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BARBITURATE DERIVATIVES AND IT’S PHARMACOLOGICAL USES: A REVIEW

 

Clinical courses

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 Barbiturates have now largely been replaced by benzodiazepines in routine medical practice - for example, in the treatment of anxiety and insomnia – mainly because benzodiazepines are significantly less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.

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