Acute PoisoningMichael Eddleston

NPIS EdinburghSpR in Clinical Toxicology, RIE

NPIS

Edinburgh

THE IMPORTANCE OF PHARMACOLOGYYou 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 of the physiological action of drugs.What to do in cases of poisoning, William Murrell, 1925

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Edinburgh

EPIDEMIOLOGYmost 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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Edinburgh

APPRAISAL OF THE POISONED PATIENThistory from patienttablets / circumstances foundclinical features (TOXIDROMES)Opiateanticholinergicstimulantmetabolic acidosis

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Edinburgh

Gastric lavageWard 3, Royal Infirmary of Edinburgh, 1973(courtesy of Alex Proudfoot)

PREVENTION OF ABSORPTION

activated charcoalbinds non-specificallybinds about 1/10 of charcoal weight(charcoal dose 50 g in an adult)Slow release products

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Edinburgh

Christophersen et al, Br J Clin Pharmacol 2002; 53: 312-7.

ACTIVATED CHARCOAL

timing - use within 1 hourairway - dont if problemsagent - eg iron, lithium, hydrocarbons NOT bound

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Edinburgh

PARACETAMOLNPIS

EdinburghPROBLEMSIndications for treatmentStaggered overdoseLate presentationsReactions to antidoteInterpretation of results in poisoning

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Edinburgh

ParacetamolQuantity Activity Quantity RISK FACTORS IN PARACETAMOL OD

PARACETAMOL: RISK FACTORSNPIS

EdinburghNutritional deficiencyEating disordersAlcoholism Malabsorption syndromesAIDS?? Acute starvation(CLUE: Blood urea)

PARACETAMOL: RISK FACTORSNPIS

EdinburghEnzyme inducers: carbamazepinephenytoinbarbituratesrifampicinSt Johns wortchronic ethanol

PARACETAMOL: RISK FACTORSNPIS

EdinburghEnzyme inducers: carbamazepinephenytoinbarbituratesrifampicinSt Johns wortchronic ethanol

CLUE: Gamma GT

Schmidt et al Hepatol 2002; 35: 876-882.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 Coxs F test)

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Edinburgh

ParacetamolQuantity Activity Quantity RISK FACTORS IN PARACETAMOL OD

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Edinburgh

Outcome ALT >1000 related to original plasma level and time of ingestion- ORAL NACRumack 2002 Clin Toxicol 40: 3-20.

Current use of AcetylcysteineNPIS

Edinburgh Before 4 hours- WAIT until 4 hours4-8 Hours- Blood sample and wait **8- 24 Hours- Treat on history, do bloodsAfter 24 hours- Do bloods unless toxic

STAGGERED INGESTION use first dose time for treatment decisions**ASSUMES RESULT SOON

What to do if patient presents >20h post ingesionNPIS

EdinburghDo 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

PARACETAMOL: ANTIDOTENPIS

EdinburghAcetylcysteine IV

Adverse effects Vomiting flushinghypotensionbronchospasm Anaphylactoid reaction - treat with antihistamines

Intravenous acetylcysteineNPIS

Edinburghadverse reactions common Treatment is symptomatic: antihistamine and beta agonists. NOT ANAPHYLAXISfatalities 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.

Risk factors for ADRs to acetylcysteine NPIS

Edinburghasthmatics 2.9 (95% CI 2.1, 4.7) more likely to develop ADR allergy to other medicines not a risk factor

Schmidt and Dalhoff. BJCP 2001:51; 87-91)

What to do after 20 hours antidote?? NPIS

EdinburghTransaminase, sensitive. If normal or less than 2x elevated risk of hepatotoxicity is low

INR more specific, if above 1.3

ALWAYS also check creatinine

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 POISONINGcardiac effects - diltiazem, verapamil

peripheral effects - dihydropyridines (eg nifedipine, amlodipine)

Both seen in overdoseBeware bradycardic hypotensive patient

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Edinburgh

MANAGEMENT OF CALCIUM ANTAGONIST POISONINGCNS effects often seen late

hypotension and rhythm disturbance

hyperglycaemia and lactic acidosis

beware slow release preparations

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Edinburgh

TREATMENT OF CALCIUM ANTAGONIST POISONINGatropinecalciumglucagoncatecholaminescardiac pacinginsulin and glucose

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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 verapamil1 amlodipine and atenolol

Yuan et al. Clin Tox 1999; 37, 463-74 NPIS

Edinburgh

ANTIDEPRESSANTSTricyclicsamitriptyline dosulepinSNRIvenlafaxineSSRIsparoxetinefluoxetinesertralinecitalopramNRIreboxetine

Presynaptic -2 antgstmirtazepine

MAOIphenelzineSMAOImoclobemide

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Edinburgh

TRICYCLICSACTIONSAmine reuptake inhibitorsAnticholinergicsMembrane effects (Na channel blockade)AntihistamineTOXICITYArrythmias and fits

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Edinburgh

ANTIDEPRESSANTSECG of patient at risk:QRS > 100ms possible arrythmia (higher risk for fits) > 160ms definite arrythmia

Dosulepin (Dothiepin ) most toxic

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Edinburgh

ANTIDEPRESSANTSTreatment of patient at risk:Monitor using serial 12 lead ECGsConsider Bicarbonate IV if risk factors (QRS >100, and decreased conscious level) are present

Magnesium additionally if torsade

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Edinburgh

Metabolic acidosisDefinition: process that lowers serum HCO3-Occurs when H+ ion production exceeds bodys ability to compensate adequately via buffering or ventilation

Mechanisms of metabolic acidosis in poisoningIncreased acid productionImpaired acid elimination

Mechanisms of increased acid productionPoisons 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 eliminationToxic metabolites damage kidneys (ethylene glycol)Poison causes distal RTA (eg toluene)

CalculationsNote 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] andrequest a measured osmolality on a blood sample

Osmol Gap = measured osmolality calculated osmolality

AG & metabolic acidosisHigh AGOccurs when an acid is paired with an unmeasured anion (eg lactate, formate)

Normal AGOccurs 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 acidosisOsmol 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/LHowever, normal range has problems due to wide variability between people and assays

Toxins associated with a high osmol gapMannitolAlcohols: ethanol, etylene glycol, isopropanol, methanol, propylene glycolDiatrizoate (amidothizoate)GlycerolAcetoneSorbitol

Metabolism of toxic alcoholsEthylene glycol

Glyceraldehyde

Glycolate

Glyoxylate

Oxalate

Methanol

Formaldehyde

Formate

The mountainMycyk & Aks, 2003

METHANOL & ETHYLENE GLYCOL

action - CNS depressantsmetabolic toxicity secondary to metabolites- formic acid, aldehydes- renal failure, blindnessTreatment - block metabolic production- ethanol- fomepizoleincrease removal- dialysis

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Edinburgh

Metabolism of toxic alcoholsEthylene glycol

Glyceraldehyde

Glycolate

Glyoxylate

Oxalate

Methanol

Formaldehyde

Formate

DELIBERATE RELEASE

Irritant gases- ChlorineToxic chemicals- CyanideNerve agents- sarin, VX

Infective agents-anthrax

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Edinburgh

NERVE AGENTS

Cholinesterase inhibitorsBronchorrhoeaIncreased gut motilitySmall pupilsCNS activity, Fits

AtropineOximes

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Edinburgh

CARE AFTER RECOVERYNPIS

Edinburgh1. psycho-social assessment 2. approximately 15% of patients have psychiatric illness3. most never re-attend with self harm

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