Download General anaesthetics

General anaesthetics
(dr. P. Sobczynski)
Introduction
Any general anaesthetic can be divided into three components - narcosis (sleep), analgesia (pain
relief), and relaxation (muscular relaxation). Different surgical operations require different proportions
of these components. Once a patient is unconscious this is not always clear how much analgesia an
agent is providing. However some agents undoubtedly provide some more analgesia than the others
and this becomes clear with subnarcotic concentrations. Hence nitrous oxide, a poor anaesthetic has
become the self administered analgesic in trauma victims or labouring mothers by self inhalation
devices. In the early days of anaesthesia (up to the first half of XX century, when single agents were
used such as ether or chloroform, all the components of the triad had to be obtained from a single
drug. The main problem was that muscular relaxation was provided by these agents only at a deeper
levels of anaesthesia. The proportions of the narcotic and analgesic components were greatly in excess
of those required for operations. Hence the patient sometimes took hours to regain consciousness and
suffered side effects such as intractable vomiting.
Modern anaesthetic agents act independently on the each component of the triad thus allowing them
to be more easily adjusted to individual requirement. In particular, the introduction of muscle relaxants
has meant that relaxation
may be obtained from a syringe while the patient is only lightly
anaesthetised .
Inhalational anaesthetic agents
Inhalational anaesthetic agents depend on uptake by the lungs and subsequent diffusion across the
alveolar capillary membrane into the bloodstream. Apart from using this method of administration ,
the volatile anaesthetic agents exert their effects like any other drug dissolved in blood, and therefore
in terms of anaesthesia , possess important properties of hypnosis, analgesia, and relaxation in varying
degrees. Although at present inhalational agents are generally used for maintenance of anaesthesia it is
perfectly feasible to use them for induction especially in small children who invariably have fear of
needles.
We consider these agents in terms of their contribution towards a balanced anaesthetic technique and
therefore their relative properties in terms of hypnosis, analgesia and relaxation. The only agent to
possess all three properties is ether, which at the same time is explosive and therefore little used today.
In addition to their pharmacological contribution to general anaesthesia, the volatile anaesthetic agents
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must be considered in terms of their effects on blood pressure, cardiac output, respiration, peripheral
circulation and other clinical effects.
The uptake and metabolism of inhalational agents
The rate of uptake from the alveolus into the blood stream depends upon the following.
Solubility of the agent in blood - this is governed by the blood - gas solubility coefficient. The higher
the blood gas solubility coefficient the more soluble is the agent in blood. If the solubility is low, only
the minute amount of volatile anaesthetic will by taken up by pulmonary blood from the alveolus and
therefore the alveolar concentration will rise rapidly as well as brain concentration. This mechanism is
associated with a rapid induction of general anaesthesia. Typical clinical example is rapid induction of
anaesthesia with agents possessing low solubility coefficient (below 1.5 - sevoflurane, desflurane ).
This is in contrast to agents with high solubility in blood which take longer period of time to induce
anaesthesia (halothane, ether).
 Cardiac output
As the cardiac output (synonymous with pulmonary blood flow) rises more of the agent is removed
from the alveolus and therefore the arterial blood tension takes longer to rise and induction of
anaesthesia takes longer.
 Changes in ventilation
The larger the ventilation the shorter is the induction of anaesthesia
 Tissue uptake
Tissue blood solubility - most anaesthetics are equally soluble in tissue and blood. with fat tissue being
an exception (fats are known to store inhalational anaesthetics)
 Tissue blood flow
The organs with rich blood (brain, liver, heart) supply become saturated much quicker than vessel poor tissues (fat, bone).
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Metabolism and distribution of inhalational agents
The majority of volatile anaesthetic agents are excreted unchanged in the expired air. A small
proportion of almost every agent is metabolised within the liver and these metabolites are then
excreted in the bile and urine. The degree of metabolism varies between agents:
20% - halothane
2% - sevoflurane
0.2% - isoflurane
0.004% - N2O reductive metabolism to N2 in the gut
Pharmacodynamics of inhaled anaesthetics
Minimum alveolar concentration (MAC) of an inhaled anaesthetics, which prevents skeletal muscle
movement in response to a noxious stimulus (surgical skin incision), is the standard by which inhaled
anaesthetics are compared. The fact that the alveolar concentration reflects the partial pressure at the
site of anaesthetic action (e.g. brain) has made MAC the most useful index of anaesthetic potency.
Similar MAC concentrations of inhaled anaesthetics produce equivalent depression of the central
nervous system and MAC values for inhaled anaesthetics are additive. For example, 0.5 MAC nitrous
oxide plus 0.5 MAC isoflurane has the same effect at the brain as does 1 MAC concentration of either
anaesthetic alone.
Intravenous agents
Intravenous induction of anaesthesia is most frequently used in adults, although gas induction is
almost always possible except where this is unacceptable to the patient. The aim of an intravenous
anaesthetic induction agent is to induce surgical anaesthesia within a few seconds and to maintain
them there for several minutes until the maintenance anaesthetic has taken over. The action of
intravenous anaesthetic depends largely on a bolus dose being injected rapidly and reaching the brain ,
the brain level in turn being proportional to plasma drug concentration. The plasma level then falls
due to dilution, redistribution, protein binding, and metabolism. As the brain level falls, the effect of
the drug wears off and the patient wakes up.
Total intravenous anaesthesia (TIVA)
Intravenous agents are commonly used just to provide induction of general anaesthesia although it
becomes more and more popular to maintain general anaesthesia with these agents. Short-acting drugs
such as propofol are best suited to conduct total intravenous anaesthesia since accumulation does not
occur and titration of the drug to the individual needs of the patient is possible. The main advantages
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of TIVA over inhalational anaesthesia are the lack of environmental pollution, pleasant recovery
with no hang-over and lower incidence of nausea and vomiting.
However the adequate depth of anaesthesia can be a problem since at present we do not have “depth of
anaesthesia “monitors.
Hazards of intravenous induction agents
The most severe hazards associated with the use of intravenous agents are cardiovascular collapse
related to hypovolaemic shock, or in patients with cardiovascular disease. Hypotension is largely due
to peripheral vasodilatation and partly to direct myocardial depression.
Intravenous agents can also produce apnoe and should not be used in patients with obstructed airway.
Hypersensitivity reactions to most of these agents are documented, particularly thiopentone .
Extravascular injection of intravenous anaesthetics may produce severe irritation, particularly with
thiopentone, which is an extremely alkaline agent and can cause tissue necrosis. Accidental intraarterial injection of barbiturates may produce symptoms of arterial obstruction within the forearm and
the hand. This is related to the alkaline nature of the solution forming crystals within the small vessels
and obstructing blood flow. Accidental intra-arterial injection should be followed by injection of a
vasodilator and, if necessary , a sympathetic block of the affected limb.
Individual intravenous agents
Barbiturates
 Chemistry and pharmacokinetics
- derivatives of barbituric acid: thiobarbiturates (thiopental) and methylated oxybarbiturate
(methohexital)
- hypnotic activity introduced by the addition of side chains into pyrimidine ring (position 5)
- rapid redistribution allows cessation of hypnotic effect
- metabolised in the liver at a slow rate
- thiopentone 5 - 18 hours
- methohexitone 2-6 hours

Pharmacodynamics
Central nervous system
- dose dependent hypnosis with depression of EEG activity
- significant brain protection ((by reduction in cerebral blood flow and CMRO2)
- hyperalgesic effect in subanaesthetic doses
Cardiovascular system
- cardiovascular depression due to venodilation and impairment of myocardial contractility
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- increased heart rate
Respiratory system
- transient central respiratory depression after induction dose
- laryngeal and tracheal reflexes remain intact

Clinical uses and doses
- induction of general anaesthesia
thiopentone (2.5%) 2.5 - 4.5 mg/kg i.v.
methohexithone (1%) 1 mg/kg i.v.
- anticonvulsants (facilitates the action of GABA and increases the threshold of normal brain
structures - thiopentone)
- brain protection (after head trauma especially in paediatric patients)
 Postoperative sequelae
- thrombosis and phlebitis
- nausea and vomiting
- paralysis and death in patients suffering from acute intermittent porphyria (induction of aminolevulinic acid synthetase).
Etomidate
 Chemistry and pharmacokinetics
- carboxylated imidazole compound
- water insoluble (formulated with several solvents)
- metabolised in the liver (ester hydrolysis)
- excretion (kidney)
- rapid redistribution (and dissipation of clinical effect)
- elimination half-time 3.0-5.0 hours

Pharmacodynamics
Central nervous system
- hypnosis in one arm-brain circulation time
- some brain protection ((by reduction in cerebral blood flow and CMRO2)
- high incidence of myoclonic movement
Cardiovascular system
- minimal effect - the induction agent of choice in compromised patients
Respiratory system
- minimal effect on ventilation
Endocrine effects
- adrenocortical suppression following induction dose is not significant

Clinical uses and doses
- induction of general anaesthesia 0.2 - 0.6 mg/kg i.v.
- maintenance of general anaesthesia 10 µg/kg/min
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Diazepam
 Chemistry and pharmacokinetics
- virtually insoluble in water (hence high incidence of venous thrombosis, phlebitis,, and local
irritation)
- a lipid emulsified formulation available
- absorption after intramuscular administration erratic
- high protein bounding (96-99%)
- distribution half time 30-60 min.
- elimination half-time 20-50 hours
- metabolism - oxidative hepatic microsomal pathway (to oxazepam) and then glucuronide
conjugation

Pharmacodynamics
Central nervous system
- dose related effects (from mild sedation to deep coma)
- neither analgesic nor antianalgetic effect
- antegrade amnesia
- some cerebral protection
- tolerance with long-term therapy
Cardiovascular system
- minimal cardiovascular depression
Respiratory system
- modest depression
- additive effects with opioids and other hypnotics

Clinical uses
- relief of anxiety
- supplementation of regional anaesthesia
- induction and maintenance of anaesthesia
- control of grand mal seizures
Midazolam

Pharmacokinetics
- high protein bounding (96%)
- distribution half-time 5-10 min.
- elimination half-time 2-4 hours
- metabolism - oxidative hepatic microsomal pathway or

glucuronide conjugation
Pharmacodynamics
Central nervous system
- dose related effect on cerebral metabolism and blood flow
- some brain protection against hypoxic events
- increases seizure threshold
- cerebral blood flow
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Cardiovascular system
- hypotension when used with larger doses
Respiratory system
- central depression of respiratory drive
- additive effects with opioids

Clinical uses
- premedication
- supplementation of regional anaesthesia
- induction and maintenance of anaesthesia
- relief of postoperative anxiety
- sedation in ICU
Ketamine
 Chemistry and pharmacokinetics
- phencyclidine derivative
- stereoisomers (equal amounts in commercial preparation
- metabolised in the liver by microsomal enzymes
- elimination half-time 2-3 hours, dependent on liver blood flow
- water soluble metabolites excreted by the kidneys

Pharmacodynamics
Central nervous system
- dose related hypnosis and analgesia
- state of dissociative anaesthesia) : depression of thalamoneocortical projection system and
stimulation of parts of the limbic system
- the presence of unpleasant emergence reaction
the rise in intracranial pressure and CMRO2
Cardiovascular system
- stimulation of the cardiovascular system (systemic hypertension and tachycardia)
Respiratory system
- minimal effect on ventilation
- bronchial smooth muscle relaxant

Clinical uses and doses
- induction of general anaesthesia 0.5-2.0 mg/kg i.v. or 4-6 mg/kg i.m.
- maintenance of general anaesthesia 15-45 µg/kg/min i.v.
- sedation and analgesia 0.2-0.8 mg/kg i.v.
 Contraindications
- patients with increased ICP
- patients with ischaemic heart disease
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Propofol
 Chemistry and pharmacokinetics
- an alkyphenol derivative
- insoluble in water (formulated as lipid emulsion)
- rapidly metabolised in the liver (and probably extrahepatic sites)
- elimination half-time 4-24 hours but irrelevant to clinical effect hours
- water soluble metabolites excreted by the kidneys

Pharmacodynamics
Central nervous system
- hypnosis in one arm-brain circulation time
- some brain protection ((by reduction in cerebral blood flow and CMRO2)
tolerance possible with repeat anaesthesia
Cardiovascular system
- decrease in blood pressure after induction dose
Respiratory system
- 30% incidence of apnoea
- decrease in tidal volume and respiratory frequency

Clinical uses and doses
- induction of general anaesthesia 1-2.5 mg/kg i.v.
- maintenance of general anaesthesia 50-150 µg/kg/min i.v.
- sedation (ICU) 25-75 µg/kg/min i.v.
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