CENTRAL NERVOUS SYSTEM DEPRESSANTS GENERAL The central nervous system depressants are drugs sulfonmethanes (Table X) comprise drugs that that relieve anxiety (sedatives) or induce sleep cause, in high dose, sedation, stupor, coma, impaired (hypnotics). Chemical groups of the monoureides cognition, loss of behavioural controls and ataxia. (Table II), sulfonmethanes (Table X), and the In addition, there is experimental or experiential miscellaneous agents (Table XI) comprise drugs evidence that at least one member of each of these which have low or no dependence liability but which subgroups causes dependence of the barbiturate- have high central nervous system and other organ alcohol type, manifested by nervousness, agitation, toxicity. These drugs are largely obsolete and insomnia, confusion, convulsions and delirium production is generally low. The bromides have following abrupt discontinuation after long-conti- similar dangers. nued high dosage. A small number of individual The chemical groups of the barbiturates (Table I), drugs have also been shown to substitute for barbital chloral and derivatives (Table III), the tertiary in dogs or monkeys dependent on those substances, acetylenic alcohols (Table IV), the carbamic acid that is, have been shown to have physical dependence esters of monohydroxy alcohols (Table V), the capacity of the barbiturate type, and in such in- carbamic acid esters of glycols (Table VI), the stances cross-tolerance was clearly demonstrated. piperidinediones (Table VII), the quinazolinones The cyclic ether, paraldehyde, has similar character- (Table VIII), the benzodiazepines (Table IX) and the istics. DIUREIDES (BARBITURATES) The fact that the barbiturates (Table I) are drugs of central nervous system depressants. Kalinowsky's of dependence is now so well accepted that it is idea was expanded to include the group of drugs difficult to remember how long this fact was denied listed under substances that cause dependence of the and how long it took to gain general acceptance of barbiturate-alcohol type. 87 barbiturate-type dependence. The first cases of The characteristics of dependence of the barbitu- dependence were described as long ago as 1914 116 rate-alcohol type include: and 1915.125 The general clinical aspects of the (1) strong psychic dependence; intoxication and of the withdrawal manifestations (2) intoxication manifested by sedation, sleep, were reported in 1928 119 and further detailed in a coma, stupor, impaired cognition and judgement, monograph 120 in 1934. Dependence with withdraw- and ataxia; al convulsions in dogs was demonstrated in 1939 128 and confirmed later.84, 82 Numerous cases of with- (3) development of tolerance which is partly bio- drawal convulsions and delirium were reported chemical due to induction of increased amounts of around the world from 1914 to 1950, but the concept drug-metabolizing enzymes in the liver and to that the barbiturates caused physical dependence " cellular" tolerance within the central nervous continued to be denied until the experimental de- system (tolerance to this type of drug, in contrast to monstration of the condition in controlled experi- opiates, has a definite limit); ments in man 78, 93, 95, 96, 103, 104, 106, 129 in 1950 and (4) partial crossed tolerance between members of subsequent years. the group; Kalinowsky I" was the first to recognize that (5) a dangerous type of physical dependence convulsions on withdrawal of barbiturates, alcohol manifested by anxiety, insomnia, weakness, tremors, and other drugs represented a general type of EEG abnormalities, convulsions and delirium on reaction common to several different chemical types withdrawal. -10 - _ 0 ,W . 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