GENERAL ANESTHETICS

Learning objectives

i. Defination of key terms (general anaesthesia, MAC, blood gas ratios,

anaesthesia induction and maintenance)
ii. Know classes of drugs used (Inhalation and intravenous and examples)
iii. Outline the desired characteristics of an ideal anaesthetic drug/drug
combinations
iv. Key pharmacological characteristics of general anaesthetic agents
v. Describe the stages of anaesthesia
vi. Drugs co-adminstered with anaesthetic agents (analgesics and muscle
relaxants-the anaesthesia triad)
vii. Describe the general anaesthesia technique
viii. Explain the concept of balanced anaesthesia

I. Definition
 General anaesthesia is a medically-induced loss of consciousness with
concurrent loss of protective reflexes due to anaesthetic agents.
 the patient is unarousable to verbal, tactile, and painful stimuli
 Can be induced by inhaled or intravenous (IV) anaesthetic drugs

II. Characteristic of an Ideal general anaesthetic drug

 Induce loss of consciousness smoothly and rapidly,
 Allow for prompt recovery of cognitive function after its administration is
discontinued.
 possess a wide margin of safety and be devoid of adverse effects

Currently combinations of intravenous and inhaled drugs are used, taking advantage
of their individual favourable properties while minimizing their adverse reactions

III. General anaesthetic drugs

Classes

A. Inhalation anaesthetics
a) Volatile liquid anaesthetics
b) Gaseous anaesthetics

B. Intravenous anaesthetic
IV. Inhalation general anaesthetics

A. Main Examples
i. Volatile liquid anaesthetics
a) Isoflurane
b) Desflurane
c) Sevoflurane
d) Enflurane
e) Methoxyflurane
f) Halothane

ii. Gaseous anaesthetics

i. Nitrous oxide

B. Pharmacokinetics

Administration

 Gaseous anaesthetics require suitable equipment for storage and

administration.
 Volatile liquid anaesthetics are administered using calibrated vaporisers, using
air, oxygen,or nitrous oxide-oxygen mixtures as the carrier gas.
 To prevent hypoxia, the inspired gas mixture should contain a minimum of
25% oxygen at all times. Higher concentrations of oxygen (greater than 30%)
are usually required during inhalational anaesthesia when nitrous oxide is
being administered.

Distribution

Inhaled anaesthetics distribute into the blood, fat and the CNS

Achievement of a brain concentration of an inhaled anesthetic to provide adequate

anesthesia requires transfer of the anesthetic from the alveolar air to the blood and
from the blood to the brain. The rate at which a therapeutic concentration of the
anesthetic is achieved in the brain depends on the solubility properties of the
anesthetic, its concentration in the inspired air, the volume of pulmonary ventilation,
the pulmonary blood flow, and the partial pressure gradient between arterial and
mixed venous blood anesthetic concentrations.

 The concentration of an inhaled anesthetic in a mixture of gases is proportional to its

partial pressure (or tension).

 Blood:gas partition coefficient (ratio)- defines the relative affinity of an anesthetic

for the blood compared with that of inspired gas and is a useful index of solubility

 Rate of onset and recovery of inhalation anaesthetics

 Rates of onset and recovery of inhaled anaesthetics depend on the blood–gas ratio
 The more soluble the anesthetic in the blood, the slower the anesthesia.
 Anesthetics with high blood–gas ratios are associated with slow onset.
 Anesthetics with high blood–gas ratios are associated with slow recovery.
 Anesthetics with low blood–gas ratios have fast onset and recovery.
 The time to recovery from inhalation anesthesia depends on the rate of elimination of
anesthetics from the brain

Elimination

 Clearance of inhaled anesthetics via the lungs is the major route of elimination from the body.
However, hepatic metabolism may also contribute to the elimination of some volatile
anesthetics.
 Inhaled anesthetics that are relatively insoluble in blood (ie, low blood:gas partition coefficient)
and brain are eliminated at faster rates than more soluble anesthetics.

 The time to recovery from inhalation anesthesia depends on the rate of elimination of
anesthetics from the brain.

C. Pharmacodynamics

a. Mechanism of action

Depress spontaneous and evoked activity of neurons in many regions of the brain. This is
probably due to following mechanism (s):

 Nonspecific interactions of these agents with the lipid matrix of the nerve membrane
(the Meyer-Overton principle)
 Direct interaction of anaesthetic drugs with the ligand-gated ion channel family,
leading to in ion flux. In particular, inhaled anaesthetic agents facilitate the activity of
the GABAA receptor-chloride channel, which is a major mediator of inhibitory synaptic
transmission
  membrane hyperpolarization (ie, an inhibitory action) via their activation of potassium
channels.

b. Dose-response relationship- Minimal alveolar anesthetic concentration (MAC)

cocept

 MAC (minimal alveolar anesthetic concentration): the concentration of inhaled

anesthetic (as a % of inspired air) at which 50% of patients do not respond to a
surgical stimulus. i.e the anesthetic concentration that produces immobility in 50%
of patients exposed to a noxious stimulus.
 MAC is therefore a measure of potency: ED50 of inhaled anaesthetic agents.
 The more lipid soluble the anesthetic, the lower the MAC and the greater the
potency.
 MAC values are lower in the elderly and in the presence of opiates or sedative-
hypnotics.

 MAC values are additive. For example, nitrous oxide (60-70%) can be used as a
"carrier" gas producing 40% of a MAC, thereby decreasing the anesthetic
requirement of inhaled volatile and intravenous anesthetics. The addition of
nitrous oxide (60% tension, 40% MAC) to 70% of a volatile agent's MAC would
yield a total of 110% of a MAC, a value sufficient for surgical anesthesia in most
patients.

The dose of anesthetic gas that is being administered can be stated in multiples of
MAC. A dose of 1 MAC of any anesthetic prevents movement in response to surgical
incision in 50% of patients; however, individual patients may require 0.5-1.5 MAC.

D. Systemic Effects of Inhaled Anesthetics

a. Cardiovascular system:
 Mean arterial preasure: Halothane, desflurane, enflurane, sevoflurane, and isoflurane
all decrease mean arterial pressure in direct proportion to their alveolar concentration
 Heart rate: halothane causes bradycardia because of direct vagal stimulation. In
contrast, enflurane, and sevoflurane have little effect, and both desflurane and
isoflurane increase heart rate.
 All inhaled anesthetics tend to increase right atrial pressure in a dose-related fashion,
which reflects depression of myocardial function.

b. Respiratory system
 With the exception of nitrous oxide, all inhaled anesthetics in current use
cause a dose-dependent decrease in tidal volume and an increase in
respiratory rate.
 All volatile anesthetics are respiratory depressants, as indicated by a reduced
response to
 Volatile anesthetics increase the apneic threshold (PaCO2 level below which apnea
occurs through lack of CO2-driven respiratory stimulation) and decrease the
ventilatory response to hypoxia.
  Inhaled anesthetics also depress mucociliary function in the airway. Thus, prolonged
anesthesia may lead to pooling of mucus and then result in atelectasis and
postoperative respiratory infections.

c. Brain
 Inhaled anesthetics decrease the metabolic rate of the brain

 the more soluble volatile agents increase cerebral blood flow because they decrease
cerebral vascular resistance. The increase in cerebral blood flow is clinically
undesirable in patients who have increased intracranial pressure because of a brain
tumor or head injury because increased cerebral blood flow increase cerebral blood
volume, thereby increasing intracranial pressure. This can be minimized by
hyperventilating before the volatile agent is started, the increase in intracranial pressure can
be minimized.

d. Kidneys
Volatile anesthetics decrease the glomerular filtration rate and renal blood flow, and
increase the filtration fraction. Since renal blood flow decreases during general
anesthesia in spite of well-maintained or even increased perfusion pressures (due to
increased renal vascular resistance), autoregulation of renal flow may be impaired.

e. Liver
Volatile anesthetics cause a concentration-dependent decrease in hepatic blood
flow ranging from 15% to 45% below the preinduction (baseline) value .

f. Uterus
the halogenated anesthetics are potent uterine muscle relaxants and produce this
effect in a concentration-dependent fashion. This pharmacologic effect can be
used to advantage when profound uterine relaxation is required for an intrauterine
fetal manipulation or manual extraction of a retained placenta during delivery.

E. Adverse effects/ toxicity

a. Hepatotoxicity-halothane
b. Nephrotoxicity-Metabolism of methoxyflurane, enflurane, and sevoflurane leads to
the formation of fluoride ions, and this has raised questions concerning the
nephrotoxicity of these three volatile anesthetics.

c. Malignant hyperthermia- an autosomal dominant genetic disorder of skeletal muscle

that occurs in susceptible individuals undergoing general anesthesia with volatile
agents and muscle relaxants (eg, succinylcholine). associated with mutations in the
gene loci corresponding to the skeletal muscle ryanodine receptor (RyRl).

The malignant hyperthermia syndrome consists of the rapid onset of tachycardia and
hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, and acid-base
imbalance with acidosis that follows exposure to a triggering agent.
 Rx: administration of dantrolene (to reduce calcium release from the sarcoplasmic
reticulum) and appropriate measures to reduce body temperature and restore electrolyte
and acid-base balance.

d. Hematotoxicity-Prolonged exposure to nitrous oxide decreases methionine synthase

activity and theoretically can cause megaloblastic anemia, a potential occupational
hazard for staff working in inadequately ventilated dental operating suites.

F. Clinical Use of Inhaled Anesthetics

a) Volatile anesthetics are rarely used as the sole agents for both induction and
maintenance of anesthesia.
b) Most commonly, they are combined with intravenous agents as part of a
balanced anesthesia technique.
c) The low blood:gas coefficients of desflurane and sevoflurane afford a more
rapid recovery and fewer postoperative adverse effects than halothane,
enflurane, and isoflurane.

Summarized pharmacokinetic/pharmacodynamics Properties of main inhaled

anaesthetic agents
V. Intravenous General anaesthetics

A. Main examples
i. Barbiturates (eg, thiopental, methohexital)
ii. Benzodiazepines (eg, midazolam, diazepam, lorazepam)
iii. Propofol
iv. Ketamine
v. Opiates (Fentanyl)
vi. etomidate

Midazolam
Benzodiazepine used primarily for premedication because of their sedative,
anxiolytic, and amnestic properties, and to control acute agitation

 Preoperative sedation
 Anterograde amnesia
 Induction of anaesthesia
 Outpatient surgery

NB- Depresses respiratory function

Propofol
– Used for induction and maintenance of anesthesia

- recovery is more rapid and patients are able to ambulate earlier after general
anesthesia.
– Antiemetic
– CNS and cardiac depressant
Fentanyl
– Opiate used for induction and maintenance of anesthesia

-Fentanyl and droperidol (a butyrophenone related to haloperidol)

administered together produce analgesia and amnesia and combined with
nitrous oxide provide a state referred to as neuroleptanesthesia.
– Depresses respiratory function

Ketamine
– Used for induction of anesthesia

-produces a dissociative anesthetic state characterized by catatonia, amnesia, and

analgesia, with or without loss of consciousness
-Has analgesic activity
– Causes Cardiovascular stimulation-
– increases intracranial pressure

 associated with postoperative disorientation, sensory and perceptual illusions

(hallucinations), and vivid dreams (so-called emergence phenomena).
Diazepam, 0.2-0.3 mg/kg, or midazolam, 0.025-0.05 mg intravenously, given
before the administration of ketamine reduce the incidence of these adverse
effects.
 ketamine is very useful for poor-risk geriatric patients and high-risk patients in
cardiogenic or septic shock because of its cardiostimulatory properties

NB- Ketamine is the only intravenous anesthetic that possesses both analgesic
properties and the ability to produce dose-related cardiovascular stimulation

Thiopental

 A barbiturate commonly used for induction of anesthesia

 rapidly crosses the blood-brain barrier and, if given in sufficient dosage,
produces loss of consciousness (hypnosis) in one circulation time
 rapidly diffuses out of the brain and other highly vascular tissues and is
redistributed to muscle and fat

 single dose of thiopental produces only a brief period of

unconsciousness
 can be used for patients with cerebral swelling (eg, head trauma, brain
tumors), because it doesent increase intracranial pressure

ETOMIDATE

 a carboxylated imidazole
 can be used for induction of anesthesia in patients with limited cardiovascular
reserve.
  causes minimal cardiovascular and respiratory depression-a major
advantage over other intravenous anaesthetic agents
 has no analgesic effects
 Causes a high incidence of pain on injection, myoclonic activity, and
postoperative nausea and vomiting.

 Dosing: Induction of anaesthesia

▶ By slow intravenous injection
▶ Adult: 150–300 micrograms/kg (max. per dose 60 mg), to be
administered over 30-60 seconds (60 seconds in patients in whom
hypotension might be hazardous)
 ▶ Elderly: 150–200 micrograms/kg (max. per dose 60 mg), to be
administered over 30-60 seconds (60 seconds in patients in whom
hypotension might be hazardous)

B. Induction and recovery profiles of intravenous anaesthetics

C. Mechanism of action

Depress spontaneous and evoked activity of neurons in many regions of the brain. This is
probably due to following mechanism (s):

 Nonspecific interactions of these agents with the lipid matrix of the nerve
membrane (the Meyer-Overton principle)
 Direct interaction of anaesthetic drugs with the ligand-gated ion channel family,
leading to in ion flux. In particular, inhaled anaesthetic agents facilitate the activity
of the GABAA receptor-chloride channel, which is a major mediator of inhibitory
synaptic transmission
 Membrane hyperpolarization (ie, an inhibitory action) via their activation of
potassium channels.
NB: Ketamine does not produce its effects via facilitation of GABAA receptor
functions, but act via antagonism of the action of the excitatory neurotransmitter
glutamic acid on the N-methyl-D-aspartate (NMDA) receptor.

D. Clinical uses of intravenous anaesthetics

 Intravenous anaesthetics may be used either to induce anaesthesia or for maintenance of
anaesthesia throughout surgery.
 Intravenous anaesthetics nearly all produce their effect in one arm-brain circulation time.

VI. Stages of general anaesthesia

 Stage 1: Induction (Analgesia or Disorientation)

 Stage 2: Excitement or delirium
 Stage 3: Surgical anesthesia.
 Stage 4: Overdose.

Stage 1 - Induction (Analgesia or Disorientation): during this stage patient

begins to feel the anaethetic effects but has not yet become unconscious. Patients are
sedated but conversational. Breathing is slow and regular. At this stage, the patient
progresses from analgesia free of amnesia to analgesia with concurrent amnesia. This
stage comes to an end with the loss of consciousness.
Stage 2 - Excitement or Delirium: This stage is marked by features such as
disinhibition, delirium, uncontrolled movements, loss of eyelash reflex, hypertension,
and tachycardia. Airway reflexes remain intact during this phase and are often
hypersensitive to stimulation. Airway manipulation during this stage of anesthesia
should be avoided, including both the placement and removal of endotracheal tubes
and deep suctioning maneuvers. There is a higher risk of laryngospasm (involuntary
tonic closure of vocal cords) at this stage, which may be aggravated by any airway
manipulation. Consequently, the combination of spastic movements, vomiting, and
rapid, irregular respirations can compromise the patient's airway. For these reasons,
efforts are made to limit the duration and severity of this stage, which ends with
the reestablishment of regular breathing. Fast-acting anaesthetic agents help reduce
the time spent in stage 2 as much as possible and facilitate entry to stage 3.
Stage 3 – Surgical Anesthesia: This is the targeted anesthetic level for procedures
requiring general anesthesia. Ceased eye movements and respiratory depression are
the hallmarks of this stage. Airway manipulation is safe at this level. There are four
"planes" described for this stage. During plane 1, there is still regular spontaneous
breathing, constricted pupils, and central gaze. However, eyelid, conjunctival, and
swallow reflexes usually disappear in this plane. During plane 2, there are intermittent
cessations of respiration along with the loss of corneal and laryngeal reflexes. Halted
ocular movements and increased lacrimation may also occur. Plane 3 is marked by
complete relaxation of the intercostal and abdominal muscles and loss of the pupillary
light reflex. This plane is referred to as "true surgical anesthesia" because it is ideal for
most surgeries. Finally, Plane 4 is marked by irregular respiration, paradoxical rib
cage movement, and full diaphragm paralysis resulting in apnea.
 The most reliable indication that stage III has been achieved is loss of responsiveness
to noxious stimuli (eg, trapezius muscle squeeze) and reestablishment of a regular
respiratory pattern. The adequacy of the depth of anesthesia for a specific surgical
stimulus is assessed by monitoring changes in respiratory and cardiovascular
responses to the surgical stimulation, as well as electroencephalographic (EEG-based)
cerebral indices.
Stage 4 - Overdose: This stage occurs when too much anesthetic agent is given
relative to the amount of surgical stimulation, which results in worsening of an already
severe brain or medullary depression. This stage begins with respiratory cessation and
ends with potential death. Skeletal muscles are flaccid, and pupils are fixed and dilated
at this stage.Blood pressure is typically significantly lower than normal, with weak
and thready pulses due to the suppression of the cardiac pump and vasodilation in the
peripheral bloodstream. Without cardiovascular and respiratory support, this stage is
lethal. Hence, the anesthetist's goal is to transition the patient as soon as possible to
stage 3 of anesthesia and keep them there for the duration of the operation.

NB: the "balanced anesthesia" approach which uses several types of medications for induction
(such as intravenous anesthetics, analgesics, neuromuscular blockers, and benzodiazepines), can
disguise the characteristic clinical markers of each defined anesthesia stage.

VII. Anaesthesia techniques

The anesthetic technique will vary according to the proposed type of diagnostic, therapeutic, or
surgical intervention.
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.

Total intravenous anaesthesia

This is a technique in which major surgery is carried out with all drugs given intravenously. Respiration
can be spontaneous, or controlled with oxygen-enriched air. Neuromuscular blocking drugs can be
used to provide relaxation and prevent reflex muscle movements. The main problem to be overcome
is the assessment of depth of anaesthesia. Target Controlled Infusion (TCI) systems can be used to
titrate intravenous anaesthetic infusions to predicted plasma-drug concentrations in ventilated adult
patients.

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. Muscle relaxants are commonly used to
facilitate tracheal intubation and optimize surgical conditions. Local anesthetics are often administered
by tissue infiltration and peripheral nerve blocks to provide perioperative analgesia In addition, potent
opioid analgesics and cardiovascular drugs (eg, b blockers, alpha 2 agonists, calcium channel
blockers) are used to control autonomic responses to noxious (painful) surgical stimuli.
VIII. Anaesthesia Dosing

Individual dosing requirements vary considerably and the recommended doses are
only a guide. Smaller doses are indicated in ill, shocked, or debilitated patients and
in significant hepatic impairment, while robust individuals may require larger doses.
The required dose of induction agent may be less if the patient has been
premedicated with a sedative agent or if an opioid analgesic has been used.

The doses of all intravenous anaesthetic drugs should be titrated to effect (except
when using ‘rapid sequence induction’); lower doses may be required in
premedicated patients.

IX. Anaesthesia adjuvants (Pre-medication and peri-operative drugs)

Premedicants can be given the night before major surgery; a further, smaller dose
may be required before surgery. Alternatively, the first dose may be given on the day
of the procedure.

Drugs that reduce gastric pH

 prophylaxis against acid aspiration.

 An H2-receptor antagonist can be used before surgery to increase the pH and
reduce the volume of gastric fluid.
 Antacids- clear’ (nonparticulate) antacids such as sodium citrate

Antimuscarinic drugs (Atropine sulphate, Glycopyrronium bromide, Hyoscine

hydrobromide)

 premedicants to dry bronchial and salivary secretions which are increased by

intubation, upper airway surgery,
 Also to prevent bradycardia and hypotension associated with drugs such as
propofol

Sedative drugs (Benzodiazepines-Diazepam, lorazepam, temazepam, Midazolam)

and Dexmedetomidine

 To minimize fear and anxiety before a procedure (including the night before)
Analgesics

 Non-opioid analgesics- paracetamol, ibuprofen, diclofenac, ketoprofen,

Ketorolac trometamol
 Opioid analgesics-fentanyl
 Always consider prescribing pre-emptive analgesia to ensure that the patient’s
pain is managed when the effects of local anaesthesia wears off.

Neromascular blocking drugs/Skeletal muscle relaxants

Muscle relaxants are used mainly in anesthesia protocols or in the ICU to afford muscle
relaxation and/or immobility. They interact with nicotinic Ach receptors at the neuromuscular
junction.

Neuromuscular blocking drugs used in anaesthesia are also known as muscle relaxants. By
specific blockade of the neuromuscular junction they enable light anaesthesia to be used
with adequate relaxation of the muscles of the abdomen and diaphragm. They also relax the
vocal cords and allow the passage of a tracheal tube. Their action differs from the muscle
relaxants used in musculoskeletal disorders that act on the spinal cord or brain

A. Nondepolarizing (competitive)

Compete with acetylcholine for receptor sites at the neuromuscular junction and their action can be
reversed with anticholinesterases such as neostigmine

– Reversible with AChE inhibitors

– Progressive paralysis (face, limbs, respiratory muscle)

– No effects on cardiac and smooth muscle

– No CNS effects

Examples

 Pancuronium bromide
 Rocuronium bromide
 vecuronium bromide
 atracurium
 besilate
 cisatracurium
 mivacurium

atracurium (rapid recovery, safe in hepatic or renal impairment

Depolarizing (noncompetitive)

– Nicotinic agonists

– Specific drug example: succinylcholine/ Suxamethonium

Two phases of pharmacological effect:

Phase I: depolarization, fasciculation, prolong depolarization, flaccid paralysis;

Phase II:desensitization

– AChE inhibitors increases phase I; may reverse phase II

– Rapidly hydrolyzed by pseudocholinesterase: short duration

– Cautions: atypical pseudocholinesterase; hyperkalemia; malignant hyperthermia

Malignant hyperthermia- a life-threatening syndrome characterized by muscle rigidity,

hyperthermia, hypertension, acidosis, and hyperkalemia. This is treated with Dantrolene

B. Centrally Acting Skeletal Muscle Relaxants

 Benzodiazepines through GABAA receptors

 Baclofen through GABAB receptors
 Use: spasticity