PCTH 325 - General AnaestheticsNov 5th 2013 (9:30-10:50) Location – Woodward 6
M Walker ([email protected])Anesthesiology, Pharmacology & Therapeutics, Faculty of
Medicine, UBC
Slides adapted from, and courtesy of,
Dr. Stephan Schwarz
1
General Anaesthesia • Anaesthesia (GB) or Anesthesia (US) from
Greek αν = an -, "without"; and αἴσθησις, =
aisthēsis, "sensation”- Wiki.
• Two types of anaesthesia: General and
Local
• General involves actions on CNS
• Local involves local actions on nerves at, or
close to, site of injection
Totally different molecular mechanisms of
actions for the two types 2
Historical approaches to managing
surgical and other types of pain
• Use of natural “drugs”: Opium poppy ( morphine), Mandrake (mandragora) root, Coca leaves, Ethanol, Marijuana
• Use of physical methods: Nerve compression, Application of cold (cryoanalgesia), Phlebotomy
For surgical pain SPEED was of the essence: prior to the use of general anaesthetics surgery could be successful, but painful.
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Pharmacological progress to
modern anaesthesia
• 1275 Discovery of diethyl ether by alchemist Raymundus
Lullus.
• 1540 First synthesis of diethyl ether ( an easily vapourized
liquid) by Valerius Cordus and the discovery of its analgesic
properties by Paracelsus, but not used for such.
• 1776 Synthesis of nitrous oxide (N2O, ‘laughing’ gas) by
Priestley (used as a recreational inhaled drug).
• 1790s suggestions of using ether and N2O to reduce
consciousness in surgery; instead, used for ‘fun and frolics’.
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Evolution of inhaled general anaesthesia
• 1842 N2O used clinically
• 1845/6 Wells and Morton (US) introduced N2O into dentistry, and diethyl ether into general anaesthesia .
• 1847 Introduction of chloroform by James Simpson –much later was discontinued due to hepato- and lethal cardiac arrhythmias
• 1929 Another anaesthetic gas – cyclopropane (at ICI)
• 1950’s Halothane invented by Raventos (at ICI)
Since then ‘sons and daughters’ of halothane
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Progress with general vapour/gaseous
general anaesthetic was slow
• Ether and then chloroform entered regular use
but associated with many anaesthesia-related
deaths – especially chloroform
• Nitrous oxide unfortunately not sufficiently
potent, but a useful adjuvant
• Cyclopropane a useful flammable addition
• Injectables introduced slowely (thiopentone)
• 1950s introduction of HALOTHANE
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Today general anaesthesia involves:
• Altering, by pharmacological means,
physiological status to produce states
characterized by
– Hypnosis (= loss of consciousness; “sleep”)
– Analgesia
– Amnesia
– Immobility
– Inhibition of autonomic and sensory nerve reflexes
– Muscle relaxation ()
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Evolution of inhaled vapour general
anaesthetics• 1956 Introduction of halothane
• 1981 Introduction of isoflurane
• 1990s Introduction of sevoflurane & desflurane
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Structures of some inhaled gaseous or vapour anesthetics
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Anesthetic uptake: vapourization – ventilation –
lung alveolar into blood - from there to the brain
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Physiochemical and physiological factors
determining inhaled anaesthetic uptake
• Solubility of general anaesthetic in blood
• Partial pressure of general anaesthetic in air
and blood, i.e. difference between alveolar and
pulmonary venous blood concentrations of
anaesthetic
• Ventilation of the alveoli where exchange
occurs between blood and air
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The higher the blood solubility,
the slower the uptake!
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Solubility of inhaled anesthetics
Anaesthetic Agent Blood/Gas Partition
Coefficient
Nitrous Oxide 0.47
Desflurane 0.42
Sevoflurane 0.6
Isoflurane 1.4
Halothane 2.3
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Alveolar concentration (FA) versus inspired
concentration (Fl ) as FA/Fl ratio over time
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Possible mechanisms of action of
general anaesthetics
• Classic theories:
– Lipid theory (Mayer-Overton Rule)
– Protein theory
• Inhaled anesthetics suppress excitable tissues, e.g. by:
– Facilitation of inhibition
• ↑ GABAA receptor-mediated transmission
• ↑ Background (“leak”) K+ conductance
– Inhibition of excitation
• ↓ Glutamate & ACh receptor-mediated transmission
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The Meyer-Overton rule
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CNS effects of inhaled general anaesthetics
• Central nervous system
– Decrease in cerebral metabolic rate
• Greatest with isoflurane (no EEG at 2 MAC): ?cerebral protection
• Enflurane: epileptic (spike-wave) EEG activity
– Cerebral vasodilatation
• Increase in cerebral blood flow
• N2O: only modest effect (low potency)
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Lung effects of inhaled anaesthetics
• Respiratory system
– Respiratory depression
• Increase in rate & decrease in depth of breathing (tidal volume)
• Net effect: reduction in alveolar ventilation & elevation of PaCO2
• Decrease in respiratory response to elevation of PaCO2
– Decrease in airway resistance
• Advantage for patients with asthma
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Cardiovascular effects of inhaled anaesthetics
• Cardiovascular system
– Decrease in arterial blood pressure as a result of
• Reduction of cardiac output (e.g. halothane), and/or
• Reduction of systemic vascular resistance (e.g. isoflurane)
– Ventricular arrhythmias (halothane)
• “Sensitization” of the myocardium to circulating
catecholamines
– N2O: mild sympathetic stimulation 20
Effects on other organs of inhaled anaesthetics
• Kidneys
– Reduction in renal blood flow
– Decrease in glomerular filtration rate & urinary output
• Skeletal Muscle
– Muscle relaxation
– Potentiate effects of non-depolarizing muscle relaxing drugs
• Uterus
– Uterine relaxation
– May lead to uterine atony & severe blood loss in parturition
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Clinical uses of inhaled general anaesthetics
• Induction of general anaesthesia
• Maintenance of general anaesthesia
• Major component in balanced general
anaesthesia
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Today’s General Anaesthesia
• Currently a Mix and Match of drugs
- Inhaled Anaesthetics, Injected General
Anaesthetic Drugs, Supplemental Drugs as well
as appropriate Devices
Inhaled Anaesthetic
– Mainly halogenated ethers – N2O , O2
• Anaesthetic injected drugs - propofol,
narcotics (morphine-like, e.g. fentanyl).
• Ancillary drugs - neuromuscular blocking drugs,
autonomic drugs, CNS drugs23
Other injectable anaesthetic injectable drugs
(most not given to man)
• Variety of different non-volatile chemicals produce
anaesthesia in animals and man.
Barbiturates (thiopental, pentobarbital)
Propofol
Ketamine
Chloralose (chloral hydrate + glucose)
Xylazine
Urethane
Some steroids
Alphaxalone/alphadolone, propanidid.
Except for steroids, a diverse group of small molecules24
• A barbiturate Now being replaced
• Useful for rapid induction of hypnosis
(lacks analgesic properties!)
• ‘Mechanism of action’ {Possibly facilitation
of inhibitory neurotransmission via GABAA
receptors)
Intravenous anaesthetic drugs(Thiopental)
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• Pharmacokinetics
– Rapid induction of anaesthesia (less than 20 seconds)
– Short duration of action since brain concentration falls rapidly due to redistribution of drug to other tissues
– Patients normally wakes ~5 min after a single i.v. bolus injection
– If tissues become saturated with drug, (e.g., as a result of continuous infusion, or repeated doses), the long elimination half-life of 10 hours or more determines recovery of consciousness.
Thiopental 1
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• Adverse effects
– Hypotension
• Exaggerated in the presence of blood loss
(Pearl Harbor experience)
• Dose reductions necessary for elderly
– Respiratory depression
– Histamine release
– Arterial occlusion possible
Thiopental 2
27
Latest and ‘best’ – Propofol 1
• 2,6-diisopropylphenol
• 1980’s answer to thiopental
• Useful for sedation, induction, and
maintenance of anaesthesia
(TIVA: total intravenous anaesthesia)
• Smooth induction; “pleasant” dreams
• Rapid, clear-headed awakening
• Antiemetic properties
• Like halothane, another ICI drug
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Propofol 2
• Mechanism of action
– Facilitation of inhibitory neurotransmission
via GABAA receptors
• Pharmacokinetics
– Rapid induction similar to thiopental;
more rapid wakening (~3 min after i.v. bolus)
– Rapid metabolism in the liver; t1/2 ~1 h
– No significant redistribution useful for
infusion29
Clinical pharmacodynamics
of thiopental versus propofol
(Glen et al. 1980)30
Propofol 3
• Adverse effects
– Respiratory depression & apnea
– Pronounced hypotension
• Greater than thiopental
• Dose reductions required for the elderly
– Pain possible upon injection
Water insoluble, therefore drug is solubilized in an egg
lecithin/soy bean oil mixture - a formulation encouraging
bacterial growth so drug is only used shortly after opening a
sterile ampoule
– Potential for sepsis 31
• Phencyclidine (PCP)-derivative
(“Angel Dust”)
• “Dissociative anaesthesia”
– Patients appear conscious without
responding to sensory input
– Profound analgesia & amnesia
• Little cardio-respiratory depression
• Preserved airway reflexes;
bronchodilation
• Unpleasant dreams are common
Ketamine 1
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Ketamine 2
• Clinical use
– Induction of anaesthesia in trauma or shock
– Battlefield surgery
– Analgesia in burn patients
– Intramuscular injection for induction in children
• Mechanism of action
– Antagonist at NMDA (N-methyl-D-aspartate) receptors
• Pharmacokinetics
– Rapid induction after i.v. bolus (slower than thiopental and propofol)
– Hepatic metabolism; t1/2 ~3 h33