The barbiturates are a group of drugs that are derived barbituric acid. These drugs act on the central nervous system as sedatives and are capable of generating a wide variety of brain effects.
In fact, the action of barbiturates on the central nervous system can lead from mild sedation to total anesthesia. The effect caused depends mainly on the dose of the drug consumed.
Although the main action of barbiturates is sedation, these drugs are also used as anxiolytics, hypnotics and anticonvulsants since they are capable of performing such effects at the brain level.
Likewise, barbiturates are characterized by causing analgesic effects on the organism, although such effects tend to be weak and not very permanent, which is why they are not usually used for therapeutic purposes of anesthesia.
At present, there is a notable controversy about the role of barbiturates as psychotherapeutic drugs. These substances have a high potential for addiction, both physical and psychological, and generate a large number of side effects.
In fact, during the last few years, barbiturates have been displaced in the treatment of conditions such as anxiety and insomnia due to benzodiazepines, since the latter are safer drugs with higher efficacy rates.
In this article we review the main characteristics of barbiturates. Its mechanism of action is explained, the effects generated at the brain level, as well as the toxicity mechanisms of these drugs.
Characteristics of barbiturates
Barbiturates are a family of drugs that come from barbituric acid, a substance that was first synthesized in 1864 by the German chemist Adolf von Baeyer.
The synthesis of barbituric acid was carried out through the combination of urea (a product obtained from animal waste) and malonic acid (an acid derived from apples).
Through the mixture of these two substances an acid was obtained which Baeyer and his collaborators named as barbituric acid.
Originally, barbituric acid was not a pharmacologically active substance, so it was not used as a drug. However, after its appearance a large number of chemists began to investigate a wide variety of barbituric acid derivatives.
Initially, no therapeutic value was found for barbituric acid derivatives, until in 1903, two German chemists, Emil Fischer and Josef von Mering, discovered sedative properties in the substance. As a result of that moment, the substance began to be commercialized under the name of Veronal.
Currently, barbiturates are marketed through the pentothal, which is used to induce anesthesia and by the name of phenobarbital as an anticonvulsant drug.
However, both drugs are nowadays in some disuse due to the high addiction produced by their consumption and the limited range of beneficial effects of barbiturates.
Mechanism of action
Barbiturates are fat-soluble substances that dissolve easily in body fat. Through its administration in the body, the substance reaches the bloodstream.
Being a psychoactive substance, barbiturates travel through the blood to the brain regions. They easily cross the blood-brain barrier and enter specific regions of the brain.
At the cerebral level, barbiturates are characterized by multiple actions on their target cell, that is, on neurons.
Action on GABA
First, barbiturates stand out by binding to the gamma-aminobutyloid receptor ( GABA ), the brain’s main inhibitory neurotransmitter. When coupled to these receptors, barbiturates produce a calcium influx that hyper-polarizes the neuron and blocks the nerve impulse.
In this sense, barbiturates act as nonspecific depressants of the central nervous system, producing effects both at the pre-synaptic level and at the post-synaptic level.
At present, the specific site of binding of barbiturates on the GABA receptor is not known. However, it is known to be different from benzodiazepines.
Fluamecenyl, a competitive antagonist drug of benzodiazepines, has no antagonistic activity against barbiturates. This fact shows that both substances have different binding points.
On the other hand, radiological studies in which GABA and benzodiazepines labeled with barbiturates are administered together have shown that the latter increase the binding to the GABA receptor.
This last assessment is important when it comes to justifying the significant increase in toxicity when the consumption of barbiturates is combined with other psychoactive substances.
Action on glutamate
Barbiturates are characterized by not acting only on GABA receptors, but also affect the functioning of glutamate. Specifically, the barbiturates are coupled to the glutamate receptors AMPA, NMDA and kainate receptors.
The role of glutamate in the brain is antagonistic to that of GABA. That is, instead of inhibiting, it excites the functioning of the central nervous system.
In this case, the barbiturates selectively antagonize the AMPA and kainate receptors, which is why they also act as depressants by reducing the excitability of glutamate.
The voltage-dependent sodium channels contribute to the depolarization of the neuron to generate the electrical impulses. In fact, certain studies show that the activity of barbiturates is related to these channels, producing contractions well above those considered as therapeutic.
Finally, it should be noted that barbiturates influence the voltage dependent channels of potassium, which affect the re-polarization of the neuron. In this sense, it has been observed that some barbiturates inhibit the channels at very high concentrations, which causes an excitation of the neuron.
This factor about the activity of barbiturates could explain the highly convulsive effect generated by some of these drugs, such as methohexital.
Barbiturates are characterized by various pharmacological actions. Due to their different mechanisms of action, these substances do not perform a single activity at the brain level.
On the one hand, barbiturates are antiepileptic drugs due to their anticonvulsant actions, which do not seem to reflect the nonspecific depression they generate in the central nervous system.
On the other hand, although barbiturates lack analgesic activity, they do produce substances that can be used as sedatives or anxiolytics. Although for the treatment of anxiety they have been replaced by benzodiazepines since they are safer and more effective.
In this sense, barbiturates are drugs that are currently indicated for the treatment of acute seizures due to epilepsy, cholera, eclampsia, meningitis, tetanus and toxic reactions to local anesthetics and strychnine.
However, the therapeutic adequacy of barbiturates for the treatment of acute seizures does not extend to all drugs of this type, with phenobarbital being the only barbiturate recommended.
On the other hand, it is noteworthy that barbiturates are used today to treat strokes and as an anticonvulsant drug in neonates, since they are effective drugs in such cases.
In fact, unlike what happens with the treatment of anxiety disorders, where benzodiazepines have left the barbiturates in disuse, phenobarbital is the drug of choice among neonatologists for anticonvulsant purposes, relegating benzodiazepines to a second level.
Barbiturates vs benzodiazepines
The panorama about barbiturates as tools of pharmacotherapy has changed radically as a result of the appearance of benzodiazepines.
In fact, before benzodiazepines emerged as anxiolytic drugs, barbiturates were the main drugs to treat anxiety and sleep disturbances.
However, the side effects, the addiction and the dangerousness that the consumption of barbiturates implies, motivated the investigation of new pharmacological options to treat this type of affections.
In this sense, the benzodiacpeinas are today much safer, more effective and suitable drugs to treat anxiety disorders. Likewise, benzodiazepines are currently used more frequently for the treatment of sleep disturbances.
The main differences between both drugs are the following.
Mechanism of action
The mechanism of action of barbiturates is characterized by the coupling to GABA receptors, increasing the intracellular chlorine entry, as well as the action on glutamate, reducing its activity.
This fact induces sedation, euphoria and other mood disorders. In addition, the non-specific depressant action generated by barbiturates causes respiratory depression and, if high doses are consumed, can cause cardiovascular depression and death.
The mechanism of action of benzodiazepines, on the other hand, is characterized by specific binding to GABA receptors, generating a controlled entry of chlorine into the interior of the neuron, and hyper-polarization or neuronal inhibition.
The consumption of benzodiazepines at therapeutic doses also inhibits neurons through unknown mechanisms not linked to the action of GABA. The main effects of these substances are sedation and relaxation of the skeletal muscle.
Likewise, overdoses of benzodiazepines cause a minor inhibitory effect on the central nervous system, resulting in safer drugs.
Currently, barbiturates are only indicated for the treatment of certain types of epileptic seizures and as anticonvulsant drugs in neonates.
Benzodiazepines for their part are drugs indicated for the treatment of anxiety and agitation, psychosomatic diseases and delirium tremens. Likewise, they are used as muscle relaxants and anticonvulsant and sedative drugs.
The side effects caused by the consumption of barbiturates are usually large and serious. These medications usually cause dizziness, loss of consciousness, dysarthria, ataxia, paradoxical stimulation due to disinhibition of behavior, and depression of the nervous system, respiratory function and cardiovascular system.
In contrast, the side effects of benzodiazepines are more limited and lighter. These drugs can cause dizziness, loss of consciousness, ataxia, behavioral disinhibition and dermatitis.
Tolerance and dependence
The consumption of barbiturates causes tolerance and dependence with ease. This means that the body increasingly requires higher doses to experience the desired effects and, subsequently, requires the consumption of the substance to function properly (addiction).
The dependence of barbiturates is similar to that of chronic alcoholism. When a person dependent on barbiturates suppresses consumption, they usually experience a withdrawal syndrome characterized by seizures, hyperthermia and delirium.
Benzodiazepines, on the other hand, only generate dependence if they are consumed chronically and at high doses. As with barbiturates, the suppression of benzodiazepine consumption may produce a withdrawal pattern similar to that of chronic alcoholism.
Barbiturates interact with more than 40 drugs due to the enzymatic alteration they produce in the liver. In contrast, benzodiazepines only experience a summing effect with alcohol.
Toxicity of barbiturates
Barbiturates are drugs that can be toxic through different mechanisms. The main ones are:
The main toxic factor of barbiturates lies in the amount of consumption. In this sense, the lethal dose of these drugs depends on the duration of the action.
For example, in butabarbital, a plasma dose of 2-3 g / mL produces sedation, one of 25 induces sleep and a concentration greater than 30 g / mL can produce coma.
However, excessive doses of any type of barbiturate produce coma and death on the consumer.
Barbiturates are highly liposoluble drugs, which can cause the accumulation of the substance in adipose tissue. This fact can be a source of toxicity when these reserves are mobilized.
Mechanism of action
From a toxicological point of view, barbiturates generate neurotoxicity due to an increase in the entry of calcium into the neuron.
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Specifically, it is postulated that barbiturates could act in the mitochondria of neurons, causing an inhibition that would lead to a reduction in the synthesis of ATP.
Finally, barbiturates are enzymatic inducers, so they are drugs that increase the metabolism of drugs such as some hormonal antagonists, antirrhythmics, antibiotics, anticoagulants, coumarin, antidepressants, antipsychotics, immunosuppressants, corticosteroids and estrogens.