Medical toxicology and adverse drug experience最新文献

Recent widespread abuse of cocaine has resulted in an alarming increase in emergency department admissions for acute treatment of this toxic drug. Highly publicized cocaine-associated deaths of prominent athletes have awakened both the medical community and the general public to the possible devastating effects of this so-called 'champagne of drugs'. A potent central nervous system stimulant, cocaine produces symptoms that include changes in activity, mood, blood pressure, cardiac rhythm, respiration and body temperature. The adverse effects of cocaine, which may progress rapidly to death, include cerebrovascular accidents, myocardial infarction, sudden cardiac arrhythmias, pneumomediastinum, rhabdomyolysis with myoglobinuric renal failure and intestinal ischaemia. In addition, cocaine has been implicated in obstetric and neonatal complications. Because of the exceedingly rapid progression of the 'cocaine reaction' to a fatal outcome, it is imperative that clinicians know how to recognise and manage the symptoms of cocaine overdose.

In order to avoid inappropriate therapy and prolonged morbidity, it is important to recognise when a patient's rheumatic complaints are due to drugs. However, this is often difficult because of the large number of drugs that have been implicated and the diversity of clinical presentations. Arthropathy may be seen with several different syndromes, including drug-induced lupus erythematosus (DILE), serum sickness and gout. The most widely reported of these is DILE, which usually develops after some months or even years of drug therapy. While many authors do not specifically require their presence for the diagnosis of DILE, antinuclear antibodies have been detected in the great majority of reported patients with DILE, whatever the causative drug. In contrast, patients who develop arthropathy soon after commencing a drug rarely have antinuclear antibodies and appear to be distinct from patients with DILE. Apart from arthropathy, a number of other syndromes that appear to have an immunological basis may be induced by drugs. Cutaneous vasculitis is not uncommon and drugs are frequently considered to be the aetiological factor. Whether drugs may cause larger vessel systemic vasculitis is less certain. Rarely, polymyositis and scleroderma-like syndromes have been associated with drug therapy. Corticosteroid-induced osteoporosis is a complication of all the corticosteroid preparations that are widely used at present. However, the development of deflazacort, a so-called 'bone-sparing' steroid, has raised the possibility that the effect of corticosteroids on bone may be separable, at least in part, from the other actions of these drugs. Data have been conflicting with regard to whether there is a 'safe' dose of corticosteroid. Similarly, it is unclear whether prophylactic therapy with agents such as calcium, fluoride and vitamin D is beneficial. Nonetheless, recent findings suggest that approaches will be developed to minimise the risk of osteoporosis in patients who require corticosteroids. There are a number of other ways in which drugs may affect bones. Osteomalacia is a well-known but uncommon complication of treatment with anticonvulsants and occasionally other drugs. The mechanism probably relates to the induction of hepatic enzymes and the consequent increased metabolism of vitamin D in patients with borderline levels initially. Osteosclerosis may also result from drug therapy; usually with fluoride or retinol (vitamin A) and its analogues. With continued research, the true spectrum of drug-induced rheumatic syndromes should become more clearly defined.(ABSTRACT TRUNCATED AT 400 WORDS)

Black widow spider (Latrodectus mactans) envenomation is found throughout both the temperate and tropical latitudes, and is one of the leading causes of death from arthropod envenomations worldwide. The venom is highly neurotoxic, affecting the presynaptic motor endplate to allow massive noradrenaline (norepinephrine) and acetylcholine release into synapses causing excessive stimulation and fatigue of the motor end plate and muscle. Clinically, patients develop a bite site lesion and pain, abdominal pain and tenderness, and lower extremity pain and weakness within minutes to hours of envenomation. Symptoms progress over several hours, then subside over 2 to 3 days. The recommended treatment of 'common' envenomation is calcium gluconate 10% intravenously, titrated to relief of symptoms; antivenin, although effective, may cause hypersensitivity and serum sickness reactions, and should be restricted to life-threatening envenomations only. Brown recluse spider (Loxosceles reclusa) envenomations are seen in the Americas and in Europe, and are endemic to the south and central United States. The venom contains at least 8 enzymes, consisting of various lysins (facilitating venom spread) and sphingomyelinase D, which causes cell membrane injury and lysis, thrombosis, local ischaemia, and chemotaxis. Local envenomations begin as pain and itching that progresses to vesiculation with violaceous necrosis and surrounding erythema, and ultimately ulcer formation. Systemic envenomations may be life threatening, and present with fever, constitutional symptoms, petechial eruptions, thrombocytopenia, and haemolysis with haemoglobinuric renal failure. Treatment of local envenomations is conservative (local wound care, cryotherapy, elevation, tetanus prophylaxis, and close follow-up); systemic envenomation requires supportive care and treatment of arising complications, corticosteroids to stabilise red blood cell membranes, and support of renal function. Dapsone 100mg daily has emerged as a promising therapeutic agent in both animal studies and clinical trials. Over 650 species of scorpions are known to cause envenomation (mostly in children under 10 years); they are endemic mostly in arid and tropical areas. Different venoms and clinical presentations are seen across the different species. Most commonly, an inflammatory local reaction occurs with envenomation, which is treated with wound debridement and cleaning, tetanus prophylaxis, and antihistamines. Occasionally the venom is allergenic, and the resultant allergic reaction is treated in a standard fashion.(ABSTRACT TRUNCATED AT 400 WORDS)

Striated musculature is considered unusually tolerant to all kinds of injuries, and rhabdomyolysis associated with drug overdose or chronic drug intake is a rare event. This may be because striated musculature, in contrast to other tissues such as liver and kidney, shows little affinity for most drugs. Several different types of drug-induced rhabdomyolysis may be distinguished, and the clinical features of the condition may vary widely, from moderate myalgia to involvement of groups of muscles to involvement of the total skeletal musculature. In clinically asymptomatic rhabdomyolysis, early diagnosis is only made if routine laboratory tests include determination of serum creatine kinase. Determination of myoglobin in serum and urine is more sensitive and allows earlier diagnosis of muscle necrosis. Myoglobinaemia may lead to toxin-induced tubular necrosis, and impairment of renal function or even acute renal failure. About 10% of all cases of acute renal failure are due to rhabdomyolysis. Fulminant rhabdomyolysis may be associated with excessive hyperkalaemia and hypocalcaemia which may induce further life-threatening complications. Therefore, early diagnosis of rhabdomyolysis is most important for prevention of its potentially life-threatening sequelae. Therapy of rhabdomyolysis consists of supportive and specific measures. Early diagnosis may help to prevent life-threatening sequelae like acute renal failure, electrolyte imbalance and shock. Withdrawal of the incriminated drug or detoxification in drug overdose should be followed by supportive measures including infusion therapy and correction of dehydration and electrolyte imbalances. Forced diuresis with sodium bicarbonate may protect the kidney function from acidosis and precipitation of myoglobin in tubules. Elimination of myoglobin from plasma may be enhanced by plasmapheresis. In patients with acute renal failure, haemodialysis is necessary. In malignant hyperthermia, immediate infusion of dantrolene sodium is required. This drug also seems to have a beneficial effect in neuroleptic malignant syndrome. The repair mechanisms of striated musculature function extremely well. The prognosis of muscular atrophy after the acute stage of rhabdomyolysis is excellent. The same is true for the prognosis of acute renal failure. However, the extent of complications or survival of the acute stage of rhabdomyolysis strongly depend on early diagnosis and start of adequate therapy.

Patients with severe hypertension and/or congestive heart failure (n = 281) who were unresponsive to other therapies and intolerant to captopril received enalapril treatment (mean dose 19.5 mg/day) under study conditions as part of a Compassionate Use Program. Many of these patients had serious concurrent disorders known to predispose them to a greater risk of adverse experiences and death. The mean duration of enalapril treatment was 29 weeks, with a range of 1 day to approximately 3.5 years. Enalapril was generally well tolerated, and the estimated long term probability of patients terminating enalapril therapy because of adverse effects was low. 20 patients had discontinued captopril treatment because of low white blood cell counts; during subsequent enalapril treatment these reactions resolved in 14 patients, persisted in 2 patients, and could not be evaluated in 4 patients. Captopril-related proteinuria improved or resolved in 9 and persisted in 2 of 15 patients, taste disturbances resolved in 35 and persisted in 2 of 38 patients; and rash resolved in all but 7 of 178 patients during enalapril treatment. 18 patients (6%) discontinued enalapril treatment because of lack of efficacy; 6 of these 18 patients died due to a progression of heart failure, and another 11 patients died for other reasons. The deaths were considered unrelated to therapy with enalapril. Adverse reactions were the reason for discontinuation of enalapril treatment in 53 patients (19%). The most common adverse experiences that resulted in discontinuation of enalapril were: impairment of renal function (5%), hypotension (2%) and rash (2%). No neutropenia, proteinuria, or new taste disturbances were recorded as reasons for discontinuation.(ABSTRACT TRUNCATED AT 250 WORDS)

128 case reports of drug-induced mania were reviewed. Steroids, levodopa and other dopaminergic agents, iproniazid, sympathomimetic amines, triazolobenzodiazepines and hallucinogens were the agents that most commonly induced manic syndromes. The most common characteristics of drug-induced manic episodes were increased activity, rapid speech, elevated mood, and insomnia. Patients who developed mania often had a prior history, family history, or current symptoms of mood disturbance. The episodes were most commonly treated by discontinuing or reducing the dose of causative agent. Discontinuation of the inciting drug and treatment with neuroleptic agents were equally efficacious: lithium treatment was less effective. The majority of agents that induce mania have an effect on monoaminergic systems.

Carbamazepine is the drug of first choice in the treatment of simple and complex partial seizures and trigeminal and glossopharyngeal neuralgias. It is usually preferred to phenobarbitone or phenytoin because of its powerful antiepileptic activity combined with a relative lack of adverse effects. In this article the mechanisms of action and pharmacological properties of carbamazepine are outlined in order to explain the pathogenesis of most side and toxic effects. Most of these effects, namely those affecting the nervous or cardiovascular systems, correlate well with an increased concentration of the drug in plasma and disappear spontaneously upon discontinuation of therapy. Other, less frequent toxic effects, namely aplastic anaemia or fatal hepatitis, may be ascribed to unforeseeable idiosyncratic reactions. Carbamazepine poisoning, usually accidental and sometimes secondary to the coadministration of other drugs, yields a clinical picture with neurological and cardiovascular signs. The outcome is usually favourable, sometimes with spontaneous improvement, and death is a distinct rarity. No specific antidotes are available. The oral administration of activated charcoal has been shown to be an effective therapeutic measure significantly reducing the plasma half-life of the drug.

Chlordiazepoxide 40mg daily was used to prevent delerium tremens in a 64-year-old female with alcoholic liver disease. After 20 days, the drug was stopped because of the onset of progressive drowsiness. The kinetics of chloridazepoxide were within the predicted range for patients with liver disease, but the elimination half-lives of desmethylchlordiazepoxide and demoxepam were greatly prolonged at 346 hours and 150 hours, respectively. It is suggested that metabolite accumulation may have contributed to the coma, which is an unusual reaction to chlordiazepoxide.