Medical toxicology and adverse drug experience最新文献

Snake envenomation is a major cause of death and disability in the developing countries, particularly India and Southeast Asia. Species variation in venom components, yield, and lethality leads to quite different clinical presentations and mortality. Venomous snakes are divided into 5 families. Bites of the Viperidae, Crotalidae and Colubridae usually cause primarily local effects and bleeding; the Elapidae most commonly cause neurological symptoms, particularly paralysis; while the Hydrophidae cause paralysis and myolysis. Venoms are complex mixtures of enzymes, peptides and metalloproteins. 26 enzymes have been identified, and 10 of those are found in most venoms. Components have been identified that act as procoagulants, anticoagulants, hyaluronidases, RNases, DNases, postsynaptic toxins and presynaptic toxins. Other peptides induce capillary leak syndrome, haemolysis and shock. The clinical results of envenomation vary widely, and there may be no envenomation with a bite. Syndromes reported include oedema, haemolysis, shock, bleeding, pituitary failure, renal failure, myonecrosis, and combinations of the above. First aid measures that have been proposed include tourniquets, constricting bands, tight crepe bandages, incision and suction, cryotherapy, and high voltage electric shock. None of these has been shown to be effective except usage of a crepe bandage for Australian elapid bite. Tourniquets or cryotherapy, if used for extended periods may lead to gangrene. The most important first aid measure is rapid transport to comprehensive medical care. There is some controversy about medical treatment in the United States, but less in other countries. Supportive measures routinely required include intravenous fluids, tetanus prophylaxis and antibiotics. Anticholinergics may be useful in elapid bite. Intubation and ventilation may be necessary. Unproven surgical approaches include excision of envenomated tissues and fasciotomy. The former is disfiguring, the latter should be reserved for those patients with demonstrated increased intracompartmental pressure. More than 100 antivenins are produced by about 36 laboratories worldwide. The products are effective, but carry a high risk of serum sickness and a lesser risk of anaphylaxis. A more effective and less reactive product is under development.

Priapism is characterised by a persistent erection that cannot be relieved by sexual intercourse or masturbation. Although priapism subsides spontaneously in a few days, impotence frequently follows. Both vascular and neural mechanisms are implicated in the pathophysiology of priapism, but it is not clear which initiates the process. Idiopathic cases of priapism are the most frequent (near 50%); other medical conditions that can result in priapism are haematological diseases (mainly sickle cell anaemia and leukaemia), traumatism, and neoplastic processes. Drug-induced priapism comprises about 30% of cases. The drugs most frequently implicated are psychotropic drugs (phenothiazines and trazodone), antihypertensives (mainly prazosin) and heparin. Recently, the intracavernosal injection of vasoactive drugs (papaverine and phentolamine) has been described in patients treated for impotence. With the exception of heparin, an alpha-adrenergic blocking mechanism has been suggested in the priapism-inducing action of these drugs. A significant number of anecdotal case reports link priapism and drugs, and it is possible that certain cases of idiopathic priapism could be reclassified if accurate pharmacological anamnesis were to be performed. Priapism must be considered a urological emergency. Surgical procedures are the most preferred treatment for this condition but, in selected cases, drug treatment seems to be an alternative approach.

Scores of drugs in common clinical use are capable of inflicting various degrees of damage to the kidney. Similarly, a large number of widely employed chemicals may adversely affect renal tissue as part of their toxic potential. A xenobiotic may damage the kidney by more than one mechanism. For example, NSAIDs may cause decreased renal perfusion, interstitial nephritis, primary glomerulopathy and/or altered potassium homeostasis. A large number of drugs and chemicals inflict their damage on the renal tubular cell secondary to intracellular accumulation to concentrations substantially higher than in the plasma or in other tissues. These include aminoglycosides, mercury and carbon tetrachloride and cephaloridine. Drug-induced interstitial nephritis is characterised by inflammatory lesions of the renal interstitium developed after at least 7 to 10 days of therapy. The immunological nature of this reaction is suggested by the associated fever, maculopapular rash and arthralgia observed in some of the patients. Although eosinophilia, eosinophiluria, and raised blood IgE levels are characteristic, immunoglobulins are not deposited in renal tissue, and the basic mechanism has not been elucidated. Renal biopsy demonstrates oedema and interstitial inflammatory reaction, mainly with lymphocytes, monocytes, eosinophils and plasma cells. Less frequent, vasculitis of small vessels or granulomatous reaction may develop, leading to necrotising glomerulonephritis. The drugs most commonly causing acute interstitial nephritis are methicillin, ampicillin, cephalosporins, rifampicin (rifampin), sulphonamides, phenindione and allopurinol. Other penicillins, NSAIDs, phenytoin, thiazides and frusemide (furosemide) are less frequently associated with this syndrome. Drugs and chemicals may affect renal function by pharmacologically decreasing glomerular filtration rate and/or renal blood flow. These include the NSAIDs, radiological contrast media and cyclosporin. Normal renal function depends upon an intact glomerular apparatus. Many drugs and chemicals are capable of damaging the glomerulus, causing its increased permeability to large molecules such as proteins. Several drugs including d-penicillamine, thiopronine, captopril, pyrithioxine and methimazole, are believed to exert their damage through their sulfhydryl group which bind with high affinity to glomerular structures. A variety of xenobiotics or their metabolites may be deposited in the renal tubule causing obstruction of urine flow and a secondary damage to tubular epithelium. Sulphonamides, methotrexate and ethylene glycol are good examples.(ABSTRACT TRUNCATED AT 400 WORDS)

Although many cases of beta-adrenoceptor antagonist (beta-blocker) poisoning are uneventful, a proportion develop serious and sometimes fatal cardiovascular system depression with severe hypotension. As beta-adrenergic tone is not essential for cardiovascular function in health, there is no physiological reason why total beta-adrenoceptor blockade should have serious consequences in the resting individual. The toxic actions of beta-blockers appear to be related to properties such as membrane depressant activity and possibly due to actions on beta-adrenoceptors distinct from those in the cardiovascular system. Most reports of serious adverse effects following overdosage concern beta-blockers with significant membrane depressant activity, and in particular propranolol and oxprenolol, with which progressive heart block and bradycardia are features. Sotalol toxicity, with its unique electrophysiological action, is a special case. Animal experiments confirm that beta-blockers with membrane depressant activity are more toxic than the newer more selective ones, such as atenolol and nadolol. However, experimental models also reveal that artificial ventilation markedly reduces the toxicity of all beta-blockers tested, suggesting a respiratory depressant action with very high doses. Treatment of serious overdosage in man should include maintenance of adequate ventilation. High dose intravenous glucagon is recommended, because its inotropic action depends on direct stimulation of adenylate cyclase. beta-Agonists such as isoprenaline (isoproterenol) or prenalterol may be effective, but the nature of agonist-competitive antagonist interactions may necessitate the use of unrealistically large doses to overcome very high tissue beta-blocker concentrations.

Aluminum is now recognised as an important toxin causing considerable morbidity and mortality, particularly in patients with chronic renal failure. Diseases that have been associated with aluminium include dialysis dementia, renal osteodystrophy and Alzheimer's disease. Aluminum also has an effect on red blood cells, parathyroid glands and chromosomes. Accumulation of aluminium in the body tends to occur when the gastrointestinal barrier is circumvented. This has been identified as a problem during dialysis or intravenous fluid administration. Renal functional impairment results in decreased aluminum excretion and promotes accumulation of the element in the body. Many sources have been shown to be contaminated with aluminium. These include the water used for dialysis; medicines containing aluminium, such as aluminium-containing phosphate binding gels; total parenteral nutrition solutions; processed human serum albumin; intravenous fluids in infants; and other environmental and industrial sources. The management of aluminium toxicity involves the identification of these contaminated sources and subsequent removal of the element. This includes regular monitoring of water used in dialysis. The use of aluminium-containing phosphate binding gels in patients with compromised renal function should be reviewed and alternatives sought. The development of effective aluminium-free phosphate binders is desirable. Once a patient has aluminium toxicity, desferrioxamine (deferoxamine) has been shown to be an effective agent in its chelation and removal.

Agranulocytosis is a rare but potentially serious adverse side effect of many drugs. Although it was recognised as an idiosyncratic type of drug reaction more than 50 years ago, its pathogenesis is still not fully understood. Drug-related antibodies are responsible for the neutropenia in the so-called 'immune' or 'aminopyrine' type of agranulocytosis. In contrast to former assumptions, the disappearance of leucocytes is not only due to rapid destruction of circulation cells, but it can result also from failure of the production of granulopoetic cells. In some other groups of drugs there is no evidence of immune-mediated disease, but direct toxicity to bone marrow cells has been observed using biochemical methods or inhibition of the growth of granulopoetic colonies in semisolid culture media. Until now it has not been possible to define the enzymatic abnormality which could explain this metabolic type of idiosyncrasy. The quantification of the incidence of potentially drug-induced agranulocytosis in general, and in particular its association with single drugs, requires studies on large populations and the use of strict epidemiological methodology to prevent reporting of grossly biased results. Data from recent case control studies show definitely lower risks for some relevant groups of drugs than formerly appreciated. As expected, agranulocytosis has been observed in association with some recently introduced drugs. This underlines the necessity for continued postmarketing monitoring of potential haematological side effects and for further case control studies to furnish data to aid prescribing physicians and health authorities in decision-making.

Histamine H2-receptor antagonists are widely used in the treatment of gastrointestinal diseases related to gastric acid hypersecretion. Cimetidine was introduced into medical practice in 1976 and ranitidine, famotidine and nizatidine in 1981, 1985 and 1987, respectively. Haematological adverse effects are relatively uncommon and most have been reported in cases of cimetidine administration. These adverse effects are reviewed under 4 main headings: (a) blood cytopenias and leucocytosis; (b) coagulation disorders related to drug interactions with oral anticoagulants; (c) reduction of dietary iron absorption; and (d) reduction of dietary cobalamin absorption. 85 reported cases of blood cytopenias attributed to these drugs are reviewed, of which 75 (88%) were associated with cimetidine therapy. In postmarketing surveillance studies, the incidence of cimetidine-associated blood cytopenia has been evaluated at about 2.3 per 100,000 patients. Neutropenia and agranulocytosis are by far the most frequently encountered. Whatever the drug or the type of cytopenia, this adverse effect is almost always rapidly reversible when treatment is stopped. Moreover, in several cases other factors such as underlying diseases or additional drugs could have been responsible, at least partly, for the cytopenia. The pathophysiological basis of these adverse effects remains poorly explained. Various mechanisms have been proposed, which in some cases are probably associated: (a) direct toxicity for haemopoietic stem cells; (b) drug-induced immune reactions leading to blood or bone marrow cell damage, and (c) drug interactions, with increased and prolonged action of potentially haematotoxic drugs. Mechanisms (a) and (c) appear to be of particular clinical importance in cases of impaired renal elimination of H2-receptor antagonists. Cimetidine and probably to a lesser extent ranitidine potentiate the action of oral anticoagulants of both coumarin and indanedione structure. This may result in haemorrhagic complications. Such action is a consequence of the reduced hepatic metabolism of oral anticoagulants through a dose-dependent, reversible inhibition of cytochrome P450. Malabsorption of dietary iron and cobalamin appears to result from inhibition of gastric secretion by the H2-receptor antagonists. This is of no clinical importance in short term treatment, but long term use of H2-receptor antagonists may theoretically contribute to the occurrence of iron or cobalamin deficiency anaemia.

Prolactin secretion is affected by various diseases as well as by many drugs in humans and animals. While marked hyperprolactinaemia suggests the presence of a pituitary tumor, moderate changes may also occur in various endocrine or non-endocrine disorders. Drugs can interfere with prolactin regulation via complex mechanisms at the hypothalamus or at the pituitary site, but possible changes in prolactin metabolism are poorly understood as yet. This survey of the literature up to June 1986 covers the influence of various groups of drugs and agents on the plasma prolactin level under various conditions. It contains information that will facilitate evaluation of whether hyper- or hypoprolactinaemia may result from therapeutic intervention or must be related to an underlying disease. It is obvious that more subtle changes can be revealed by the use of dynamic tests either to stimulate or to suppress prolactin secretion.

14 patients with heavy metal poisoning received 2,3-dimercaptosuccinic acid (DMSA). 12 subjects were given 30 mg/kg/day for 5 days; 1 subject was started on a lower dose because of a history of atopy; another subject was treated for 15 days because of very high initial blood lead concentrations. In the 9 subjects who had lead poisoning, DMSA decreased blood lead concentrations by 35 to 81%, and induced a 4.5- to 16.9-fold increase in mean daily urinary excretion of the metal. In the acutely arsenic-poisoned case, the plasma arsenic concentration on day 7 was half the pretreatment value, while no clear decrease was observed in a chronically exposed subject. In 3 mercury cases, DMSA increased daily mercury urinary excretion 1.5-, 2.8- and 8.4-fold, respectively, while blood mercury concentrations remained below detection limits. No serious side effects were observed and 3 weeks after administration of the drug the clinical condition of all subjects was either stable or improved. These results indicate the efficacy of DMSA for lead poisoning in humans and provide a rationale for further investigating its usefulness in mercury and arsenic poisoning cases.