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MEDICAL EMERGENCY ON
PARACETAMOL POISONING
INTRODUCTION
 Paracetamol , also known as acetaminophen or
APAP (N- acetyl-p-aminophenol)
 It is a deethylated active me...
ACTIONS
 To date mechanism of action is not completely
understood.
 The main mechanism proposed is the inhibition of
cyc...
 has negligible antiinflammatory action - inability
to inhibit COX in the presence of peroxides which
are generated at si...
Paracetamol Combinations
 Available as IR(immediate release) – 325mg and
500mg doses , ER(extended release) – 650mg
 For...
MECHANISM OF TOXICITY
 A small proportion of acetaminophen is
metabolized by a phase I reaction to a
hepatotoxic metaboli...
 The binding of acetaminophen to hepatocyte
macromolecules is believed to lead to
centrilobular hepatic necrosis
 Even i...
NORMAL LIVER
CENTRILOBULAR
NECROSIS
CLINICAL FEATURES
 Phase I (0-24 h) Anorexia, nausea, vomiting
 Phase II (24-72 h) Right upper quadrant pain,
elevated l...
 Acetaminophen causes dose-related centrilobular
hepatic necrosis after single-time-point ingestions, as
intentional self...
Minimum toxic doses for single ingestion
 Adults – 7.5-10 g
 Children – 150mg/kg:200mg/kg in healthy
children aged 1-6 y...
INVESTIGATIONS
 Serum acetaminophen concentration
 Liver function tests – ALT, AST, Bilirubin(Direct and
indirect), alka...
 Blood levels of acetaminophen correlate with
severityof hepatic injury (levels >300 μg/mL 4 h
after ingestion are predic...
FACTORS THAT ALTER RISK
 Induced P450 : chronic alcohol,
barbiturates, phenobarbital, isoniazid,
 Glutathione depletion:...
 Therefore, in chronic alcoholics, the
toxic dose of acetaminophen may be as
low as 2 g, and alcoholic patients should
be...
Management
 As there are no early symptoms that predict
acetaminophen toxicity, poisoning severity
following an acute ing...
Rumack-Matthew nomogram
 Rumack-Matthew nomogram (the acetaminophen
toxicity nomogram or acetaminophen nomogram), is
used...
 The upper line of the nomogram is the “probable”
line, also known as the Rumack-Matthew line. About
60% of patients with...
 Treatment includes gastric lavage, supportive
measures, and oral administration of activated
charcoal or cholestyramine ...
ANTIDOTE: N-
ACETYLCYSTEINE
 N-acetylcysteine is the accepted antidote for
acetaminophen poisoning and is given to all pa...
 In addition, when N-acetylcysteine is
administered late following acetaminophen
ingestion to patients with evidence of h...
Indications for N-acetylcysteine
therapy
 Serum acetaminophen concentration drawn at four hours
or more following acute i...
Common protocols
 20 hour IV protocol — The 20 hour intravenous
(IV) protocol for N-acetylcysteine treatment has
been use...
 72 hour oral protocol — The 72 hour oral (PO) dosing
protocol for N-acetylcysteine treatment has been used
successfully ...
Other protocols
 A 12-hour protocol for N-acetylcysteine treatment -
involves the administration of 100 mg/kg of N-
acety...
 In most patients, either the oral or IV route is
acceptable. IV administration is favored for
patients with any of the f...
NAC adverse effects
 ‘Non-IgE mediated anaphylaxis (previously called
anaphylactoid reactions) with intravenous
administr...
 with oral N-acetylcysteine develop nausea and
vomiting. Serotonin 5-HT3 receptor antagonists
(eg, ondansetron) are usefu...
Methionine
 An alternative antidote is methionine 2.5 g orally
(adult dose) every 4 hours to a total of 4 doses
upto a to...
DELAYED PRESENTATION
 If patient presents 8-24 hours or later after an
acute ingestion, initiate therapy immediately and
...
Chronic Ingestion
 If a patient presents after multiple ingestions or
chronic ingestion of supratherapeutic doses of
acet...
Extended-Release Acetaminophen
Overdose
 Extended-release acetaminophen consists of
acetaminophen 325 mg in immediate rel...
Extended-Release Acetaminophen
Overdose
 Given these findings, recommended
management for overdose of ER preparations
inc...
LIVER TRANSPLANTATION
 If signs of hepatic failure (e.g., progressive jaundice,
coagulopathy, confusion) occur despite N-...
CONCLUSION
 Because of the limited safety margin between
safe and toxic doses, the FDA has recommended
that the daily dos...
References
 Harrison 19/e
 Davidson 22/e
 API 10/e
 www.medscape.in
 www.uptodate.in
 The essential of forensic medi...
Medical emergency on paracetamol poisoning
Medical emergency on paracetamol poisoning
Medical emergency on paracetamol poisoning
Medical emergency on paracetamol poisoning
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Medical emergency on paracetamol poisoning

  1. 1. MEDICAL EMERGENCY ON PARACETAMOL POISONING
  2. 2. INTRODUCTION  Paracetamol , 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
  3. 3. ACTIONS  To 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
  4. 4.  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.
  5. 5. Paracetamol Combinations  Available 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,
  6. 6. MECHANISM OF TOXICITY  A 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.”
  7. 7.  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.
  8. 8. NORMAL LIVER CENTRILOBULAR NECROSIS
  9. 9. CLINICAL FEATURES  Phase I (0-24 h) Anorexia, nausea, vomiting  Phase 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
  10. 10.  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
  11. 11. Minimum toxic doses for single ingestion  Adults – 7.5-10 g  Children – 150mg/kg:200mg/kg in healthy children aged 1-6 years. Fatal dose : 20-25 g Fatal period : 2 to 4 days
  12. 12. INVESTIGATIONS  Serum acetaminophen concentration  Liver function tests – ALT, AST, Bilirubin(Direct and indirect), alkaline phosphatase  Prothromin time with International normalised ratio  RBS  Renal function tests(electrolytes, BUN, creatinine)  Lipase and amylase(c/o abdominal pain)  Arterial blood gas analysis and ammonia  Urinanalysis( for hematuria and proteinuria)  ECG(to detect additional clues for co-ingestants)  CT brain(if altered mental status)
  13. 13.  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
  14. 14. 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
  15. 15.  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.
  16. 16. Management  As 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.
  17. 17. Rumack-Matthew nomogram  Rumack-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
  18. 18.  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).
  19. 19.  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
  20. 20. ANTIDOTE: N- ACETYLCYSTEINE  N-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
  21. 21.  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.
  22. 22. 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
  23. 23. 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
  24. 24.  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 by  A dose of 70 mg/kg PO every four hours for a total of 17 doses  The 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.
  25. 25. 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 .
  26. 26.  In most patients, either the oral or IV route is acceptable. IV administration is favored for patients with any of the following:  Vomiting  Contraindications to oral administration (ie,pancreatitis,bowel ileus or obstruction, bowel injury)  Hepatic failure  Patients who refuse oral administration  Patients with evidence of hepatic failure
  27. 27. 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),
  28. 28.  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.
  29. 29. Methionine  An 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.
  30. 30. DELAYED PRESENTATION  If 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.
  31. 31. Chronic Ingestion  If 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.
  32. 32. 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
  33. 33. 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.
  34. 34. LIVER TRANSPLANTATION  If 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
  35. 35. CONCLUSION  Because 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
  36. 36. References  Harrison 19/e  Davidson 22/e  API 10/e  www.medscape.in  www.uptodate.in  The essential of forensic medicine and toxicology by K. Narayan reddy  The essentials of medical theraupetics by KD tripathi
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