General Anesthetic Drugs

General Anesthesia and General
Anesthetic Drugs
General anesthesia is a state of drug-induced
reversible inhibition of central
nervous function, during which surgical
procedures can be carried out in the absence
of consciousness, responsiveness
to pain, defensive or involuntary movements,
and significant autonomic reflex
responses .
The required level of anesthesia depends
on the intensity of the pain-producing
stimuli, i.e., the degree of nociceptive
stimulation. The skilful anesthetist,
therefore, dynamically adapts the
plane of anesthesia to the demands of
the surgical situation. Originally, anesthetization
was achieved with a single
anesthetic agent (e.g., diethylether—
first successfully demonstrated in 1846
by W. T. G. Morton, Boston). To suppress
defensive reflexes, such a “mono-anesthesia”
necessitates a dosage in excess
of that needed to cause unconsciousness,
thereby increasing the risk of paralyzing
vital functions, such as cardiovascular
homeostasis . Modern anesthesia
employs a combination of different
drugs to achieve the goals of surgical
anesthesia (balanced anesthesia). This
approach reduces the hazards of anesthesia.
In C are listed examples of drugs
that are used concurrently or sequentially
as anesthesia adjuncts. In the case
of the inhalational anesthetics, the
choice of adjuncts relates to the specific
property to be exploited (see below).
Muscle relaxants, opioid analgesics such
as fentanyl, and the parasympatholytic
atropine are discussed elsewhere in
more detail.
Neuroleptanalgesia can be considered
a special form of combination anesthesia,
in which the short-acting opioid
analgesics fentanyl, alfentanil, remifentanil
is combined with the strongly
sedating and affect-blunting neuroleptic
droperidol. This procedure is used in
high-risk patients (e.g., advanced age,
liver damage).
Neuroleptanesthesia refers to the
combined use of a short-acting analgesic,
an injectable anesthetic, a short-acting
muscle relaxant, and a low dose of a
neuroleptic.
In regional anesthesia (spinal anesthesia)
with a local anesthetic,
nociception is eliminated, while
consciousness is preserved. This procedure,
therefore, does not fall under the
definition of general anesthesia.
According to their mode of application,
general anesthetics in the restricted
sense are divided into inhalational
(gaseous, volatile) and injectable agents.
Inhalational anesthetics are administered
in and, for the most part, eliminated
via respired air. They serve to
maintain anesthesia. Pertinent substances
are considered on.
Injectable anesthetics are
frequently employed for induction.
Intravenous injection and rapid onset of
action are clearly more agreeable to the
patient than is breathing a stupefying
gas. The effect of most injectable anesthetics
is limited to a few minutes. This
allows brief procedures to be carried out
or to prepare the patient for inhalational
anesthesia (intubation). Administration
of the volatile anesthetic must then
be titrated in such a manner as to counterbalance
the waning effect of the injectable
agent.
Increasing use is now being made
of injectable, instead of inhalational, anesthetics
during prolonged combined
anesthesia (total intravenous anesthesia—
TIVA).
“TIVA” has become feasible thanks
to the introduction of agents with a suitably
short duration of action, including
the injectable anesthetics propofol and
etomidate, the analgesics alfentanil und
remifentanil, and the muscle relaxant
mivacurium. These drugs are eliminated
within minutes after being adminstered,
irrespective of the duration of
anesthesia.
Inhalational Anesthetics
The mechanism of action of inhalational
anesthetics is unknown. The diversity
of chemical structures (inert gas
xenon; hydrocarbons; halogenated hydrocarbons)
possessing anesthetic activity
appears to rule out involvement of
specific receptors. According to one hypothesis,
uptake into the hydrophobic
interior of the plasmalemma of neurons
results in inhibition of electrical excitability
and impulse propagation in the
brain. This concept would explain the
correlation between anesthetic potency
and lipophilicity of anesthetic drugs (A).
However, an interaction with lipophilic
domains of membrane proteins is also
conceivable. Anesthetic potency can be
expressed in terms of the minimal alveolar
concentration (MAC) at which
50% of patients remain immobile following
a defined painful stimulus (skin
incision). Whereas the poorly lipophilic
N2O must be inhaled in high concentrations
(>70% of inspired air has to be replaced),
much smaller concentrations
(< 5%) are required in the case of the
more lipophilic halothane.
The rates of onset and cessation of
action vary widely between different inhalational
anesthetics and also depend
on the degree of lipophilicity. In the case
of N2O, there is rapid elimination from
the body when the patient is ventilated
with normal air. Due to the high partial
pressure in blood, the driving force for
transfer of the drug into expired air is
large and, since tissue uptake is minor,
the body can be quickly cleared of N2O.
In contrast, with halothane, partial pressure
in blood is low and tissue uptake is
high, resulting in a much slower elimination.
Given alone, N2O (nitrous oxide,
“laughing gas”) is incapable of producing
anesthesia of sufficient depth for
surgery. It has good analgesic efficacy
that can be exploited when it is used in
conjunction with other anesthetics. As a
gas, N2O can be administered directly.
Although it irreversibly oxidizes vitamin
B12, N2O is not metabolized appreciably
and is cleared entirely by exhalation.
Halothane (boiling point [BP]
50 °C), enflurane (BP 56 °C), isoflurane
(BP 48 °C), and the obsolete methoxyflurane
(BP 104 °C) have to be vaporized by
special devices. Part of the administered
halothane is converted into hepatotoxic
metabolites . Liver damage may result
from halothane anesthesia. With a
single exposure, the risk involved is unpredictable;
however, there is a correlation
with the frequency of exposure and
the shortness of the interval between
successive exposures.
Up to 70% of inhaled methoxyflurane
is converted to metabolites that
may cause nephrotoxicity, a problem
that has led to the withdrawal of the
drug.
Degradation products of enflurane
or isoflurane (fraction biotransformed
<2%) are of no concern.
Halothane exerts a pronounced hypotensive
effect, to which a negative inotropic
effect contributes. Enflurane
and isoflurane cause less circulatory depression.
Halothane sensitizes the myocardium
to catecholamines (caution: serious
tachyarrhythmias or ventricular
fibrillation may accompany use of catecholamines
as antihypotensives or tocolytics).
This effect is much less pronounced
with enflurane and isoflurane.
Unlike halothane, enflurane and isoflurane
have a muscle-relaxant effect that
is additive with that of nondepolarizing
neuromuscular blockers.
Desflurane is a close structural relative
of isoflurane, but has low lipophilicity
that permits rapid induction and recovery
as well as good control of anesthetic
depth.
Injectable Anesthetics
Substances from different chemical
classes suspend consciousness when
given intravenously and can be used as
injectable anesthetics . Unlike inhalational
agents, most of these drugs affect
consciousness only and are devoid
of analgesic activity (exception: ketamine).
The effect cannot be ascribed to
nonselective binding to neuronal cell
membranes, although this may hold for
propofol.
Most injectable anesthetics are
characterized by a short duration of action.
The rapid cessation of action is
largely due to redistribution: after
intravenous injection, brain concentration
climbs rapidly to anesthetic levels
because of the high cerebral blood flow;
the drug then distributes evenly in the
body, i.e., concentration rises in the periphery,
but falls in the brain—redistribution
and cessation of anesthesia .
Thus, the effect subsides before the drug
has left the body. A second injection of
the same dose, given immediately after
recovery from the preceding dose, can
therefore produce a more intense and
longer effect. Usually, a single injection
is administered. However, etomidate
and propofol may be given by infusion
over a longer time period to maintain
unconsciousness.
Thiopental and methohexital belong
to the barbiturates which, depending on
dose, produce sedation, sleepiness, or
anesthesia. Barbiturates lower the pain
threshold and thereby facilitate defensive
reflex movements; they also depress
the respiratory center. Barbiturates
are frequently used for induction
of anesthesia.
Ketamine has analgesic activity that
persists beyond the period of unconsciousness
up to 1 h after injection. On
regaining consciousness, the patient
may experience a disconnection
between outside reality and inner mental
state (dissociative anesthesia). Frequently
there is memory loss for the duration
of the recovery period; however,
adults in particular complain about distressing
dream-like experiences. These
can be counteracted by administration
of a benzodiazepine (e.g., midazolam).
The CNS effects of ketamine arise, in
part, from an interference with excitatory
glutamatergic transmission via ligand-
gated cation channels of the
NMDA subtype, at which ketamine acts
as a channel blocker. The non-natural
excitatory amino acid N-methyl-Daspartate
is a selective agonist at this receptor.
Release of catecholamines with
a resultant increase in heart rate and
blood pressure is another unrelated action
of ketamine.
Propofol has a remarkably simple
structure. Its effect has a rapid onset and
decays quickly, being experienced by
the patient as fairly pleasant. The intensity
of the effect can be well controlled
during prolonged administration.
Etomidate hardly affects the autonomic
nervous system. Since it inhibits
cortisol synthesis, it can be used in the
treatment of adrenocortical overactivity
(Cushing’s disease).
Midazolam is a rapidly metabolized
benzodiazepine that is used for
induction of anesthesia. The longer-acting
lorazepam is preferred as adjunct
anesthetic in prolonged cardiac surgery
with cardiopulmonary bypass; its amnesiogenic
effect is pronounced.