Common Poisonings

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• Common Poisonings
• MB/PhD Seminar 2004
• Kevin OShaughnessy
• Department of Medicine (CPU)

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General Points about Poisoning

• Per annum in the UK there are
• some 300,000 cases of poisoning
• 100,000 hospital admissions for poisoning
  (in-patient mortality lt1 )
• 3,500-4000 deaths from poisoning (1000 of these
  are due to CO)
• Remember
• drug history may be unreliable
• 65 of drugs used are prescribed to the patient,
  a relative or friend
• 30 of self-poisonings involve multiple drugs
• 50 of drug-overdose also involve alcohol
• . Question witnesses or family about ANY access
  to drugs or ANY bottles found.
• . There may be clues from the clinical signs (eg
  pin-point pupils with opiates), signs of
  solvent/ethanol abuse or signs of IV drug use
  (venepuncture sites).

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and their Management

• The role of antidotes is restricted to a minority
  of drugs.
• In most cases of overdose, survival is crucially
  dependent on supportive care .
• Monitor the airway (recovery position /-
  intubation)
• Maintain normoxia (/- IPPV)
• Maintain body temperature
• Correct any hypotension (/- volume expansion)
  or hypertension
• Correct acid-base or electrolyte disturbance
• Treat any fits (DZP /- IPPV)
• Monitor for dysrrhythmias (2ary role of
  antiarrhythmics)
• Beware of skin blistering and rhabdomyolysis.
• Remember to take account of concurrent medical
  problems eg an IV drug user may be septicaemic or
  have hepatitis, SBE or HIV-related disease.

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ASPIRIN

• One of the commonest drugs taken in OD
• Across all age-groups, 20 men and 30 women take
  OTC analgesics regularly
• Reduction in paracetamol pack size in 1998 has
  led to shift in UK consumption in favour of
  NSAIDs

• Occasionally poisoning follows topical
  application of salicylic acid in keratolytics or
  ingestion of methyl salicylate ('oil of
  wintergreen).
• 1ary toxic effect is to uncouple oxidative
  phosphorylation.
• Presentation
• Salicylismsweating, vomiting, epigastric pain,
  tinnitus and blurring of vision.
• Early respiratory alkalosis (not seen in
  children) precedes the later metabolic acidosis.
• In severe overdose, acidosis reduces the
  ionization of salicylic acid enhances CNS
  penetration gt agitation, tremor and fits
  eventually to coma and respiratory depression.

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ASPIRIN

• Complications
• Electrolyte Disturbance universal
• hypokalaemia and deranged Na (high gt low)
• glucose (hyper gt hypo)
• Pulmonary oedema (often non-cardiogenic) acute
  renal failure.
• Hypoprothrombinaemia is very rare.
• Significant GI bleeds are surprisingly
  infrequent.
• Management - therapeutic salicylate is lt300mg/l
  (2.2 mmol/l)
• Mild/moderate salicylism requires only
  rehydration KCl supplements.
• Marked salicylism or levels gt 750mg/l need
  specific elimination therapy
• (1) Oral activated charcoal (50g 4 hourly)
• (2) Forced alkaline diuresis NO LONGER
  RECOMMENDED - it is no more effective than simple
  alkalinisation (eg 1 L 1.26 NaHCO3 over 2 hrs
  and repeated to keep the urinary pH gt 7.5).
• (3) Haemodialysis is required for any of the
  following level gt1000mg/1 (7.25 mmol/l)
  persistent/progressive acidosis deteriorating
  level of consciousness.

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PARACETAMOL
Paracetamol (Acetaminophen, Tylenol ) NB
component of compound analgesics such as
co-codamol, co-dydramol co-proxamol and amongst
OTCs some Alka-Seltzer , Anadin and
Beechams-Powders preparations.

• 15 20 tablets (7.5-10g) overdose
• Causes severe centrilobular necrosis of the
  liver
• 10 have renal toxicity (acute tubular necrosis)
• Accounts for 200 deaths/year in UK

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Paracetamol Metabolism
O
O
O
HN C CH3
HN C CH3
HN C CH3
60
40
OH
O
O
Sulphate
glucuronide
CYP2E - minor pathway except in overdose!
O
HON C CH3
NABQI
OH
8
O
Detoxifcation of NABQI consumes GSH
N C CH3
O
GSH
d ve
(Glutathione-S-transferase)
O
HN C CH3
S G
OH
9
Protection by glutathione (GSH) and its
substitution with exogenous N-acetyl-cysteine
Tripeptide (?-ECG). Present in all cells high
in hepatocytes 5mM
SH
O
COO-
CH2
H
-OOC CH2 N C CH N C CH2 CH2 - CH
H
O
NH3

• Exogenous GSH cannot enter hepatocyte
• NAC is SH donor to scavenge NABQI
• Also protects intracellular levels of GSH in
  hepatocytes
• Depletion of GSH by gt80 causes toxicity

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PARACETAMOL

• Presentation
• Apart from mild nausea, vomiting and anorexia,
  patients presenting within 24 hrs of ingestion
  are generally asymptomatic.
• Hepatic necrosis becomes apparent at 24-36 hrs
  with
• right subchondral pain/tenderness
• reappearance of vomiting and neuroglycopenia
• Deepening Encephalopathy over the next 72 hrs.
• Complications
• The predictable consequences of liver failure
  i.e. metabolic acidosis, hypoglycaemia, cerebral
  oedema, cardiac arrhythmias and GI bleeding.
• 10 of patients develop renal impairment from
  acute tubular necrosis - occasionally in the
  absence of hepatic failure.
• Very rarely patients with G6PD deficiency develop
  methaemoglobinaemia and haemolysis.
• Prognostic features
• Untreated, the fatal dose in adults is usually
  gt10g - lower in chronic alcoholics or subjects
  with underlying liver disease or treated
  epileptics.
• A PT of 20s at 24 hrs indicates significant
  hepatocellular damage the more rapid the rise in
  PT thereafter the poorer the prognosis.
• In patients developing hepatic failure, a poor
  prognosis is suggested by (1) arterial pH lt7.3
  (2) prothrombin time gt100s (3) creatinine of
  gt300 mol/l. They should be considered for early
  liver transplantation.

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PARACETAMOL

• Management
• Within 4 hrs of ingestion lavage (?) or activated
  charcoal
• Paracetamol levels checked at 4hrs compared to
  treatment curve (200mg/1 or 1.32mmol/l at 4h
  joined to with 6mg/1 or 0.04mmol/l at 24h). Some
  60 of patients above the line develop severe
  liver damage defined as AST gt1000. 
• Patients on or above the line should be given IV
  N-acetylcysteine
• up to 10 have a rash, bronchospasm or
  hypotension during the IVI (acts as a mast cell
  releaser). Stopping and giving chlorpheniramine
  IV usually allows the IVI to be safely restarted.

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CARBON MONOXIDE

• HSE limit 200ppm (0.02) causes headaches in 2-3
  hours cf gt10,000ppm (1) that can cause death in
  a few minutes.
• The commonest sources are
• smoke inhalation
• poorly maintained domestic gas/oil appliances
• deliberate inhalation of car exhaust fumes
• Causes intense tissue hypoxia by two mechanisms
• interrupts electron transport in mitochondria
• blocks tissue O2 delivery
• competes with O2 for binding to Hb (Ka CO
  220-fold gt 02)
• alters shape of the HbO2 dissociation curve (less
  sigmoidal)

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CARBON MONOXIDE

• Signs of hypoxia without cyanosis - 'cherry-red'
  colouration most obvious post mortem!
• Symptoms signs correlate with COHb
• lt30 causes only headache and dizzyness
• 50-60 produces syncope, tachypnoea, tachycardia
  and fits
• gt60 increasing risk of cardiorespiratory failure
  and death.
• NB Pulse-oximetry unhelpful it measures
  functional saturation

Non-smoker 1 Smoker 5-8 Jogger in London
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CARBON MONOXIDE

• Management
• Check ABG - PaO2 may be normal but metabolic
  acidosis indicates severe poisoning.
• Give O2 by mask unless comatose then IPPV with
  FiO2 1 (t1/2 COHb 320 mins on room air vs 80
  mins at 100). Also consider if severely
  acidotic or evidence of myocardial ischaemia.
• Control fits with IV diazepam.

NEJM 20023471057
Hyperbaric 02 will shorten the washout of COHb
further (half-life of 25 mins at 2 atmospheres),
but access and transfer times to a hyperbaric
chamber may make this impractical. Recent trial
suggest may be worthwhile (cognitive sequelae at
6/52 were reduced from 35/76 to 19/76 by this Rx
.
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CARBON MONOXIDE

• Complications
•  
• Sites at particular risk are
• CNS - cerebral, cerebellar or midbrain
  (Parkinsonism and akinetic-mutism)
• Myocardium - ischaemia/infarction
• Skeletal muscle - rhabdomyolysis/myoglobinuria
• Skin - erythyema to severe blistering.
• NB (1) Anaemia, increased metabolic rate (e.g.
  children) and underlying ischaemic heart disease
  all increase susceptibility to CO.
• (2) Neurological recovery depends on the duration
  of hypoxic coma complete recovery has been
  reported in young subjects (under 50) after up to
  21 hrs versus 11 hrs in older ones.

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COCAINE
Leaves contain up to 10mg/g of cocaine
According to forensic experts, around 80 per
cent of all banknotes in circulation are
contaminated with drugs, a figure that rises to
99 per cent in the London area. Research by Mass
Spec Analytical, the Bristol-based forensics
company which analyses banknotes seized by police
and customs, shows that cocaine is the most
common substance The Observer from Nov 10,
2002.
Erythroxylon Coca

• Coca leaves chewed by Pre-Columbian Indians for
  several millennia
• 1884, Koller discovers efficacy as ophthalmic
  local anaesthetic
• Freud adds his endorsement the same year, Uber
  Coca
• Merck and Parke Davis compete for commercial
  production
• Widespread addition to wines (Vin Mariani) and
  tonics (Pembertons)

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COCAINE

• Users, Carriers Routes of Administration
• In 1999, an estimated 1.5m Americans were
  current users and 3.7m had taken it in the past
  12 months. Hair analysis for metabolites suggests
  a 4-5 fold larger problem.
• Its subjective and sympathomimetic actions are
  often indistinguishable from amphetamine even for
  experienced users.
• Onset can be very rapid when snorted or smoked
  (freebasing 'crack').
• Occasionally massive overdose in drug smugglers
  presents after swallowed/secreted packets
  rupture.

Traub, S. J. et. al. N Engl J Med
20033492519-2526
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COCAINE

• Presentation
• Indirect sympathomimetic effects c.f.
  amphetamines
• Seizures common as well as ventricular
  arrythmias.
• Very high doses cause CNS depression particularly
  in the medullary centres with cardiorespiratory
  failure.
• Complications
• Vasoconstrictor effects on the coronary
  circulation - even with angiographically normal
  vessels.
• Hypertensive strokes.
• Psychotic reactions (c.f. amphetamine psychosis).
  
• Cocaine can cause seizures in epileptics in
  'recreational' doses but for non-epileptics
  presentation in status epilepticus generally
  implies massive overdose which is often resistant
  to treatment and carries a poor prognosis.
• A syndrome of acute rhabdomyolysis, hyperpyrexia,
  renal failure, severe liver dysfunction and DIC
  has been reported and also carries a high
  mortality cf ecstasy.
• Patients with deficiency of serum
  pseudocholinesterase appear to be at particular
  risk of life threatening cocaine toxicity.

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COCAINE

• Management
• Monitor ECG continuously. Ensure the airway is
  clear and if the patient is comatose intubate and
  mechanically ventilate early. Watch for evidence
  of hyperpyrexia.
• Seizures IV diazepam (10-20mg IV stat and if
  necessary an IVI of up to 200mg/24hrs). If new
  focal seizures CT indicated.
• Hypertension IV GTN or phentolamine
  first-choice labetalol IV second-choice
  (inadequate ?-blockade?) NEVER pure
  beta-blockers!
• Ventricular arrythmias may be treated with
  lignocaine (100mg stat then an IVI of 4mg/min)
  provided the patient is paralysed and ventilated
  otherwise seizures may be precipitated. In
  concious patients, IV labetalol may be useful.
  Phenytoin 3rd Iine but especially useful in the
  presence of seizures.
• Hyperpyrexia prompt cooling (aim for rectal temp
  lt38.5). Chlorpromazine ? (25-50mg IM) beware
  sedation and hypotension. Dantrolene?

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OPIATES
Papaver Somniferum

• Presentation
• Pin-point pupils Coma
• Severe respiratory depression/cyanosis
• BP may be low but often well maintained
• - NB pentazocine overdose actually ? BP
• Hypotonia often marked
• - dextropropoxyphene and pethidine ? muscle tone
  and cause fits
• Complications
• All opiates can cause non-cardiogenic pulmonary
  oedema
• - but most frequent with IV heroin.
• Rhabdomyolysis is common in opiate-induced coma
• - it should be looked for in all cases.
• Substances used to dilute ('cut') illicit
  opiates may be toxic
• e.g. talc and quinine.

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OPIATES

• Prognostic features
• Non-cardiogenic pulmonary oedema carries a poor
  prognosis (it is not naloxone reversible)
• Patients ingesting paracetamolopiate
  combinations (i.e. co-proxamol and co-dydramol)
  obviously run the additional risk of paracetamol
  toxicity
• Patients with underlying ischaemic heart disease
  seem more susceptible to haemodynamic disturbance
  after naloxone is given to reverse opiate
  intoxication (see below)
• NB Renal impairment reduces the elimination of
  many opiates (or their glucuronidated
  metabolites), so prolonging their duration of
  action.

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OPIATES

• Management
• If paracetamolopiate combinations ingested
  measure a paracetamol level and treat
  accordingly.
• Specific antidote is naloxone given as IV in
  boluses of 0.4mg at 2-3 minute intervals until
  rousable and respiratory depression corrected.
• Convulsions (usually pethidine or
  dextropropoxyphene) usually respond to IV
  naloxone without additional anti-convulsant
  therapy.
• Pulmonary oedema present on admission generally
  requires IPPV.
• Important points re use of Naloxone .
• If gt2mg given with no response, revisit the
  diagnosis of opiate overdose!
• Naloxone has a short half-life compared to most
  opiates. With long-acting opiates such as
  methadone a naloxone IVI may be necessary for 48-
  72hrs.

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OPIATES

• Beware Cold Turkey!
• . Giving sufficient naloxone to completely
  reverse the effect of opiates in an
  opiate-dependent subject is likely to precipitate
  an acute withdrawal reaction.
• . Marked hypertension, acute pulmonary oedema
  and VT/VF have been observed in non-adducts given
  naloxone to reverse the effects of high
  therapeutic doses of opiates for pain.
•  
• Further points
•  
• Dextropropoxyphene alcohol can cause marked CNS
  depression. Respiratory arrest can evolve within
  lt30 mins of ingestion. Give naloxone even if the
  patient is only mildly drowsy. It also causes an
  acute cardiotoxicity with arrhythmias due to a
  membrane-stabilising effect (naloxone
  ineffective).
• The respiratory depressant effects of
  buprenorphine are not fully reversed by naloxone.
  Doxapram has been used in milder cases of
  buprenorphine overdose as a respiratory
  depressant (1-4mg/min) although severe cases may
  require IPPV.

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3,4-methylenedioxy-methamphetamine (MDMA, Ecstasy)

• MDMA synthesized by chemists at Merck in 1912 and
  patent granted in 1914 later resurfaced in
  Gottliebs CIA campaign, MKULTRA
• Used legally by psychotherapists until 1985 when
  it was first made a schedule I drug in USA
• Recreational use now exceeds 750,000 tabs/week in
  NY probably similar number in UK.
• Single tablet doses typically 50-100mg.
  Occasionally unexpected adulterants e.g.
  strychnine.

Jacob Mercks Engel-Apotheke, Darmstadt circa
1668
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3,4-methylenedioxy-methamphetamine (MDMA, Ecstasy)

• Presentation following typical of amphetamines
  but not features of usual recreational doses of E
• Sympathomimetic effects - mydriasis, ?BP, ?HR,
  skin pallor.
• Central effects - hyperexcitability,
  talkativeness and agitation.
• Paranoid features may be obvious especially in
  chronic users not applicable to E.
• Complications
• A 'heat-stroke' like syndrome rhabdomyolysis,
  hyperpyrexia (gt42 C), DIC and acute renal
  failure. It carries a poor prognosis (see
  cocaine). ? PK problem ?? CYP2D6 metaboliser
  status important
• Intracranial (and subarachnoid) haemorrhage (?
  2ary to hypertensive effect but can occur after
  single therapeutic doses and vasospasm reported
  at angiography 'string-of-beads' sign) not
  applicable to E.

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3,4-methylenedioxy-methamphetamine (MDMA, Ecstasy)

• Management
• Agitation - diazepam IV or lorazepam IM.
  Haloperidol if psychotic.
• Seizures - diazepam IV (if new focal signs urgent
  CT).
• Hypertension First choice, GTN IV or ?-blockade
  (phentolamine IV) Second choice, labetalol IV
  NEVER pure ?-blockers.
• Hyperpyrexia - prompt cooling (aim for rectal
  temp lt38.5). Chlorpromazine? (25-50mg IM) beware
  sedation and hypotension. Dantrolene?
• Acidification of the urine? - can substantially
  increase elimination but must be weighed against
  the electrolyte and pH disturbance caused.

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