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PH3501- Neuropharmacology > General Anaesthetics > Flashcards

General Anaesthetics Flashcards

1
Q

A definition

A
  • Lack of feeling
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2
Q

Basic principles of anaesthesia

A
  • Anaesthesia- abolition of sensation
  • Analgesia- Abolition of pain
  • Triad of general anesthesia
    • Need for unconsciousness
    • Need for analgesia
    • Need for muscle relaxation
      • We can reduce dose of anaesthetics
      • Stop muscle twitch/contraction
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3
Q

History of anaesthesia

A
  • Chinese acupuncture
  • Hindu- Henbane, wine and hemp
  • Greece discordes coined term anaesthesia for effects of drinking mandrake
  • Early arab writing- inhalation via the soporific sponge- sponge soaked in a dissolved solution of opium
  • Manual methods- compression, bleeding, smack on head
  • 1800 Humphry Davy
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4
Q

General Anaesthetics (GAs)

A
  • Ideal GAs should be
    • Readily controllable
    • So that induction and recovery are rapid
    • Allowing the level of anaesthesia to be adjusted as required
  • Other drugs can produce a state of insensibility and obliviousness to pain (morphine/ethanol)
    • Not used as anaesthetics since they are not readily controllable
  • The discovery of inhalation anaesthetics in 1846 paved the way for safe surgical procedures
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5
Q
A
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6
Q

Stage of anaesthesia

Stage 1- analgesia

A
  • Stage 1- analgesia
    • Patient conscious but drowsy
    • Responses to painful stimuli rediced
    • Degree of analgesia depends upon agent (Ether~ N2O >Halothane)
  • Stage 2- Excitement
    • Very hazardous state
    • Modern anaesthetic procedure are designed to counter effects which include
    • Loss of
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7
Q

Stage 2- Excitement

A
  • Stage 2- Excitement
  • Very hazardous state
  • Modern anaesthetic procedure are designed to counter effects which include
  • Loss of consciousness, No response to non-painful stimuli but reflex response to painful stimuli
  • Other reflexes (coughing/gagging in response to pharyngeal stimulation) exaggerated
  • May move around, talk incoherently, voluntary apnea, choke, vomit
  • Irregular breathing may affect the of gaseous anaesthetic agents
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8
Q

Stage 3 and 4

A
  • Stage 3- Surgical anaesthesia
    • Spontaneous movement stops, Respiration become regular
    • While anaesthesia is light, responses to pharyngeal and peritoneal stimulation remain intact
    • Deepening aanaesthesia leads to progressive loss of reflexes, increased muscles relaxation shallowed respiration with intercostal respiratory muscles failing before diaphragm
  • Stage 4- Medullary paralysis
    • Respiratation and vasomotor control cease. Death occurs within minutes
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9
Q

Aims of surgical anesthesia

A
  • Common anaesthetic approaches aim to:
    1. Produce rapid unconsciousness
      • Intravenous injection of a rapid onset, short acting barbiturate (Thiopentone)
    2. Maintain unconsciousness
      • With one of more inhalation agent (e.g. N2O and halothane)
    3. Supplement analgesia
      • With an intravenous analgesic agent (e.g. fentanyl)
    4. Produce muscle paralysis
      • With a neuromuscular blocking agent such as tubocurarine
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10
Q

How do GAs work

2 main theories

A
  1. Lipid theory of overton and Meyer
  2. Protein (receptor) theory
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11
Q

Lipid theory of anaesthetic action- observations

A
  • Overton and Meyer found
  • The close correlation between anaesthetic potency and lipid solubility
    • Series of a simple and un-reactive organic compound
    • Determined the concentration needed to produce reversible immobilisation of swimming tadpoles
    • Compared with the olive-oil: water partition coefficient
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12
Q

Lipid theory of anaesthetic action- Hypothesis

A
  • Overton and Meyer- Hypothesis
    • 1937 Meyer formulated the theory
    • Narcosis (anaesthesia) commences when any chemically indifferent substance has attained a certain molar concentration in the lipids of the cell
    • This concentration depends on the nature of the animal or cell but is independent of the narcotic
    • 1989: Halsey confirmed work of Meyer and Overton in man
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13
Q

Normal v Expanded membrane

A
  • There theory was that the molecules entered the lipids of the cell causing membrane expansion and so prevents the opening of the sodium channel so blocking it
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14
Q

Lipid theory of anaesthetic action- Evidence

A
  • Minimum Alveolar Concentration (MAC) is inversely proportional to lipid solubility
  • Measure partial pressure of anaesthetic in the lungs and measure pain response gives a measure of potency
  • More lipid soluble the more of an anaesthetic effect
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15
Q

Lipid theory- Speculations

A
  • The Meyer-Overton hypothesis reveals strong correlation between anaesthetic potency and lipid solubility
    • Does not suggest any mechanism of action of anaesthetics
  • Correlation of potency with solubility in hydrophobic solvents leads to speculation that anaesthesia is caused by an alteration of membrane function
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16
Q

Testing the lipid hypothesis

A
  1. Volume expansion
    • Supported by the phenomenon of pressure reversal of anaesthesia
17
Q

Membrane expansion hypothesis

A
  • Anaesthesia occurs because when anaesthetics occupy a cell membrane they cause it to expand
  • Evidence for the membrane expansion hypothesis
    • Anaesthetics can expand the area occupied by a mono-molecular layer of phospholipid molecules
    • Anaesthetics can increase the surface area of the erythrocyte cell membrane (2-3%)
    • Anaesthesia can be reversed by hydrostatic pressure
18
Q

Explanations-1

A
  • Is lipid bilayer volume expansion the cause
    • Supported by the phenomenon of pressure reversal of anaesthesia as increased pressure will oppose volume expansion
    • Suggest anaesthesia requires lipid volume expansion of 0.4%
  • BUT
    • Is degree of actual expansion really sufficient
    • Pressure reversal can be seen with other classes of drugs
      • Intravenous agents (barbiturates) and local anaesthetics
    • Therefore an increase in lipid volume is unlikely to explain all the actions of this class of drug s
19
Q

Explanation-2

A
  • Increase in membrane fluidity
    • The intrusion of anaesthetic agents leads to disordering of the regular packing of the hydrophobic tails of membrane phospholipids
  • Evidence
    • Electron spin resonance (ESR) spectroscopy indicate that anaesthetics increase membrane fluidity
    • Correlates with anaesthetic activity
      • Although relatively high concentrations needed
      • Equivalent to an increase in fluidity produced by the 1oC rise in temperature
      • But raising temperature reduces anaesthetic potency
20
Q

Arguments against the lipid theory

A
  • The cut off phenomenon
    • Anaesthetic potency increases steadily through a homologous series of chemical comounds as the length of the hydrocarbon chain is increased
    • Beyond a certain point potency suddenly drops even though lipid solubility continues to increase
  • In-vitro immobilization of halothane during anaesthesia
    • ESR studies in vitro indicarte that halothane molecules in the brain bind to sturable sites, and are immobilized when bound
    • Association of halothane with membrane lipids shows neither saturability nor immobilization
21
Q

Protein theory of anaesthetic action- observation

A
  • Anaesthetics interact with specific membrane proteins
    • Receptors and ligand-gated ion channels
  • Franks and Lieb- 1987
    • The close correlation between anaesthetic potency and the potency of luciferase inhibition for a wide range of anaesthetic compound
    • Luciferase is soluble protein, therefore, interaction with lipid not necessary
    • Suggests anaesthetics bind to a hydrophobic domain of the protein and alter its function
    • Several anaesthetics act in enantio-selective manner isoflurane, barbiturates, etomidate, neuroactive steroids
22
Q

Cellular sites of action

A
  • During surgical anaesthesia, condition along peripheral nerves is largely unaffected- if lipid theory is correct this would be affected
    • I.e. different from actions of local anaesthetics
    • Axonal condution is only affected at concentrations >> than those used for general anaesthesia
  • Synaptic transmission is far more susceptible to anaesthetic action
  • Therefore, at the cellular level, anaesthetics mainly affect synaptic transmission
23
Q

Recording neuronal activity- the brain slice

A

*

24
Q

Recent evidence: Actions at glu and GABA synapses

A
  • We see an increase of GABA activity with the addition of halothane or Propofol
  • Bicucline (GABAA - block GABA A receptor)- effective reversal of propofol
  • Halothane BIC doesn’t reverse as much
  • There is a subtle effect of glutamate
25
Q

Effects on synaptic transmission

A
  1. Reduced Glu release at synapses
  2. Increased GABA release
    • 2b. Increased duration of GABA IPSC
  3. Reduction of the excitability of the post-synaptic cells
26
Q

What sorts of anaesthetics do we use>

A
  • Inhalation
    • Gases or Vapors
    • Usually Halogenated
  • Intravenous
    • Injection
    • Anaesthetics or induction agents
27
Q

Inhaled Anesthetics

A
  • Easy to control
  • Reversible
28
Q

Physical and chemical properties of inhaled anaesthetics

A
  • Although halogenations of hydrocarbons and ethers increase anaesthetic potency, it also increase the potential for inducing cardiac arrhythmias in the following order F<cl>
    </cl><li>Esthers that have an asymmetric hhalogenated carbon tend to be good anesthetics (such as Enflurane)</li><li>Halogenated methyl, ethyl ethers (Enflurane and Isoflurane) are more stable, are more potent and have better clinical profile than halogenated diethyl ethers</li><li>Fluorination decrease flammability and increase sstability of adjacent halogenated carbons</li><li>Complete halogenations of alkane and ethers of full halogenations of end methyl groups decrease potency and enhances convulsant activity
    <ul>
    <li>Flurothyl is a potent convulsant, with a median effective dose (ED50) for convulsions in mice of 0.00122 atm</li>
    </ul>
    </li><li>The presence of double bonds tends to increase chemical reactivity and toxicity</li>

</cl>

29
Q

Intravenous Anesthetics

A
  • Used in combination with inhaled anaesthetics to
    • Supplement general anaesthesia
    • Maintain general anaesthesia
    • Provide sedation
    • Control BP
    • Protect the brain
30
Q

Anaesthetic of the future: Xenon

A
  • Rare gas extracted from the air- synthesised from supernova
    • Very expensive to produce
  • Close to ideal anaesthetic
    • Low blood and tissue solubility- Rapid induction/ recovery
    • Potent
    • Not metabolized
    • Non-flammable
    • Minimal side effects

PH3501- Neuropharmacology (28 decks)

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