MEDICAL EMERGENCY ON PARACETAMOL POISONING

INTRODUCTIONParacetamol , also known as

acetaminophen or APAP (N- acetyl-p-aminophenol)

It is a deethylated active metabolite of phenacetin discovered in 1877 , which was used as an analgesic and antipyretic and is banned now because of its analgesic abuse nephropathy.

In 1893, was first discovered in the urine of individuals who had taken Phenacetin.

In 1950, Paracetamol tablets were in introduced in UK.

By 1963, Paracetamol was available worldwide as an over the counter drug.

ACTIONSTo date mechanism of action is not completely understood.The main mechanism proposed is the inhibition of

cyclooxygenase(COX) and recent findings suggest that it is highly selective for COX-2.

By inhibition of COX it prevents generation of prostaglandins from arachidonic acid, which are inturn converted to numerous other proinflammatory mediators.

Poor inhibitor of prostaglandin synthesis in the peripheral tissues but a potent COX inhibitor in the brain.

By Central subcortical action raising the pain threshold it raises pain threshold – Acts as an analgesic

Good and promptly acting anti pyretic by reducing PGE2 in CNS and thus lowering hypothalamic set point in the thermoregulatory centre

has negligible antiinflammatory action - inability to inhibit COX in the presence of peroxides which are generated at sites of inflammation, but are not present in the brain.Good and promptly acting anti pyretic

The ability of paracetamol to inhibit COX-3 could also account for its analgesic-antipyretic action.

does not stimulate respiration or affect acid-base balance;

does not increase cellular metabolism.does not affect platelet function or clotting factors

and is not uricosuric.Plasma t½ is 2–3 hours. Effects after an oral dose

last for 3–5 hours.

Paracetamol CombinationsAvailable as IR(immediate release) – 325mg

and 500mg doses , ER(extended release) – 650mg

Formulations and preparations – Elixirs, suspensions, tablets(meltable and chewable), capsules, rectal suppositories

Combinations – Opioids - codein, tramadol, etc..NSAIDS – Mephanamic acid,

MECHANISM OF TOXICITYA small proportion of acetaminophen is metabolized

by a phase I reaction to a hepatotoxic metabolite formed from the parent compound by the cytochrome P450 CYP2E1. This metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), is detoxified by binding to “hepatoprotective” glutathione to become harmless, water-soluble mercapturic acid, which undergoes renal excretion.

When excessive amounts of NAPQI are formed, or when glutathione levels are low, glutathione levels are depleted and overwhelmed, permitting covalent binding to nucleophilic hepatocyte macromolecules forming acetaminophen-protein “adducts.”

The binding of acetaminophen to hepatocyte macromolecules is believed to lead to centrilobular hepatic necrosis

Even in the absence of hepatotoxicity, renal failure can occur because of renal papillary necrosis.

Large doses act on brain stem and cause rapid death.

NORMAL LIVERCENTRILOBULAR NECROSIS

CLINICAL FEATURESPhase I (0-24 h) Anorexia, nausea, vomitingPhase II (24-72 h) Right upper quadrant

pain, elevated liver enzymes, PT and INR may be elevated

Phase III (72-96 h) Vomiting, symptoms of liver failure, renal failure and pancreatitis may occur

Phase IV (>4 days) Resolution of symptoms or progression to fatality

Acetaminophen causes dose-related centrilobular hepatic necrosis after single-time-point ingestions, as intentional selfharm, or over extended periods, as unintentional overdoses, when multiple drug preparations or inappropriate drug amounts are used daily for several days, e.g., for relief of pain or fever.

In these instances,8 g/d, twice the daily recommended maximum dose, over several days can readily lead to liver failure.

Use of opioid-acetaminophen combinations appears to be particularly harmful, because habituation to the opioid may occur with a gradual increase in opioid-acetaminophen combination dosing over days or weeks.

A single dose of 10–15 g, occasionally less, may produce clinical evidence of liver injury.

Fatal fulminant disease is usually (although not invariably) associated with ingestion of ≥25 g.

Minimum toxic doses for single ingestionAdults – 7.5-10 gChildren – 150mg/kg:200mg/kg in healthy

children aged 1-6 years.

Fatal dose : 20-25 g

Fatal period : 2 to 4 days

INVESTIGATIONSSerum acetaminophen concentrationLiver function tests – ALT, AST, Bilirubin(Direct and

indirect), alkaline phosphataseProthromin time with International normalised ratioRBSRenal function tests(electrolytes, BUN, creatinine)Lipase and amylase(c/o abdominal pain)Arterial blood gas analysis and ammoniaUrinanalysis( for hematuria and proteinuria)ECG(to detect additional clues for co-ingestants)CT brain(if altered mental status)

Blood levels of acetaminophen correlate with severityof hepatic injury (levels >300 μg/mL 4 h after ingestion are predictive of the development of severe damage; levels <150 μg/mL suggest that hepatic injury is highly unlikely).

Whether or not a clear history of overdose can be elicited, clinical suspicion of acetaminophen hepatotoxicity should be raised by the presence of the extremely high aminotransferase levels in association with low bilirubin levels that are characteristic of this hyperacute injury

FACTORS THAT ALTER RISK Induced P450 : chronic alcohol,

barbiturates, phenobarbital, isoniazid,Glutathione depletion: chronic

ingestion paracetamol, malnutrition, starvation, alcohol

Hepatitis C virus(HCV) infection was found to be associated with an increased risk of acute liver injury in patients hospitalized for acetaminophen overdose

Therefore, in chronic alcoholics, the toxic dose of acetaminophen may be as low as 2 g, and alcoholic patients should be warned specifically about the dangers of even standard doses of this commonly used drug.

ManagementAs there are no early symptoms that

predict acetaminophen toxicity, poisoning severity following an acute ingestion is quantified by plotting a timed serum acetaminophen concentration on the modified Rumack-Matthew nomogram, drawn no less than 4 hours after ingestion, serves as a guide for management.

Rumack-Matthew nomogramRumack-Matthew nomogram (the acetaminophen

toxicity nomogram or acetaminophen nomogram), is used to interpret serum acetaminophen concentrations in relation to time since ingestion, in order to assess potential hepatotoxicity.

The nomogram predicts the risk of hepatotoxicity on a single acetaminophen concentraion, measured at one time. It is not a prognostic tool and, hence, does not predict fulminant hepatic failure or death.

The nomogram predicts potential toxicity beginning at 4 hours after ingestion up to 24 hours after ingestion. Acetaminophen concentraions measured earlier than 4 hours post-ingestion may not be reliable. Concentrations measured 4-18 hours post-ingestion are most reliable.

The upper line of the nomogram is the “probable” line, also known as the Rumack-Matthew line. About 60% of patients with values above this line develop hepatotoxicity. The lower line on the nomogram is the “possible” line, which was subsequently added later per request of the U.S. FDA. The possible line, also known as the “treatment” line, incorporates a 25% margin of error in measurement variations or uncertainty regarding the time of ingestion.

The nomogram cannot be used if the patient presents more than 24 hours after ingestion or has a history of multiple acetaminophen ingestions. Its reliability decreases for ingestions of extended-release acetaminophen formulations or for co-ingestions of acetaminophen with agents that delay gastric emptying and acetaminophen absorption (e.g.anticholinergics or opioids).

Treatment includes gastric lavage, supportive measures, and oral administration of activated charcoal or cholestyramine to prevent absorption of residual drug.

Treatment with activated charcoal (AC), 1 g/kg (maximum dose 50 g) by mouth in all patients who present within four hours of a known or suspected acetaminophen ingestion, unless there are contraindications to its administration like sedated patients not on endotracheal tube and those presenting after 4 hours of overdose.

Studies have shown that induced emesis and gastric lavage limit the absorption of acetaminophen after simulated overdose and in clinical trials However, these therapies appear to be less effective than activated charcoal, so they are not routinely recommended.

ANTIDOTE: N-ACETYLCYSTEINEN-acetylcysteine is the accepted antidote for

acetaminophen poisoning and is given to all patients at significant risk for hepatotoxicity. Serious hepatotoxicity is uncommon and death extremely rare if N-acetylcysteine is administered within eight hours following acetaminophen overdose.

The key to effective treatment is to start therapy before the onset of liver injury, which can be defined biochemically by an elevation of the alanine aminotransferase (ALT).

In patients with high acetaminophen blood levels (>200 μg/mL measured at 4 h or >100 μg/mL at 8 h after ingestion), the administration of N-acetylcysteine reduces the severity of hepatic necrosis

In addition, when N-acetylcysteine is administered late following acetaminophen ingestion to patients with evidence of hepatic failure, it decreases mortality and improves hepatic and cerebral function

This agent provides sulfhydryl donor groups to replete glutathione,which is required to render harmless toxic metabolites that would otherwise bind covalently via sulfhydryl linkages to cell proteins,resulting in the formation of drug metabolite-protein adducts.

Indications for N-acetylcysteine therapy Serum acetaminophen concentration drawn at four hours or

more following acute ingestion of an immediate-release preparation is above the "treatment" line of the treatment nomogram for acetaminophen poisoning

A suspected single ingestion of greater than 150 mg/kg (7.5 g total dose regardless of weight) in a patient for whom the serum acetaminophen concentration will not be available until more than eight hours from the time of the ingestion.

Patient with an unknown time of ingestion and a serum acetaminophen concentration >10 mcg/mL (66 µmol/L).

Patient with a history of ingestion and evidence of ANY liver injury.

Patients with delayed presentation (>24 hours after ingestion) consisting of laboratory evidence of liver injury (ranging from mildly elevated aminotransferases to fulminant hepatic failure) and a history of excessive acetaminophen ingestion.

Common protocols 20 hour IV protocol — The 20 hour intravenous

(IV) protocol for N-acetylcysteine treatment has been used in the United Kingdom since the 1970s.

The approved 20 hour IV dosing regime is complicated and is performed as follows:

150 mg/kg in 200 mL of D5W infused over 1 hour, followed by 50 mg/kg in 500 mL of D5 W over 4 hours and then 100 mg/kg in 1000 mL of D5W over 16 hours

This treatment protocol provides a total of 300 mg/kg over 20 to 21 hours

72 hour oral protocol — The 72 hour oral (PO) dosing protocol for N-acetylcysteine treatment has been used successfully in the United States for more than 30 years, and consists of the following:

A loading dose of 140 mg/kg PO, followed byA dose of 70 mg/kg PO every four hours for a total of

17 dosesThe dose does not need to be adjusted if the patient

has been treated with activated charcoal.The incidence of hepatotoxicity for patients treated

within eight hours of ingestion is less than 10 percent, but increases to approximately 40 percent if treatment is delayed beyond 16 hours.

Other protocols A 12-hour protocol for N-acetylcysteine treatment - involves the

administration of 100 mg/kg of N-acetylcysteine over two hours as a loading dose, and then administration of 200 mg/kg over 10 hours

Intermittent IV infusion may be considered for late-presenting or chronic ingestion. A loading dose of 140 mg/kg IV (diluted in 500 mL D5W) is infused over 1 h. Maintenance doses of 70 mg/kg IV are given every 4 hours for at least 12 doses (dilute each dose in 250 mL of D5W and infuse over a minimum of 1 hour).

— Current dosing protocols for N-acetylcysteine in the United States are calculated using patient bodyweight. However, the maximum dose is based upon a weight of 100 kg for IV therapy and 110 kg for oral therapy

Clinicians often based dosing on actual weight with a low rate of adverse events .

In most patients, either the oral or IV route is acceptable. IV administration is favored for patients with any of the following:

VomitingContraindications to oral administration

(ie,pancreatitis,bowel ileus or obstruction, bowel injury)

Hepatic failurePatients who refuse oral administrationPatients with evidence of hepatic failure

NAC adverse effects‘Non-IgE mediated anaphylaxis (previously

called anaphylactoid reactions) with intravenous administration and vomiting with oral administration are the most common adverse reactions associated with N-acetylcysteine administration.

Like urticaria, flushing, angio oedema, wheezing , hypotension etc..

Patients receiving IV N-acetylcysteine warrant close monitoring and all essential medications and tools needed to treat anaphylaxis and airway emergencies should be immediately available. These include oxygen, antihistamine medication (eg, diphenhydramine and ranitidine), albuterol, epinephrine (1:1000 for intramuscular use), glucocorticoid medication (eg, methylprednisolone), a resuscitation cart, and emergency airway management equipment.

with oral N-acetylcysteine develop nausea and vomiting. Serotonin 5-HT3 receptor antagonists (eg, ondansetron) are useful antiemetics. If the patient vomits within 60 minutes of an oral dose of N-acetylcysteine, the dose of N-acetylcysteine should be repeated.

MethionineAn alternative antidote is methionine 2.5 g

orally (adult dose) every 4 hours to a total of 4 doses upto a total of 10 grams orally, but this is less effective, especially after delayed presentation.

Do not give activated charcoal as it will bind methionine.

It acts by increasing glutathione synthesis.

DELAYED PRESENTATIONIf patient presents 8-24 hours or later after

an acute ingestion, initiate therapy immediately and evaluate for laboratory evidence of hepatatoxicity.

NAC administration in such cases has decreased incidence of cerebral oedema and improved survival.

Proposed mechanism in this setting include an antioxidant effect, decreased neutrophil accumulation and improved microcirculatory blood flow supporting increased oxygen delivery to hepatic tissue.

Chronic IngestionIf a patient presents after multiple

ingestions or chronic ingestion of supratherapeutic doses of acetaminophen over hours or days, evaluate for the presence of a persistent serum APAP concentration and laboratory indicators of hepatotoxicity. Begin NAC therapy if the patient has elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels or a measurable serum APAP concentration.

Extended-Release Acetaminophen Overdose

Extended-release acetaminophen consists of acetaminophen 325 mg in immediate release (IR) form surrounding a matrix of acetaminophen 325 mg formulated for slow release. Some alteration of the elimination kinetics of this preparation may affect the reliability of the Rumack-Matthew nomogram to predict potential hepatotoxicity and subsequent treatment based on serum APAP concentrations.

Several studies show that the elimination of ER and IR APAP preparations is nearly identical after 4 hours. However, some case reports have documented APAP levels that are above the potential toxicity and treatment line on the nomogram as late as 11-14 hours after the ingestion of the ER preparation.

Extended-Release Acetaminophen Overdose

Given these findings, recommended management for overdose of ER preparations includes the measurement of 4-, 6-, and 8-hour APAP concentrations. Begin NAC therapy if any level crosses above the nomogram treatment line. If the 6-hour level is greater than the 4-hour level, begin NAC therapy.

More prolonged monitoring of APAP levels may be necessary if the patient has food in his or her stomach or has taken co-ingestants that delay gastric emptying.

LIVER TRANSPLANTATIONIf signs of hepatic failure (e.g., progressive jaundice,

coagulopathy, confusion) occur despite N-acetylcysteine therapy for acetaminophen hepatotoxicity, liver transplantation may be the only option.

The United Kingdom King's College Hospital criteria for the determination of the urgent need for transplantation after acetaminophen-induced fulminant hepatic failure include any one of the following:

Arterial pH less than 7.3 after fluid resuscitation(lactate levels >3.5 mmol/L)

Grade III or IV encephalopathy Prothrombin time (PT) greater than 100 seconds Serum creatinine level greater than 3.4 mg/dL

CONCLUSIONBecause of the limited safety margin between safe

and toxic doses, the FDA has recommended that the daily dose of acetaminophen be reduced from 4 g to 3 g (even lower for persons with chronic alcohol use), that all acetaminophen-containing products be labeled prominently as containing acetaminophen, and that the potential for liver injury be prominent in the packaging of acetaminophen and acetaminophen-containing products.

Within opioid combination products, the limit for the acetaminophen component has been lowered to 325 mg per tablet

ReferencesHarrison 19/eDavidson 22/eAPI 10/ewww.medscape.inwww.uptodate.inThe essential of forensic medicine and

toxicology by K. Narayan reddyThe essentials of medical theraupetics by

KD tripathi