GENERAL ANAESTHESIA

Pharm Abdulai J Bah

B.Pharm (Hons), MSc,
Department of
Pharmacology
COMAHS, USL
CASE STUDY

An anxious 5-year-old child with chronic otitis

media and a history of poorly controlled
asthma presents for placement of ventilating
ear tubes. General anesthesia is required for
this short elective ambulatory surgery
procedure. What pre-anesthetic medication
should be administered? Which of the three
commonly used anesthetic techniques would
you choose to use in this situation:
(1)inhalational anesthesia with sevoflurane for
induction and maintenance in combination with
nitrous oxide, (2) intravenous anesthesia with
propofol for induction and maintenance of
anesthesia in combination with remifentanil, or
(3) balanced anesthesia using propofol for
induction of anesthesia followed by a combination
of sevoflurane and nitrous oxide for maintenance
of anesthesia?
 Introduction

 The physiologic state induced by general

anesthetics typically includes analgesia, amnesia,
loss of consciousness, inhibition of sensory and
autonomic reflexes, and skeletal muscle relaxation.
The extent to which any individual anesthetic agent
can produce these effects depends on the specific
drug, the dosage, and the clinical situation.
 An ideal anesthetic drug would induce a smooth
and rapid loss of consciousness, while allowing for
a prompt recovery after its administration is
discontinued. The drug would also possess a
wide margin of safety and be devoid of adverse

effects. When used as the sole agent, none of

the currently available anesthetic agents is
capable of achieving all of these desirable
effects. The modern practice of anesthesiology
most commonly involves the use of
combinations of intravenous and inhaled drugs
(so-called balanced anesthesia techniques),
which take advantage of the favorable
properties of each agent while minimizing their
adverse reactions.
The choice of anesthetic technique will vary
according to the proposed type of diagnostic,
therapeutic, or surgical intervention to be

performed. For minor superficial surgical

procedures, oral or parenteral sedatives are often
used in combination with local anesthetics, so-
called monitored anesthesia care techniques.
These techniques provide profound analgesia, but
with retention of the patient's ability to maintain a
patent airway and to respond to verbal
commands. For more extensive surgical
procedures, anesthesia frequently includes
preoperative benzodiazepines, induction of
anesthesia with an intravenous anesthetic (eg,
thiopental or propofol), and maintenance of
anesthesia with a combination of inhaled (eg,
volatile agents, nitrous oxide) and intravenous (eg,
propofol, opioid analgesics) drugs.
GENERAL PRINCIPLES OF
SURGICAL ANESTHESIA
Unlike the practice of every other branch of
medicine, anesthesia is usually neither therapeutic
nor diagnostic. Hence, administration of general
anesthesia, has been driven by three general
objectives:
1. Minimizing the potentially deleterious direct and
indirect effects of anesthetic agents and
techniques.

2. Sustaining physiologic homeostasis during

surgical procedures that may involve major blood
loss, tissue ischemia, reperfusion of ischemic
tissue, fluid shifts, exposure to a cold
environment, and impaired coagulation.
3. Improving postoperative outcomes by choosing
techniques that block or treat components of the
surgical stress response, which may lead to
short- or long term sequelae.
Types of General Anesthesia

General anesthetics are typically administered by

intravenous injection or by inhalation. For many
years, inhalation anesthesia was used for all
types of surgical procedures. Recently,
intravenous anesthesia has become a more
widely used technique around the world.
Intravenous Anesthetics
Several different classes of intravenous drugs are
used, alone or in combination with other
anesthetic and analgesic drugs, to achieve the
desired anesthetic state. In addition, some of
these drugs are used to sedate ventilator-

dependent patients in intensive care units

(ICUs). These drugs include the following:
(1) barbiturates (eg, thiopental, methohexital);
(2) benzodiazepines (eg, midazolam, diazepam);
(3) propofol; (4) ketamine; (5) opioid analgesics
(morphine, fentanyl, sufentanil, alfentanil,
remifentanil); and (6) miscellaneous sedative-
hypnotics (eg, etomidate, dexmedetomidine).
 Inhaled Anesthetics
The most commonly used inhaled anesthetics are
isoflurane, desflurane, and sevoflurane. These
compounds are volatile liquids that are aerosolized
in specialized vaporizer delivery systems. Nitrous
oxide, a gas at ambient temperature and pressure,
continues to be an important adjuvant to the
volatile agents. However, concerns about
environmental pollution and its ability to increase
the incidence of postoperative nausea and
vomiting (PONV) have resulted in a significant
decrease in its use
Balanced Anesthesia

Although general anesthesia can be produced

using only intravenous or only inhaled anesthetic
drugs, modern anesthesia typically involves a
combination of intravenous (eg, for induction of
anesthesia) and inhaled (eg, for maintenance of
anesthesia) drugs. However, volatile anesthetics
(eg, sevoflurane) can also be used for induction of
anesthesia, and intravenous anesthetics (eg,
propofol) can be infused for maintenance of
anesthesia. Muscle relaxants are commonly used
to facilitate tracheal intubation and optimize
surgical conditions during the operation Local
anesthetics are frequently administered by tissue

infiltration and peripheral nerve blocks to provide

perioperative analgesia. In addition, potent opioid
analgesics and cardiovascular drugs (eg, blockers,
2 agonists, calcium channel blockers) are used to
control transient autonomic responses to noxious
(painful) surgical stimuli.
Stages of Anesthesia

The traditional description of the various stages of

anesthesia (the so-called Guedel's signs) were
derived from observations of the effects of inhaled
diethyl ether, which has a slow onset of central
action owing to its high solubility in blood. Using
these signs, anesthetic effects on the brain can be
divided into four stages of increasing depth of
central nervous system (CNS) depression:
I. Stage of analgesia: The patient initially
experiences analgesia without amnesia.
Later in stage I, both analgesia and amnesia are
produced. II. Stage of excitement: During this
stage, the patient often appears to be delirious

and may vocalize but is definitely amnesic.

Respiration is irregular both in volume and rate,
and retching and vomiting may occur if the patient
is stimulated. For these reasons, efforts are made
to limit the duration and severity of this light stage
of anesthesia by rapidly increasing the
concentration of the agent. This stage ends with
the reestablishment of regular breathing.
III. Stage of surgical anesthesia: This stage
begins with the recurrence of regular respiration
and extends to complete cessation of

spontaneous respiration (apnea). Four planes of

stage III have been described in terms of changes
in ocular movements, eye reflexes, and pupil size,
which may represent signs of increasing depth of
anesthesia.
IV. Stage of medullary depression: This deep
stage of anesthesia includes severe depression of
the CNS, including the vasomotor center in the
medulla, as well as the respiratory center in the
brain stem. Without circulatory and respiratory
MECHANISM OF ANESTHETIC ACTION

Among the earliest proposals to explain the

mechanism of action of anesthetics is the
concept that they interact physically rather than
chemically with lipophilic membrane components
to cause neuronal failure.
Anesthesia from Physical Interactions
with Lipophilic Membrane Components
A clear correlation exists between anesthetic
potency and the physical parameter lipid
solubility, (Meyer Overton rule).
Membrane conformational changes are observed
on exposure to anesthetics, further supporting the
importance of physical interactions that lead to
perturbation of membrane macromolecules. For
example, exposure of membranes to clinically
relevant concentrations of anesthetics causes
membranes to expand beyond a critical volume
(critical volume hypothesis) associated with nor
mal cellular function. Additionally, membrane
structure becomes disorganized, so that the
insertion of anesthetic molecules into the lipid
membrane causes an increase in the mobility of
the fatty acid chains in the phospholipid bilayer
(membrane fluidization theory).
 or prevent the interconversion of membrane lipids
from a gel to a liquid form, a process

that is assumed necessary for normal

neuronal function (lateral phase separation
hypothesis).
Anesthesia from Selective Interactions
of Anesthetics with Cellular Components
Contemporary research has shown that at clinically
relevant concentrations, various anesthetics interact
specifically with different components of the
GABAA-receptor–chloride ionophore and enhance
 chloride conductance, some directly and
others by enhancing the ac-tion of GABA.
Inhalational agents directly activate the
chloride channel as well as facilitate the
action of GABA, while barbiturates, propofol,
benzodiazepines, and etomidate primarily
enhance the action of GABA by interacting
with specific receptor sites.
Also, anesthetics enhance other processes
known to inhibit neuronal function, such as
the glycine receptor–gated chloride channel
A smaller number of anesthetics, including
ketamine, N2O, and xenon, produce

neuronal inhibition by antagonizing excitatory

neuronal transmission mediated via the N-methyl-
D-aspartic acid (NMDA) receptor. In addition,
some inhalational drugs activate K+.
channels and so contribute to hyperpolarization
and reduced neuronal excitability; they also
inhibit the function of the protein complex in-
volved in neurotransmitter release.
 Inhaled Anesthetics
Pharmacokinetics
Ensuring an adequate depth of anesthesia
depends on achieving a therapeutic concentration

of the anesthetic in the CNS. The rate at which an

effective brain concentration is achieved (ie, time
to induction of general anesthesia) depends on
multiple pharmacokinetic factors that influence the
brain uptake and tissue distribution of the
anesthetic agent. The pharmacokinetic properties
of the intravenous anesthetics and the
physicochemical properties of the inhaled agents
directly influence the pharmacodynamic effects of
these drugs, as well as the rate of recovery.
Drug Induction and Recovery Comments
Etomidate Rapid onset and moderately Provides cardiovascular
fast recovery stability; causes decreased
steroidogenesis and
involuntary muscle movements
Ketamine Moderately rapid onset and Causes cardiovascular
recovery stimulation, increased cerebral

blood flow, and emergence

reactions that impair recovery
Midazolam Slow onset and recovery; Used in balanced anesthesia
flumazenil reversal available and conscious sedation;
provides cardiovascular
stability and marked amnesia
Propofol Rapid onset and rapid recovery Used in induction and for
maintenance; can cause
hypotension; has useful
antiemetic action
Thiopental Rapid onset and rapid recovery Standard induction agent;
(bolus dose)—slow recovery causes cardiovascular
following infusion depression; avoid in porphyrias
Fentanyl Slow onset and recovery; Opioid used in balanced
naloxone reversal available anesthesia and conscious
sedation; produces marked
analgesia
Anesthetic Blood:Gas Brain:Blood Minimal Metabolism Comments
Partition Partition Alveolar
Coefficient1 Coefficient1 Concentration
(MAC) (%)2

Nitrous oxide 0.47 1.1 > 100 None Incomplete anesthetic;

rapid onset and recovery

Desflurane 0.42 1.3 6–7 < 0.05% Low volatility; poor

induction agent
(pungent); rapid recovery

Sevoflurane 0.69 1.7 2.0 2–5% Rapid onset and

(fluoride) recovery; unstable in
soda-lime
Isoflurane 1.40 2.6 1.40 < 2% Medium rate of onset and
recovery
Enflurane 1.80 1.4 1.7 8% Medium rate of onset and
recovery
Halothane 2.30 2.9 0.75 > 40% Medium rate of onset and
recovery
Methoxyflurane 12 2.0 0.16 > 70% Very slow onset and
(fluoride) recovery
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ATTENTION