Barbiturates are a group of drugs that are derived from barbituric acid . These drugs act on the central nervous system as sedatives and are capable of generating a wide variety of brain effects.
The action of barbiturates on the central nervous system can cause anything from mild sedation to total anesthesia. The effect caused mainly depends 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, as they are able to perform these effects at the brain level.
Likewise, barbiturates are characterized by causing analgesic effects in the body, although these effects tend to be weak and not very permanent, therefore, they are generally not used for the therapeutic purposes of anesthesia.
Currently, there is notable controversy over 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 due to benzodiazepines, since the latter are safer drugs with higher rates of effectiveness.
Barbiturates are a family of drugs derived from barbituric acid, a substance first synthesized in 1864 by German chemist Adolf von Baeyer.
The synthesis of barbituric acid was carried out by combining urea (a product obtained from animal waste) and malonic acid (an acid derived from apples). By mixing these two substances, an acid was obtained that Baeyer and his collaborators called barbituric acid.
At its origin, barbituric acid was not a pharmacologically active substance and therefore was not used as a medicine. However, after its emergence, 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 1903, two German chemists, Emil Fischer and Josef von Mering, discovered sedative properties in the substance. After that moment, the substance began to be marketed under the name of Veronal.
Currently, barbiturates are marketed through pentothal, which is used to induce anesthesia, and by the name of phenobarbital as an anticonvulsant drug.
However, both drugs have remained out of use today due to the high addiction produced by their consumption and the limited range of beneficial effects that barbiturates have.
Mechanism of action
Barbiturates are fat-soluble substances that dissolve easily in body fat. Through its administration into the body, the substance reaches the bloodstream.
Being a psychoactive substance, barbiturates travel through the blood to regions of the brain. They easily cross the blood brain barrier and enter specific regions of the brain.
At the brain level, barbiturates are characterized by having several actions on their target cell, that is, on neurons.
Action in GABA
First, barbiturates stand out for binding to the gamma-aminobutyl (GABA) receptor, the main inhibitory neurotransmitter in the brain. When coupled to these receptors, barbiturates produce an influx of calcium that hyperpolarizes the neuron and blocks the nerve impulse.
In this sense, barbiturates act as nonspecific depressants of the central nervous system, producing effects at both the presynaptic and postsynaptic levels.
Currently, the specific binding site of barbiturates on the GABA receptor is unknown. However, it is known to be different from that of benzodiazepines.
Fluamecenil, a competitive benzodiazepine antagonist drug, does not exhibit antagonist activity against barbiturates. This fact shows that both substances have different attachment points.
On the other hand, radiological studies in which GABA and barbiturate-labeled benzodiazepines are co-administered have shown that they enhance binding to the GABA receptor.
This last assessment is important in justifying the significant increase in toxicity when the consumption of barbiturates is combined with other psychoactive substances.
Action on glutamate
Barbiturates also affect how glutamate works; they are coupled to the glutametergic receptors AMPA, NMDA and kainate receptor.
The role of glutamate at the brain level is antagonistic to that of GABA. That is, instead of inhibiting, it stimulates the functioning of the central nervous system.
In this case, barbiturates act as antagonists of AMPA and kainate receptors selectively, and also act as depressants, reducing glutamate excitability.
Voltage-dependent sodium channels contribute to the depolarization of the neuron to generate electrical impulses. In fact, some studies show that barbiturate activity is related to these channels, producing contractions well above those considered therapeutic.
Finally, it should be noted that barbiturates influence voltage-dependent potassium channels, which affect neuron repolarization. In this sense, it has been observed that some barbiturates inhibit the channels at very high concentrations, which causes neuron excitation.
This factor on the activity of barbiturates may explain the highly convulsive effect generated by some of these drugs, such as methohexital.
Barbiturates are characterized by having several pharmacological actions. Due to their different mechanisms of action, these substances do not carry out a single activity at the brain level.
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, although barbiturates lack analgesic activity, they are substances that can be used as sedatives or anxiolytics. Although for the treatment of anxiety they have been replaced by benzodiazepines, as they are safer and more effective.
In this sense, barbiturates are drugs currently indicated for the treatment of acute crises 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.
On the other hand, it should be noted that today barbiturates are used in the treatment of stroke and as an anticonvulsant in neonates, since they are effective drugs in these cases.
In fact, contrary to what happens with the treatment of anxiety disorders, where benzodiazepines used barbiturates, phenobarbital results in a drug of first choice among neonatologists for anticonvulsant purposes, relegating benzodiazepines to the background.
Barbiturates are drugs that can be toxic through different mechanisms. The main ones are:
The main toxic factor of barbiturates is in the amount of consumption.
For example, in butabarbital, a plasma dose of 2-3 g/mL produces sedation, one in 25 induces sleep, and a concentration greater than 30 g/mL can cause coma.
However, excessive doses of any type of barbiturate cause coma and death in the consumer.
Barbiturates are highly fat-soluble drugs that can cause the substance to accumulate 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 the entry of calcium into the neuron.
Barbiturates can act on the mitochondria of neurons, causing an inhibition that would lead to a reduction in ATP synthesis.
Finally, barbiturates are enzyme inducers, therefore, they are drugs that increase the metabolism of drugs such as some hormonal antagonists, antirhythmics, antibiotics, anticoagulants, coumarins, antidepressants, antipsychotics, immunosuppressants, corticosteroids and estrogen.
Barbiturates vs benzodiazepines
The image of barbiturates as tools of pharmacotherapy has changed radically due to the emergence of benzodiazepines.
In fact, before benzodiazepines emerged as anti-anxiety drugs, barbiturates were the main drugs for treating anxiety and sleep disorders.
However, the side effects, addiction and danger of consuming barbiturates led to the investigation of new pharmacological options for the treatment of this type of condition.
In this sense, benzodiazepines are nowadays much safer, more effective and suitable drugs to treat anxiety disorders. Likewise, benzodiazepines are currently used most often in the treatment of sleep disorders.
The main differences between the two drugs are as follows:
Mechanism of action
The mechanism of action of barbiturates is characterized by the coupling to GABA receptors, increasing the entry of intracellular chlorine, as well as the action on glutamate, reducing its activity.
This fact induces sedation, euphoria and other mood disorders. In addition, the nonspecific depressant action generated by barbiturates causes respiratory depression and, if high doses are consumed, can lead to 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 neuron and hyperpolarization or neuronal inhibition.
Consumption of benzodiazepines at therapeutic doses also inhibits neurons by unknown mechanisms not linked to GABA action. The main effects of these substances are sedation and skeletal muscle relaxation.
Likewise, overdoses with benzodiazepines cause a lesser inhibitory effect on the central nervous system, resulting in safer medications.
Currently, barbiturates are indicated only for the treatment of certain types of epileptic seizures and as anticonvulsant drugs in neonates.
Benzodiazepines, however, are drugs indicated for the treatment of anxiety and agitation, psychosomatic illnesses and delirium tremens. Likewise, they are used as muscle relaxants and anticonvulsants and sedatives.
The side effects caused by the consumption of barbiturates are usually wide-ranging and severe. These drugs often cause dizziness, loss of consciousness, dysarthria, ataxia, paradoxical stimulation by disinhibition of behavior, and depression of the nervous system, respiratory function, and cardiovascular system.
On the other hand, the side effects of benzodiazepines are more limited and milder. These medications can cause dizziness, loss of consciousness, ataxia, behavioral disinhibition, and dermatitis.
Tolerance and dependence
Consumption of barbiturates easily causes tolerance and dependence. This means that the body requires higher and higher doses to experience the desired effects, and subsequently requires consumption of the substance to function properly (dependence).
The barbiturate dependence table is similar to that for chronic alcoholism. When a barbiturate-dependent person suppresses consumption, they usually experience a withdrawal syndrome characterized by seizures, hyperthermia, and delusions.
Benzodiazepines, on the other hand, only generate dependence if consumed chronically and in high doses. As with barbiturates, suppression of benzodiazepine consumption can produce a withdrawal similar to chronic alcoholism.
Barbiturates interact with more than 40 drugs due to the enzymatic change they produce in the liver. On the other hand, benzodiazepines experience only a sum effect with alcohol.
- Asano T, Ogasawara N. Chloride-dependent stimulation of GABA and benzodiazepine receptor binding by barbiturates. Brain Res 1981; 255: 212-216.
- Chang, Suk Kyu. Hamilton, Andrew D. (1988). “Molecular recognition of biologically interesting substrates: Synthesis of an artificial receptor for barbiturates employing six hydrogen bonds”. Journal of the American Chemical Society . 110(4): 1318-1319.
- Neal, MJ (February 1965). »The hyperalgesic action of barbiturates in rats». British Journal of Pharmacology and Chemotherapy . 24(1): 170-177.
- Neuroscience for Children – Barbiturates »Archived in original June 16, 2008. Retrieved 6/2/2008.
- DG Vesce Nicholls, WH Soine S. Duan et. to CM Anderson, BA Norquist. Barbiturates induce mitochondrial depolarization and potentiate excitotoxic neuronal death. the Journal of Neuroscience, November 2002; 22(21): 9203-9209.
- Teichberg VI, Tal N., Goldberg O. and Luini A. (1984) Barbiturates, alcohols and CNS excitatory neurotransmission: specific effects on kainate and quisqualate receptors. Brain Res., 291, 285-292.