Phenobarbital

IUPAC nomenclature

5-Ethyl-5-phenyl-1,3-diazinane-2,4,6-trione.

Classification

Phenobarbital is a barbiturate sedative-hypnotic.

Physiochemical Properties

Mechanism of Action

• Phenobarbital increases synaptic inhibition by acting on GABA_A Due to this, there is effect on the threshold of seizure, and there is reduction in the activity of seizure from the seizure focus.
• Phenobarbital also inhibits the calcium channel. Which results in decrease in excitory transmitter release.
• The sedative and hypnotic effects of the drug is due to the effect of drug on polysynaptic midbrain reticular formation, which controls central nervous system arousal.

Structure Activity Relationship

• Tri-keto form is most stable in aqueous solution.
• 4,6-dialcoholic tautomeric forms are least stable in aqueous solution.
• 5,5-disubstituted barbituric acid is the prime requirement for the barbituares to be sedative hypnotics.
• Esterification of either of the 1,3-diazine nitrogens decreases hypnotic activity.
• Substitution of either of the 1,3-diazine nitrogens with aliphatic carbons retains the anticonvulsive properties.
• Esterification of the 5^th-position substituents yields agents with analgesic activity but with weak hypnotic properties.
• Introduction of the polar functional group at the 5^th– position yields compounds which are fully devoid of sedative-hypnotic or anticonvulsive activity.
• As the number of carbons at R₂ carbon increases, the lipophillicity of the drug increases.
• Modification of the 2^nd-position oxygen of the barbiturate backbone with sulfur atom yields thiobarbiturate derivatives with increased lipophillicity, shorter duration of action, faster time of onset compared to oxy-derivative. [1]

Method of synthesis

i. Ethanolysis of benzyl cyanide in presence of acid to give phenylacetic acid ethyl ether.

ii. Methylene hroup of above formed compound undergoes acylation using diethyloxalate to produce diethylester of phenyloxobutandioic acid.

iii. Heating the above formed compound loses caorbon oxide and transforms into phenylmalonic ester.

iv. Above comound under goes alkylation usin ethylbromide in presence of sodium ethoxide to give α-phenyl-α-ethylmalonic ester.

v. Condensation with urea gives Phenobarbital. [2]

Therapeutic Uses

Phenobarbital is used for:

• Treatment of seizures
• For producing sedation during the time of anxiety.

Side Effects

Side effects of Phenobarbital are:

• Insomnia
• Dizziness
• Drowsiness
• Loss of coordination
• Nausea
• Vomiting
• Constipation
• Restlessness
• Headache
• Loss of appetite
• Pale skin
• Shallow breathing

MCQ

Q.1 Sedative-hypnotic effect of phenobarbital is through?

a) Increase the affinity of GABA for GABA receptors

b) Decrease the affinity of GABA for GABA receptors

c) α-inhibition

d) ß-inhibition

Q.2 Therapeutic use of drug Phenobarbital is/are?

a) Treatment of seizures

b) Sedation during time of anxeity

c) Treatment of Diabetes

d) Both a) and b)

Q.3 Which amongst the following are the correct statements with respect to the SAR of drug phenobarbital?

I. Tri-keto form is most stable in aqueous solution.

II. 4,6-dialcoholic tautomeric forms are least stable in aqueous solution.

III. 5,5-disubstituted barbituric acid is the prime requirement for the barbituares to be sedative hypnotics.

a) I, II, III

b) I, II

c) II, III

d) I

Q.4 Number of chiral centers present in the structure of Phenobarbital?

a) 0

b) 1

c) 2

d) 3

Q.5 Correct sequence for the True/False for the physiochemical properties of the drug phenobarbital

I. Molecular weight = 523.25 gm/mol

II. It appears as white crystalline shiny powder

III. Melting point is 174°C

a) TTF

b) FTF

c) TFT

d) FTT

Q.6 Correct statements for the IUPAC nomenclatures of the drugs are?

I. Phenobarbital: 5-Ethyl-5-phenyl-1,3-diazinane-2,4,6-trione

II. Triptorelin: 5-oxo-D-prolyl-L-histidyl-Ltryptophyl-L-seryl-Ltyrosyl-3-(1H-indol-2-yl)-L-alanylleucyl-L-arginyl-L-prolylglycinamide.

III. Phenylephrine: (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol

IV. Bicalutamide: (RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide.

a) I, II, III

b) I, IV

c) I, III

d)I, II, III, IV 

Q.7 Match the following drugs with their correct classifications-

a) i-D, ii-B, iii-C, iv-A

b) i-D, ii-C, iii-B, iv-A

c) i-A, ii-C, iii-B, iv-D

d) i-A, ii-C, iii-B, iv-D 

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ANSWERS

1- a

2-d

3-a

4-a

5-d

6-d

7-b

REFERENCES