General Anaesthetic Agents

Dr. Jacqueline E. Campbell

jacqueline.campbell02@uwimona.edu.jm
General Anaesthetic Agents

By the end of the lecture, the student should be able

to:
1. Name the common inhaled & intravenous
anaesthetic agents & identify their
pharmacodynamic & pharmacokinetic properties
2. Identify the molecular targets for the actions of
anaesthetic drugs
3. Describe the terms blood: gas partition coefficient
& minimum alveolar anaesthetic concentration
4. Describe the factors influencing the rate of
induction by inhaled anaesthetics
Original in the Royal College of Surgeons of England, London.
History
 first inhalation anaesthetic, nitrous oxide, discovered by
Priestly in 1776
 N2O used for 1 st time in 1844 by Horace Wells, a dentist
in Hartford, USA, for painless extraction of a tooth.
 In1846 another dentist William Morton showed use of
ether as a general anaesthetic in the 1 st classic
demonstration held in the operating room of the
Massachusetts General Hospital, Boston
We have come a long way…
Anaesthetics

 Anaesthesia – reversible condition of

comfort, inactivity & physiological stability in
a patient before, during & after performance
of a procedure
 General anaesthesia – for surgical
procedure to render patient unaware /
unresponsive to painful stimuli
Anaesthetics

Extent to which
Physiological state
individual
inducedanaesthetic
by GA typically
can produce
includes
these effects depends on
Analgesia
the
Amnesia
specific drug
Loss of consciousness
dosage
 Inhibition
clinical of sensory & autonomic reflexes
picture
Skeletal muscle relaxation
Anaesthetics

 Margin between GA & potentially fatal

respiratory & circulatory depression is
narrow; requires careful monitoring by
anaesthetist & adjustment of level of
anaesthesia
 All parts of nervous system affected by
anaesthetics -main targets appear to be
cortex, thalamus, hippocampus, midbrain
reticular formation & spinal cord
Preanaesthetic medication

use of drugs prior to anaesthesia to relieve

apprehension & facilitate smooth induction

 To relieve anxiety – benzodiazepines

 To prevent allergic reactions – antihistaminics
 To prevent nausea and vomiting – antiemetics
 To provide analgesia – opioids
 To prevent bradycardia & secretion – atropine
Types of General Anaesthesia

2 categories of anaesthetic agents :

Inhalational --- for maintenance
Intravenous --- for induction & short

procedures
Balanced Anaesthetics

GA can be produced using only i.v. or only

inhaled anaesthetic drugs , however modern
anaesthesia typically involves use of
combinations of i.v. & inhaled drugs which
takes advantage of favourable properties of
each drug while minimizing their adverse
effects
Stages of anaesthesia
I. Analgesia - ↓sensation of pain; pt remains conscious
& conversational
II. Excitement- delirium & combative behaviour ensue ; ↑
blood pressure & respiratory rate
III. Surgical anaesthesia – pt unconscious & regular
respiration returns; muscle relaxation & ↓ vasomotor
response to painful stimuli
IV. Medullary depression –↓respiratory drive ↓ vasomotor
output; w/o circulatory & respiratory support , death
rapidly ensues
Induction & Recovery

Recovery
Induction
Reverse
Time fromofadministration
induction of GA to
achievement
Depends on howof surgical
quicklyanaesthesia
anaesthetic removed
from
Depends
CNSon how fast anaesthetic reaches
CNS
Uptake & distribution of inhaled
anaesthetics
 Concentration of inhaled anaesthetic in a
mixture of gases is proportional to its partial
pressure
 Achievement of a brain concentration of an
inhaled anaesthetic necessary to provide an
adequate depth of anaesthesia requires
transfer of anaesthetic from alveolar air to the
blood & from the blood to the brain
Factors influencing rate @ which
therapeutic concentration of inhaled
anaesthetics achieved in brain
1. Solubility
2. Pulmonary ventilation
3. Partial pressure of inhaled gas
4. Alveolar blood flow
5. Arteriovenous concentration
gradient
Solubility
Blood
Agent w: gas partition
low solubility co-blood: gas coefficient) requires fewer
( low
efficient:to raise its partial pressure; equilibrium between
molecules
alveolar
 measurepartial pressure in
of solubility & arterial partial pressure rapidly
achieved → faster induction
the blood
& recovery e.g. Nitrous oxide.
 determines rate of

induction & recovery of

inhalational anesthetics
 Low coefficient implies

relative insolubility
Blood: gas partition
coefficient
 ratio of the concentrations  An anesthetic that has
of anaesthetic gas in the blood concentration of 3% &
blood & gas phases @ lung concentration of 6%
equilibrium @equilibrium would have a
 A higher blood: gas partition partition coefficient of 0.5,
coefficient shows greater showing a greater affinity for
affinity for the blood (e.g., the gas phase
2.0 equals a 2% blood
concentration & a 1% lung
concentration at
equilibrium)
Blood: gas partition
coefficient
A higher blood gas: partition coefficient means
a higher uptake of the gas into the blood &
therefore a slower induction time
BLOOD GAS PARTITION CO-EFFICIENT
 Agents with low solubility in
blood quickly saturate the
blood. The additional anesthetic
molecules are then readily
transferred to the brain.

BLOOD GAS PARTITION COEFFICIENT

Factors influencing rate @ which
therapeutic concentration of inhaled
anaesthetics achieved in brain-
 ↑ in minute ventilation
Pulmonary ventilation → increased amount of
 Rate & depth of agent ( important for
ventilation ( *minute drugs w low solubility
ventilation) affects rate b/cause they require
of ↑ in partial pressure greater amounts of
of anaesthetic in blood agent to achieve
equilibrium)
* Tidal vol. x RR
Factors influencing rate @ which
therapeutic concentration of inhaled
anaesthetics achieved in brain
Concentration
Alveolar blood in
flow
inspired air
↑ flow → more rapid uptake of drug & quicker effect
on
Increased
CNS concentration of drug in inhaled
air mixture → greater concentration in alveoli
→ ↑ arterial partial pressure of drug
Arteriovenous concentration
gradient
 Depends on uptake of drug by tissue
 High rate & extent of tissue uptake →↓
venous conc. of anaesthetic , resulting in
longer time for anaesthetic concentration of
arterial & venous blood to equilibrate
MAC
 measure of inhalational anaesthetic potency
 defined as the minimum alveolar anesthetic
concentration at which 50% of patients do not
respond to a noxious stimulus (e.g, surgical
incision)
 commonly expressed as the % of gas in a
mixture required to achieve the desired effect
 MAC values are additive
MAC

 The greater the MAC of an agent, the greater

the concentration needed to provide
anaesthesia
 So , agent w/ a high MAC has a low potency
(e.g., nitrous oxide w MAC of 100%) while
agent w low MAC has high potency (e.g.,
halothane w MAC of 0.75%)
Mechanism of GA

Varied
CNS depressants - ↑threshold for firing of
CNS neurons
 GABA inhibition : facilitated by inhaled
A
anaesthetics, barbiturates,
benzodiazepines, Propofol, Etomidate
 NMDA receptors : inhibited by Ketamine
Mechanism of GA
 Inhaled anaesthetics decrease duration of
opening of nicotinic receptor-activated
cation channels, resulting in decreased
excitatory effect of acetylcholine @
cholinergic synapses
 Strychnine –sensitive glycine receptor is
another ligand- gated ion channel that may
function as a “ target” of inhaled anaesthetics
Mechanism of action of GA

CNS neurons in different areas of brain have

different sensitivities to GA; inhibition of
neurons involved in pain pathways occurs
before inhibition of neurons in midbrain
reticular formation
Inhaled anaesthetics

Non-halogenated
Halogenated hydrocarbon
gas (easily vapourized liquid)
Nitrous
Isoflurane*
oxide
Sevoflurane*

Desflurane

Halothane**
*Commonly used UHWI
** rural areas
Malignant hyperthermia
 In genetically predisposed individuals, exposure to
inhaled anaesthetics (except N2O) results in
massive release of muscle Ca 2+ stores → tonic
muscle contraction→ life-threatening hyperthermia,
acidosis, muscle breakdown
 Can also be seen with depolarizing muscle blockers
(e.g., succinylcholine)
 Treated w dantrolene (muscle relaxant drug which
blocks Ca release channels)
Nitrous oxide
 Used for induction of GA;  If used in pt w closed
outpatient dentistry in air cavities (e.g.,
combination w O2
pneumothorax) it will
 Low potency, must be diffuse into the cavity &
combined w other agents
↑ the pressure within it
 Rapid onset of action b/c of
low blood: gas partition  MAC 100%
coefficient
 Not metabolized; eliminated
through lungs
Isoflurane
 Used for maintenance
of GA  Potential for malignant
 Minimally metabolized; hyperthermia
almost all of drug  MAC 1.4%
eliminated unchanged
in expired air
 Can cause hypotension
 Powerful coronary
vasodilator
Desflurane
 Useful for day surgery b/c of rapid onset of
action & recovery
 Eliminated unchanged in expired air
 Similar to isoflurane but w faster onset &
recovery
 Respiratory tract irritant → coughing &
bronchospasm
 Potential for malignant hyperthermia
 MAC 6%
Sevoflurane

 Used for GA especially in children

 Partially ( 3%) metabolized, detectable levels
of fluoride produced, not sufficient to cause
toxicity; remainder eliminated unchanged in
expired air
 Similar to desflurane w/ lack of respiratory
irritation
 MAC 3%
Halothane
 20% eliminated by metabolism; remainder
eliminated unchanged in expired air
 Sensitizes myocardium to effects of catecholamines
→↑risk of arrhythmia
 ↓ heart rate ↓ cardiac output → lowered b.p. &
peripheral resistance
 Toxic effects – hepatotoxicity – halothane hepatitis
( fulminant hepatic necrosis), cardiac arrhythmias,
hypotension, malignant hyperthermia
 MAC 0.75%
Intravenous drugs

 Barbiturates – thiopental*
 Etomidate*
 Benzodiazepines – midazolam*, diazepam,
lorazepam
 Propofol*
 Ketamine*
 Opioids – fentanyl, morphine
Propofol

 Induction & maintenance of anaesthesia;

used in critical care setting as continuous
infusion to provide prolonged sedation
 Potent; rapid onset & distribution
 Rapidly metabolised by liver & extra-hepatic
enzymes
 Adverse effects- hypotension, negative
inotropic effects, apnoea
Ketamine
 Produces cardiovascular
Analogue of phencyclidinestimulation
(PCP, “angel
↑ heart
dust”)
rate, b.p, cardiac
w/ output
similar properties
 Dissociative anaesthetic –pt may remain conscious although

amnesic & insensitive to pain

 Adverse effects – disorientation, sensory & perceptual

illusions, vivid & unpleasant dreams

Etomidate

 Similar to thiopental but more rapidly

metabolised
 When compared to thiopental more likely to
cause involuntary movements during
induction ; high incidence of PONV
 Prolonged infusion → possible risk of
adrenocortical suppression
Question 1

A 20 year old male patient scheduled for

surgery was anaesthesized w/ halothane &
nitrous oxide; succinylcholine was given for
skeletal muscle relaxation. He rapidly
developed tachycardia & elevated b.p.
Generalized skeletal muscle rigidity was
accompanied by marked hyperthermia.
Laboratory results revealed hyperkalemia &
acidosis
Question 1
The patient
This adverseshould
reaction
be was
treated
most
immediately
likely caused
withby
1. Atropine
Activation of brain dopamine receptors by halothane
2. Baclofen
Block of autonomic ganglia by succinylcholine
3. Dantrolene
Excessive release of calcium from the sarcoplasmic
reticulum
4. Tubocurarine
4. Release of acetylcholine from somatic nerve endings at
skeletal muscle
Question 2

Which
1. Diazepam
of the following is associated with a high
2. incidence
Ketamineof disorientation, sensory & perceptual
3.
illusions,
Midazolamvivid dreams during recovery?
4. Thiopental