Inhaled Anesthetics Mechanism of Action

Inhaled General Anesthetics

• The reduced activity of inhaled general anesthetics beyond their cutoff number could be due to problems reaching the site of action or inability to bind and induce the required conformational change.
• Cycloalkanes are more potent anesthetics than their straight-chain analogs with the same number of carbons.
• For example, the MAC of cyclopropane in rats is about one-fifth of the MAC of n-propane.

Structure-Activity Relationship (SAR) of Inhaled General Anesthetics

• Halogenating the ethers decreased flammability, enhanced stability, and increased potency.
• Higher atomic mass halogens increased potency compared to lower atomic mass halogens.
• For example, replacing the fluorine in desflurane with a chlorine to form isoflurane increased potency more than fourfold.
• Halogenated ether compounds also caused fewer laryngospasms than unhalogenated compounds.
• However, halogenation also increased the propensity of the drugs to cause cardiac arrhythmias and/or convulsions.
• Halogenated methyl ethyl ethers were found to be more stable and potent than halogenated diethyl ethers.
• For the n-alkane series, fully saturating the alkane with fluorine abolished activity except when n = 1.

Effect of Saturation

• Molecular flexibility of the inhaled anesthetics is not required.
• The addition of double and/or triple bonds to small anesthetic molecules having 6 carbon atoms or less increases potency.

Intravenous General Anesthetic Agents

• Propofol, ketamine, etomidate, and midazolam are examples of intravenous general anesthetic agents.
• Each agent has its own mechanism of action, structure-activity relationship, metabolism, and storage.

Local Anesthetics

• Local anesthetic agents produce a state of local anesthesia by reversibly blocking nerve conductances that transmit pain sensations.
• Unlike general anesthetics, local anesthetics do not cause loss of consciousness or impairment of vital central cardiorespiratory functions.
• Local anesthetics do not interact with pain receptors or inhibit the release or biosynthesis of pain mediators.

Structure-Activity Relationship (SAR) of Local Anesthetics

• The structure of most local anesthetic agents consists of three parts: a lipophilic ring, a linker of various lengths, and an amine group.
• Variation of the amine or aromatic ends changes the chemical activity of the drug.
• The aromatic ring adds lipophilicity to the anesthetic and helps the molecule penetrate biological membranes.
• Amino esters are unstable in solution and are more likely to cause allergic hypersensitivity reactions than amino amides.

Classification of Local Anesthetics

• Commonly used amino amides include lidocaine, mepivacaine, prilocaine, bupivacaine, etidocaine, and ropivacaine.
• Commonly used amino esters include cocaine, procaine, tetracaine, chloroprocaine, and benzocaine.

Synthesis of Local Anesthetics

• Procaine is synthesized in two ways: through the direct reaction of 4-aminobenzoic acid ethyl ester with 2-diethylaminoethanol or through the reaction of 4-nitrobenzoic acid with thionyl chloride.
• Procaine is a short-acting local anesthetic used for reducing painful symptoms and is widely used in infiltration, block, epidural, and spinal cord anesthesia.
• Lidocaine is synthesized from 2,6-dimethylaniline and is the most widely used local anesthetic.
• Other triazole or imidazole rings capable of H-bonding can be fused on positions 1 and 2 to increase the activity.

Benzodiazepines

• All sedative-hypnotic benzodiazepines contain the 5-phenyl-1,4-benzodiazepine-2-one backbone required for GABA activity.
• An electronegative 7-position chloro substitution is required on ring A.
• The pendant 5-phenyl ring (ring C) is required for in vivo agonism and can be substituted with ortho-electronegative halogens to increase lipophilicity.
• Para substitution on ring C leads to inactive benzodiazepines, suggesting that steric restrictions are important at this site.

Metabolism of Benzodiazepines

• Flurazepam is primarily metabolized by CYP3A4-mediated N-dealkylation and hydroxylation, yielding active N1-desalkyl and N1-hydroxyethyl metabolites.
• The long half-life of these metabolites explains the clinical findings that flurazepam exhibits faster sleep latency and decreases in total wake time following several days of use and is still efficacious for one to two nights following discontinuation.
• Quazepam is metabolized by microsomal CYP450 oxidases to yield 2-oxoquazepam, which is subsequently N-dealkylated to N-desalkyl-2-oxoquazepam.
• Both metabolites are pharmacologically active and have long durations.

Nonbenzodiazepine GABA Agonists

• Zolpidem, eszopiclone, and zaleplon are approved for insomnia and are often referred to as the Z-drugs.

Melatonin Receptor Agonists

• Melatonin is a neurohormone that is primarily synthesized in the pineal gland from its precursor serotonin.
• The sleep-promoting effects of melatonin are due to agonism of both MT1 and MT2 receptors.
• (S)-Ramelteon is a melatonin receptor agonist approved for insomnia and selectively binds to both MT1R and MT2R.