Inhaled Anesthetics Mechanism of Action

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Questions and Answers

What is the effect of adding double and/or triple bonds to small anesthetic molecules having 6 carbon atoms or less?

Decreases potency

Increases potency (correct)

Has no effect on potency

Alters the mechanism of action

Which of the following is NOT a characteristic of local anesthetics?

Producing a state of local anesthesia

Interacting with pain receptors

Reversibly blocking nerve conductances

Impairing vital central cardiorespiratory functions (correct)

What is the typical pKa range of the amine group in local anesthetics?

8.0-10.0

7.5-9.0 (correct)

6.0-7.0

5.5-6.5

What is the function of the linker in local anesthetic agents?

Usually contains either an ester or an amide Signup and view all the answers

What is the effect of varying the amine or aromatic ends of local anesthetic agents?

Changes the chemical activity of the drug Signup and view all the answers

Which of the following is NOT a part of the structure of most local anesthetic agents?

A pain receptor Signup and view all the answers

What is the function of the aromatic ring in local anesthetic agents?

Adds lipophilicity to the anesthetic and helps penetrate biological membranes Signup and view all the answers

What is the difference between local anesthetics and general anesthetics?

Local anesthetics produce a state of local anesthesia without loss of consciousness Signup and view all the answers

What is the structural requirement for GABA activity in sedative-hypnotic benzodiazepines?

5-phenyl-1,4-benzodiazepine-2-one backbone Signup and view all the answers

What is the effect of para substitution on ring C of benzodiazepines?

Leads to inactive benzodiazepines Signup and view all the answers

What is the primary metabolic pathway of flurazepam?

CYP3A4-mediated N-dealkylation and hydroxylation Signup and view all the answers

What is the elimination half-life of N1-desalkyl flurazepam?

47 to 100 hours Signup and view all the answers

What is the major urinary metabolite of flurazepam?

N1-hydroxyethyl flurazepam conjugate Signup and view all the answers

What is the effect of flurazepam on sleep latency and total wake time?

Decreases sleep latency and total wake time Signup and view all the answers

What is the metabolite of quazepam formed by microsomal CYP450 oxidases?

2-oxoquazepam Signup and view all the answers

What is the characteristic of the metabolites of quazepam?

They are pharmacologically active and have long durations Signup and view all the answers

What is the result of further hydroxylation of 2-oxoquazepam and N-desalkyl-2-oxoquazepam at the 3-position?

Formation of inactive metabolites Signup and view all the answers

What is the primary reason for residual hypnotic effects of flurazepam and quazepam?

Slow elimination of multiple active metabolites Signup and view all the answers

What is the mechanism of action of melatonin in promoting sleepiness?

Agonism of MT1 and MT2 receptors Signup and view all the answers

What is the primary function of melatonin in the body?

Regulation of circadian rhythms Signup and view all the answers

What is the characteristic of the Z-drug, which includes zolpidem, eszopiclone, and zaleplon?

Non-benzodiazepine GABA agonists Signup and view all the answers

What is the mechanism of action of (S)-Ramelteon?

Agonism of MT1 and MT2 receptors Signup and view all the answers

What is a possible reason for the reduced activity of compounds beyond their cutoff number?

Problems getting to the site of action or inability to bind to the site of action Signup and view all the answers

What is the effect of halogenation on the flammability of ether compounds?

It decreases the flammability Signup and view all the answers

What is the effect of replacing the fluorine in desflurane with a chlorine to form isoflurane?

It increases potency more than fourfold Signup and view all the answers

What is the effect of fully saturating the alkane with fluorine in the n-alkane series?

It abolishes activity except when n = 1 Signup and view all the answers

What is the result of halogenation on the propensity of drugs to cause cardiac arrhythmias and/or convulsions?

It increases the propensity Signup and view all the answers

What is the effect of halogenation on the stability of ether compounds?

It increases stability Signup and view all the answers

What is the effect of cycloalkanes compared to their straight chain analogs with the same number of carbons?

They are more potent Signup and view all the answers

What is the highest potency seen for the n-alkane series when n is 2 to 4 carbons?

When the terminal carbon contains one hydrogen Signup and view all the answers

What is the characteristic of amino esters in solution?

They are unstable Signup and view all the answers

Which of the following is a characteristic of amino amides?

They are very stable in solution Signup and view all the answers

Which local anesthetic is synthesized from 2,6-dimethylaniline?

Lidocaine Signup and view all the answers

What is the use of procaine in medical practice?

To reduce painful symptoms of various types Signup and view all the answers

Which of the following is a common use of lidocaine?

In infiltration, block, epidural, and spinal cord anesthesia Signup and view all the answers

What is the characteristic of procaine?

It is a short-acting local anesthetic Signup and view all the answers

Which of the following local anesthetics is most widely used?

Lidocaine Signup and view all the answers

What is the reaction involved in the synthesis of procaine?

All of the above Signup and view all the answers

Study Notes

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.

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Description

This quiz explores the properties of inhaled anesthetics, including their ability to bind to the site of action and induce a conformational change, and how factors like vapor pressure and blood solubility affect their potency.