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 […]
Archive for category 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 […]
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 […]
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 […]