BARBITURATE DERIVATIVES AND IT’S PHARMACOLOGICAL USES: A REVIEW

About Author:
Chaitanya Prasad Meher
Assistant professor,
Department of pharmaceutical chemistry,
Vijaya Institute Of Pharmaceutical Sciences For Women,
Enikepadu,Vijayawada (A.P)
chaitanyameher84@gmail.com

Abstract:
Barbiturates have been popular hypnotic and sedative of the last century upto 1960s, but are not used now to promote sleep or to calm patient. However they are described first because they are the prototype of CNS depressant. Barbiturates are general depressant for all excitable cells , the CNS is most sensitive where the effect is almost global, but certain areas are more succeptible. The presented review articles is deals with the various pharmacological activities associated with the barbituric acid derivative along with their chemistry.

REFERENCE ID: PHARMATUTOR-ART-1930

Introduction
Barbiturates are substituted derivatives of barbituric acid. barbiturate have variable lipid solubility ,the more soluble one are more potent and shorter acting. They are unsoluble in water but their sodium salts dissolve yielding highly alkaline solution. Barbituratesare drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, hypnotics, and anticonvulsants. Barbiturates also have analgesic effects, however these effects are somewhat weak, preventing barbiturates from being used in surgery in the absence of other analgesics. They have addiction potential, both physical and psychological. Barbiturates have now largely been replaced by benzodiazepines in routine medical practice - for example, in the treatment of anxiety and insomnia – mainly because benzodiazepines are significantly less dangerous in overdose. However, barbiturates are still used in general anesthesia, for epilepsy, and assisted suicide.

Barbituric acid was first synthesized in 1864 and has no pharmacological activity but barbital derived from barbituric acid has sedative hypnotic property. Over 2,500 derivatives of barbituric acid were synthesized and approximately 50 of them have been marketed. Currently, there are approximately 12 different barbiturates which are used medically worldwide. Barbiturates are central nervous system depressants and are used medically as sedatives, hypnotics, anaesthetics as well as anticonvulsants. Based on the duration of action, barbiturates are classified as ultra short acting, short acting, intermediate acting and long acting barbiturates. Barbiturates can beadministered both orally and intravenously. The ultra-short acting barbiturates can produce anesthesia within minutes after intravenous administration. Currently thiopental and methohexital are commonly used drugs in this category. After oral administration, the short and intermediate acting barbiturates such as amobarbital, butalbital, butabarbital, pentobarbital, secobarbital and talbutal produce pharmacological action within 15–40 min and the effect may last up to 6 h. These drugs are used for treating insomnia and may also be used to achieve preoperative sedation. Long acting barbiturates such as Phenobarbital and mephobarbital are classified as Schedule IV drugs and are medically used as anticonvulsants and also for day time sedation. The duration of action may last up to 12 h. Usually short and intermediate acting barbiturates are abused and long acting barbiturates such as phenobarbital are rarely abused. Mechanism of action of barbiturates is GABA (gamma-amino butyric acid)-mediated inhibition of synaptic transmission. At low doses, barbiturates acts as modulators of GABA receptors enhancing postsynaptic inhibitory potential by activating chloride ion channel and at higher dosage barbiturates act as GABA agonists. Barbiturates demonstrate anxiolytic effects at a dosage close to producing hypnotic effects and such dosages also affect motor skill and mood. Chronic administration of barbiturates causes dependence. Because of nonselective binding of barbiturates with GABA receptors as well as negative side effects of barbiturates in treating anxiety disorder, these drugs are mostly replaced by benzodiazepines in treating anxiety disorder . Depending on the abuse potential of barbiturates, they are classified either as a Schedule II or a Schedule III drug.

BARBITURATE (pyrimidine- 2,4,6(1H,3H,5H)-trione)

Molecular Formula    = C4H4N2O3
Formula Weight    = 128.08616
Composition    = C(37.51%) H(3.15%) N(21.87%) O(37.47%)
Molar Refractivity    = 25.53 ± 0.3 cm3
Molar Volume    = 88.0 ± 3.0 cm3
Parachor                = 232.5 ± 6.0 cm3
Index of Refraction    = 1.492 ± 0.02
Surface Tension    = 48.7 ± 3.0 dyne/cm
Density                 = 1.455 ± 0.06 g/cm3
Polarizability                = 10.12 ± 0.5 10-24cm3
Monoisotopic Mass    = 128.022192 Da
Nominal Mass    = 128 Da
Average Mass                 = 128.0862 Da

Structure Activity Relationship Of Barbiturates(SAR) :
One of the ways of making potentially biologically active compounds is modification on C-5 of barbituric acid. Combination of barbituric acid moiety with other pharmacophoric groups gives possibility to synthesized numerous derivatives with potential biological effect.

Two active active hydrogen atoms at position 5:5 have appropriate substituent (alkyl or aryl) group to produce hypnotic activity
Double bond in alkyl substituent produce compounds more readily prove to oxidation & short acting.
Branched chain isomer shows greater activity & shorter duration.
Short chain at C-5 resist oxidation & are long acting
Methylation of imide hydrogen I,e transition from 5,5 disubstituted to 1,5,5 trisubstitutedbarbituric reduces duration increases onset.
Replacement of sulphuric at C-2 by C=O produces thiobarbituric with rapid onset.
Polar groups(OH ,CO, COOH) at 5-alkyl group reduces activity.
Halogen atom at 5-alkyl group enhance activity.

Barbiturate derivatives with pharmacological activity

CONCLUSION
The discovery of barbituric acid subsequently led to the introduction of many other barbiturate derivatives, fueling the discoveries of a broad new class of therapeutics that would quickly dominate both the medical and social circles in the early 20th century .Chemistry of Barbituricacids attracts great attention becausebarbituric acid derivatives are of great importance for biology and medicine. Barbituric acid derivative are well known drugs with activity at central nervous system (CNS), and specific activity as anticonvulsant, sedative- hypnotics ,anxyiolytics and tranquilizer. These Barbituric acid derivatives are widely used for long time in medicine as anticonvulsants, narcotics and soporifics.

REFERENCES
1.Chocholova L, Radil-Weiss T. Effect of allobarbital on focal epilepsy in rats. PhysiologiaBohemoslovaca. 1971;20(4):325-34.
2.Carissimi M, NuoviBarbituriciAlogenati. Farmaco.Ediozionescientifica. 17(6):390-413. (1962).
3.Kim, H. -S.; Wan, X.; Mathers, D. A.; Puil, E. (2004). "Selective GABA-receptor actions of amobarbital on thalamic neurons".British Journal of Pharmacology143 (4): 485–494.
4.Reddemann H, Turk E. Oramon poisoning in infancy and childhood. Observations on 12 aprobarbital poisonings (German). Das Deutsche Gesundheitswesen. 1966 May 12;21(19):878-81.
5.Okudzhava, V. M.; Chankvetadze, B. G. (1989). "Pharmacological characteristics of an anti-convulsive drug Benzonal and the evaluation of its therapeutic effectiveness (literature review)" (in russian). Zhurnalnevropatologii i psikhiatriiimeni S.S. Korsakova (Moscow) 89 (11): 136–145.
6.Yih TD, Rossum JM. Peculiar pharmacokinetics of brallobarbital as a source of complications in Vesparaxintoxication.Xenobiotica. 1976 Jun;6(6):355-62.
7.Eddy, N. B.; Halbach, H.; Isbell, H.; Seevers, M. H. (1965). "Drug dependence: Its significance and characteristics". Bulletin of the World Health Organization32 (5): 721–733
8.Takamura N, Maruyama T, Chosa E, Kawai K, Tsutsumi Y, Uryu Y, Yamasaki K, Deguchi T, Otagiri M. Bucolome, a potent binding inhibitor for furosemide, alters the pharmacokinetics and diuretic effect of furosemide: potential for use of bucolome to restore diuretic response in nephrotic syndrome. Drug Metabolism and Disposition. 2005 Apr;33(4):596-602
9.Mittmann U, Schmidt HD, Schmier J, Wirth RH (1976). "Hemorrhagic shock with fixed hypotension and with spontaneous recovery of blood pressure.A comparison of two shock models".Basic Research in Cardiology71 (1): 47–59.
10.Martin, J. R.; Godel, T.; Hunkeler, W.; Jenck, F.; Moreau, J.-L.; Sleight, A. J.; Widmer, U. (2000). Psychopharmacological Agents.
11.Walther T, Meyer FP, Puchta K, Walther H. Effect of an acute dose of crotylbarbital on reaction time and attention testing in healthy human subjects. International Journal of Clinical Pharmacology, Therapy and Toxicology. 1983 Jun;21(6):306-10.
12.Vander Brook MJ, Cartland GF. A Pharmacologic Study of 5-Allyl-5-Cyclopentenyl Barbituric Acid (Cyclopal). Journal of Pharmacology And Experimental Therapeutics, 1944, 80(2): 119-125
13.Eddy NB, Halbach H, Isbell H, Seevers MH. Drug dependence: Its significance and characteristics. Bulletin of the World Health Organisation. 1965;32:721-733.
14.Butler, T. C. (1950). "The rate of penetration of barbituric acid derivatives into the brain".The Journal of Pharmacology and Experimental Therapeutics100 (2): 219–226.
15.Takenoshita, R.; Toki, S. (2004). "New aspects of hexobarbital metabolism: Stereoselective metabolism, new metabolic pathway via GSH conjugation, and 3-hydroxyhexobarbital dehydrogenases" (in japanese) (pdf). Yakugakuzasshi : Journal of the Pharmaceutical Society of Japan124 (12): 857–871.
16.Snyder, J. A.; Link, K. P. (1953). Journal of the American Chemical Society75 (8): 1881
17.Irwin S, Stagg Rd, Dunbar E, Govier Wm (March 1956). "Methitural, a new intravenous anesthetic: comparison with thiopental in the cat, dog and monkey". The Journal of Pharmacology and Experimental Therapeutics116 (3): 317–25.
18.Katzung, Bertram G., Basic and Clinical Pharmacology, 10th ed., p. 406-407
19.Stravitz, R. T.; Kramer, A. H.; Davern, T.; Shaikh, A. O. S.; Caldwell, S. H.; Mehta, R. L.; Blei, A. T.; Fontana, R. J. et al. (2007). "Intensive care of patients with acute liver failure: Recommendations of the U.S. Acute Liver Failure Study Group". Critical Care Medicine35 (11): 2498–2508.
20.Hans Brandenberger; Robert A. A. Maes (1997).Analytical Toxicology: For Clinical, Forensic, and Pharmaceutical Chemists. Walter de Gruyter. p. 348
21.Kwan P, Brodie MJ (September 2004). "Phenobarbital for the treatment of epilepsy in the 21st century: a critical review". Epilepsia45 (9): 1141–9.
22.Eddy NB, Halbach H, Isbell H, Seevers MH. Drug dependence: Its significance and characteristics. Bulletin of the World Health Organisation. 1965;32:721-733.
23.Williams, Denis (1 August 1956). "Treatment of Epilepsy with Mysoline".Proceedings of the Royal Society of Medicine49 (8): 589–91
24.Holck HG, Riedesel CC, Robidoux FA. Studies on tolerance and cross-tolerance to Nostal (propallylonal; isopropyl-beta-bromallylbarbituricacid.Journal of the American Pharmaceutical Association. 1950 Nov;39(11):630-7.
25.Raymond Eller Kirk; Donald Frederick Othmer (1993).Encyclopedia of Chemical Technology: Chlorocarbons and chlorohydrocarbons-C2 to combustion technology. Wiley
26.Sulman, F. G.; Pfeifer, Y.; Tal, E. (1976). "Migraine therapy by enzyme induction with proxibarbital" (in german).Therapie der Gegenwart115 (12): 2088–2103
27.Kessing, S. V.; Tarding, F.; Thomsen, A. C. (1963). "Reposal, A New Hypnotic. I. Pharmacodynamic Activity" (in denish).Ugeskrift for laeger125: 1735–1738
28.Meder, F. (1952). "Our experiences with Rectidon basal anesthesia" (in german).Zentralblatt fur Gynäkologie74 (48): 1895–1896.