General Anesthetics

By
Dr. Y. S. OZARDE
 CONTENTS

 What are General anesthetics

 Inhalation anesthetics: Halothane*,
Methoxyflurane, Enflurane, Sevoflurane, Isoflurane,
Desflurane
 Ultra short acting barbitutrates: Methohexital
sodium*, Thiamylal sodium, Thiopental sodium
 Dissociative anesthetics: Ketamine hydrochloride
 Synthesis of Halothane, Methohexital, Ketamine
What are General Anesthetics?

 A drug that brings about a reversible loss of

consciousness.
 Administered by an anesthesiologist in order
to induce or maintain general anesthesia to
facilitate surgery
 History

 William Morton administered ether to a patient

having a neck tumor removed at the Massachusetts
General Hospital, Boston, in October 1846

 The discovery of the diethyl ether as general

anesthesia was the result of a search for means of
eliminating a patient’s pain perception and
responses to painful stimuli.

(CH3CH2)2O
 Classification

1. Inhalation anesthetics: Halothane, Methoxyflurane,

Enflurane, Sevoflurane, Isoflurane, Desflurane
2. Ultra short acting barbitutrates: Methohexital
sodium, Thiamylal sodium, Thiopental sodium
3. Dissociative anesthetics: Ketamine hydrochloride
1. Inhalation Anesthetics
– Gasses or Vapors
– Usually Halogenated
2. Intravenous Anesthetics
– Injections
– Anesthetics or induction agents
 Inhalation Anesthetics
F H F F
Cl
F Cl Cl2HC OCH3 CH OCHF2
F Br F F F
Halothane Methoxyflurane Enflurane

CF3 Cl F

F3C OCH2F F3C OCHF2 F3C OCHF2

Sevoflurane Isoflurane Desflurane
Dissociative anesthetics

Cl CH3
HN

HCl
O
Ketamine
 Physical and Chemical Properties of
Inhaled Anesthetics
 Halogenations of hydrocarbons & ethers increase potency
 Halogenation increase the potential for inducing cardiac
arrhythmias in the following order F<Cl<Br
 Ethers that have an asymmetric halogenated carbon tend to be
good anesthetics (e.g. 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 flammibity & increase stability of adjacent
halogenated carbons
 Complete halogenations of alkane & ethers or full halogenations
of end methyl groups decrease potency & enhances convulsant
activity
 The presence of double bonds tends to increase chemical
reactivity and toxicity
Overview
8 1 2

7 C C O C 3

6 5 4

MW 1 2 3 4 5 6 7 8
Diethyl ether 74 H H CH3 H H H H H
Fluroxene 126 H H =CH2 H F F F
Methoxyflurane 165 F H H H F Cl H Cl
Desflurane 168 H F H F F F F F
Isoflurane 184 H F H F Cl F F F
Enflurane 184 F F H F F Cl H F
Sevoflurane 200 H H F H CF3 F F F
Ultra short acting barbitutrates
O O
CH2
N CH3 HN CH2CH=CH2
NaO NaS
N CH3 N CH(CH2)CH3
H3C O
O CH3
Methohexital Sodium Thiamylal Sodium
O
HN C2H5
NaS
N CH(CH2)CH3

O CH3
Thiopental Sodium
Intravenous Anesthetics

 Used in combination with Inhaled anesthetics to:

– Supplement general anesthesia
– Maintain general anesthesia
– Provide sedation
– Control blood pressure
– Protect the brain
Essential Components of Anesthesia

 Analgesia- perception of pain eliminated

 Hypnosis- unconsciousness
 Depression of spinal motor reflexes
 Muscle relaxation

* These terms together emphasize the role of

immobility and of insensibility!
Hypotheses of General Anesthesia
1. Lipid Theory: based on the 2. Protein (Receptor)Theory:
fact that anesthetic action based on the fact that anesthetic
is correlated with the potency is correlated with the
oil/gas coefficients. ability of anesthetics to inhibit
 The higher the solubility of enzymes activity of a pure,
anesthetics is in oil, the soluble protein
greater is the anesthetic Explain the GABAA receptor is a
potency. potential target of anesthetics
 SAR Irrelevant action

3. Binding theory: Anesthetics bind to hydrophobic portion of the ion

channel
 Mechanism of Action
UNKNOWN!!
 Most Recent Studies
General Anesthetics acts on the CNS by modifying
the electrical activity of neurons at a molecular level
by modifying functions of ION CHANNELS

This may occur by anesthetic molecules binding

directly to ion channels or by their disrupting the
functions of molecules that maintain ion channels
Cont on Mechanism

 Proteins involved in neuronal excitability

– Voltage-gated ion channels, such as sodium,
potassium, and calcium channels
– Ligand-gated ion channel super family and
– G protein-coupled receptors super family.
 Anesthetic
Suppression of
Physiological
Response to
Surgery
 Pharmacokinetics of Inhaled
Anesthetics

1. Amount that reaches the brain

Indicated by oil:gas ratio (lipid solubility)
2. Partial Pressure of anesthetics
5% anesthetics = 38 mmHg
3. Solubility of gas into blood
The lower the blood:gas ratio, the more anesthetics will arrive at
the brain
4. Cardiac Output
Increased CO= greater Induction time
Pathway for General Anesthetics
Variables that Control Partial Pressure
in Brain

 Direct Physician's Control

– Solubility of agent
– Concentration of agent in inspired by air
– Magnitude of alveolar ventilation

 Indirect Physician’s Control

– Pulmonary blood flow-function of CO
– Arteriovenous concentration gradient
Rate of Entry into the Brain: Influence
of Blood and Lipid Solubility
MAC

 A measure of potency
 1MAC is the concentration necessary to
prevent responding in 50% of population.
 Values of MAC are additive:
– Avoid cardiovascular depressive concentration of
potent agents.
Increase in Anesthetic Partial Pressure in Blood
is Related to its Solubility
 General Actions of Inhaled Anesthetics

 Respiration: Depressed respiration and response to CO2

 Kidney: Depression of renal blood flow and urine output
 Muscle: High enough concentrations will relax skeletal
muscle
 Cardiovascular System: Generalized reduction in arterial
pressure and peripheral vascular resistance. Isoflurane
maintains CO and coronary function better than other agents
 Central Nervous System: Increased cerebral blood flow and
decreased cerebral metabolism
Toxicity and Side Effects
 Depression of respiratory drive
– Decreased CO2 drive (medullary chemoreceptors), Takes
MORE CO2 to stimulate respiration
 Depressed cardiovascular drive
 Gaseous space enlargement by NO
 Fluoride-ion toxicity from Methoxyflurane
Metabolized in liver = release of Fluoride ions
Decreased renal function allows fluoride to accumulate =
nephrotoxicity
 Malignant hyperthermia
– Rapidly cool the individual and administer Dantrolene to
block S.R. release of Calcium
Halothane : Synthesis

Cl H F H F H
3HF/130°C Br2
F Cl F Cl
SbCl3
Cl Cl F H F Br
Trichloroethylene 2-chloro-1,1,1- Halothane
trifluoroethane
Methohexital: Synthesis
CH3CHO H3C CH3
H3C MgBr
HO

PBr3
O
Diethyl
C2H5O CH3 malonate
H3C CH3
C2H5O Sodium
CH3 ethoxide Br
O

Sodium Allyl
ethoxide bromide

O
O CH2
CH2 H
N CH3
C2H5O CH3 N-Methyl O
Urea
N CH3
C2H5O CH3
H3C O
O
Ketamine: Synthesis
Cl MgBr Cl Cl
NMgBr NH
N H3O+

2-Chloro benzonitrile

H3O+
Cl
Cl Cl
NCH3
O O
CH3NH2 Br2
OH
NaOH Br

Cl CH3
HN
HCl
Heat

O
Thank You