Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 11) doc

Poisoning, overdose, antidotes SYNOPSIS Deliberate and accidental self-poisoning Principles of treatment Poison-specific measures General measures Specific poisonings: cyanide, methanol,

Poisoning, overdose, antidotes

SYNOPSIS

Deliberate and accidental self-poisoning

Principles of treatment

Poison-specific measures

General measures

Specific poisonings: cyanide, methanol,

ethylene glycol, hydrocarbons, volatile

solvents, heavy metals, herbicides and

pesticides, biological substances (overdose of

medicinal drugs is dealt with under individual

agents)

Incapacitating agents: drugs used for torture

drugs, and psychotropic drugs is increasing Re-peated episodes are not rare.1 Prescribed drugs are used in over 75% of episodes but teenagers tend to favour nonprescribed analgesics available by direct sale, e.g paracetamol, which is important bearing

in mind its potentially serious toxicity The mortality rate of self-poisoning is very low (less than 1% of acute hospital admissions), but 'completed' suicides by poisoning still number 3500 per annum in England and Wales

Accidental self-poisoning causing admission to hospital occurs predominantly amongst children under 5 years, usually with medicines left within their reach or with domestic chemicals, e.g bleach, detergents

Self-poisoning

Deliberate self-poisoning A curious by-product

of the modern 'drug and prescribing explosion'

is the rise in the incidence of nonfatal deliberate

self-harm The majority of people who do this lack

serious suicidal intent and are therefore termed

parasuicides In over 90% of instances in the UK,

poisoning is the means chosen, usually by

medi-cines taken in overdose and these amount to at least

70 000 hospital admissions per annum in England

and Wales (population 51 million) Two or more

drugs are taken in over 30% of episodes, not

including alcohol which is also taken in over 50%

of the instances; the use of hypnotic and sedative

Principles of treatment

Successful treatment of acute poisoning depends on

a combination of speed and common sense, as well

as on the nature of the poison, the amount taken and the time which has since elapsed The majority

of those admitted to hospital require only observa-tion and medical and nursing supportive measures

1 An extreme example is that of a young man who, over a period of 6 years, was admitted to hospital following 82 episodes of self-poisoning, 31 employing paracetamol; he had had a disturbed, unhappy upbringing and had been expelled from both the Danish Navy and the British Army Prescott L F et al 1978 British Medical Journal 2: 1399.

9 P O I S O N I N G , O V E R D O S E , A N T I D O T E S

while they metabolise and eliminate the poison

Some require a specific antidote or a specific

measure to increase elimination Intensive care

facilities are needed by only a few In the UK

the centres of the National Poisons Information

Service provide information and advice over the

telephone throughout the day and night.2

Poison-specific measures

IDENTIFICATION OF THE POISON(S)

The key pieces of information are:

• the identity of the substance(s) taken

• the dose(s)

• the time that has since elapsed Adults may be

sufficiently conscious to give some indication of

the poison or may have referred to it in a suicide

note, or there may be other circumstantial

evidence Rapid (1-2 h) biochemical 'screens' of

plasma or urine are available but are best reserved

for seriously ill or unconscious patients in whom

the cause of coma is unknown Analysis of plasma

for specific substances is essential in suspected

cases of paracetamol or iron poisoning, to indicate

which patients should receive antidotes; it is also

required for salicylate, lithium and some sedative

drugs, e.g trichloroethanol derivatives,

phenobarbitone, when a decision is needed about

using urine alkalinisation, haemodialysis or

haemoperfusion Response to a specific antidote

may provide a diagnosis, e.g dilatation of

constricted pupils and increased respiratory rate

after i.v naloxone (opioid poisoning) or arousal

from unconsciousness in response to i.v

flumazenil (benzodiazepine poisoning)

PREVENTION OF FURTHER

ABSORPTION OF THE POISON

From the environment

When a poison has been inhaled or absorbed

through the skin, the patient should be taken from

2 Telephone numbers are to be found in the British National

Formulary (BNF).

the toxic environment, the contaminated clothing removed and the skin cleansed

From the gut

Oral adsorbents Activated charcoal (Carbomix, Medicoal) reduces drug absorption better than syrup of ipecacuanha or gastric lavage, is easiest

to administer and has fewest adverse effects It consists of a very fine black powder prepared from vegetable matter, e.g wood pulp, coconut shell, which is 'activated' by an oxidising gas flow at high temperature to create a network of fine (10-20-nm) pores to give it an enormous surface area in relation to weight (1000 m2/g) This binds

to, and thus inactivates, a wide variety of compounds in the gut Thus it is simpler to list the exceptions, i.e substances that are not adsorbed

by charcoal which are: iron, lithium, cyanide, strong acids and alkalis, and organic solvents and corrosive agents

Indeed, activated charcoal comes nearest to fulfilling the long-sought notion of a 'universal antidote'.3 It should be given as soon as possible after a potentially toxic amount of a poison has been ingested, and whilst a significant amount remains yet unabsorbed (thus ideally within 1 h)

To be most effective, 5-10 times as much charcoal as poison, weight for weight, is needed; in the adult

an initial dose of 50-100 g is usual If the patient

is vomiting, the charcoal should be given through

a nasogastric tube Activated charcoal also accelerates elimination of poison that has been absorbed (see p 155)

Activated charcoal, although unpalatable, appears

to be relatively safe but constipation or mechanical bowel obstruction may be caused by repeated use Aspiration of charcoal into the lungs can cause hypoxia through obstruction and arteriovenous shunting Charcoal adsorbs and thus inactivates

3 For centuries it was supposed not only that there could be, but that there actually was, a single antidote to all poisons This was Theriaca Andromachi, a formulation of 72 (a magical number) ingredients amongst which particular importance was attached to the flesh of a snake (viper) The antidote was devised by Andromachus whose son was physician to the Roman Emperor, Nero (AD 37-68).

ipecacuanha but may be used after successful

emesis if this method has been deemed necessary;

methionine, used orally for paracetamol poisoning,

is also adsorbed

Other oral adsorbents have specific uses Fuller's

earth and bentonite (both natural forms of

alumi-nium silicate) bind and inactivate the herbicides,

paraquat (activated charcoal is superior) and diquat;

cholestyramine and colestipol will adsorb warfarin

Gastric lavage incurs dangers as well as benefits; it

is best confined to the hospitalised adult who is

believed to have taken a potentially life-threatening

amount of a poison within 1 h (or longer in the case

of drugs that delay gastric emptying, e.g aspirin,

tricyclic antidepressants, sympathomimetics,

theo-phylline, opioids) Lavage is probably worth

under-taking in any unconscious patient who is believed

to have ingested poison, and provided the airways

are protected by a cuffed endotracheal tube

Para-doxically, lavage may wash an ingested substance

into the small intestine, enhancing its absorption

Leaving activated charcoal in the stomach after

lavage is appropriate to lessen this risk

Neverthe-less, patients who have ingested tricyclic

anti-depressants or centrally depressant drugs must be

subject to continued monitoring after the lavage

The passing of a gastric tube, naturally, takes

second place to emergency resuscitative measures,

institution of controlled respiration or suppression

of convulsions Nothing is gained by aspirating the

stomach of a corpse

Emesis has been used for children and also for

adults who refuse activated charcoal or gastric

lavage, or if the poison is not absorbed by activated

charcoal Its routine use in emergency departments

has been abandoned, as there is no clinical trial

evidence that the procedure improves outcome

for poisoned patients Emesis is induced, in fully

conscious patients only, by Ipecacuanha Emetic

Mixture, Pediatric (BNF), 10 ml for a child 6-18

months, 15 ml for an older child and 30 ml for an

adult, i.e all ages may receive the same preparation

but in a different dose, which is followed by a

tumblerful of water (250 ml) The active constituent

of ipecacuanha is emetine; it can cause prolonged

vomiting, diarrhoea and drowsiness that may be

confused with effects of the ingested poison Even

P O I S O N - S P E C I F I C M E A S U R E S

fully conscious patients may develop aspiration pneumonia after ipecacuanha

Both emesis and lavage are contraindicated for corrosive poisons, because there is a risk of perfora-tion of the gut, and for petroleum distillates, as the danger of causing inhalational chemical pneumonia outweighs that of leaving the substance in the stomach

Cathartics or whole-bowel irrigation4 have been used for the removal of sustained-release formula-tions, e.g theophylline, iron, aspirin Evidence of benefit is conflicting Activated charcoal in repeated (10 g) doses is generally preferred Sustained-release formulations are now common, and patients have died from failure to recognise the danger of continued release of drug from such products, after apparently successful gastric lavage

Specific antidotes reduce or abolish the effects of poisons through a variety of mechanisms, which may be categorised as follows:

• receptors, which may be activated, blocked or bypassed

• enzymes, which may be inhibited or reactivated

• displacement from tissue binding sites

• exchanging with the poison

• replenishment of an essential substance

• binding to the poison (including chelation)

4 Irrigation with large volumes of a polyethylene glycol-electrolyte solution, e.g Klean-Prep, by mouth causes minimal fluid and electrolyte disturbance (it was developed for preparation for colonoscopy) Magnesium sulphate may also be used.

5 Mithridates the Great (7132-63 BC) king of Pontus (in Asia Minor) was noted for 'ambition, cruelty and artifice' 'He murdered his own mother and fortified his constitution

by drinking antidotes' to the poisons with which his domestic enemies sought to kill him (Lempriere) When his son also sought to kill him, Mithridates was so disappointed that he compelled his wife to poison herself He then tried to poison himself, but in vain; the frequent antidotes which he had taken in the early part of his life had so strengthened his constitution that he was immune He was obliged to stab himself, but had to seek the help of a slave to complete his task Modern physicians have to be content with less comprehensively effective antidotes, some of which are listed in Table 9.1.

9 P O I S O N I N G , O V E R D O S E , A N T I D O T E S

TABLE 9.1 Some specific antidotes, indications and modes of action (see Index for a fuller account of individual drugs)

acetylcysteine

atropine

benzatropine

calcium gluconate

desferrioxamine

dicobalt edetate

digoxin-specific antibody

fragments (FAB)

dimercaprol (BAL)

ethanol

flumazenil

folinic acid

glucagon

isoprenaline

methionine

naloxone

neostigmine

oxygen

penicillamine

phenoxybenzamine

phentolamine

phytomenadione

(vitamine K 1 )

pralidoxime

propranolol

protamine

Prussian blue (potassium

ferric hexacyanoferrate)

sodium calciumedetate

unithiol

paracetamol, chloroform, carbon tetrachloride cholinesterase inhibitors, e.g organophosphorus insecticides

p-blocker poisoning drug-induced movement disorders hydrofluoric acid, fluorides iron

cyanide and derivatives, e.g acrylonitrile digitalis glycosides

arsenic, copper, gold, lead, inorganic mercury ethylene glycol, methanol

benzodiazepines folic acid antagonists e.g methotrexate, trimethoprim

P-adrenoceptor antagonists

p-adrenoceptor antagonists paracetamol

opioids antimuscarinic drugs carbon monoxide copper, gold, lead, elemental mercury (vapour), zinc hypertension due to oc-adrenoceptor agonists, e.g with MAOI, clonidine, ergotamine

as above coumarin (warfarin) and indandione anticoagulants

cholinesterase inhibitors, e.g organophosphorus insecticides

P-adrenoceptor agonists, ephedrine, theophylline, thyroxine

heparin thallium (in rodenticides) lead

lead, elemental and organic mercury

Replenishes depleted glutathione stores Blocks muscarinic cholinoceptors Vagal block accelerates heart rate Blocks muscarinic cholinoceptors Binds or precipitates fluoride ions Chelates ferrous ions

Chelates to form nontoxic cobalti-and cobalto-cyanides

Binds free glycoside in plasma, complex excreted

in urine Chelates metal ions Competes for alcohol and acetaldehyde dehydrogenases, preventing formation of toxic metabolites

Competes for benzodiazepine receptors Bypasses block in folate metabolism Bypasses blockade of the B-adrenoceptor;

stimulates cyclic AMP formation with positive cardiac inotropic effect

Competes for p-adrenoceptors Replenishes depleted glutathione stores Competes for opioid receptors Inhibits acetylcholinesterase, causing acetylcholine

to accumulate at cholinoceptors Competitively displaces carbonmonoxide from binding sites on haemoglobin

Chelates metal ions Competes for oc-adrenoceptors (long-acting) Competes for oc-adrenoceptors (short-acting) Replenishes vitamin K

Competitively reactivates cholinesterase Blocks P-adrenoceptors

Binds ionically to neutralise Potassium exchanges for thallium Chelates lead ions

Chelates metal ions

Table 9.1 illustrates these mechanisms with

antidotes that are of therapeutic value

CHELATING AGENTS

Chelating agents are used for poisoning with heavy

metals They incorporate the metal ions into an inner

ring structure in the molecule (Greek: chele, claw) by

means of structural groups called ligands (Latin:

ligare, to bind); effective agents form stable,

biolog-ically inert complexes that are excreted in the urine

Dimercaprol (British Anti-Lewisite, BAL) Arsenic

and other metal ions are toxic in low concentration because they combine with the SH groups of essential enzymes, thus inactivating them Dimer-caprol provides SH groups which combine with the metal ions to form relatively harmless ring compounds which are excreted, mainly in the urine

As dimercaprol, itself, is oxidised in the body and renally excreted, repeated administration is necessary to ensure that an excess is available until all the metal has been eliminated

Dimercaprol may be used in cases of poisoning

by antimony, arsenic, bismuth, gold and mercury

(inorganic, e.g HgCl2)

Adverse effects are common, particularly with

larger doses, and include nausea and vomiting,

lachrymation and salivation, paraesthesiae,

muscu-lar aches and pains, urticarial rashes, tachycardia

and a raised blood pressure Gross overdosage may

cause overbreathing, muscular tremors,

convul-sions and coma

Unithiol (dimercaptopropanesulphonate, DMPS)

effectively chelates lead and mercury; it is well

tolerated

Sodium calciumedetate is the calcium chelate of

the disodium salt of ethylenediaminetetra-acetic

acid (calcium EDTA) It is effective in acute lead

poisoning because of its capacity to exchange

calcium for lead: the lead chelate is excreted in

the urine, leaving behind a harmless amount of

calcium Dimercaprol may usefully be combined

with sodium calciumedetate when lead poisoning

is severe, e.g with encephalopathy

Adverse effects are fairly common, and include

hypotension, lachrymation, nasal stuffiness,

sneez-ing, muscle pains and chills Renal damage can

occur

Dicobalt edetate Cobalt forms stable, nontoxic

complexes with cyanide It is toxic (especially if

the wrong diagnosis is made and no cyanide is

present), causing hypertension, tachycardia and

chest pain; consequent cobalt poisoning is treated

by giving sodium calcium edetate and i.v glucose

Penicillamine (dimethylcysteine) is a metabolite of

penicillin that contains SH groups; it may be used

to chelate lead and also copper (see Hepatolenticular

degeneration) Its principal use is for rheumatoid

arthritis (see Index)

Desferrioxamine: see Iron.

ACCELERATION OF ELIMINATION OF

THE POISON

Techniques for eliminating poisons have a role

that is limited, but important when applicable

P O I S O N - S P E C I F I C M E A S U R E S

Each method depends, directly or indirectly, on removing drug from the circulation and successful use requires that:

• The poison should be present in high concentration in the plasma relative to that in the rest of the body, i.e it should have a small distribution volume

• The poison should dissociate readily from any plasma protein binding sites

• The effects of the poison should relate to its plasma concentration

Methods used are:

Repeated doses of activated charcoal

Activated charcoal by mouth not only adsorbs ingested drug in the gut, preventing absorption into the body (see above), it also adsorbs drug that diffuses from the blood into the gut lumen when the concentration there is lower; because binding is irreversible the concentration gradient is main-tained and drug is continuously removed; this has been called 'intestinal dialysis' Charcoal may also adsorb drugs that are secreted into the bile, i.e

by interrupting an enterohepatic cycle Evidence shows that activated charcoal in repeated doses effectively adsorbs (shortens t1/2 of) phenobarbital (phenobarbitone), carbamazepine, theophylline, quinine, dapsone and salicylate.6 Repeated-dose activated charcoal is increasingly preferred to alkalinisation of urine (below) for phenobarbitone and salicylate poisoning Activated charcoal in an initial dose of 50-100 g should be followed by not less than 12.5 g/h; the regular hourly administra-tion is more effective than larger amounts less often

Alteration of urine pH and diuresis

By manipulation of the pH of the glomerular filtrate, a drug can be made to ionise, become less lipid-soluble, remain in the renal tubular fluid, and

so be eliminated in the urine (see p 97) Mainte-nance of a good urine flow (e.g 100 ml/h) helps this process but it is the alteration of tubular fluid

pH that is all important The practice of forcing

6 Bradberry S M, Vale A J 1995 Journal of Toxicology: Clinical Toxicology 33(5): 407-416.

9 P O I S O N I N G , O V E R D O S E , A N T I D O T E S

diuresis with frusemide (furosemide) and large

volumes of i.v fluid does not add significantly to

drug clearance but may cause fluid overload; it is

obsolete Alkalinisation may be used for salicylate

(>500mg/l + metabolic acidosis, or in any case

> 750 mg/1), phenobarbital (75-150 mg/1) or phenoxy

herbicides, e.g 2,4-D, mecoprop, dichlorprop The

objective is to maintain a urine pH of 7.5-8.5 by an

i.v infusion of sodium bicarbonate Available

preparations of sodium bicarbonate vary between

1.2 and 8.4% (1 ml of the 8.4% preparation contains

1 mmol of sodium bicarbonate) and the

con-centration given will depend on the patient's fluid

needs

Acidification may be used for severe, acute

amphetamine, dexfenfluramine or phencyclidine

poisoning The objective is to maintain a urine pH

of 5.5-6.5 by giving i.v infusion of arginine

hydro-chloride (10 g) over 30 min, followed by ammonium

chloride (4 g) 2-hourly by mouth It is rarely

necessary Phenoxybenzamine should be adequate

for amphetamine-like drugs (a-adrenoceptor block)

Such artificial methods of removing poison from the body are invasive, demand skill and experience

on the part of the operator and are expensive in manpower Their use should therefore be confined

to cases of severe, prolonged or progressive clinical intoxication, when high plasma concentration indi-cates a dangerous degree of poisoning, and when removal by haemoperfusion or dialysis constitutes

a significant addition to natural methods of elimination

• Haemodialysis is effective for: salicylate (> 750 mg/1 + renal failure, or in any case

> 900 mg/1), isopropanol (present in aftershave lotions and window-cleaning solutions), lithium and methanol

• Haemoperfusion is effective for: phenobarbitone (> 100-150 mg/1, but repeat-dose activated charcoal by mouth appears to be as effective, see above) and other barbiturates, ethchlorvynol, glutethimide, meprobamate, methaqualone, theophylline, trichloroethanol derivatives

Peritoneal dialysis

Peritoneal dialysis involves instilling appropriate

fluid into the peritoneal cavity Poison in the blood

diffuses into the dialysis fluid down the

concen-tration gradient The fluid is then drained and

replaced The technique requires little equipment

but is one-half to one-third as effective as

haemo-dialysis; it may be worth using for lithium and

methanol poisoning

Haemodialysis and haemoperfusion

A temporary extracorporeal circulation is established,

usually from an artery to a vein in the arm In

hae-modialysis, a semipermeable membrane separates

blood from dialysis fluid and the poison passes

passively from the blood, where it is present in high

concentration The principle of haemoperfusion

is that blood flows over activated charcoal or an

appropriate ion-exchange resin which adsorbs

the poison Loss of blood cells and activation of

the clotting mechanism are largely overcome by

coating the charcoal with an acrylic hydrogel which

does not reduce adsorbing capacity, though the

patient must be anticoagulated with heparin

General measures

INITIAL ASSESSMENT AND RESUSCITATION

The initial clinical review should include a search for known consequences of poisoning, which include: impaired consciousness with flaccidity (benzodiazepines, alcohol, trichloroethanol) or with hypertonia (tricyclic antidepressants, antimuscarinic agents), hypotension, shock, cardiac arrhythmia, evidence of convulsions, behavioural disturbances (psychotropic drugs), hypothermia, aspiration pneu-monia and cutaneous blisters, burns in the mouth (corrosives)

Maintenance of an adequate oxygen supply is the

first priority A systolic blood pressure of 80 mmHg can be tolerated in a young person but a level below

90 mmHg will imperil the brain or kidney of the elderly Expansion of the venous capacitance bed

is the usual cause of shock in acute poisoning and blood pressure may be restored by placing the patient in the head-down position to encourage venous return to the heart, or by the use of a colloid

plasma expander such as gelatin or etherified starch

External cardiac compression may be necessary and

should be continued until the cardiac output is

self-sustaining, which may be a long time when

the patient is hypothermic or poisoned with

cardio-depressant drugs, e.g tricyclic anticardio-depressants,

(3-adrenoceptor blockers The airway must be sucked

clear of oropharyngeal secretions or regurgitated

matter

Supportive treatment

The salient fact is that patients recover from most

poisonings provided they are adequately

oxy-genated, hydrated and perfused, for, in the majority

of cases, the most efficient mechanisms are the

patients' own and, given time, they will inactivate

and eliminate all the poison Patients require the

standard care of the unconscious, with special

attention to the problems introduced by poisoning

which are outlined below

Airway maintenance is essential; some patients

require a cuffed endotracheal tube but seldom for

more than 24 h

Ventilation needs should be assessed, if necessary

supported by blood gas analysis A mixed

respira-tory and metabolic acidosis is common Hypoxia

may be corrected by supplementing the inspired

air with oxygen but mechanical ventilation is

necessary if the PaCO2 exceeds 6.5 kPa

Hypotension is common and in addition to the

resuscitative measures indicated above, infusion of

a combination of dopamine and dobutamine in low

dose may be required to maintain renal perfusion

Convulsions should be treated if they are

persistent or protracted Diazepam i.v is the first

choice

Cardiac arrhythmia frequently accompanies

poison-ing, e.g with tricyclic antidepressants, theophylline,

B-adrenoceptor blockers Acidosis, hypoxia and

electrolyte disturbance are often important

contri-butory factors; the emphasis of therapy should be

to correct these and to resist the temptation to resort

to an antiarrhythmic drug If arrhythmia leads

S O M E P O I S O N I N G S

to persistent peripheral circulatory failure, then

an appropriate drug ought to be used, e.g a p-adrenoceptor blocker for poisoning with a sympathomimetic drug

Hypothermia may occur if temperature regulation

is impaired by CNS depression Core temperature must be monitored by a low-reading rectal ther-mometer, while the patient is nursed in a heat retain-ing 'space blanket'

Immobility may lead to pressure lesions of

periph-eral nerves, cutaneous blisters and necrosis over bony prominences

Rhabdomyolysis may result from prolonged

press-ure on muscles, from agents that cause muscle spasm or convulsions (phencyclidine, theophylline)

or be aggravated by hyperthermia due to muscle contraction, e.g with MDMA ('ecstasy') Aggressive volume repletion and correction of acid-base abnor-mality may be needed, and urine alkalinisation may prevent acute tubular necrosis

PSYCHIATRIC AND SOCIAL ASSESSMENT

Most cases of self-poisoning are precipitated by interpersonal or social problems, which should be addressed Major psychiatric illness ought to be identified and treated

'There are said to be occasions when a wise man chooses suicide—but generally speaking it is not in

an excess of reasonableness that people kill themselves Most men and women die defeated '7

Some poisonings

(for medicines: see individual drugs)

Many substances used in accidental or

self-7 Voltaire (pseudonym of Francios-Marie Arouet, French writer, 1694-1778).

8 Based on Kulig K1992 New England Journal of Medicine 326:1677-1681.

9 P O I S O N I N G , O V E R D O S E , A N T I D O T E S

poisoning cause dysfunction of the central or

auto-nomic nervous systems and produce a variety of

effects which may be usefully grouped to aid the

identification of the agent(s) responsible

Antimuscarinic syndromes consist of tachycardia,

dilated pupils, dry, flushed skin, urinary retention,

decreased bowel sounds, mild elevation of body

temperature, confusion, cardiac arrhythmias and

seizures They are commonly caused by

antipsych-otics, tricyclic antidepressants, antihistamines,

anti-spasmodics and many plants (see p 160)

Cholinergic (muscarinic) syndromes comprise

sali-vation, lachrymation, abdominal cramps, urinary

and faecal incontinence, vomiting, sweating, miosis,

muscle fasciculation and weakness, bradycardia,

pulmonary oedema, confusion, CNS depression

and fitting Common causes include

organophos-phorus and carbamate insecticides, neostigmine

and other anticholinesterase drugs, and some fungi

(mushrooms)

Sympathomimetic syndromes include tachycardia,

hypertension, hyperthermia, sweating, mydriasis,

hyperreflexia, agitation, delusions, paranoia, seizures

and cardiac arrhythmias These are commonly

caused by amphetamine and its derivatives, cocaine,

proprietary decongestants, e.g ephedrine, and

theophylline (in the latter case, excluding

psych-iatric effects)

Sedatives, opioids and ethanol cause signs that

may include respiratory depression, miosis,

hypo-reflexia, coma, hypotension and hypothermia

Poisonings by (nondrug) chemicals

Cyanide causes tissue anoxia by chelating the

ferric part of the intracellular respiratory enzyme,

cytochrome oxidase Poisoning may occur as a

result of self-administration of hydrocyanic (prussic)

acid, by accidental exposure in industry, through

inhaling smoke from burning polyurethane foams

in furniture, through ingesting amygdalin which is

present in the kernels of several fruits including

apricots, almonds and peaches (constituents of

the unlicensed anticancer agent, laetrile), or from

excessive use of sodium nitroprusside for severe hypertension.9 The symptoms of acute poisoning are due to tissue anoxia, with dizziness, palpita-tions, a feeling of chest constriction and anxiety; characteristically the breath smells of bitter almonds

In more severe cases there is acidosis and coma Inhaled hydrogen cyanide may lead to death within minutes but when it is ingested as the salt several hours may elapse before the patient is seriously ill Chronic exposure damages the nervous system causing peripheral neuropathy, optic atrophy and nerve deafness

The principles of specific therapy are as follows:

• Dicobalt edetate to chelate the cyanide is the

treatment of choice when the diagnosis is certain (see p 155) The dose is 300 mg given i.v over one minute (5 min if condition is less serious), followed immediately by a 50 ml i.v infusion of glucose 50%; a further 300 mg of dicobalt edetate should be given if recovery is not evident within one minute

• Alternatively, a two-stage procedure may be followed by i.v administration of:

(1) sodium nitrite, which rapidly converts

haemoglobin to methaemoglobin, the ferric ion of which takes up cyanide as

cyanmethaemoglobin (up to 40%

methaemoglobin can be tolerated);

(2) sodium thiosulphate, which more slowly

detoxifies the cyanide by permitting the formation of thiocyanate When the diagnosis is uncertain, administration of thiosulphate plus oxygen is a safe course There is evidence that oxygen, especially if at high pressure (hyperbaric), overcomes the cellular

9 Or in other more bizarre ways 'A 23-year-old medical student saw his dog (a puppy) suddenly collapse He started external cardiac massage and a mouth-to-nose ventilation effort Moments later the dog died, and the student felt nauseated, vomited and lost consciousness On the victim's arrival at hospital, an alert medical officer detected a bitter almonds odour on his breath and administered the accepted treatment for cyanide poisoning after which he recovered It turned out that the dog had accidentally swallowed cyanide, and the poison eliminated through the lungs had been inhaled by the master during the mouth-to-nose resuscitation/ Journal of the American Medical Association

1983 249: 353.

anoxia in cyanide poisoning; the mechanism is

uncertain, but oxygen should be administered

Carbon monoxide (CO) is formed when substances

containing carbon and hydrogen are incompletely

combusted; poisoning results from inhalation

Oxygen transport to cells is impaired and

myo-cardial and neurological injury result; delayed (2-4

weeks) neurological sequelae include parkinsonism

and cerebellar signs The concentration of CO in

the blood may confirm exposure (cigarette smoking

alone may account for up to 10%) but is no guide to

the severity of poisoning Patients with signs of

cardiac ischaemia or neurological defect may be

treated with hyperbaric oxygen, although the

evi-dence for its efficacy is conflicting and transport

to hyperbaric chambers may present logistic

problems

Lead poisoning arises from a variety of

occupa-tional (such as house renovation and stripping

old paint), and recreational sources Environmental

exposure had been a matter of great concern, as

witness the protective legislation introduced by many

countries to reduce pollution, e.g by removing lead

from petrol

Lead in the body comprises a rapidly

exchange-able component in blood (2%, biological t1/, 35 d)

and a stable pool in dentine and the skeleton (95%,

biological t1/2 25 y)

In severe lead poisoning sodium calciumedetate

is commonly used to initiate lead excretion It

chelates lead from bone and the extracellular space

and urinary lead excretion of diminishes over 5 days

thereafter as the extracellular store is exhausted

Subsequently symptoms (colic and encephalopathy)

may worsen and this has been attributed to

redistri-bution of lead from bone to brain Dimercaprol

is more effective than sodium calciumedetate at

chelating lead from the soft tissues such as brain,

which is the rationale for combined therapy with

sodium calciumedetate More recently succimer

(2,3-dimercaptosuccinic acid, DMSA), a water-soluble

analogue of dimercaprol, has been increasingly

used instead Succimer has a high affinity for lead,

is suitable for administration by mouth and is better

tolerated (has a wider therapeutic index) than

dimercaprol It is licenced for such use in the USA

but not the UK

S O M E P O I S O N I N G S

Methanol is widely available as a solvent and in

paints and antifreezes, and may be consumed as a cheap substitute for ethanol As little as 10 ml may cause permanent blindness and 30 ml may kill, through its toxic metabolites Methanol, like ethanol,

is metabolised by zero-order processes that involve the hepatic alcohol and aldehyde dehydrogenases, but whereas ethanol forms acetaldehyde and acetic acid which are partly responsible for the unpleasant effects of 'hangover', methanol forms formaldehyde and formic acid Blindness may occur because aldehyde dehydrogenase present in the retina (for the interconversion of retinol and retinene) allows the local formation of formaldehyde Acidosis is due to the formic acid, which itself enhances pH-dependent hepatic lactate production, so that lactic acidosis is added

The clinical features are severe malaise, vomiting, abdominal pain and tachypnoea (due to the acidosis) Loss of visual acuity and scotomata indicate ocular damage and, if the pupils are dilated and non-reactive, permanent loss of sight is probable Coma and circulatory collapse may follow

Therapy is directed at:

• Correcting the acidosis Achieving this largely

determines the outcome; sodium bicarbonate is given i.v in doses up to 2 mol in a few hours, carrying an excess of sodium which must be managed Methanol is metabolised slowly and the patient may relapse if bicarbonate

administration is discontinued too soon

• Inhibiting methanol metabolism Ethanol, which

occupies the dehydrogenase enzymes in preference to methanol, competitively prevents metabolism of methanol to its toxic products A single oral dose of ethanol 1 ml/kg (as a 50% solution or as the equivalent in gin or whisky) is followed by 0.25 ml/kg/h orally or i.v., aiming

to maintain the blood ethanol at about

100 mg/100 ml until no methanol is detectable in

the blood Fomepizole (4-methylpyrazole), also a

competitive inhibitor of alcohol dehydrognase, has proved effective in severe methanol poisoning and is less likely to cause cerebral depression

• Eliminating methanol and its metabolites by

dialysis Haemodialysis is 2-3 times more effective than is peritoneal dialysis Folinic

9 P O I S O N I N G , O V E R D O S E , A N T I D O T E S

acid 30 mg i.v 6-hourly may protect against

retinal damage by enhancing formate

metabolism

Ethylene glycol is readily accessible as a

consti-tuent of antifreezes for car radiators It has been

used criminally to give 'body' and sweetness to white

table wines Metabolism to glycolate and oxalate

causes acidosis and renal damage, and usually the

sit-uation is further complicated by lactic acidosis In

the first 12 hours after ingestion the patient appears

as though intoxicated with alcohol but does not

smell of that; subsequently there is increasing

acidosis, pulmonary oedema and cardiac failure,

and in 2-3 days renal pain and tubular necrosis

develop because calcium oxalate crystals form

in the urine Acidosis is corrected with i.v sodium

bicarbonate and hypocalcaemia with calcium

gluco-nate As with methanol (above), ethanol or

fome-pizole is given competitively to inhibit the

meta-bolism of ethylene glycol and haemodialysis is used

to eliminate the poison

Hydrocarbons, e.g paraffin oil (kerosene), petrol

(gasoline), benzene, chiefly cause CNS depression

and pulmonary damage from inhalation It is vital

to avoid aspiration into the lungs during attempts

to remove the poison or in spontaneous vomiting

Gastric aspiration should be performed only if a

cuffed endotracheal tube is effectively in place, if

necessary after anaesthetising the subject

Volatile solvent abuse or 'glue sniffing', is common

among teenagers, especially males The success of

the modern chemical industry provides easy access

to these substances as adhesives, dry cleaners, air

fresheners, deodorants, aerosols and other products

Various techniques of administration are employed:

viscous products may be inhaled from a plastic bag,

liquids from a handkerchief or plastic bottle The

immediate euphoriant and excitatory effects are

replaced by confusion, hallucinations and delusions

as the dose is increased Chronic abusers, notably of

toluene, develop peripheral neuropathy, cerebellar

disease and dementia; damage to the kidney, liver,

heart and lungs also occurs with solvents Over 50%

of deaths from the practice follow cardiac

arrhyth-mia, probably caused by sensitisation of the

myo-cardium to catecholamines and by vagal inhibition

from laryngeal stimulation when aerosol propellants are sprayed into the throat

Standard cardiorespiratory resuscitation and antiarrhythmia treatment are used for acute solvent

poisoning Toxicity from carbon tetrachloride and

chloroform involves the generation of phosgene (a

1914-18 war gas) which is inactivated by cysteine, and by glutathione which is formed from cysteine; treatment with N-acetylcysteine, as for poisoning with paracetamol, is therefore recommended

Poisoning by herbicides and pesticides Organophosphorus pesticides are

anticholineste-rases; poisoning and its management are described

on page 437 Organic carbamates are similar

Dinitro-compounds Dinitro-orthocresol (DNOC)

and dinitrobutylphenol (DNBP) are used as selective weed killers and insecticides, and cases of poison-ing occur accidentally, e.g when safety precautions are ignored These substances can be absorbed through the skin and the hands, face or hair are usually stained yellow Symptoms and signs indi-cate a very high metabolic rate (due to uncoupling

of oxidative phosphorylation); copious sweating and thirst proceed to dehydration and vomiting, weakness, restlessness, tachycardia and deep, rapid breathing, convulsions and coma Treatment is urgent and consists of cooling the patient and attention

to fluid and electrolyte balance It is essential to differentiate this type of poisoning from that due

to anticholinesterases because atropine given to patients poisoned with dinitro-compound will stop sweating and may cause death from hyperthermia

Phenoxy herbicides (2,4-D, mecoprop, dichlorprop)

are used to control broad-leaved weeds Ingestion causes nausea, vomiting, pyrexia (due to uncoupl-ing of oxidative phosphorylation), hyperventilation, hypoxia and coma Their elimination is enhanced

by urine alkalinisation Organochlorine pesticides, e.g dicophane (DDT), may cause convulsions in acute overdose Treat as for status epilepticus

Rodenticides include warfarin and thallium (see

Table 9.1); for strychnine, which causes convulsions, give diazepam