CLINICAL PHARMACOLOGY 2003 (PART 11)

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CLINICAL PHARMACOLOGY 2003 (PART 11)

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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. Repeated 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...

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  1. 9 Poisoning, overdose, antidotes SYNOPSIS drugs, and psychotropic drugs is increasing. Re- peated episodes are not rare.1 Prescribed drugs are Deliberate and accidental self-poisoning used in over 75% of episodes but teenagers tend to Principles of treatment favour nonprescribed analgesics available by direct Poison-specific measures sale, e.g. paracetamol, which is important bearing General measures in mind its potentially serious toxicity. Specific poisonings: cyanide, methanol, The mortality rate of self-poisoning is very low ethylene glycol, hydrocarbons, volatile (less than 1% of acute hospital admissions), but solvents, heavy metals, herbicides and 'completed' suicides by poisoning still number 3500 pesticides, biological substances (overdose of per annum in England and Wales. medicinal drugs is dealt with under individual Accidental self-poisoning causing admission to agents) hospital occurs predominantly amongst children Incapacitating agents: drugs used for torture under 5 years, usually with medicines left within their reach or with domestic chemicals, e.g. bleach, detergents. Self-poisoning Principles of treatment Deliberate self-poisoning. A curious by-product Successful treatment of acute poisoning depends on of the modern 'drug and prescribing explosion' a combination of speed and common sense, as well is the rise in the incidence of nonfatal deliberate as on the nature of the poison, the amount taken self-harm. The majority of people who do this lack and the time which has since elapsed. The majority serious suicidal intent and are therefore termed of those admitted to hospital require only observa- parasuicides. In over 90% of instances in the UK, tion and medical and nursing supportive measures poisoning is the means chosen, usually by medi- cines taken in overdose and these amount to at least 1 70 000 hospital admissions per annum in England An extreme example is that of a young man who, over a and Wales (population 51 million). Two or more period of 6 years, was admitted to hospital following 82 episodes of self-poisoning, 31 employing paracetamol; he drugs are taken in over 30% of episodes, not had had a disturbed, unhappy upbringing and had been including alcohol which is also taken in over 50% expelled from both the Danish Navy and the British Army. of the instances; the use of hypnotic and sedative Prescott L F et al 1978 British Medical Journal 2: 1399. 151
  2. 9 POISONING, OVERDOSE, ANTIDOTES while they metabolise and eliminate the poison. the toxic environment, the contaminated clothing Some require a specific antidote or a specific removed and the skin cleansed. measure to increase elimination. Intensive care facilities are needed by only a few. In the UK the centres of the National Poisons Information From the gut Service provide information and advice over the telephone throughout the day and night.2 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 Poison-specific measures consists of a very fine black powder prepared from vegetable matter, e.g. wood pulp, coconut shell, IDENTIFICATION OF THE POISON(S) which is 'activated' by an oxidising gas flow at high temperature to create a network of fine The key pieces of information are: (10-20-nm) pores to give it an enormous surface • the identity of the substance(s) taken area in relation to weight (1000 m 2 /g). This binds • the dose(s) to, and thus inactivates, a wide variety of • the time that has since elapsed. Adults may be compounds in the gut. Thus it is simpler to list the sufficiently conscious to give some indication of exceptions, i.e. substances that are not adsorbed the poison or may have referred to it in a suicide by charcoal which are: iron, lithium, cyanide, note, or there may be other circumstantial strong acids and alkalis, and organic solvents and evidence. Rapid (1-2 h) biochemical 'screens' of corrosive agents. plasma or urine are available but are best reserved Indeed, activated charcoal comes nearest to for seriously ill or unconscious patients in whom fulfilling the long-sought notion of a 'universal the cause of coma is unknown. Analysis of plasma antidote'.3 It should be given as soon as possible for specific substances is essential in suspected after a potentially toxic amount of a poison has cases of paracetamol or iron poisoning, to indicate been ingested, and whilst a significant amount which patients should receive antidotes; it is also remains yet unabsorbed (thus ideally within 1 h). required for salicylate, lithium and some sedative To be most effective, 5-10 times as much charcoal as drugs, e.g. trichloroethanol derivatives, poison, weight for weight, is needed; in the adult phenobarbitone, when a decision is needed about an initial dose of 50-100 g is usual. If the patient using urine alkalinisation, haemodialysis or is vomiting, the charcoal should be given through haemoperfusion. Response to a specific antidote a nasogastric tube. Activated charcoal also may provide a diagnosis, e.g. dilatation of accelerates elimination of poison that has been constricted pupils and increased respiratory rate absorbed (see p. 155). after i.v. naloxone (opioid poisoning) or arousal Activated charcoal, although unpalatable, appears from unconsciousness in response to i.v. to be relatively safe but constipation or mechanical flumazenil (benzodiazepine poisoning). bowel obstruction may be caused by repeated use. Aspiration of charcoal into the lungs can cause hypoxia through obstruction and arteriovenous PREVENTION OF FURTHER shunting. Charcoal adsorbs and thus inactivates ABSORPTION OF THE POISON From the environment 3 For centuries it was supposed not only that there could be, When a poison has been inhaled or absorbed but that there actually was, a single antidote to all poisons. This was Theriaca Andromachi, a formulation of 72 (a through the skin, the patient should be taken from magical number) ingredients amongst which particular importance was attached to the flesh of a snake (viper). The 2 Telephone numbers are to be found in the British National antidote was devised by Andromachus whose son was Formulary (BNF). physician to the Roman Emperor, Nero (AD 37-68). 152
  3. POISON-SPECIFIC MEASURES 9 ipecacuanha but may be used after successful fully conscious patients may develop aspiration emesis if this method has been deemed necessary; pneumonia after ipecacuanha. methionine, used orally for paracetamol poisoning, Both emesis and lavage are contraindicated for is also adsorbed. corrosive poisons, because there is a risk of perfora- Other oral adsorbents have specific uses. Fuller's tion of the gut, and for petroleum distillates, as the earth and bentonite (both natural forms of alumi- danger of causing inhalational chemical pneumonia nium silicate) bind and inactivate the herbicides, outweighs that of leaving the substance in the paraquat (activated charcoal is superior) and diquat; stomach. cholestyramine and colestipol will adsorb warfarin. Cathartics or whole-bowel irrigation4 have been Gastric lavage incurs dangers as well as benefits; it used for the removal of sustained-release formula- is best confined to the hospitalised adult who is tions, e.g. theophylline, iron, aspirin. Evidence of believed to have taken a potentially life-threatening benefit is conflicting. Activated charcoal in repeated amount of a poison within 1 h (or longer in the case (10 g) doses is generally preferred. Sustained- of drugs that delay gastric emptying, e.g. aspirin, release formulations are now common, and patients tricyclic antidepressants, sympathomimetics, theo- have died from failure to recognise the danger of phylline, opioids). Lavage is probably worth under- continued release of drug from such products, after taking in any unconscious patient who is believed apparently successful gastric lavage. to have ingested poison, and provided the airways are protected by a cuffed endotracheal tube. Para- SPECIFIC ANTIDOTES5 doxically, lavage may wash an ingested substance into the small intestine, enhancing its absorption. Specific antidotes reduce or abolish the effects of Leaving activated charcoal in the stomach after poisons through a variety of mechanisms, which lavage is appropriate to lessen this risk. Neverthe- may be categorised as follows: less, patients who have ingested tricyclic anti- • receptors, which may be activated, blocked or depressants or centrally depressant drugs must be bypassed subject to continued monitoring after the lavage. • enzymes, which may be inhibited or reactivated The passing of a gastric tube, naturally, takes • displacement from tissue binding sites second place to emergency resuscitative measures, • exchanging with the poison institution of controlled respiration or suppression • replenishment of an essential substance of convulsions. Nothing is gained by aspirating the • binding to the poison (including chelation). stomach of a corpse. 4 Emesis has been used for children and also for Irrigation with large volumes of a polyethylene glycol- adults who refuse activated charcoal or gastric electrolyte solution, e.g. Klean-Prep, by mouth causes lavage, or if the poison is not absorbed by activated minimal fluid and electrolyte disturbance (it was developed for preparation for colonoscopy). Magnesium sulphate may charcoal. Its routine use in emergency departments also be used. has been abandoned, as there is no clinical trial 5 Mithridates the Great (7132-63 BC) king of Pontus (in Asia evidence that the procedure improves outcome Minor) was noted for 'ambition, cruelty and artifice'. 'He for poisoned patients. Emesis is induced, in fully murdered his own mother ... and fortified his constitution conscious patients only, by Ipecacuanha Emetic by drinking antidotes' to the poisons with which his domestic enemies sought to kill him (Lempriere). When his Mixture, Pediatric (BNF), 10 ml for a child 6-18 son also sought to kill him, Mithridates was so disappointed months, 15 ml for an older child and 30 ml for an that he compelled his wife to poison herself. He then tried to adult, i.e. all ages may receive the same preparation poison himself, but in vain; the frequent antidotes which he but in a different dose, which is followed by a had taken in the early part of his life had so strengthened his tumblerful of water (250 ml). The active constituent constitution that he was immune. He was obliged to stab himself, but had to seek the help of a slave to complete his of ipecacuanha is emetine; it can cause prolonged task. Modern physicians have to be content with less vomiting, diarrhoea and drowsiness that may be comprehensively effective antidotes, some of which are confused with effects of the ingested poison. Even listed in Table 9.1. 153
  4. 9 POISONING, OVERDOSE, ANTI DOTES TABLE 9.1 Some specific antidotes, indications and modes of action (see Index for a fuller account of individual drugs) Antidote Indication Mode of action acetylcysteine paracetamol, chloroform, carbon tetrachloride Replenishes depleted glutathione stores atropine cholinesterase inhibitors, e.g. organophosphorus Blocks muscarinic cholinoceptors insecticides p-blocker poisoning Vagal block accelerates heart rate benzatropine drug-induced movement disorders Blocks muscarinic cholinoceptors calcium gluconate hydrofluoric acid, fluorides Binds or precipitates fluoride ions desferrioxamine iron Chelates ferrous ions dicobalt edetate cyanide and derivatives, e.g. acrylonitrile Chelates to form nontoxic cobalti-and cobalto-cyanides digoxin-specific antibody digitalis glycosides Binds free glycoside in plasma, complex excreted fragments (FAB) in urine dimercaprol (BAL) arsenic, copper, gold, lead, inorganic mercury Chelates metal ions ethanol ethylene glycol, methanol Competes for alcohol and acetaldehyde dehydrogenases, preventing formation of toxic metabolites flumazenil benzodiazepines Competes for benzodiazepine receptors folinic acid folic acid antagonists e.g. methotrexate, Bypasses block in folate metabolism trimethoprim glucagon P-adrenoceptor antagonists Bypasses blockade of the B-adrenoceptor; stimulates cyclic AMP formation with positive cardiac inotropic effect isoprenaline p-adrenoceptor antagonists Competes for p-adrenoceptors methionine paracetamol Replenishes depleted glutathione stores naloxone opioids Competes for opioid receptors neostigmine antimuscarinic drugs Inhibits acetylcholinesterase, causing acetylcholine to accumulate at cholinoceptors oxygen carbon monoxide Competitively displaces carbonmonoxide from binding sites on haemoglobin penicillamine copper, gold, lead, elemental mercury (vapour), zinc Chelates metal ions phenoxybenzamine hypertension due to oc-adrenoceptor agonists, Competes for oc-adrenoceptors (long-acting) e.g. with MAOI, clonidine, ergotamine phentolamine as above Competes for oc-adrenoceptors (short-acting) phytomenadione coumarin (warfarin) and indandione Replenishes vitamin K (vitamine K1) anticoagulants pralidoxime cholinesterase inhibitors, e.g. organophosphorus Competitively reactivates cholinesterase insecticides propranolol P-adrenoceptor agonists, ephedrine, Blocks P-adrenoceptors theophylline, thyroxine protamine heparin Binds ionically to neutralise Prussian blue (potassium thallium (in rodenticides) Potassium exchanges for thallium ferric hexacyanoferrate) sodium calciumedetate lead Chelates lead ions unithiol lead, elemental and organic mercury Chelates metal ions Table 9.1 illustrates these mechanisms with Dimercaprol (British Anti-Lewisite, BAL). Arsenic antidotes that are of therapeutic value. and other metal ions are toxic in low concentration because they combine with the SH groups of essential enzymes, thus inactivating them. Dimer- CHELATING AGENTS caprol provides SH groups which combine with Chelating agents are used for poisoning with heavy the metal ions to form relatively harmless ring metals. They incorporate the metal ions into an inner compounds which are excreted, mainly in the urine. ring structure in the molecule (Greek: chele, claw) by As dimercaprol, itself, is oxidised in the body means of structural groups called ligands (Latin: and renally excreted, repeated administration is ligare, to bind); effective agents form stable, biolog- necessary to ensure that an excess is available until ically inert complexes that are excreted in the urine. all the metal has been eliminated. 154
  5. POISON-SPECIFIC MEASURES 9 Dimercaprol may be used in cases of poisoning Each method depends, directly or indirectly, on by antimony, arsenic, bismuth, gold and mercury removing drug from the circulation and successful (inorganic, e.g. HgCl2). use requires that: Adverse effects are common, particularly with • The poison should be present in high larger doses, and include nausea and vomiting, concentration in the plasma relative to that in the lachrymation and salivation, paraesthesiae, muscu- rest of the body, i.e. it should have a small lar aches and pains, urticarial rashes, tachycardia distribution volume and a raised blood pressure. Gross overdosage may • The poison should dissociate readily from any cause overbreathing, muscular tremors, convul- plasma protein binding sites sions and coma. • The effects of the poison should relate to its plasma concentration. Unithiol (dimercaptopropanesulphonate, DMPS) effectively chelates lead and mercury; it is well Methods used are: tolerated. Repeated doses of activated charcoal Sodium calciumedetate is the calcium chelate of the disodium salt of ethylenediaminetetra-acetic Activated charcoal by mouth not only adsorbs acid (calcium EDTA). It is effective in acute lead ingested drug in the gut, preventing absorption into poisoning because of its capacity to exchange the body (see above), it also adsorbs drug that calcium for lead: the lead chelate is excreted in diffuses from the blood into the gut lumen when the urine, leaving behind a harmless amount of the concentration there is lower; because binding is calcium. Dimercaprol may usefully be combined irreversible the concentration gradient is main- with sodium calciumedetate when lead poisoning tained and drug is continuously removed; this has is severe, e.g. with encephalopathy. been called 'intestinal dialysis'. Charcoal may also Adverse effects are fairly common, and include adsorb drugs that are secreted into the bile, i.e. hypotension, lachrymation, nasal stuffiness, sneez- by interrupting an enterohepatic cycle. Evidence ing, muscle pains and chills. Renal damage can shows that activated charcoal in repeated doses occur. effectively adsorbs (shortens t1/2 of) phenobarbital (phenobarbitone), carbamazepine, theophylline, Dicobalt edetate. Cobalt forms stable, nontoxic quinine, dapsone and salicylate.6 Repeated-dose complexes with cyanide. It is toxic (especially if activated charcoal is increasingly preferred to the wrong diagnosis is made and no cyanide is alkalinisation of urine (below) for phenobarbitone present), causing hypertension, tachycardia and and salicylate poisoning. Activated charcoal in an chest pain; consequent cobalt poisoning is treated initial dose of 50-100 g should be followed by not by giving sodium calcium edetate and i.v. glucose. less than 12.5 g/h; the regular hourly administra- tion is more effective than larger amounts less often. Penicillamine (dimethylcysteine) is a metabolite of penicillin that contains SH groups; it may be used Alteration of urine pH and diuresis to chelate lead and also copper (see Hepatolenticular degeneration). Its principal use is for rheumatoid By manipulation of the pH of the glomerular arthritis (see Index). filtrate, a drug can be made to ionise, become less lipid-soluble, remain in the renal tubular fluid, and Desferrioxamine: see Iron. 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 ACCELERATION OF ELIMINATION OF pH that is all important. The practice of forcing THE POISON Techniques for eliminating poisons have a role 6 Bradberry S M, Vale A J 1995 Journal of Toxicology: Clinical that is limited, but important when applicable. Toxicology 33(5): 407-416. 155
  6. 9 POISONING, OVERDOSE, ANTIDOTES diuresis with frusemide (furosemide) and large Such artificial methods of removing poison from volumes of i.v. fluid does not add significantly to the body are invasive, demand skill and experience drug clearance but may cause fluid overload; it is on the part of the operator and are expensive in obsolete. Alkalinisation may be used for salicylate manpower. Their use should therefore be confined (>500mg/l + metabolic acidosis, or in any case to cases of severe, prolonged or progressive clinical > 750 mg/1), phenobarbital (75-150 mg/1) or phenoxy intoxication, when high plasma concentration indi- herbicides, e.g. 2,4-D, mecoprop, dichlorprop. The cates a dangerous degree of poisoning, and when objective is to maintain a urine pH of 7.5-8.5 by an removal by haemoperfusion or dialysis constitutes i.v. infusion of sodium bicarbonate. Available a significant addition to natural methods of preparations of sodium bicarbonate vary between elimination. 1.2 and 8.4% (1 ml of the 8.4% preparation contains • Haemodialysis is effective for: salicylate 1 mmol of sodium bicarbonate) and the con- (> 750 mg/1 + renal failure, or in any case centration given will depend on the patient's fluid > 900 mg/1), isopropanol (present in aftershave needs. lotions and window-cleaning solutions), lithium Acidification may be used for severe, acute and methanol. amphetamine, dexfenfluramine or phencyclidine • Haemoperfusion is effective for: phenobarbitone poisoning. The objective is to maintain a urine pH (> 100-150 mg/1, but repeat-dose activated of 5.5-6.5 by giving i.v. infusion of arginine hydro- charcoal by mouth appears to be as effective, see chloride (10 g) over 30 min, followed by ammonium above) and other barbiturates, ethchlorvynol, chloride (4 g) 2-hourly by mouth. It is rarely glutethimide, meprobamate, methaqualone, necessary. Phenoxybenzamine should be adequate theophylline, trichloroethanol derivatives. for amphetamine-like drugs (a-adrenoceptor block). Peritoneal dialysis Peritoneal dialysis involves instilling appropriate General measures fluid into the peritoneal cavity. Poison in the blood diffuses into the dialysis fluid down the concen- INITIAL ASSESSMENT AND tration gradient. The fluid is then drained and RESUSCITATION replaced. The technique requires little equipment but is one-half to one-third as effective as haemo- The initial clinical review should include a search dialysis; it may be worth using for lithium and for known consequences of poisoning, which methanol poisoning. include: impaired consciousness with flaccidity (benzodiazepines, alcohol, trichloroethanol) or with hypertonia (tricyclic antidepressants, antimuscarinic Haemodialysis and haemoperfusion agents), hypotension, shock, cardiac arrhythmia, A temporary extracorporeal circulation is established, evidence of convulsions, behavioural disturbances usually from an artery to a vein in the arm. In hae- (psychotropic drugs), hypothermia, aspiration pneu- modialysis, a semipermeable membrane separates monia and cutaneous blisters, burns in the mouth blood from dialysis fluid and the poison passes (corrosives). passively from the blood, where it is present in high Maintenance of an adequate oxygen supply is the concentration. The principle of haemoperfusion first priority. A systolic blood pressure of 80 mmHg is that blood flows over activated charcoal or an can be tolerated in a young person but a level below appropriate ion-exchange resin which adsorbs 90 mmHg will imperil the brain or kidney of the the poison. Loss of blood cells and activation of elderly. Expansion of the venous capacitance bed the clotting mechanism are largely overcome by is the usual cause of shock in acute poisoning and coating the charcoal with an acrylic hydrogel which blood pressure may be restored by placing the does not reduce adsorbing capacity, though the patient in the head-down position to encourage patient must be anticoagulated with heparin. venous return to the heart, or by the use of a colloid 156
  7. SOME POISONINGS 9 plasma expander such as gelatin or etherified starch. to persistent peripheral circulatory failure, then External cardiac compression may be necessary and an appropriate drug ought to be used, e.g. a should be continued until the cardiac output is p-adrenoceptor blocker for poisoning with a self-sustaining, which may be a long time when sympathomimetic drug. the patient is hypothermic or poisoned with cardio- depressant drugs, e.g. tricyclic antidepressants, (3- Hypothermia may occur if temperature regulation adrenoceptor blockers. The airway must be sucked is impaired by CNS depression. Core temperature clear of oropharyngeal secretions or regurgitated must be monitored by a low-reading rectal ther- matter. mometer, while the patient is nursed in a heat retain- ing 'space blanket'. Supportive treatment Immobility may lead to pressure lesions of periph- eral nerves, cutaneous blisters and necrosis over The salient fact is that patients recover from most bony prominences. poisonings provided they are adequately oxy- genated, hydrated and perfused, for, in the majority Rhabdomyolysis may result from prolonged press- of cases, the most efficient mechanisms are the ure on muscles, from agents that cause muscle patients' own and, given time, they will inactivate spasm or convulsions (phencyclidine, theophylline) and eliminate all the poison. Patients require the or be aggravated by hyperthermia due to muscle standard care of the unconscious, with special contraction, e.g. with MDMA ('ecstasy'). Aggressive attention to the problems introduced by poisoning volume repletion and correction of acid-base abnor- which are outlined below. mality may be needed, and urine alkalinisation may prevent acute tubular necrosis. Airway maintenance is essential; some patients require a cuffed endotracheal tube but seldom for PSYCHIATRIC AND SOCIAL more than 24 h. ASSESSMENT Ventilation needs should be assessed, if necessary Most cases of self-poisoning are precipitated by supported by blood gas analysis. A mixed respira- interpersonal or social problems, which should be tory and metabolic acidosis is common. Hypoxia addressed. Major psychiatric illness ought to be may be corrected by supplementing the inspired identified and treated. air with oxygen but mechanical ventilation is 'There are said to be occasions when a wise man necessary if the PaCO2 exceeds 6.5 kPa. chooses suicide—but generally speaking it is not in an excess of reasonableness that people kill Hypotension is common and in addition to the themselves. Most men and women die defeated.. .'7 resuscitative measures indicated above, infusion of a combination of dopamine and dobutamine in low dose may be required to maintain renal perfusion. Some poisonings Convulsions should be treated if they are persistent or protracted. Diazepam i.v. is the first (for medicines: see individual drugs) choice. Common toxic syndromes8 Cardiac arrhythmia frequently accompanies poison- ing, e.g. with tricyclic antidepressants, theophylline, Many substances used in accidental or self- B-adrenoceptor blockers. Acidosis, hypoxia and electrolyte disturbance are often important contri- 7 Voltaire (pseudonym of Francios-Marie Arouet, French butory factors; the emphasis of therapy should be writer, 1694-1778). to correct these and to resist the temptation to resort 8 Based on Kulig K1992 New England Journal of Medicine to an antiarrhythmic drug. If arrhythmia leads 326:1677-1681. 157
  8. 9 POISONING, OVERDOSE, ANTI DOTES poisoning cause dysfunction of the central or auto- excessive use of sodium nitroprusside for severe nomic nervous systems and produce a variety of hypertension.9 The symptoms of acute poisoning effects which may be usefully grouped to aid the are due to tissue anoxia, with dizziness, palpita- identification of the agent(s) responsible. tions, a feeling of chest constriction and anxiety; characteristically the breath smells of bitter almonds. Antimuscarinic syndromes consist of tachycardia, In more severe cases there is acidosis and coma. dilated pupils, dry, flushed skin, urinary retention, Inhaled hydrogen cyanide may lead to death within decreased bowel sounds, mild elevation of body minutes but when it is ingested as the salt several temperature, confusion, cardiac arrhythmias and hours may elapse before the patient is seriously ill. seizures. They are commonly caused by antipsych- Chronic exposure damages the nervous system otics, tricyclic antidepressants, antihistamines, anti- causing peripheral neuropathy, optic atrophy and spasmodics and many plants (see p. 160). nerve deafness. The principles of specific therapy are as follows: Cholinergic (muscarinic) syndromes comprise sali- • Dicobalt edetate to chelate the cyanide is the vation, lachrymation, abdominal cramps, urinary treatment of choice when the diagnosis is certain and faecal incontinence, vomiting, sweating, miosis, (see p. 155). The dose is 300 mg given i.v. over muscle fasciculation and weakness, bradycardia, one minute (5 min if condition is less serious), pulmonary oedema, confusion, CNS depression followed immediately by a 50 ml i.v. infusion of and fitting. Common causes include organophos- glucose 50%; a further 300 mg of dicobalt edetate phorus and carbamate insecticides, neostigmine should be given if recovery is not evident within and other anticholinesterase drugs, and some fungi one minute. (mushrooms). • Alternatively, a two-stage procedure may be followed by i.v. administration of: Sympathomimetic syndromes include tachycardia, (1) sodium nitrite, which rapidly converts hypertension, hyperthermia, sweating, mydriasis, haemoglobin to methaemoglobin, the ferric hyperreflexia, agitation, delusions, paranoia, seizures ion of which takes up cyanide as and cardiac arrhythmias. These are commonly cyanmethaemoglobin (up to 40% caused by amphetamine and its derivatives, cocaine, methaemoglobin can be tolerated); proprietary decongestants, e.g. ephedrine, and (2) sodium thiosulphate, which more slowly theophylline (in the latter case, excluding psych- detoxifies the cyanide by permitting the iatric effects). formation of thiocyanate. When the diagnosis is uncertain, administration of Sedatives, opioids and ethanol cause signs that thiosulphate plus oxygen is a safe course. may include respiratory depression, miosis, hypo- reflexia, coma, hypotension and hypothermia. There is evidence that oxygen, especially if at high pressure (hyperbaric), overcomes the cellular Poisonings by (nondrug) chemicals 9 Or in other more bizarre ways. 'A 23-year-old medical Cyanide causes tissue anoxia by chelating the student saw his dog (a puppy) suddenly collapse. He started ferric part of the intracellular respiratory enzyme, external cardiac massage and a mouth-to-nose ventilation effort. Moments later the dog died, and the student felt cytochrome oxidase. Poisoning may occur as a nauseated, vomited and lost consciousness. On the victim's result of self-administration of hydrocyanic (prussic) arrival at hospital, an alert medical officer detected a bitter acid, by accidental exposure in industry, through almonds odour on his breath and administered the accepted inhaling smoke from burning polyurethane foams treatment for cyanide poisoning after which he recovered. It in furniture, through ingesting amygdalin which is turned out that the dog had accidentally swallowed cyanide, and the poison eliminated through the lungs had been present in the kernels of several fruits including inhaled by the master during the mouth-to-nose apricots, almonds and peaches (constituents of resuscitation/ Journal of the American Medical Association the unlicensed anticancer agent, laetrile), or from 1983 249: 353. 158
  9. SOME POISONINGS 9 anoxia in cyanide poisoning; the mechanism is Methanol is widely available as a solvent and in uncertain, but oxygen should be administered. paints and antifreezes, and may be consumed as a cheap substitute for ethanol. As little as 10 ml may Carbon monoxide (CO) is formed when substances cause permanent blindness and 30 ml may kill, containing carbon and hydrogen are incompletely through its toxic metabolites. Methanol, like ethanol, combusted; poisoning results from inhalation. is metabolised by zero-order processes that involve Oxygen transport to cells is impaired and myo- the hepatic alcohol and aldehyde dehydrogenases, cardial and neurological injury result; delayed (2-4 but whereas ethanol forms acetaldehyde and acetic weeks) neurological sequelae include parkinsonism acid which are partly responsible for the unpleasant and cerebellar signs. The concentration of CO in effects of 'hangover', methanol forms formaldehyde the blood may confirm exposure (cigarette smoking and formic acid. Blindness may occur because alone may account for up to 10%) but is no guide to aldehyde dehydrogenase present in the retina (for the severity of poisoning. Patients with signs of the interconversion of retinol and retinene) allows cardiac ischaemia or neurological defect may be the local formation of formaldehyde. Acidosis is treated with hyperbaric oxygen, although the evi- due to the formic acid, which itself enhances pH- dence for its efficacy is conflicting and transport dependent hepatic lactate production, so that lactic to hyperbaric chambers may present logistic acidosis is added. problems. The clinical features are severe malaise, vomiting, abdominal pain and tachypnoea (due to the acidosis). Lead poisoning arises from a variety of occupa- Loss of visual acuity and scotomata indicate ocular tional (such as house renovation and stripping damage and, if the pupils are dilated and non- old paint), and recreational sources. Environmental reactive, permanent loss of sight is probable. Coma exposure had been a matter of great concern, as and circulatory collapse may follow. witness the protective legislation introduced by many Therapy is directed at: countries to reduce pollution, e.g. by removing lead from petrol. • Correcting the acidosis. Achieving this largely Lead in the body comprises a rapidly exchange- determines the outcome; sodium bicarbonate is able component in blood (2%, biological t1/, 35 d) given i.v. in doses up to 2 mol in a few hours, and a stable pool in dentine and the skeleton (95%, carrying an excess of sodium which must be biological t1/225 y). managed. Methanol is metabolised slowly and In severe lead poisoning sodium calciumedetate the patient may relapse if bicarbonate is commonly used to initiate lead excretion. It administration is discontinued too soon. chelates lead from bone and the extracellular space • Inhibiting methanol metabolism. Ethanol, which and urinary lead excretion of diminishes over 5 days occupies the dehydrogenase enzymes in thereafter as the extracellular store is exhausted. preference to methanol, competitively prevents Subsequently symptoms (colic and encephalopathy) metabolism of methanol to its toxic products. A may worsen and this has been attributed to redistri- single oral dose of ethanol 1 ml/kg (as a 50% bution of lead from bone to brain. Dimercaprol solution or as the equivalent in gin or whisky) is is more effective than sodium calciumedetate at followed by 0.25 ml/kg/h orally or i.v., aiming chelating lead from the soft tissues such as brain, to maintain the blood ethanol at about which is the rationale for combined therapy with 100 mg/100 ml until no methanol is detectable in sodium calciumedetate. More recently succimer (2,3- the blood. Fomepizole (4-methylpyrazole), also a dimercaptosuccinic acid, DMSA), a water-soluble competitive inhibitor of alcohol dehydrognase, analogue of dimercaprol, has been increasingly has proved effective in severe methanol used instead. Succimer has a high affinity for lead, poisoning and is less likely to cause cerebral is suitable for administration by mouth and is better depression. tolerated (has a wider therapeutic index) than • Eliminating methanol and its metabolites by dimercaprol. It is licenced for such use in the USA dialysis. Haemodialysis is 2-3 times more but not the UK. effective than is peritoneal dialysis. Folinic 159
  10. 9 POISONING, OVERDOSE, ANTI DOTES acid 30 mg i.v. 6-hourly may protect against from laryngeal stimulation when aerosol propellants retinal damage by enhancing formate are sprayed into the throat. metabolism. Standard cardiorespiratory resuscitation and antiarrhythmia treatment are used for acute solvent Ethylene glycol is readily accessible as a consti- poisoning. Toxicity from carbon tetrachloride and tuent of antifreezes for car radiators. It has been chloroform involves the generation of phosgene (a used criminally to give 'body' and sweetness to white 1914-18 war gas) which is inactivated by cysteine, table wines. Metabolism to glycolate and oxalate and by glutathione which is formed from cysteine; causes acidosis and renal damage, and usually the sit- treatment with N-acetylcysteine, as for poisoning uation is further complicated by lactic acidosis. In with paracetamol, is therefore recommended. the first 12 hours after ingestion the patient appears as though intoxicated with alcohol but does not smell of that; subsequently there is increasing Poisoning by herbicides and pesticides acidosis, pulmonary oedema and cardiac failure, and in 2-3 days renal pain and tubular necrosis Organophosphorus pesticides are anticholineste- develop because calcium oxalate crystals form rases; poisoning and its management are described in the urine. Acidosis is corrected with i.v. sodium on page 437. Organic carbamates are similar. bicarbonate and hypocalcaemia with calcium gluco- nate. As with methanol (above), ethanol or fome- Dinitro-compounds. Dinitro-orthocresol (DNOC) pizole is given competitively to inhibit the meta- and dinitrobutylphenol (DNBP) are used as selective bolism of ethylene glycol and haemodialysis is used weed killers and insecticides, and cases of poison- to eliminate the poison. ing occur accidentally, e.g. when safety precautions are ignored. These substances can be absorbed Hydrocarbons, e.g. paraffin oil (kerosene), petrol through the skin and the hands, face or hair are (gasoline), benzene, chiefly cause CNS depression usually stained yellow. Symptoms and signs indi- and pulmonary damage from inhalation. It is vital cate a very high metabolic rate (due to uncoupling to avoid aspiration into the lungs during attempts of oxidative phosphorylation); copious sweating to remove the poison or in spontaneous vomiting. and thirst proceed to dehydration and vomiting, Gastric aspiration should be performed only if a weakness, restlessness, tachycardia and deep, rapid cuffed endotracheal tube is effectively in place, if breathing, convulsions and coma. Treatment is urgent necessary after anaesthetising the subject. and consists of cooling the patient and attention to fluid and electrolyte balance. It is essential to Volatile solvent abuse or 'glue sniffing', is common differentiate this type of poisoning from that due among teenagers, especially males. The success of to anticholinesterases because atropine given to the modern chemical industry provides easy access patients poisoned with dinitro-compound will stop to these substances as adhesives, dry cleaners, air sweating and may cause death from hyperthermia. fresheners, deodorants, aerosols and other products. Various techniques of administration are employed: Phenoxy herbicides (2,4-D, mecoprop, dichlorprop) viscous products may be inhaled from a plastic bag, are used to control broad-leaved weeds. Ingestion liquids from a handkerchief or plastic bottle. The causes nausea, vomiting, pyrexia (due to uncoupl- immediate euphoriant and excitatory effects are ing of oxidative phosphorylation), hyperventilation, replaced by confusion, hallucinations and delusions hypoxia and coma. Their elimination is enhanced as the dose is increased. Chronic abusers, notably of by urine alkalinisation. Organochlorine pesticides, toluene, develop peripheral neuropathy, cerebellar e.g. dicophane (DDT), may cause convulsions in disease and dementia; damage to the kidney, liver, acute overdose. Treat as for status epilepticus. heart and lungs also occurs with solvents. Over 50% of deaths from the practice follow cardiac arrhyth- Rodenticides include warfarin and thallium (see mia, probably caused by sensitisation of the myo- Table 9.1); for strychnine, which causes convulsions, cardium to catecholamines and by vagal inhibition give diazepam. 160
  11. SOME POISONINGS 9 Paraquat is a widely used herbicide which is mushrooms (liberty cap), which may be taken extremely toxic if it is ingested; a mouthful of specifically for this effect ('magic mushrooms'). commercial solution taken and spat out may be • Cardiovascular, e.g. from foxglove (Digitalis), enough to kill. Ulceration and sloughing of the oral mistletoe (Viscum album)) and lily-of-the-valley and oesophageal mucosa are followed 5-10 days (Convallaria) which contain cardiac glycosides later by renal tubular necrosis and subsequently that cause vomiting, diarrhoea and cardiac there is pulmonary oedema followed by pulmonary arrhythmia. fibrosis; whether the patient lives or dies depends • Hepatotoxic, e.g. from Amanita phalloides (death largely on the condition of the lung. Treatment cap mushroom), from Senecio (ragwort) and is urgent and includes activated charcoal or Crotalatia and from 'bush teas' prepared from aluminium silicate (Fuller's earth) by mouth as these plants in the Caribbean. Aflatoxin, from adsorbents, gastric lavage, and osmotic purgation Aspergillusflavus, a fungus which contaminates (magnesium sulphate). Haemodialysis or haemop- foods, is probably a cause of primary liver erfusion may have a role in the first 24 h, the cancer. rationale being that reducing the plasma con- • Convulsant, e.g. from water dropwort (Oenanthe} centration by using these methods protects the and cowbane (Cicuta), which contain the related kidney, failure of which allows the slow but relentless and very dangerous substances, oenanthotoxin accumulation of paraquat in the lung. and cicutoxin. • Cutaneous irritation, e.g. directly with nettle Diquat is similar to paraquat but the late pulmo- (Urtica), or dermatitis following sensitisation nary changes may not occur. with Primula. • Gastrointestinal symptoms, nausea, vomiting, diarrhoea and abdominal pain occur with Poisoning by biological substances numerous plants. Many plants form substances that are important Treatment of plant poisonings consists mainly for their survival either by enticing animals which of activated charcoal to adsorb toxin in the gastro- disperse their spores, or by repelling potential pre- intestinal tract. Inducing emesis with ipecacuanha dators. Poisoning occurs when children eat berries may make the diagnosis more difficult for vomiting or chew flowers, attracted by their colour; adults is often the earliest sign of poisoning. Convulsions may mistake nonedible for edible varieties of should be controlled with diazepam. In 'death cap' salad plants and fungi (mushrooms) for they may mushroom poisoning, penicillin may be used to resemble each other closely and some are greatly displace toxin from plasma albumin, provided prized by epicures. haemodialysis is being used, which latter may also The range of toxic substances that these plants benefit the renal failure. produce is reflected in a diversity of symptoms which may be grouped broadly thus: Biological agents as weapons • Atropinic, e.g. from deadly nightshade (Atropa belladonna) and thorn apple (Datura), causing Many natural agents can cause life-threatening dilated pupils, blurred vision, dry mouth, infections but their recruitment as biological weapons flushed skin, confusion and delirium. against communities of people requires particular • Nicotinic, e.g. from hemlock (Conium) and qualities of infectivity, pathogenicity, stability and Laburnum, causing salivation, dilated pupils, ease of production. Among the pathogens that may vomiting, convulsions and respiratory paralysis. be considered candidates for this horrific purpose • Muscarinic, e.g. from Inocybe and Clitocybe fungi are Bacillus anthracis (the causal agent of anthrax), (mushrooms), causing salivation, lachrymation, Brucella (brucellosis), Clostridium botulinum (botu- miosis, perspiration, bradycardia and lism), Francisella tularensis (tularaemia), Yersinia bronchoconstriction, also hallucinations. pestis (plague), and variola virus (smallpox). Drugs • Hallucinogenic, e.g. from psilocybin-containing used for the treatment and prophylaxis of some of 161
  12. 9 POISONING, OVERDOSE, ANTI DOTES the bacterial infections appear in Table 11.1 (p. 211). The onset of symptoms occurs immediately Vaccines are kept in special centres to immunise on exposure (an important factor from the point of against anthrax, plague and smallpox, and an view of the user) and they disappear dramatically: antitoxin for botulism. That it has been thought At one moment the exposed person is in their grip. necessary even to make reference to the subject of Then he either stumbles away, or the smoke plume bioterrorism is surely a sad commentary on the veers or the discharge from the grenade stops, and, times in which we live. immediately, the symptoms begin to roll away. Within a minute or two, the pain in the chest has Incapacitating agents gone and his eyes, although still streaming, are open. Five or so minutes later, the excessive (harassing, disabling, antiriot agents) salivation and pouring tears stop and a quarter of Harassing agents may be defined as chemical an hour after exposure, the subject is essentially substances that are capable when used in field back to normal.10 conditions, of rapidly causing a temporary Exposed subjects absorb small amounts only, disablement that lasts for little longer than the and the plasma t1/2 is about 5 seconds. period of exposure.10 Investigations of the effects of CS are difficult in The pharmacological requirements for a safe and 'field use', but some have been done and at present effective harassing agent must be stringent (it is there is no evidence that even the most persistent hardly appropriate to refer to benefit versus risk). rioter will suffer any permanent effect. The hazard As well as potency and rapid onset and offset of to the infirm or sick seems to be low, but plainly it effect in open areas under any atmospheric condi- would be prudent to assume that asthmatics or tion, it must be safe in confined spaces where bronchitics could suffer an exacerbation from high concentration may be very high and may affect concentrations, though bronchospasm does not an innocent, bedridden invalid should a projectile occur in healthy people. Vomiting seems to be due enter a window. to swallowing contaminated saliva. Transient loose- ness of the bowels may follow exposure. Hazard CS (chlorobenzylidene malononitrile, a tear 'gas') from CS is probably confined to situations where is a favoured substance at present. This is a solid the missiles are projected into enclosed spaces. that is disseminated as an aerosol (particles of 1 micron diameter) by including it in a pyrotechnic CN (chloroacetophenone, a tear gas) is generally mixture. The spectacle of its dissemination has been used as a solid aerosol or smoke; solutions (Mace) rendered familiar by television. It is not a gas, it is are used at close quarters. an aerosol or smoke. The particles aggregate and settle to the ground in minutes so that the risk of CR (dibenzoxazepine) was put into production in prolonged exposure out of doors is not great. 1973 after testing on army volunteers. In addition to the usual properties (above) it may induce a According to the concentration of CS to which a transient rise in intraocular pressure. Its solubility person is exposed, the effects vary from a slight allows use in water 'cannons'. pricking or peppery sensation in the eyes and nasal 'Authority' is reticent about the properties of all passages up to the maximum symptoms of these substances and no further important informa- streaming from the eyes and nose, spasm of the tion is readily available. eyelids, profuse lachrymation and salivation, This brief account has been included, because, retching and sometimes vomiting, burning of the in addition to helping victims, even the most mouth and throat, cough and gripping pain in the well-conducted and tractable students and doctors chest.11 11 Home Office Report (1971) of the enquiry into the medical 10 Health aspects of chemical and biological weapons. 1970 and toxicological aspects of CS. pt II. HMSO, London: Cmnd WHO Geneva. 4775. 162
  13. SOME POISONINGS 9 may find themselves exposed to CS smoke in our thiopentone, that cannot be independently confirmed. troubled world; and some may even feel it their But accused people, convinced of their own inno- duty to incur exposure. The following points are cence, sometimes volunteer to undergo such tests. worth making: The problem of discerning truth from falsehood remains. • Wear disposable plastic gloves, for the object of In some countries drugs are used for judicial treating the sufferer is frustrated if the physician execution, e.g. combinations of thiopentone, potas- becomes affected. sium, curare, given intravenously. • 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 GUIDETO FURTHER READING contaminated hair. Cutaneous erythema is usual and blistering may occur with high Dawson A H, Whyte IM 1999 Therapeutic drug concentrations of CS and CN in warm, moist monitoring in drug overdose. British Journal of conditions. Clinical Pharmacology 48: 278-283 • The eyes should be left to irrigate themselves; Ernst A, Zibrak J D 1998 Carbon monoxide poisoning. raised intraocular pressure may cause acute New England Journal of Medicine 339:1603-1608 glaucoma in those over 40 years. Evison D, Hinsley D, Rice P 2002 Chemical weapons. British Medical Journal 324: 332-335 Flanagan R J et al 1990 Alkaline diuresis for acute DRUGS USED FORTORTURE, poisoning with chlorophenoxy herbicides and INTERROGATION AND JUDICIAL ioxynil. Lancet 335: 454-458 EXECUTION Fraunfelder F T 2000 Is CS gas dangerous? British Regrettably, drugs have been and are being used for Medical Journal 320: 458-459 torture, sometimes disguised as 'interrogation' or Hawton K et al 1999 Effects of a drug overdose in a 'aversion therapy'. Facts are, not surprisingly, hard television drama on presentation to hospital for to obtain, but it seems that suxamethonium, halluci- self poisoning: time series and questionnaire study. nogens, thiopentone, neuroleptics, amphetamines, British Medical Journal 318: 972-977 apomorphine and cyclophosphamide have been Henry J A1992 Ecstasy and the dance of death. British employed to hurt, frighten, confuse or debilitate in Medical Journal 305: 5-6 such ways as callous ingenuity can devise. When Jones A L, Volans G 1999 Management of self the definition of criminal activity becomes per- poisoning. British Medical Journal 319: 1414-1417 verted to include activities in defence of human Khan A S, Morse S, Lillibridge S 2000 Public-health liberty, the employment of drugs offers inducement preparedness for biological terrorism in the USA. to inhuman behaviour. Such use, and any doctors Lancet 356:1179-1182 or others who engage in it, or who misguidedly Reisman R E 1994 Insect stings. New England Journal allow themselves to believe that it can be in the of Medicine 331: 523-527 interest of victims to monitor the activity by others, Shannon M 2000 Ingestion of toxic substances by must surely be outlawed. children. New England Journal of Medicine 342: It might be urged that it is justifiable to use drugs 186-191 to protect society by discovering serious crimes Tibbies P M, Edelsberg J S 1996 Hyperbaric-oxygen such as murder. There is no such thing as a 'truth therapy. New England Journal of Medicine 334: drug' in the sense that it guarantees the truth of what 1642-1648 the subject says. There always must be uncertainty Yih J-P 1995 CS gas injury to the eye. British Medical of the truth of evidence obtained with drugs, e.g. Journal 311: 276 163
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