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 […]

Multiple Drug Use Epidemiology, Correlates, and Consequences

The initial focus is on the conceptual issues essential to the understanding of multiple drug use. This is followed by a discussion of the developmental nature of multiple drug use and the various strategies that have been designed to measure multiple use. The third section of the paper contains a review of the extent of multiple drug use in various segments of society with data from the Monitoring-the-Future surveys of high school seniors, the National Survey on Drug Abuse, and the Treatment Outcome Prospective Study of drug abuse treatment clients. The conclusion is that multiple drug use is pervasive. The next section deals with several consequences associated with multiple drug use: automobile accidents, delinquency, and emergency room visits. The final section outlines some of the prevention and treatment implications of multiple drug use from a public policy perspective. In a study of the effects of a single drug upon behavior, the implications are manifold. Dosage levels, modes of administration, baseline states, the expectations of the subjects and of the investigators, the environment in which the drug is taken — all these variables, and others as well, make human psychochemical studies difficult and complex. 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 […]

Measuring the Developmental Nature of Multiple Drug Use

There have been a number of studies in which attempts have been made to measure or assess multiple drug use. Some of these are from general populations while others are focused on specific subpopulations of users. The studies are grouped more on the basis of the approach taken to assessing multiple drug use than on the patterns uncovered. There are at least four different groupings of studies and some studies fit into more than one grouping. Developmental Patterns of Onset of Use One of the most influential attempts to describe patterns of multiple drug use is the “stages of drug use” model developed by Kandel. Kandel posited that persons proceed from licit to illicit drugs and from use of less to more serious drugs. The stages of drug use involvement that she identified were: (1) no use of any drugs; (2) use of beer or wine; (3) use of cigarettes and/or hard liquor; (4) use of marijuana; and (5) use of illicit drugs other than marijuana. Although it is not made explicit by Kandel, there is an implication that the drugs from the earlier stages of development are “carried forward” into the later stages of drug involvement. Thus, a marijuana user is likely to continue his or her use of cigarettes/hard liquor and beer Read more […]