BARBITURATES: CHARACTERISTICS, MECHANISM OF ACTION AND EFFECTS - ARTE - 2024

The barbiturates are a group of drugs derived from barbituric acid. These drugs act on the central nervous system as sedatives and are capable of generating a wide variety of cerebral effects.

The action of barbiturates on the central nervous system can cause from mild sedation to total anesthesia. The effect caused depends largely 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 carrying out such effects at the brain level.

Likewise, barbiturates are characterized by causing analgesic effects on the body, although such effects are usually weak and not very permanent, so they are not usually used for therapeutic anesthesia purposes.

At present there is considerable 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, in recent years, barbiturates have been displaced in the treatment of conditions such as anxiety and insomnia by benzodiazepines, since the latter are safer drugs with higher rates of efficacy.

History

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 that Baeyer and his collaborators named as barbituric acid.

Barbituric acid molecule. Source: Arrowsmaster

In its origin, 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 derivatives of barbituric acid.

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 marketed under the name Veronal.

Currently, barbiturates are marketed through pentothal, which is used to induce anesthesia, and under the name phenobarbital as an anticonvulsant drug.

However, both drugs have now fallen into disuse due to the high addiction produced by their consumption and the limited range of beneficial effects that barbiturates present.

Mechanism of action of barbiturates

Barbiturates are fat-soluble substances that dissolve easily in the body's 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 brain level, barbiturates are characterized by having multiple actions on their target cell, that is, on neurons.

Action on GABA

First, barbiturates stand out for binding to the gamma-aminobutic receptor (GABA), the main inhibitory neurotransmitter in the brain. 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 binding site of barbiturates on the GABA receptor is not known. However, it is known to be different from benzodiazepines.

Fluamecenyl, a competitive antagonist drug for benzodiazepines, does not have antagonistic activity against barbiturates. This fact shows that both substances have different binding points.

On the other hand, radiological studies in which GABA and barbiturate-labeled benzodiazepines are administered together have shown that the latter increase binding to the GABA receptor.

This last observation 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 also affect the way glutamate works; they bind to glutametergic receptors AMPA, NMDA, and kainate receptors.

The role of glutamate at the brain level is antagonistic to that of GABA. That is, instead of inhibiting, it excites the functioning of the central nervous system.

In this case, barbiturates act as antagonists of AMPA and kainate receptors in a selective way, therefore they also act as depressant substances by reducing the excitability of glutamate.

Structural formula of L-Glutamate. Source: Jü

The voltage-gated 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 therapeutic.

Finally, it should be noted that barbiturates influence voltage-gated potassium channels, 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, a fact that causes an excitation of the neuron.

This factor regarding the activity of barbiturates could explain the highly convulsive effect generated by some of these drugs, such as methohexital.

Effects edit

Barbiturates are characterized by presenting various pharmacological actions. Due to their different mechanisms of action, these substances do not carry out a single activity at the brain level.

Antiepileptic drugs

On the one hand, barbiturates are antiepileptic drugs thanks to their anticonvulsant actions, which do not seem to reflect the nonspecific depression they generate in the central nervous system.

Sedatives or anxiolytics

On the other hand, despite the fact that barbiturates lack analgesic activity, they do result in 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 suitability of barbiturates for the treatment of acute seizures does not extend to all drugs of this type, with phenobarbital being the only recommended barbiturate.

Others

On the other hand, it should be noted 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, contrary to what happens with the treatment of anxiety disorders, where benzodiazepines have left barbiturates in disuse, phenobarbital is the first-choice drug among neonatologists for anticonvulsant purposes, relegating benzodiazepines to the background.

Barbiturate toxicity

Assessment of damages resulting from drug use. Source: Nutt, David, Leslie A King, William Saulsbury, Colin Blakemore

Barbiturates are drugs that can be toxic through different mechanisms. The main ones are:

Administered dose

The main toxic factor of barbiturates lies in the amount of consumption.

For example, in butabarbital, a plasma dose of 2-3 g / mL produces sedation, a plasma dose of 25 induces sleepiness, and a concentration greater than 30 g / mL can produce coma.

However, excessive doses of any type of barbiturate produce coma and death in the consumer.

Pharmacokinetics

Barbiturates are highly fat-soluble drugs, a fact that can cause the accumulation of the substance in adipose tissue. This 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 calcium influx into the neuron.

Barbiturates could act on the mitochondria of neurons, causing an inhibition that would lead to a reduction in ATP synthesis.

Interaction

Finally, barbiturates are enzyme inducers, so they are drugs that increase the metabolism of drugs such as some hormonal antagonists, antirrhythmics, antibiotics, anticoagulants, coumarinz, antidepressants, antipsychotics, immunosuppressants, corticosteroids and estrogens.

Barbiturates vs benzodiazepines

The landscape of barbiturates as tools of pharmacotherapy has changed radically with the advent of benzodiazepines.

In fact, before benzodiazepines emerged as anxiolytic drugs, barbiturates were the main drugs to treat anxiety and sleep disorders.

However, the side effects, the addiction and the danger associated with the consumption of barbiturates, motivated the investigation of new pharmacological options to treat these types of conditions.

In this sense, benzodiazepines are nowadays much safer, more effective and adequate drugs to treat anxiety disorders. Likewise, benzodiazepines are currently used more frequently for the treatment of sleep disorders.

The main differences between the two drugs are the following:

Mechanism of action

The mechanism of action of barbiturates is characterized by their coupling to GABA receptors, increasing intracellular chlorine entry, as well as the action on glutamate, reducing its activity.

This fact induces sedation, euphoria, and other mood disturbances. In addition, the non-specific depressant action generated by barbiturates causes respiratory depression and, if high doses are consumed, it can cause cardiovascular depression and death.

The mechanism of action of benzodiazepines is characterized by specific binding to GABA receptors, generating a controlled influx of chlorine into the neuron, and hyperpolarization or neuronal inhibition.

The use 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, benzodiazepine overdoses cause a minor inhibitory effect on the central nervous system, resulting in safer drugs.

Indications

At present, barbiturates are only indicated for the treatment of certain types of epileptic seizures and as anticonvulsant drugs in neonates.

Benzodiazepines are drugs indicated for the treatment of anxiety and agitation, psychosomatic illnesses and delirium tremens. Likewise, they are used as muscle relaxants and anticonvulsant and sedative drugs.

Side effects

The side effects caused by the consumption of barbiturates are usually wide and serious. These drugs often cause dizziness, loss of consciousness, dysarthria, ataxia, paradoxical stimulation due to disinhibition of behavior, and depression of the nervous system, respiratory function, and the cardiovascular system.

In contrast, the side effects of benzodiazepines are more limited and mild. These drugs can cause dizziness, loss of consciousness, ataxia, behavioral disinhibition, and dermatitis.

Tolerance and dependency

The consumption of barbiturates causes tolerance and dependence easily. 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 picture of dependence on 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 delusions.

On the other hand, benzodiazepines only generate dependence if they are consumed chronically and at high doses. As with barbiturates, withdrawal of benzodiazepines can produce a withdrawal pattern similar to that of chronic alcoholism.

Drug interactions

Barbiturates interact with more than 40 drugs due to the enzymatic alteration that they produce in the liver. In contrast, benzodiazepines only experience a summative effect with alcohol.

References

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