General Anaesthetics 2014-2015

Pharmaceutical Chemistry of Organic Medicinals

Lecture Notes

Introduction
 Anesthetics are drugs, which produce anesthesia, a condition of inability to appreciate sensation.
 Two types of anesthesia: local anesthesia and general anesthesia.
 In local anesthesia, the anesthesia is confined to a portion of the body and the patient is conscious.
 In general anesthesia, the anesthesia extends to the entire body and under which the patient is
unconscious, in a state of muscular relaxation and insensibility to pain.
 Anesthetics are depressant drugs that produce a partial or total loss of the sense of pain. In the case of general
anesthetics, this is accompanied by a loss of consciousness.
 The first demonstration of such a drug was conducted in 1844 by Samuel Cooley, who demonstrated the effects
of nitrous oxide on a Pharmacy student. During the demo, the student fell and injured his leg (but he didn't feel
it until later).

General anesthesia occurs in 4 distinct stages:

 Stage I - analgesia results from an increase in circulating endorphins, and there is a mild depression of
cortical centers. This is the type of anesthesia referred to as twilight sleep.
 Stage II - this stage is characterized by a loss of consciousness. It is also a critical period, since delerium
and increased involuntary activity, as well as hypersecretion, can occur. Secretions can be managed with an
anticholinergic agent, but it is best to get through Stage II as quickly as possible. Stage I and Stage II
together are referred to as induction.
 Stage III - this is the stage of anesthesia known as surgical anesthesia, and most surgical procedures are
performed during this stage. There is a general loss of spinal reflexes and muscle tone.
 Stage IV - this undesirable stage is characterized by respiratory depression, and other manifestations of
overdose.

 Most general anesthetics are non-specific agents, in that their activity depends on their lipid solubility rather than
their structure. Inhaled and exhaled gas containing the agent equilibrates with the lung tissue, and then with the
blood. In the brain, which has a great deal of vasculature, the agent equilibrates between the blood and neural
tissue, depressing neurons and causing the pharmacological effect.
 MAC – minimum alveolar concentration is the measure of potency (ventilation and concentration is
proportional to the onset of anesthesia)

General Anesthetic Agents

 Ether and chloroform - these agents are the anesthetics from hell, because they have all of the negative
traits of this class of drug. Ethyl ether is potent, and has a good margin of safety, but it is flammable,
explosive, it forms peroxides, it produces an unpleasant induction phase, is irritating, and produces nausea
and vomiting during recovery. Chloroform is also potent, and produces good skeletal muscle relaxation, but
has a narrow margin of safety, produces liver and kidney toxicity, cardiac arrest and arrhythmias, and it can
produce severe hypotension. The ideal general anesthetic is non-flammable, gives good muscle relaxation,
has an uncomplicated induction and recovery, is non-toxic, and is easy to administer.
 Non-halogenated hydrocarbons - all of these will work, and the longer the chain, the higher the potency.
However, they have a tendency to produce cardiovascular toxicity. Cyclopropane (U.S.P.) is the only one still
in use, and it is explosive.
 Ethers - Like hydrocarbons, the longer the chain, the more potent the anesthetic. However, increasing
chain length also increases toxicity and reduces induction time. Ethyl ether is seldom used, and divinyl ether
is explosive and produces deep anesthesia too quickly.
 Halogenated hydrocarbons - Addition of a halogen can reduce or eliminate flammability, and can also
increase potency. Depending on the halogen, some of these compounds can cause arrhythmias and/or renal
or hepatic toxicity. Compounds containing only bromine are generally not useful. Compounds containing
only chlorine are subject to limited use, are toxic, and can cause arrhythmias. The best of the chlorinated
agents are ethyl chloride and trichloroethylene, shown below.
General Anaesthetics 2014-2015
Pharmaceutical Chemistry of Organic Medicinals
Lecture Notes

 Fluorinated hydrocarbons are the most useful of the general anesthetics, and were first discovered as
offshoots of the nuclear weapons program. Addition of a fluorine decreases flammability, boiling point and
the incidence of catechol-induced arrhythmias (these increase as the size of the halogen increases, and F is
the smallest halogen).
 Halothane, USP (Fluothane) - the first fluorinated hydrocarbon to be introduced, and not all that great of a
drug. It is a poor muscle relaxant, and has some toxicity and propensity to cause catechol-induced
arrhythmias.
 Methoxyflurane (Penthrane) - this analog is somewhat better, but still causes some arrhythmias and other
toxicity. It also causes a slow induction period.
 Enflurane, U.S.P. (Enthrane) - a pretty good anesthetic, but has unsatisfactory analgesia in Stage I.
 Isoflurane (Forane) - the best general anesthetic so far, it has no commonly observed ill effects.
 Nitrous oxide - This is the least toxic anesthetic, but is also the least potent. It causes good analgesia, but
is a poor muscle relaxant.

3. Intravenous Anesthetic
 the development of new intravenous anesthetic appears to be more favorable both chemically and economically
than does the development of inhalation anesthetics.
 trace amounts of inhalation anesthetics polluting the operating room environment have been implicated in a
variety of ailment, which affect operating room personnel.
 Often used in combination with inhalation anesthetic to induce or sustain surgical anesthesia
 Disadvantages include: inability to be removed once administered, induction complications, tissue irritation and
damage, recovery reactions, hypersensitivity reactions
 Includes
 Ultra-short acting barbiturates: thiopental, thiamylal, methohexital
 Cyclohexylamines: ketamine
 Benzodiazepnes: diazepam, midazolam
 Butyrophenones: droperidol
 Imidazole: etomidate
 Dialkylphenol: propofol