Tranquilizers are psychotropic medicinal agents, possessing ability to eliminate or relieve neurotic manifestations, fear, anxiety, emotional tension, sleep disorders.
In 1946 the first modern tranquilizer – meprobamate was synthesized and in 1955 it was introduced into clinical practice. However, the year 1960 is the most significant in history of tranquilizers, since this year derivatives of benzodiazepine (chlordiazeloxid and diazepam in particular), superior in efficacy all preceding tranquilizing drugs, possessing expressed psychotropic and equal in balance somatotropic action, which is realized through normalization of vegetative disorders became used. Over the last 20 years throughout the world more than 500 million of people have used tranquilizers. In the USA at the beginning of 80-ties, annually 800 tons of tranquilizers were received. It is known that more than 60% of patients were using tranquilizers without doctor’s prescription.
There exist several approaches to classification of tranquilizers:
According to chemical structure basic groups of tranquilizers are:
1) derivatives of glycerol (meprobamat);
2) derivatives of benzodiazepine (elenium, diazepam, lorazepam, phenazepam, klonazepam, alprazolam);
3) derivatives of trimetoxybenzoic acid (trioxazin);
4) derivatives of azapiron (buspiron);
5) derivatives of another chemical structure (amizil, hydroxizin, oxylidin, mebicar, mexydol).
Considering duration of action:
1) of long-term action (excretion half life more than 20 hours): chloriazepoxid, diazepam, clorazelat;
2) of medium action (excretion half life – from 5 to 20 hours): lorazepam, oxazepam, alprazolam;
3) of short-term action (excretion half life – less than 5 hours): triazolam
By pharmacodynamic principle:
1) agents with anxiolytic action predominantly: diazepam, chlordiazepoxid, lorazepam, alprazolam, klonazepam, phenazepam;
2) agents with hypnotic effect predominantly: triazolam, temazepam, flunitrazepam, midazolam, brotizolam, diazepam;
3) agents with anti-convulsive action predominantly: klonazepam, diazepam, nitrazepam, phenazepam, chlodiazepoxid;
4) agent of neuroleptic properties: klozalin:
5) agent with anti-depressive activity: alprazolam.
Tranquilizers act mainly on the structures of limbic system and hypothalamus, that is on the structures, connected with regulation of emotional functions (these structures are called “palesic circle палезийный круг). Basis mechanism of benzodiazepine action is directed at non-selective bounding with all subtypes of GABA-receptor complex, opening of chlorine canals and potentiating inhibitory processes in CNS.
It is widely believed, that benzodiazepines cause inhibitory effect as for neurons of “system of punishment” (that is system on which subjective sensations of negative stimuli depend).
Main effect of tranquilizers is anxiolytic one (anti-anxiety). Anxiolytic action is manifested in the decrease of anxiety, fear (anti-fobia action), mental tension.
Sedative (calming) action is manifested in the decrease of psycho-motor excitability, daily activity, decrease of concentration of attention, decrease of reaction rate, etc.
Hypnotic effect is manifested in facilitation of sleep onset and increase of its duration. Inhibiting action of tranquilizers on the CNS causes mutual potency of effects of hypnotic, narcotic and analgesic means.
Muscle relaxing effect (relaxation of skeletal musculature) while using tranquilizers as a rule is positive factor to relive tension, excitation, motor one including. Together with this, obtained effect may limit usage of agents in patients, whose activity requires quick psychic and physical reaction. It is necessary to take into account, that muscle relaxing action may be manifested in flaccidity, weakness, etc.
Anti-convulsive action is manifested in oppression of epileptic activity spreading, appearing in epileptogenic foci.
In the spectrum of action of some tranquilizers there is distinguished vegetate-stabilizing effect (normalization of functional activity of autonomous nervous system). Clinically this effect may be manifested in decrease of vegetative manifestations of anxiety (tachycardia, arterial hypertension, perspiration, disturbances in functioning of digestive system, etc.).
Usage of tranquilizers in clinical practice is connected in the main with their anti-anxiety action. Though, tranquilizers may have all pharmacologic properties, typical for this group, expressiveness and ratio of effects in various agents may be different; this causes specific features of their usage in clinical practice.
Indications to their usage are various:
1) neurotic, borderline states with phenomena of tension, anxiety, alarm, fear;
2) psychotic states (depressive anxiety, affective-delusive, etc.) in combination with antidepressants, neuroleptics;
3) sleep disorders;
4) abstinence disorders in chronic alcoholism, etc. toxicomania, treatment of meta-alcoholic psychoses;
5) premedication before narcosis, being a component of combined narcosis;
6) psychosomatic diseases (ulcer of the stomach or duodenum, etc.);
7) cardio-vascular disturbances with sympatho-adrenal tendency (practically all tranquilizers have a mild sympatholitic and moderate hypotensing effects;
8) anti-paroxismal and anti-convulsive action in particular;
9) antihistamine, antiemetic, anti-itching action
One of the practically significant properties of tranquilizers is their ability to increase the threshold of pain sensitivity, which is manifested in such agents as diazepam, phenazepam, mebikar, making their expediency in a complex treatment of different pain syndromes.
Contraindications (mainly for BZD): severe myasthenia, porphyria, increased sensitivity to BZD.
Due to a wide usage of tranquilizers in clinical practice and their popularity in population, there exists risk of side-effects development. All side effects of tranquilizers may be divided into several groups:
1) possible inhibition of CNS in simultaneous taking with anti-convulsive agents, alcohol, barbiturates.
2) possible accumulation of medicinal agent with active metabolites in elderly patients and those of somatically aggravated patients (BZD in patients with marked anti-sclerotic changes of the brain may cause state of torpor, to provoke hallucinatory (delirious) psychoses, and in case of a prolonged usage – marked muscle relaxation with the following hypodynamic complications);
3) paradoxical reactions (excitation, aggressiveness, euphoria);
4) disorder of cognitive processes (memory decrease, concentration decrease), driving car is not recommended;
5) withdrawal syndrome (symptom complex of anxiety disorder in a more severe form), as an index of physical dependence;
6) psychic dependence ( actual for BZD), development of so-called benzodiazepine toxicomania (more often in persons with psychopathic features of personality, inclined to formation of dependences, in persons suffering from alcoholism and narcomania);
7) risk of abuse (sufficiently great number of suicidal attempts of poisoning with BZD, with lethal outcome including);
8) it is not well to bear in mind using tranquilizers during pregnancy (especially in the first trimester), in the period of lactation. This is connected with the fact, that tranquilizers freely penetrate through placenta barrier and may inhibit respiratory activity of a child as well as to impair correct development of a fetus (“bendzodiazepine children”). Among side-effects of benzodiazepines, taken during pregnancy and lactation are hypothermia, hypotonia and inhibition of respiration in a fetus, as well as physical dependence and withdrawal syndrome in the newborns.
9) in case of sudden withdrawal of BZD agents, after prolonged usage, tremor, anxiety, excitation, convulsions may occur. BZD dose should be lessened gradually.
10) parenteral introduction of BZD inhibits respiratory center, especially in combination with neuroleptics, antidepressants, hypnotic and anesthetic means.
It should be remembered, that treatment with tranquilizers may be carried out under doctor’s supervision, as usage of tranquilizers may lead to habituation development, as well as to formation of drug dependence and development of withdrawal syndrome. Because of a high risk of habituation development, taking tranquilizers by children and adolescents before 18 years of age is justified only in exceptional cases, in case of justified indications; therewith length of treatment course must be minimal.
Due to weakening of concentration and decrease of psychomotor reactions rate, administration of tranquilizers to out-patients should be restricted, especially to the patients, whose work requires increased concentration and high-rate psychic and physical reaction (drivers, dispatchers, etc.).
Administering tranquilizers for treatment of anxious disturbances, principle of gradual rise of dose – from minimally effective to optimal in order to achieve therapeutic effect (acute states are the exception) should be observed. Course of treatment must be as short as possible, after this repeated assessment of patient’s state is necessary, to decide on necessity of following therapy. In case, when prolonged treatment is necessary (up to several months), treatment course is recommended to be carried out by intermitted method: cessation using drug for some days’ period with the following administration of the same individually selected dose. To decrease risk of development of withdrawal syndrome when drug is withdrawn, dose is recommended to be reduced gradually.
It should be noted, that situation with inadequate and sometimes ignorant usage of tranquilizers, especially those, administered by internists, is relevant. Uncontrolled usage of BZD, in particular phenazepam – the cheapest home tranquilizer, makes one to remember, that this agent is one of the strongest in its anxiolytic activity (it does not give in to some neuroleptics), but leads to the same consequences. So, this agent, as well as other BZD being over-the-counter drug, kept at home in a first-aid-set is inadmissibly. The same situation is with hypnotic agents (uncontrolled and long-term taking of reladorm, elenium, imovan, ivadal, and other medicines practically always leads to poorly-curable forms of sleeplessness). Widely used application of drugs of vegetative origin – phyto-tranquilizers, (Novopassit, Persen, etc.) which have sedative effect and evident positive action (small toxicity, absence of addiction, etc.) causes negative consequences, connected with self-treatment or inadequate treatment of states, requiring psychiatric help exclusively.