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
NPIS
of the physiological action of drugs.”
What to do in cases of poisoning, William Murrell, 1925
Edinburgh
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
NPIS
Edinburgh
APPRAISAL OF THE POISONED
PATIENT
• history from patient
• tablets / circumstances found
• clinical features (“TOXIDROMES”)
» Opiate
» anticholinergic
» stimulant
» metabolic acidosis
NPIS
Edinburgh
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)
NPIS
• Slow release products
Edinburgh
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
NPIS
Edinburgh
PARACETAMOL
PROBLEMS
• Indications for treatment
• Staggered overdose
• Late presentations
• Reactions to antidote
• Interpretation of results in poisoning
NPIS
Edinburgh
Paracetamol
Quantity
Activity
Quantity
NPIS
RISK FACTORS IN PARACETAMOL OD
Edinburgh
PARACETAMOL: RISK FACTORS
Nutritional deficiency
Eating disorders
Alcoholism
Malabsorption syndromes
AIDS
?? Acute starvation
(CLUE: Blood urea)
NPIS
Edinburgh
PARACETAMOL: RISK FACTORS
Enzyme inducers:
carbamazepine
phenytoin
barbiturates
rifampicin
St Johns wort
chronic ethanol
NPIS
Edinburgh
PARACETAMOL: RISK FACTORS
Enzyme inducers:
carbamazepine
phenytoin
barbiturates
rifampicin
St Johns wort
chronic ethanol
NPIS
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
NPIS
RISK FACTORS IN PARACETAMOL OD
Edinburgh
NPIS
Edinburgh
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
•
•
•
•
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
NPIS
for treatment decisions
**ASSUMES RESULT SOON
Edinburgh
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
NPIS
Edinburgh
PARACETAMOL: ANTIDOTE
Acetylcysteine IV
Adverse effects
Vomiting
flushing
hypotension
bronchospasm
NPIS
Anaphylactoid reaction - treat
with antihistamines
Edinburgh
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.
NPIS
Edinburgh
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
NPIS
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
NPIS
Edinburgh
STIMULANTS
•
•
•
•
•
•
amphetamine
ecstasy
cocaine
LSD
psilocybe mushrooms
phencyclidine
NPIS
Edinburgh
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
NPIS
Edinburgh
CALCIUM ANTAGONIST
POISONING
• cardiac effects - diltiazem, verapamil
• peripheral effects - dihydropyridines
(eg nifedipine, amlodipine)
Both seen in overdose
Beware bradycardic hypotensive patient
NPIS
Edinburgh
MANAGEMENT OF CALCIUM
ANTAGONIST POISONING
• CNS effects often seen late
• hypotension and rhythm disturbance
• hyperglycaemia and lactic acidosis
NPIS
• beware slow release preparations
Edinburgh
TREATMENT OF CALCIUM
ANTAGONIST POISONING
•
•
•
•
•
•
atropine
calcium
glucagon
catecholamines
cardiac pacing
insulin and glucose
NPIS
Edinburgh
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
NPIS
Yuan et al. Clin Tox 1999; 37, 463-74
Edinburgh
ANTIDEPRESSANTS
Tricyclics
SNRI
SSRIs
NRI
amitriptyline dosulepin
venlafaxine
paroxetine fluoxetine
sertraline citalopram
reboxetine
Presynaptic -2 antgst
mirtazepine
NPIS
MAOI
SMAOI
phenelzine
moclobemide
Edinburgh
TRICYCLICS
ACTIONS
Amine reuptake inhibitors
Anticholinergics
Membrane effects (Na channel blockade)
Antihistamine
NPIS
TOXICITY
Arrythmias and fits
Edinburgh
ANTIDEPRESSANTS
ECG of patient at risk:
QRS > 100ms possible arrythmia
(higher risk for fits)
> 160ms definite arrythmia
Dosulepin (Dothiepin )
most toxic
NPIS
Edinburgh
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
NPIS
Magnesium additionally if torsade
Edinburgh
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
NPIS
- fomepizole
increase removal- dialysis
Edinburgh
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
NPIS
Edinburgh
NERVE AGENTS
Cholinesterase inhibitors
– Bronchorrhoea
– Increased gut motility
– Small pupils
– CNS activity, Fits
NPIS
Atropine
Oximes
Edinburgh
CARE AFTER RECOVERY
1. psycho-social assessment
2. approximately 15% of patients have
psychiatric illness
3. most never re-attend with self harm
NPIS
Edinburgh