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LF260 Neuropharmacology > Lecture 11: General anesthetics > Flashcards

Lecture 11: General anesthetics Flashcards

1
Q

Anesthesia causes 3 main neurophysiological changes

A
  • Unconsciousness
  • Analgesia (response to painful stimuli)
  • Loss
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2
Q

Local anesthetics

A

Act locally to block nerve conduction (lignocaine)

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3
Q

General anesthetics

A

Act in the brain to cause a loss of consciousness

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4
Q

Stage 1 of anesthesia

A
  • Still awake but drowsy
  • Distorted perception
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5
Q

Stage 2 of anesthesia (excitation)

A
  • Loss of consciousness
  • Inhibition depressed before motor centers
    • Exaggerated reflexes
  • Stimulation of CNS: uncontrolled movements, vocalizations
  • Loss of temp control: flushing of skin
  • Irregular breathing n cardiac dysrhythmia
  • Dangerous phase
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6
Q

Stage 3 of anesthesia

A
  • Regular breathing
  • Cough n vomit reflex depressed
  • Pupils initially constrict but get deeper into stage pupils dilate
  • Large skeletal muscles relax
  • Drop in BP
  • Corneal reflex disappears
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7
Q

Stage 4 of anesthesia

A

No ventilation [respiratory medulla oblongata]

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8
Q

What is the basis of Guedel’s classification for monitoring anesthesia, and why may it not be applicable to paralyzed patients?

A
  • Observing muscular movements, including respiratory muscles, to monitor anesthesia
  • W paralyzed patients: clinical signs become undetectable, making Guedel’s classification less applicable in such cases
  • Also not reliable bc it can be obscured by the use of multiple anesthetic agents, leading to limitations in its reliability and relevance in modern anesthesia practice.
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9
Q

Why can the use of multiple agents obscure the signs in Guedel’s classification during anesthesia?

A

Combined effects of different agents may complicate the interpretation of muscular movements and clinical signs → challenges in accurately assessing the stages of anesthesia using this classification.

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10
Q

How does the amplitude of high-frequency components of EEG change with the deepening of anesthesia, and what other frequency changes are observed?

A
  • Anesthesia deepens → the amplitude of the high-frequency components of EEG decreases + accompanied by an increase in lower frequencies.
  • Pattern is indicative of the changes in neural activity associated with different depths of anesthesia.
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11
Q

What factors contribute to changes in EEG during anesthesia, and how are these changes agent-dependent?

A
  • Changes in EEG during anesthesia are influenced by the type of anesthetic agent used, meaning different anesthetic agents may produce distinct EEG patterns.
  • Additionally, various pathophysiological events such as hypotension, hypoxia, and hypercapnia can affect the EEG.
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12
Q

What is the Patient State Index (PSI), and how was it developed to assess hypnosis during anesthesia?

A
  • EEG method developed by comparing large numbers of EEGs during the induction, maintenance, and emergence phases of anesthesia.
  • It serves as a tool for assessing the level of hypnosis in a patient based on the observed EEG patterns.
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13
Q

Describe the Cerebral Function Monitor (CFM) and its role in monitoring brain activity during anesthesia

A
  • Filters, semi-logarithmically compresses, and rectifies the EEG signal.
  • It represents the overall electrocortical background activity of the brain, providing a means to monitor and assess cerebral function during anesthesia
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14
Q

What is the Bispectral Index (BIS), and how is it derived for assessing the depth of anesthesia?

A
  • Stats based, empirically derived complex parameter
  • Takes into account various features of EEG to provide numerical value that reflects the patient’s level of consciousness during anesthesia
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15
Q

3 major theories for GA mechanisms of action

A
  • Lipid theory
  • Protein theory
  • Combination of both
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16
Q

What is the lipid theory and why is it outdated?

A
  • GA dissolve in the cell membrane of neurons and glia → changes in membrane properties (e.g. bilayer thickness, order parameters, and curvature elasticity)
    • These changes may affect the proteins present in the membrane, resulting in anesthesia.
  • Theory is considered outdated [non-specific]
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17
Q

What evidence supports the lipid theory?

A
  • Pressure reversal: increasing pressure pushes agents out of the membrane thus patient will recover
  • No defined chemical structure of GA
    • Variety of different compounds w different structures
    • Don’t bind to a single receptor or channel
  • Meyer-Overton correlation: correlates the potency of anesthetics with their lipid solubility
    • Expectation: the better the solubility, the more effective the GA would be
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18
Q

Describe the experimental setup involving tadpoles used to support the Meyer-Overton correlation in the lipid theory of GA

A
  • Conscious tadpoles would float to the top, hanging from a mucus thread.
  • When anesthetized, they would fall to the bottom.
  • This simple assay served as a behavioral indicator of consciousness.
  • The Meyer-Overton correlation was supported by the finding that anesthetic potency correlated with lipid solubility
  • EXAMPLE: methoxyflurane, which is highly soluble in olive oil and is a potent anesthetic.
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19
Q

Explain the role of nitrogen in the experiment and how its behavior in olive oil supports the lipid theory of GA mechanism

A
  • Nitrogen poorly dissolves in olive oil, requiring large amounts to induce anesthesia.
  • This behavior aligns with the lipid theory, suggesting that lipid solubility is a factor in anesthetic potency.
  • The correlation between poor solubility of nitrogen in olive oil and the need for a higher concentration for anesthesia supports the idea that anesthetics work by dissolving in the lipid membrane.
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20
Q

Problems associated w the lipid theory

A
  • Stereoisomer
    • Identical molecules but mirror images of each other
    • One will be anesthetic but another inactive
  • Both isomers should be active if they’re just dissolving in the membrane [same lipid solubility]
  • New compounds don’t fit the Meyer-Overton correlation
  • Cut off effect: increasing carbon chain length
    • Make the compound should make more lipid soluble [making it more hydrophobic]
    • Effect of anesthetic decreases
    • However, if the lipid theory were true then making it more soluble would make it more potent thereby a more effective anesthetic
  • Non-immobilizers
    • Similar in lipid solubility to anesthetics yet not anesthetics
  • Small increase in temperature produces similar changes in membrane density and fluidity but do not produce anesthesia
  • Similar correlation w partition of GAs into protein
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21
Q

What is the protein theory?

A
  • GA bind to specific membrane proteins
  • 3 major proteins
    • GABA A receptor (inhibitory)
    • 2 pore K+ channels (controls resting potential)
    • NMDA receptor (excitatory)
22
Q

Explain the role of the GABA A receptor in the mechanism of anesthesia, and how anesthetics enhance its effectiveness

A
  • The GABA A receptor has a chloride channel.
  • Anesthetics enhance the potency and effectiveness of GABA → suppressing brain activity.
  • Since all interneurons release GABA and it acts through various receptors, the modulation of the GABA A receptor contributes to the mechanism of anesthesia.
23
Q

What is the significance of 2-pore K+ channels in the context of anesthesia, and how do anesthetics affect their function?

A
  • 2-pore K+ channels are leak channels in neuronal membranes selectively permeable to potassium, determining membrane potential.
  • Anesthetics increase the permeability of these channels → increase in membrane potential → more negative → switching neurons off.
  • Enhancing the effect of these channels contributes to the overall mechanism of anesthesia, particularly in controlling resting potential.
24
Q

Describe the role of NMDA receptors in the nervous system and how blocking them contributes to the mechanism of anesthesia.

A
  • Excitatory receptors in nervous systems
  • Thus blocking will inhibit excitatory neurotransmission
  • Prevents NMDA receptor activation → suppression of neuronal activity n anesthetic effect
25
Q

Describe an experimental approach involving the expression of GABA A channels in a cell line to investigate the mechanism of general anesthetics

A
  • Cell line expressing GABA A channels is utilized.
  • Chlorine currents are recorded, and the cell line is fused with general anesthetics.
  • AIM: observe whether GABA currents become larger in the presence of the anesthetics, providing insights into the impact of anesthetics on GABA A receptor function.
26
Q

How can the knowledge of the binding site of general anesthetics on a receptor be used to study the mechanism of anesthesia?

A
  • If the binding site of general anesthetics on a receptor is known, the receptor can be mutated to prevent binding.
  • Expressing this mutated receptor in an experimental animal allows researchers to investigate whether the animal becomes less sensitive to the anesthetic, providing information about the specific binding interactions contributing to anesthesia.
27
Q

What is the significance of mutating different residues in the GABA A receptor to study general anesthetics?

A

Mutating different residues in the GABA A receptor, where general anesthetics no longer bind, allows researchers to assess whether the anesthetic loses its potency. This approach helps identify specific amino acid residues crucial for the binding and action of anesthetics on the receptor.

28
Q

Explain the findings related to mutated GABA receptors and their impact on specific anesthetics such as propofol and alphaxalone.

A
  • Mutated GABA receptors may result in propofol losing its activity, indicating that the mutated receptor is essential for propofol’s action.
  • However, if the mutated receptor has no effect on alphaxalone, it suggests that alphaxalone might not rely on the same binding site or interactions for its anesthetic effect.
29
Q

What are the criteria for identifying relevant anesthetic protein targets?

A
  • Reversibly alters target function at clinically relevant concentrations
    • Use clinically relevant concentrations: MAC, similar to EC 50
  • Protein target expressed in appropriate anatomical location in the brain/spinal cord
  • Stereo-selective effects in vivo parallel actions on the target in vitro
  • Target exhibits appropriate sensitivity and insensitivity to model n non-anaesthetic compounds
30
Q

What are the brain regions involved in the sleep-wakefulness cycle, and what can be expected regarding protein targets in these regions?

A
  • Brainstem and Midbrain Nuclei
  • These regions play a crucial role in controlling sleep and consciousness.
  • Protein targets related to the sleep-wakefulness cycle are expected to be expressed in these areas.
31
Q

Describe the involvement of histamine and noradrenaline in the sleep-wakefulness cycle and how it relates to anesthetic drugs.

A
  • Histamine (TMN Nuclei):
    • The tuberomammillary nucleus (TMN) releases histamines, acting as an arousal transmitter.
    • Anti-histamines cross the blood-brain barrier (BBB) n cause drowsiness.
    • Recent evidence suggests that anesthetics may not primarily work through histaminergic pathways.
  • Noradrenaline (LC):
    • The locus coeruleus (LC) releases noradrenaline, which is also involved in arousal.
  • Relation to Anesthetic Drugs:
    • Anesthetic drugs are expected to work in these areas, as they are essential for regulating the sleep-wakefulness cycle and consciousness.
32
Q

Properties of an ideal anesthetics

A
  • Rapid action n recovery
  • Minimal irritant properties
  • Miscible w air/oxygen (no risk of explosion)
  • Analgesic
  • Muscle relaxant
33
Q

Minimum alveolar concentration

A

Alveolar partial pressure of an inhaled anesthetic, which prevents movement in response to a standard noxious stimulus in 50% of patients.

34
Q

Describe the pharmacokinetics of inhaled agents

A
  • Greater the solubility in the blood
    • Determined by Blood/ gas co-efficient
    • Blood acts as a reservoir, taking the anesthetic away so that the pressure can’t rise
      • Thereby slowing the onset
  • Reduced rate of rise of alveolar partial pressure
  • Reduced rate of rise of brain partial pressure
  • Slower rate of anaesthesia onset
35
Q

Factors affecting the rate of equilibration of inhalation anesthetics

A
  • Increase in cardiac output → delays induction
  • Decrease in cardiac output → overdosage
  • Lean tissues → faster equilibration [fast perfusion, rapid equilibration]
  • Longer operation, slower recovery
36
Q

What factors influence the rate of recovery from anesthesia, and how does the elimination of inhaled anesthetics primarily occur?

A
  • Reduction of Inspired Concentration → anesthetic speeds up recovery.
  • High Alveolar Ventilation → accelerates the elimination of anesthetic.
  • Anesthetics w blood gas solubility → recover more quickly.
  • Short Duration of Anesthesia in low perfusion tissues → leading to faster recovery.
37
Q

How does the elimination of inhaled anesthetics primarily occur?

A
  • Ventilation in the lungs
  • The rate of reduction of alveolar partial pressure determines the pace of recovery.
38
Q

Characteristics of propofol

A
  • Potentiates GABAA receptor responses
  • Rapidly metabolized in the liver.
  • Distributes in fatty tissues: high lipophilicity.
39
Q

Uses of propofol

A
  • Used as an induction agent.
  • After a bolus, patients wakes up within 5 to 10 minutes.
  • Pleasant effects: mood-altering, antiemetic
  • Maintenance agent in “total intravenous anaesthesia”
    • It is given in conjunction with an opioid and muscle relaxants.
    • Can causes apnoea (respiratory depression) and a fall in blood pressure due to effects on myocardial contractility and peripheral resistance
40
Q

Characteristics of thiopental

A
  • Barbiturate (enhancing GABA A receptor effects)
  • Highly lipid soluble: crosses BBB extremely rapidly n produces unconsciousness in 20-30s
    • Consciousness returns in 10 to 20 minutes [rapid redistribution to other tissues]
  • Metabolizes slowly in liver w half life of 9h
  • Sedative effects can persist for up to 24h n can accumulate
  • Poor analgesic, muscle relaxant
  • May produce cardiorespiratory depression
41
Q

Etomidate

A
  • Induction of anesthesia
  • Rapid recovery w no hangover
42
Q

Ketamine

A
  • Rarely used [hallucinations]
  • Abuse potential n dependence
  • Used in pediatrics
  • Used if repeated administration is required
  • Novel treatment for depression
43
Q

Commonly used inhaled anesthetics

A
  • Halothane
  • Isoflurane
  • Sevoflurane
  • Desflurane
44
Q

What are some characteristics shared by commonly used inhaled anesthetics?

A
  • Volatile liquids → produces fast consciousness, smooth induction n recovery
  • Induction w IV agents is often preferred
45
Q

How do inhaled anesthetics affect cardiovascular parameters?

A
  • Produce a dose-dependent lowering of mean arterial pressure.
  • Act on myocardial function and peripheral vascular resistance.
46
Q

Describe the respiratory effects of inhaled anesthetics and their impact on the metabolic rate of the brain

A
  • Respiratory effects: depress respiration → increase in arterial carbon dioxide levels and impairment of oxygen exchange.
  • Brain metabolic rate: decrease the metabolic rate of the brain, despite an increase in cerebral blood flow.
47
Q

Describe the basic process of delivering inhaled anesthetics using a vaporizer and a breathing system

A
  • Volatile liquid placed in a vaporizer.
  • Flush with oxygen from the cylinder.
  • Control flow of oxygen via a valve.
  • Oxygen drives the anesthetic through a tube into the endotracheal tube for the patient.
  • During exhalation, the breath goes through the exhalation valve and then through a scavenger.
  • The scavenger includes a CO2 absorbing system.
48
Q

Halothane

A
  • Potent
  • Smooth induction
  • Non-irritant [seldom induces coughing/breath holding]
  • Moderate muscle relaxation [needs muscle relaxants for abdominal surgery]
  • Not widely used [associated w severe hepatotoxicity], instead replaced w compounds of similar structures
49
Q

Isoflurane

A
  • Less potent than halothane
  • Fall in BP
  • Depresses respiration
  • Muscle relaxation n potentiate muscle relaxants
  • May cause hepatotoxicity but risks much less than halothane
50
Q

Nitrous oxide

A
  • Used for maintenance of anesthesia n analgesia
  • 50-66% oxygen
  • Potency too low for anesthesia alone thus used w other agents
  • Used in obstetrics (gas n air) for pain during labour
51
Q

How do neuromuscular blocking drugs contribute to anesthesia, and what are some examples of these drugs?

A
  • Contribution to Anesthesia:
    • Enable lighter levels of anesthesia.
    • Relax vocal cords, facilitating tracheal tube placement.
    • Require respiration to be assisted/controlled until the drug is inactivated.
  • Examples of Neuromuscular Blocking Drugs:
    • Atracurium, Cisatracurium, Mivacurium, Suxamethonium.
52
Q

Describe the characteristics of Suxamethonium and its use in anesthesia

A
  • Rapid onset, short duration (2-6 minutes).
  • Useful for tracheal intubation.
  • Often administered with another muscle relaxant to ensure adequate muscle relaxation.
  • Depolarizing neuromuscular blocker with a short half-life.

LF260 Neuropharmacology (14 decks)

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