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Structural formula of barbituric acid: parent compound of barbiturates.

Barbiturates are salts and derivatives of barbituric acid . In the pharmaceutical sense, they are barbituric acid derivatives with a noteworthy effect on GABA A receptors and thus belong to the group of GABAergics . They usually have a depressant effect on the central nervous system. For many decades from the early 20th century onwards, barbiturates were the epitome of sleeping pills . Due to undesirable side effects, barbiturates have not been approved as sleeping pills in Germany and Switzerland since 1992. With a few exceptions, they are subject to the Narcotics Prescription Ordinance (BtMVV) in Germany . Thiopental and methohexital are available as short-term injection anesthetics. Barbital is used in biochemistry as a buffer in the form of veronal acetate buffer .

Barbituric acid (malonylurea) was first produced by Adolf von Baeyer in 1864 . The first barbiturate with a sleep-inducing effect, barbital , was synthesized by Emil Fischer in 1903 . More than 2500 derivatives are known today. Non-GABAergic barbiturates are being researched in terms of their effect on enzymes and their antioxidant properties.

Mechanism of action

The mechanism of action is not yet fully understood. An effect on ionotropic receptors was recognized . The interaction takes place in the membrane receptor section at the interfaces of the subunits .

At GABA A receptors of the synaptic type αβγ, barbiturates exert similar effects to etomidate and propofol . There is evidence that they occupy the etomidate-homologous binding site on γ + β - and act there as allosteric co-agonists . They lengthen the duration of the opening of the channel caused by the neurotransmitter GABA , moderately enlarge its lumen and thus increase the influx of anions into the cell. The left shift of the GABA dose-effect curve and the simultaneous moderate increase in GABA efficiency (E max ) are characteristic. The strength and direction of the modulation depend on the substituents in position 5 of the molecule. As a rule, and in a therapeutically desirable manner, they increase the function of the receptor. In contrast, barbiturates are known which inhibit the GABA A receptor function and z. B. cause convulsions. This effect, which is usually inherent in the R (+) isomer , is noticeable in the case of sterically bulky and conformationally more rigid substituents, e.g. B. phenyl . In the case of (formerly) medicinally used racemates , such an anti-GABAergic effect does not show through, the pro-GABAergic effect predominates.

At the nicotine receptors of the Torpedo α2βγδ type , barbiturates act on the γ + α - interface.

In sub-anesthetic doses, barbiturates inhibit the excitatory (exciting) glutamatergic AMPA receptor , in anesthetic doses they also inhibit certain ( tetrodotoxin-sensitive ) voltage-dependent sodium channels .


The nature of the substituents determines the pharmacokinetics of the compounds by determining the degree of lipophilicity . Within certain limits, lipophilicity is favored by the inclusion of an aromatic , a high number of carbon atoms in the side chains and the replacement of a carbonyl oxygen atom with sulfur. The more lipophilic the derivative, the more efficiently it crosses the blood-brain barrier , the faster its onset of action, and the shorter its overall effect because it redistributes itself more quickly (different compartments). A more lipophilic derivative is metabolized more hepatically , a more hydrophilic one is excreted renally unchanged . The rate of metabolism is stereoselective .


The affinity for different types of receptors also results in a broad spectrum of activity. They have a dose-dependent effect, from sedating to hypnotic ( sleep ) to narcotic . In addition, they have an anticonvulsant effect (against epilepsy ) and hyperalgesic (promotes pain).

Side effects

In hypnotic doses ("sleeping pills")
Morning hangover , paradoxical excitement (especially in children and seniors; an inhibition can also have an exciting effect in the form of an inhibition of the inhibition), allergic reaction, risk of porphyria with an acute attack. The overall sleep duration, which is increased by barbiturates in the first few nights of use, is reduced to the initial value and even below within a short time - usually 8 to 10 days - through tolerance development . Also of importance is the high potential for dependency with difficult, in extreme cases life-threatening withdrawal symptoms on withdrawal, comparable to alcohol (see alcohol-induced delirium tremens ).
In narcotic dosage
Respiratory depression and decrease in cardiac output .

One of the biggest problems with barbiturates therapy is the fact that they have a very narrow therapeutic range , that is, it can easily be overdosed. There is a risk of central respiratory paralysis (see intoxication ). Accidental paravenous or arterial injection of strongly basic barbiturate salts can cause tissue damage.


Since most of the preparations have been withdrawn from sale, only three are essentially used medicinally:

Compared to benzodiazepines , barbiturates not only stimulate sleep, but also, in higher doses, force sleep, so that they can be used in very rare exceptional situations in non- approved use with otherwise uncontrollable sleep disorders . Barbiturates have been replaced by benzodiazepines in most areas of application.

Use outside of human medicine

Fast-acting barbiturates are also used in combination with other agents in the United States for injection execution . In the context of euthanasia in Switzerland , for example, pentobarbital is used by the euthanasia organizations EXIT and Dignitas . In veterinary medicine it is used to euthanize animals.


With chronic use, barbiturates induce cytochrome p 450 -3A enzymes in the liver and thereby accelerate their own breakdown - which leads to increased tolerance development - as well as that of some other drugs and thus weakens their effect. These include a. Oral anticoagulants of the coumarin type, oral contraceptives (birth control pills), various other anti-epileptic drugs, glucocorticoids , and much more.

In addition, barbiturates naturally interact with all other sedating and respiratory-depressant drugs such as alcohol, benzodiazepines, opiates and the like. a. Valproic acid and monoamine oxidase inhibitors of any kind increase the effect of the barbiturate.


Acute poisoning
First, disturbances of consciousness set in up to a deep coma . The central respiratory paralysis , which leads to a lack of oxygen in the brain in the medium term, is critical . It is critical to barbiturate poisoning lethality .
Poisoning therapy
The first priority is to ensure an adequate supply of oxygen. The patient may need to be ventilated . Cardiopulmonary resuscitation should be carried out in the event of cardiac arrest .

The elimination is carried alkalization of blood with sodium promoted. Forced diuresis is recommended for long-acting barbiturates . In addition, various measures can be taken to remove the poison from the body: gastric lavage under protection against intubation, activated charcoal, osmotic laxatives, dialysis if anesthesia is likely to be long.

The risk of suicide was a major problem with barbiturate therapy. In the late 1960s, an average of 3 people in the UK died from suicide using sleeping pills. This was one of the reasons for the great success of the less toxic benzodiazepines .


Barbiturates can be synthesized from (di) substituted malonic acid esters by condensation with urea or dicyandiamide . If thiourea is used, thiobarbiturates are obtained analogously.


What the GABAergic barbiturates have in common is that they are twice substituted on the fifth ring atom of the barbituric acid ring with organic radicals (R 1 , R 2 ). In thiobarbiturates, the oxygen atom on the second ring member is replaced by sulfur .

Surname structure R 1 R 2 (Thio) barbiturate (O / S)
Barbituric acid Base body of the barbiturates with numbering
Barbiturates thiobarbiturates

Basic body of thiobarbiturates with numbering
-H -H O
Allobarbital 1) -CH 2 -CH = CH 2 -CH 2 -CH = CH 2 O
Amobarbital 1) -C 2 H 5 - (CH 2 ) 2 -CH (CH 3 ) 2 O
Barbital 1) -C 2 H 5 -C 2 H 5 O
Butabarbital 1) -C 2 H 5 -CH (CH 3 ) -C 2 H 5 O
Butalbital 1) -CH 2 -CH = CH 2 -CH 2 -CH (CH 3 ) 2 O
Cyclobarbital 1) -C 2 H 5 –C 6 H 9 (cyclohexenyl-1) O
Heptabarbital 1) -C 2 H 5 –C 7 H 11 (cycloheptenyl-1) O
Methohexital O
Pentobarbital 1) -C 2 H 5 -CH (CH 3 ) -C 3 H 7 O
Phenobarbital 2) -C 2 H 5 –C 6 H 5 (phenyl) O
Secobarbital 1) -CH 2 -CH = CH 2 -CH (CH 3 ) -C 3 H 7 O
Thial barbital 1) -CH 2 -CH = CH 2 –C 6 H 9 (cyclohexenyl-1) S.
Thiobarbital 1) -C 2 H 5 -C 2 H 5 S.
Thiopental -C 2 H 5 -CH (CH 3 ) -C 3 H 7 S.
Vinyl bit 1) -CH = CH 2 -CH (CH 3 ) -C 3 H 7 O

1) No longer commercially available as a medicinal product.
2) The pure R (+) - isomer has a proconvulsive effect. See distomer .

Other derivatives are no longer available as a drug: Aprobarbitone , alphenal , barbexaclone , Brallobarbital , Butobarbital , butallylonal , Crotylbarbital , Cyclopal , Ethallobarbital , witch Thal , hexobarbital , mephobarbital , metharbital , methylphenobarbital , narcobarbital , Probarbital , Propallylonal , proxibarbital , Proxibarbital , Reposal , BUTABARBITAL , Talbutal , Thiamylal , Thiobutabarbital and Vinbarbital .

Primidone works partly as a prodrug .

Chemical proof

By means of the Zwikker reaction , colored complexes are formed with those barbiturates that are not substituted on nitrogen. Chromatographic methods ( thin-layer and gas chromatography ), mass spectrometry and radioimmunoassays are also used for analysis .

Individual evidence

  1. ^ Adolf Baeyer: Studies on the uric acid group. In: Justus Liebig's Annals of Chemistry. Vol. 131, No. 3, 1864, pp. 291-302. doi: 10.1002 / jlac.18641310306
  2. E. Fischer, J. von Mering: About a new class of sleeping pills. In: Therapy of the Present. Vol. 44, 1903, pp. 97-101.
  3. Qureshi AM, Mumtaz S, Rauf A, Ashraf M, Nasar R, Chohan ZH: New barbiturates and thiobarbiturates as potential enzyme inhibitors . In: J Enzyme Inhib Med Chem . 30, No. 1, 2015, pp. 119-25. doi : 10.3109 / 14756366.2014.895717 . PMID 24666295 .
  4. Figueiredo J, Serrano JL, Cavalheiro E, Keurulainen L, Yli-Kauhaluoma J, Moreira VM, Ferreira S, Domingues FC, Silvestre S, Almeida P: Trisubstituted barbiturates and thiobarbiturates: Synthesis and evaluation as bacterial antibacterial oxidase inhibitors, antioxidants, antioxidants and anti-proliferative agents . In: Eur J Med Chem . 143, 2018, pp. 829-842. doi : 10.1016 / j.ejmech.2017.11.070 . PMID 29223098 .
  5. Jump up ↑ Moon KM, Lee B, Jeong JW, Kim DH, Park YJ, Kim HR, Park JY, Kim MJ, An HJ, Lee EK, Ha YM, Im E, Chun P, Ma JY, Cho WK, Moon HR, Chung HY: Thio-barbiturate-derived compounds are novel antioxidants to prevent LPS-induced inflammation in the liver . In: Oncotarget . 8, No. 53, 2017, pp. 91662–91673. doi : 10.18632 / oncotarget.21714 . PMID 29207675 . PMC 5710955 (free full text).
  6. These are contact areas where the sub-units of a channel face each other.
  7. The genetically different subunits were designated with Greek letters. In order to be able to differentiate between interfaces, the opposite sides of the sub-units are marked with plus and minus according to the following classification principle. In the top view of the extracellular space, one side of each subunit is marked with plus, the second side clockwise with minus.
  8. Jayakar SS, Zhou X, Savechenkov PY, Chiara DC, Desai R, Bruzik KS, Miller KW, Cohen JB: Positive and Negative Allosteric Modulation of an α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the γ + -β- interface . In: J. Biol. Chem. . 290, No. 38, 2015, pp. 23432-46. doi : 10.1074 / jbc.M115.672006 . PMID 26229099 . PMC 4645599 (free full text).
  9. Ziemba AM, Forman SA: Correction for Inhibition Leads to an Allosteric Co-Agonist Model for Pentobarbital Modulation and Activation of α1β3γ2L GABAA Receptors . In: PLoS ONE . 11, No. 4, 2016, p. E0154031. doi : 10.1371 / journal.pone.0154031 . PMID 27110714 . PMC 4844112 (free full text).
  10. Desai R, Savechenkov PY, Zolkowska D, Ge RL, Rogawski MA, Bruzik KS, Forman SA, Raines DE, Miller KW: Contrasting actions of a convulsant barbiturate and its anticonvulsant enantiomer on the α1 β3 γ2L GABAA receptor account for their in vivo effects . In: J. Physiol. (Lond.) . 593, No. 22, 2015, pp. 4943-61. doi : 10.1113 / JP270971 . PMID 26378885 . PMC 4650410 (free full text).
  11. Hamouda AK, Stewart DS, Chiara DC, Savechenkov PY, Bruzik KS, Cohen JB: Identifying barbiturate binding sites in a nicotinic acetylcholine receptor with [3H] allyl m-trifluoromethyldiazirine mephobarbital, a photoreactive barbiturate . In: Mol. Pharmacol. . 85, No. 5, 2014, pp. 735-46. doi : 10.1124 / mol.113.090985 . PMID 24563544 . PMC 3990015 (free full text).
  12. a b c d e f g h T. Karow, R. Lang-Roth: General and special pharmacology and toxicology. Edition 19, 2011, pp. 967-970.
  13. p. 51; Müller et al .; Neurology and psychiatry for study and practice; 2011
  14. see: P450 Drug Interaction Table . Retrieved July 4, 2012.
  15. Gudrun Späth (1982): Poisonings and acute drug overdoses.
  16. ^ Bangen, Hans: History of the drug therapy of schizophrenia. Berlin 1992, ISBN 3-927408-82-4 p. 24
  17. a b Entry on barbiturates. In: Römpp Online . Georg Thieme Verlag, accessed on April 13, 2011.

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