treatment with phytomenadione is not required. If the INR is 4.0 or more, phytomenadione 10 mg by slow intravenous injection (100 µg/kg body weight for a child) should be administered.