Ototoxicity is a disabling adverse effect of several widely used classes of drugs, such as diuretics, anti-inflammatory agents, antineoplastic agents and aminoglycoside antibiotics. High-dose therapy with either diuretics or anti-inflammatory agents is primarily associated with acute and transient impairment of hearing or tinnitus. In contrast, long term treatment with antineoplastic agents or aminoglycoside antibiotics is typically associated with delayed and irreversible loss of hearing; lesion in the organ of Corti include the destruction of auditory sensory cells. Vestibular function can also be compromised by ototoxic drugs. Occasional cases of ototoxicity have been reported for a variety of other therapeutic compounds and environmental toxins. In addition, the simultaneous administration of multiple agents which are potentially ototoxic can lead to synergistic loss of hearing. Exposure to loud noise may also potentiate the hearing loss due to cochleotoxic drugs. Ototoxic agents can impair the sensory processing of sound at many cellular or subcellular sites. However, the molecular mechanisms of ototoxicity have not been established for most of these drugs, and structure-toxicity relationships have not been determined. It has therefore been difficult to predict the ototoxic potential of new drugs, and rational approaches to the prevention of ototoxicity are still lacking. The clinical and experimental features of ototoxicity are reviewed for several classes of drugs, with an emphasis on current knowledge of the mechanism and the possibilities for the prevention of ototoxicity for each.

The literature was reviewed for cases of cutaneous pigmentation induced by rifampicin overdosage. 29 examples have been described, in which 2 general groups of individuals were observed. The first consisted of older individuals (average age 27.1 years) who attempted suicide. A prior history of suicide attempts, depression and substance abuse was a predominant factor in these patients. The second group included generally younger patients (average age 2.9 years) in whom misformulation of rifampicin preparations for treatment of Haemophilus influenzae Type B resulted in bright reddish-orange discoloration to the skin. The time to clinical appearance of skin discoloration was approximately 2.2 hours after administration. Periorbital or facial oedema occurred in 72.4% of the patients, pruritus in 62.1% and either nausea, vomiting or diffuse abdominal tenderness in 51.7%. Limited laboratory data are available but these indicate that all patients had elevated levels of total bilirubin. Histological examination in selected individuals revealed rifampicin crystal deposits in the nasopharynx, gastrointestinal tract and lining of the aorta. In adults, it appears that a dose of at least 14 g of rifampicin is necessary before cardiovascular-pulmonary arrest occurs. Other than general supportive measures, very few methods are described in the literature for the treatment of acute intoxications with this drug. A differential diagnosis of other causes of reddish-orange pigmentation is discussed, together with clinical information to differentiate these cases from toxic rifampicin ingestion.

Potassium is one of the most abundant ions in the human body and yet it is difficult to assess potassium balance. Potassium chloride is extensively used as a potassium supplement, both by physicians as a therapeutic modality and by the general public, mostly in the form of salt substitute. Therapeutically, both the oral and intravenous forms of potassium are utilised. Overdose of potassium is not as frequently encountered in clinical practice as hyperkalaemia (excess potassium in the body) due to acute or chronic renal disease. Potassium homeostasis is maintained very delicately and is governed by the daily consumption of potassium and the renal excretion mechanisms. Any change in these or related factors can present as hyperkalaemia. However, potassium overdoses leading to serious consequences do occur. Orally, the dose of potassium has to be large enough so that the normal excretory mechanisms for potassium are overcome and clinical toxicity occurs. It takes a much bigger dose of ingested potassium to produce toxicity in a person with normal renal function than in patients with compromised renal function. Potassium toxicity manifests in significant, characteristic, acute cardiovascular changes with ECG abnormalities. Besides cardiovascular effects, neuromuscular manifestations in the form of general muscular weakness and ascending paralysis occur. Gastrointestinal symptoms manifest as nausea, vomiting, paralytic ileus, and local mucosal necrosis which may lead to perforation. It is imperative when treating hyperkalaemia that the whole clinical picture is taken into account rather than the numerical potassium values. Only the extracellular potassium can be measured in the laboratory, yet 98% of the body potassium is intracellular and cannot be measured. In acute overdose situations due to ingestion of potassium salt, the general principles of treatment for overdoses should be followed. Calcium chloride infusion, dextrose and insulin in water, and correction of acidosis with sodium bicarbonate are helpful in controlling the acute, life-threatening cardiac arrhythmias. These modalities do not remove the excess potassium from the body. That is achieved either by utilising ion-exchange resins or by mechanically removing potassium via haemodialysis. To curtail inadvertent or accidental potassium overdoses, physicians should prescribe any potassium supplements very carefully to their patients and monitor the plasma potassium periodically.

A previously healthy 17-year-old man was admitted in coma following major overdosage with ibuprofen and minor overdosage of doxepin (plasma concentrations 809 and 0.49 mg/L, respectively). Initially, potassium chloride (20 mmol 3-hourly) was infused because of mild hypokalaemia (K+ 2.8 mmol/L). 14 hours after admission the patient developed a hypermetabolic state with pyrexia, metabolic acidosis and progressive respiratory failure despite ventilation at 16 L/min, and a malignant broad complex tachycardia was associated with acute hyperkalaemia (K+ 8.3 mmol/L). The arrhythmia resolved with correction of the hyperkalaemia. Chest x-rays showed diffuse opacification throughout both lung fields and subsequently there was transient impairment of renal function, with evidence of mild rhabdomyolysis. Ventilatory support was required for 60 hours and a chest x-ray at 6 days showed extensive bilateral nodular shadowing, which was still present at follow-up 4 weeks later.

Since most of the toxicity associated with class 1B antiarrhythmic drugs is dose-related, this review examines adverse effects seen in both therapeutic practice and accidental or premeditated overdose. Toxicity is very common with these agents and can be life-threatening. A high percentage of patients must discontinue therapy because of adverse effects. Mexiletine and tocainide are structural analogues of lignocaine (lidocaine) and toxicity is similar with all 3 drugs. With gradual intoxication (the most common form) central nervous system effects such as lightheadedness, dizziness, drowsiness and confusion are seen first. Seizures and respiratory arrest can occur. Cardiovascular toxicity is manifested by progressive heart block, reduced cardiac contraction, hypotension and asystole. Both mexiletine and tocainide may have proarrhythmic effects. Gastrointestinal toxicity is also common. Shock, hypotension, cardiac failure and beta-blocker therapy reduce lignocaine clearance and enhance the risk of intoxication during routine therapy. Both lignocaine and mexiletine elimination is impaired in severe liver disease while tocainide clearance is reduced in renal failure. Management of toxicity is largely supportive and symptomatic. Lignocaine infusion must be discontinued and decontamination of the gut in the case of oral preparations is recommended. Serious intoxication requires intensive care unit admission. Haemodialysis or haemoperfusion may be helpful in serious lignocaine and tocainide poisoning. In institutions where extracorporeal circulatory assistance is available, massive lignocaine poisoning has been successfully treated with this intervention. In the therapeutic setting serious toxicity can be prevented by close clinical surveillance and appropriate dose reduction in patients with reduced drug clearance. Because of the large interindividual variation in lignocaine pharmacokinetic parameters, therapeutic drug monitoring is recommended if results can be reported quickly. Mexiletine and tocainide have stereoselective metabolism and assays do not distinguish the more active isomers. Therapeutic drug monitoring is less useful in this situation.

The currently recommended dosage regimen for methylene blue (intermittent bolus dose) in the treatment of methaemoglobinaemia caused by dapsone is often inadequate. This is due to the long half-life of dapsone which provides a continuing oxidative stress that can cause a recurrence of clinically significant methaemoglobinaemia. Methylene blue infusion is effective, as demonstrated in an illustrative case report, and should be supported by repeated doses of activated charcoal to enhance dapsone elimination. The principles of treatment of methaemoglobinaemia due to dapsone can be applied to methaemoglobinaemia due to any agent producing prolonged oxidative stress.

A study of 1943 potentially toxic ingestions occurring in children under 6 years of age was conducted by 3 geographically and demographically diverse poison centres to determine the incidence of exposures to poison. Of the total group, 30.1% indicated that the child had experienced a prior poison exposure (12.0% in children under 1 year of age, and 41.3% of children between the ages of 3 and 5 years). Most repeaters (68.9%) experienced only 1 prior ingestion (range 1 to 15). Two prior ingestions were reported in 17.6% of repeaters; 3 prior ingestions in 4.4%. A profound effect of age on type of substance ingested was observed, with drugs accounting for 11.0% of ingestions in children under the age of 1 year, 23.2% in 1-year-old, and 49.9% in 2- to 5-year-old. A corresponding age-related decline in ingestions of household and personal care products was also noted. Although less marked than the age effect, a statistically significant propensity to re-ingest similar types of poisons was observed. Among repeaters, those with a prior ingestion of a drug subsequently ingested another drug 1.49 times more frequently than expected. A similar trend was observed with products (1.24 times more frequently) and plants (2.00 times more frequently).

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.

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.

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.

Inorganic bismuth salts are poorly soluble in water: solubility is influenced by the acidity of the medium and the presence of certain compounds with (hydr)oxy or sulfhydryl groups. The analysis of bismuth in biological material is not standardised and is subject to large variation; it is difficult to compare data from different studies, and older data should be approached with caution. The normal concentration of bismuth in blood is between 1 and 15 micrograms/L, but absorption from oral preparations produces a significant rise. Distribution of bismuth in the organs is largely independent of the compound administered or the route of administration: the concentration in kidney is always highest and the substance is also retained there for a long time. It is bound to a bismuth-metal binding protein in the kidney, the synthesis of which can be induced by the metal itself. Elimination from the body takes place by the urinary and faecal routes, but the exact proportion contributed by each route is still unknown. Elimination from blood displays multicompartment pharmacokinetics, the shortest half-life described in humans being 3.5 minutes, and the longest 17 to 22 years. A number of toxic effects have been attributed to bismuth compounds in humans: nephropathy, encephalopathy, osteoarthropathy, gingivitis, stomatitis and colitis. Whether hepatitis is a side effect, however, is open to dispute. Each of these adverse effects is associated with certain bismuth compounds. Bismuth encephalopathy occurred in France as an epidemic of toxicity and was associated with the intake of inorganic salts including bismuth subnitrate, subcarbonate and subgallate. In the prodromal phase patients developed problems in walking, standing or writing, deterioration of memory, changes in behaviour, insomnia and muscle cramps, together with several psychiatric symptoms. The manifest phase started abruptly and was characterised by changes in awareness, myoclonia, astasia and/or abasia and dysarthria. Patients recovered spontaneously after discontinuation of bismuth. Intestinal lavage, forced diuresis and haemodialysis have been tried without positive effects on the clinical condition of the patient or on blood bismuth concentration, and the use of dimercaprol as an antidote has produced reports of both positive and negative findings. To confirm the diagnosis of bismuth encephalopathy, it is essential to find elevated bismuth concentrations in blood, plasma, serum or CSF. A safety level of 50 micrograms/L and an alarm level of 100 micrograms/L have been suggested in the past, but no proof is available to support the choice of these levels.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.