phenobarbital

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of phenobarbital
General
Non-proprietary name phenobarbital
other names
  • 5-ethyl-5-phenylbarbituric acid ( IUPAC )
  • Phenobarbitalum ( Latin )
Molecular formula C 12 H 12 N 2 O 3
Brief description

White, crystalline powder or colorless crystals

External identifiers / databases
CAS number 50-06-6
EC number 200-007-0
ECHA InfoCard 100,000,007
PubChem 4763
DrugBank DB01174
Wikidata Q407241
Drug information
ATC code

N03 AA02

Drug class
properties
Molar mass 232.24 g mol −1
Melting point
  • 156 ° C (polymorph 1)
  • 167 ° C (polymorph 2)
  • 178 ° C (polymorph 3)
pK s value

7.3

solubility

little in water (1110 mg l −1 at 25 ° C)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
06 - Toxic or very toxic 08 - Dangerous to health

danger

H and P phrases H: 301-317-351-360D
P: 201-280-301 + 310-308 + 313
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Phenobarbital (original trade name: Luminal ; manufacturer: initially Bayer , since the 1990s Desitin ) is a drug from the group of barbiturates introduced in 1912 and is used in the treatment of epilepsy as well as for anesthesia . It was a widely used sleep aid well into the second half of the 20th century. Phenobarbital is a marketable and prescribable narcotic according to German narcotics law .

synthesis

Phenobarbital is produced by a condensation reaction between ethyl phenyl malonic acid diethyl ester and urea .

Phenobarbital synthesis.svg

Clinical information

Application areas (indications)

Phenobarbital is not effective in absences (although it is approved for treatment), or in the prevention and treatment of febrile seizures. Because of its risks ( addiction , poisoning ) and the availability of alternatives ( e.g. benzodiazepines ), no finished drugs containing phenobarbital have been approved as sleeping pills since 1992 .

Type and duration of application

The tablets are i. d. Usually taken in two doses throughout the day. Treatment for epilepsy is usually long-term treatment. If the seizures are suddenly stopped, the attacks can recur with increased severity; counteracting this is tapering off the dose. With prolonged use of phenobarbital there is a risk of dependence .

Contraindications (contraindications)

Phenobarbital must not be used in:

Phenobarbital should only be given after a very careful risk-benefit assessment and under strict surveillance

Drug interactions

With simultaneous administration of other centrally acting drugs (psychotropic drugs, painkillers and sleeping pills, anti-allergic drugs ) and alcohol, phenobarbital can increase their effects and their side effects. Phenobarbital, an increase in the formation of drug-degrading enzymes effect ( enzyme induction of cytochrome P450 1A2 , cytochrome P450 2C8 and cytochrome P450 3A ), the degradation of some drugs, such as oral medications for inhibiting blood coagulation , corticoids , lamotrigine , thyroid hormones , doxycycline , chloramphenicol , azole antifungals , Griseofulvin , or oral contraceptives ( the pill ) can accelerate the liver and thus cause a loss of effectiveness. Concomitant treatment with felbamate and phenobarbital can increase the blood concentration of phenobarbital and decrease that of felbamate.

Use during pregnancy and breastfeeding

Malformations are more common in children of mothers who were treated with phenobarbital during pregnancy . Phenobarbital crosses the placenta well and may only be used during pregnancy after careful risk-benefit assessment. Treatment with phenobarbital can lead to a folic acid deficiency , which promotes malformations. Therefore, folic acid should also be taken before and during pregnancy. Monitoring of the development of the unborn child with ultrasound and α-fetoprotein determination is recommended. Withdrawal symptoms in newborns of mothers treated with phenobarbital have been described.

Phenobarbital is excreted in breast milk . The concentration in breast milk is around 10 to 45% of the maternal blood concentration. Women treated with high doses of phenobarbital should not breastfeed.

Special patient groups

In patients with liver cirrhosis , the half-life increases to 4–8 days. Even with impaired renal function, elimination is considerably delayed, which is why a dose adjustment may be necessary.

Adverse effects (side effects)

The overall incidence of adverse effects in adults is around 23%. Serious side effects that lead to treatment interruption occur in approximately 4% of cases. The following side effects are very common (≥10%) to be expected: undesirably severe calming and tiredness (sleepiness, fatigue, drowsiness, prolonged reaction time), dizziness, headache , impaired coordination of movement sequences ( ataxia ), impaired judgment, disorientation, disorder of the Sexual function (decreased libido , erectile dysfunction (impotence)). In the morning after the evening dose, overhang effects (impaired concentration, residual tiredness) can affect the reaction time. In children and older patients, states of excitement can often (1–10%) occur (“ paradoxical reactions ” with restlessness, aggressiveness and disorientation). With prolonged use in high doses, dependence can develop. With abrupt discontinuation after long-term use, withdrawal symptoms may occur.

Poisoning / overdose

Signs of poisoning or overdose with phenobarbital can include dizziness , mental and physical immobility ( stupor ), drop in blood pressure, kidney failure , drop in body temperature, skin blisters, disturbances in eye movements ( nystagmus ), decreased attention, weakened tendon reflexes , disorders of balance regulation and movement coordination ( Ataxia ), drowsiness ( somnolence ), sleep, coma, inadequate breathing ( respiratory depression ) and / or shock with initially narrow pupils and later wide open .

Treatment of phenobarbital overdose consists of respiratory and circulatory stabilization, gastric lavage (if appropriate) followed by intensive monitoring and, if necessary, treatment depending on the patient's condition. Phenobarbital can be washed out from the blood ( hemodialysis , hemoperfusion ).

Pharmacological properties

Mechanism of action (pharmacodynamics)

Phenobarbital is a strong sedative and sleeping aid and works against seizures . The effect is strongly dose-dependent and ranges from calming to light dampening and sleep to anesthesia .

Phenobarbital acts - like other barbiturates - by binding to the GABA A - receptor . GABA is the main inhibitory neurotransmitter of the central nervous system (CNS) in mammals . The binding site for barbiturates at the GABA A receptor differs from the binding sites for GABA itself and also from that for benzodiazepines . Like benzodiazepines, barbiturates increase the GABA effect on the receptor. In contrast to benzodiazepines, however, they do not increase the probability of the GABA A receptor being open , but rather ensure that the channel remains open longer after GABA has been bound. Barbiturates also block AMPA receptors (a subset of glutamate receptors ). Glutamate is the main excitatory neurotransmitter in the CNS. This combination of strengthening the inhibiting GABA effect and blocking the exciting glutamate effect explains the depressant effect of these drugs well.

Absorption and distribution in the body (pharmacokinetics)

The uptake into the body after oral or intramuscular administration is almost complete. Maximum phenobarbital concentrations in the blood are observed after 6–18 hours after oral administration and after 3–5 hours after intramuscular administration. Maximum concentrations in the brain were measured after 20–60 minutes after intravenous administration  . Concentrations of 15-25 μg / ml are required for anticonvulsant effectiveness. Concentrations above 40 μg / ml are considered toxic . The plasma half-life of phenobarbital depends on age, liver function and the pH of the urine. It is 3–7 days in newborns, 3 days in children and 2–4 days in adults. The plasma protein binding is 40 to 60%.

Bioavailability

The bioavailability of a drug is u. a. determined by its galenic properties and is therefore product-dependent. Luminal ® has a bioavailability between 80 and 100%.

Metabolism (metabolism)

Phenobarbital is mainly metabolized in the liver . An intermediate metabolic pathway leads via the coupling to glucuronic acid and excretion via the bile. 10–40% is excreted unchanged in the urine. About 10-20% of the drug is excreted per day. By increasing the formation of some drug-degrading enzymes , such as cytochrome P450 3A4, phenobarbital increases both its own breakdown and the breakdown of other drugs.

toxicology

The LD 50 in the mouse was determined to be 323 mg / kg ( oral ) and 234 mg / kg for intraperitoneal administration. The corresponding data for the rat were 660 and 190 mg / kg. An LD 50 of 125 mg / kg after oral administration was described in the cat and 185 mg / kg after intravenous administration in the rabbit .

Analytics

The qualitative and quantitative detection of phenobarbital succeeds after adequate sample preparation by coupling the HPLC or gas chromatography with the mass spectrometry . The coupling of gas chromatography with mass spectrometry has also been described for detection in hair .

Further information

history

The first barbiturate, Barbital ( Veronal ® ), was synthesized in 1902 by Emil Fischer and Joseph von Mering ( Bayer AG) and was soon u. a. also used to treat epilepsy. Fischer synthesized a number of similar substances by 1904, including phenobarbital. Bayer introduced phenobarbital in 1912 under the trade name Luminal ® as a sleeping aid. In the same year Alfred Hauptmann first described the antiepileptic effects of phenobarbital. His contribution to the treatment of epilepsy is now considered to be his greatest scientific achievement. For this reason, the Alfred Hauptmann Prize for Epilepsy Research has been awarded since 1979.

The Luminal ® trademark was transferred from Bayer to Desitin Arzneimittel GmbH for Germany and several other countries in the 1990s .

Luminal scheme in National Socialism

In the time of National Socialism , phenobarbital was used for the targeted killing of the sick and disabled. In 1940 Paul Nitsche developed and tested the Luminal scheme in the Leipzig-Dosen sanatorium with the assistance of senior physicians Georg Renno and Herbert Schulze , in which phenobarbital was administered in slightly overdosed three times a day over several days. In connection with the systematic malnutrition taking place at the same time, this quickly led to the death of the patient from pneumonia. The method of killing was unremarkable, as the administration of phenobarbital as a sedative was common practice. 60 patients were murdered in this first series of experiments in dozen. The Luminal scheme was first used to murder around 5,000 handicapped children in child “euthanasia” . In the second phase of the National Socialist " euthanasia ", Aktion Brandt , phenobarbital was also used to murder a far larger number of adults.

Today's meaning

Phenobarbital is the most widely used anticonvulsant in developing countries. However, it is still widely used in more affluent countries, although - with the exception of a few rare epilepsy syndromes - it is classified as the remedy of the more remote choice. Phenobarbital was added to the World Health Organization's Essential Medicines List in 1977 by the World Health Organization (WHO) .

Along with potassium bromide  , phenobarbital is considered the first choice for treating pets with seizures .

Overdoses of the active ingredient are used in executions with lethal injection, for example in the United States of America. In the USA, the active ingredient is to be used again in executions at the state level of those sentenced to death in 2019.

The active ingredient is often used in suicides , including mass suicide by the religious group Heaven's Gate . The Luminal trademark, which is over 100 years old, is the title:

and the name of a post-punk - record labels from Providence ( Rhode Iceland ).

Trade names

Monopreparations

Aphenylbarbit (CH), Luminaletten (D), Luminal (D, CH), Generics (D, CH)

Web links

Commons : Phenobarbital  - collection of images, videos, and audio files

Individual evidence

  1. ↑ a b c Entry on phenobarbital in the GESTIS substance database of the IFA , accessed on July 23, 2016(JavaScript required) .
  2. ↑ a b c Entry on phenobarbital. In: Römpp Online . Georg Thieme Verlag, accessed on September 9, 2014.
  3. ↑ a b c d Entry on phenobarbital in the ChemIDplus database of the United States National Library of Medicine (NLM)
  4. ↑ European Pharmacopoeia Commission (Ed.): European Pharmacopoeia 5th Edition . tape 5.0-5.7 , 2006.
  5. ↑ Technical information Luminal Desitin as of December 2008.
  6. ↑ AW Frahm, HHJ Hager, F. v. Bruchhausen, M. Albinus, H. Hager: Hager's handbook of pharmaceutical practice. Volume 4: Substances AK. Birkhäuser, 1999, ISBN 3-540-52688-9 , p. 124.
  7. ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (22 July) 2019, pp. 508-517, pp. 510 f.
  8. ↑ X. Zhang, Z. Lin, J. Li, Z. Huang, Y. Rao, H. Liang, J. Yan, F. Zheng: Rapid determination of nine barbiturates in human whole blood by liquid chromatography-tandem mass spectrometry. In: Drug Test Anal. 9 (4), Apr 2017, pp. 588-595. PMID 27368111
  9. ^ H. Tian, ​​X. Zhou, C. Chen, Y. He, H. Yu, X. Zheng: Simultaneous Determination of Phenobarbital, Pentobarbital, Amobarbital and Secobarbital in Raw Milk via Liquid Chromatography with Electron Spray Ionization Tandem Mass Spectrometry. In: Korean J Food Sci Anim Resour. 37 (6), 2017, pp. 847-854. PMID 29725206
  10. ↑ M. Giusiani, S. Chericoni, R. Domenici: Identification and quantification of phenobarbital in a mummified body 10 years after death. In: J Forensic Sci. 57 (5), Sep 2012, pp. 1384-1387. PMID 22607089
  11. ↑ FL Roveri, BA Paranhos, M. Yonamine: Determination of phenobarbital in hair matrix by liquid phase microextraction (LPME) and gas chromatography-mass spectrometry (GC-MS). In: Forensic Sci Int. 265, Aug 2016, pp. 75-80. PMID 26829332
  12. ↑ G. Kramer. First use of barbiturate for epilepsy in 1903 by the Göttingen neurologist and psychiatrist Ludwig Wilhelm Weber. Z Epileptol 2017; 30: 230-231
  13. ↑ A. Hauptmann: Luminal in epilepsy. In: Munch Med Wochenschr. 59, 1912, pp. 1907-1909.
  14. ↑ E. Kumbier, K. Haack: How a sleeping pill became an anti-epileptic - The discovery of the anti-epileptic effect of phenobarbital by Alfred Hauptmann. In: Current Neurology. 31, 2004, pp. 302-306, doi: 10.1055 / s-2003-817879 .
  15. ^ B. Böhm, H. Markwardt: Hermann Paul Nitsche (1876–1948). On the biography of a reform psychiatrist and main actor in Nazi “euthanasia”. In: Stiftung Sächsische Gedenkstätten (Ed.): National Socialist Euthanasia Crimes. Contributions to the processing of their history in Saxony. Sandstein, Dresden 2004, ISBN 3-937602-32-1 , p. 87.
  16. ^ P. Kwan, MJ Brodie: Phenobarbital for the Treatment of Epilepsy in the 21st Century: A Critical Review. In: Epilepsia. 45, 2004, pp. 1141-1149, doi: 10.1111 / j.0013-9580.2004.12704.x PMID 15329080
  17. ↑ M. Baldy-Moulinier, A. Covanis, S. D'Urso et al .: Therapeutic strategies against epilepsy in Mediterranean countries. In: Seizure. 7, 1998, pp. 513-520. PMID 9888499
  18. ^ WHO Model List of Essential Medicines . (PDF; 442 kB) accessed on September 20, 2012.
  19. ^ PM Dowling: Update on therapy of canine epilepsy. In: Can Vet J. 40, 1999, pp. 595-598. PMID 12001345 .
  20. ↑ New method of execution: Trump administration wants to carry out death sentences for the first time in 16 years . ISSN  0174-4909 ( faz.net [accessed July 25, 2019]).
  21. ↑ New method of execution: Trump administration wants to carry out death sentences for the first time in 16 years . ISSN  0174-4909 ( faz.net [accessed July 25, 2019]).