Acetaminophen poisoning
INTRODUCTION
Acetaminophen, also known as paracetamol, a popular and widely
available over-the-counter analgesic, is a frequently reported medicinal
agent associated with toxic ingestions. Injury to the liver following the
ingestion of acetaminophen is the most common cause of serious
morbidity and of death, although organ systems other than the liver may
also be affected.
MECHANISM OF POISONING
Acetaminophen is metabolized almost exclusively in the liver. More
than 90% is directly converted to nontoxic glucuronide and sulfate
conjugates and less than 5 % is excreted unchanged in the urine. The rest
(approximately 5 %) is oxidized by various cytochrome P-450 enzymes,
producing the reactive electrophile N-acetyl-p-benzoquinoneimine
(NAPQI) .Normally, NAPQI combines immediately with glutathione to
form a nontoxic mercaptide conjugate. Cytochrome P-450 enzymes are
also found in the kidney, and some NAPQI is formed there. Glutathione
depletion occurs in acetaminophen overdose when: the rate of utilization
of glutathione exceeds its rate of formation, or in states of nutritional
depletion when glutathione stores are inadequate. If glutathione levels fall
below 30 % of normal, the highly reactive NAPQI can bind instead to
cellular macromolecules that contain cysteine. This covalent binding of
NAPQI causes hepatocellular damage at many sites in the liver, although
centrilobular necrosis predominates. Renal injury may also occur owing
to the production of NAPQI by P-450 enzymes in the renal parenchyma.
CLINICAL PRESENTATION
Early recognition of an acute acetaminophen overdose is essential, as
the prognosis is best when antidotal treatment is initiated within 8 hours
of the overdose.There are 4 clinical stages in acetaminophen poisoning:
Table - Clinical Stages of Acetaminophen Toxicity
Stage
Time
Characteristics
Following
Ingestion
I
0.5 to 24 hr
II
24 to 48 hr
Anorexia, nausea, vomiting, malaise, pallor,
diaphoresis
Resolution of the above characteristics; right upper
quadrant abdominal pain and tenderness; elevated
Stage
Time
Following
Ingestion
Characteristics
bilirubin prothrombin, time, hepatic transaminases,
oliguria
III
IV
72 to 96 hr
Peak liver function abnormalities; anorexia, nausea,
vomiting, malaise may reappear; fulminant hepatic
failure (FHF) with metabolic acidosis, , and renal
dysfunction may be apparent
4 d to 2 wk
Resolution of hepatic dysfunction in survivors.
Oliguric renal failure can develop; death may occur
in patients with FHF
Agents Implicated in Induction of the Cytochrome P-450 Causing
Increased aceta.Toxicity like: Carbamazepine, Ethanol, Isoniazid,
Phenobarbital,Phenytoin,Sulfonylureas and Rifampin. Renal injury can
develop, even in cases where hepatotoxicity is mild This is attributed to
local injury by in situ production of NAPQI in the renal tubular P-450
enzymes. Acute renal failure also occurs in severe cases of acute hepatic
failure as a consequence of liver injury (hepatorenal syndrome)
TREATMENT
1-Activated charcoal, 1 g/kg within 4 hr of ingestion
2. N-Acetylcysteine: Dose: Loadingdose: 140 mg/kg PO once.
Maintenance: 70 mg/kg PO every 4 hours for 17 doses . Administer
first dose within 8 hr of ingestion , repeat dose if vomiting occurs within
1 hr of dose administration. It can be given IV. It can be given in
pregnancy.
3. Delayed presentation >24 hr post ingestion : treated with NAC if
APAP level measurable or if hepatic transaminases are elevated
Chronic Ingestion:
If ACETA .level measurable or hepatic
transaminases elevated, treat with NAC for 24 to 36 hr, then reassess
levels.
salicylates poisoning
INTRODUCTION :
Since its introduction 100 years ago, aspirin (acetylsalicylic acid) has
been widely prescribed and used as an antipyretic, analgesic, and antiinflammatory agent. Aspirin has also found new uses, including
prophylactic therapy for migraine headaches and colon cancer, and as an
antiplatelet agent for prevention of cerebrovascular and coronary
ischemia. Aspirin has a much higher fatality ratio than acetaminophen or
ibuprofen.
Mechanism of poisoning:
Salicylates produce analgesic, antipyretic, and anti-inflammatory effects.
This occurs predominantly through inhibition of COX, with subsequent
decrease in the production of PGs and related autacoids. Therapeutic
doses of acetylsalicylic acid are 10 to 20 mg/kg for children and 650 to
1000 mg every 4 to 6 hours for adults. This will produce a serum
salicylate level of 3 to 6 mg/dL. The potentially toxic acute dose is
greater than 150 mg/kg, with serious toxicity possible when 300 to 500
mg/kg is ingested, or roughly one adult tablet/kg.Chronic toxicity occurs
when more than 100 mg/kg is taken daily, particularly in infants and the
elderly.
Toxicity : 1-Salicylate directly stimulates the CNS respiratory center in
the medulla, resulting in hyperventilation characterized by an increase in
both the depth and rate of respiration.
2- Salicylates also uncouple
mitochondrial oxidative phosphorylation, causing an increase in oxygen
consumption and CO2 production. This further enhances respiratory
stimulation, leading to respiratory alkalosis. 3- In compensatory
response, the kidneys excrete HCO3‫ ־‬as well as sodium and potassium,
and this contributes to the metabolic acidosis. The metabolic acidosis is
aggravated by increased pyruvic and lactic acids from inhibition of
mitochondrial respiration. 4_Disruption of Krebs cycle metabolism and
glycolysis leads to gluconeogenesis and lipolysis, with increased ketone
formation. The salicylate ion itself makes a small contribution to the
resultant anion gap metabolic acidosis . 5- Dehydration also occurs
from hyperpnea, vomiting, and diaphoresis and fever caused by increased
skeletal muscle metabolism. Increased Na, K, and water elimination
accompany HCO3‫ ־‬renal excretion, aggravating dehydration and
hyperlacticemia. K and HCO3‫ ־‬are depleted, and H+ shift to the
extracellular space. Inhibition of liver lactate elimination also contributes
to metabolic acidosis. 6-Salicylates increase permeability of the
pulmonary vasculature to fluid and protein, and pulmonary lymph flow
and protein clearance increase.These mechanisms can cause
noncardiogenic pulmonary edema in the severely toxic patient .7- Other
physiologic effects include vasoconstriction of the auditory
microvasculature, resulting in tinnitus. Salicylates enhance insulin
secretion from pancreatic islet cells and thus can cause hypoglycemia, but
they also decrease peripheral glucose utilization, which can cause
hyperglycemia.In addition to gastrointestinal irritation, salicylates
stimulate the medullary chemoreceptor trigger zone to cause nausea and
vomiting.
8- Hematologic effects include inhibition of platelet
aggregation, decrease of factor VII, and hypoprothrombinemia. In severe
cases, hepatotoxicity can result in decreased production of factors II, VII,
IX, and X. Despite this, bleeding disorders and prolongation of the
prothrombin time are mild and uncommon.
CLINICAL PRESENTATION
Clinical effects of salicylate toxicity depend on the serum level, patient
age, and acuity of ingestion. Children and the elderly are more
susceptible to toxicity than adolescents and adults and are likely to
develop metabolic acidosis as the predominant acid-base disturbance.
Chronic therapeutic misuse in infants and the elderly is associated with
the highest mortality, from both delays in diagnosis and a higher
salicylate conce. in the CSF.
Clinical Features of Toxicity : The earliest manifestations of salicylate
intoxication occur when serum salicylate levels reach 25 to 30 mg/dL are:
Nausea, vomiting, and epigastric discomfort, Tinnitus and deafness,
Sweating, hyperpyrexia inchildren, and dehydration, Hyperpnea and
tachypnea. Moderate toxicity: 1-A mixed picture of respiratory with
concomitant metabolic acidosis is present in most adults (in children
acidosis may predominate).2- Severe hypokalemia can result from
vomiting, intracellular shifts in exchange for hydrogen ions, and urinary
losses.3- Hypoglycemia often occurs, particularly in children. 4-In
addition to tachypnea from direct CNS stimulation, respiratory distress
and hypoxia can result from aspiration or pulmonary edema. Severe
toxicity : are usually associated with acidemia and cerebral edema.
Agitation, confusion, irritability, and restlessness are early findings. This
is followed by lethargy and then coma. Seizures may also occur due to
cerebral edema or reduced brain glucose.
Treatment of Salicylate Toxicity
Gastric Lavage:
Only for a large and potentially life-threatening ingestion (30–60 g)
within an hour of ingestion. Do not use for chronic ingestion.
Activated Charcoal:
1 g/kg PO initially. Repeat doses at 2 to 4 hours of 25 g, or 0.5 g/kg.
Hydration and Electrolyte Imbalance:
Initially 1 to 2 L normal saline (10–20 mL/kg in children).
Correct hypokalemia aggressively.
Urinary Alkalinization:
1–2 mEq/kg of NaHCO3 bolus intravenously, then 850 mL of D5W with
150 mL of 8.4% NaHCO3 and infuse at 250 mL/hr
Add 20–40 mEq potassium to each liter of fluid. Adjust dose for renal
dysfunction.
Exercise caution in chronic toxicity and in the elderly because of the risk
of noncardiogenic pulmonary edema.
Monitor urine and serum pH.
Hemodialysis Indications:
1-Serum levels greater than 100 mg/dL in acute ingestion
2-Serum levels higher than 60 mg/dL in chronic intoxication
3-Pulmonary edema
4-Renal failure
5-Congestive heart failure
6-Nonresponse to standard therapy
7-Altered mental status and acidemia
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
The NSAIDs are typically classified by chemical structure into five
organic acid derivatives and the alkanone nabumetone. The five organic
acid families are (1) indole/ acetic acids (etodolac, indomethacin, and
sulindac); (2) heteroaryl acetic acids (tolmetin, diclofenac, and
ketorolac); (3) arylpropionic acids (ibuprofen, naproxen, flurbiprofen,
ketoprofen, oxaprozin, and fenoprofen); (4) anthranilic acids (mefenamic
acid and meclofenamate); and (5) enolic acids: (a) oxicams (piroxicam)
and (b) pyrazolidinediones (phenylbutazone).
Mechanism of poisoning
NSAIDs, except nabumetone, inhibit the synthesis and release of PGs by
reversible, competitive inhibition of COX activity. Among the older
NSAIDs, NSAIDs, except nabumetone, inhibit COX-1, which is found in
blood vessels, stomach, and kidney,thus lead to the occurrence of GI or
renal adverse effects seen in acute or chronic exposure
settings.Nabumetone is an exception it selectively inhibits COX-2. It is
converted to an acetic acid derivative in vivo; thus, it can produce an
anion gap metabolic acidosis in large doses. However, nabumetone’s
selective inhibition of COX-2 results in decreased adverse GI adverse
effects. Some NSAIDs are nonselective inhibitors of both (COX-1) and
(COX-2). NSAIDs also interfere with PG-mediated platelet aggregation
through inhibition of COX and subsequent inhibition of thromboxane A 2
(TXA2) synthesis. TXA2 causes vasoconstriction and enhances platelet
aggregration. Thus this inhibition may lead to increased bleeding times as
well as bleeding complications.
CLINICAL PRESENTATION:
Acute and chronic Systemic
presentation in NSAID poisoning can be as follow:
Table- Clinical Presentation of NSAID Toxicity
Acute
Gastrointestinal
Abdominal pain, nausea,
bleeding, vomiting
Central Nervous Coma, confusion, dizziness,
System
seizures, tinnitus
Chronic
Enteropathies,
gastritis
Psychosis
Metabolic
Anion gap acidosis
(arylpropionic acids,
nabumetone)
Neutropenia
Renal
Azotemia, acute renal
insufficiency
Interstitial nephritis,
papillary necrosis
Elevation of
Hepatic
Elevation of transaminases
transaminases, hepatic
failure
TREATMENT :General supportive care, evaluation, and gastrointestinal
decontamination with activated charcoal are indicated . Multiple-dose
activated charcoal may be indicated for enhanced elimination of
piroxicam and the enterohepatically recirculated drugs: nabumetone,
naproxen, and sulindac.
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