Medical toxicology and adverse drug experience最新文献

Syndromes due to the abrupt withdrawal of drug treatment occur mainly with adrenal corticosteroids and agents with an action on either the cardiovascular system or central nervous system. The abrupt withdrawal of antihypertensive therapy typically results in symptoms of overactivity in the sympathetic nervous system. Clonidine and beta-adrenoceptor antagonists are clinically the most important of these agents, but numerous other drugs have been implicated. Overall, the problem is small when viewed in the context of the huge scale of prescribing of antihypertensive medicines. A more serious problem is the occurrence of crescendo angina following the abrupt withdrawal of beta-adrenoceptor antagonists. Although other factors may be involved, adaptive up-regulation of beta-adrenoceptor density is the most likely cause of crescendo angina, and renders the patient more susceptible to sympathetic nervous stimulation following withdrawal of treatment. Besides leading to a recrudescence of the disease being treated, the withdrawal of corticosteroids can cause a variety of syndromes. In particular, problems can arise as a result of treatment-induced suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Another steroid withdrawal syndrome of unknown aetiology, without significant abnormalities of the HPA axis occurring, has been described. Benign intracranial hypertension may rarely follow steroid withdrawal in children. The syndromes associated with withdrawal of drugs which have an action on the CNS are poorly understood. Withdrawal of neuroleptic drugs can be followed by symptoms that resemble those described following withdrawal of anticholinergic drugs, and those agents with the greatest muscarinic-receptor-blocking properties are those which are most frequently implicated. However, the less common withdrawal dyskinesias are thought to reflect up-regulation of dopaminergic receptors during long term treatment. Gastrointestinal symptoms predominate following the abrupt withdrawal of antidepressants but hypomania and an 'akathisia-like' syndrome have been reported. Barbiturates are no longer recommended as hypnotics because of severe effects of withdrawal and the existence of safer alternatives. Short acting barbiturates can be withdrawn by replacement with either phenobarbitone (phenobarbitol) or diazepam and subsequent gradual reduction in dose. The recognition of dependency on benzodiazepines has been slow because of the similarity of mild withdrawal symptoms to the original problem which led to treatment being offered.(ABSTRACT TRUNCATED AT 400 WORDS)

Glutethimide poisoning is characterised by coma, anticholinergic poisoning syndrome, hypotension, and other complications. Previous studies have shown that the severity of intoxication does not correlate with plasma glutethimide concentrations in individual patients. Glutethimide is partly converted to 4-hydroxyglutethimide, a metabolite which accumulates in the plasma of humans, and which has been thought to contribute to coma after plasma glutethimide concentrations have fallen. We followed plasma concentrations of glutethimide and 4-hydroxyglutethimide in a man who overdosed with glutethimide. Plasma 4-hydroxyglutethimide concentrations did not correlate with the degree of coma in our patient, and actually rose as the patient awakened. Other studies also indicate that 4-hydroxyglutethimide may not play an important role in glutethimide poisoning.

Theophylline, with its narrow therapeutic margin, is a common cause of iatrogenic and deliberate overdose. Most cases of self-poisoning are with sustained release preparations, with peak concentrations occurring up to 12 or more hours after overdose. Toxic symptoms are often seen at concentrations above 15 mg/L. Theophylline is metabolised within the cytochrome P-450 system, with an average total body clearance of 50 to 60 ml/min. Clearance is, however, affected by many factors such as other drugs or disease, and in overdose zero order kinetics may result in prolonged half-lives. Toxicity is characterised by agitation, tremor, nausea, vomiting, abdominal pains, seizures, and tachyarrhythmias. Hypokalaemia and metabolic acidosis are more profound in acute toxicity, and hypercalcaemia is usually present. Seizures occur at lower concentrations after chronic over-medication than after acute overdose. Gastric lavage should be performed in all patients presenting early, and an oral multiple dose charcoal regimen started with 50 to 100g charcoal, repeating with 50g doses and checking theophylline concentrations at 2- to 4-hour intervals. Multiple dose charcoal can be expected to double the clearance of theophylline, being as effective as a haemodialysis. Of the invasive techniques available, charcoal haemoperfusion is the most effective, increasing clearance 4- to 6-fold. Supportive care is particularly important. The aggressive supplementation of potassium, treatment of emesis with droperidol and ranitidine, and treatment of tachyarrhythmias and hypotension (possibly with propranolol), together with oral multiple dose charcoal may obviate the need for haemoperfusion. Seizures suggest increased morbidity and mortality. Charcoal haemoperfusion should be considered if plasma concentrations are greater than 100 mg/L in an acute intoxication or greater than 60 mg/L in a chronic intoxication. The decision to haemoperfuse should not be based on plasma concentrations alone, but an overall evaluation of the patient's laboratory and clinical status.

Adverse systemic reactions associated with the use of topical ophthalmic timolol, chloramphenicol, phenylephrine and cyclopentolate are surveyed, with special emphasis on precautions and contraindications for these ophthalmic drug preparations. Systemic reactions secondary to timolol, a beta-adrenergic antagonist indicate that it should be used with caution in patients with asthma or a history of asthma, chronic obstructive pulmonary disease or cardiovascular disease and in those patients receiving systemic administration of beta-blockers or verapamil. Because significant blood dyscrasias or aplastic anaemia have been reported following topical ophthalmic chloramphenicol, the only absolute indication in ocular conditions is an organism that is resistant to all other antibiotics. Both 2.5% and 10% phenylephrine have been associated with cardiovascular effects and should be used with caution in selected patients on monoamine oxidase inhibitors, tricyclic antidepressants or atropine or in those with hypertension, advanced arteriosclerotic changes, aneurysms, orthostatic hypotension, long-standing insulin-dependent diabetes and in children with low bodyweights. Central nervous system toxicity secondary to cyclopentolate is dose-related and can be avoided by use of minimal concentrations and avoidance of unnecessary repetition of administration. Occlusion of the nasolacrimal passage with finger pressure immediately after instillation of any eyedrop also decreases the amount of drug that is absorbed systemically.

The toxicities of antimalarial drugs vary because of the differences in the chemical structures of these compounds. Quinine, the oldest antimalarial, has been used for 300 years. Of the 200 to 300 compounds synthesised since the first synthetic antimalarial, primaquine in 1926, 15 to 20 are currently used for malaria treatment, most of which are quinoline derivatives. Quinoline derivatives, particularly quinine and chloroquine, are highly toxic in overdose. The toxic effects are related to their quinidine-like actions on the heart and include circulatory arrest, cardiogenic shock, conduction disturbances and ventricular arrhythmias. Additional clinical features are obnubilation, coma, convulsions, respiratory depression. Blindness is a frequent complication in quinine overdose. Hypokalaemia is consistently present, although apparently self-correcting, in severe chloroquine poisoning and is a good index of severity. Recent toxicokinetic studies of quinine and chloroquine showed good correlations between dose ingested, serum concentrations and clinical features, and confirmed the inefficacy of haemodialysis, haemoperfusion and peritoneal dialysis for enhancing drug removal. The other quinoline derivatives appear to be less toxic. Amodiaquine may induce side effects such as gastrointestinal symptoms, agranulocytosis and hepatitis. The main feature of primaquine overdose is methaemoglobinaemia. No cases of mefloquine and piperaquine overdose have been reported. Overdose with quinacrine, an acridine derivative, may result in nausea, vomiting, confusion, convulsion and acute psychosis. The dehydrofolate reductase inhibitors used in malaria treatment are sulfadoxine, dapsone, proguanil (chloroguanide), trimethoprim and pyrimethamine. Most of these drugs are given in combination. Proguanil is one of the safest antimalarials. Convulsion, coma and blindness have been reported in pyrimethamine overdose. Sulfadoxine can induce Lyell and Stevens-Johnson syndromes. The main feature of dapsone poisoning is severe methaemoglobinaemia which is related to dapsone and to its metabolites. Recent toxicokinetic studies confirmed the efficacy of oral activated charcoal, haemodialysis and haemoperfusion in enhancing removal of dapsone and its metabolites. No overdose has been reported with artemesinine, a new antimalarial tested in the People's Republic of China. The general management of antimalarial overdose include gastric lavage and symptomatic treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

The use of thrombolytic agents to dissolve coronary artery thrombi causing acute transmural myocardial infarctions has been shown to decrease short term mortality, and improve left ventricular function, in patients with acute transmural myocardial infarction. Several thrombolytic agents are currently available which differ mainly in cost, antigenicity, and mechanism of action. Current investigations are being directed at finding safer, more effective thrombolytic agents and at developing optimal therapy following thrombolysis. The complications of thrombolytic therapy are for the most part minor and reversible. Immediate and delayed hypersensitivity to streptokinase is rare. Hypotension and arrhythmias commonly accompany myocardial reperfusion and are usually benign and self-limited. Haemorrhagic complications are the most frequent and serious problems following the use of thrombolytic agents. They can be lessened by the proper selection of patients to avoid those at high risk of bleeding. The avoidance of unnecessary arterial and venous punctures will decrease the incidence of minor but annoying local bleeding. Those agents which are activated at the site of thrombi will hopefully cause fewer bleeding episodes, but early experience with these agents has not been able to demonstrate a lower rate. With careful attention to patient selection and follow-up, thrombolytic agents can be safely and effectively used in the management of patients with acute myocardial infarction.