Toxicology of Antidepressant Drugs

As many pharmacodynamic effects carry over from animals to man, many toxic effects may also be predicted from observations made in animals. However, some important toxic effects are not predictable from animal studies (WHO, 1966) and this limitation may apply particularly to drugs acting on the central nervous system, such as the antidepressants. Nevertheless, the recognition of species differences and similarities in responses is considered as an important means of predicting toxic effects in man. In the following, some degree of correlation is attempted by the comparison, whenever feasible, between toxicity in laboratory animals and adverse effects described in man, particularly in cases of acute intoxication. However, due to the differing amount of data that was available on various drugs and the widely varying experimental conditions employed, such a comparison may not always prove to be reliable. The following review has been restricted to antidepressants in clinical use and, as far as evidence was available from the literature, concentrated on two main categories of antidepressants, the monoamine oxidase (MAO) inhibitors and the tricyclics. The lithium salts are considered in a separate chapter of this volume. Read more […]

Toxicology of Antidepressant Drugs: Tricyclic Antidepressants

Animal Toxicity General Toxicology The LD 50 values for a number of tricyclic antidepressants, when administered to mice and rats in single oral or parenteral doses, are listed in Table Acute LD50 valuesa of some tricyclic antidepressants. Acute poisoning by tricyclic antidepressants usually leads to symptoms of central excitation followed at the higher and lethal dose levels by central inhibition. The symptomatology includes muscular weakness, twitching, stupor, respiratory disorders, ataxia, and tonic-clonic convulsions. Table Acute LD50 valuesa of some tricyclic antidepressants Imipramine Doxepine Nortriptyline Viloxazine Maprotiline Mouse i.v. p.o. 35 666 15- 20 148-178 26 327 60 1000 31 660- 900 Rat i.v. p.o. 22 625 13- 19 346-460 22 502 60-77 2000 38- 52 760-1050 a The values given are for LD50, single administration, in mg/kg body weight It is evident from Table Acute LD50 valuesa of some tricyclic antidepressants or from the reports of Pluviage () and of Ueki et al. () that no major differences in the acute toxicity of tricyclic antidepressants are apparent. Information on animal studies relating to the tolerance of tricyclic antidepressants Read more […]

Tricyclic Antidepressants: Teratology

Antidepressants comprise only a small portion in the vast assortment of drugs that may be taken by pregnant women. In a sample of 3,072 subjects, the number of gravid women receiving antidepressant drugs was estimated to be in the order of 0.1 % (). Similar to other drugs that are used much more frequently during pregnancy (), particularly during the first trimester (the most sensitive period of embryonal development), some antidepressants have been suspected to carry a teratogenic risk. In a short note published 1972, McBride reported on one child with amelia and mentioned two others with a similar limb deformity he felt were caused by imipramine taken by the mothers in early pregnancy. Two further cases were subsequently reported (). Doubt was, however, cast upon the validity of the McBride’s notion of a causal relation between imipramine or other tricyclic antidepressants such as amitriptyline and congenital abnormalities. The Australian Drug Evaluation Committee (1973) and the results of further clinical and epidemiologic studies failed to associate the ingestion of these drugs in early pregnancy with malformations (). Likewise, neither on account of the review presented by one manufacturer () nor on the basis Read more […]

Tricyclic Antidepressants: Intoxication in Man

Effects of Acute Overdose Most of the numerous publications on acute intoxication with tricyclic antidepressants deal with attempted suicide in adults or with accidental selfpoisoning in children. Taking into account the difficulty in establishing the dose ingested – particularly in the case of children and of successful suicides – it is not surprising that it is difficult to predict the severity of an acute intoxication from the dose apparently taken. In children, fatalities have occurred with doses below 500 mg and survival with doses as high as approximately 1,700 mg. In adults, doses below 1,000 mg may already prove fatal but survival has been reported with doses up to 4,000 mg or higher (). In children, the critical dose level for imipramine seems to lie around 500 mg. Of a survey comprising 34 cases, only two children who had ingested less died whereas only three with larger doses survived (). Adults, who have ingested 1,000 – 2,000 mg still have a good chance of recovery whereas the risk of a fatality becomes far greater at levels of over 2,000 mg (). In relation to body weight, an LD50 value for imipramine has been determined for children at 40 – 50 mg/kg and for adults at 30 – 50 mg/ kg (). The symptoms Read more […]

Benzodiazepines in the Treatment of Alcoholism

This post comprises three sections that cover the main aspects of benzodiazepines and alcohol: (1) the basic pharmacology of benzodiazepines; (2) use of benzodiazepines in the treatment of withdrawal; and (3) the use of benzodiazepines in treating alcoholics. The basic studies suggest that a major site of action of alcohol may be the GABA/benzodiazepine receptor complex and that compensatory alterations in this complex may underly withdrawal. In the section on alcohol withdrawal, interactions between the GABA/benzodiazepine receptor complex, sympathetic nervous system, and hypothalamic-pituitary-adrenal axis are discussed. Use of benzodiazepines in the treatment of the alcohol withdrawal syndrome are reviewed, including the possibility that the benzodiazepines may prevent withdrawal-induced “kindling”. Lastly, we review indications for, and efficacy of, benzodiazepines in long-term treatment of patients with alcoholism. Benzodiazepines are not indicated for the treatment of alcoholism. Furthermore, they have very few indications in alcoholics and their dependency-producing potency has to be appreciated when they are used in patients with alcoholism. The benzodiazepines () are a group of compounds that were first Read more […]

Alcohol and Panic Attacks

Panic attacks with and without agoraphobia are more common among alcoholics than the rest of the population. The simplest explanation may be that certain patients with panic attacks drink alcohol to alleviate anticipatory anxiety. The relationship between panic attacks and alcoholism may, however, be complex. Both alcohol withdrawal and panic attacks have been demonstrated to be associated with noradrenergic overactivity. Furthermore, tolerance to alcohol seems to be partly conditioned, at least in experimental animals, and it involves physiological changes compatible with sympathetic activation. Tolerance is not maintained in experimental animals with central noradrenergic lesions. Thus, noradrenergic activation may play an important role both in conditioning tolerance and panic attacks. Another phenomenon pertinent to alcohol withdrawal, with implications for panic attacks, is kindling. Repeated alcohol withdrawals may lead to kindling. This was first postulated based on a retrospective chart review of patients with alcohol dependence which showed that repeated withdrawals became progressively more severe. More recently, it was demonstrated that blunted responsiveness of noradrenergic a2-autore-ceptors was positively Read more […]

Consequences of Multiple Drug Use: Specifying the Causes

In order to illustrate these points, three specific consequences of drug use will be discussed in some detail below. These three consequences are traffic accidents, involvement in delinquent/criminal acts by youth and young adults, and emergency room visits related to drug abuse. Traffic Accidents The Monitoring-the-Future surveys contain several questions concerning traffic accidents. The seniors are first asked how many accidents (i.e., a collision involving property damage or personal injury — not bumps or scratches in parking lots) they had while they were driving in the past 12 months. If the answer is one or more, the senior is asked how many occurred after he/she was drinking alcoholic beverages and then how many occurred after he/she was smoking marijuana or hashish. By piecing together the information from these separate questions, it is possible to estimate the proportion that would be due to alcohol, to marijuana, and to alcohol and marijuana. The data in Table “Motor Vehicle Accidents and Their Connection to Use of Alcohol, Use of Marijuana, and Use of Both Alcohol and Marijuana” are for seniors in the class of 1980 classified according to the extent of alcohol and marijuana use reported during the Read more […]

The Epidemiology of Multiple Drug Use

How much multiple drug use is there? What proportion of the population at any one point in time is using/abusing multiple substances? Has use of multiple substances become more normative in the recent past as opposed to exclusive use of a favorite drug? What are the principal consequences of multiple drug use? Do these consequences differ according to pharmacological parameters for interactive potential or are there other parameters of almost equal predictive value? To what extent are the consequences attributed to single drugs (traffic accidents labeled as alcohol related) really the result of impaired judgment and performance from ingestion of multiple substances? These are just a few of the questions that need to be addressed within the scientific and public policy communities. In the following section some epidemiological data pertinent to understanding the “extent” of multiple drug use are presented. Monitoring-the-Future Studies Each year since 1975, researchers at the Institute for Social Research at the University of Michigan have administered questionnaires to about 17,000 high school seniors attending schools randomly chosen to be representative of all high schools in the continental United States. These Read more […]

Desipramine and Imipramine Alone and Together with Alcohol in Relation to Driving Safety

STUDY: Landauer, A.A., and G. Milner. Desipramine and Imipramine Alone and Together with Alcohol in Relation to Driving Safety. Pharmacopsychiatric Neuropsychopharmakologia, 4:265-275. 1971. Site: Department of Psychology, University of Western Australia, and Mental Health Services of Western Australia. Subjects: Twenty-seven medical students served as paid experimental subjects. Their mean age was 23.1 years (S.D. = 1.5), and mean weight was 73.7 kg (S.D. = 8.7). Method: In this controlled laboratory study, the subjects were randomly divided into three groups of nine each. The three groups received either imipramine, desipramine, or placebo, the drugs being administered in tablet form, one at night before the experiment and the second on the morning of the experimental day – i.e., at a 12- to 14-hour interval. Alcohol was diluted with lime juice, syrup, and water and had to be drunk in less than 15 minutes Subjects were required not to drink alcoholic beverages on the day before the test. On test day, after a light breakfast, a medical examination, and the second tablet dose, they were asked to complete a questionnaire rating themselves on their present state, and on anything felt or experienced since Read more […]

Cocaine abuse treatment strategies

Strategies devised to treat cocaine abuse have existed since its intractable lure for some first became obvious almost a century ago. During this period no generally accepted or successful treatment has emerged. Chronic cocaine abuse has been assumed to cause no physiologic withdrawal state on discontinuation because of insufficient evidence for an abstinence syndrome of major physiological changes like the classic sort characterizing sedative or opiate withdrawal (). Cocaine abuse has thus been assumed to be a “psychological dependence” rather than one involving neurophysiological adaptations, and currently used treatments consist of psychological strategies aimed at modifying addictive behaviors. Issues related to current psychological strategies will be discussed first, followed by a summary of evidence indicating cocaine abuse may cause neuroadaptation. The latter includes a review of pharmacological strategies, aimed at reversal of such adaptation, which may hold future potential as adjuncts in cocaine abuse treatment. Cocaine abuse treatment strategies: Current treatments Potential New Directions in Treatment Despite the past assumption that cocaine abuse is a “psychological addiction,” it is plausible Read more […]