PARACETAMOL AND

SALICYLATE POISONING
PARACETAMOL

 Paracetamol , also known as acetaminophen or

 APAP (N- acetyl-p-aminophenol) 4-hydroxyacetanilide
 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.
 MECHANISM OF ACTION
 The main mechanism proposed is the inhibition of
cyclooxygenase(COX) and recent findings suggest that it is highly
selective for POX.
 By inhibition of COX it prevents generation of prostaglandins from
arachidonic acid, which are in turn 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
– Acts as an analgesic
 Good and promptly acting anti pyretic
by reducing PGE2 in CNS
 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.
 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
 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.”
 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.
 CLINICAL FEATURES
Phase 1
 0.5-24 hours after ingestion
 Patients may be asymptomatic or report anorexia, nausea or vomiting,
and malaise
Physical examination may reveal pallor, diaphoresis, malaise, and fatigue
Phase 2
 18-72 h after ingestion
 Patients generally develop right upper quadrant abdominal pain,
anorexia, nausea, and vomiting
 Right upper quadrant tenderness
 elevated liver enzymes, PT and INR
 Phase 3 : Hepatic phase
 72-96 h after ingestion
 Patients may have continued nausea and vomiting, abdominal pain, and a
tender hepatic edge
 Hepatic necrosis and dysfunction are associated with jaundice,
coagulopathy, hypoglycemia, and hepatic encephalopathy
  ALT - often between 2000 and 10,000 U/L
 Acute renal failure develops in some critically ill patients
 Death from multiorgan failure may occur
Phase 4 : Recovery phase
 4 days to 3 weeks after ingestion
Patients who survive critical illness in phase 3
have complete resolution of symptoms
and organ failure
 TOXIC DOSES
Minimum toxic doses for single ingestion
 Adults – 7.5-10 g
 Children – 150mg/kg
 200mg/kg in healthychildren aged 1-6 years.

 Fatal cases usually involve doses of at least 15 to 25 g

 In heavy drinkers, daily doses of 2 to 6 g
have been associated with fatal hepatotoxicity
 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
 Urineanalysis( for hematuria and proteinuria)
 ECG(to detect additional clues for co-ingestants)
 CT brain(if altered mental status)
 Blood levels of acetaminophen correlate with severity of 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 hyper acute injury
 INTERACTIONS
 Induced P450 : chronic alcohol, barbiturates,
phenobarbital, isoniazid,
 Glutathione depletion: malnutrition, starvation, alcohol
 Hepatitis C virus(HCV) infection wasfound to be
associated with an increased risk of acute liver injury in
patients hospitalized for acetaminophenOverdose
 Chronic alcoholics - toxic dose of paracetamol may be as
low as 2 grams
 Management

 Treatment includes gastric lavage, supportive measures,

and oral administration of activated charcoal or
cholestyramine to prevent absorption ofresidual 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,
 MANAGEMENT
If < 8 hours :
 Tx of choice – activated charcoal 1g/kg
 Check GM, FBC, RP, LFT, ABG, PCM TDM at 4 hours post-
ingestion
If 8-24 hours & suspicious of large overdose (> 7.5g ) :
 Start NAC  stop if level below therapeutic line & INR/LFT
normal
If Unknown Time of overdose
 Determine serum acetaminophen levels
 Determine INR levels, RP, LFT
 Treat with Acetylcysteine if S.Acetaminophen
or transaminases (ALT, AST) are detected
 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).
 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 cellproteins,resulting in
the formation of drug metabolite -protein adducts.
 INDICATIONS FOR NAC
 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 >150 mg/kg (7.5 g total dose
regardless of weight) in a patient for whom the s.acetaminophen
concentration will not be available until more than 8hours from the
time of the ingestion.
 Patient with an unknown time of ingestion and a serum
concentration >10 mcg/mL (66 µmol/L).
 Patient with a history of ingestion and evidence of ANY liver injury.
 Patients with delayed presentation (>24 hrs)
consisting of laboratory evidence of liver injury
(ranging from mildly elevated aminotransferases
to fulminant hepatic failure)
72 hour oral protocol [Oral ]
 Loading dose 140 mg/kg
 Maintenance dose 70 mg/kg every 4 hours for 17 doses
 The dose does not need to be adjusted if the patient has been
treated with activated charcoal.
20 hour IV dosing regime
 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 300mg/kg over 20
to 21 hours
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.
 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 indicators of hepatotoxicity.
 Begin NAC if elevated AST & ALT levels
or a measurable serum APAP concentration.
 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.
 urticaria, flushing, angio oedema, wheezing , hypotension
 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 im use),
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.
 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
 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
SALICYLATES

 The salicylates originally were derived from salicin, 
 the active ingredient in willow bark, which Hippocrates us
ed 2500 years ago for treating pain and fever
 ASA METABOLISM:
 Salicylic acid (HS) is a weak acid: 
 In an acidic environment like the stomach, more of the drug will
be absorbed compared with tissues at a higher pH
 Salicylates also are absorbed readily in the unionized form from
the small intestine
  In therapeutic doses Aspirin is thought to cause spasm of the
 pyloric sphincter
 Salicylate is conjugated with glycine in the liver
 A small amount of aspirin is excreted unchanged in the urine 
TOXICOKINETICS
 Salicylates are rapidly absorbed from the stomach
 Therapeutic serum salicylate levels should not exceed 30 mg/100
ml.
 Salicylic acid and methyl salicylate are readily absorbed through
intact skin.
 Salicylates distribute well into plasma; saliva; milk; and spinal,
peritoneal and synovial fluid and into body tissues.
 Metabolism occurs chiefly in the liver, where salicylates
are broken down into salicyluric acid, ether glucoronide,
ester glucoronide, and gentisic acid
 The half-life is 2-4 hours at therapeutic levels,
but may increase to 20 hours at toxic levels
 Salicylates stimulate the respiratory centre in the brainstem
leading to hyperventilation and respiratory alkalosis.
 They also interfere with Krebs cycle, inhibit production of
ATPand increase lactate production, leading to ketosis and a
wide anion-gap metabolic acidosis.
 In children, respiratory alkalosisis and Metabolic acidosis is
Predominant feature.
 Respiratory acidosis in salicylate overdose indicates grave
prognosis and is seen in salicylate induced pulmonary
oedema,CNS depression From mixed overdose,or severe
fatigue due to prolonged hyperventilation
 MECHANISM OF ACTION
 Aspirin inhibits COX irreversibly by acetyl­ating one of its serine
residues; return of COX activity depends on synthesis of fresh
enzyme.
 Interferes with aerobic metabolism by means of uncoupling of mitoc
hondrial oxidative phosphorylation. 
 Interruption of a series of enzyme‐
mediated mitochondrial functions and increased anaerobic metabolis
m with cellular conversion of pyruvate to lactate and rapid developm
ent of lactic acidosis
 The inefficiency of anaerobic metabolism results in less energy being
 used to create ATP and release of the energy created during the 
 metabolism of glucose in the electron transport chain as heat, so salic
ylate poisoned patients may become febrile.
 The presence of acetasalicylic acid or salicylate molecules probably con
tributes little to the acidotic state
 Interference with oxidative phosphorylation causes glycogen depletion, 
gluconeogenesis, and catabolism of proteins and free fatty acids, the end
 result being low serum glucose levels and central
nervous system (CNS) hypoglycemia relative to serum glucose levels
 USES
 Sodium salicylate and acetyl salicylic acid:
a. Antipyretic.
b. Analgesic.
c. Treatment of rheumatoid arthritis.
Low-dose aspirin is used in the prophylaxis of cerebrovascular ischaemic
events,Angina pectoris
 Sodium aminosalicylate:
It is used sometimes as a second-line drug in themanagementof
tuberculosis.
 Bismuth subsalicylate:
It is used to treat diarrhoea, and as prophylaxis for travellers diarrhoea
New derivatives of salicylic acid:
 Mesalamine (5-aminosalicylic acid) is used as a suppository Or rectal
suspension Enema For Its Local Effects In The treatment Of
Inflammatory Bowel disease
 Olsalazine (sodium
azodisalicylate) ,Sulfasalazine(salicylazosulfapyridine) in ulcerative
colitis,
 Diflunisal in the treatment of musculoskeletal sprains and osteoarthritis.
 Benorylate (4-acetamidophenyl-o-acetylsalicylate),an ester of aspirin and
paracetamol.
The usual therapeutic dose in adults is 4 gm/day.
Toxicity can result if this is exceeded.
Manifestations are a combination of those in aspirin
and paracetamol poisoning with tendency toward
centrilobular hepatic necrosis
.
 Locally acting salicylates:
Salicylic acid is a keratolytic agent.
Methyl salicylate (oil of wintergreenoil), is used for the local treatment
of musculoskeletal pain And inflammation.
 5 ml of oil of wintergreen is equivalent to approximately
7000 mg of salicylate or 21.7 adult aspirin tablets.
 Homomenthyl salicylate (homosalate) is a sunscreen
agent and contains 46% salicylic acid.
 Trolamine salicylate used in the management of OA,
10 grams of cream contains 500 mg of salicylic acid)
 DRUG INTERACTIONS

 Salicylate and/or acetazolamide

The syndrome of effects reported
 are confusion, fatigue, hyperchloraemic metabolic acidosis,
 incontinence, lethargy, and somnolence
 Alcohol warning

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CLINICAL (TOXIC) FEATURES
 Acute Poisoning:
Early—Nausea, vomiting, sweating, tinnitus (ringing
or hissing), vertigo, and hyperventilation due to respiratory alkalosis.
Late—Deafness, hyperactivity, agitation, delirium,
convulsions, hallucinations, hyperpyrexia. Coma is unusual.
 Complications—Metabolic acidosis, pulmonary
oedema, rhabdomyolysis, cardiac depression, thrombocytopenic
purpura.Gastrointestinal bleeding
 Reye’s syndrome
Dehydration ,hypokalaemia,
QT prolongation
 CHRONIC POISONING (SALICYLISM)
 low onset of confusion, agitation,lethargy,disorientation,slurred speech,
 hallucinations,convulsions,And coma.
 hearing loss, nausea, dyspnoea, tachycardia,fever.
 Pseudosepsis syndrome characterised by fever, leukocytosis,
hypotension,and multi-organ system failure:
ARDS,ARF,coagulopathy (DIC), Prolongation of PT and PTT,
thrombocytopenia, hypofibrinogenaemia,
 Chronic maternal ingestion is associated with
an increased incidence of stillbirths,
antepartum/postpartum bleeding,
Prolonged pregnancy/labour,
Lower Birth weight.
 TREATMENT
 There is no antidote for salicylate poisoning.
Goal of treatment:
 prevent further GI absorption of the drug, 
 prevent its entry into the CNS 
 Enhance removal of drug from CNS
 increase elimination of the drug from the body
 MANAGEMENT
 Stomach wash may be beneficial upto 12 hours after
ingestion, since toxic doses of salicylates often cause
pylorospasm and delayed gastric emptying.
 Activated charcoal (AC): each gram of
AC can adsorb 550 mg of the drug.
 A 10:1 ratio of AC to salicylate ingested appears to result in maximum
efficiency.
 Urinary alkalinisation: Alkalinisation of both blood and urine can be
achieved with intravenous sodium bicarbonate.
Dose of NaHCO3 –
– For mild poisoning: 1 mEq/kg of NaHCO3 is added to the first bottle of
5% dextrose.
If alkalinisation (i.e. urinary pH between 7.5 and 8.5) is not achieved
in a few hours, it can be repeated.
– For severe poisoning: Additional bolus therapy of 50 to 100 mEq of
NaHCO3 over 1 to 2 hours .
Alkalinisation should be stopped when serum salicylate level falls below
35 mg/100 ml.
.

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 Haemodialysis: must be considered in the presence of cardiac or renal
failure, intractable acidosis, convulsions, severe fluid imbalance, or a
serum salicylate level more than 100 mg/100ml.
 cerebral oedema require immediate dialysis. Charcoal haemoperfusion
produces better salicylate clearance than haemodialysis.
 Supportive measures:
 Correction of fluid and electrolyte imbalance
 Correct dehydration with 0.9% saline 10 to 20 ml/kg/hr over 1 to 2
hours until a good urine flow is obtained (at least 3 to 6 ml/kg/hr).
 Hypoprothrombinaemia can be corrected
by 2.5 to 5mg of vitamin K IV every day.
 Hyperpyrexia must be tackled by cooling measures (e.g.ice in the axilla and
groin).

 Correction of metabolic acidosis with NaHCO3

 Correction of hypocalcaemia with calcium gluconateIV(5 to 10 mL in

adults).

 Correction of hypoglycaemia with glucose IV(50 ml5%dextrose or1 ml/kg).

 Treatment of convulsions with benzodiazepines.

 Mild cerebral oedema and elevated

intracranial pressure (ICP) can be managed by

head elevation and administration of mannitol

 Treatment of Reye’s syndrome:
 Admit the patient to an intensive care unit.
 Raise the head-end of bed (40 degree).
 Mannitol IV (0.2 to 1.0 gm/kg).
 Acute hyperventilation may be helpful.
 Short acting barbiturates in resistant cases
REFERENCES

 The essentials of medical theraupetics by KDTripathi 187-191,199-200

 Modern Medical Toxicology, 4th Edition VV Pillay -. 411-421
 Oxford Handbook of Clinical Medicine 9th Ed
 Hill JB. Salicylateintoxication. N EnglJ Med 1973; 288:1110
 Temple AR. Pathophysiologyof aspirin overdosagetoxicity, with implications 
for management. Pediatrics 1978; 62:873.
 O’Malley, Management of the salicylate‐
poisoned patient. Emerg Med Clin N Am 2007;25: 333–346
 http://www.nhs.uk/Conditions/Poisoning/Pages/Symptoms.aspx
 http://emedicine.medscape.com/article/820200-overview
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