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Basic Pharmacology > 14. Anaesthetics > Flashcards

14. Anaesthetics Flashcards

1
Q

What is an anaesthetic?

A

drugs used to prevent pain for a limited time for surgical or other procedure

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2
Q

Compare local and general anaesthetic

A
  • local prevent pain/nociception in localised area and prevent tactile sensation
  • general includes loss of consciousness
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3
Q

Historical anaesthetics

A
  • pre 1840s used alcohol, cannabis, opium, ice, blow to head
  • 1842 - ether for tooth extraction
  • 1844 - nitrous oxide dental
  • 1847 - chloroform (obstetric)
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4
Q

2 classes of anaesthetics

A
  • inhalation ones
  • intravenous ones
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5
Q

List some inhalation anaesthetics

A
  • halothane
  • nitrous oxide
  • enflurane
  • isoflurane
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6
Q

List intravenous anaesthetics

A
  • thiopental
  • etomidate
  • propofol
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7
Q

2 mechanism of action theories for anaesthetics

A
  • lipid theory/Meyer Overton theory
  • ion channel theory
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8
Q

Explain the lipid/Meyer Overton theory

A
  • strong relationship between anaesthetic potency and lipid solubility
  • originally thought these agents interacted with lipid bilayer of plasma membrane causing membrane expansion and consequent inability of membrane to facilitate changes in protein configuration and signalling
  • largely discredited
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9
Q

Explain ion channel theory

A
  • anaesthetics target number of ligand gated ion channels
  • including GABAa, glycine NMDA
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10
Q

Physicochemical properties of inhalation anaesthetics

A
  • depth of anaesthesia determined by concentration in brain and spinal cord
  • blood/gas partition coefficient, measure of blood solubility
  • oil:gas partition coefficient, measure of lipid solubility
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11
Q

Explain the blood/gas partition coefficient as a measure of blood solubility in inhalation anaesthetics

A
  • low (e.g nitrous oxide) is rapid infuction, recovery
  • high (e.g halothane) is slow induction, recovery
  • lower the solubility in blood, faster the induction and recovery
  • less drug needs to be transferred via lungs to produce equilibrium
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12
Q

Oil:gas partition coefficient as a measure of lipid solubility for inhalation anaesthetics

A
  • main factor to determine potency, since brain high lipophilicity
  • lower the oil:gas pc, the less potent the GA
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13
Q

2 reasons pharmacokinetics are important for inhalation anaesthetics

A
  • vascularisation of tissue determines tissue levels of anaesthetics
  • ventilation rate
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14
Q

How does vascularisation of tissue determine tissue levels of anaesthetics?

A
  • brain good blood flow - high levels
  • body fat has poor blood flow so anaesthetic doesn’t accumulate in body fat
  • within reason and obesity causes issues
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15
Q

How does ventilation rate affect inhalation anaesthetics?

A
  • effect rate of removal of anaesthetic
  • anaesthetics cause respiratory depression and so require controlled ventilation
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16
Q

Inhaled anaesthetics mainly eliminated via …

A

lungs

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17
Q

Give the limited hapatic metabolism for
- methoxyflurane
- halothane
- isoflurane
- desflurane
- sevoflurane

A
  • methoxyflurane - extensive (60%) hepatic metabolism resulting in nephrotoxic fluoride ion (no longer used)
  • halothane - 15% (hepatotoxic)
  • isoflurane 0.5%
  • 0.5%
  • 3%
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18
Q

List side effects of inhaled anaesthetics

A
  • malignant hyperthermia
  • cardiovascular
  • respiration
  • hepatic toxicity (mainly halothane)
  • kidney issues
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19
Q

What is malignant hyperthermia?

A
  • rare but most common with halothane and isoflurane
  • hypermetabolism, muscle rigidity, muscle injury and increased sympathetic nervous system activity, hyperthermia
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20
Q

What cardiovascular problems are side effects of inhaled anaesthetics?

A
  • can cause hypotension (except nitrous oxide)
  • decreased output and decreased vascular resistance
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21
Q

How is respiration affected by inhaled anaesthetics?

A
  • depressed respiration
  • more so with the fluranes, iso then des then sevo
22
Q

How do inhaled anaesthetics affect the kidneys?

A
  • depressed glomerular filtration and urine output
  • not really a problem as decreased cardiac output and vasodilation too
  • usually given fluids too
23
Q

Give 4 intravenous anaesthetics

A
  • thiopental sodium
  • etomidate
  • ketamine
  • propofol
24
Q

Intravenoud anaesthetics have a … onset of action around … and are used for …

A
  • short, around 20 seconds
  • used for induction previously but not maintenance too
25
Q

Thiopental and etomidate act on …

A

GABAa receptor (on alpha1/beta3 subunit interface)

26
Q

Difference between etomidate and thiopental

A
  • etomidate has a wider therapeutic window between anaesthesia and respiratory depression
  • has a therapeutic index of 26 compared to 2.5 of thiopental which is rapidly metabolised
27
Q

Propofol acts on …

A

GABAa receptor of beta3/beta3 or alpha1/beta3 subunit interface

28
Q

How quickly is propofol metabolised?

A
  • very rapidly
  • extrahepatic, elimination via plasma/esterases and lungs
  • rapid recovery, no hangover, TI of 3
  • day case surgery
29
Q

Ketamine is a …
Explain ads and disads

A
  • NMDA receptor antagonist
  • less hypotension than the etomidate/propofol
  • rarely used due to hallucinations, psychosis
  • does have some good analgesic effect
30
Q

History of local anesthetics

A
  • cocaine first used
  • 1860 first isolated
  • 1884 used local anaesthetic
  • 1905 synthetic analogue procaine developed
31
Q

Mechanism of action for local anaesthetics

A
  • local anesthetics block electrical signalling in neurones by blocking voltage gated sodium ion channels
32
Q

What is neuronal signalling?

A
  • transfer of info along and between neurons
  • electrical is the action potential
  • chemical is neurotransmission
33
Q

Explain resting potential

A
  • sodium ions and chloride iions concentrated outside
  • potassium and A- ions concentrated inside
  • ionic charge between inside and outside is uneven
  • inside is negative to outside (-60 to -90 mV)
34
Q

All cells have a membrane potential but …

A
  • neurones are special because they can rapidly alter their membrane potential
  • depends on voltage-gated ion channels
35
Q

Why are voltage gated sodium ion channells essential for action potential?

A
  • crucial to initiate and propagate the action potential and electrical signalling
36
Q

Voltage gated sodium ion channels are made of … subunits. Give them

A
  • 3
  • alpha, beta 1 and beta 2
37
Q

How are voltage gated ion channels structured?

A
  • the alpha-subunit is a single polypeptide. it contains extracellular domains, 4 transmembrane domains each comprising 6 alpha-helical regions
  • beta subunits flank the alpha unit. the beta 2 is covalently linked to alpha, beta 1 is not linked
  • two beta-units anchor the alpha subunit into the lipid membrane
38
Q

Role of the alpha subunit in voltage gated channels

A
  • contains in the hydrophobic domains voltage sensors
  • these change their orientation when voltage varies
  • this orientation determines the configuration of the entire domain and controls opening and closing of a pore
39
Q

Effect of local anaesthetics on voltage gated ion channels

A
  • thought to interact with alpha subunit and physically ‘plug’ the transmembrane pore
  • anaesthetic binding area located in the inner end of the channel so drug gains access intracellularly
40
Q

What is the ideal structure of a local anaesthetic to bind and plug voltage gated channel?

A
  • unionised form gains access through nerve sheath and axon membrane
  • ionised forms bind in channel
  • most anesthetics are weak bases
41
Q

General structure of local anaesthetic

A
  • aromatic (lipophilic) group on left
  • ester or amide bond
  • and amine (basic) sidechain/group on right
42
Q

Why is local anaesthetic structure important to role?

A
  • basic side chain ensures molecules are ionised at physiological pH
  • aromatic domain ensures lipid solublity
  • duration of action limited by hydrolysis of ester/amide bond and lipid solubility of agent
  • allows lipid-soluble base to enter axon
  • inside the axon the pH is lower - more acidic environment and ionisation takes place
43
Q

How are esters metabolised?

A
  • in plasma by esterases
  • except cocaine - shorter half life
44
Q

How are amides metabolised?

A
  • in liver by CYP 3A4, 1A2
  • longer half life consequences in those with liver failure
45
Q

How does an anaesthetic injection lead to no depolarization?

A
  • anaesthetic is a weak base, injected as a hydrochloride salt in acid solution - suitable for injection
  • following injection, pH icnreases (as higher pH of tissues) and free base is released (lipid soluble)
  • lipid soluble free base enters the axon - inside the axon the pH is lower - environment is more acidic
  • re-ionization takes place
  • re-ionized portion enters the sodium ion channels and blocks them, preventing depolarization
46
Q

How can we manipulate local anaesthetics?

A
  • restrict site of action and prolong durations of action - coadminister adrenaline, local vasoconstriction via alpha 1 adrenoreceptors
  • accelerate the speed of onset of anaesthetic - use slightly alkaline solution, assists absorption of anaesthetic in nerve tissue
47
Q

Do all nerves show similar susceptibility to local anaesthetics?

A
  • different axons have different sensitivities
  • block conduction in small diatmeter fibres more effectively than large
  • small myelinated axons more than non-myelinated axons more than large myelinated axons
  • nosciceptive pain fibres are small diameter and particularly sensitive
  • motor axons are large and less sensitive
48
Q

What is the use dependent block?

A
  • the depth of block increases with increase in action potential frequency
  • known as ‘use dependent block’
  • channels in 3 states (resting, open, inactive)
  • use dependent block occurs as anaesthetic gains access to and has higher affinity for channels more readily when open and/or inactive
49
Q

Unwanted side effects of local anaesthetics

A
  • occur due to local anaesthetic into systemic circulation
  • CNS, confusion and agitation
  • cardio and hypotension
  • inhibition of sympathetic activity and inhibition of sodium conductance in cardiac tissue
50
Q

Limitation of local anaesthetic

A
  • not very effective in infected or inflamed tissue
  • can’t penetrate

Basic Pharmacology (16 decks)

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