The document provides an overview of general anaesthesia. It discusses the aims and requirements of general anaesthesia including unconsciousness, analgesia, muscle relaxation and physiological stability. It describes the processes involved such as pre-medication, induction, maintenance of anaesthesia and muscle relaxation. Common intravenous agents for induction and maintenance like thiopental, propofol and ketamine are explained. Inhalational agents including nitrous oxide, halothane, sevoflurane and isoflurane are also discussed. Their properties, mechanisms of action, advantages and disadvantages are summarized.

1. GENERAL ANAESTHESIA
NEUROPHARMACOLOGY
[DR S. N. KANYIMBA]

2. Introduction
• General anesthesia (GA) is the state produced when a patient
receives medications for amnesia, analgesia, muscle paralysis, and
sedation
• GA is characterised by loss of consciousness, analgesia, amnesia,
skeletal muscle relaxation, and inhibition of autonomic and sensory
reflexes
• An anesthetized patient can be thought of as being in a controlled,
reversible state of unconsciousness
• Anesthesia enables a patient to tolerate surgical procedures that
would otherwise inflict unbearable pain, potentiate extreme
physiologic exacerbations, and result in unpleasant memories
2

3. Introduction …. cont’d
Aim of GA
• To depress CNS functions whilst maintaining the functions of other vital body
organs
• General anesthesia uses intravenous and inhaled agents to allow adequate
surgical access to the operative site
Requirements during and after GA
• Unconsciousness
• Analgesia
• Muscle relaxation
• Maintenance of physiological stability
• Suppression of visceral reflexes
• Amnesia
No one anaesthetic agent can achieve all these effects; therefore GA involves the
use of combinations of different types of drugs
Balanced anaesthesia: refers to a combination of drugs used to take advantage of
individual drug properties while attempting to minimize their adverse effects
3

4. Processes involved in GA
1. Pre-medication
2. Induction of anaesthesia
3. Initiation and maintenance of muscle relaxation
4. Maintenance of anaesthesia
5. Analgesia
4

5. Pre-medication
Aims of pre-medication
• Reduce anxiety
• Reduce salivary and respiratory secretions
• Suppress autonomic reflexes
• Produce amnesia
• Provide adjuvants for the maintenance of GA
Drugs used in pre-medication
• Anti-muscarinic drugs (atropine, hyoscine and glycopyronium)
• Benzodiazepines (diazepam, temazepam, lorazepam and
midazolam)
5

6. Pre-medication …. cont’d
Uses of anti-muscarinic drugs
• To suppress bronchial and salivary secretions which are increased
by intubation, upper airway surgery and some inhalation
anaesthetics
• To prevent bradycardia and salivation caused by neostigmine
• To prevent bradycardia and hypotension associated with drugs such
as halothane, propofol and suxamethonium
Uses of benzodiazepines
Anxiolysis, sedation and amnesia, and as adjuvants to general
anaesthetics
6

7. Muscle relaxation in GA
Muscle relaxants are either depolarizing or non-depolarizing agents
Depolarizing agent: suxamethonium (succinylcholine)
• Acts rapidly within seconds and last for approximately 5 minutes (3-
6 minutes)
• Used during induction of anaesthesia to provide muscle relaxation
of short duration (e.g. immediately after thiopental or before
tracheal intubation)
• Adverse effects: histamine release producing a rash, bradycardia,
somatic pain resulting from fasciculation , hyperkalaemia, persistent
neuromuscular blockade due to pseudocholinesterase deficiency
(affects 1:7,000 of population), malignant hyperthermia, increased
intra-ocular pressure and increased gastric pressure
7

8. Non-depolarizing muscle relaxants
• Examples: tubo-curarine, atracurium, vencuronium,
gallamine and pancuronium
• MOA: competitive antagonism of acetylcholine nicotinic
receptors
• Have durations of action ranging from 15 minutes to
more than 1 hour
• Used for both initiation and maintenance muscle
relaxation, and when mechanical ventilation is necessary
• Reversed with neostigmine (anticholinesterase)
8

9. Induction and maintenance of anaesthesia
Induction
• It is the transformation of an awake patient into an anesthetized one
• Induction is usually done with intravenous drugs, which produce rapid
effects with minimal unpleasant effects
• Can also be done with inhalational anaesthetics (e.g. sevoflurane)
Maintenance
• At this point, the drugs used to initiate the anesthetic are beginning to
wear off, and the patient must be kept anesthetized with a maintenance
agent
• Maintenance is usually done with inhalational anaesthetics (can be done
with intravenous anaesthetic for some surgical procedures e.g. ketamine,
midazolam and propofol)
9

10. Mechanism of action of GA drugs
• They interact with ligand-gated membrane ion channels
• They increase potassium efflux through potassium
channels resulting in hyperpolarization (this inhibits
neuronal activity)
• They increase activity of GABAA receptors and reduce
activation of excitatory receptors (glutamate and
nicotinic)
• GA drugs affect all brain functions (motor, sensory, reflex
activity, respiratory and autonomic regulation)
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11. Commonly used anaesthetic drugs
Intravenous GA drugs
Thiopental, propofol, etomidate, ketamine and midazolam
Inhalational anaesthetics
Nitrous oxide, halothane, sevoflurane, isoflurane, enflurane and
desflurane
Induction agents
IV drugs and sevoflurane
Maintenance agents
Inhalational agents, ketamine, midazolam and propofol (given as
slow IV infusion)
11

12. Thiopental sodium
• A barbiturate
• Induction is smooth and rapid (10 – 30 seconds)
• Has no analgesic effects
• Short-acting: awakening from a moderate dose is rapid due
to redistribution of the drug into other tissues
• Adverse effects: laryngeal spasm, respiratory depression,
hypotension
• Should be used with caution and reduce dose in severe
congestive cardiac failure, shock, acute intestinal
obstruction and renal impairment
• Contraindicated in acute intermittent porphyria or variegate
porphyria
12

13. Etomidate
• An induction agent that produces rapid recovery without
hangover effects
• Causes minimal cardio-respiratory changes during induction
therefore may be used in CVS disease
• Has no analgesic effect
• Should not be used for maintenance anaesthesia as it
suppresses adrenocortical function on continuous
administration
• Adverse effects: pain at injection site, postoperative nausea
and vomiting
13

14. Propofol
• Has rapid onset of action and rapid recovery
• Has no hang-over effects, and does not cause post-
operative nausea and vomiting
• Used for both induction and maintenance of anaesthesia
• Has no analgesic effect
• Causes CVS and respiratory depression, and should
therefore used with caution in CVS disease and
hypovolaemia. Monitor blood pressure closely.
• Causes bradycardia (antidote used is atropine)
• Preferred maintenance anaesthetic agent for day-care
surgery
14

15. Ketamine
• MOA: blocks the effects of glutamate at NMDA (N-mono-
methyl-D-aspartate) receptors
• Administered IV or IM
• Not as rapidly acting as other IV anaesthetics
• Recovery is relatively slow and is associated with
hallucinations and psychotic manifestations. The
hallucinations can be reduced by a benzodiazepine.
• Analgesic at sub-anaesthetic doses
• Increases sympathetic activity (therefore contra-indicated in
hypertension) and increases intracranial pressure (avoid in
increased intracranial pressure)
• Hallucinations, psychosis and increased sympathetic activity
are due to activation of sigma receptors
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16. Ketamine …. cont’d
• Does not depress the cardiovascular system (increases
sympathetic system) and has minimal respiratory depressant
effect
• Useful for rapid induction of anaesthesia in patients who
require a high degree of sympathetic activity (e.g.
hypotension, shock, cardiac tamponade)
• Can be used in poor risk surgical patients e.g. patients with
poor CVS function or hypovolaemia
• Also useful for repeated anaesthesia e.g. in burns, and short
surgical or diagnostic procedures
• Used mainly for paediatric anaesthesia especially when
repeated anaesthesia is required
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17. Inhalational anaesthetic agents
• May be gases or volatile liquids
• Can be used for induction and maintenance of anaesthesia
• May also be used following induction with an IV anaesthetic
agent
• Must be given with oxygen at higher concentrations than air
• They are all respiratory depressants (therefore assisted or
controlled ventilation is usually necessary with their use in
anaesthesia)
• All inhalation anaesthetic agents (except nitrous oxide) can
trigger malignant hyperthermia (characterized by muscle
spasms and rise in body temperature with acidosis)
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18. Anesthetic vapors (volatile liquids)
• These are chlorofluorocarbons, which are delivered with
precision from vaporizers and directly into the patient's
inhaled gas stream using oxygen as the delivery vehicle
• They may be mixed with nitrous oxide, a much weaker
anesthetic gas
• The prototype of modern anesthetic vapors is halothane
(halothane produces a hepatotoxic metabolite)
• Others are sevoflurane, isoflurane, desflurane, enflurane
and methoxyflurane (methoxyflurane is now obsolete
because it produces a nephrotoxic metabolite)
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19. Depth of anaesthesia with inhalational agents
Depth of anaesthesia is determined by partial pressure of the inhalational
agent in cerebral arterial blood which in turn determines its diffusion into
and partial pressure within brain tissue
Partial pressure of the anaesthetic agent in arterial blood is determined by:
• Partial pressure of the agent in alveolar gas
• Solubility of the anaesthetic agent in the blood (expressed as blood/gas
partition)
Partial pressure of the agent in alveolar gas depends on:
• its concentration in inspired air
• alveolar ventilation
• rate of diffusion of the agent from the alveolar gas into blood (the more
lipid soluble, the faster it will diffuse)
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20. Properties of inhalational agents: Partition coefficient
• The more soluble in blood, the higher the partition
coefficient
• The lower the partition coefficient (low solubility in
blood), the more rapid the anaesthesia and recovery
• Agents which are not very soluble produce rapid effects
and recovery is fast because it is the free form which
easily diffuses
• If there is need for rapid recovery, select an agent with a
very low partition coefficient
20

21. Properties of inhalational agents: Minimum alveolar
concentration (MAC)
• Potency of anaesthetic gases is expressed as MAC
• MAC is the minimum concentration of gas in the lungs that will
produce a state of anaesthesia in 50% of subjects
• An anaesthetic agent with a high MAC is not very potent
• MAC is an additive function for inhaled anaesthetic agents
• MAC decreases with increasing age, pregnancy, hypothermia and
hypotension
• MAC decreases in the presence of adjuvant drugs such as other
general anaesthetics, opioids, sedative-hypnotics, or other CNS
depressants
• MAC is independent of gender and weight
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22. MAC values and blood:gas partition coefficients for commonly uses
inhalational agents
ANAESTHETIC
AGENT
MAC BLOOD:GAS PARTITION COEFFICIENT
Nitrous oxide 104 0.45
Desflurane 6 0.45
Sevoflurane 2 0.65
Enflurane 1.68 1.9
Isoflurane 1.15 1.4
Halothane 0.75 2.4
Methoxyflurane 0.16 12
22

23. Characteristics of an ideal inhalational anaesthetic
agent
• High potency (low MAC value)
• Low solubility in blood and tissues (low partition
coefficient)
• Resistance to physical and metabolic degradation
• Should not injure vital tissues
• Should not cause seizures, respiratory irritation, and
circulatory stimulation
• Should produce anesthesia while allowing the use of
a high concentration of oxygen
23

24. Nitrous oxide
• Weak anaesthetic agent that cannot be used as the sole anaesthetic
agent
• Very potent analgesic agent: can be used for analgesia in sub-
anaesthetic doses in a 50:50 mixture with oxygen (50% N2O/50%
O2). Entonox is a commercial preparation and is used in obstetric
analgesia and dressing burns.
• For anaesthetic purposes, nitrous oxide is used in a 70:30 mixture
with oxygen and is used for short procedures (less than one hour)
• Prolonged administration of nitrous oxide has a risk of bone
marrow suppression (inhibits DNA synthesis)
• Can not be used as an anaesthetic agent alone without causing
hypoxia
• Its use in anaesthesia is mainly for its analgesic properties
24

25. Halothane
• Is potent, non-irritant and causes smooth induction
• Produces moderate muscle relaxation
• Adverse effects: hepatotoxicity (due to a hepatotoxic metabolite),
bradycardia, cardio-respiratory depression, predisposes to
ventricular arrhythmias (avoid adrenaline infusions with halothane
use – sensitizes the myocardium to catecholamines), hypotension
• Potent anaesthetic but poor analgesic agent
• Can be used for gaseous induction in children
• 20% is metabolized in the liver and the metabolite can cause hepatic
dysfunction
• Occasionally causes severe hepatitis that can progress to liver
necrosis
• Depresses myocardial contractility and can induce arrhythmias
25

26. Isoflurane
• Potent anaesthetic but poor analgesic agent
• Less cardio-depressant than halothane but causes
greater respiratory depression
• Does not sensitize the myocardium to catecholamines
• Causes less reduction in blood pressure and has less risk
of hepatotoxicity compared to halothane
• Reduces peripheral resistance and can cause reduction
in the blood directed to the coronary circulation
('coronary steal'): therefore avoid in ischaemic heart
disease
• Few adverse effects have been reported
26

27. Enflurane, desflurane and sevoflurane
• These have less risk of hepatoxicity compared to halothane
• Enflurane, desflurane and sevoflurane have lower potency
compared to halothane
• Enflurane: causes cardio-respiratory depression, reduces cardiac
output and blood pressure more than halothane, and increases risk
of seizures (avoid in epilepsy)
• Desflurane: faster onset and recovery compared to halothane. Has
a pungent smell and causes choking (it is irritant to the respiratory
tract – therefore avoid in bronchial asthma and chronic obstructive
pulmonary disease).
• Sevoflurane: rapidly acting, recovery is very rapid therefore there is
need for early post-operative analgesia. Suitable for use as an
induction agent. Produces a nephrotoxic metabolite.
• Methoxyflurane: produces a nephrotoxic metabolite (thus
withdrawn from clinical use)
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28. Special anaesthetic techniques
• Dissociative anaesthesia: state of analgesia with light hypnosis
(done with ketamine). The patient feels dissociated from their
surroundings, there is analgesia and amnesia, with or without
loss of consciousness. Premedication with a benzodiazepine is
done to prevent the psychosis that occurs during recovery.
• Neuroleptanalgesia: state of analgesia with the patient able to
cooperate. A combination of a neuroleptic with a high efficacy
opioid analgesic is used. Example is droperidol + fentanyl (or
alfentanil)
• Neuroleptanaesthesia: use of a neuroleptic and high efficacy
opioid analgesic to supplement GA with nitrous oxide
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29. ENDE