(for medicines: see individual drugs)
Common toxic syndromes8
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.
poisoning cause dysfunction of the central or autonomic 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 antipsychotics, tricyclic antidepressants, antihistamines, antispasmodics and many plants (see p. 160).
Cholinergic (muscarinic) syndromes comprise salivation, 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 psychiatric 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, palpitations, 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 myocardial 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 evidence for its efficacy is conflicting and transport to hyperbaric chambers may present logistic problems.
Lead poisoning arises from a variety of occupational (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 exchangeable component in blood (2%, biological t\ 35 d) and a stable pool in dentine and the skeleton (95%, biological t1/^ 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 redistribution 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.
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 acid 30 mg i.v. 6-hourly may protect against retinal damage by enhancing formate metabolism.
Ethylene glycol is readily accessible as a constituent 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 situation 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 gluconate. As with methanol (above), ethanol or fome-pizole is given competitively to inhibit the metabolism 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 arrhythmia, probably caused by sensitisation of the myocardium 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 anticholinesterases; 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 poisoning 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 indicate 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 uncoupling 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.
Paraquat is a widely used herbicide which is extremely toxic if it is ingested; a mouthful of commercial solution taken and spat out may be enough to kill. Ulceration and sloughing of the oral and oesophageal mucosa are followed 5-10 days later by renal tubular necrosis and subsequently there is pulmonary oedema followed by pulmonary fibrosis; whether the patient lives or dies depends largely on the condition of the lung. Treatment is urgent and includes activated charcoal or aluminium silicate (Fuller's earth) by mouth as adsorbents, gastric lavage, and osmotic purgation (magnesium sulphate). Haemodialysis or haemop-erfusion may have a role in the first 24 h, the rationale being that reducing the plasma concentration by using these methods protects the kidney, failure of which allows the slow but relentless accumulation of paraquat in the lung.
Diquat is similar to paraquat but the late pulmonary changes may not occur.
Many plants form substances that are important for their survival either by enticing animals which disperse their spores, or by repelling potential predators. Poisoning occurs when children eat berries or chew flowers, attracted by their colour; adults may mistake nonedible for edible varieties of salad plants and fungi (mushrooms) for they may resemble each other closely and some are greatly prized by epicures.
The range of toxic substances that these plants produce is reflected in a diversity of symptoms which may be grouped broadly thus:
• Atropinic, e.g. from deadly nightshade (Atropa belladonna) and thorn apple (Datura), causing dilated pupils, blurred vision, dry mouth, flushed skin, confusion and delirium.
• Nicotinic, e.g. from hemlock (Conium) and Laburnum, causing salivation, dilated pupils, vomiting, convulsions and respiratory paralysis.
• Muscarinic, e.g. from Inocybe and Clitocybe fungi (mushrooms), causing salivation, lachrymation, miosis, perspiration, bradycardia and bronchoconstriction, also hallucinations.
• Hallucinogenic, e.g. from psilocybin-containing mushrooms (liberty cap), which may be taken specifically for this effect ('magic mushrooms').
• Cardiovascular, e.g. from foxglove (Digitalis), mistletoe (Viscum album)) and lily-of-the-valley (Convallaria) which contain cardiac glycosides that cause vomiting, diarrhoea and cardiac arrhythmia.
• Hepatotoxic, e.g. from Amanita phalloides (death cap mushroom), from Senecio (ragwort) and Crotalatia and from 'bush teas' prepared from these plants in the Caribbean. Aflatoxin, from Aspergillus flavus, a fungus which contaminates foods, is probably a cause of primary liver cancer.
• Convulsant, e.g. from water dropwort (Oenanthe) and cowbane (Cicuta), which contain the related and very dangerous substances, oenanthotoxin and cicutoxin.
• Cutaneous irritation, e.g. directly with nettle (Urtica), or dermatitis following sensitisation with Primula.
• Gastrointestinal symptoms, nausea, vomiting, diarrhoea and abdominal pain occur with numerous plants.
Treatment of plant poisonings consists mainly of activated charcoal to adsorb toxin in the gastrointestinal tract. Inducing emesis with ipecacuanha may make the diagnosis more difficult for vomiting is often the earliest sign of poisoning. Convulsions should be controlled with diazepam. In 'death cap' mushroom poisoning, penicillin may be used to displace toxin from plasma albumin, provided haemodialysis is being used, which latter may also benefit the renal failure.
Many natural agents can cause life-threatening infections but their recruitment as biological weapons against communities of people requires particular qualities of infectivity, pathogenicity, stability and ease of production. Among the pathogens that may be considered candidates for this horrific purpose are Bacillus anthracis (the causal agent of anthrax), Brucella (brucellosis), Clostridium botulinum (botulism), Francisella tularensis (tularaemia), Yersinia pestis (plague), and variola virus (smallpox). Drugs used for the treatment and prophylaxis of some of the bacterial infections appear in Table 11.1 (p. 211). Vaccines are kept in special centres to immunise against anthrax, plague and smallpox, and an antitoxin for botulism. That it has been thought necessary even to make reference to the subject of bioterrorism is surely a sad commentary on the times in which we live.
(harassing, disabling, antiriot agents)
Harassing agents may be defined as chemical substances that are capable when used in field conditions, of rapidly causing a temporary disablement that lasts for little longer than the period of exposure.10
The pharmacological requirements for a safe and effective harassing agent must be stringent (it is hardly appropriate to refer to benefit versus risk). As well as potency and rapid onset and offset of effect in open areas under any atmospheric condition, it must be safe in confined spaces where concentration may be very high and may affect an innocent, bedridden invalid should a projectile enter a window.
CS (chlorobenzylidene malononitrile, a tear 'gas') is a favoured substance at present. This is a solid that is disseminated as an aerosol (particles of 1 micron diameter) by including it in a pyrotechnic mixture. The spectacle of its dissemination has been rendered familiar by television. It is not a gas, it is an aerosol or smoke. The particles aggregate and settle to the ground in minutes so that the risk of prolonged exposure out of doors is not great.
According to the concentration of CS to which a person is exposed, the effects vary from a slight pricking or peppery sensation in the eyes and nasal passages up to the maximum symptoms of streaming from the eyes and nose, spasm of the eyelids, profuse lachrymation and salivation, retching and sometimes vomiting, burning of the mouth and throat, cough and gripping pain in the chest.11
10 Health aspects of chemical and biological weapons. 1970 WHO Geneva.
The onset of symptoms occurs immediately on exposure (an important factor from the point of view of the user) and they disappear dramatically:
At one moment the exposed person is in their grip. Then he either stumbles away, or the smoke plume veers or the discharge from the grenade stops, and, immediately, the symptoms begin to roll away. Within a minute or two, the pain in the chest has gone and his eyes, although still streaming, are open. Five or so minutes later, the excessive salivation and pouring tears stop and a quarter of an hour after exposure, the subject is essentially back to normal.10
Exposed subjects absorb small amounts only, and the plasma t'/2 is about 5 seconds.
Investigations of the effects of CS are difficult in 'field use', but some have been done and at present there is no evidence that even the most persistent rioter will suffer any permanent effect. The hazard to the infirm or sick seems to be low, but plainly it would be prudent to assume that asthmatics or bronchitics could suffer an exacerbation from high concentrations, though bronchospasm does not occur in healthy people. Vomiting seems to be due to swallowing contaminated saliva. Transient looseness of the bowels may follow exposure. Hazard from CS is probably confined to situations where the missiles are projected into enclosed spaces.
CN (chloroacetophenone, a tear gas) is generally used as a solid aerosol or smoke; solutions (Mace) are used at close quarters.
CR (dibenzoxazepine) was put into production in 1973 after testing on army volunteers. In addition to the usual properties (above) it may induce a transient rise in intraocular pressure. Its solubility allows use in water 'cannons'.
'Authority' is reticent about the properties of all these substances and no further important information is readily available.
This brief account has been included, because, in addition to helping victims, even the most well-conducted and tractable students and doctors
11 Home Office Report (1971) of the enquiry into the medical and toxicological aspects of CS. pt II. HMSO, London: Cmnd 4775.
may find themselves exposed to CS smoke in our troubled world; and some may even feel it their duty to incur exposure. The following points are worth making:
• Wear disposable plastic gloves, for the object of treating the sufferer is frustrated if the physician becomes affected.
• Contaminated clothing should be put in plastic bags and skin should be washed with soap and water. Showering or bathing may cause symptoms to return by releasing the agent from contaminated hair. Cutaneous erythema is usual and blistering may occur with high concentrations of CS and CN in warm, moist conditions.
• The eyes should be left to irrigate themselves; raised intraocular pressure may cause acute glaucoma in those over 40 years.
DRUGS USED FORTORTURE, INTERROGATION AND JUDICIAL EXECUTION
Regrettably, drugs have been and are being used for torture, sometimes disguised as 'interrogation' or 'aversion therapy'. Facts are, not surprisingly, hard to obtain, but it seems that suxamethonium, hallucinogens, thiopentone, neuroleptics, amphetamines, apomorphine and cyclophosphamide have been employed to hurt, frighten, confuse or debilitate in such ways as callous ingenuity can devise. When the definition of criminal activity becomes perverted to include activities in defence of human liberty, the employment of drugs offers inducement to inhuman behaviour. Such use, and any doctors or others who engage in it, or who misguidedly allow themselves to believe that it can be in the interest of victims to monitor the activity by others, must surely be outlawed.
It might be urged that it is justifiable to use drugs to protect society by discovering serious crimes such as murder. There is no such thing as a 'truth drug' in the sense that it guarantees the truth of what the subject says. There always must be uncertainty of the truth of evidence obtained with drugs, e.g.
thiopentone, that cannot be independently confirmed. But accused people, convinced of their own innocence, sometimes volunteer to undergo such tests. The problem of discerning truth from falsehood remains.
In some countries drugs are used for judicial execution, e.g. combinations of thiopentone, potassium, curare, given intravenously.
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