Cytokines and Toxicity in Acetaminophen Overdose

Cytokines and Toxicity in Acetaminophen Overdose

1. Laura P. James , MD2. Pippa M. Simpson , PhD3. Henry C. Farrar , MD4. Gregory L. Kearns , PharmD, PhD5. Gary S. Wasserman , DO6. Jeffrey L. Blumer , PhD, MD7. Michael D. Reed , PharmD8. Janice E. Sullivan , MD9. Jack A. Hinson , PhD10. The Pediatric Pharmacology Research Unit Network

1. From the Departments of Pediatrics (Dr James, Dr Simpson, Dr Farrar) and Pharmacology (Dr James, Dr Hinson), University of Arkansas for Medical Sciences and Arkansas Children's Hospital (Dr James, Dr Simpson, Dr Farrar), Little Rock, Arkansas; Departments of Pediatrics (Dr Kearns, Dr Wasserman) and Pharmacology (Dr Kearns), University of Missouri–Kansas City, Division of Pediatric Clinical Pharmacology and Medical Toxicology (Dr Kearns, Dr Wasserman), The Children's Mercy Hospitals and Clinics, Kansas City, Missouri; Department of Pediatrics and Pharmacology (Dr Blumer, Dr Reed), Case Western Reserve University, and the Division of Pediatric Pharmacology and Critical Care Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio (Dr Blumer, Dr Reed); Departments of Pediatrics and Pharmacology/Toxicology, University of Louisville and Kosair Children's Hospital, Louisville, Kentucky (Dr Sullivan); and the National Institute of Child Health and Human Development, Bethesda, Maryland (The Pediatric Pharmacology Research Unit Network).

1. Laura P. James, MD, Department of Pediatrics, Section of Clinical Pharmacology and Toxicology, Arkansas Children's Hospital, 800 Marshall Street, Little Rock, AR 72202; e-mail: [email protected].

AbstractSeveral cytokines have been reported to have hepatoprotective properties in animal models of acetaminophen toxicity. To investigate the relationships of cytokines and toxicity in acetaminophen overdose, blood samples were collected from patients following acute ingestions of acetaminophen. Samples for cytokine analysis were collected at the time of routine clinical monitoring in 111 patients (90 females; mean age 13.6 years). Plasma concentrations of interleukin 6, interleukin 8, interleukin 10, and monocyte chemoattractant protein 1 were analyzed by enzyme-linked immunosorbent assay. Patients were stratified by toxicity severity, defined by the maximal values of hepatic transaminase elevation. Levels of interleukin 6, interleukin 8, and monocyte chemoattractant protein 1 were higher in patients with serum alanine

aminotransferase > 1000 IU/L, and monocyte chemoattractant protein 1 had the strongest association with toxicity. Monocyte chemoattractant protein 1 values were higher in patients with greater delays in N-acetylcysteine treatment and in patients with higher values of prothrombin time. Monocyte chemoattractant protein 1 elevation in acetaminophen overdose may represent an innate, immunomodulary response of the liver to earlier events in the toxicity. An understanding of the role of cytokine responses in acetaminophen overdose may be relevant to the future development of new therapies for acetaminophen toxicity.

Acetaminophen cytokines monocyte chemoattractant protein 1

Article Notes Presented in part at the annual meeting of the North American Congress of Clinical

Toxicology 2002 and the annual meeting of the American Society for Clinical Pharmacology and Therapeutics, March 2004. Published in abstract form by the Journal of Arkansas Medical Society 2004;100:424-425. Supported by grant DK02971 (LPJ) and grant 2 U10 HD31324 (LPJ), 2 U01 HD31313 (GLK), 2 HD31323 (JLB), and U10 HD 9495934 (JES), Network of Pediatric Pharmacology Research Units, National Institute of Child Health and Human Development, and by grant GM-58884 (JAH), National Institute of General Medical Sciences.

DOI: 10.1177/0091270005280296

Received April 28, 2005. Accepted July 9, 2005. Acetaminophen overdose in Jamaica   Sobredosis de acetaminofén en Jamaica     MO Mills; MG Lee Department of Medicine, The University of the West Indies, Kingston 7, Jamaica, West

Indies Correspondence    

ABSTRACT Acetaminophen is a dose dependent hepatotoxin which is frequently associated with

intentional self-harm. Forty-nine cases of parasuicide attempts involving paracetamol only or in combination with another drug were treated at the UHWI, Jamaica, between 1994–2004. The majority were women (84%) and the mean age was 23 years. Acetaminophen was the only agent ingested in 71% of cases; 29% involved an additional drug. Patients presented an average of 6.5 hours after ingestion (range 1–45 hours). Serum transaminases were elevated in 18% of cases and N-acetylcysteine (NAC) therapy given in 55%. The mean duration of hospitalization was three days.

One patient developed liver failure and there were no deaths. Education of the public and medical profession is needed to increase awareness of the potential toxic effects of acetaminophen overdose. N-acetylcysteine therapy should be given early in suspected cases.

RESUMEN El acetaminofén es una hepatotoxina dosis-dependiente, frecuentemente asociada

con intenciones auto-destructivas. Cuarenta y nueve casos de intentos parasuicidas que involucraban paracetamol o combinación con otra droga, fueron tratados en el UHWI, Jamaica, entre 1994-2004. En la mayoría de los casos se trataba de mujeres (84%) y la edad promedio fue 23 años. El acetaminofén fue el único agente ingerido en 71% de los casos; 29% involucraron un medicamento adicional. Las transaminasas en suero fueron elevadas en 18% de los casos y se aplicó terapia de N-acetilcisteína en el 55% de los casos. La duración promedio de hospitalización fue de tres días. Uno de los pacientes tuvo un fallo hepático y no hubo muertes. Se requiere la educación del público y la profesión médica a fin de aumentar la conciencia sobre los efectos tóxicos potenciales de la sobredosis de acetaminofén. La terapia con N-acetilcisteína (NAC) debe aplicarse tan pronto como el caso despierte sospecha.

    INTRODUCTION Acetaminophen (paracetamol) is a commonly used analgesic which can be purchased

by consumers over the counter and is responsible in 30% to 50% of cases of accidental and non-accidental drug overdose (1). Acetaminophen overdose, either alone, or in combination with other drugs, is the commonest cause of intentional self-harm (1) and also accounts for 60% of cases of acute liver failure leading to orthotopic liver transplant in the United Kingdom (UK) and the United States of America (USA) (2, 3).

Acetaminophen is potentially hepatotoxic resulting in a dose dependent destruction of hepatocytes through its metabolite N-acetyl-P-benzoquinone-imine (NAPQI) (4). Normally, 95% of ingested acetaminophen is conjugated with sulfate and glucuronide and excreted via the kidneys and 5% is metabolized via cytochrome p 450 (CYP2E1) to form NAPQI which is usually conjugated by glutathione and is excreted by the kidneys as a water soluble conjugate. N-acetyl-P-benzoquinone-imine is formed in excess when the normal conjugation of acetaminophen to water soluble metabolites in the liver is overwhelmed by toxic ingestion. At toxic levels, glutathione becomes fully consumed and NAPQI binds to hepatocyte cell proteins resulting in necrosis through disruption of normal membrane integrity (3).

The recommended maximum adult dose of acetaminophen is 4g in 24 hours. The toxic effects are usually seen in patients taking above 7g in 24 hours (5). However, this threshold is lower in alcoholics who exhibit induction of cytochrome p 450 and therefore metabolize acetaminophen to its toxic component more rapidly (4).

There has been no previous study reported on the effects of acetaminophen overdose in Jamaica. This study reviews the clinical features and outcomes of patients with a parasuicide event with acetaminophen overdose, seen at the University Hospital of the West Indies, Jamaica, over a ten-year period from 1994 to 2004.

  SUBJECTS AND METHODS

A review was performed of patients' medical records at the University Hospital of the West Indies (UHWI), Jamaica, for the ten-year period from 1994 to 2004. The International Classification and Diagnosis (ICD) 9 and 10 coding systems was used to identify individuals with a parasuicide event involving paracetamol, using paracetamol, acetaminophen and parasuicide as the key search terms. Information was obtained with regards to patients' age, gender, weight and date of presentation to hospital. The agent ingested whether only acetaminophen or in combination with another drug, dosage, time between ingestion and presentation to hospital were also obtained. Results of liver transaminases, prothrombin time, serum albumin and bilirubin or whether the patient was admitted to hospital were documented. Whether N-acetylcysteine (NAC) therapy or gastric lavage was given, duration of admission to hospital, history of alcohol use and psychiatric history were also recorded.

  RESULTS In the 10-year interval between 1994 and 2004, 49 cases presented to the

emergency department, UHWI, with parasuicide attempt involving paracetamol overdose, either alone or in combination with another drug. There were 41 (84%) females and eight (16%) males. The age ranged from 14 to 39 years, with a mean age of 23 years. There were ten cases in 2001 and 2004, six cases in 1999, five cases in 2000, four cases in 2003 and three cases in 2002 (Figure). Thirty-five (71%) cases involved paracetamol as the only drug ingested. Paracetamol and antibiotics were ingested in five (10%), paracetamol and NSAIDS in three (6%) and paracetamol and antidepressants in three (6%) cases. The others combined paracetamol with miscellaneous drugs. The paracetamol dosages ingested, estimated from patient's or caregiver's history, ranged from 2g to 30g. In two cases, no estimate of the ingested dose was recorded. In five cases, the estimated dose recorded was below accepted criteria for toxic overdose (range 2g to 4g). Chronic alcohol intake was present in five (10%). A psychiatric history was present in five (10%). Patients presented an average of 6.5 hours (range 1–45 hours) after ingestion.

  Serum transaminases (SGOT, AST) were evaluated at presentation in 40 (82%) of the

cases. Four of the cases without serum transaminases were estimated to have taken

a non-toxic dose of paracetamol. No record of transaminases was present in five of the cases in which toxic doses were ingested. Serum transminase (SGOT, AST) was elevated at presentation in 9/49(18%) cases, one patient had marked elevation (6900 IU/l) whilst the others had levels between 4 – 6 times the upper limit of normal. Serum albumin was normal in 28 cases, low in two and was not recorded in 15 cases. The prothrombin time was normal in 21 cases. It was not done in 17 and elevated in only one case.

Gastric lavage was performed in twenty-six (53%) patients. N-acetylcysteine was administered in twenty-seven (55%) patients soon after presentation. Forty-five patients (92%) were admitted to hospital. Duration of admission ranged from one to eight days with a mean of three days. One patient developed liver failure and there were no deaths.

  DISCUSSION Acetaminophen is one of the most widely used analgesics and antipyretics worldwide

(3). It is a dose dependent hepatotoxin and acetaminophen overdose is the commonest aetiology of acute liver failure in the USA and UK, and the incidence of this problem is increasing (2, 3, 6).

Acetaminophen overdose is usually diagnosed by the appropriate history suggesting toxic ingestion and confirmed by serum acetaminophen levels. In many patients, there is a delay in seeking medical attention as symptoms may be delayed or an overdose may be taken unintentionally. Unintentional liver damage from self-medication for pain or fever with acetaminophen is well recognized (2). Also, in severe cases, the diagnosis may be delayed as patients frequently develop encephalopathy quite rapidly preventing an adequate history.

In the present study, 71% of cases involved only acetaminophen ingestion. In the remaining cases (29%), other agents were also ingested. This is similar to a recent study on acetaminophen hepatotoxicity in which 22% of patients ingested two drugs including narcotic analgesics (2).

Acetaminophen may cause elevation of serum transaminases even when used in therapeutic doses (6). In the present study, the serum transminases were elevated in only 18% of patients. In another study, it was found that over one-third of patients taking therapeutic doses of acetaminophen had significant elevation of serum transaminase levels. All were asymptomatic. In addition, acetaminophen concentration in serum was near or below the limits of assay detection (6). However, measurement of serum acetaminophen protein adducts, which represents liver injury specific to acetaminophen, may reliably identify acetaminophen hepatotoxicity in doubtful cases (3).

The risk of severe and possibly fatal liver damage after overdosage cannot be adequately assessed from either the amount ingested or early symptoms (7, 8). The biochemical indicators which suggest paracetamol induced severe hepatic injury are grossly elevated serum transaminases (greater than 1000 IU). O'Grady et al have validated criteria which are used to assess the severity of paracetamol ingestion and the likelihood of benefiting from a liver transplant (9). These criteria utilize the serum prothrombin time, serum creatinine, pH and presence or absence of hepatic encephalopathy.

Acetaminophen overdose is treated by administering NAC which is a glutathione precursor. When administered soon after overdose, it replenishes mitochondrial and cytosolic gluthatione stores that have been depleted (7). It is most effective when administered within the first eight hours of ingestion. The decision to administer NAC is guided by a nomogram comprising the acetaminophen level determined from a serum sample (5). N-acetylcysteine, a powerful antioxidant, may protect against further hepatic damage. Treatment less than ten hours after overdose is highly likely to prevent death and likely to result in fewer patients developing severe liver damage (7). It may also be beneficial when administered up to 24 hours after

ingestion in reducing the morbidity associated with acetaminophen toxicity. It may also be of benefit in acetaminophen-induced fulminant hepatic failure. In the present study, NAC was administered in over half of the patients soon after presentation and may have contributed to the satisfactory outcomes of patients in this series.

In order to decrease the morbidity and mortality of acetaminophen toxicity, specific measures should be considered. Education of the public, pharmacists and physicians regarding the potential toxic effects of acetaminophen is important. In the UK, legislation to reduce the size of packs of acetaminophen sold over the counter, and thus the number of tablets available in the household, has significantly reduced the size of overdoses with consequent reduction in morbidity and mortality (10, 11). In addition, physicians must consider acetaminophen, in patients presenting with suicide attempts and since specific therapy is available, it is important to measure serum acetaminophen and to administer NAC in patients with or without clinical liver involvement. If toxic ingestion is suspected clinically, NAC should be administered even in the absence of detectable acetaminophen levels or without a nomogram.

There are several limitations with the present study. This study was a retrospective review and although all cases of acetaminophen parasuicides were identified from the UHWI coding system, missed and unreported cases may have been excluded. In addition, the data obtained from the files were not uniform for all cases. The dose of paracetamol ingested may not have been accurate as this depended on patients and family members recall and estimation. It is difficult to estimate the overall problem of acetaminophen overdose in Jamaica in this review. The number of cases is relatively small compared to developed countries. A prospective study is needed to determine prevalence of this problem and should include surveillance of all parasuicides for overdose.

  REFERENCES 1. Robinson D, Smith AMJ, Johnston GD. Severity of overdose after restriction of

paracetamol availability: retrospective study. Brit Med J 2000; 321: 926–7.        [ Links ]

2. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42: 1364–72.        [ Links ]

3. Davern TJ, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 2006; 130: 687–94.        [ Links ]

4. Makin A, Williams R. Paracetamol hepatotoxicity and alcohol consumption in deliberate and accidental overdose QJM 2000; 93: 341–9.        [ Links ]

5. Sherlock S, Dooley J. Drugs and the liver. In: Diseases of the liver and biliary system. 10th edn. Blackwell Science. 1997; 337–69.        [ Links ]

6. Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily. A randomized controlled trial. J AMA 2006; 296: 87–93.        [ Links ]

7. Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning Lancet 1995; 346: 547–52.        [ Links ]

8. Farrell GC. Liver disease caused by drugs, anesthetics and toxins. In: Feldman M, Friedman LS, Sleisenger MH (eds). Gastrointestinal and liver disease. 7th edn. Saunders 2002; 1403–47.        [ Links ]

9. O'Grady JG, Alexander GJ, Hayllan KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gasteroenterol 1989; 97: 439–45.        [ Links ]

10. Hawton K, Townsend E, Deeks J, Appleby L, Gunnell D, Bennewith O. et al. Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study. BMJ 2001; 322: 1203–7.        [ Links ]

11. Hawton K, Simkin S, Deeks J, Cooper J, Johnson A, Waters K, et al. UK legislation on analgesic packs: before and after study of long term effects on poisonings. BMJ 2004; 329: 1076–9.        [ Links ]

NATIONAL POISON CENTREUNIVERSITI SAINS MALAYSIA

What is PRN?

PRN is the National Poison Centre set up based on the services provided by the Integrated Drug and Poison Information Service (IDPIS), Universiti Sains Malaysia since 1982. IDPIS evolves from several research activities carried out towards strengthening the health care services, particularly in the areas of information technology and informatics. It is aimed at auditing of health information as well as upgrading and strengthening the handling of drug and poison information directed towards health and allied professionals as well as the lay public.

Why PRN?

To reduce the mortality, morbidity, cost and occurrence of poisoning in a manner that strives for excellence, compassion and innovation.

How does PRN meets the above mission?

By making available services so as:

1. to reduce the risk and the occurrence of poisoning, 2. to encourage optimum treatment of poisoning cases, by:

o providing information on poisons and advice in poisoning cases o conducting research and documenting poisoning incidences o coordinating and conducting poison awareness and prevention education, and o carrying out analytical tests and interpretations of laboratory results.

What services are available?

They are four (4) types of services; two (2) of which are currently available, viz:

Drug and Poison Information Services

to function as the main resource centre in providing information on toxicity and risk of poisons.

to assist in the management of poisoning cases. to systematically disseminate drug and poison information and advise through the

use of efficient, reliable and cost-effective methods.

Research and Documentation Services

to compile information on poisonous substances on a continuous basis. to develop computer applications in order to facilitate information transfer and

use by the Drug and Poison Information Services. to research into systematic collection of poisoning data and information through

toxicovigilance and toxicokinetic studies.

Poison Education and Prevention Services

to conduct and coordinate a systematic and continuous education and prevention programs in the training of allied and health professionals and the public.

to collaborate with governmental and non-governmental agencies as well as other related bodies in carrying out its activities.

to train students of health sciences students in the area of toxicology and poisoning.

Toxicology Laboratory Services

to provide supportive services in the identification of poison so as to assist diagnosis, management and prognosis of the poisoning cases.

to be involved in surveillance program on population at risk to poisons. to collaborate with the development of governmental and non-governmental

agencies on analytical methods.

Who should use PRN?

Health and allied professionals Members of the public Governmental and regulatory agencies Non-governmental organizations Mass media, and other related bodies

When and how to use the service of PRN?

For emergency calls, trained pharmacists and professionals will be assigned to provide the necessary information needed using the resources available at PRN. Depending on cases, follow-up call(s) will be made to ensure the delivery of PRN continued support and assistance.

When should PRN be consulted?

When faced with:

1. Acute and chronic poisonings involving, o drugs and medicals products o pesticides. o household and industrial chemicals. o natural toxins.

2. Misuse and abuse of medicines/drugs. 3. Drug-related problems including adverse reactions.

Detailed information may also be obtained upon completion of more extensive research and consultation.

What is required when contacting PRN?

In cases of exposure to poisons, please be ready with the following information.

Name, age and weight of the victim. Caller's telephone number (this is important for follow-up calls). Name of product involved - read one at a time, the information written on labels, if any. Quantity of substance involved (provide estimate as accurate as possible). Time of the incident. Signs and symptoms. First aids given.

How does PRN operate?

How to collaborate with PRN?

The Centre welcomes collaborative efforts as part of its enrichment program in areas pertaining to toxicologic and related research. Please contact the Director of the National Poison Centre, Universiti Sains Malaysia, 11800 Penang, Malaysia for further discussion.

Tel: 04-6570099Fax: 04-6568417E.mail: [email protected]

What to Expect When Calling PRN?In cases of actual poisoning exposure,

1. the phone will be answered by a pharmacist or a scientist, who will be required to obtain a basic history and patient status report in order to provide better follow-up services.

2. the pharmacists are trained and capable of interpreting literature and references in making recommendations relative to the hazards of a suspected poisoning, termination of the toxic exposure, symptomatic or supportive care, antidotal therapy, ancillary drug use, and indications for procedures like diuresis or dialysis.

3. you will receive information that are condensed and concised for resources available at PRN, unless otherwise requested.

4. all information is recorded on a specific report form (as enclosed) for ease of follow-up and continuity.

5. when necessary you will be assisted in making arrangements for toxicological analyses, patient transfer, or obtaining specific consultations.

6. as a matter of routine, in order to monitor the outcome and also to maintain accurate and complete records, one or more follow-up calls will be made to assess the patient's progress and obtain further history.

Your cooperation in all these are much appreciated. Thank you.

PRN CONSULT

Review of Paracetamol PoisoningRahmat Awang, Pharm.D

Painkillers are generally available over-the-counter. The range includes aspirin, paracetamol and non-steroidal anti-inflammatory drugs. In children, paracetamol is the drugs of choice as an analgesic/antipyretic because it is relatively safe and easily accessible. In many similar instances it is also the preferred drug for adults. Unless properly used and stored such drugs can result in poisoning especially involving children. PRN CONSULT reviews some of the salient points in paracetamol poisoning. Paracetamol (acetaminophen, N-acetyl-p-aminophenol), is a major metabolite of phenacetin and acetanilide.

In some countries like the US, paracetamol accounted for 7% of the annual reported poisoning incidences and while in England, it is the leading cause of death from overdose, accounting for about 150 cases annually. Over the past few years, paracetamol has also been reported in some poisoning exposure in the country.

Should we be alarmed when somebody ingests an overdose of paracetamol?

Yes! Paracetamol is primarily hepatotoxic and may be fatal. However, if managed early, the likelihood of such consequences may be reduced.

An overdose of paracetamol can cause serious liver injury especially if the amount ingested is more than 140mg/kg in children or more than 6-7 gm in adults. Ingestion of more than 10gm (20 tablets of 500mg each) in adult may in fact be fatal. The risk for hepatotoxicity may even be increased if the patient also drinks alcohol, and/or on drugs that interacts with paracetamol such as barbiturates and other enzyme inducers.

How does the poisoning manifest itself?

Hepatotoxicity may be evident as late as day 4 from the time of ingestion. The manifestations associated with paracetamol poisoning may develop in 4 phases. Phase 1 which is between 1/2 to 24 hours post-ingestion may be seen with patient complaining of anorexia, nausea, vomiting and diaphoresis. Children however may look pale, quite ill and drowsy. These symptoms subside in phase 2, between day 1 and 3. Instead, patient may complain of right upper quadrant pain if there is any hepatic injury. Clinical laboratory tests when carried out may show elevation of SGPT, SGOT, LDH, bilirubin and prolongation of PT. Renal function may decline but BUN remains within normal limits. Following this, the patient may develop jaundice, coagulation defects and renal failure in day 3-5 (phase 3). Myocardial damage though has been reported is rare. Hepatic encephalopathy has also been observed. Nausea and vomiting may reappear. Biopsy may reveal centrilobular necrosis. Hepatic failure may result in death. If damage is reversible, complete resolution may occur in day 4 to week 2 (phase 4).

How can one predict the likelihood of hepatoxicity from paracetamol poisoning?

One approach which is simple but crude is to determine how much and how long ago was the drug taken. If the amount ingested is as stated above, then the likelihood is great, especially when the presence of signs and symptoms are evident. Patients admitted into the hospital should have their CBC, platelets, PT, bilirubin, BUN, electrolytes, glucose, SGPT, SGOT, alkaline phosphatase profiles checked.

Another more reliable approach is to determine the paracetamol plasma level and then plotting this value onto the Rumack-Matthew Nomogram (Figure 1). The nomogram provides a good correlation between the paracetamol plasma level with the risk of hepatotoxicity. For example, a 4-hour paracetamol plasma level at various concentrations have been correlated with the following risk:

>300mcg/ml

250-300mcg/ml150-250mcg/ml120-150mcg/ml< 120mcg/ml

liver damage* and fatalities very likely25% chance of developing acute renal failure40% chance of developing liver damage*25% chance of developing liver damage*5% chance of developing liver damage*relatively non-toxic

*Liver damage is indicated by plasma SGOT or SGPT level of greater than 40 IU/L, a PT of 1.3 times normal and plasma bilirubin >1mg/dl.

It is therefore highly desirable to draw the paracetamol plasma level when the amount ingested is close to or more than the amount needed to cause hepatic injury. This holds true if the timing for plasma level determination is appropriate i.e. between 4 and 16 hours post-ingestion.

Another approach is to determine the half-life of paracetamol. Plasma half-life for paracetamol in normals is about 1-2 hours. If half-life is more than 4 hours, it may be suggestive of hepatotoxicity.

How does one uses the Rumack-Matthew Nomogram? What precautions does one have to take in interpreting the information?

The Rumack-Matthew Nomogram (Figure 1) estimates the potential for hepatotoxicity from paracetamol poisoning. In addition, it is also used to indicate the need for N-acetylcysteine (NAC) therapy. It is based on a semi-logarithmic plot of plasma paracetamol levels vs time. A plasma level that falls above the red line indicates a potential for toxicity and requires NAC treatment. Anyone who uses this nomogram however, has to understand that the nomogram is applicable only when the poisoning involves a single acute ingestion and that the blood level is drawn between 4 and 16 hours. Blood levels drawn before 4 hours may not represent peak levels since absorption is not complete and those drawn after 16 hours may not be predictive of potential hepatotoxicity or the need for NAC therapy.

How does paracetamol result in hepatotoxicity?

Paracetamol is rapidly absorbed and metabolised by the liver primarily to sulfate and a glucuronide metabolites. Depletion of hepatic glutathione leads to the formation of toxic metabolites (? N-acetyl-benzoquinoneimine) which bind to hepatic macromolecules resulting in hepatic necrosis.

How does one manage paracetamol poisoning case?

In cases involving recent substantial ingestion, emesis is indicated unless the patient could rapidly become obtunded, comatose, convulsing. Emesis is most effective if initiated within 30 minutes. If available, syrup of ipecac at a dose of 30 ml in an adult or 15ml in a child of 1-12 years old is recommended. Charcoal administration with or without gastric lavage is also a preferred method of decontamination. However, its use may delay initiation of oral NAC since the antidote may be adsorbed by the charcoal rendering NAC ineffective.

NAC is an effective antidote for paracetamol poisoning when indicated. Dosing regimen for oral NAC is in the form of a 5% solution in a soft drink or juice starting with a loading dose of 140mg/kg followed by a maintenance dose of 70mg/kg every 4 hours for a total of 17 doses. IV administration of NAC can also be used.

The following situations warrant the use of NAC:

1. if initial plasma paracetamol level is toxic on the nomogram. The therapy should be continued until the entire course is completed even if subsequent levels falls below the treatment line.

2. if a toxic dose (7.5gms) is suspected to have been ingested within 16 hours of ingestion. Some Poison Centre recommend NAC therapy be given even up to 24 hours post-ingestion. Administration of NAC should never be delayed for lack of a paracetamol level. Loading dose should be administered but should be discontinued if level is below the nomogram treatment line.

3. if paracetamol half-life is more than 4 hours.

Side-effects associated with the use of NAC include bronchospasm and anaphylaxis. Anaphylactic reactions may be life-threatening and thus treatment should be made readily available.

Selected Paracetamol Products:

Algesic*Beamin/Junior*Benadryl C&F*Beserol*Biogesic*CalpolCodopar 118*Coritab*Decolgen*DhamolFebricol*FeprilHorgesic*

Junior DisprolMILIMilico*NaprexNorgesic*Nortes*OpigesicPanadeine*PanadolPanadol for ChildrenParadine*Parakol*Parclorphen*

ParmolPartamolRedonReno*Rhinitab II*SetamolSetramine*SetromolSinutab*Sinuzin-D*Trangesic*Uphamol/Uphamol Jr

* Combination product containing Paracetamol

Check your medications on eHealthMe: many drug interactions, side effects, or effectiveness can not be detected when drugs are approved. They may be found only after drugs have been used by millions of people and for a long time. On eHealthMe, you can study 30 million real world outcomes of 25,000 drugs since 1977 from FDA and community. What's more, you can drill down to any outcome or interacting drug. Check now >

On Oct, 16, 2010: 24,850 people reported to have side effects when using Benadryl. Among them, 29 people (0.12%) have Hepatotoxicity.

Time on Benadryl when people have Hepatotoxicity * :

< 1 month1 - 6 months

6 - 12 months

1 - 2 years 2 - 5 years 5 - 10 years 10+ years

Hepatotoxicity 100.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00%

Gender of people who have Hepatotoxicity when using Benadryl * :

Female Male

Hepatotoxicity 77.42% 22.58%

Age of people who have Hepatotoxicity when using Benadryl * :

0-1 2-9 10-19 20-29 30-39 40-49 50-59 60+

Hepatotoxicity 0.00% 0.00% 3.57% 10.71% 25.00% 17.86% 7.14% 35.71%

Severity of Hepatotoxicity when using Benadryl * :None.

* Approximation only.

Drugs in real world that are associated with: Hepatotoxicity

Real world uses, side effects, and user comments of: Benadryl (24,888 reports)

1. Metabolisme Obat

Sebagian besar obat bersifat lipofilik sehingga membuat mereka mampu menembus

membran sel intestinal. Obat kemudian diubah lebih hidrofilik melalui proses-proses

biokimiawi di dalam hepatosit, menghasilkan produk-produk larut air yang diekskresi ke

dalam urin atau empedu. Biotransformasi hepatik ini melibatkan jalur oksidatif utamanya

melalui sistem enzim sitokrom P-450.

Gambar 1. Metabolisme obat

2. Sistem Enzim yang Berperan Dalam Detoksifikasi

a. Sistem tahap I

Sistem detoksifikasi tahap I, melibatkan terutama enzim supergene sitokrom P-

450, secara umum merupakan enzim pertahanan pertama melawan bahan asing. Sebagian

besar bahan kimia dimetabolisme melalui biotransformasi tahap I. Pada reaksi umum

tahap I, enzim sitokrom P-450 (CYP450) menggunakan oksigen dan sebagai kofaktor,

NADH, untuk menambah kelompok reaktif, misalnya hidroksil radikal. Sebagai hasil dari

tahap ini dalam detoksifikasi, diproduksi suatu molekul reaktif yang lebih toksik daripada

molekul awal. Apabila molekul reaktif ini tidak berlanjut pada metabolisme selanjutnya,

yaitu tahap II (konjugasi), dapat menyebabkan kerusakan pada protein, RNA, dan DNA

di dalam sel. Beberapa penelitian menunjukkan bukti terhadap hubungan antara

terjadinya induksi tahap I dan/atau berkurangnya aktivitas tahap II dengan meningkatnya

resiko penyakit, misalnya kanker, SLE, dan penyakit Parkinson.

Gambar 2. Detoksifikasi hepar

b.       Sistem tahap II

Reaksi konjugasi pada tahap II umumnya mengikuti aktivasi tahap I, dimana akan

mengakibatkan xenobiotik yang telah larut air dapat diekskresikan melalui urin atau

empedu. Beberapa macam reaksi konjugasi terdapat di dalam tubuh, termasuk

glukoronidasi, sulfas, dan konjugasi glutation serta asam amino. Reaksi ini memerlukan

kofaktor yang tercukupi melalui makanan.

Banyak yang diketahui mengenai peran dari sistem enzim tahap I pada

metabolism bahan kimia seperti halnya aktivasinya oleh racun lingkungan dan komponen

makanan tertentu. Walau begitu, peran detoksifikasi tahap I pada praktek klinik tidak

terlalu diperhatikan. Kontribusi dari sistem tahap II lebih diperhatikan dalam penelitian

dan praktek klinik. Dan hanya sedikit yang diketahui saat ini mengenai peran sistem

detoksifikasi pada metabolism zat endogen.

Gambar 3. Sistem Enzim pada Detoksifikasi Hepar

3. Mekanisme hepatotoksisitas

Mekanisme jejas hati karena obat yang mempengaruhi protein transport pada

membran kanalikuli dapat terjadi melalui mekanisme apoptosis hepatosit karena asam

empedu. Terjadi penumpukan asam-asam empedu di dalam hati karena gangguan transport

pada kanalikuli yang menghasilkan translokasi Fas sitoplasmik ke membran plasma, dimana

reseptor-reseptor ini mengalami pengelompokan sendiri dan memacu kematian sel melalui

apoptosis. Disamping itu, banyak reaksi hepatoseluler melibatkan sistem sitokrom P-450

yang mengandung heme dan menghasilkan reaksi-reaksi energi tinggi yang dapat membuat

ikatan kovalen obat dengan enzim, sehingga menghasilkan ikatan baru yang tidak punya

peran.

Kompleks enzim-obat ini bermigrasi ke permukaan sel di dalam vesikel-vesikel

untuk berperan sebagai imunogen-imunogen sasaran serangan sitolitik sel T, merangsang

respons imun multifaset yang melibatkan sel-sel sitotoksik dan berbagai sitokin. Obat-obat

tertentu menghambat fungsi mitokondria dengan efek ganda pada beta-oksidasi dan enzim-

enzim rantai respirasi. Metabolit-metabolit toksis yang dikeluarkan dalam empedu dapat

merusak epitel saluran empedu.

Kerusakan dari sel hepar terjadi pada pola spesifik dari organella intraseluler yang

terpengaruh. Hepatosit normal terlihat di tengah-tengah gambar yang dipengaruhi melalui 6

cara (Gambar 4).

a. Kerusakan hepatosit : Ikatan kovalen dari obat ke protein intraseluler dapat

menyebabkan penurunan ATP, menyebabkan gangguan aktin. Kegagalan perakitan

benang-benang aktin di permukaan hepatosit menyebabkan rupturnya membran

hepatosit.

b. Gangguan protein transport : obat yang mempengaruhi protein transport di membran

kanalikuli dapat mengganggu aliran empedu. Hilangnya proses pembentukan vili dan

gangguan pompa transport misal multidrug resistance–associated protein 3 (MRP3)

menghambat ekskresi bilirubin, menyebabkan kolestasis.

c. Aktivasi sel T sitolitik : ikatan kovalen dari obat pada enzim P-450 dianggap

imunogen, mengaktifkan sel T dan sitokin dan menstimulasi respon imun multifaset.

d. Apoptosis hepatosit : aktivasi jalur apoptosis oleh reseptor Fas TNF-? menyebabkan

berkumpulnya caspase interseluler, yang berakibat pada kematian sel terprogram

(apoptosis).

e. Gangguan mitokondria : beberapa obat menghambat fungsi mitokondria dengan efek

ganda pada ?-oksidasi (mempengaruhi produksi energi dengan cara menghambat

sintesis dinucleotide adenine nicotinamide dan dinucleotide adenine flavin, yang

menyebabkan menurunnya produksi ATP) dan enzim rantai respirasi.

f. Kerusakan duktus biliaris : metabolit racun yang diekskresikan di empedu dapat

menyebabkan kerusakan epitel duktus biliaris.

Gambar 4. Mekanisme hepatotoksisitas

4. Faktor Resiko

a. Ras : beberapa obat memiliki perbedaan toksisitas terhadap ras tertentu. Misal, ras kulit

hitam akan lebih rentan terhadap toksisitas isoniazid. Laju metabolisme dikontrol oleh

enzim P-450 dan itu berbeda pada tiap individu

b. Umur : reaksi obat jarang terjadi pada anak-anak. Resiko kerusakan hepar meningkat

pada orang dewasa oleh karena penurunan klirens, interaksi obat, penurunan aliran darah

hepar, variasi ikatan obat, dan volume hepar yang lebih rendah. Ditambah lagi,

kurangnya asupan makanan, infeksi, dan sering mondok di rumah sakit menjadi alasan

penting akan terjadinya hepatotoksisitas obat.

c. Jenis Kelamin : walaupun alasannya tidak diketahui, reaksi obat pada hepar lebih

banyak pada wanita.

d. Konsumsi alkohol : peminum alkohol akan lebih rentan pada toksisitas obat karena

alkohol menyebabkan kerusakan hepar dan perubahan sirotik yang mengubah

metabolisme obat. Alkohol menyebabkan deplesi simpanan glutation yang

menyebabkannya lebih rentan terhadap toksisitas obat

e. Penyakit hepar : pada umumnya, pasien dengan penyakit hati kronis tidak semuanya

memiliki peningkatan resiko kerusakan hepar. Walaupun total sitokrom P-450 berkurang,

beberapa orang mungkin terpengaruh lebih dari yang lainnya. Modifikasi dosis pada

penderita penyakit hati harus berdasarkan pengetahuan mengenai enzim spesifik yang

terlibat dalam metabolisme. Pasien dengan infeksi HIV dan Hepatitis B atau C, resiko

efek hepatotoksik meningkat jika diberikan terapi antiretroviral. Pasien dengan sirosis

juga resikonya meningkat terhadap dekompensasi pada obat

f. Faktor genetik : gen unik mengkode tiap protein P-450. Perbedaan genetik pada enzim

P-450 menyebabkan reksi abnormal terhadap obat, termasuk reaksi idiosinkratik.

Debrisoquine merupakan obat antiaritmia yang menyebabkan rendahnya metabolisme

karena ekspresi dari P-450-II-D6. Hal ini dapat diidentifikasi dengan amplifikasi PCR

dari gen mutasi.

g. Penyakit lain : seseorang dengan AIDS, malnutrisi, dan puasa lebih rentan terhadap

reaksi obat karena rendahnya simpanan glutation

h. Formulasi obat : obat-obatan long-acting lebih menyebabkan kerusakan hepar

dibandingkan dengan obat-obatan short-acting

5. Manifestasi Klinis

Gambaran klinis hepatotoksisitas karena obat sulit dibedakan secara klinis dengan

penyakit hepatitis atau kolestasis dengan etiologi lain. Riwayat pemakaian obat-obatan atau

substansi hepatotoksik lain harus dapat diungkap. Onset umumnya cepat, gejala berupa

malaise dan ikterus, serta dapat terjadi gagal hati akut berat terutama bila pasien masih

meminum obat tesebut setelah awitan hepatotoksisitas. Apabila jejas hepatosit lebih

dominan maka konsentrasi aminotransferase dapat meningkat hingga paling tidak lima kali

batas atas normal, sedangkan kenaikan konsentrasi alkali fosfatase dan bilirubin menonjol

pada kolestasis. Mayoritas reaksi obat idiosikratik melibatkan kerusakan hepatosit seluruh

lobul hepatik dengan derajat nekrosis dan apoptosis bervariasi. Pada kasus ini gejala

hepatitis biasanya muncul dalam beberapa hari atau minggu sejak mulai minum obat dan

mungkin terus berkembang bahkan sesudah obat penyebab dihentikan pemakaiannya.

Tabel 1. Reaksi Obat dan Sel yang Dipengaruhinya

6. Diagnosis

Berdasarkan international concensus criteria maka diagnosis hepatotoksisitas karena

obat berdasarkan :

- waktu dari mulai minum obat dan penghentian obat sampai awitan reaksi nyata adalah

sugestif (5-90 hari dari awal minum obat) atau kompatibel (kurang dari lima hari atau

lebih dari 90 hari sejak mulai minum obat dan tidak lebih 15 hari dari penghentian

obat untuk reaksi hepatoseluler dan tidak lebih dari 30 hari dari penghentian obat

untuk reaksi kolestatik) dengan hepatotoksisitas obat.

- Perjalanan reaksi sesudah penghentian obat adalah sangat sugestif (penurunan enzim

hati paling tidak 50% dari konsentrasi di atas batas atas normal dalam 8 hari) atau

sugestif (penurunan enzim hati paling tidak 50% dari konsentrasi di atas batas atas

normal dalam 30 hari untuk reaksi hepatoseluler dan 180 hari untuk reaksi kolestatik)

dari reaksi obat.

- Alternatif sebab lain telah dieksklusi dengan pemeriksaan teliti, termasuk biopsi hati

tiap kasus.

- Dijumpai respons positif pada pemaparan ulang dengan obat yang sama paling tidak

kenaikan dua kali lipat enzim hati.

Dikatakan reaksi drugs related jika semua ketiga kriteria terpenuhi atau jika dua dari

tiga kriteria pertama terpenuhi dengan respons positif pada pemaparan ulang obat.

Mengidentifikasi reaksi obat dengan pasti adalah hal yang sulit tetapi kemungkinan

sekecil apapun adanya reaksi terhadap obat harus dipertimbangkan pada setiap pasien

dengan disfungsi hati. Riwayat pemakaian obat harus diungkap dengan seksama termasuk di

dalamnya obat herbal atau obat alternatif lainnya. Obat harus selalu menjadi diagnosis

banding pada setiap abnormalitas tes fungsi hati dan/atau histologi. Keterlambatan

penghentian obat yang menjadi penyebab berhubungan dengan resiko tinggi kerusakan hati

persisten. Bukti bahwa pasien tidak sakit sebelum minum obat, menjadi sakit selama minum

obat dan membaik secara nyata setelah penghentian obat merupakan hal esensial dalam

diagnosis hepatotoksisitas karena obat.

Tabel 2. Kerusakan Hepar dan Penyebabnya

7. Hepatotoksisitas obat anti tuberkulosis (OAT)

Obat anti tuberculosis terdiri dari isoniazid, rifampisin, pirazinamid, dan

etambutol/streptomisin, dan tiga obat yang disebut pertama bersifat hepatotoksik. Faktor-

faktor resiko hepatotoksisitas yang pernah dilaporkan adalah usia lanjut, pasien perempuan,

status nutrisi buruk, konsumsi tinggi alkohol, memiliki dasar penyakit hati, karier hepatitis

B, prevalensi hepatitis viral yang meningkat di negara sedang berkembang,

hipoalbuminemia, tuberculosis lanjut, serta pemakaian obat yang tidak sesuai aturan dan

status asetilatornya. Telah dibuktikan secara meyakinkan adanya keterkaitan HLA-DR2

dengan tuberkulosis paru pada berbagai populasi dan keterkaitan varian gen NRAMP1

dengan kerentanan terhadap tuberkulosis, sedangkan resiko hepatotoksisitas karena obat anti

tuberkulosis berkaitan juga dengan tidak adanya HLA-DQA1*0102 dan adanya HLA-

DQB1*0201 disamping usia lanjut, albumin serum < 3,5 gram/dl dan tingkat penyakit yang

moderat atau tingkat lanjut berat. Dengan demikian resiko hepatotoksisitas pada pasien

dengan obat anti tuberkulosis dipengaruhi faktor-faktor klinis dan genetik. Pada pasien TBC

dengan hepatitis C atau HIV mempunyai resiko hepatotoksisitas terhadap obat anti

tuberkulosis lima dan empat kali lipat. Sementara pasien tuberkulosis dengan karier HbsAg-

positif dan HbeAg-negatif yang inaktif dapat diberikan obat standar jangka pendek INH,

rifampisin, etambutol dan/atau pirazinamid dengan syarat pengawasan tes fungsi hati paling

tidak dilakukan setiap bulan. Sekitar 10% pasien tuberkulosis yang mendapatkan isoniazid

mengalami kenaikan konsentrasi aminotransferase serum dalam minggu-minggu pertama

terapi yang nampaknya menunjukkan respons adaptif terhadap metabolit toksik obat.

Isoniazid dilanjutkan atau tidak tetap akan terjadi penurunan konsentrasi aminotransferase

sampai batas normal dalam beberapa minggu. Hanya sekitar 1% yang berkembang menjadi

seperti hepatitis viral; 50% kasus terjadi pada 2 bulan pertama dan sisanya baru muncul

beberapa bulan kemudian.

8. Hepatotoksisitas obat kemoterapi

Jejas hati yang timbul selama kemoterapi kanker tidak selalu disebabkan oleh

kemoterapi itu sendiri. Klinisi harus memperhatikan faktor-faktor lain seperti reaksi obat

terhadap antibiotik, analgesik, antiemetik, atau obat lainnya. Problem-problem medis yang

sudah ada sebelumnya, tumor, imunosupresi, virus hepatitis dan infeksi lain, serta defisiensi

nutrisi atau nutrisi parenteral total, semuanya mungkin mempengaruhi kerentanan hospes

terhadap terjadinya jejas hati. Sebagian besar reaksi hepatotoksisitas obat bersifat

idiosinkratik, melalui mekanisme imunologik atau variasi pada respons metabolik pejamu.

Siklofosfamid, suatu alkylating agent, diubah oleh sistem sitokrom P-450 di hati menjadi 4-

hydroxycyclophosphamide. Meskipun mengalami metabolism di hati, siklofosfamid dapat

diberikan pada keadaan enzim hati dan/atau bilirubin yang meningkat. Melfalan dengan

cepat dihidrolisis dalam plasma dan sekitar 15% diekskresi tanpa perubahan dalam urin.

Pada dosis yang dianjurkan tidak bersifat hepatotoksisitas, hanya menimbulkan abnormalitas

tes fungsi hati sementara pada dosis tinggi pada transplantasi sumsum tulang otology.

Klorambusil berhubungan dengan kerusakan hati. Busulfan, kelas alkilsulfonat, cepat hilang

dari darah dan diekskresikan lewat urin. Metabolisme lewat hati tidak begitu penting

sehingga pada dosis standar tidak menimbulkan hepatotoksisitas. Cytosine Arabinoside

(Ara-C) efek hepatotoksisitasnya belum jelas. 5-FU tidak menimbulkan kerusakan hati bila

diberikan secara per oral dan jarang dilaporkan menimbulkan hepatotoksisitas pada

pemberian intravena. Akan tetapi berbeda bila diberikan secara intraarterial dengan pompa

infuse untuk terapi metastasis hepar karena kanker kolorektal dimana terjadi hepatotoksisitas

berupa jejas hepatoseluler dengan peningkatan aminotransferase, alkali fosfatase, dan

bilirubin serum, atau terjadinya striktur duktus biliaris intrahepatik atau ekstrahepatik

dengan peningkatan bilirubin dan alkali fosfatase. 6-mercaptopurine (6-MP) bersifat

hepatotoksik terutama bila dosis melebihi dosis yang biasa digunakan (dosis dewasa 2

mg/kg) dan dapat berupa hepatoseluler atau kolestatik. Perbedaan rute obat oral atau

parenteral tidak mengubah sifat hepatotoksisitasnya. Azatioprin (AZ) memiliki sifat

hepatotoksisitas meskipun jarang terjadi. Hepatotoksisitas berupa peningkatan konsentrasi

bilirubin serum dan alkali fosfatase dengan peningkatan sedang konsentrasi

aminotransferase dan secara histologik berupa kolestasis dengan nekrosis parenkim hati

yang bervariasi. 6-thioguanine dikenal menyebabkan penyakit oklusi vena. Metotreksat

(MTX) pada dosis standar diekskresi tanpa perubahan melalui urin. Pada dosis tinggi

sebagian dimetabolisir oleh hati menjadi 7-hydroxymethotrexate. Pada terapi rumatan

leukemia akut anak-anak, metotreksat dapat menimbulkan fibrosis dan sirosis hati. Pada

pemakaian dosis tinggi, MTX meningkatkan aminotransferase dan lactate dehydrogenase

(LDH). Pasien arthritis rematoid atau psoriasis dengan MTX dosis kumulatif kurang dari 2

gram mempunyai insidens hepatotoksisitas yang rendah meskipun durasi terapinya lama, 24-

48 bulan. Dengan demikian pemakaian MTX dosis rendah jangka panjang dapat

menimbulkan fibrosis/sirosis, sementara dosis tinggi menyebabkan perubahan tes fungsi

hati. Gemcitabine sering menyebabkan kenaikan transaminase sementara tetapi tidak

bermakna. Mitoksantron mempunyai insidens toksisitas serius lebih rendah dibandingkan

obat-obat kanker antrasiklin yang lain, dan hanya menimbulkan kenaikan konsentrasi AST

dan ALT sementara saja. Insidensi disfungsi hati karena pemakaian bleomycin sangat

rendah. Hepatotoksisitas mitomysin belum jelas, tetapi ditemukan dalam konsentrasi tinggi

dalam empedu. Paclitaxel dan docetaxel sebagian besar diekskresi melalui hati dan perlu

hati-hati pada pasien dengan gangguan fungsi hati. Etoposide tidak menimbulkan

hepatotoksisitas pada dosis standar meskipun diekskresikan terutama dalam empedu.

Cisplatin jarang menyebabkan hepatotoksisitas pada dosis standar tetapi kadang-kadang

dijumpai kenaikan AST. Pada dosis tinggi cisplatin menimbulkan kenaikan AST dan ALT.

Procarbazine dikenal dapat menyebabkan hepatitis granulomatosa. Hydroxyurea dapat

menimbulkan toksisitas hati dan pernah dilaporkan sebagai penyebab peliosis hepatis.

9. Hepatotoksisitas obat anti inflamasi non steroid

Obat anti inflamasi nonsteroid (OAINS) merupakan salah satu obat yang sering

diresepkan meskipun penggunaannya tidak selalu tepat sasaran. Resiko epidemiologik

hepatotoksisitas golongan obat ini rendah (1-8 kasus per 100.000 pasien pengguna OAINS).

Hepatotoksisitas karena OAINS dapat terjadi kapan saja setelah obat diminum, tetapi efek

samping berat sangat sering terjadi dalam 6-12 minggu dari awal pengobatan. Ada dua pola

klinis utama hepatotoksisitas karena OAINS. Pertama, adalah hepatitis akut dengan ikterus,

demam, mual, transaminase naik sangat tinggi, dan kadang-kadang dijumpai eosinofilia.

Pola yang lain adalah dengan gambaran serologik (Anti Nuclear Factor – positif) dan

histologik (inflamasi periportal dengan infiltrasi plasma dan limfosit serta fibrosis yang

meluas ke dalam lobul hepatik) dari hepatitis kronik aktif. Tes fungsi hati dapat kembali

normal dalam 4-8 minggu sejak penghentian obat penyebab. Dua mekanisme utama

bertanggungjawab atas jejas hati oleh OAINS, yaitu hipersensitivitas dan aberasi metabolik.

Meskipun masih perlu diteliti lebih lanjut, faktor-faktor resiko hepatotoksisitas idiosinkratik

karena OAINS meliputi perempuan, umur >50 tahun, dan penyakit autoimun yang

mendasari. Faktor resiko lain adalah paparan obat lain yang juga bersifat hepatotoksik pada

saat bersamaan. Reaksi hipersensitivitas sering mengalami titer anti-nuclear factor atau

antibodi anti smooth-muscle yang bermakna, limfadenopati, dan eosinofilia. Aberasi

metabolik dapat terjadi karena polimorfisisme genetic yang dapat mengubah kerentanan

terhadap bermacam-macam obat. Pasien yang mengalami hepatotoksisitas karena OAINS

harus dianjurkan untuk tidak minum OAINS lagi selamanya. Parasetamol merupakan obat

pilihan untuk analgesic sedangkan aspirin dapat digunakan sebagai pengganti OAINS,

karena toksisitas OAINS berhubungan dengan struktur molekul cincin diphenylamine yang

tidak dimiliki aspirin.

10. Pengobatan Reaksi Obat

Kecuali penggunaan N-acetylcysteine untuk keracunan asetaminofen (parasetamol),

tidak ada antidotum spesifik terhadap setiap obat. Terapi efek hepatotoksik obat terdiri dari

penghentian segera obat-obatan yang dicurigai. Jika dijumpai reaksi alergi berat dapat

diberikan kortikosteroid, meskipun belum ada bukti penelitian klinis dengan kontrol.

Demikian juga penggunaan ursodiol pada keadaan kolestatik. Pada obat-obatan tertentu

seperti amoksisilin, asam klavulanat dan fenitoin berhubungan dengan sindrom dimana

kondisi pasien memburuk dalam beberapa minggu sesudah pengobatan dihentikan dan perlu

waktu berbulan-bulan untuk pulih seperti sedia kala. Prognosis gagal hati akut karena reaksi

idiosinkratik obat buruk, dengan angka mortalitas lebih dari 80%.