29: Toxicology

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Section 29 Toxicology

Edited by Lindsay Murray

29.1 Approach to the poisoned patient

Introduction

Drug overdose in adults usually occurs in the context of self-poisoning, which may be either recreational or an act of deliberate self-harm.

Deliberate self-poisoning is one of the commonest reasons for general hospital admission in the UK1 and accounts for 1–5% of all public hospital admissions in Australia.2,3 The bulk of the medical management of cases presenting to hospital is carried out in the emergency department (ED), and the emergency physician is expected to be expert in the field. Although the management must vary considerably according to the nature and severity of the poisoning, some general principles apply.

Above all, it must be remembered that the acute overdose presentation is only a discrete time-limited event in the course of the underlying condition, which is usually psychiatric or social in origin.

Cardiovascular manifestations of poisoning include tachycardia, bradycardia, hypertension, hypotension, conduction defects and arrhythmias (Table 29.1.2). Bradycardia is relatively rarely observed and is associated with a number of potentially life-threatening ingestions. Tachycardia is commonly observed and is usually benign. It may be due to intrinsic sympathomimetic or anticholinergic effects of a drug, or a reflex response to hypotension or hypoxia. Hypotension is also commonly observed and may be due to a number of different causes (Table 29.1.2). Hypertension is unusual. Severe hypertension is usually associated with illicit drug use and is important because it may produce complications such as intracerebral haemorrhage.

Table 29.1.2 Cardiovascular effects of poisoning

CNS manifestations of poisoning include decreased level of consciousness, agitation or delirium, seizures and disordered temperature regulation. A decreased level of consciousness is a common presentation of poisoning and is associated with many drugs, some of which are listed in Table 29.1.1. Although usually a direct drug effect, CNS depression is occasionally secondary to hypoglycaemia, hypoxia or hypotension. Common causes of agitation or delirium following overdose are listed in Table 29.1.3. Toxic seizures are potentially life-threatening, and important causes are listed in Table 29.1.4.

Table 29.1.3 Toxic causes of agitation or delirium

Alcohol
Anticholinergic syndrome
Antidepressants

Atypical antipsychotic agents

Benzodiazepines and other sedative-hypnotics
Cannabis
Hallucinogenic agents
Serotonin syndrome
Sympathomimetic syndrome

Theophylline
Withdrawal syndromes

Table 29.1.4 Toxic causes of seizures

Amphetamines
Bupropion
Carbamazepine
Chloroquine
Cocaine
Isoniazid
Mefanamic acid
Theophylline
Tramadol
Tricyclic antidepressants
Venlafaxine

Hypothermia is usually a complication of environmental exposure secondary to a decreased level of consciousness or altered behaviour. Hyperthermia is a direct toxic effect and causes are listed in Table 29.1.5. Severe hyperthermia is rapidly lethal if not corrected.

Table 29.1.5 Toxic causes of hyperthermia

Amphetamines
Anticholinergics
Cocaine
MAO inhibitors
Salicylates
Serotonin syndrome

Metabolic and other manifestations of poisoning include hyper- and hypoglycaemia, hyper- and hyponatraemia, acidosis and alkalosis and hepatic failure.

Acute poisoning is distinguished from many other forms of acute illness in that, given appropriate supportive care over a relatively short period, a full recovery can usually be expected. A small number of potentially fatal poisonings may demonstrate progressive toxicity despite full supportive care. These are the so-called cellular toxins, and include colchicine, iron, salicylate, cyanide, paracetamol, theophylline and digoxin. In some of these cases early aggressive gastrointestinal decontamination, timely administration of antidotes or the institution of techniques of enhanced elimination may be life saving.

Mortality or morbidity may also result from specific complications of a poisoning. These include trauma, pulmonary aspiration, adult respiratory distress syndrome, rhabdomyolysis, renal failure and hypoxic encephalopathy. These complications usually occur prior to arrival in the ED.

Pulmonary aspiration frequently complicates a period of decreased level of consciousness or a seizure. It is a leading cause of in-hospital morbidity and mortality following overdose. This complication is characterized by rapid onset of dyspnoea, cough, fever, wheeze and cyanosis.

Rhabdomyolysis occurs as a direct toxic effect (rare) or secondary to excessive muscular hyperactivity, seizures, hyperthermia or prolonged coma with direct muscle compression. The urine is dark and acute renal failure can develop secondary to tubular deposition of myoglobin.

Assessment

Risk assessment

A risk assessment should be made as soon as possible in the management of the poisoned patient. Only resuscitation is a greater priority (see Table 29.1.6). Risk assessment is a distinct quantitative cognitive step through which the clinician attempts to predict the likely clinical course and potential complications for the individual patient at that particular presentation.4 An accurate risk assessment allows informed decision-making in regard to all subsequent management steps including duration and intensity of supportive care and monitoring, screening and specialized testing, decontamination, enhanced elimination, antidotes and disposition. Factors that are taken into account when formulating this risk assessment include: the agent(s), the dose, the time since ingestion, the clinical features present and patient factors (Table 29.1.6). Specialized testing may refine risk assessment. Access to specialized poisons information in the form of a poisons information centre or in-house databases is often necessary to formulate an accurate risk assessment.

Table 29.1.6 Risk assessment-based approach to poisoning

Supportive care and monitoring Investigations

Decontamination Enhanced elimination Antidotes Disposition

Reproduced from Toxicology Handbook. Murray L, Daly F, Little M, Cadogan M. Elsevier, Sydney 2007.

Physical examination

The focused physical examination of the poisoned patient aims to:

The initial physical examination of the overdose patient in many ways parallels the primary survey of the trauma patient. The airway, breathing and circulation are assessed and stabilized as necessary. The level of consciousness should be assessed, the presence of seizure activity noted and the blood glucose and temperature measured.

A more complete examination is carried out when the patient is stable. This should include a full neurological examination, including assessment of the level of consciousness and mental status, pupil size, muscle tone and movements and the presence or absence of focal neurological signs. Poisoning normally causes global CNS depression, and focal signs suggest an alternative diagnosis or a CNS complication such as cerebral haemorrhage.

Other features that should be specifically sought are any evidence of associated trauma, the state of hydration, the condition of the skin, in particular the presence of pressure areas, the presence or absence of bowel sounds and the condition of the urine.

Several toxic autonomic syndromes, or ‘toxidromes’, have been described in relation to poisoning. The principal ones are listed in Table 29.1.7. Identification of these syndromes may narrow the differential diagnosis in cases of unknown poisoning.5

Table 29.1.7 Toxic autonomic syndromes or ‘toxidromes’

Toxidrome Features Common causes
Anticholinergic Agitated delirium Antihistamines
Tachycardia Benztropine
Hyperthermia Carbamazepine
Dilated pupils Phenothiazines
Dry flushed skin Plant poisonings
Urinary retention Tricyclic antidepressants
Ileus  
Mixed cholinergic Brady- or tachycardia Organophosphates
Hypo- or hypertension Carbamates
Miosis or mydriasis  
Sweating  
Increased bronchial secretion  
Gastrointestinal hyperactivity  
Muscle weakness  
Fasciculations  
Mixed α- and β-adrenergic Hypertension Amphetamines
Tachycardia Cocaine
Mydriasis  
Agitation  
β-Adrenergic Hypotension Caffeine
Tachycardia Salbutamol
Hypokalaemia Theophylline
Hyperglycaemia  
Serotonin Altered mental status Amphetamines
Autonomic dysfunction Antihistamines
Fever Monoamine oxidase inhibitors
Hypertension NSSRIs
Sweating SSRIs
Tachycardia Tricyclic antidepressants (Usually combined overdose)
Motor dysfunction  
Hyperreflexia  
Hypertonia (esp. lower limbs)  
Myoclonus  

NSSRI, non-selective serotonin re-uptake inhibitor; SSRI, selective serotonin re-uptake inhibitor.

Treatment

The management of poisoning should be approached in a systematic way. Following initial resuscitation, further treatment is informed by the risk assessment (Table 29.1.6).

Resuscitation, supportive care and monitoring

Supportive care is the key element in the management of poisoning. The vast majority of poisonings result in temporary dysfunction of one or more of the body systems. If appropriate support of the system in question is instituted in a timely fashion and continued until the toxic substance is metabolized or excreted, a good outcome can be anticipated. In severe poisonings supportive care may be very aggressive, and possible interventions are listed in Table 29.1.8.

Table 29.1.8 Supportive care measures for the poisoned patient

Airway Endotracheal intubation
Breathing Supplemental oxygen
Ventilation
Circulation Intravenous fluids
Inotropes
Antihypertensives
Antiarrhythmics
Defibrillation/cardioversion
Cardiac pacing
Cardiopulmonary bypass
Metabolic Hypertonic dextrose
Hypertonic saline
Insulin/dextrose
Calcium salts
Sodium bicarbonate
Agitation/delirium Benzodiazepines
Butyrophenones
Seizures Benzodiazepines
Barbiturates
Body temperature External rewarming
External cooling
Impaired renal function Rehydration
Haemodialysis

The specific supportive management of a number of manifestations or complications of poisoning warrants further mention insofar as it may differ from the standard management of such conditions with other aetiologies.

Cardiopulmonary arrest from poisoning should be aggressively resuscitated. Direct current cardioversion is rarely successful in terminating toxic arrhythmias and should not take precedence over establishing adequate ventilation and oxygenation, cardiac compressions, correction of acidosis or hypovolaemia and the administration of specific antidotes. Resuscitative efforts should be continued beyond the usual timeframe. In cardiac arrest due to drugs with direct cardiac toxicity, the use of cardiopulmonary bypass or extracorporeal membrane oxygenation (ECMO) until the drug is metabolized may be life-saving.

In general, intravenous benzodiazepines are the drugs of choice for control of toxic seizures. Large doses may be required. Hypoxia and hypoglycaemia must be corrected if they are contributory factors. Patients with toxic seizures do not generally need long-term anticonvulsant therapy. Isoniazid-induced seizures are not controlled without administration of an adequate dose of the specific antidote, pyridoxine.

The management of pulmonary aspiration is essentially supportive, with supplemental oxygenation and intubation and mechanical ventilation if necessary. Neither prophylactic antibiotics nor corticosteroids have been shown to be helpful in the management of this condition, which is essentially a chemical pneumonitis.

Toxic hypertension rarely requires specific therapy. Most cases are mild and simple observation is sufficient. Agitation or delirium is a feature of many intoxications associated with hypertension, and adequate sedation with benzodiazepines usually lowers the blood pressure. Severe toxic hypertension is most likely in toxicity from cocaine or amphetamine-type drugs, and treatment may be indicated to avoid complications such as cardiac failure or intracerebral haemorrhage. The drug of choice in this situation is sodium nitroprusside by intravenous infusion. The extremely short duration of action of this vasodilator allows accurate control of hypertension during the toxic phase, and avoids the development of hypotension once toxicity begins to wear off.

Management of rhabdomyolysis consists of treatment of the causative factors, fluid resuscitation and careful monitoring of fluids and electrolytes. The role of mannitol and urinary alkalinization in reducing the risk of renal failure is not clear. Established acute renal failure requires haemodialysis, often for up to 6 weeks.

Decontamination

The aim of decontamination of the gastrointestinal tract is to bind or remove ingested material before it is absorbed into the circulation and able to exert its toxic effects. This is a very attractive concept and has long been considered one of the fundamental interventions in management of the overdose patient.

However, gastrointestinal decontamination should not be regarded as a routine procedure in the management of the patient presenting to the ED following an overdose. The decision to perform gastrointestinal decontamination and the choice of method should be based on an assessment of the likely benefit, the likely risk and the resources required. Gastrointestinal decontamination should only be considered where there is likely to be a significant amount of a significantly toxic material remaining in the gut. It is never indicated when the risk assessment predicts a benign course. Efforts at decontamination technique should never take precedence over the institution of appropriate supportive care.

Three basic approaches to gastrointestinal decontamination are available: gastric emptying, administration of an adsorbent and catharsis.

Gastric emptying can be attempted by the administration of an emetic, most commonly syrup of ipecac, or by gastric lavage. In volunteer studies both of these techniques removed highly variable amounts of marker substances from the stomach even if performed immediately after ingestion, and the effect diminished rapidly with time to the point of being negligible after one hour.6,7 Clinical outcome trials have failed to demonstrate improved outcome as a result of routine gastric emptying in addition to administration of activated charcoal, except, perhaps, in patients presenting unconscious within 1 h of ingestion.810

The principal adsorbent available to clinicians is activated charcoal (AC), which effectively binds most pharmaceuticals and chemicals, and is currently the decontamination method of choice for most poisonings. Materials that do not bind well to charcoal are listed in Table 29.1.9.

Table 29.1.9 Materials that do not bind well to activated charcoal

Alcohols

Corrosives

Hydrocarbons Metals and their salts

Charcoal is ‘activated’ by treatment in acid and steam at high temperature. This process removes impurities and greatly increases the surface area available for binding. Activated charcoal is packaged as a 50 g dose premixed with water or sorbitol, which is likely to be sufficient for the majority of ingestions. Adult patients are usually able to drink AC slurry from a cup. If the level of consciousness is too impaired to allow this, they should be intubated first. Administration of AC is absolutely contraindicated unless the patient has an intact or protected airway.

Volunteer studies demonstrate that the effect of AC diminishes rapidly with time and that the greatest benefit occurs if it is administered within 1 h. There is as yet no evidence that AC improves clinical outcome.11

There is no evidence to suggest that the addition of a cathartic such as sorbitol to AC improves clinical outcome.12,13

Apart from rarely employed endoscopic and surgical techniques, whole-bowel irrigation (WBI) is the most aggressive form of gastrointestinal decontamination. Polyethylene glycol solution (Golytely™) is administered via a nasogastric tube at a rate of 2 L/h until a clear rectal effluent is produced. This usually takes about 6 h and requires one-to-one nursing. In volunteer studies, this technique reduced the absorption of slow-release pharmaceuticals and so may be of benefit in life-threatening overdoses of these agents.13,14 Again, clinical benefit has not yet been conclusively demonstrated.15 The use of WBI has also been reported in the management of potentially toxic ingestions of iron, lead and packets of illicit drugs. Whole-bowel irrigation is contraindicated if there is evidence of ileus or bowel obstruction, and in patients who have an unprotected airway or haemodynamic compromise.16

Enhanced elimination

A number of techniques are available to enhance the elimination of toxins from the body. Their use is rarely indicated, as only a very few drugs capable of causing severe poisoning have pharmacokinetic parameters that render them amenable to these techniques (Table 29.1.10).

Table 29.1.10 Techniques of enhanced elimination

Technique Suitable toxin
Repeat-dose activated charcoal Carbamazepine
Dapsone
Phenobarbitone
Phenytoin
Salicylate
Theophylline
Urinary alkalinization Phenobarbitone
Salicylate
Haemodialysis Ethylene glycol
Lithium
Methanol
Salicylate
Theophylline
Haemoperfusion Theophylline

Repeat-dose AC (25–50 g every 3–4 h) may enhance drug elimination by interrupting the enterohepatic circulation or by ‘gastrointestinal dialysis’. Gastrointestinal dialysis is the movement of a toxin across the gastrointestinal wall from the circulation into the gut down a concentration gradient that is maintained by charcoal binding. For this technique to be effective, a drug must undergo considerable enterohepatic circulation or, in the case of ‘gastrointestinal dialysis’, have a small volume of distribution, small molecular weight, low protein binding, slow endogenous elimination and bind to charcoal.16,17 The advantages of this technique are that it is non-invasive and simple to carry out.

Alkalinization of the urine enhances urinary excretion of drugs that are filtered at the glomerulus and are unable to be reabsorbed across the tubular epithelium when in an ionized form at alkaline pH. For elimination to be effectively enhanced by this method, the drug must be predominantly eliminated by the kidneys in the unchanged form, have a low pKa, be distributed mainly to the extracellular fluid compartment and be minimally protein bound.18

Haemodialysis (HD) and haemoperfusion (HP) are both very invasive techniques and for that reason are reserved for potentially life-threatening intoxications. Only a small number of drugs that have small volumes of distribution, slow endogenous clearance rates, small molecular weights (HD) and bind to charcoal (HP) will have their rates of elimination significantly enhanced by these procedures.

Antidotes

Very few drugs have effective antidotes. Occasionally, however, timely use of an antidote may be life saving or substantially reduce morbidity, time in hospital or resource requirements. Antidotes that may be indicated in the ED setting are listed in Table 29.1.11. However, it must be remembered that antidotes are also drugs, and are frequently associated with adverse effects of their own. An antidote should only be used where a specific indication exists, and then only at the correct dose, by the correct route, and with appropriate monitoring. Because many antidotes are so infrequently used, obtaining sufficient supplies when the need arises can be difficult. Every ED must review its stocking of antidotes and have a plan for obtaining further supplies should the need arise.

Table 29.1.11 Useful emergency antidotes

Poisoning Antidote
Atropine Physostigmine
Benzodiazepines Flumazenil
Cyanide Dicobalt edetate, hydroxocobalamin
Digoxin Digoxin-specific Fab fragments
Insulin Dextrose
Iron Desferoxamine
Isoniazid Pyridoxine
Methaemoglobinaemia Methylene blue
Methanol and ethylene glycol Ethanol, fomepizole
Organophosphates and carbamates Atropine, oximes
Opioids Naloxone
Paracetamol N-acetyl cysteine
Sulphonylureas Dextrose, octreotide
Tricyclic antidepressants Sodium bicarbonate
Warfarin, brodifacoum Vitamin K

Clinical investigation

Investigations should only be performed if they are likely to affect the management of the patient. They are employed as either screening tests or for specific purposes.

In poisoning, screening tests aim to identify occult toxic ingestions for which early specific treatment might improve outcome. The recommended screening tests for acute poisoning are the 12-lead ECG and the serum paracetamol level. The ECG is used to exclude conduction defects, which may predict potentially life-threatening cardiotoxicity. The serum paracetamol is useful to ensure that paracetamol poisoning is diagnosed within the time available for effective antidotal treatment.

Other specific investigations may be indicated to exclude important differential diagnoses, confirm a specific poisoning for which significant complications might be anticipated, assess the severity of intoxication, assess response to treatment or assess the need for a specific antidote or enhanced elimination technique.

The patient with only minor manifestations of poisoning may require no other blood tests apart from a screening paracetamol level. Pregnancy should be excluded in women of childbearing age by serum or urine β-HCG if necessary. More seriously ill patients may require electrolyte, renal and liver function tests and a full blood count, creatine kinase and arterial blood gases. Urinalysis reveals myoglobinuria in significant rhabdomyolysis.

Routine qualitative drug screening of urine or blood in the overdose patient is rarely useful in planning management.

Measurement of serum drug concentrations is only useful if this provides important diagnostic or prognostic information, or assists in planning management. Some drug levels that may be useful are listed in Table 29.1.12. For most cases, drug overdose management is guided by clinical findings and not by drug levels. Some drugs commonly taken in overdose for which serum concentrations are of no value in planning management are listed in Table 29.1.13.

Table 29.1.12 Drug levels that may be helpful in the management of selected cases of overdose

Carbamazepine
Digoxin
Dilantin
Lithium
Iron
Paracetamol
Phenobarbitone
Salicylate
Theophylline
Valproate

Table 29.1.13 Drug levels that are not helpful in the management of overdose

CNS drugs Cardiovascular drugs
Antidepressants ACE inhibitors
Benzodiazepines Beta-blockers
Benztropine Calcium channel blockers
Cocaine Clonidine
Newer antipsychotics  
Opiates  
Phenothiazines  

Radiology has a limited role in the management of overdose. A chest X-ray is indicated in any patient with a significantly decreased level of consciousness, seizures or hypoxia. It may show evidence of pulmonary aspiration. A computerized tomography scan of the head may be indicated to exclude other intracranial pathology in the patient with an altered mental status. The abdominal X-ray is useful in evaluating overdose of radio-opaque metals including iron, lithium, potassium, lead and arsenic.

Disposition

Both the medical and the psychiatric disposition of the overdose patient must be considered. A good risk assessment is essential to determining timely and safe disposition.

The majority of overdose patients who remain stable at 4–6 h after the ingestion do not need further close monitoring and may be admitted to a non-monitored bed until manifestations of toxicity completely resolve. An emergency observation ward is ideal for this purpose.

Any patient who develops clinical manifestations of intoxication severe enough to require the institution of specific supportive care measures requires admission to an intensive care environment. A few patients will require admission for prolonged monitoring based on the history of the ingestion. For example, anyone with a history of ingestion of colchicine, organophosphates, slow-release theophylline or slow-release calcium channel blockers requires admission because of the possibility of delayed onset of severe toxicity.

Psychiatric evaluation of deliberate self-poisoning cases is indicated as soon as the patient’s medical condition permits. All such patients must be continuously supervised until the psychiatric evaluation has taken place.

References

1 Hawton K, Fagg J. Trends in deliberate self-poisoning and self-injury in Oxford. British Medical Journal. 1992;304:1409-1411.

2 McGrath J. A survey of deliberate self-poisoning. Medical Journal of Australia. 1989;150:317-322.

3 Pond SM. Prescription for poisoning. Medical Journal of Australia. 1995;162:174-175.

4 Murray L, Daly F, Little M, Cadogan M, editors. Toxicology handbook. Sydney: Elsevier, 2007.

5 Kulig K. Initial management of ingestion of toxic substances. New England Journal of Medicine. 1992;326:1677.

6 Krenzelok EP, McGuigan M, Lheureux P. Position statement: ipecac syrup. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology – Clinical Toxicology. 1997;35(7):699-709.

7 Vale JA. Position statement: gastric lavage. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology – Clinical Toxicology. 1997;35(7):711-719.

8 Kulig K, Bar-Or D, Kantrill SV, et al. Management of acutely poisoned patients without gastric emptying. Annals of Emergency Medicine. 1990;14:562-567.

9 Merigian KS, Woodard M, Hedges JR, et al. Prospective evaluation of gastric emptying in the self-poisoned patient. American Journal of Emergency Medicine. 1990;8:479-483.

10 Pond SM, Lewis-Driver DJ, Williams G, et al. Gastric emptying in acute overdose: a prospective randomised controlled trial. Medical Journal of Australia. 1995;163:345-349.

11 Chyka PA, Seger D. Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology – Clinical Toxicology. 1997;35(7):721-741.

12 Barceloux D, McGuigan M, Hartigan-Go K. Position statement: cathartics. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology – Clinical Toxicology. 1997;35(7):743-752.

13 Kirshenbaum LA, Mathew SC, Sitar DS, et al. Whole-bowel irrigation versus activated charcoal in sorbitol for the ingestion of modified-release pharmaceuticals. Clinical Pharmacology Therapy. 1989;46:264-271.

14 Smith SW, Ling LJ, Halstenson CE. Whole-bowel irrigation as a treatment for acute lithium overdose. Annals of Emergency Medicine. 1991;20:536-539.

15 Tenenbein M. Position statement: whole bowel irrigation. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology – Clinical Toxicology. 1997;35(7):753-756.

16 Pond SM. Role of repeated oral doses of activated charcoal in clinical toxicology. Medical Toxicology. 1986;1:3-11.

17 Chyka PA. Multiple-dose activated charcoal and enhancement of systemic drug clearance: summary of studies in animals and human volunteers. Clinical Toxicology. 1995;33:399-405.

18 Winchester JF. Active methods for detoxification. In Haddad LM, Shannon MW, Winchester JF, editors: Clinical management of poisoning and drug overdose, 3rd edn, Philadelphia: WB Saunders, 1998.

19 Whyte IM, Dawson AH, Buckley NA, et al. A model for the management of self-poisoning. Medical Journal of Australia. 1997;167:142-146.

20 Lee V, Kerr JF, Braitberg G, et al. Impact of a toxicology service on a metropolitan teaching hospital. Emergency Medicine. 2001;13:37-42.

29.2 Cardiovascular drugs

Pharmacokinetics

Standard CCB preparations are rapidly absorbed from the gastrointestinal tract, with onset of action occurring within 30 min.1 Pharmacokinetic parameters are shown in Table 29.2.1. Verapamil and diltiazem undergo significant first-pass hepatic clearance. Verapamil is metabolized to norverapamil, which possesses 15–20% of verapamil’s pharmacological activity and is renally excreted. Diltiazem is metabolized to deacetyldiltiazem, which has half the potency of the parent compound and undergoes biliary excretion. The elimination half-lives of all CCBs may be prolonged following massive overdose. Amlodipine has a longer plasma half-life (30–50 h) than other CCBs.

Importantly, slow-release preparations of both verapamil and diltiazem are widely prescribed and are associated with much longer times to peak plasma concentration and clinical effect.

Absorption of β-blockers is rapid, with peak clinical effects occurring within 1–4 h. Pharmacokinetic parameters of the principal β-blockers are detailed in Table 29.2.2. Agents with high lipid solubility, such as propranolol, penetrate the blood–brain barrier better than the water-soluble agents, and hence cause greater central nervous system (CNS) toxicity.

Pathophysiology

CCBs antagonize the entry of extracellular calcium into cardiac and smooth muscle, but not skeletal muscle. Upon entry into cells, calcium participates in mechanical, electrical and biochemical reactions. It is involved in excitation–contraction of cardiac and smooth muscles, as well as phase 0 depolarization in the sinus and atrioventricular (AV) nodes by calcium influx through channels.2 CCBs affect myocardial contractility and slow conduction through the sinus and AV nodes. Contraction of smooth muscle is mediated by calcium influx, which is inhibited by CCBs. This results in vasodilatation and secondary reflex tachycardia from an increase in sympathetic activity.

The different classes of CCB have somewhat different pharmacological and toxic effects, as a consequence of their different binding characteristics to the dihydropyridine (DHP) receptors. Verapamil, a phenylalkylamine, produces more profound cardiac conduction defects and equal reductions in systemic vascular resistance when compared with other CCBs on a mg/kg basis.1 Verapamil is more likely to produce symptomatic decreases in blood pressure, heart rate and cardiac output than diltiazem, a benzothiazepine. The DHPs, which include amlodipine, felodipine, lercanidipine and nifedipine preferentially bind to vascular smooth muscle and predominantly decrease systemic and coronary vascular resistance. With the exception of felodipine, they also produce a reflex tachycardia by the unloading of baroreceptors.

β-blockers prevent the binding of catecholamines to β receptors (β1, β2). β1 receptors are located in the myocardium, kidney and eye, and β2 receptors in adipose tissue, pancreas, liver and both smooth and skeletal muscle. β1 stimulation produces increased chronotropy and inotropy in the heart, increased renin secretion in the kidney and increased aqueous humor production. β2 stimulation relaxes smooth muscle in the blood vessels, bronchial tree, intestinal tract and uterus.

Blockade of β receptors results in increased intracellular cAMP concentrations, with a resultant blunting of the metabolic, chronotropic and inotropic effects of catecholamines. Some β-blockers, especially propranolol, may also impede sodium entry via myocardial fast inward sodium channels, thus slowing phase 0 of the action potential. This results in a prolonged QRS duration on the electrocardiogram and produces cardiotoxicity in overdose more like that of the tricyclic antidepressants.

The different β-blockers have slightly differing pharmacological properties, including selectivity for β adrenoreceptors, intrinsic sympathomimetic activity and membrane-stabilizing activity. The relative affinity for β adrenoreceptors may influence expression of toxicity. Atenolol, esmolol and metoprolol are β1-selective agents, and therapeutic use of these drugs is less likely to produce the peripheral vasoconstriction, bronchospasm and disturbances in glucose homoeostasis that result from β2 inhibition. However, pharmacological specificity decreases with increasing dose.3 Several β-blockers have partial agonist activity such that, although they block the β receptor to catecholamines, they also weakly stimulate the receptor. This partial agonist activity may have a protective effect in overdose.

Clinical features

Cardiovascular

Metabolic

β-blockers

In one large series of patients with β-blocker overdose, 30–40% of patients remained asymptomatic and only 20% developed severe toxicity.4 Toxicity is more likely to develop after ingestion of propranolol, in patients with pre-existing cardiac disease or where there is co-ingestion of other drugs with effects on the cardiovascular system, especially CCBs and cyclic antidepressants.4,5 If β-blocker toxicity is to develop, it is usually observed within 6 h of ingestion.5,6

Sinus node suppression and conduction abnormalities and decreased contractility are typical. First-degree AV block, AV dissociation, right bundle branch block and intraventricular conduction delay have been reported.

Propranol overdose is characterized by cardiotoxicity including prolongation of the QRS interval and ventricular arrhythmias that more closely resemble tricyclic antidepressant overdose; a consequence of the sodium channel blocking effects.

Sotalol has both β-blocker activity and class III antiarrhythmic properties. Class III drugs lengthen the duration of the QT interval owing to prolongation of the action potential in His-Purkinje tissue. Therefore, ventricular arrhythmias are more common with sotalol.

Hypotension occurs as a result of negative inotropic effect. In addition, CNS effects, such as depressed conscious level and seizures, can occur, especially with the more lipid-soluble and membrane-depressant agents such as propranolol. Hypoglycaemia is reported following atenolol overdose.

Treatment

The primary aim in both β-blocker and CCB toxicity is to restore perfusion to vital organs by increasing cardiac output, and the methods used are similar.

Supportive management may include airway and ventilatory support, intravenous fluid administration, transcutaneous or transvenous pacing and administration of inotropes. Severe cases may require placement of a Swan–Ganz catheter and invasive blood pressure monitoring.

Oral-activated charcoal should be administered as soon as practicable to all patients presenting within 2–4 h of ingestion, and to all those presenting after ingestion of slow-release preparations. More aggressive decontamination, with whole-bowel irrigation, is indicated following overdose with slow-release CCBs.7

A number of drugs play a role in the management of significant CCB or β-blocker poisoning, although none is a completely effective antidote. Suggested doses are shown in Table 29.2.4.

Table 29.2.4 Useful drugs in the management of CCB and β-blocker toxicity

  CCBs β-Blockers
Calcium 0.5–1 g (5–10 mLs) calcium chloride or 1–2 g (10–20 mLs) calcium gluconate i.v. over 5–10 minutes. Repeat every 10–15 minutes as required. Further administration guided by serum calcium concentrations.  
Catecholamines Adrenaline (epinephrine) infusion started at 1 μg/kg/min and titrate to maintain organ perfusion. Isoprenaline or adrenaline (epinephrine) infusion titrated to maintain organ perfusion.
Glucagon A bolus dose of 5–10 mg followed by an infusion of 1–5 mg/h. A bolus dose of 5–10 mg followed by an infusion of 1–5 mg/h.
Hyperinsulinaemia euglycaemia Actrapid 1 U/kg i.v. bolus followed by 0.5–1 U/kg/hr infusion. Give with 50% dextrose 50 mL followed by infusion to maintain euglycaemia. Actrapid 1 U/kg i.v. bolus followed by 0.5–1 U/kg/hr infusion. Give with 50% dextrose 50 mL followed by infusion to maintain euglycaemia.

Calcium, an inotropic agent, is the initial drug of choice for CCB toxicity. Administration must be closely monitored, with ionized calcium measured 30 min after commencing the infusion, and then second-hourly.8 Catecholamines are useful in attempting to restore adequate tissue perfusion.

Glucagon, a polypeptide hormone of pancreatic origin, enhances myocardial performance by increasing intracellular cAMP concentrations. This increase in cAMP triggers the release of cAMP-dependent protein kinase, which activates the calcium channels, causing an increase in heart rate and myocardial contractility. It works independently from that of the β-adrenoreceptor stimulation of the heart. Use of glucagon is supported only by case reports and some animal studies. There are no clinical trials supporting its efficacy in either calcium channel or beta-blocker poisoning and its role in management of these poisoning is questioned.9 It is frequently difficult to source adequate stocks of glucagon for use as an inotropic agent.

Hyperinsulinaemic euglycaemia therapy (HIET) is increasingly advocated as therapy for hypotension unresponsive to fluids, calcium salts and inotropes. This therapy is supported by animal work10,11 and promising initial human case reports12 but again clinical trials are lacking. Insulin administration switches cardiac cell metabolism from fatty acids to carbohydrates. It restores calcium fluxes and improves myocardial contractility. The recommended initial dose of actrapid is 1 U/kg i.v. followed by an infusion of 0.5–1 U/kg/h. This should be accompanied by an initial bolus dose of 50 mL 50% dextrose followed by an infusion to maintain euglycaemia.13

Severe propranolol toxicity is usually due to sodium channel blockade and treatment as for tricyclic antidepressant poisoning, including intubation, ventilation and sodium bicarbonate, is appropriate.

There are no clinically effective methods of enhancing the elimination of CCBs or β-blockers.

Clinical features

Two distinct clinical presentations of digoxin toxicity are observed: acute and chronic. Both are characterized by cardiac arrhythmias, and virtually all types of arrhythmia have been reported in the context of digoxin toxicity.14

Acute digoxin overdose in adults is usually intentional. The therapeutic margin for digoxin is relatively narrow, and any ingestion with suicidal intent is regarded as potentially life-threatening.

The non-cardiac manifestations of toxicity are nausea and vomiting and hypokalaemia. Nausea and vomiting occur early and may be the presenting complaint. The most common cardiac manifestations are sinus bradycardia, sinoatrial node arrest and first-, second- or third-degree heart block. Ventricular tachycardia and fibrillation may occur. In significant acute overdose progressive worsening of the conduction disturbance over a period of hours is usually observed.

Chronic digoxin toxicity may be precipitated by therapeutic errors, intercurrent illnesses that decrease renal elimination of digoxin or by drug interactions. Common drug interactions include those with quinidine, CCBs, amiodarone and indometacin. The patient is commonly elderly. Reduced muscle mass and reduced renal function in the elderly mean that both the volume of distribution and rate of elimination of digoxin may be substantially reduced.

Nausea and vomiting are also common manifestations of chronic digoxin toxicity and are frequent presenting symptoms. Neurological manifestations are characteristic of chronic toxicity and include visual disturbances, weakness and fatigue. The most common cardiovascular manifestations of chronic digoxin toxicity are arrhythmias, and these may be sinus bradycardia, atrial fibrillation with slowed ventricular response or a junctional escape rhythm, atrial tachycardia with block and ventricular tachycardia and fibrillation.

Death from digoxin toxicity results from pump failure, severe cardiac conduction impairment or ventricular arrhythmia.

Clinical investigation

The most important investigations are the ECG, serum electrolytes and creatinine and serum digoxin concentration.

The ECG is invaluable in documenting the type and severity of any cardiac conduction defect. Serial ECGs may demonstrate worsening of the cardiac conduction defects as toxicity progresses.

In acute poisoning the serum potassium rises as Na-K ATPase function is progressively impaired. Hyperkalaemia denotes significant acute digoxin toxicity. Prior to the availability of a specific antidote for digoxin poisoning, a serum potassium concentration >5.5 mEq/L was associated with a high probability of lethal outcome.16 Hyperkalaemia is not usually observed in chronic digoxin toxicity. In fact, these patients are frequently hypokalaemic and hypomagnesaemic secondary to chronic diuretic use. Both these electrolyte disorders are important as they exacerbate digoxin toxicity.

Serum digoxin concentrations are extremely useful in assessing and confirming toxicity, but must be carefully interpreted in the context of the clinical presentation. They do not accurately correlate with clinical toxicity. Therapeutic concentrations are usually quoted as 0.6–2.3 nmol/L (0.5–1.8 μµg/L). Significant chronic toxicity may be associated with relatively minor elevations of the serum digoxin concentration. This is particularly the case in the presence of pre-existing cardiac disease, hypokalaemia or hypomagnesaemia. Following acute overdose the serum digoxin concentration is relatively high compared to tissue concentrations, until distribution is completed by 6–12 h post ingestion. However, early concentrations greater than 15 nmol/L indicate serious poisoning.

Treatment

The best outcome is associated with early recognition of digoxin toxicity.

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