THE MANAGEMENT OF DRUG OVERDOSE

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Transcript THE MANAGEMENT OF DRUG OVERDOSE

Acute Poisoning
Michael Eddleston
NPIS Edinburgh
SpR in Clinical Toxicology, RIE
NPIS
Edinburgh
THE IMPORTANCE OF PHARMACOLOGY
“You may experience a difficulty in
remembering the antidotes for the various
poisons. If so, rest assured that your
knowledge of pharmacology is defective.
All rational treatment of cases of poisoning
is founded on a correct appreciation
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of the physiological action of drugs.”
What to do in cases of poisoning, William Murrell, 1925
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EPIDEMIOLOGY
• most common cause of medical
presentation accounting for 10-20% of
acute medical admissions (RIE 3000 of
15000/annum)
• females > males, but male rate rising
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APPRAISAL OF THE POISONED
PATIENT
• history from patient
• tablets / circumstances found
• clinical features (“TOXIDROMES”)
» Opiate
» anticholinergic
» stimulant
» metabolic acidosis
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Gastric lavage
Ward 3, Royal
Infirmary of
Edinburgh, 1973
(courtesy of Alex
Proudfoot)
PREVENTION OF ABSORPTION
• activated charcoal
• binds non-specifically
• binds about 1/10 of charcoal weight
• (charcoal dose 50 g in an adult)
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• Slow release products
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Christophersen et al, Br J Clin Pharmacol 2002; 53: 312-7.
ACTIVATED CHARCOAL
• timing - use within 1 hour
• airway - don’t if problems
• agent - eg iron, lithium, hydrocarbons
NOT bound
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PARACETAMOL
PROBLEMS
• Indications for treatment
• Staggered overdose
• Late presentations
• Reactions to antidote
• Interpretation of results in poisoning
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Paracetamol
Quantity
Activity
Quantity
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RISK FACTORS IN PARACETAMOL OD
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PARACETAMOL: RISK FACTORS
Nutritional deficiency
Eating disorders
Alcoholism
Malabsorption syndromes
AIDS
?? Acute starvation
(CLUE: Blood urea)
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PARACETAMOL: RISK FACTORS
Enzyme inducers:
carbamazepine
phenytoin
barbiturates
rifampicin
St Johns wort
chronic ethanol
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PARACETAMOL: RISK FACTORS
Enzyme inducers:
carbamazepine
phenytoin
barbiturates
rifampicin
St Johns wort
chronic ethanol
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CLUE: Gamma GT
Edinburgh
The cumulative survival rates for every time to acetylcysteine
for each alcohol subgroup. There was a significant difference
between the chronic and other subgroups (p < 0.0001 by Cox’s
F test)
Schmidt et al Hepatol 2002; 35: 876-882.
Paracetamol
Quantity
Activity
Quantity
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RISK FACTORS IN PARACETAMOL OD
Edinburgh
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Outcome – ALT >1000 related to original plasma level
and time of ingestion- ORAL NAC
Rumack 2002 Clin Toxicol 40: 3-20.
Current use of Acetylcysteine
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Before 4 hours
4-8 Hours
8- 24 Hours
After 24 hours
- WAIT until 4 hours
- Blood sample and wait **
- Treat on history, do bloods
- Do bloods unless toxic
• STAGGERED INGESTION – use first dose time
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for treatment decisions
**ASSUMES RESULT SOON
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What to do if patient presents >20h
post ingesion
• Do bloods (U&E, LFTs, INR, pcm)
• If transaminase less than 2x elevated,
INR < 1.4, creatinine normal, and
paracetamol is not detected:
• The patient has not been poisoned and
can be safely discharged home
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PARACETAMOL: ANTIDOTE
Acetylcysteine IV
Adverse effects
Vomiting
flushing
hypotension
bronchospasm
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Anaphylactoid reaction - treat
with antihistamines
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Intravenous acetylcysteine
• adverse reactions common
• Treatment is symptomatic: antihistamine and
beta agonists. NOT ANAPHYLAXIS
• fatalities uncommon (usually miscalculation),
caution in asthmatics
• Patients with a late presentation seem to have
a higher incidence of anaphylactoid reactions
that relates to lower paracetamol levels.
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Risk factors for ADRs to acetylcysteine
• asthmatics 2.9 (95% CI 2.1, 4.7) more
likely to develop ADR
• allergy to other medicines not a risk
factor
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Schmidt and Dalhoff. BJCP 2001:51; 87-91)
Edinburgh
What to do after 20 hours antidote??
• Transaminase, sensitive.
If normal or less than 2x elevated risk
of hepatotoxicity is low
• INR more specific, if above 1.3
• ALWAYS also check creatinine
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STIMULANTS
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amphetamine
ecstasy
cocaine
LSD
psilocybe mushrooms
phencyclidine
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STIMULANTS
• Key issue is control of central excitation
and hyperthermia
• Use of judicious HIGH DOSES of diazepam
and cooling
• Watch for coronary spasm and infarction
• Caution with antipsychotics
and flumazenil
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CALCIUM ANTAGONIST
POISONING
• cardiac effects - diltiazem, verapamil
• peripheral effects - dihydropyridines
(eg nifedipine, amlodipine)
Both seen in overdose
Beware bradycardic hypotensive patient
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MANAGEMENT OF CALCIUM
ANTAGONIST POISONING
• CNS effects often seen late
• hypotension and rhythm disturbance
• hyperglycaemia and lactic acidosis
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• beware slow release preparations
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TREATMENT OF CALCIUM
ANTAGONIST POISONING
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atropine
calcium
glucagon
catecholamines
cardiac pacing
insulin and glucose
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INSULIN-GLUCOSE AS ADJUNCTIVE
THERAPY FOR CALCIUM CHANNEL
ANTAGONIST POISONING
• insulin 10-30 u/hr with dextrose
(mean 0.5 IU/kg/hr) in five patients:
4 verapamil
1 amlodipine and atenolol
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Yuan et al. Clin Tox 1999; 37, 463-74
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ANTIDEPRESSANTS
Tricyclics
SNRI
SSRIs
NRI
amitriptyline dosulepin
venlafaxine
paroxetine fluoxetine
sertraline citalopram
reboxetine
Presynaptic -2 antgst
mirtazepine
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MAOI
SMAOI
phenelzine
moclobemide
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TRICYCLICS
ACTIONS
Amine reuptake inhibitors
Anticholinergics
Membrane effects (Na channel blockade)
Antihistamine
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TOXICITY
Arrythmias and fits
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ANTIDEPRESSANTS
ECG of patient at risk:
QRS > 100ms possible arrythmia
(higher risk for fits)
> 160ms definite arrythmia
Dosulepin (Dothiepin )
most toxic
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ANTIDEPRESSANTS
Treatment of patient at risk:
Monitor using serial 12 lead ECGs
Consider Bicarbonate IV if risk
factors (QRS >100, and decreased
conscious level) are present
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Magnesium additionally if torsade
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Metabolic acidosis
• Definition: process that lowers serum HCO3• Occurs when H+ ion production exceeds body’s
ability to compensate adequately via buffering or
ventilation
Mechanisms of metabolic acidosis in poisoning
• Increased acid production
• Impaired acid elimination
Mechanisms of increased acid production
• Poisons are acids (eg HCl vs. sulphuric acid)
• Poisons have acid metabolites (eg metabolism of
alcohols to acids)
• Poisons affect ATP consumption/production in
mitochondria (eg pcm, valproate, ARVs, metformin,
CO, cyanide, formate, +++ adrenergic stimulation)
[uncoupling oxidative phosphorylation or inhibiting
cytochromes of the electron transport chain]
• Poisons create ketoacids (eg ethanol, isoniazid)
Mechanisms of impaired acid elimination
• Toxic metabolites damage kidneys (ethylene glycol)
• Poison causes distal RTA (eg toluene)
Calculations
• Note the low pH (or high H+)
• Then calculate Anion Gap (AG)
AG = [Na+] – ([Cl-] + [HCO3-])
Usual range = 12 +/- 4 m/Eq/L (more recently 7 +/- 4)
• If toxic alcohols suspected, calculate osmolality:
2 x [Na+] + [glucose] + [urea] and
request a measured osmolality on a blood sample
Osmol Gap = measured osmolality – calculated
osmolality
AG & metabolic acidosis
• High AG
Occurs when an acid is paired with an unmeasured
anion (eg lactate, formate)
• Normal AG
Occurs with gain of both H+ and Cl- ions, or a loss of
HCO3- and retention of Cl-, preserving
electroneutrality
• However, AG can be affected by errors of calculation
or assay and by many disease states.
So the lack of a high AG does not exclude any
particular cause
Use of the osmol gap in patients with a high AG
metabolic acidosis
• Osmol gap may provide extra information if a toxic
alcohol is suspected.
• However, be aware that other medical conditions
such as ketoacidosis and renal failure also cause a
raised OG
• Normal osmol gap = less than 10 +/- 6 mOsm/L
• However, normal range has problems due to wide
variability between people and assays
Toxins associated with a high osmol gap
• Mannitol
• Alcohols: ethanol, etylene glycol, isopropanol,
methanol, propylene glycol
• Diatrizoate (amidothizoate)
• Glycerol
• Acetone
• Sorbitol
Metabolism of toxic alcohols
• Ethylene glycol
• Methanol
• Glyceraldehyde
• Formaldehyde
• Glycolate
• Formate
• Glyoxylate
• Oxalate
The mountain
Mycyk & Aks, 2003
METHANOL & ETHYLENE GLYCOL
• action - CNS depressants
metabolic toxicity secondary to metabolites
- formic acid, aldehydes
- renal failure, blindness
• Treatment
- block metabolic production
- ethanol
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- fomepizole
increase removal- dialysis
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Metabolism of toxic alcohols
• Ethylene glycol
• Methanol
• Glyceraldehyde
• Formaldehyde
• Glycolate
• Formate
• Glyoxylate
• Oxalate
DELIBERATE RELEASE
• Irritant gases• Toxic chemicals• Nerve agents-
Chlorine
Cyanide
sarin, VX
• Infective agents-
anthrax
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NERVE AGENTS
Cholinesterase inhibitors
– Bronchorrhoea
– Increased gut motility
– Small pupils
– CNS activity, Fits
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Atropine
Oximes
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CARE AFTER RECOVERY
1. psycho-social assessment
2. approximately 15% of patients have
psychiatric illness
3. most never re-attend with self harm
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