THIOPENTAL Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

Thiopental

IUPAC nomenclature

5-ethyl-5-pentan-2-yl-2-sulfanylidene-1,3-diazinane-4,6-dione

Classification

Thiopental is a barbiturate sedative-hypnotic.

 

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 242.36 g/mol
2 Physical appearance Solid
3 Melting point 158-160°C
4 Octanol/water partition coefficient 2.85
5 Solubility 96 mg/L in water
6 Presence of ring Pyrimidine
7 Number of chiral centers 2
 

 

 

Mechanism of Action

i. Drug binds with different binding sites associated with chloride ionopore at the GABAA

ii. This results in increase in the duration of time for the opening of the chloride ionopore.

iii. As a result, the post synaptic inhibitory effect of GABA in the thalamus is prolonged.

 

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 barbiturates 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 5th-position substituents yields agents with analgesic activity but with weak hypnotic properties.
  • Introduction of the polar functional group at the 5th– 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 2nd-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. Alkylation of malonicester

ii. Cyclization with thiourea in presence of sodium ethoxide to yield thiopental. [2]

Therapeutic Uses

Thiopental is used:

  • In the induction phase of general anesthesia
  • To induce anesthesia in animals
  • To induce medical comas
  • To terminate the seizure
  • For the purpose of euthanasia
  • To execute prisoner’s by lethal injection

 

Side Effects

Side effects of Thiopental are:

  • Cardiovascular and respiratory depression
  • Hypotension
  • Apnea
  • Airway obstruction
  • Headache
  • Agitated emergence
  • Prolonged somnolence
  • Nausea

 

MCQ

 Q.1 “5-ethyl-5-pentan-2-yl-2-sulfanylidene-1,3-diazinane-4,6-dione” is the IUPAC nomenclature of which drug?

a) Tacrine

b) Thiopental

c) Vecuronium

d) Pralidoxime

Q.2 Molecular weight of thiopental is?

a) 350 gm/mol

b) 36 gm/mol

c) 165.54 gm/mol

d) 475.3 gm/mol

Q.3 Match the following with correct classifications of the drugs.

i.  Thiopental A. Muscarinic agonist
ii. Carbachol B. Nicotinic antagonist
iii. Trospium C. Barbiturate sedative-hypnotic
iv. Doxacurium D. Muscarinic antagonist

 a) i-C, ii-A, iii-D, iv-B

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

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

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

Q.4 Correct steps for the mechanism of action of the drug Thipental?

I. Decrease in GABA affinity

II. Binding of Drug with GABAA receptor

III. Increase in GABA affinity

IV. Increase in opening duration of the chloride channel

a) IV – II – I

b) I – III – IV

c) I – II – IV

d) II – III – IV

Q.5   Correct sequence for True and False for the given statements related with the SAR of drug Thiopental.

  • 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

a) TFFT

b) FTTF

c) FFTF

d) TTTT

Q.6 Starting materials for the synthesis of thiopental is/are?

a) Ethylbenzoate

b) Ethylchloroformate

c) Methyl 2-ethyl-2,3-dimethylhexanoate

d) None of the above

 Q.7 The drug thiopental is mainly used for?

a) Inducing medical comas

b) Termination of seizures

c) Purpose of euthanasia

d) All of the above

 

 

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ANSWERS

1-b

2-b

3-a

4-d

5-d

6-c

7-d

 

REFERENCES

[1] Lemke TL, Zito SW, Roche VF, Williams DA. Essentials of Foye’s principles of medicinal chemistry. Wolters Kluwer; 2017, 490-91

[2] Narimani H, Kohzadi H. A practical and convenient method for the synthesis of anesthetic drug thiopental: using thiourea and sodium ethoxide. Iranian Chemical Communication. 2014 Feb 1;2:48-55.

 

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