Overdose and Toxicity

Given the narrow margin between therapeutic and toxic plasma lithium levels, the physician must emphasize the prevention of lithium toxicity through adequate salt and water intake, especially during hot weather and exercise. Toxic lithium levels can cause severe neurotoxic reactions, with symptoms such as dysarthria, ataxia, and in- 

Divalproex sodium was approved by the FDA for the treatment of mania and is commonly used for all phases of bipolar disorder, as well as mood instability due to other causes. 

Although many mechanisms have been proposed, the basis for the mood-stabilizing effects of valproate is most likely concordant with 

Circulatory failure (decreased blood pressure, cardiac arrhythmias, conduction abnormalities) 

Generalized convulsions Oliguria and renal failure Death 

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The concept of clearance is useful in pharmacokinetics because clearance is usually constant over a wide range of concentrations, provided that ehmination processes are not saturated. Saturation of biotransformation and excretory processes may occur in overdose and toxic okinetic effects should be considered. If a constant fraction of drug is eliminated per unit time, the elimination follows first-order kinetics. However, if a constant amount of drug is eliminated per unit time, the elimination is described by zero-order kinetics. Some drugs, for example, ethanol, exhibit zero-order kinetics at normal or non-intoxicating concentrations. However, for any drug that exhibits first-order kinetics at therapeutic or nontoxic concentrations, once the mechanisms for elimination become saturated, the kinetics become zero order and clearance becomes variable.3... 

Because of their mechanism of action, bile acid sequestrants can potentially bind with and decrease the oral absorption of almost any other drug. Because these anion-exchange resins contain numerous positive charges, they are much more likely to bind to acidic compounds than to basic compounds or nonelectrolytes. This is not an absolute, however, because cholestyramine and colestipol have been reported to decrease the oral absorption of propranolol (a base) and the lipid-soluble vitamins. A, D, E, and K (nonelectrolytes). As a result, the current recommendation is that all other oral medication should be administered at least 1 hour before or 4 hours after cholestyramine and colestipol. Interestingly, this drug interaction has been used in a beneficial manner to treat digitalis overdose and toxicity. 

The incentive to utilize for the first time tt-tt complexation for selectively removing overdosed and toxic lipophilic aromatic compounds from blood originated from the work of Dust on binding dopamine derivatives to trinitrobenzene [47]. In that and other subsequent publications [42,48-50], spectroscopic methods are described for quantitative determination of complexation as well as how to calculate binding constants and activation energies. 

Treatment with imipramine, the most studied TCA, leaves 45% to 70% of patients panic free. Both desipramine and clomipramine have demonstrated effectiveness in PD as well. Despite their efficacy, TCAs are considered second- or third-line pharmacotherapy due to poorer tolerability and toxicity on overdose.48,49 TCAs are associated with a greater rate of discontinuation from treatment than SSRIs.53 PD patients taking TCAs may experience anticholinergic effects, orthostatic hypotension, sweating, sleep disturbances, dizziness, fatigue, sexual dysfunction, and weight gain. Stimulant-like side effects occur in up to 40% of patients.49... 

Augmenting antidepressants with lithium has repeatedly been shown to be effective. But lithium is a difficult medication to take. It is very dangerous in overdose and can quickly reach toxic levels due to fluid loss from diarrhea, profuse sweating, or high fevers. Even at treatment levels, lithium can produce unpleasant side effects such as dizziness, frequent urination, and tremors. Despite all its problems, lithium... 

Symptoms of overdose with meperidine are qualitatively different from those of morphine in that seizures rather than sedation are common. Respiratory depression and miosis are present. While naloxone reverses overdose-associated toxicity, its use in patients who have received large, frequent doses of meperidine may precipitate seizures. 

Whereas tertiary amine TCAs are more potent than secondary amine TCAs in terms of sites of action mediating adverse effects, they are less potent than secondary amine TCAs in terms of antidepressant efficacy based on the results of the plasma drug level studies reviewed earlier in this chapter. That fact further increases the safety and tolerability of secondary amine versus tertiary amine TCAs (411). Nevertheless, secondary amine TCAs are still toxic when taken in overdose, and this issue must always be considered when applying treatment in a patient who poses a substantial suicide risk. 

Sarko J Antidepressants, old and new. A review of their adverse effects and toxicity in overdose. Emerg Med Clin North Am 2000 18(4) 637. [PMID 11130931]... 

The therapeutic blood level is greater than 150 mg L-1 but symptoms of toxicity occur at blood levels of around 300 mg L-1. Therefore, knowledge of the blood level is important, particularly when aspirin is given in repeated doses. In children, therapeutic overdosage is responsible for the majority of fatalities from aspirin. When an overdose is suspected, measurement of the plasma level on two or more occasions will allow an estimate to be made of the severity of the overdose and whether the plasma level has reached its maximum. For interpretation of the blood level, the Done nomogram can be used. An overdose of 50 to 300 mg tablets in adults will give rise to moderate to severe toxicity and a blood level of 500 to 750 mg L-1 at 12 hours. The blood level must be interpreted with caution, however, because... 

Amphetamines are often combined with cocaine to extend the high. Cocaine creates a rush but it is short-lived. Adding amphetamines extends the high for up to ten hours. Using these drugs together increases the chances of an overdose and increases toxic effects. 

Information on pemoline s tolerance and toxicity is not available. However, as with almost any drag, there is a chance of psychological and/or physical dependence with excessive doses and/or long-term misuse (57). In comparison to methylphenidate and amphetamine, pemoline has the least potential for abuse (39). Benowitz (41) suggests that approximately 3 mg/kg pemoline should be considered life-threatening. Treatment for overdose is similar to what has been recommended for methylphenidate and amphetamine. In cases of overdose, the administration of chlorpromazine has been found useful for decreasing the amount of CNS overstimulation (57). 

Methotrexate is administered by the intravenous, intrathecal, or oral route. Up to 90% of an oral dose is excreted in the urine within 12 hours. The drug is not subject to metabolism, and serum levels are therefore proportionate to dose as long as renal function and hydration status are adequate. Dosages and toxic effects are listed in Table 55-3. The effects of methotrexate can be reversed by administration of leucovorin (citrovorum factor). Leucovorin rescue has been used with accidental overdose or experimentally along with high-dose methotrexate therapy in a protocol intended to rescue normal cells while still leaving the tumor cells subject to its cytotoxic action. 

A review of the use of process and treatment plant chemicals is required to identify those that have the potential to contribute to toxicity. For each chemical the following should be determined i) availability of current MSDS and toxicity test data for species of interest, ii) purpose and volume used (volumes used are typically available from the supplier), iii) whether the amount can be reduced or reused, iv) whether less toxic alternatives are available, and v) if it is possible to avoid discharge of the chemical (U.S. EPA, 1989 1999). Even a slight overdosing of effluent treatment chemicals (e.g., polymers, chlorine) could result in potentially toxic concentrations in the final effluent, since these chemicals do not have the... 

TABLE 11.4 Toxic Reactions to Stimulants Usually in Overdose and Occasionally at Low Doses... 

Item taken from the 2002 FDA-approved overdose section of the labels for Dexedrine, Adderall, and Adderall XR, but not Ritalin. The remainder was taken from the Ritalin label with some overlap. The Dexedrine and Adderall labels both state that individual patient responses to amphetamines vary widely and toxic symptoms occasionally occur as an idiosyncrasy at doses as low as 2 mg. The Adderall XR label also states that patient responses vary widely and toxic symptoms may occur at low doses. Any of the symptoms can occur with any of the stimulants at routine clinical doses. 

In 225 patients who had taken overdoses of antidepressant drugs in suicide attempts, venlafaxine and citalopram were more likely to be associated with seizures than mir-tazapine and nefazodone and 5HT toxicity was more common after overdose of venlafaxine (94). These findings confirm the potential toxicity of venlafaxine in overdose and also suggest a pro-convulsant effect of large doses of citalopram. 

Cases of lithium toxicity in a municipal hospital over a 10-year period involved eight women (mean age 66 years) neurological symptoms were the most common presentations (151). Two were acute overdoses and the rest were chronic intoxications. There was one death (group not specified). 

Of 56 patients with lithium toxicity, 42 had initially overdosed and they were compared with those who had toxicity that was described as inadvertent and associated with volume depletion (545). The initial lithium concentration was lower in the cases of intentional overdose than in the cases of inadvertent intoxication (2.4 mmol/l versus 3.4 mmol/l). Hemodialysis for lithium toxicity was required in 9% of those who had taken an intentional overdose compared with 50% of those who had inadvertent intoxication. These findings were in contrast to the amount of lithium taken during the 24 hours before hospitalization, which was much higher in those who had taken an intentional overdose, because of the large inhibitory effect of dehydration on lithium excretion. 

Drug overdose Acute toxicity requiring emergency medical treatment is rare. When it occurs there is a typical sympathomimetic syndrome, which should be treated with fluids, control of hyperthermia, bed rest, and, if necessary, sedation with benzodiazepines (1). 

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