General Anesthetics

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What are General Anesthetics?

•       A drug that brings about a reversible loss of consciousness.

•       Not for therapeutic or diagnostic procedures

•       These drugs are generally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery.

FUNCTIONS OF GENERAL ANESTHETICS:

Analgesia (pain relief)

Amnesia

Loss of consciousness

Impairment of all skeletal muscle (motionlessness)

Weakened autonomic responses

Reversible

*Not all anesthetics bring about all these.

SHORT HISTORICAL BACKGROUND

Dr. Crawford W. Long -a surgeon and pharmacist

                                           -diethyl ether used as anesthetic in 1842

                                                     

Dr. William Morton -diethyl ether publicized as anesthetic in 1846

CLASSIFICATION OF GENERAL ANESTHETICS:

•       INHALATIONAL

                -liquid inhalation

                -gaseous inhalation

•       INTRAVENOUS

STRUCTURE-ACTIVITY RELATIONSHIP

•      Although halogenations of hydrocarbons and ethers increase anesthetic potency, it also increase the potential for inducing cardiac arrhythmias in the following order F<Cl<Br.1

•      Ethers that have an asymmetric halogenated carbon tend to be good anesthetics (such as Enflurane).

    Halogenated methyl ethyl ethers (Enflurane and Isoflurane) are more stable, are more potent, and have better clinical profile than halogenated diethyl ethers.

•      Fluorination decrease flammability and increase stability of adjacent halogenated carbons.

•      Complete halogenations of alkane and ethers or full halogenations of end methyl groups decrease potency and enhances convulsant activity. Flurorthyl (CF3CH2OCH2CF3) is a potent convulsant, with a median effective dose (ED50) for convulsions in mice of 0.00122 atm.

•      The presence of double bonds tends to increase chemical reactivity and toxicity.

LIQUID INHALATION ANESTHETICS

• Diethyl ether
• Halothane
• Methoxyflurane
• Enflurane
• Isoflurane
• Desflurane
• Sevoflurane

Diethyl ether

•       a volatile liquid

•        first anesthetic used

•        causes a slow induction of and slow emergence from narcosis

•        irritating and explosive (flammable)

•        post-op nausea & vomiting

•        no longer used in modern anesthesiology

•       IUPAC name: ethoxyethane or diethyl ether

Halothane

•       an alkyl halide

•       only inhalational anesthetic agent containing a bromine atom

•        common in pedia due to lack of airway irritation

•        rapid induction & emergence

•        non-flammable

•        may cause liver damage

•       IUPAC name: 2-bromo-2-chloro-1,1,1-trifluoroethane

Methoxyflurane

•       halogenated ether

•       non-flammable

•       skeletal muscle relaxant

•       no bronchial irritation

•       slow induction and recovery

•       Nephrotoxic due to fluoride ion and oxalate metabolites

•                                70% metabolized due to lesser number of fluorine

•       IUPAC name: 2,2-dichloro-1,1-difluoroethyl methyl ether

Enflurane

•       halogenated ether

•       retained the ether structure, but substituted hydrogen by halogen atoms

•       non-flammable

•       less potential liver damage

•       low frequency of adverse CV effects

•       relatively easy induction

•       CI to epileptic patients

•       IUPAC name: 2-chloro-1,1,2,-trifluoroethyl difluoromethyl ether

Isoflurane

•       structural isomer of enflurane

•       retained the ether structure, but substituted hydrogen by halogen atoms

•       non-flammable

•       lesser potential liver damage as compared to enflurane

•       IUPAC name: 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether

Desflurane

•       modern liquid inhalational anesthetic

•       not metabolized because it is highly-fluorinated methyl ethyl ether

•       non-flammable

•       it is a greenhouse gas

•       IUPAC name: 2-(difluoromethoxy)-1,1,1,2-tetrafluoro-ethane

Sevoflurane

•       modern liquid inhalational anesthetic

•       not metabolized because it is highly-fluorinated methyl ethyl ether

•       non-flammable

•       IUPAC name: 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane

GASEOUS INHALATION ANESTHETICS

• Cyclopropane
• Nitrous oxide
• Ethylene

Cyclopropane

•       obsolete and rarely used

•       highly explosive when mixed with oxygen

•       stored in orange colored cylinders at 75 psi

•       fast onset of action

•       IUPAC name: cyclopropane

Nitrous oxide

•       “laughing gas”

•       Only anesthetic agent that is inorganic

•       used only for short operations and in dentistry

•       weak anesthetic

•       good analgesic

•       IUPAC name: nitrous oxide or dinitrogen monoxide

Ethylene

•       unsaturated hydrocarbon

•       obsolete

•       highly explosive and flammable when mixed with oxygen

•       IUPAC name: ethylene or ethene

INTRAVENOUS ANESTHETICS

• Ketamine
• Thiamylal
• Thiopental
• Methohexital
• Etomidate
• Propofol

Ketamine

•       Structural relative of medically dicontinued agent phencyclidine (PCP)

•       for dissociative anesthesia (esp. children)

•       CV stimulation, advantage to elderly and those in shock

•       bronchodilator

•       post-op hallucinations and delirium

•       popular veterinary anesthetic

•       IUPAC name: (RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone

Thiopental

•       most widely used ultra-short acting anesthetic barbiturate

•       consciousness regained w/in 30mins

•       CV depression

•       used for short operations

•       2 alkyl side chains impart lipophilicity

•       IUPAC name: (RS)-[5-ethyl-4,6-dioxo-5-(pentan-2-yl)-1,4,5,6-tetrahydropyrimidin-2-yl]sulfanide

Thiamylal

•       highly hydrophobic

•       induction in surgical anesthesia

•       ultra-short acting anesthetic barbiturate

•       unconsciousness w/in secs, consciousness regained w/in 30mins

•       IUPAC name: 5-allyl-5-(1-methylbutyl)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione

Methohexital

•       N-methyl barbiturate that increases

lipophilicity of the compound

•       rapid onset of narcosis

•       unsaturated bonds in the side chains

increase rate of drug degradation

•       IUPAC name: 5-hex-3-yn-2-yl-1- methyl-5-prop-2-enyl-1, 3-diazinane-2,4,6-trione

Etomidate

•       Short-acting IV anesthetic used for general anesthesia and sedation

•       Contains a 4-carboxylic acid ester-substituted imidazole moiety

•       IUPAC name: ethyl 3-[(1R)-1-phenylethyl]imidazole-4-carboxylate

Propofol

•       Short-acting IV anesthetic used for induction and maintenance of general anesthesia and sedation

•       unrelated to barbiturates

•       more rapid and clear recovery

•       not an analgesic, so combined w/ opioids

•       “milk of amnesia”

•       IUPAC name: 2,6-diisopropylphenol

LIST OF DRUGS AVAILABLE IN THE MARKET

INHALATION ANESTHETICS

GENERIC	BRAND	MANUFACTURER
Enflurane	Enthrane	Abbott
Enflurane	Endurane	Singapore Pharmawealth Lifesciences
Enflurane	Phil Pharmawealth/Minrad Enflurane	Minrad
Isoflurane	Aerrane	Baxter Healthcare
Isoflurane	Florane	Singapore Pharmawealth Lifesciences
Isoflurane	Forane	Abbott
Isoflurane	Pascual Isoflurane	Rhodia
Isoflurane	Phil Pharmawealth/Minrad Isoflurane	Minrad
Desflurane	Suprane	Baxter Healthcare
Sevoflurane	Sevo	Singapore Pharmawealth Lifesciences
Sevoflurane	Sevorane Pen	Abbott
*Methoxyflurane	Penthrane	Abbott
*Halothane	Fluothane	---
*Not available in the Philippines. INTRAVENOUS ANESTHETICS
GENERIC	BRAND	MANUFACTURER
Ketamine HCl	Ketacor	Duopharma (M) Sdn Bhd
Ketamine HCl	Ketamax	Rotexmedica
Ketamine HCl	Ketazol	Korea United Pharma
Thiopental Sodium	Pentazol	Swiss Parenterals
Thiopental Sodium	Penthal	Oboi
Thiopental Sodium	Pentobrim	Rotexmedica
Thiopental Sodium	Pentothal	Hospira
Propofol	Diprifol	Dong Kook Pharm
Propofol	Diprivan	AstraZeneca
Propofol	Fresofol	Fresenius Kabi
Propofol	Hospira Propofol	Hospira
Propofol	IV-Pro	Claris Lifesciences
Propofol	Lipuro	B Braun
*Thiamylal Na	Surital Sodium	---
*Etomidate	Amidate	Hospira
*Methohexital Sodium	Brevital Sodium	JHP Pharmaceuticals

*Not available in the Philippines.

REFERENCES

Block, J., Beale, J. (2004). Wilson and Gisvold’s Textbook of Organic Medicinals and Pharmaceutical Chemistry.11^th ed, pp. 485-488. Lippincott Williams and Wilkins.

Gringauz, A. (1997). Introduction to Medicinal Chemistry: How Drugs Act and Why. pp. 564-571. Canada: Wiley-Veh.

Nogrady, T. (1988). Medicinal Chemistry: A Biochemical Approach. 2nd ed, pp. 11-16. New York: Oxford University Press, Inc.

MIMS Philippines. (2009). CMPMedica Asia Pte Ltd.