Hypnotics

HYPNOTICS (Hypnotica), constituting a pharmacotherapeutic subgroup within the group of narcotic agents, are characterized by the ability to induce a state close to physiological sleep. The belonging of hypnotics to so-called indifferent narcotics determines a number of physico-chemical and pharmacological properties common with the latter (see Narcotic substances); the main differences between hypnotics and inhalation anesthetics reduce to the following: 1) being in the vast majority of cases solids, hypnotics are absorbed and eliminated from the body significantly more slowly, which is why the pharmacological effect they cause is much more prolonged; 2) the hypnotic effect is associated with a more superficial action, predominantly restricted to the functions of the brain (however, with an increase in dosage, hypnotics can lead to deep narcosis of the entire central nervous system, which is why some of them, such as urethane, hedonal, pernocton, and others, were used for general anesthesia); 3) the complexity and diversity of the chemical composition and structure of hypnotics lead to a greater diversity in their distribution, action, and fate in the body. Chemically, hypnotics are classified according to two main principles: 1) The presence in the hypnotic molecule of certain chemical elements—halogen, sulfur, nitrogen. In view of the fact that the presence of chlorine affects the side effects of hypnotics incomparably more sharply, chlorine-containing preparations are often isolated into a special group (chloral hydrate, amylene chloral, chloralurethane, isopral, aleydrin, voluntal, etc.), which is not done for bromine-containing hypnotics (bromural, neuronal, noctal, pernocton). If the presence of chlorine has a quite definite significance for the pharmacological action of hypnotics, the presence of nitrogen and sulfur has significance not in itself, but in connection with the structural features of the molecule. 2) Belonging to a specific type of chemical compounds—a significantly more perfect principle (using which halogen-containing hypnotics can be isolated into special subgroups): aldehydes (paraldehyde, chloral hydrate), ketones (hypnone), alcohols (amylene hydrate, isopral), sulfones (few hypnotics containing sulfur: sulfonal, trional, tetronal); the most numerous nitrogen-containing hypnotics: carbamic acid derivatives (urethane, hedonal, aponal, voluntal, aleydrin), urea derivatives (adalin, bromural, abasin), barbituric acid derivatives (veronal, proponal, dial, noctal, pernocton, amytal, diogenal, luminal, nirvanol, fanodorm, somnifen). The practical value of chemical classification for pharmacotherapy is lowered by the fact that the indications for the use of individual hypnotics can be different despite a great similarity in their structure and, conversely, be of the same type for hypnotics of various composition and structure. This follows already from a number of discrepancies between the chemical classification and the clinical experience used by Renner in his clinical classification of hypnotics (see below). Still, when judging the features of the hypnotic action of individual preparations, their side effects, and their fate in the body, familiarity with chemical composition and structure is of great importance; amidst all the difficulties of studying the connection between the physico-chemical nature of hypnotics and their action, it is clear that it is precisely upon this nature that the diversity of effect of even closely related substances depends (cf. the different absorption, distribution, and absorbability of compounds containing different alkyl radicals, etc.). Experience accumulated since the introduction into practice of the first typical hypnotic—chloral hydrate (Liebreich, 1869)—makes it possible to establish the requirements demanded of a good hypnotic. Various preparations satisfy them to an unequal degree. These requirements are as follows: 1. Absence of local action causing heartburn, eructation, nausea, vomiting. When using preparations of chloral hydrate, paraldehyde, amylene hydrate, and others, weakening of the local action is necessary: taking hypnotics in a large amount of water or using enveloping substances (syrups, gums, mucilages). 2. Fairly rapid onset of sleep: if it depends mainly on the absorbability of the preparation, the latter in turn is usually associated with solubility in water. Therefore, poorly soluble preparations are recommended to be washed down with a large amount of water or carbonated beverages (as an exception, poorly soluble proponal produces rapid sleep). The patient must be warned by the physician about how long before sleep he must take the hypnotic (this time varies for different preparations from 1/2 to 1 hour). Late onset of sleep is produced by chloral hydrate (?), chloralamid, sulfonal, trional, tetronal, somnifen, veronal, luminal, nirvanol (substances belonging to the third group of hypnotics according to Renner). 3. Absence of complications during the process of falling asleep. Since indications for prescribing hypnotics may be determined by a disturbance of the falling-asleep process, Renner has isolated into the first group of his classification substances that facilitate falling asleep ("soporifics"): bromural, adalin, diogenal, aponal, aleydrin, voluntal. In case of a disturbance of sleep itself, the use of substances characterized by a more significant narcotic effect is indicated, which, according to Renner, include paraldehyde, amylene hydrate, acetal, methylal, hypnone, hedonal, urethane (2nd group according to Renner) and the aforementioned substances of the 3rd group, characterized by a later onset of sleep. If when using "soporifics" the patient feels that he can fall asleep, then upon the use of proper "hypnotics" a feeling of narcotization may arise even without psychological readiness for sleep ("the patient must fall asleep"). This state can be subjectively unpleasant and even lead to a feeling of fear when falling asleep, which was more frequently noted upon the prescription of barbituric acid derivatives. In some cases, sleep may be hindered by excitation, which in its origin probably coincides with the excitation of alcoholic intoxication. It can arise not only with fast-acting hypnotics (amylene hydrate, dial, proponal), but also with delayed-action substances (chloral hydrate, chloralamid, chloralose, sulfonal); here dose evidently has significance (cf. the soporific action of small amounts of beer and the sleep-disrupting action of strong wines and vodka) and the individual characteristics of the patient. Mental changes upon taking hypnotics, in the absence of the mentioned complications, boil down mainly to the appearance of a feeling of fatigue, difficulty in perception, and slowed associations, and are quite close to the state of drowsiness and falling asleep. 4. Reliability of the hypnotic effect. Since the latter depends not only on the hypnotic, but also on the individuality of the subject, failure can occur with the use of any hypnotic. Among other hypnotics, however, a group of substances less reliable in their action stands out: neuronal, dormiol, isopral, dial, curral, proponal (4th group according to Renner). One should also mention here the unreliable urethane, used sometimes only in pediatric practice. According to Grabfield, the most reliable hypnotics are chloral hydrate and veronal (94-97% onset of sleep). 5. Sufficient depth and duration of sleep. This requirement is important when there is a disturbance not in falling asleep, but in sleep itself, and it is realized thanks to specific ratios of the processes of intake and elimination of the aforementioned hypnotics (of the 2nd, 3rd, and 4th groups according to Renner). 6. Fairly rapid elimination or inactivation of hypnotics. If with excessive rapidity of these processes premature awakening of the patient may occur, their slowing can lead to an undesirable lengthening of sleep, the appearance of undesirable post-hypnotic symptoms, and upon repeated administration of hypnotics (occurring in habitual insomnia)—to the cumulation of both the substance and the effect of action. Retention in excretion and the danger of cumulation are more pronounced when using substances of the 3rd group, especially sulfones (sulfonal, trional) and barbituric acid derivatives. The cessation of the hypnotic action is promoted by a decrease in the concentration of hypnotics in the blood due to the alteration of hypnotic substances in the body (conversion of chloral hydrate into urochloralolic acid, urethane into urea, etc.). Acceleration of the elimination process of hypnotics and the removal of unabsorbed preparation from the intestine can be achieved by prescribing diuretics and laxatives. Upon repeated prescription of hypnotics, to avoid cumulation, after 3-4 days of intake, a break of several days should be made. 7. Absence of side effects in the action of hypnotics. Local action symptoms and symptoms complicating the process of falling asleep were discussed above. Of great importance is the onset of a post-hypnotic symptom complex very similar to a hangover (dizziness, headaches, vomiting, speech disturbance, gait disturbance, etc.). It is more frequently observed upon prescribing substances of the 3rd and 4th groups. When prescribing chlorine-containing substances, a harmful effect on the circulation is particularly often discovered, which is why they are contraindicated or must be used with caution in cardiovascular patients, in old age, with a tendency to bleeding, etc. These same substances, especially with prolonged use, more easily disrupt metabolism (especially protein metabolism) and can lead to degenerative processes in parenchymatous organs.

When prescribing sulfones (sulfonal, trional), hematoporphyrinuria may occur. It should be noted that the unreliability of the hypnotic effect, especially when combined with the occurrence of more pronounced side effects (or complications in general), usually indicates an unfortunate choice of drug for a given patient, a violation of the rules for taking the medicine, or even the absence of indications for prescribing hypnotics in general. 8. Absence of habituation. The latter can be prevented or weakened mainly by the rational use of hypnotics. Habituation, expressed as a weakening of the hypnotic effect, occurs to a greater or lesser extent with all hypnotics, without, however, the development of tolerance to the side effects. Therefore, a significant excess of the hypnotic dose is possible without severe intoxication only with less harmful preparations (paraldehyde). One should be wary of exceeding doses of chloral hydrate in alcoholics, who may exhibit "tolerance" to the hypnotic effect and reduced resistance to side effects on the circulatory system. Habituation, expressed as the appearance of a craving for hypnotics, has been described more frequently with some of them (chloralism, veronalism, luminalism). The craving for a certain type of hypnotic is more pronounced, apparently, in the case of luminal and dial. Given certain shortcomings in the action of various hypnotics, the best of the "sedative" ones is, according to a number of authors, adalin, and the best of the strictly "hypnotic" ones is veronal. The desire to weaken the harmful effect of individual preparations by reducing their doses, along with the desire to use the selective and potentiating action of various substances, has led to the prescription and manufacture of numerous combination preparations, such as somnacetin (veronal + phenacetin + codeine), veramon (veronal + pyramidon), codeonal (veronal + codeine), eglatol (chloral hydrate + antipyrin + caffeine + methylurethane), etc., classified by Renner in the 5th group. However, some of these preparations apparently do not provide potentiation and do not lead to sleep if the dose of the corresponding component (e.g., veronal) is not sufficient for this or if the sleep disturbance is not caused by reasons eliminated by other components (pyramidon for neuralgias, codeine for cough). In other cases, potentiation takes place, and the hypnotic dose of, for example, somnacetin, according to Noorden, is twice as small for a human, and according to Hondelink, 20 times as small for a chaffinch, than the hypnotic dose of veronal. -- In setting forth the requirements for a good hypnotic, the question of the pharmacological features of the hypnotic effect is only partially covered. The latter, at an average dose, occurs only under conditions favorable to the onset of normal night sleep, and does not occur when given during the day. In Hondelink's experiments (on birds), when the daily cycle of sleep and wakefulness was disrupted by changing external conditions (constant stay in a brightly lit room) and a state of readiness for sleep arose, hypnotic doses turned out to be significantly smaller than the doses causing daytime sleep under normal conditions (the difference for urethane is 2 times, chloral hydrate 8 times, veronal 8-16 times, somnifen 32 times). Various authors note cases where a single dose of a hypnotic could produce good sleep on the subsequent night without drowsiness occurring during the period of daytime wakefulness. If in these cases, besides psychological factors (suggestion), pharmacological action also takes part, they are good examples of the dependence of the hypnotic effect on the daily periodicity of body functions. Thus, the analysis of the hypnotic action of hypnotics is complicated by the fact that interacting exogenous and endogenous factors take part in it. The nature of the action of individual hypnotics can, however, be determined indirectly by the effect they exert on the body when prescribed for other indications. Many hypnotics are prescribed as sedatives (mainly the 1st group according to Renner's classification), lowering the excitability of motor functions (luminal), painkillers (luminal, chloral hydrate, nirvanol, etc.), etc. These indications determine the choice of hypnotics in individual cases, as well as the combination of hypnotics with other agents (see above). The question of the pharmacological features of the hypnotic action is closely related to the methodology of testing hypnotics. The Utrecht Pharmacological Institute recently developed a method for testing hypnotics on birds sleeping in a certain position (on a branch or on a perch). Disruption or loss of this postural reflex, occurring with an increase in the dose of a hypnotic, indicates the onset of a general narcotic effect. According to Hondelink, the narcotic dose exceeds the hypnotic dose for chloralose by 10 times, for veronal by 10 times, for chloral hydrate and somnifen by 8 times, and only by 3-4 times for urethane, which thus, as in clinical testing, is not so much a hypnotic as a narcotic agent. In distinguishing the hypnotic effect from the narcotic effect in humans, one should be guided by somatic changes characteristic of physiological sleep, the possibility of awakening upon appropriate stimulation, etc. In connection with the greater refinement of the questions of the physiology and pathology of sleep, the localization of functions associated with wakefulness and sleep (Mautner, Economo, and others), studies have arisen on the localization of the action of various hypnotics. A number of authors localize the narcotic action of some substances predominantly in the cortex (alcohol, amylene hydrate, paraldehyde, chloral hydrate, bromine), and others in the stem part of the brain (veronal, luminal, urethane, chloretone, nirvanol, somnifen). Such a "physiological" or "pharmacological" classification cannot be considered generally accepted; its discrepancy with the "clinical" classification of Renner used above should be noted, the first group of which (according to Wuth and others) consists of hypnotics acting predominantly on the cortex. It should be noted here that the distribution of individual hypnotics in Renner's classification raises doubts, for example, the classification of chloral hydrate into the group of hypnotics causing late sleep onset, etc. The widespread use of hypnotics in medical practice, the infatuation of doctors with new drugs generously produced and advertised abroad by various firms, and the mass consumption of hypnotics by patients themselves without a doctor's prescription have long aroused justified protest. Each case of sleep disturbance must be carefully diagnosed, since it is often associated with circulatory disorders or other disturbances that are subject to causal treatment, or finally with an improper lifestyle of the patient. It should also be pointed out that even in cases of so-called essential insomnia, physiotherapeutic measures are often more preferable and effective. In cases of poisoning with hypnotics, characterized by a state of deep anesthesia with more or less sharply expressed disorders of the blood circulation (drop in blood pressure) and respiration (weak, superficial respiration or Cheyne-Stokes respiration), it is recommended: 1) gastric lavage and administration of a laxative salt through a probe (preferably in combination with charcoal as an adsorbent); 2) cleansing enema; 3) intravenous administration of 100 cm³ of a 25-40% grape sugar solution (or instead of the 4th measure, subcutaneous administration of 500.0 of a 5% solution); 4) subcutaneous administration of 600-800 cm³ of physiological saline solution (1-2 hours after the third measure); 5) administration of cardiovascular agents (digalen, strophanthin, adrenaline, sympatol), especially those simultaneously exciting the central nervous system (caffeine, camphor, atropine); 6) warming the body (heating pads, diathermy, in particular of the renal region to improve diuresis); 7) prevention of complications, especially pulmonary ones (mustard plaster, wraps, etc.); 8) some authors recommend lumbar puncture, since in a number of poisoning cases an increased pressure of the cerebrospinal fluid was detected; 9) in case of respiratory insufficiency, inhalations of O₂ with CO₂.