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 […]

Differential Drug Effects as a Function of the Controlling Consequences

One of the central themes during the initial period in the development of behavioral pharmacology was the issue of whether motivational factors influence the effects drugs have on behavior. Though seemingly a straightforward question, the translation of this problem into an experimentally addressable form was, and continues to be, somewhat difficult. Motivational concepts almost inevitably pose formidable experimental problems, and studies designed to resolve those problems have often yielded equivocal results. Typically, however, the question has been approached experimentally by comparing the effects of various drugs on behavior controlled by different types of events, e.g., food presentation and escape from electric shock. Presumably, different events and the behavioral consequences associated with them engendered different motivational states. The influence of motivational factors as determinants of drug action should then be reflected by differential changes in overt behavior when the organism is given certain drugs. This approach had one rather substantial problem that was not always recognized. Behavioral consequences are important in several different ways, not only when they differ on some hedonic dimension, Read more […]

Drug effects on behavior maintained by food, electric-shock presentation and stimulus-shock termination

Although early experiments did not find differences in drug effects depending on the type of event, more recent studies have reported several instances in which the maintaining event appeared to influence the effects of several drugs on behavior. For example, morphine, methadone, and the narcotic antagonists naloxone and nalorphine decreased responding maintained under 5-minute fixed-interval food-presentation schedules at doses that increased responding comparably maintained by the presentation of an electric shock (). Under similar schedule conditions, both amphetamine () and cocaine () increased responding maintained by these two events. However, appropriate doses of pentobarbital, ethanol, and chlordiazepoxide increased responding maintained by food, while only decreasing responding under shock-presentation schedules (). These findings suggested that there were several conditions under which certain drugs appeared to affect similar performances maintained under comparable schedules in an event-dependent manner. Further, as shown in Figure Effects of chlordiazepoxide on different control rates of responding under S-minute fixed-interval schedules of food or shock presentation. The event pen was defected downward 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 […]

Sedatives

An assessment of the relationship between sedatives and driving accidents requires the survey of literature dealing with: (1) the effects of sedatives on actual driving behaviors, (2) the epidemiological studies of sedatives and traffic accidents, and (3) the physiological, psychological, and behavioral effects of sedatives on factors related to driving. Only a few studies have tested the effects of sedatives either in a simulator or in the field. Loomis and West () tested eight subjects in a driving simulator from 1 to 6 hours after they were given various drugs. The simulator consisted of an automobile steering wheel and brake accelerator pedals arranged as in a standard automobile. The steering wheel operated a model car placed on a moving belt 150 ft. long and 30 in. wide with an opaque l-in. strip running down it lengthwise, which simulated the road bed. The strip was shifted randomly, moving smoothly from side to side as the belt advanced. Accelerator and brake pedals actuated and controlled the rate of belt movement, and the steering wheel controlled the position of the model car. A light source placed 14 in. above the car was capable of producing an amber, red, or green light. The subject was required to Read more […]

General Tranquilizers

Current methodology for determining plasma levels of diazepam and its active metabolites employs electron-capture gas chromatography and can measure 1- to 10-ng quantities (). When a group of people are administered diazepam at a particular dose, there is a wide range of plasma concentrations of diazepam (). This range, in 13 subjects administered 15 mg of oral diazepam daily for a week or more, is 16 to 400 ng/ml (). Garattini et al. () found a range of 10 to 250 ng/ml in 27 subjects given a single 15-mg oral dose. A half-life of 38 to 92 minutes has been measured by this group in five female subjects. Kleijn et al. () calculated a half-life of 20 to 42 hours after 10 mg three times a day, about 0.5 mg/kg/day orally in five subjects. This great variability in plasma concentration is a major problem in interpreting drug effects on human performance. Perhaps the factors that influence plasma concentration curves can be identified and controlled. With seven subjects, Linnoila et al. () showed that ingestion of food increases plasma levels of diazepam 6, 7, and 8 hours after intravenous administration of 0.3 mg of diazepam per kg. They suggest that enterohepatic recycling of diazepam is occurring. Kleijn et al. () Read more […]

Cocaine Abuse: A Review of Current and Experimental Treatments

Cocaine abuse is a recently revived drug problem that is again generating great popular concern. Unfortunately, scientific evaluation of cocaine abuse treatment has been surprisingly sparse kind no consensus exists regarding optimal treatment strategies. This review summarizes current treatment issues and regimens. as well as preliminary data on new, approaches to cocaine abuse treatment. Since this chapter will deal with treatment of the cocaine abuser, it is important from the outset to define what is meant by that term. Although in some settings any use of illegal drugs equals abuse such a definition is more legal than medical and will not he used here. Instead the definition of drug abuse found elsewhere in the field will be employed namely…“the nonprescription use of psychoactive chemicals by an individual to alter his her psychological state in a situation in which the individual or society incurs some harm” (). The great majority of cocaine users applying for treatment fit into this definition. The most common exception is the individual who defines his use as recreational controlled and nonharmful but is brought to treatment by another (e.g. spouse, parent), while the significant other views the cocaine Read more […]

Internal Stimulus Control and Subjective Effects of Drugs

For many years psychotropic drugs have been characterized and classified using methods designed to measure their subjective effects in humans (). This research approach has two principal purposes: 1) to investigate the efficacy of a drug in attenuating unwanted subjective states in patients (e.g., pain, anxiety, depression), 2) to investigate the abuse potential of new drugs by comparing their subjective effects in experienced drug abusers to those produced by known drugs of abuse. In regard to the latter, such methods have been used to determine whether there are any common subjective states produced by all drugs of abuse (e.g., euphoria). Systematic studies of subjective methods for drug classification have been conducted at the Addiction Research Center (ARC) in Lexington, Kentucky, now part of the National Institute on Drug Abuse. A major mission of the ARC has been to evaluate new analgesic compounds to determine whether they produced morphine-like effects. The subjective effects of morphine and related compounds were an important aspect of this evaluation. The research demonstrated that morphine and related narcotic analgesics produced a unique spectrum of subjective effects that can be reliably discriminated Read more […]

History of Drug Exposure as a Determinant of Drug Self-Administration

The purpose of this paper is to review how a drug’s effectiveness in initiating and maintaining self-administration can be influenced by a subject’s past experience with drugs. Drug self-administration by humans and laboratory animals is considered an instance of operant behavior (), controlled by the subject’s genetic constitution, past history, and the current circumstances of drug availability (of Skinner, 1938). The influence of history of drug exposure on current drug-maintained behavior may be controlled, in turn, by the particular drugs and doses employed and the conditions under which the drug is administered. This discussion will focus on the ways in which a history of drug exposure can control later drug self-administration in laboratory animals. Effects of history of drug exposure on initiation of drug self-administration In order to study drug self-administration by laboratory animals, an experimenter must set up a situation in which subjects are exposed to some contingency between the occurrence of a specific response and delivery of a particular drug. For many drugs, no explicit behavioral or pharmacologioal history is necessary for the drug to maintain behavior. In one initial study, for example, Read more […]