Medical toxicology and adverse drug experience最新文献

This paper comprehensively reviews the worldwide situation regarding acute overdosage of dextropropoxyphene (propoxyphene). The changing epidemiology of this type of poisoning over the last 20 years is described with discussion of concurrent trends and, in particular, the effects of different preventive measures adopted in various countries. The clinical pharmacology of dextropropoxyphene relevant to the clinical toxic effects resulting from acute overdosage is described, and the management is detailed. In particular, the importance of early diagnosis and treatment is stressed in view of the potentially lethal complications that may suddenly occur with this poisoning. Recommendations for the correct use of the specific narcotic antagonist, naloxone, are made, together with other intensive supportive measures. As dextropropoxyphene is frequently taken together with other toxic agents, the concomitant effects of alcohol and sedative drugs are described and the treatment of paracetamol (acetaminophen) in combination with dextropropoxyphene is emphasised. The most effective preventive measures for the future are suggested, but caution is advised regarding the prescription for 'at risk' patients of alternative analgesics, which may be no safer in overdosage.

Antidepressant drugs in common use are reviewed in terms of their risks and benefits. A simple classification divides these into tricyclic antidepressants, monoamine oxidase inhibitors and second generation antidepressants. Risks may arise from the correct use of an antidepressant, from its incorrect or inappropriate use, or due to its failure to reverse the depression. The greatest risk is to leave the depression untreated. Risks due to adverse drug effects are generally predictable but in some cases are unexpected and have led to the withdrawal of the drug from the market. Assessing the benefits of antidepressant drugs is more difficult. Rating scales can be used in this context and the fact that the majority of antidepressant drugs have a similar degree of efficacy serves to emphasise the importance of making a risk-benefit assessment of each drug. This has been presented for the more widely used drugs. Safety in overdose is a particularly important benefit. The ideal antidepressant should specifically reverse depressive illness without toxic effects. Although no drug at present measures up to this it is clear that antidepressants should be prescribed, as their benefits outweigh their risks.

Clinical toxicology and poison control have not benefited from the same epidemiological and demographical scrutiny that other health care disciplines have, because of the lack of a meaningful, appropriate database from which to undertake those analyses. Since the creation of the American Association of Poison Control Centers National Data Collection System in 1982 many of the former obstacles of data collection have been overcome. A system has been devised which apparently meets the needs of busy regional poison control centres willing to participate in data collection, and thus provide a large database of human poisoning experience. The data collected by poison control centres and maintained in the National Data Collection System afford a new, powerful tool with which to address issues of demography, epidemiology, risk assessment, product surveillance and regulatory affairs. While the system affords these potentials, certain limitations of the data must be understood so that the data are not misinterpreted. Additionally, we have attempted to identify strengths of the system as well as areas in need of improvement and refinement.

The concepts underlying the notion of a risk-benefit ratio for anticonvulsant therapy have determined the development of the drug treatment of epilepsy over many years. The risk element in the ratio arises from the various possible physical and psychological adverse effects of anticonvulsant therapy; the benefit is derived from the capacity of therapy to prevent seizures and thus reduce the disadvantages which result from having epilepsy. The physical adverse effects of anticonvulsant therapy may involve many tissues and organs. The drugs tend to depress cerebral, cerebellar and brain stem function, and may slow peripheral nerve conduction. Prolonged intake may cause hypocalcaemia and osteoporosis, folate depletion, various haematological and immunological abnormalities, and overgrowth of subcutaneous and gingival tissues. Idiopathic reactions may involve the skin, lymph nodes, liver, pancreas, kidney and thyroid, and cause electrolyte disturbances, while maternal anticonvulsant intake during pregnancy may be associated with an increased incidence of fetal malformations. Local reactions may occur at drug administration sites, and anticonvulsants may interact pharmacokinetically and pharmacodynamically with co-administered drugs. The taking of anticonvulsants sometimes has undesirable psychological effects on both the patient and his or her family. Epilepsy itself often results in adverse psychological consequences which emanate from the uncertainty and insecurity that is imposed by the unpredictable occurrence of seizures, from the limitations epilepsy sets on the patient's lifestyle and employment prospects, and from unfavourable community attitudes towards the disorder. Contemporary anticonvulsant therapy is not fully effective in all patients, but to the extent that it can control seizures it may help alleviate these emotional burdens that are a result of epilepsy. The consensus of present day medical opinion is that, in the great majority of clinical situations, the benefits of anticonvulsant therapy outweigh the disadvantages. However, to provide optimal management for individual patients, the risk-benefit ratio of therapy must be repeatedly assessed at all stages of a patient's treatment, and therapeutic decisions taken in the light of the ratio as it applies to the individual.

Seven cases of crystalluria following primidone overdose have been reported since the 1950s. An eighth case of primidone crystalluria following overdose is presented. Because of low aqueous solubility (600 mg/L at 37 degrees C) which is directly proportional to temperature, any factor increasing renal excretion of unchanged primidone predisposes to crystal formation. Renal clearance is dependent on dosage because of negligible protein binding, zero-order conversion to phenobarbitone (phenobarbital) and first-order conversion to phenylethylmalonamide. Therapy with other anticonvulsants known to induce the metabolism to phenobarbitone does not appear to be protective against crystalluria in overdose situations. The critical serum primidone concentration for crystalluria presence seems to be 80 mg/L. There is evidence for nephrotoxicity of the crystals themselves if formed in vivo (actual crystal presence during voiding). The chemical phenomenon of supersaturation of a solution is protective against in vivo crystal formation with subsequent nephrotoxicity. Vigorous hydration to augment elimination and to lessen the propensity for renal toxicity is recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs) effectively control the symptoms of many of the rheumatic diseases although they have little effect on the underlying causes. Their effect is mainly on the mediators of the inflammatory process. Unfortunately, these mediators have important physiological roles in the maintenance of health, particularly in the gastrointestinal tract and the kidney, so that their inhibition results in many unwanted reactions of varying severity. The mechanisms underlying these reactions are described. Their occurrence varies, both qualitatively and quantitatively, and an attempt is made to assess these differences, although it may be that they are related directly to differences in dosage and therapeutic efficacy. In addition, immunologically mediated adverse reactions occur. These mechanisms are outlined and related to the clinical picture. There are considerable differences in frequency of reactions between the compounds: in particular there is a wide variation in the rate of dermatological reactions of this type. Agranulocytosis has been particularly associated with the pyrazolone compounds, although it has been reported with most others. Aplastic anaemia, which may not be an immune-mediated reaction, is also thought of as a pyrazolone reaction, but the incidence with indomethacin approaches a similar level. Although all drugs analysed may cause hepatic reactions, these are rare except with the now withdrawn benoxaprofen. Several types of immunologically mediated renal reactions occur and these rarities are also described. Paracetamol does not have any effect on the inflammatory mediators. Anxieties about this substance relates to the parent compound phenacetin and its necrotic effect on the renal papillae. There is extensive literature on this subject concerning not only paracetamol, but also aspirin and other NSAIDs. This is also assessed and summarised. The danger of paracetamol as a direct hepatic toxin in self-poisoning is discussed. Novel NSAIDs are introduced and others withdrawn with frequent and monotonous regularity. Sometimes the reasons have some medical or scientific plausibility, but often they are over-reactions by registration authorities or pharmaceutical companies in response to uninformed media publicity. The problems of the numerically and scientifically accurate collection and assessment of adverse reaction data are legion and as a result useful agents have been lost. Some of these difficulties are described, and some non-drug 'adverse reactions' are described.(ABSTRACT TRUNCATED AT 400 WORDS)