Methohexital Sodium: Structure,Synthesis,SAR,Mechanism,Uses

Methohexital Sodium

Structure –

Methohexital Sodium, also known by its brand name Brevital Sodium, is a barbiturate derivative and a short-acting intravenous general anesthetic. Its chemical structure can be represented as:

Methohexital Sodium

The chemical formula of methohexital sodium is C14H17N2NaO3, indicating that it contains 14 carbon atoms, 17 hydrogen atoms, 2 nitrogen atoms, 1 sodium atom, and 3 oxygen atoms. The sodium ion is present as a positively charged counterion to balance the negative charge on the molecule.

Methohexital sodium is a white or slightly yellowish crystalline powder that is highly soluble in water and has a bitter taste. It is typically supplied as a sterile powder that is reconstituted with sterile water for injection prior to use.

Synthesis –

The synthesis of Methohexital Sodium involves several steps. Here is a simplified representation of the synthesis route:

  1. Condensation of 5-allyl-5-(1-methylbutyl)barbituric acid with methanesulfonyl chloride and triethylamine in the presence of dimethylformamide to form the corresponding methanesulfonate ester.

Methohexital Sodium

  1. The methanesulfonate ester is then reacted with sodium ethoxide in ethanol to form the sodium salt of the barbiturate intermediate.

Methohexital Sodium

  1. The sodium salt is then reacted with 1,6-dibromohexane in DMF to form the corresponding hexyl derivative.

Methohexital Sodium

4. The final step involves the neutralization of the sodium salt with hydrochloric acid to form the hydrochloride                  salt, which is then converted to the sodium salt using sodium hydroxide or sodium bicarbonate.

Methohexital Sodium

The resulting product is Methohexital Sodium, which is a white crystalline powder that is highly water-soluble and can be used as an intravenous anesthetic.


  • The SAR (Structure-Activity Relationship) of Methohexital Sodium is primarily governed by the presence of a barbiturate nucleus, which confers its anesthetic activity. The barbiturate nucleus contains a pyrimidine ring system that is fused with a diazepine ring, as shown in the Methohexital Sodium structure.
  • The pharmacological activity of Methohexital Sodium is primarily determined by the substituents attached to the barbiturate nucleus. The presence of an ethyl group at the C5 position of the pyrimidine ring and a hexyl group at the C5 position of the diazepine ring are critical for its anesthetic activity.
  • The ethyl group at the C5 position is essential for enhancing the lipophilicity of the molecule, which enables it to cross the blood-brain barrier and exert its anesthetic effect. The hexyl group at the C5 position of the diazepine ring is responsible for increasing the duration of the anesthetic effect.
  • The substituents at the C1 and C3 positions of the pyrimidine ring also play a crucial role in the anesthetic activity of Methohexital Sodium. The presence of a methyl group at the C1 position enhances the anesthetic potency of the molecule, while the presence of a butyl group at the C3 position increases its duration of action.
  • In summary, the SAR of Methohexital Sodium is primarily governed by the presence of the barbiturate nucleus and the nature of the substituents attached to it. The ethyl and hexyl groups at the C5 position of the pyrimidine and diazepine rings, respectively, are critical for its anesthetic activity, while the substituents at the C1 and C3 positions modulate its potency and duration of action.

Mechanism –

  • Methohexital Sodium is a short-acting barbiturate that exerts its anesthetic effect by enhancing the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. The exact mechanism of action of Methohexital Sodium is not fully understood, but it is believed to involve multiple molecular targets.
  • One of the primary targets of Methohexital Sodium is the GABA-A receptor, a ligand-gated ion channel that mediates the majority of inhibitory neurotransmission in the brain. Methohexital Sodium binds to a specific site on the GABA-A receptor complex, known as the benzodiazepine binding site, which enhances the activity of GABA at the receptor. This results in an increase in chloride ion influx into the neuron, hyperpolarizing the membrane potential and reducing neuronal excitability, ultimately leading to sedation and anesthesia.
  • Methohexital Sodium also exerts its anesthetic effect by modulating other neurotransmitter systems, including the N-methyl-D-aspartate (NMDA) receptor and the voltage-gated sodium and potassium channels. Methohexital Sodium inhibits the activity of NMDA receptors, which play a key role in the perception of pain and the formation of memories.
  • By blocking NMDA receptors, Methohexital Sodium reduces the perception of pain and impairs memory formation during anesthesia. Methohexital Sodium also modulates the activity of voltage-gated ion channels, which are involved in generating and propagating action potentials in neurons. By reducing the activity of these channels, Methohexital Sodium reduces neuronal excitability and enhances the sedative and anesthetic effects.
  • In summary, the mechanism of action of Methohexital Sodium involves multiple molecular targets, including the GABA-A receptor, NMDA receptor, and voltage-gated ion channels. By enhancing the activity of inhibitory neurotransmitters and reducing the activity of excitatory neurotransmitters, Methohexital Sodium produces its sedative and anesthetic effects.

Uses –

Methohexital Sodium is a short-acting barbiturate that is primarily used as an intravenous anesthetic for the induction of general anesthesia. Its fast onset and short duration of action make it particularly useful for short surgical procedures or diagnostic procedures that require sedation. Some of the specific uses of Methohexital Sodium include:

  1. Induction of general anesthesia: it  is commonly used as a single agent for the induction of general anesthesia, particularly for short surgical procedures such as dental or ophthalmic procedures.
  2. Sedation for diagnostic procedures: it  can also be used to provide sedation for diagnostic procedures such as EEG (electroencephalography) or MRI (magnetic resonance imaging) scans.
  3. Emergency seizures: it  may be used to treat emergency seizures due to its rapid onset of action and short duration.
  4. Anesthesia for electroconvulsive therapy (ECT): it may be used as an anesthetic agent for patients undergoing electroconvulsive therapy (ECT).

it  is not typically used for long-term sedation or as a chronic treatment for any medical condition due to the potential for addiction and abuse. It is only administered in a medical setting under the supervision of a trained healthcare provider.

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