PHARMACOLOGY – Neurology Module
GENERAL ANAESTHETICS
General Anaesthetics – Introduction
• Balanced general anaesthesia is characterized by the primary neurophysiologic effects – unconsciousness,
amnesia, analgesia, inhibition of autonomic reflexes, and skeletal muscle relaxation, which should be
tailored for the intended procedure.
• Achieving all requirements with a single drug would require high supra-anaesthetic doses that would cause
adverse effects such as slow and unpleasant recovery, and can cause even death by loss of cardiovascular
reflexes and respiratory paralysis.
• Therefore, the general anaesthetics are hardly used in isolation; Multiple intravenous and inhaled
anaesthetic drugs, combined with other agents like neuromuscular blocking medicines, sedatives, etc. are
used together to produce balanced anaesthesia.
• All successful general anaesthetics are given intravenously or by inhalation, because these routes enable
closest control over blood concentrations as well as their rapid elimination, and thus of effect on the brain.
• Many simple, unreactive compounds can produce general anaesthesia (Eg: inert gas xenon); The potency
and effectiveness are closely correlated with lipid solubility, NOT with the chemical structure.
❖ According to the Overton–Meyer hypothesis; the more lipid-soluble drugs (i.e. with higher oil:gas partition
coefficient) tend to be the more potent anaesthetics, but such a correlation is not invariable. Some anaesthetic
agents are not lipid soluble and many lipid-soluble substances are not anaesthetics.
General Anaesthetics – Pharmacological Effects
• Although all parts of the nervous system are affected, the main targets are cortex, thalamus, hippocampus,
midbrain reticular formation and the spinal cord.
• General anaesthetics acts mainly by interaction with membrane ligand-gated ion channels. Most enhance
the activity of inhibitory GAB𝐀𝐀 receptors and other cys-loop ligand-gated ion channels (such as glycine,
nicotinic acetylcholine, serotonin etc).
• Other important effects are; (1) The activation of a subfamily of potassium channels (the two-pore domain
K + channels) – by inhalational agents; and (2) The inhibition of excitatory NMDA receptors.
• Thus at the cellular level, they affect synaptic transmission and neuronal excitability rather than axonal
conduction (unlike local anaesthetics).
• Most (except ketamine, nitrous oxide and xenon, which act by inhibiting NMDA-receptors) produce similar
neurophysiological effects and differ mainly in respect of their pharmacokinetic properties and toxicity.
• Most cause cardiovascular depression by effects on the myocardium and blood vessels, as well as on the
nervous system. Halogenated anaesthetic agents are likely to cause cardiac dysrhythmias.
General Anaesthetics – Classification
• Inhalation anaesthetic agents –
Gaseous (non-volatile) anesthetics – Clinically administered at room temperature in its gaseous
state (Eg: Nitrous oxide, Xenon)
Volatile anesthetics (Halogenated agents) – Have low vapor pressures and thus high boiling
points so that they are liquids at room temperature and sea-level ambient pressure; Hence,
require precision vaporizers for administration (Eg: Halothane; hepatotoxic, which is less used
and replaced by, Isoflurane, Sevoflurane and Desflurane)
• Intravenous anaesthetic agents – Propofol, Ketamine, Etomidate, Thiopental
INTRAVENOUS ANAESTHETIC AGENTS
Intravenous anaesthetic agents – Introduction
• Intravenous anaesthetic agents act more rapidly than inhalation agents, producing unconsciousness in
about 20 seconds, as soon as the drug reaches the brain from its site of injection.
• They are used for induction of anaesthesia; Patients may prefer an injection to a face mask delivering
inhalational agents.
7 ©AScS – 2019 A/L Batch
, PHARMACOLOGY – Neurology Module
• They are NOT suitable for maintenance of anaesthesia as their elimination from the body is relatively slow
compared with that of inhalation agents.
Exceptions
o Propofol can be used as a continuous Infusion for maintenance as its elimination is fast.
o Ketamine can be administered as a single bolus for short operations without the need for an
inhalation agent as its duration of action is sufficient.
• The intravenous anesthetics are lipophilic and preferentially partition into highly perfused lipophilic tissues
(such as brain, spinal cord), which accounts for their rapid onset of action.
(01) Propofol
• An alkyl phenolic derivative that has replaced thiopental as an IV anaesthetic; Can be used for both
induction as well as maintenance.
• Its mechanism of action is poorly understood, but thought to be related to the effects on GABA-mediated
chloride channels in the brain, by reducing dissociation of GABA from GABA receptors.
• Advantages –
o Extremely lipid-soluble and stable in solution.
o Possible to be used as a continuous infusion – suitable for maintenance.
o Rapid onset – acts in one arm-to-brain circulation time (about 20 – 40 s), and rapid rate of
redistribution (t 1⁄ = 2 − 4 min) makes it short acting.
2
o Suppress laryngeal reflexes and has NO effect on bronchial smooth muscle tone.
o Has anticonvulsant actions.
o Rapid recovery and short waking-to-walking time (minimal “hangover” effect).
❖ Extensively metabolized by the liver and extrahepatic sites (such as lungs), and the
metabolism follows first order kinetics, resulting in rapid metabolism.
o Low incidence of post-operative nausea and vomiting.
Propofol – Clinical Indications
• Induction of general anaesthesia.
• Maintenance – Total intravenous anesthesia (TIVA), Target control infusions (TCI) and Day case
surgeris/outpatient surgeries (due to less marked and shorter-lasting residual effects)
• Prolonged sedation in ICUs and procedures.
Propofol – Adverse Effects
• Pain on IV injection (less with medium chain triglyceride emulsions)
• Allergic reactions
• Vasodilation and Hypotension → Reflex tachycardia; But severe bradycardia also has been reported.
• Transient apnoea
• Propofol infusion syndrome (when given for a long period i.e. in ICU to maintain sedation, particularly to
children) – severe metabolic acidosis, rhabdomyolysis, hyperkalaemia, lipaemia, hepatomegaly, renal failure,
arrhythmia and cardiovascular collapse.
• Drug interactions – Neuromuscular blockers (increases depth of blockade interacting with atracurium and
vecuronium. However, NO increase in duration of action).
Propofol – Cautions Propofol – Contraindications
• Cardiac disease – Poor LV function, Mitral/ • Allergy to drug and its solvents
Aortic valvular stenosis etc., due to the • Children < 3 year of age (FDA)
reduced cardiac output • Inability to maintain airways
• Respiratory impairment
• Hypovolaemic patients
• Elderly patients
• Allergies – egg, soya
8 ©AScS – 2019 A/L Batch
GENERAL ANAESTHETICS
General Anaesthetics – Introduction
• Balanced general anaesthesia is characterized by the primary neurophysiologic effects – unconsciousness,
amnesia, analgesia, inhibition of autonomic reflexes, and skeletal muscle relaxation, which should be
tailored for the intended procedure.
• Achieving all requirements with a single drug would require high supra-anaesthetic doses that would cause
adverse effects such as slow and unpleasant recovery, and can cause even death by loss of cardiovascular
reflexes and respiratory paralysis.
• Therefore, the general anaesthetics are hardly used in isolation; Multiple intravenous and inhaled
anaesthetic drugs, combined with other agents like neuromuscular blocking medicines, sedatives, etc. are
used together to produce balanced anaesthesia.
• All successful general anaesthetics are given intravenously or by inhalation, because these routes enable
closest control over blood concentrations as well as their rapid elimination, and thus of effect on the brain.
• Many simple, unreactive compounds can produce general anaesthesia (Eg: inert gas xenon); The potency
and effectiveness are closely correlated with lipid solubility, NOT with the chemical structure.
❖ According to the Overton–Meyer hypothesis; the more lipid-soluble drugs (i.e. with higher oil:gas partition
coefficient) tend to be the more potent anaesthetics, but such a correlation is not invariable. Some anaesthetic
agents are not lipid soluble and many lipid-soluble substances are not anaesthetics.
General Anaesthetics – Pharmacological Effects
• Although all parts of the nervous system are affected, the main targets are cortex, thalamus, hippocampus,
midbrain reticular formation and the spinal cord.
• General anaesthetics acts mainly by interaction with membrane ligand-gated ion channels. Most enhance
the activity of inhibitory GAB𝐀𝐀 receptors and other cys-loop ligand-gated ion channels (such as glycine,
nicotinic acetylcholine, serotonin etc).
• Other important effects are; (1) The activation of a subfamily of potassium channels (the two-pore domain
K + channels) – by inhalational agents; and (2) The inhibition of excitatory NMDA receptors.
• Thus at the cellular level, they affect synaptic transmission and neuronal excitability rather than axonal
conduction (unlike local anaesthetics).
• Most (except ketamine, nitrous oxide and xenon, which act by inhibiting NMDA-receptors) produce similar
neurophysiological effects and differ mainly in respect of their pharmacokinetic properties and toxicity.
• Most cause cardiovascular depression by effects on the myocardium and blood vessels, as well as on the
nervous system. Halogenated anaesthetic agents are likely to cause cardiac dysrhythmias.
General Anaesthetics – Classification
• Inhalation anaesthetic agents –
Gaseous (non-volatile) anesthetics – Clinically administered at room temperature in its gaseous
state (Eg: Nitrous oxide, Xenon)
Volatile anesthetics (Halogenated agents) – Have low vapor pressures and thus high boiling
points so that they are liquids at room temperature and sea-level ambient pressure; Hence,
require precision vaporizers for administration (Eg: Halothane; hepatotoxic, which is less used
and replaced by, Isoflurane, Sevoflurane and Desflurane)
• Intravenous anaesthetic agents – Propofol, Ketamine, Etomidate, Thiopental
INTRAVENOUS ANAESTHETIC AGENTS
Intravenous anaesthetic agents – Introduction
• Intravenous anaesthetic agents act more rapidly than inhalation agents, producing unconsciousness in
about 20 seconds, as soon as the drug reaches the brain from its site of injection.
• They are used for induction of anaesthesia; Patients may prefer an injection to a face mask delivering
inhalational agents.
7 ©AScS – 2019 A/L Batch
, PHARMACOLOGY – Neurology Module
• They are NOT suitable for maintenance of anaesthesia as their elimination from the body is relatively slow
compared with that of inhalation agents.
Exceptions
o Propofol can be used as a continuous Infusion for maintenance as its elimination is fast.
o Ketamine can be administered as a single bolus for short operations without the need for an
inhalation agent as its duration of action is sufficient.
• The intravenous anesthetics are lipophilic and preferentially partition into highly perfused lipophilic tissues
(such as brain, spinal cord), which accounts for their rapid onset of action.
(01) Propofol
• An alkyl phenolic derivative that has replaced thiopental as an IV anaesthetic; Can be used for both
induction as well as maintenance.
• Its mechanism of action is poorly understood, but thought to be related to the effects on GABA-mediated
chloride channels in the brain, by reducing dissociation of GABA from GABA receptors.
• Advantages –
o Extremely lipid-soluble and stable in solution.
o Possible to be used as a continuous infusion – suitable for maintenance.
o Rapid onset – acts in one arm-to-brain circulation time (about 20 – 40 s), and rapid rate of
redistribution (t 1⁄ = 2 − 4 min) makes it short acting.
2
o Suppress laryngeal reflexes and has NO effect on bronchial smooth muscle tone.
o Has anticonvulsant actions.
o Rapid recovery and short waking-to-walking time (minimal “hangover” effect).
❖ Extensively metabolized by the liver and extrahepatic sites (such as lungs), and the
metabolism follows first order kinetics, resulting in rapid metabolism.
o Low incidence of post-operative nausea and vomiting.
Propofol – Clinical Indications
• Induction of general anaesthesia.
• Maintenance – Total intravenous anesthesia (TIVA), Target control infusions (TCI) and Day case
surgeris/outpatient surgeries (due to less marked and shorter-lasting residual effects)
• Prolonged sedation in ICUs and procedures.
Propofol – Adverse Effects
• Pain on IV injection (less with medium chain triglyceride emulsions)
• Allergic reactions
• Vasodilation and Hypotension → Reflex tachycardia; But severe bradycardia also has been reported.
• Transient apnoea
• Propofol infusion syndrome (when given for a long period i.e. in ICU to maintain sedation, particularly to
children) – severe metabolic acidosis, rhabdomyolysis, hyperkalaemia, lipaemia, hepatomegaly, renal failure,
arrhythmia and cardiovascular collapse.
• Drug interactions – Neuromuscular blockers (increases depth of blockade interacting with atracurium and
vecuronium. However, NO increase in duration of action).
Propofol – Cautions Propofol – Contraindications
• Cardiac disease – Poor LV function, Mitral/ • Allergy to drug and its solvents
Aortic valvular stenosis etc., due to the • Children < 3 year of age (FDA)
reduced cardiac output • Inability to maintain airways
• Respiratory impairment
• Hypovolaemic patients
• Elderly patients
• Allergies – egg, soya
8 ©AScS – 2019 A/L Batch
