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Anaesthetic FRCA Primary - eLFH Pharmacology > eLFH - Inhaled Anaesthetic Agents and Oxygen Toxicity > Flashcards

eLFH - Inhaled Anaesthetic Agents and Oxygen Toxicity Flashcards

1
Q

Mechanism of oxygen toxicity

A

Note complex and not fully understood

Hyperoxia produces highly oxidative, partially reduced active metabolites

Radicals interfere with basic metabolic pathways and enzyme systems - especially those containing sulphydryl groups

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2
Q

Examples of highly oxidative, partially reduced active metabolites produced in hyperoxia

A

Hydrogen peroxide

Hydroxyl radicals

Oxygen free radicals - e.g. Superoxide

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3
Q

Types of oxygen toxicity triggers

A

Normobaric oxygen

Hyperbaric oxygen

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4
Q

Effects on pulmonary function exerted by hyperoxia in normobaric conditions

A

Range from atelectasis to tracheobronchitis to severe alveolar injury

Direct dose dependent and time dependent effect

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5
Q

Process of hyperoxia leading to impaired pulmonary function

A

Hyperoxia

Endothelial neutrophil and macrophage recruitment
Release of inflammatory mediators

Reduction in surfactant production
Interstitial oedema
ARDS

Impaired gas exchange + Hypoxia

Pulmonary fibrosis at 1 week

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6
Q

Normobaric oxygen at different FiO2 and time before detectable changes to pulmonary function

A

FiO2 1.0 = 12 hours
FiO2 0.8 = 24 hours
FiO2 0.6 = 36 hours
FiO2 0.5 = indefinitely

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7
Q

Effect of high FiO2 on lung volumes

A

Absorption atelectasis

May be responsible for reduced vital capacity and increased shunt fraction

Results by 2 mechanisms

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8
Q

Mechanism 1 for absorption atelectasis

A

Seen in dependent areas of lung

Airway occlusion forms trapped gas pockets - no longer ventilated

Initial pressure in these pockets is atmospheric, but as gas exchange occurs total partial pressure becomes sub-atmospheric

Continued gas exchange down partial pressure gradients results in collapse of these pockets and absorption atelectasis occurs

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9
Q

Mechanism 2 for absorption atelectasis

A

Inspired gas ventilates alveolar units and alveolar uptake removes this gas into blood

Alveolar volume is balance between alveolar ventilation and alveolar uptake

If alveolar uptake falls below a critical value, the alveolus will collapse

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10
Q

How does high FiO2 promote absorption atelectasis

A

On air, arterial PO2 is ~13 kPa
Extraction of 4.5 ml/dL of O2 by metabolically active tissue results in venous PO2 ~ 6.5 kPa

On FiO2 1.0, arterial PO2 is much higher ~ 89 kPa
Due to sigmoid shape of O2 dissociation curve, venous PO2 only increases by a fraction to ~7kPa

Therefore greater alveolar to mixed venous PO2 gradient created - stimulates more rapid O2 uptake and therefore faster alveolar collapse by mechanism 1 and 2

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11
Q

Special considerations for neonates younger than 44 weeks post conception age

A

Avoid concentrations of O2 greater than 10.6 kPa for more than 3 hours

Therefore saturations kept around 90%

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12
Q

Reason for lower oxygen concentrations and saturations in neonates younger than 44 weeks

A

Hyperoxia in these neonates associated with:
- Retinopathy
- Necrotising enterocolitis
- Bronchopulmonary dysplasia
- Intracranial haemorrhage

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13
Q

Reason for maintaining normoxia post cardiac arrest or traumatic head injury

A

Initial hyperoxia is associated with worse outcomes

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14
Q

The Bert effect

A

Effect of hyperoxia on the CNS under hyperbaric conditions

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15
Q

The Bert effect at 2 atmospheres

A

Paraesthesia
Nausea
Facial twitching
Myopia

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16
Q

The Bert effect at above 2 atmospheres

A

Convulsions may predominate

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17
Q

The Smith effect

A

Pulmonary changes seen from hyperoxia under hyperbaric conditions

Similar picture to pulmonary changes seen under normobaric conditions but are accelerated

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18
Q

Inhalation anaesthetic agents compartment model

A

Inhaled anaesthetic agents conform to a multi-compartment pharmacokinetic model

Lungs considered as additional compartment in series from which central compartment is dosed

At equilibrium:
Agent partial pressure in alveoli = Partial pressure in central compartment (arterial) = Partial pressure at effect site (brain)

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19
Q

Factors which affect inhalation agent distribution from central compartment (i.e. arterial compartment)

A

Peripheral compartment blood supply

Compartment capacity (tissue : gas coefficient)

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20
Q

Factors which determine uptake of inhalation agent from lungs to central (arterial) compartment

A

Alveolar fractional concentration

Blood : gas coefficient

Cardiac output

Alveolar : venous gradient

Concentration effect and Second gas effect

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21
Q

Determinants of alveolar fractional concentration (FA)

A

Alveolar ventilation - increases FA

Fi - increases FA

FRC - decreases FA (acts as reservoir which prolongs filling time and reduces rate of FA rise)

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22
Q

Effect of alveolar fractional concentration on inhalation agent anaesthesia time

A

Alveolar fractional concentration provides driving force for diffusion of agent into blood

Higher FA reduces time for onset / equilibrium

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23
Q

Blood : gas coefficient definition

A

Ratio of amount of anaesthetic agent in the blood to that in gas when the 2 phases are of equal volume and pressure in equilibrium at 37 degrees Celsius

24
Q

Effect of Blood : gas coefficient on speed on inhalation agent onset

A

Lower blood : gas coefficient have greater speed of action

Lower solubility results in more rapid build in arterial and effect site partial pressure of agent

Partial pressure of agent determines effect

25
Q

Effect of cardiac output on anaesthetic agent speed on onset

A

At low CO, the effective volume is reduced and therefore alveolar concentration and blood concentration equilibrate quicker

Therefore low CO produces more rapid induction

Explains why elderly / critically unwell patients require lower doses of anaesthetic agent

26
Q

Why is effect of cardiac output on anaesthetic agent onset less pronounced with more modern anaesthetic agents

A

Lower blood solubility of modern agents

27
Q

Alveolar : venous gradient definition

A

Gradient between alveolar partial pressure of anaesthetic agent and venous partial pressure

Not present at induction but generated as an agent leaches from peripheral compartments into venous system - reduces alveolar : venous gradient and drives agent into the arterial circulation

28
Q

Concentration effect description

A

Explains attributes of nitrous oxide and xenon as carrier gases

Rate of rise in alveolar fractional concentration is disproportionate to the Fi when high concentrations of carrier gas are given

29
Q

Concentration effect explanation

A

Occurs with carrier gases as they are non potent and therefore delivered at high fractional inspired concentration

As carrier agent diffuses from alveolus into bloodstream, large percentage of alveolar volume is lost

Further gas is thus drawn into alveolus disproportionately increasing the concentration of the other carried gases (augmented ventilation)

High volumes of carrier gas required

30
Q

Effects of the concentration effect

A

Second gas effect

Diffusion hypoxia

N2O FA/Fi profile

31
Q

Second gas effect

A

Augmented ventilation increases alveolar fractional concentration of both carrier gas and the anaesthetic agent

This provides greater gradient to drive agent into bloodstream and increases uptake

32
Q

Diffusion hypoxia

A

Reverse of the second gas effect

During emergence, high volumes of N2O diffuse into alveolus increasing its FA but therefore reducing FA of oxygen

May lead to hypoxaemia if not battled by supplementing FiO2

33
Q

N2O FA/Fi profile

A

Uptake rate of 70% N2O is higher than Desflurane, whereas uptake rate of 20% N2O is lower than Desflurane

At high volumes, the concentration effect overcomes the advantage that Desflurane has over N2O in terms of lower solubility

34
Q

Mechanism of anaesthetic agents inducing hypnosis

A

Poorly understood because what causes consciousness awareness is unanswered

May impair connectivity between networks of higher order neurones found within frontal parietal cortices and thalamus

Theory that anaesthetic agents act at specific target sites - stimulate inhibitory receptors or inhibit excitatory receptors

35
Q

Historic theories of anaesthetic agent mechanisms of action that have now largely been excluded

A

Meyer-Overton - Lipid solubility

Critical volume - change in membrane volume

Lateral phase separation - change in membrane fluidity

36
Q

Receptor targets of general anaesthetics

A

Gamma aminobutyric acid A (GABA a) receptors

Strychnine sensitive glycine receptors

Glutamate receptor family (NMDA, AMPA)

Nicotinic acetylcholine receptors

5-Hydroxytryptamine receptors (5HT)

Mainly post synaptic receptors

37
Q

Inhibitory neurotransmitters

A

GABA

Glycine

38
Q

Stimulatory neurotransmitters

A

Glutamate (NMDA and AMPA receptors)

Nicotinic acetylcholine

39
Q

Ionotropic receptors (ion channels)

A

GABA A

NMDA

40
Q

Metabotropic receptors (G protein coupled receptors activating intracellular pathways)

A

GABA B

Glutamate subtype

Adreno-receptors

41
Q

General anaesthetic agents which act on GABA A receptor

A

Nearly all inhalation and intravenous agents

42
Q

GA agents which inhibit NMDA receptors

A

Ketamine

Nitrous oxide

Xenon

43
Q

Receptor actions of Propofol and Thiopentone

A

Stimulate GABA receptors

Stimulate Glycine receptors

Inhibit neuronal ACh receptors

44
Q

Subtypes of GABA receptors and their features

A

GABA A - post synaptic, ionotropic

GABA B - pre synaptic, metabotropic

45
Q

Structure of GABA receptors

A

Pentameric (5 subunits)

Over 30 isomers - may be composed of alpha, beta, gamma, delta, echo or pi subunits

46
Q

Predominant subunit configuration of GABA recpeptors

A

2 alpha subunits
2 beta subunits
1 gamma subunit

47
Q

Action of GABA receptors

A

Inhibitory

Binding of natural ligand GABA to alpha subunit open central Cl- ion channel

Influx of chloride ions hyperpolarises the neuronal membrane

Therefore inhibits action potential transmission

48
Q

Inhalation anaesthetic agent binding site on GABA receptor

A

Alpha subunit

49
Q

Intravenous anaesthetic agent binding site on GABA receptor

A

Beta subunit

50
Q

Benzodiazepine binding site on GABA receptor

A

Alpha subunit / alpha-gamma interface

51
Q

What determines pharmacological actions of different anaesthetic agents given their binding sites on GABA receptors

A

Different subunit configuration of different GABA receptor isomers and the location within the CNS of each isomer

52
Q

Structure of NMDA receptor

A

4 subunits

2 types of subunit - GluN1 and GluN2

53
Q

Action of NMDA receptors

A

Excitatory

Natural co-ligands Glutamate and Glycine bind at GluN1 subunits and GluN2 subunits respectively

Opens calcium ion channel

Influx of Ca2+ modulates post synaptic actions

54
Q

Action of ketamine, nitrous oxide and xenon

A

Non-competitive NMDA receptor antagonists

55
Q

NMDA acronym stands for

A

N-Methyl-D-Aspartate

56
Q

Action of Magnesium on NMDA receptors

A

Mg2+ binds to open NMDA channel inhibiting passage of Ca2+

57
Q

Actions of alcohol on NMDA receptor function

A

Alcohol mediates its effects of tolerance, dependence and withdrawal symptoms via its effect on NMDA receptor number and function

Anaesthetic FRCA Primary - eLFH Pharmacology (10 decks)

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