Medical toxicology and adverse drug experience最新文献

Hallucinogenic drugs are unique in that they produce the desired hallucinogenic effects at what are considered non-toxic doses. The hallucinogenic drugs can be categorised into 4 basic groups: indole alkaloid derivatives, piperidine derivatives, phenylethylamines and the cannabinols. The drugs reviewed include lysergic acid diethylamide (LSD), phencyclidine (PCP), cocaine, amphetamines, opiates, marijuana, psilocybin, mescaline, and 'designer drugs.' Particularly noteworthy is that each hallucinogen produces characteristic behavioural effects which are related to its serotonergic, dopaminergic or adrenergic activity. Cocaine produces simple hallucinations, PCP can produce complex hallucinations analogous to a paranoid psychosis, while LSD produces a combination of hallucinations, pseudohallucinations and illusions. Dose relationships with changes in the quality of the hallucinatory experience have been described with amphetamines and, to some extent, LSD. Flashbacks have been described with LSD and alcohol. Management of the intoxicated patient is dependent on the specific behavioural manifestation elicited by the drug. The principles involve differentiating the patient's symptoms from organic (medical or toxicological) and psychiatric aetiologies and identifying the symptom complex associated with the particular drug. Panic reactions may require treatment with a benzodiazepine or haloperidol. Patients with LSD psychosis may require an antipsychotic. Patients exhibiting prolonged drug-induced psychosis may require a variety of treatments including ECT, lithium and l-5-hydroxytryptophan.

The adverse reactions seen following administration of neuromuscular blocking agents are mainly cardiovascular. Due to the lack of specificity for the nicotinic receptor at the neuromuscular junction, these agents may interact with receptors in autonomic ganglia and muscarinic receptors in the heart. Furthermore, muscle relaxants may have histamine-releasing properties. The cardiovascular effects vary with potency and specificity of the drug, depending mainly on the chemical structure. Pancuronium, fazadinium and especially gallamonium block cardiac muscarinic receptors, and tachycardia may be seen. Atracurium, metocurine and in particular d-tubocurarine have histamine-releasing properties and may cause flushing, hypotension and tachycardia. Vecuronium has no effect on the cardiovascular system. The effect of succinylcholine on heart rate differs between children, where bradycardia is seen, and adults in whom tachycardia may follow. However, bradycardia may occur in adults following a single dose. Succinylcholine increases plasma potassium, especially in patients with nerve damage, and arrhythmias may be observed. The neuromuscular adverse effects of succinylcholine, such as fasciculations and increased gastric and intraocular pressure, may be prevented by precurarisation. Many drugs interact with neuromuscular blocking agents and there is often a potentiation of the neuromuscular effect. This is of clinical importance in the case of antibiotics, inhalational anaesthetics, lithium and cyclosporin. Difficulty in reversing the block may occur with calcium channel blockers and polymyxin. However, some drugs, such as phenytoin, carbamazepine and lithium, may cause resistance to neuromuscular blocking agents. Furthermore, clinically important interactions exist between individual neuromuscular blocking drugs. Precurarisation with a non-depolarising drug prolongs the onset of succinylcholine, and conversely a prolonged effect of non-depolarising drugs is seen following succinylcholine. The effect of succinylcholine is markedly prolonged if the drug is administered during recovery from pancuronium blockade or following neostigmine for reversal. Succinylcholine is hydrolysed by plasma cholinesterase, and drugs which decrease the activity of this enzyme may produce a prolonged block, i.e. contraceptive pills, cyclophosphamide, echothiopate and organophosphate.

Synthetic orally active angiotensin-converting enzyme (ACE) inhibitors have been successfully used in the treatment of congestive heart failure and hypertension, particularly in hypertensive subjects with increased renin-angiotensin-aldosterone-system activity. Adverse skin reactions, angioneurotic oedema and rapidly decreasing lung function in asthmatics have been reported following medication with ACE inhibitors. Furthermore, these drugs have been associated with a persistent dry cough in subjects without previous known bronchial hyper-reactivity. There is reason to believe that an ACE inhibitor-induced cough is due to an increased inflammatory state in the airways of susceptible individuals, and that this cough might thereby have pathophysiological features in common with the cough seen as an early symptom of asthma. All inflammatory responses, wheal and flare reactions, infiltration of neutrophils, eosinophils, basophils and monocytes were enhanced by ACE inhibitors. A dose-response relationship for the proinflammatory effect of the ACE inhibitor has been demonstrated.

Reye's syndrome is a hepatic encephalopathy with fatty infiltration of the liver and is due to mitochondrial dysfunction. Knowledge of the mechanisms causing Reye's syndrome has been gained from the study of Reye's syndrome-like diseases, including inborn errors of mitochondrial energy production, viral disease and toxicological injury. Entry of fatty acids into mitochondria or beta-oxidation itself may be impaired. Toxins such as hypoglycin, pentanoate, valproate, salicylate, and their metabolites inhibit beta-oxidation pathways and can produce Reye's syndrome-like presentations. Biochemical manifestations of the diverse causes of Reye's syndrome-like disorders are similar and include: hypoglycaemia due to impaired gluconeogenesis, accumulation of fatty acids, fatty acyl CoAs, and acyl carnitines with depletion of free CoA and carnitine. Accumulated products may further injure mitochondria and exacerbate impaired beta-oxidation, uncouple oxidative phosphorylation or increase mitochondrial permeability. Mitochondrial swelling and steatosis of hepatic cells are the histological result. With the advances of biochemical techniques for the study of organic acid excretion patterns, serum fatty acid patterns and identification of enzymatic deficiencies in cells from patients with Reye's syndrome-like presentations, it is clear that Reye's syndrome is, in part, a collection of various inborn errors and toxicological states. Circumstances such as viral disease, prolonged fasting and drugs may precipitate clinical expression of these deficiencies as Reye's syndrome. As work progresses, further causes of Reye's syndrome will be identified.

Cases of hexapropymate poisoning requiring intensive care in an urban region of Sweden (420,000 inhabitants) were collected over 2.5 years (1985 to 1987). Only patients with serum hexapropymate concentrations above 5.5 mg/L (30 mumol/L) and with a negative history for intake of tricyclic antidepressants, phenothiazines, barbiturates, antihistaminic drugs and opiates were included. Clinical data about 8 intoxication events in 6 patients were evaluated retrospectively. Initial symptoms included coma, hypotension, hypothermia, and hypoventilation. Maximum coma depth (Glasgow coma score) was 3 to 5 in 5 out of 8 events. On 7 occasions assisted ventilation was required (for 12 hours or more in 5 events). There was no relationship between serum concentrations of hexapropymate and severity of clinical symptoms. All patients survived. Detailed analysis of the drug elimination in one patient showed a terminal elimination half-life of 21 hours, which is longer than previously reported (5 hours). The indications for use of this hypnotic drug may vary between doctors since an 8-fold variation was seen in drug prescription between Swedish counties in 1987. Poisoning with hexapropymate is a serious condition which may require symptomatic treatment in the intensive care unit. The clinical picture is similar to that seen in patients with burbiturate intoxication. There is no role for active forced elimination of the drug. It is questionable whether the clinical value of the drug is outweighted by its toxicity.

The widespread use of phenytoin results in frequent accidental and intentional toxicity. Metabolism is enzymatic and can be described by Michaelis-Menten kinetics. This results in an increased half-life in overdose situations and a protracted clinical course which may last a week or more. The primary toxicity is on the central nervous system. The most common initial finding in mild toxicity is nystagmus. As concentrations increase ataxia, decreased coordination, hyper-reflexia, slurred speech and diplopia may develop. Progressive increases result in confusion, lethargy and coma. Various methods tried to increase elimination including dialysis, haemoperfusion, diuresis and plasmaphoresis have been ineffective and are not without risk. Meticulous supportive care including ventilation if necessary should provide a good clinical outcome. Multiple-dose activated charcoal may be helpful in shortening the duration of symptoms.

Amiodarone is an extremely effective antiarrhythmic agent for the treatment of both life-threatening ventricular arrhythmias and refractory supraventricular tachyarrhythmias. Subjective minor side effects are common with amiodarone but rarely require discontinuation of therapy and are often handled by dose reduction. Serious end-organ toxicity, including pulmonary fibrosis and drug-induced hepatitis, have been the most common indications for discontinuing amiodarone therapy in these patients.

Anabolic steroids are used therapeutically for various disorders and as ergogenic aids by athletes to augment strength, muscular development, and to enhance performance. There is a wide range of concomitant temporary and permanent adverse effects with steroid administration. Several well-documented adverse actions of these hormones may develop rapidly within several weeks or less (i.e. altered reproductive function) or require up to several years of steroid intake (i.e. liver carcinoma). More recent studies indicate that glucose intolerance, insulin resistance, increased cardiovascular disease risk profiles, cerebral dangers, musculoskeletal injuries, prostate cancer, psychosis and schizophrenic episodes, among others, accompany anabolic steroid intake. There is, at present, no evidence to support the claim that athletes are less susceptible to adverse effects than those individuals receiving hormone treatment in a clinical setting. Based on the available information which has accumulated primarily from cross-sectional, short term longitudinal, and case studies, there is a need: (a) to develop a comprehensive battery of specific and sensitive markers of adverse effects, particularly those that would be able to detect the onset of adverse actions; and (b) to conduct controlled long term longitudinal studies in order to fully understand the extensiveness and mechanisms involved in the occurrence of adverse effects.

Acute pancreatitis has a high morbidity and significant mortality. Among its many causes ethanol is pre-eminent, but many other drugs have also been incriminated. This article begins with a definition of the mechanisms, pathogenesis and clinical features of acute pancreatitis; it then critically reviews the evidence for drugs, excluding ethanol, as being causative. The drugs which have been implicated are considered under 3 headings: definite associations, probable associations and unlikely associations. A brief outline of possible treatment, strategies and prognosis associated with acute pancreatitis concludes the article.

We report 3 cases and review the published literature on sodium azide ingestion. A 38-year-old man intentionally ingested 2 tablespoonsful of sodium azide in water and developed seizures, coma, hypotension and fatal ventricular arrhythmias within 2 hours. A 33-year-old male ingested an unknown quantity of sodium azide. In the emergency department he was unconscious and underwent immediate intubation and gastric lavage. Nitrite therapy was instituted without improvement. He remained acidotic despite bicarbonate therapy and developed hypotension which was unresponsive to pressor agents. He died approximately 8 hours after admission despite resuscitative efforts. A 52-year-old male ingested 1.5 to 2g of sodium azide and survived for 40 hours. Nitrite therapy was ineffective. The role of sodium nitrite in treating sodium azide toxicity by producing methaemoglobin which complexes with azide is discussed.