PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by...

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PCTH 325 - General Anaesthetics Nov 5 th 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

Transcript of PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by...

Page 1: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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

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Page 2: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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

Page 3: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 4: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 5: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 6: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 7: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 8: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

Evolution of inhaled vapour general

anaesthetics• 1956 Introduction of halothane

• 1981 Introduction of isoflurane

• 1990s Introduction of sevoflurane & desflurane

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Page 9: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

Structures of some inhaled gaseous or vapour anesthetics

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Page 10: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

Anesthetic uptake: vapourization – ventilation –

lung alveolar into blood - from there to the brain

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Page 11: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 12: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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Page 13: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

The higher the blood solubility,

the slower the uptake!

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Page 14: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 15: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

Alveolar concentration (FA) versus inspired

concentration (Fl ) as FA/Fl ratio over time

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Page 16: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 17: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

The Meyer-Overton rule

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Page 18: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 19: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 20: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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

Page 21: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 22: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

Clinical uses of inhaled general anaesthetics

• Induction of general anaesthesia

• Maintenance of general anaesthesia

• Major component in balanced general

anaesthesia

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Page 23: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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

Page 24: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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

Page 25: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

• 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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Page 26: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

• 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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Page 27: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

• 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

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Page 28: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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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Page 29: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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

Page 30: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

Clinical pharmacodynamics

of thiopental versus propofol

(Glen et al. 1980)30

Page 31: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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

Page 32: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

• 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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Page 33: PCTH 325 - General Anaesthetics · modern anaesthesia • 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. • 1540 First synthesis of diethyl ether ( an easily vapourized

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