PHARMACOLOGY OF

ANAESTHETICS
Prajogo Wibowo
Faculty of Medicine Hang Tuah University
Aims of Anaesthesia
Triad of anaesthesia

• Neuromuscular blocking agents for muscle

relaxation
• Analgesics/regional anaesthesia for analgesia
• Anaesthetic agents to produce unconsciousness

Why unconscious patient require analgesia ?

Stages of Anesthetics
In 1920 Guedel defined the clinical
stages of a slowly deepening inhalation
anesthesia with ether. The gradual but
significant changes in the parameters of
respiration, pupil size, and reflex
characteristics during induction and
course of anesthesia are reproducible
and allow an interpretation of the level
of consciousness or the depth of
anesthesia (stages I-IV) at any given
moment. Even today, assessment of the
depth of anesthesia is based on Guedel's
classification, with the addition of
cardiovascular parameters.
Guedel’s classification
Stages of Anesthetic (Ether)
Estimation of the risk of anesthesia
(ASA scale)
• ASA 1: healthy patient.
• ASA 2: patient with stable, treated illness like arterial
hypertension, diabetes mellitus, asthma bronchiale,
obesity
• ASA 3: patient with systemic illness decreasing
sufficiency like heart illness, late infarct
• ASA 4: patient with serious illness influencing his state
like renal insufficiency, unstable hypertension,
circulatory insufficiency
• ASA 5: patient in life threatening illness
• ASA 6: brain death-potential organ donor
Inhaled anesthetics
• Inhaled anesthetics, both volatile and gaseous, are
taken up through gas exchange in the alveoli of the
lung. Uptake from the alveoli into the blood and
distribution and partitioning into the effect
compartments within the body are important
determinants of the kinetics of these agents.
• As stated previously, an ideal anesthetic should have a
rapid onset (induction) and offset (emergence). To
achieve this, the effect site concentration within the
CNS (brain and spinal cord) will need to change rapidly.
The speed of induction of anesthetic effects
depends on several factors
1. Solubility—The more rapidly a drug
equilibrates with the blood, the more quickly the
drug passes into the brain to produce anesthetic
effects. Drugs with a low blood:gas partition
coefficient (eg, nitrous oxide) equilibrate more
rapidly than those with a higher blood
solubility (eg, halothane)
 2. Inspired gas partial pressure—A high partial
pressure of the gas in the lungs results in more
rapid achievement of anesthetic levels in the
blood. This effect can be taken advantage of by
the initial administration of gas concentrations
higher than those required for maintenance of
anesthesia.
• 3. Ventilation rate—The greater the
ventilation, the more rapid is the rise in
alveolar and blood partial pressure of the agent
and the onset of anesthesia. This effect is
taken advantage of in the induction of the
anesthetic state.
 4. Pulmonary blood flow—At high pulmonary
blood flows, the gas partial pressure rises at a
slower rate; thus, the speed of onset of
anesthesia is reduced. At low flow rates, onset is
faster. In circulatory shock, this effect may
accelerate the rate of onset of anesthesia with
agents of high blood solubility.
 5. Arteriovenous concentration gradient—
Uptake of soluble anesthetics into highly
perfused tissues may decrease gas tension in
mixed venous blood. This can influence the rate
of onset of anesthesia because achievement of
equilibrium is dependent on the difference in
anesthetic tension between arterial and venous
blood.
Elimination
• Inhaled anesthesia is terminated by redistribution of the drug from
the brain to the blood and elimination of the drug through the
lungs. The rate of recovery from anesthesia using agents with low
blood:gas partition coefficients is faster than that of anesthetics
with high blood solubility. This important property has led to the
introduction of several newer inhaled anesthetics (eg, desflurane,
sevoflurane), which, because of their low blood solubility, are
characterized by recovery times that are considerably shorter than
is the case with older agents. Halothane and methoxyflurane are
metabolized by liver enzymes to a significant extent. Metabolism
of halothane and methoxyflurane has only a minor influence on the
speed of recovery from their anesthetic effect but does play a role
in potential toxicity of these anesthetics.
Nitrous Oxide (N2O)
• It is a colourless, odourless, noninflammable
gas which is approx. 1 1⁄2 times heavier than
air. It is non-irritating with a sweet taste.
• Nitrous oxide is used for induction and
maintenance of anaesthesia. It is widely used
as carrier gas for other volatile agents in
general anaesthesia. The usual concentration
used is 70 percent N2O + 30 percent O2 along
with some muscle relaxants or other potent
anaesthetics. Nitrous oxide, if administered
along with air, it produces a stage of
excitement and delirium and also produce
amnesia. Hence, the name ‘laughing gas’
• It is eliminated unchanged from the body, via
the lungs. Despite its high fat solubility, it is
rapidly eliminated through lungs within 2 to 5
minutes after its withdrawal.
• Nitrous oxide, due to its analgesic action in
subanaesthetic concentration, is employed for
minor operation like tooth extraction, for
obstetrical analysis, painful procedures such
as changing dressing of burns. It is cheap and
very commonly used.
• Prolonged administration of nitrous oxide as in
cases of tetanus, may cause bone marrow
depression and agranulocytosis.
CYCLOPROPANE
• It is a colourless gas with sweet odour and
taste, available as liquid under pressure. It
produces analgesia without loss of
consciousness in 1 to 2 percent concentration,
in 6 to 8 percent it produces loss of
consciousness while 20 to 25 percent is
required to produce surgical anaesthesia. It has
a low blood solubility.
• The induction and recovery are rapid and
smooth. Blood pressure and cardiac
contractility are well maintained with
cyclopropane even on prolonged
administration. Muscle relaxant activity is fairly
good. Because of its highly inflammable and
explosive nature, the close circuit has to be
used to conserve the drug and to keep its
concentration in the operating room low.
• Because of its smooth induction and non-irritant to the
respiratory passage, the danger of overdosage must be
watched for.
• Cyclopropane also sensitizes the myocardium to
adrenaline and may produce a variety of cardiac
irregularities such as tachycardia and fibrillation. That is
the reason for avoiding cyclopropane anaesthesia in
pheochromocytoma and thyrotoxicosis. Cyclopropane
shock (in patients with sepsis) is another drawback,
which produces a sudden fall of blood pressure with
collapse.
ETHER (DIETHYL ETHER)
• It is a colourless, volatile liquid with a pungent odour
and produces irritating vapours which are
inflammable and explosive. It is one of the first
substances to be employed for general anaesthesia. It is a
potent agent and produces full anaesthesia when inhaled
in low concentration. A concentration of 10 to 15% in the
inspired air is usually required for induction. It produces
prolonged and unpleasant induction with salivation
and marked respiratory secretions. For this atropine
must be given prior to anaesthesia for inhibition of these
secretions.
• Respiration and blood pressure are generally
well maintained because of reflex stimulation
and high sympathetic tone.
• Because of its slow induction and recovery,
irritant property and other disadvantages ether
is rarely used these days and may be
occasionally used as a supplement to nitrous
oxide-oxygen mixture in children.
TRICHLOROETHYLENE
• It is a clear, colourless liquid with a
characteristic odour but a blue dye is added for
distinction from chloroform. It is a potent
analgesic with a rapid onset of action but
muscular relaxation with this agent is
inadequate. Induction and recovery are slow.
• It may produce tachypnea and bradycardia and
sensitizes the myocardium to adrenaline and
cardiac arrhythmias can occur probably due to
hypoxic release of adrenaline.
Halothane
• It is a volatile liquid, non-irritant and non-
inflammable. It is most widely used volatile
anaesthetic due to its smooth and rapid
induction. It inhibits laryngeal and pharyngeal
reflexes in upper planes of surgical
anaesthesia.
•
• Halothane causes relatively greater depression
of respiration. It inhibits intestinal and
uterine contractions. Cardiac output is also
reduced by 20 to 50 percent when anaesthesia
is induced by inspiration of halothane at 0.8 to
1.2 percent concentration, which is necessary
for surgical anaesthesia. Heart rate is slowed
during anaesthesia, tachy arrhythmias may also
occur in the presence of halothane.
• Halothane causes dose-dependent reductions of
renal blood flow and glomerular filtration rate
as a result of fall in blood pressure.
• Hepatitis occurs in susceptible individuals with
repeated use.
• It causes decrease in uterine muscle tone.
• Elimination of halothane may continue for 24 to
48 hours after prolonged administration.
Recovery is smooth and reasonably quick. It
is currently one of the most popular
anaesthetic used due to its non-irritant, non-
inflammable, pleasant and rapid action.
ENFLURANE
• It is a clear, colourless, noninflammable liquid
with a mild, sweet odour and consid- ered to be
a useful alternative to halothane. Induction of
anaesthesia, appropriate for surgery may be
achieved within 10 minutes after approximately
4 percent enflurane in inhaled.
• Arterial blood pressure decreases progressively
as the depth of anaesthesia is increased with
enflurane, about the same degree as it does with
halothane inhalation. The anaesthesia produces
rapid induction with quick recovery.
• Enflurane can be used for prolonged operations
such as cholecystectomy and other abdominal
surgery which requires profound muscular
relaxation. It stimulates salivary and respiratory
secretions. Uterine relaxation is similar to
halothane.
• No unusual effect on the gastrointes- tinal tract
has been reported with enflurane anaesthesia,
however, certain evidence of hepatic impairment
has been obtained during and after surgi- cal
anaesthesia. Hepatic necrosis prob- ably occurs
with enflurane in rare instances.
• Heart rate decreases little and reduction of
cardiac output is less marked. Fall in blood
pressure is similar to that caused by halothane,
arrhythmias are rare.
ISOFLURANE
• It is a isomer of enflurane and its chemi- cal and
physical properties are similar to enflurane, but
it is approximately 11⁄2 times more potent, more
volatile. It has a lower blood: gas solubility
coefficient than enflurane. It produces rapid
induction and recovery.
• Systemic arterial blood pressure de- creases
progressively with increasing depth of
anaesthesia with isoflurane. It also in- creases
heart rate but arrhythmias are not precipitated.
Isoflurane depresses respira- tion as
concentration is increased. Uterine and skeletal
muscle relaxation is similar to enflurane.
• During anaesthesia, depression of renal blood
flow, decrease in rate of glomerular filtration
and urinary flow are reported but these changes
are rapidly reversed during recovery.
METHOXYFLURANE
• It is a clear, colourless liquid with a sweet and
fruity odour. It is noninflammable and non-
explosive in air or oxygen in anesthetic
concentrations. It is the most potent inhalational
anaesthetic which has a good analgesic and
muscle relaxant properties. Renal blood flow,
glomerular filtration rate and urine flow are
reduced as with the halothane.
• It also produces the respiratory and
cardiovascular depression as with halothane but
bradycardia is more prominent.
• Methoxyflurane damages renal tubules leading
to inability to concentrate urine and uremia.
Because of its renal toxicity, it should not be
used to achieve profound anesthesia nor for
prolonged periods of time.
• This agent is used due to certain advantages i.e.
it provides profound analgesia and good
relaxation of skeletal muscles, uterine
contractions are not inhibited and postoperative
nausea and vomiting are not troublesome. But,
due to its renal toxicity, its use as a general
anesthetic is limited.
• It is a noninflammable, non-irritant agent and
chemically related to ether. Induction with this
agent is smooth and rapid. The respiratory,
hemodynamic and other changes caused by
desflurane are similar to those of isoflurane.
This agent is undergoing clinical trial.
SEVOFLURANE
• This is also a new compound and undergoing
clinical trial. It is noninflammable, non-irritant
agent. It produces more rapid induction and
termination of anesthesia than observed with
other inhalational agents. The respiratory and
circulatory ef- fects of sevoflurane resemble
those of isoflurane.
 IV ANESTHETICS
• Intravenous anesthetics are mainly used for
rapid induction of anesthesia, which is then
maintained by an inhalational agent. They also
serve to reduce the amount of maintenance
anesthetics.
Barbiturate
THIOPENTONE SODIUM
• It is an ultra short acting thiobarbiturate. The
sodium salts are highly soluble in water yielding
a very alkaline solution (pH 10.5 to 11), which
must be prepared freshly before injection.
Induction is generally smooth and takes
approximately 10 to 30 seconds.
• Thiopentone sodium is usually given as 92.5
percent solution, initially 100 to 150 mg over 10-
15 seconds and repeated if necessary depending
upon the patient’s response after 20-30 seconds.
On repeated administration the extracerebral
sites are gradually filled up and lower doses
produces anesthesia which lasts longer.
• Because of its poor analgesic property, the
painful procedures should not be carried out
under its influence unless an opioid or nitrous
oxide has been given.
• Adverse effects include laryngospasm, which
occurs generally when respiratory secretions or
other irritants are present. Shivering and
delirium may occur during recovery.
Postoperative pain induces restlessness. Nausea
and vomiting are uncommon. It can precipitate
acute intermittent porphyria in susceptible
individuals.
METHOHEXITONE SODIUM
• It is preferred to thiopentone sodium for short
procedures and out patients due to its rapid
recovery. It is approximately three times more
potent than thiopentone sodium with quicker
and briefer action.
• The only disadvantages associated with its use
are that induction is less smooth, rest-lessness is
more common, as is coughing and hiccup.
Propanidid
• It is an oily liquid eugenol derivative and less
potent than thiopentone. It is a very short acting
intravenous anaesthetic and specially used for
very short outpatient op- erations and dental
procedures.
• Adverse effects include laryngospasm, high
incidence of hypersensitivity reactions,
tachycardia, respiratory depression and
sometimes hypotension. Local irritation and
thrombophlebitis occur due to the alkalinity of
the solution. It is occasionally used as an
alternative to thiopentone.
KETAMINE
• It is a new non-barbiturate anesthetic agent and
pharmacologically related to phencyclidine, a
hallucinogen. Intravenous ketamine produces
unconsciousness and analgesia within 30
seconds. It can be given by intramuscular route
also. It acts on the cerebral cortex and
subcortical areas.
• The drug increases the heart rate, cardiac output
and blood pressure which is due to sympathetic
stimulation. Respiration is not depressed,
muscle tone increases and reflexes are not
abolished during anesthesia. Ketamine has been
recommended for short operations, un- pleasant
therapeutic and diagnostic procedures in
children, operation in shocked patients and in
obstetrics.
• Adverse reactions include delirium,
hallucinations and unpleasant dreams. It should
not be used in hypertensives and in patient with
ischaemic heart disease.
Fentanyl-Droperidol Combination
• Fentanyl is a potent short acting analge- sic
related to pethidine and belongs to group of 4-
acyl-anilinopiperdines. Droperidol is a rapidly
acting potent neuroleptic butyrophenone
derivative related to haloperidol. In
combination, these agents produce a state of
‘neurolept analgesia.’
• The fixed dose combination of fentanyl (0.05 mg) and
droperidol (2.5 mg/ml), 4 to 6 ml is diluted in glucose
solution and infused IV over 10 minutes.
• Patient remains drowsy but conscious. Respiratory
depression is marked and predictable. There is slight fall
in blood pressure. Heart rate often decreases but
myocardium is not sensitized to adrenaline.
• It is recommended for endoscopies, angiographies, burn
dressings etc.
Premedication
Main reasons for premedication:
• Anxiolysis - lack of threat
• Sedation - calming down
• Amnesia - lack of memories of perioperative
period
Overview
• Intravenous and inhalational anaesthetics
• Analgesics – simple, opioids
• Muscle relaxants
• Decurarization
INTRAVENOUS ANAESTETICS
Stages of anaesthetics
• Induction – putting asleep
• Maintenance – keeping the patient asleep
• Reversal – waking up the patient
Intravenous anaesthetics
• Onset of anaesthesia within one arm – brain
circulation time – 30 sec
• Effect site brain
▫ Propofol
▫ Thiopentale
▫ Etomidate
▫ Ketamine
General anaesthetic-how do they work
• TASK – EXPLAIN
1. Loss of conscious awareness
2. Loss of response to noxious stimuli
3. Reversibility

• Anatomical site of action

▫ Brain : thalamus, cortex
▫ Spinal cord
 GA – how do they work

Molecular theories

• Linear correlation between the lipid solubility

and potency
 GA – how do they work

Molecular theories
• Critical volume hypothesis
▫ Disruption of the function of ionic channels
• Perturbation theory
▫ Disruption of annular lipids assoc. with ionic
channels
• Receptors
▫ Inhibitory – GABA A, glycin enhance
▫ Excitatory - nAch, NMDA inhibit
 GA – how do they work

GABAA receptor
 Intravenous anaesthetics

Thiopentale
• Barbiturate
• Dose 3-7 mg/kg
• Effects : hypnosis, atiepileptic,
antanalgesic
• Side effects
▫ CVS: myocardiac depression, CO
▫ Reduction in MV, apnea
 Intravenous anaesthetics

Thiopentale
• Problems with use
▫ Extremely painfull and limbtreatening when given
intra-arterially
▫ Hypersensitivity reactions 1: 15 000
• Contraindications
▫ Porphyria
Propofol
• Phenolic derivative
• Dose 1- 2.5 mg/kg
• Effects : hypnosis
• Side effects
▫ CVS: myocardiac depression, SVR, CO
▫ Respiratory depression
▫ Hypersensitivity 1 : 100 000
Propofol
• Other effects
▫ Pain on induction
▫ Nausea and vomiting less likely
▫ Better for LMA placement then thiopentale

• Relative contraindications
▫ Children under 3
Etomidate
• Ester
• Dose 0.3 mg/kg
• Effects : hypnosis
• Side effects
▫ CVS: very little effect on HR, CO, SVR
▫ Minimal respiratory depression
 Intravenous anaesthetics

Etomidate
• Problems with use
▫ Pain on injection
▫ Nausea and vomiting
▫ Adrenocortical suppression
▫ Hypersensitivity reaction 1: 75 000

• Relative Contraindications
▫ Porphyria
Ketamine
• Phencyclidine derivative

• CV effects -  HR, BP, CO, O2 consumption

• RS -  RR, preserved laryngeal reflexes
• CNS – dissociative anaesthesia, analgesia,
amnesia

• Use – analgesic in Emerg. Med

 Intravenous anaesthetics

Pharmakokinetics
• Recovery from single bolus 5-10 min
 Intravenous anaesthetics

Choice of induction agent

• 1. Are any agents absolutely contraindicated ?
▫ Hypersensitivity, porphyria
• 2. Are there any patient related factors ?
▫ CVS status
▫ Epilepsy
• 3. Are there any drug related factors ?
▫ Egg allergy
 Intravenous anaesthetics

Induction + maintenance
SUMMARY – IV anaesthetics
• Mechanism of action – via receptors
• Used for anaesthesia and sedation
• Used for induction
• Propofol used for maintenance as well
• Thiopentale, propofol, etomidate
• All cause CV and respiratory depression
INHALATIONAL ANAESTETICS
 Inhalational anaesthetics

Anaesthetic gases
• Isoflurane
• Sevoflurane

• Halothane
• Enflurane
• Desflurane

• N2O – nitrous oxide

 Inhalational anaesthetics

Anaesthetic gases
• Any agent that exists as a liquid at room
temperature is a vapour
• Any agent that cannot be liquefied at room
temperature is a gas

▫ Anaesthetic ‘gases’ are

administered via
vaporizers
 Inhalational anaesthetics

Potency
• MAC – that concentration required to prevent
50 % of patients moving when subjected to
standart midline incision

• Sevoflurane MAC 1.8 %

• Isoflurane MAC 1.17 %
 Inhalational anaesthetics

Potency
• MAC – that concentration required to prevent
50 % of patients moving when subjected to
standart midline incision

• Sevoflurane MAC 1.8 %

• Isoflurane MAC 1.17 %
 Inhalational anaesthetics

Respiratory and cardiovascular effects

• All volatile anaesthetics
cause  MV and RR
• Isoflurane is irritant vapour
•  SVR, blood pressure falls,
 HR
• Isoflurane - ? Coronary steel
 Inhalational anaesthetics

Metabolism and toxicity

• Isoflurane (0.2 %)and Sevoflurane(3.5%) are
metabolized by liver
• F- ions are produced - ? Renal impairment
• Iso and Sevo trigger malignant hyperthermia
• N2O
▫ Megaloblastic anaemia
▫ Teratogenic
▫ PONV
SUMMARY – inhalational anaesthetics
• Mechanism of action – via receptors
• Used for induction (sevoflurane)
• And maintenance of anaesthesia
• Commonly used : Sevoflurane, Isoflurane
• Dose dependent CV and respiratory depression
• All, but N2O trigger malignant hyperthermia
NEUROMUSCULAR BLOCKING AGENTS
Neuromuscular blocking agents
• Exclusively used in anaesthesia
and intensive care
• Two classes
▫ Depolarizing
 succinylcholine
▫ Non depolarizing
 Vecuronium - aminosteroid
 Atracurium - benzylisoquinolinium
 Neuromuscular blocking agents

Use of NMBs
• Tracheal intubation
• Surgery where muscle
relaxation is essential
• Mechanical ventilation
 Neuromuscular blocking agents

Neuromuscular junction
 Neuromuscular blocking agents

Mechanism of action
• Depolarizing
▫ Structurally related to Ach
▫ First activating muscle fibres, then preventing
further response

• Non depolarizing
• Compete with Ach at nicotinic receptor at the
neuromuscular junction
 Neuromuscular blocking agents

Choice for tracheal intubation

Elective surgery Emergency surgery

Standart induction Rapid sequence induction

Non depolarizing agent Succinylcholine

Intubating doses
Succinylcholine 1 – 2 mg/kg

Vecuronium 0.1 mg/kg

Atracurium 0.5 mg/kg

 Neuromuscular blocking agents

To maintain paralysis
• Non depolarizing muscle relaxants

Succinylcholine No

Vecuronium 0.02 – 0.03 mg/kg

Atracurium 0.1 – 0.2 mg/kg

 Neuromuscular blocking agents

Succinylcholine pharmacokinetics

• Duration of action : 3 - 5 min

• Metabolism – plasma cholinesterase
▫ Cave: suxamethonium apnea
 Neuromuscular blocking agents

Succinylcholine - adverse effects

• Bradycardia
• Muscle pain – ‘sux’ pain
• Transient raised pressure in eye, stomach and
cranium
• Raise in potassium
 Neuromuscular blocking agents

Succinylcholine - contraindications
• Patient related contraindications
▫ Malignant hyperpyrexia
▫ Anaphylaxis to SCh
▫ Succinycholine apnea
• Clinical contraindications
▫ Denervation injury
▫ Penetrating eye injury
 Neuromuscular blocking agents

Non depolarizing muscle relaxants

• Choice of NMBs
▫ Personal preference
▫ Atracurium better in renal or hepatic failure
▫ Avoid atracurium in asthmatic patients
 Neuromuscular blocking agents

Reversal
• Acetylcholine esterase inhibitor – neostigmine
▫ Increases concentration of Ach at NMJ
• Neostigmine acts at all sites where acetylcholine
esterase is present including heart

What effect this might have and how this can be

overcome?
 Neuromuscular blocking agents

Neostigmine
• Dose of neostigmine – 0.05 mg/kg
• In > 50 kg man 2.5 mg
• Given with atropine 0.5 mg
 Neuromuscular blocking agents

Peripheral nerve stimulator

• Check the depth of
neuromuscular blockade
• Determine that
neuromuscular blockade is
reversible
• Check that blockade has been
reversed safisfactorily
SUMMARY – muscle relaxants
• Mechanism of action – via acetylcholine
receptor
• Used to facilitate tracheal intubation,
mechanical ventilation and surgery
• Depolarizing – Succinylcholine
▫ Lots of side effects
• Non depolarizing – Vecuronium, Atracurium
▫ Minimal CV and Resp. effects