COMMENTARY
Drug Safety 7 (3): 170-177. 1992 0114-5916/92/0005-0170/$04.00/0 © Adis International Limited. All rights reserved. DRS148
Recent Developments in the Management of Paracetamol (Acetaminophen) Poisoning John Janes and Phillip A. Routledge Welsh National Poisons Unit. Llandough Hospital, Penarth, South Glamorgan, Wales
Contents 170 171 172 172 172 174 174 174 175 176
Summary
Summary I. Toxicity of Paracetamol and the Effect of Antidotes 2. Clinical Aspects of Treatment 2.1 Methionine 2.2 Acetylcysteine 2.2.1 Adverse Effects of Acetylcysteine 2.3 The Role of Phytomenadione (Vitamin K) 3. Effect of Enzyme Induction 4. Indications for Liver Transplantation 5. Paracetamol Poisoning in Pregnancy
Paracetamol (acetaminophen) poisoning accounts for almost a third of admissions to our district poisons unit, and is the commonest cause of death in such patients. Antidotal treatment may be effective up to 10h after overdose with oral methionine or up to 24h with acetylcysteine (not ISh as previously suggested for the latter). Patients taking paracetamol overdose while also receiving drugs which induce hepatic enzymes are more susceptible to liver damage, and antidotal treatment may be necessary at lower plasma paracetamol concentrations (50% of the normal treatment line). As survival following liver transplantation is now increasing, it is important to identify early prognostic indicators in fulminant hepatic failure, so that those patients with a high chance of fatal outcome can be considered for transplantation. Useful indicators are the presence of acidosis, marked prolongation of prothrombin time or a continued rise in prothrombin time on day 4 after the overdose. There is no evidence that paracetamol or acetylcysteine are teratogenic in pregnancy. Delays in administering acetylcysteine after paracetamol poisoning in pregnancy have been shown to increase the risk of spontaneous abortion and fetal death. Thus, acetylcysteine should be started as early as possible where treatment is indicated.
Management of Paracetamol Poisoning
Comprehensive reviews of paracetamol (acetaminophen) poisoning have been performed by Prescott (1983) and by Ellenhorn and Barceloux (1988). The aim of this article is to review current trends in the management of paracetamol poisoning, particularly late treatment, treatment in patients with hepatic enzyme induction, the role of early consideration of liver transplantation and overdose in pregnancy. Paracetamol is a popular drug to take in overdose, accounting for a third of approximately 1000 admissions to the Cardiff Poisons Treatment Unit each year (fig. I). It is often taken on impulse without any suicidal intent and without knowledge of its potentially fatal consequences. In 1989, in England and Wales, there were 164 deaths attributed to paracetamol poisoning alone, with many more where paracetamol had been taken in combination with other drugs (Office of Population Censuses & Surveys 1989).
1. Toxicity of Paracetamol and the Effect of Antidotes The dose resulting in toxicity is variable. As little as paracetamol 5.8g has been reported to be associated with liver damage (Fernandez & Fernandez-Brito 1977), although doses greater than 15g are more regularly associated with this complication. The plasma concentration of paracetamol is more closely related to the risk ofliver damage than
171
is dose. Certainly, little reliance can be placed on the dose claimed to have been taken by the patient, and various amounts may be lost following vomiting or gastric lavage (Prescott 1983). Paracetamol is largely metabolised to glucuronide and sulphate conjugates which are excreted in the urine (Davis et al. 1976). Hepatotoxicity is a consequence of conversion of a small fraction of the ingested paracetamol to a highly reactive arylating metabolite, N-acetyl-P-benzoquinoneimine (NABQI), by cytochrome P450-dependent mixed function oxidase (Miner & Kissinger 1979; Mitchell et al. 1974). In therapeutic doses NABQI is detoxified by glutathione, but with larger doses the normal excretory pathways become saturated and an increasing amount of NABQI is formed, thus depleting hepatic glutathione stores. NABQI is then free to cause hepatic necrosis. The exact mechanism of hepatotoxicity is unclear. Cell damage may result from irreversible covalent binding of NABQI to vital hepatocyte proteins (Jollow et al. 1973; Potter et al. 1973). Neither covalent binding nor hepatic necrosis occurs until glutathione levels are reduced to 20 to 30% of normal (Mitchell et al. 1973). Another postulated mechanism is that NABQI oxidises thiol groups in key enzymes within the hepatocyte, in particular Ca++-translocases, leading to elevation of cytosolic calcium ions and eventual cell death (Moore et al. 1985). Methionine and acetylcysteine replenish glutaParacetamol , / (acetaminophen) 29%
Other NSAIDs 3%
-1fj1m..._-.:\
Others 19% Benzodiazepines 20% Other tranquillisers 4%
Antidepressants 7%
Fig. 1. Drugs taken by patients admitted to the Welsh National Poisons Unit (1989).
Drug Safety 7 (3) 1992
172
thione stores in the liver and kidney. In addition, acetylcysteine may allow repair of oxidative damage by generating cysteine or glutathione (Boobis et al. 1986), and may act as a source of sulphate to enable conjugation of paracetamol (Slattery & Levy 1977). It has also been suggested that acetylcysteine may act as an antioxidant to prevent inflammatory responses initiated by oxidative damage (Jaeschke & Mitchell 1989) and to prevent microvascular plugging which extends ischaemia around the zone of injury in the periacinar region of the liver (Rappoport 1979). The possible beneficial effect of acetylcysteine in late treatment where the liver is already damaged suggests that this drug may have additional effects (Boobis et al. 1986). Tee et al. (1986) have shown that incubation with acetylcysteine of hamster hepatocytes already damaged by paracetamol results in increased cell survival. They argue that this secondary protective effect results from reduction ofthiol groups previously oxidised by NABQI (see above), permitting re-establishment of calcium homeostasis and thus preventing cell death. It has also been suggested that acetylcysteine may improve microcirculatory blood flow in hepatic failure, particularly in patients with paracetamol-induced liver failure. The mechanism may be via the effect of the L-isomer of acetylcysteine on restoring normal vascular responsiveness to endothelial derived relaxant factor (EDRF), although this hypothesis is as yet untested (Harrison et al. 1991). The increase in oxygen delivery, whatever the mechanism, may also be important in any late response to acetylcysteine in paracetamol poisoning.
2. Clinical Aspects of Treatment Treatment is based on the phnciple of preventing gluthathione depletion with glutathione precursors, as glutathione itself does not enter cells readily (Prescott & Matthew 1974). 2.1 Methionine Methionine is thought to act by maintaining glutathione synthesis, and is given orally. However, absorption may be unreliable in the presence
of vomiting - an early sign in paracetamol poisoning. It has generally been thought to be less effective than intravenous acetylcysteine (Prescott 1983). It is ineffective if given 10 or more hours after overdose and is said to be potentially hazardous when given at later stages in patients with impending severe liver damage, as it has been claimed that it may aggravate or precipitate hepatic encephalopathy (Phear et al. 1965). The normal dose is 2.5g initially, followed by 3 further doses of 2.5g 4-hourly. Its advantage is that it is cheap and easy to administer, provided the patient is not vomiting. It may also be useful up to IOh after overdose in patients who develop an adverse reaction to intravenous acetylcysteine (but see below). It has been suggested that addition of methionine to paracetamol tablets might protect against hepatotoxicity and nephrotoxicity and one such formulation is available in the UK ('Pameton'), although many other formulations are used more widely. 2.2 Acetylcysteine There is clear evidence of the value of oral and intravenous acetylcysteine in the treatment of paracetamol poisoning (Prescott et al. 1979; Smilkstein et al. 1988). In a retrospective study of patients treated with oral acetylcysteine, Smilkstein et al. (1988) found minimal hepatotoxicity regardless of the initial paracetamol concentration when acetylcysteine was started within 8h of ingestion, and no difference in outcome whether it was started at 0 to 4 or 4 to 8h. Efficacy decreases with further delay. Because delay may occur between overdose and admission, and between admission and the results of paracetamol estimates becoming available to medical staff, we commence treatment with intravenous acetylcysteine immediately if the patient has taken more than paracetamol 109, and then discontinue treatment if paracetamol concentrations 4h or longer after the overdose are subsequently found to be below the relevant treatment line (fig. 2). This avoids delay in initiating therapy while awaiting results (Canalese et al. 1981) since such avoidable delays have been associated with fatalities (Brahams 1989; Meredith et al. 1986). The
Management of Paracetamol Poisoning
200
:2:
100
Cl
.§.
Drug Safety 7 (3): 170-177. 1992 0114-5916/92/0005-0170/$04.00/0 © Adis International Limited. All rights reserved. DRS148
Recent Developments in the Management of Paracetamol (Acetaminophen) Poisoning John Janes and Phillip A. Routledge Welsh National Poisons Unit. Llandough Hospital, Penarth, South Glamorgan, Wales
Contents 170 171 172 172 172 174 174 174 175 176
Summary
Summary I. Toxicity of Paracetamol and the Effect of Antidotes 2. Clinical Aspects of Treatment 2.1 Methionine 2.2 Acetylcysteine 2.2.1 Adverse Effects of Acetylcysteine 2.3 The Role of Phytomenadione (Vitamin K) 3. Effect of Enzyme Induction 4. Indications for Liver Transplantation 5. Paracetamol Poisoning in Pregnancy
Paracetamol (acetaminophen) poisoning accounts for almost a third of admissions to our district poisons unit, and is the commonest cause of death in such patients. Antidotal treatment may be effective up to 10h after overdose with oral methionine or up to 24h with acetylcysteine (not ISh as previously suggested for the latter). Patients taking paracetamol overdose while also receiving drugs which induce hepatic enzymes are more susceptible to liver damage, and antidotal treatment may be necessary at lower plasma paracetamol concentrations (50% of the normal treatment line). As survival following liver transplantation is now increasing, it is important to identify early prognostic indicators in fulminant hepatic failure, so that those patients with a high chance of fatal outcome can be considered for transplantation. Useful indicators are the presence of acidosis, marked prolongation of prothrombin time or a continued rise in prothrombin time on day 4 after the overdose. There is no evidence that paracetamol or acetylcysteine are teratogenic in pregnancy. Delays in administering acetylcysteine after paracetamol poisoning in pregnancy have been shown to increase the risk of spontaneous abortion and fetal death. Thus, acetylcysteine should be started as early as possible where treatment is indicated.
Management of Paracetamol Poisoning
Comprehensive reviews of paracetamol (acetaminophen) poisoning have been performed by Prescott (1983) and by Ellenhorn and Barceloux (1988). The aim of this article is to review current trends in the management of paracetamol poisoning, particularly late treatment, treatment in patients with hepatic enzyme induction, the role of early consideration of liver transplantation and overdose in pregnancy. Paracetamol is a popular drug to take in overdose, accounting for a third of approximately 1000 admissions to the Cardiff Poisons Treatment Unit each year (fig. I). It is often taken on impulse without any suicidal intent and without knowledge of its potentially fatal consequences. In 1989, in England and Wales, there were 164 deaths attributed to paracetamol poisoning alone, with many more where paracetamol had been taken in combination with other drugs (Office of Population Censuses & Surveys 1989).
1. Toxicity of Paracetamol and the Effect of Antidotes The dose resulting in toxicity is variable. As little as paracetamol 5.8g has been reported to be associated with liver damage (Fernandez & Fernandez-Brito 1977), although doses greater than 15g are more regularly associated with this complication. The plasma concentration of paracetamol is more closely related to the risk ofliver damage than
171
is dose. Certainly, little reliance can be placed on the dose claimed to have been taken by the patient, and various amounts may be lost following vomiting or gastric lavage (Prescott 1983). Paracetamol is largely metabolised to glucuronide and sulphate conjugates which are excreted in the urine (Davis et al. 1976). Hepatotoxicity is a consequence of conversion of a small fraction of the ingested paracetamol to a highly reactive arylating metabolite, N-acetyl-P-benzoquinoneimine (NABQI), by cytochrome P450-dependent mixed function oxidase (Miner & Kissinger 1979; Mitchell et al. 1974). In therapeutic doses NABQI is detoxified by glutathione, but with larger doses the normal excretory pathways become saturated and an increasing amount of NABQI is formed, thus depleting hepatic glutathione stores. NABQI is then free to cause hepatic necrosis. The exact mechanism of hepatotoxicity is unclear. Cell damage may result from irreversible covalent binding of NABQI to vital hepatocyte proteins (Jollow et al. 1973; Potter et al. 1973). Neither covalent binding nor hepatic necrosis occurs until glutathione levels are reduced to 20 to 30% of normal (Mitchell et al. 1973). Another postulated mechanism is that NABQI oxidises thiol groups in key enzymes within the hepatocyte, in particular Ca++-translocases, leading to elevation of cytosolic calcium ions and eventual cell death (Moore et al. 1985). Methionine and acetylcysteine replenish glutaParacetamol , / (acetaminophen) 29%
Other NSAIDs 3%
-1fj1m..._-.:\
Others 19% Benzodiazepines 20% Other tranquillisers 4%
Antidepressants 7%
Fig. 1. Drugs taken by patients admitted to the Welsh National Poisons Unit (1989).
Drug Safety 7 (3) 1992
172
thione stores in the liver and kidney. In addition, acetylcysteine may allow repair of oxidative damage by generating cysteine or glutathione (Boobis et al. 1986), and may act as a source of sulphate to enable conjugation of paracetamol (Slattery & Levy 1977). It has also been suggested that acetylcysteine may act as an antioxidant to prevent inflammatory responses initiated by oxidative damage (Jaeschke & Mitchell 1989) and to prevent microvascular plugging which extends ischaemia around the zone of injury in the periacinar region of the liver (Rappoport 1979). The possible beneficial effect of acetylcysteine in late treatment where the liver is already damaged suggests that this drug may have additional effects (Boobis et al. 1986). Tee et al. (1986) have shown that incubation with acetylcysteine of hamster hepatocytes already damaged by paracetamol results in increased cell survival. They argue that this secondary protective effect results from reduction ofthiol groups previously oxidised by NABQI (see above), permitting re-establishment of calcium homeostasis and thus preventing cell death. It has also been suggested that acetylcysteine may improve microcirculatory blood flow in hepatic failure, particularly in patients with paracetamol-induced liver failure. The mechanism may be via the effect of the L-isomer of acetylcysteine on restoring normal vascular responsiveness to endothelial derived relaxant factor (EDRF), although this hypothesis is as yet untested (Harrison et al. 1991). The increase in oxygen delivery, whatever the mechanism, may also be important in any late response to acetylcysteine in paracetamol poisoning.
2. Clinical Aspects of Treatment Treatment is based on the phnciple of preventing gluthathione depletion with glutathione precursors, as glutathione itself does not enter cells readily (Prescott & Matthew 1974). 2.1 Methionine Methionine is thought to act by maintaining glutathione synthesis, and is given orally. However, absorption may be unreliable in the presence
of vomiting - an early sign in paracetamol poisoning. It has generally been thought to be less effective than intravenous acetylcysteine (Prescott 1983). It is ineffective if given 10 or more hours after overdose and is said to be potentially hazardous when given at later stages in patients with impending severe liver damage, as it has been claimed that it may aggravate or precipitate hepatic encephalopathy (Phear et al. 1965). The normal dose is 2.5g initially, followed by 3 further doses of 2.5g 4-hourly. Its advantage is that it is cheap and easy to administer, provided the patient is not vomiting. It may also be useful up to IOh after overdose in patients who develop an adverse reaction to intravenous acetylcysteine (but see below). It has been suggested that addition of methionine to paracetamol tablets might protect against hepatotoxicity and nephrotoxicity and one such formulation is available in the UK ('Pameton'), although many other formulations are used more widely. 2.2 Acetylcysteine There is clear evidence of the value of oral and intravenous acetylcysteine in the treatment of paracetamol poisoning (Prescott et al. 1979; Smilkstein et al. 1988). In a retrospective study of patients treated with oral acetylcysteine, Smilkstein et al. (1988) found minimal hepatotoxicity regardless of the initial paracetamol concentration when acetylcysteine was started within 8h of ingestion, and no difference in outcome whether it was started at 0 to 4 or 4 to 8h. Efficacy decreases with further delay. Because delay may occur between overdose and admission, and between admission and the results of paracetamol estimates becoming available to medical staff, we commence treatment with intravenous acetylcysteine immediately if the patient has taken more than paracetamol 109, and then discontinue treatment if paracetamol concentrations 4h or longer after the overdose are subsequently found to be below the relevant treatment line (fig. 2). This avoids delay in initiating therapy while awaiting results (Canalese et al. 1981) since such avoidable delays have been associated with fatalities (Brahams 1989; Meredith et al. 1986). The
Management of Paracetamol Poisoning
200
:2:
100
Cl
.§.
