General anaesthetics Flashcards
1
Q
what are the three main types of anaesthesia ?
A
- local
- regional
- general
2
Q
what happens when general anaesthetic is administered to a patient ?
A
they lose consciousness and enter a coma-like state
essentially a medically induced coma
3
Q
around the 1800s, what were the three compounds used as inhaled general anaesthetics ?
A
- nitrous oxide
- ether
- chloroform
4
Q
what was the first gaseous anaesthetic discovered ?
A
(diethyl) ether
5
Q
what was chloroform popularly used for ?
A
as an analgesic for childbirth
6
Q
what were some problems associated with the use of ether and chloroform ?
A
- ether is highly inflammable- chloroform is hepatotoxic and causes cardiac dysrhythmias
7
Q
what was the world’s most widely used general anaesthetic or the first ‘modern’ anaesthetic?
A
halothane
8
Q
what are some benefits of halothane ?
A
non-flammable and less toxic than chloroform
9
Q
why has halothane, although still widely used in the developing world, been largely replaced in the healthcare systems in wealthier countries ?
A
- it causes liver damage with repeated use (unlike other inhaled agents) due to a substantial amount (~20%) is metabolised in the liver
- product of metabolism is trifluroacetic acid, which causes hepatitis
- problem for patients and staff
10
Q
what does the process of a patient losing consciousness under GA depend on ?
A
it is time and dose dependent
11
Q
what is depth of anaesthesia ?
A
a continuum
12
Q
draw a diagram for Arthur Guedel’s framework for how a patient’s depth of anaesthesia is categorised into four stages, and state the 4 stages
A
- Stage I: Induction/Anagesia
- Stage II: Excitement
- Stage III: Surgical anaesthesia
- Stage IV: Anaesthetic overdose
13
Q
what happens in Stage I of anaesthesia ?
A
(Induction/Anagesia): px conscious but drowsy, reduced pain response
14
Q
what happens in Stage II of anaesthesia?
A
(Excitement): px may become delerious and hypersensitive to stimulation (pain response preserved). May have increased gag reflex making intubation difficult. Concerns include chocking, breath holding, vomiting and movement. Time in this stage must be limited
15
Q
what happens in stage III of anaesthesia ?
A
(Surgical Anaesthesia): desired stage for surgery. 4 ‘planes’ or substages within stage III. As you move through the planes there is progressive shallowing of breathing and loss of muscle tone and reflexes. Plane 3 is the ideal state of surgery because of relaxation of abdominal and thoracic muscles. Plame 4 results in apnea due to diaphragm paralysis
16
Q
what happens in stage IV of anaesthesia ?
A
(Anaesthetic overdose): ther eis medullary paralysis, cessation of respiration and loss of vasomotor control. Without rapid intervention, the px will die
17
Q
by taking into account the 4 stages of anaesthetics, what would be some goals of the anaesthetist ?
A
- achieve a pleasant and rapid induction
- as little time as possible in stage II
- get patient to stage III quickly
- make surgery easy for surgeon
- staye out of stage IV
- achieve a rapid recovery from anaesthesia with minimal post-op pain
18
Q
what is balanced anaesthesia ?
A
combining a range of drugs
19
Q
an example of an anesthetic protocol: what drugs are ysed and their purpose
A
20
Q
what is a GA that is an inert mono-atomic gas ?
A
xenon
21
Q
what is a GA that has a steroid based structure ?
A
alfaxalone (vetinary anaesthetic)
22
Q
due to GAs having a large diversity in their structures, what was suggested as their mechanism of action ?
A
the drugs don’t act at a protein target, but that they potentially act on membrane lipids (lipid theory)
23
Q
what did the work of Overton and Meyere suggest to support the theory that GAs act on membrane lipids ?
support for the lipid theory
A
they reported that the potency of GA is directly proportional to its lipophilicity
24
Q
if the membrane is proposed to be the site of action of GAs, what two ideas potentially explain the effect of GAs on the membrane ? (lipid theories)
A
- fluidization
- volume expansion
these are lipid theories
25
what is the idea of fluidization in relation to the effects of GA's on the membrane?
## Footnote
lipid theory
fluidization suggests that the membrane becomes less 'stiff' as anaesthetic accumulates in it
## Footnote
similar to the effect of unsaturated fatty acids in membrane lipids
26
what is the idea of volume expansion in relation to the effects of GA's on the membrane ?
## Footnote
lipid theory
volume expansion suggests that the thickness of the membrane alters
27
what were fluidization and volume expansion of the membrane (as a result of the effects of GA's) presumed to affect ?
## Footnote
lipid theory
the behaviour of the ion channels and receptors in the membrane
28
what is the key point of lipid theories (fluidization and volume expansion) ?
they explain drug action in terms of the AMOUNT of anaesthetic that accumulates in the membrane (which is related to the drug's lipid solubility)
29
explain fluidisation as a lipid theory (for a mechanism of action of GA's) ?
The anaesthetic causes the membrane to become more fluid. As the normal operation of the channel (in the membrane) depends on interaction with the solvent it is dissolved in (the membrane), its function is altered and it closes.
## Footnote
with no GA membrane channel functions normally
30
explain colume expansion as a lipid theory (for a mechanism of action of GA's) ?
The GA causes the membrane to thicken. This alters interactions between the membrane and channels/receptors within it, causing their function to change
## Footnote
with no GA membrane channel functions normally
31
give 4 problems or evidence against the lipid theories.
## Footnote
(lipid theories are an explanation of action for general anaesthetics
- the potency of alykl alcohols increases up to 13 carbons in length (increases lipid solubility), but this is the cutoff point for potency despite the continued increase in lipid solubility. The fact that potency peaks around a specific size suggests that the mechanism of action is likely not just about how well the molecule dissolves in the membrane, but rather about how well it can bind to a protein with a pocket of a defined size.
- stereoisomers of anaesthetics have identical effects on membranes, but can differe in the anaesthetic potency
- temperature changes fluidize membranes but do not produce effects similar to GAs
- not all liphophilic molecules are GAs
32
what is the current theory of how GA's work ?
protein theories
33
what is the protein theory for the action of GA's (give an example)?
GA's work by interacting with membrane proteins and altering their function
- initially thought that GA's changed protein structure
- more likely that GA's alter the way proteins move between conformational states
e.g. ion channels might have a higher likelihood of opening in the presence of GA's
34
how do the protein theories explain the lipophilic nature of GA's ?
proposese that the binding sites on target proteins are located in their membrane regions, and so the drug would have to dissolve in the bilayer to be able to access target site
35
in terms of the protein theory, how can the Meyer-Overton correlation be explained ?
the fact that GA's have to cross the BBB in order to exert their actions, which depends on lipophilicity
36
what are the suggested target proteins of GA's and how do they exert their effect at these receptors?
- potentiate GABA-A receptors and strychnine-sensitive glycine receptors (extrasynaptic GABA-A receptors important)
- potentiate two-pore-domain potassium channels
- inhibit NMDA type ionotropic glutamate receptors
37
what do two-pore potassium channels include ?
## Footnote
two-pore potassium channels are a family
- include 'leak channels' which are open at resting MP and determine RMP
38
what is different about two pore-domain potassum channels (including leak channels) ?
- 2 pore forming domains in each subunit
- 4 TMD/ 2P (2 pore forming domains)
- assemble as dimers with each subunits 2 pore forming domains contributing to the lining of the channels
39
what happens when two-pore domaine potassium channels open ?
we get hyperpolarisation (inhibitory)
40
so what do compound that potentiate 2PD potassium channels do ?
produce inhibition
41
what are the 4 types of general anaesthetics ?
- inhalation
- intravenous
- neurolept
- dissociative
42
what is inhalational anaesthesia ?
uses volatile agent that can be mixed with air or oxgen and delivered to patient via a mask
43
what are the advantages of inhalational anaesthesia ?
- easy to maintain a certain level of anaesthesia by adjusting the mixture of gas
-rapid equilibrium between inhaled gas and patient's tissues
- most GA's only undergo limited metabolism in the body, leaving by the same route they entered: the lungs.
- this can give rapid emergence anaesthesia (recovers consciousness quickly)
44
what are some disadvantages of inhalational anaesthesia ?
- longer induction and marked stage II compared to intravenous agents
- require complex and expensive equpiment, and mask can cause psychological distres to px
- metabolities can be a significant source of toxicity for both px and operating staff
- can also be damaging to the environment (2000x greenhouse gas effect of CO2)
45
flurane toxicity
- flurane genral anaesthetics generates fluoride when metabolished
- can cause renal toxicity
46
why is halothane no longer in widespread use ?
- when metabolished is converted to bromide and trifluoroacetic acid
- can cause liver toxicity, leukaemia, spontaneous abortions, birth defects
47
how are injected or orally administered anaesthetics expressed in potency ?
ED 50 with units of mg/kg
48
how is inhaled anaesthetic potency expressed ?
- as its minimum alveolar concentration (MAC)
49
what is MAC ?
- minimium alveolar concentration
- this is the minimum conc. of the anaesthetic at 1 atm pressure that is needed to prevent movement in 50% of subjects in response to incision
50
what is a determinant of induction and recovery speed ?
blood gas partition coefficient
51
what is the blood-gas partition coefficient ?
(parameter) a measure of how well the drug dissolves in blood compared with gas
52
what does a drug with a low blood-gas partition give ?
rapid induction and rapid recovery
## Footnote
so we are looking for drugs or GAs with low solubility in blood
53
why is it desierable to have a low blood-gas partition coefficient with GA's ?
a poorly soluble anaesthetic will fill the blood reservoir more quickly (as it dissolves poorly in blood) and then floods into the tissues faster, determining faster induction
54
what happens if we have a high blood-gas partition coefficient ?
- agent with high BGPC dissolves well in blood
- fills reservoir slowly
- gets to surrounding tissues slower
- slower induction
55
what is the oil-gas partition coefficient ?
a measurement of anaesthetic lipid solubility
56
what does high lipid solubility for GAs mean ?
high potency, due to being able to cross BBB
57
how can the oil gas partition coefficient impact the pharmocokinetics of GAs ?
- if GA highly soluble in fat(lipid), lots of GAs partition into fatty tissue
- GA in blood is eliminated quickly
- but because fatty tissue has poor blood supply, GA takes a long time to leave tissue (remains)
- leaves patients with slow recovery or 'hangover' due to anaesthetic in the fat slowly leaking back into blood
(will eventually leave the body via the lungs)
58
what does it mean if we have a high oil-gas partition coefficient ?
the fatter the patient, the more fat-soluble GAs are, meaning slower recovery or 'hangover' as GA takes longer to leave the tissue due to the poor blood supply in fatty tissue
59
what might suxamethonium be used for during general anaesthesia ?
to facilitate intubation
60
what is suxamethonium ?
a depolarising blocker of the skeletal neuromuscular junction. It produces neuromuscular block and so is suitable for intubation. It does not have any effect on the patient's level of consciousness and does not provide any analgesia.
61
where does a higher MAC value indicate ?
higher MAC = lower potency
62
what are the two most common inhalational anaesthetics used in the UK ?
nitrous oxide and isoflurance
## Footnote
desflurane and sevoflurance are becoming more popular but are moer expensive
63
where is halothane listed and not listed ?
not in BNF
but in WHO essential medicines list
64
what are 4 haloethers ?
-halothane
- isoflurane
- sevoflurane
- desflurance
(all inhalation anaesthetics)
65
what are the target proteins of haloether compounds and what does this do ?
## Footnote
3 marks
- potentiate GABA-A receptors for increased inhibitory transmission
- inhibit NMDA receptors leading to decreased excitatory transmission
- potentiate two-pore domain potassium channels leading to increase neuronal inhibition
66
what are some advantages of isoflurane ?
- most comonly used GA
- it is cheap
- low toxicity as not significantly metabolised
- does not promote convulsions unlike some other GAs
67
what are some disadvantages of isoflurane ?
- concerns that it can induce neurodegeneration (shown in neonatal animal models)
(greater tendency to promote neurodegeneration than sevoflurane)
- coronary vasodilation properties may worsen ischaemia in parts of the heart supplied by vessles with atherosclerosis (phenomenon also known as 'coronary steal')
(occurs because blood is diverted away from ischaemic areas into dilated blood vessles)
68
why is sevoflurance names the 'anaesthetic of choice'/ what are the advantages ?
- rapid induction and recovery due to low BGPC
- some metabolism to release fluoride but not significant amounts
- unlike desflurance, does not produce respiratory tract irritation
69
what are some disadvantages of sevoflurane ?
- low BGPC is good, but recovery can be so rapid that post-op pain relief is frequently needed
- expensive at 5x cost of halothane
- some evidence for neurodegeneration being cause, but less likely than isoflurance
70
what are some advantages of desflurane ?
- low BGPC, more than sevoflurance, so suitable for obese patients
- optically active: has a chiral carbon but is used as a recaemic mixture
71
what are some disadvantages of desflurance ?
- low potency
- has 3700x the greenhouse gas potential of CO2
- more expensive than isofluranee, but same as sevoflurane
- although little metabolism, can produce significant irritation of respiratory tract that can lead to coughing
- can also cause high levels of sympathetic activity which is dangerous in patients whose cardiac function is comprimised
72
what are the potential mechanisms of nitrous oxide ?
- moderatley potent blocker of NMDA receptors
- weaker potentiating actions at GABA-A receptors and other targets for anxiolytic and analgesic effects
73
what kind of GA is nitrous oxide ?
inhalational anaesthetic
74
what is the potency of nitrous oxide, and why is this bad ?
- low potency
- cannot be used to produce surgical anaesthesia on its own
- even with 80% mixture with oxygen it does not produce loss of consciousness
75
what is entonox and what is it for ?
- nitrous oxide mixed 50/50 with oxygen
- produce analgesia or with other volatile anaesthetics in surgical situations such as trauma or obstetrics
76
why is the potency of nitrous oxide so low ?
due to low oil gas partition coefficient
77
nitrous oxide also has a low blood-gas partition coefficient, why is this problematic ?
- when px stops receiving it, it can transfer rapidly from blood into lungs
- this reduces partial pressure of oxygen in the lungs
- in px's that have been recently scuba diving, nitrous oxide can transfer from the liquid phase of the blood into nitrous oxide bubbles (which do not normally cause problems) and expand them to cause gas emboli
78
what are some problems that nitrous oxide can cause ?
- foetal abnormalities if used in early pregnancy
- cause or exacerbate vitamin B12 deficiency
- 300x greenhouse gas potential than CO2
79
what is Xenon ?
- nobel gas
- general anaesthetic
80
what are some advantages as Xenon as a GA ?
- extremeley low reactivity
- not metabolised in the body, so little toxicity
- little greenhouse gas potential
81
what are the proposed mechanisms of action of Xenon as a GA ?
via anatagonism of glycine site on NMDA receptors
82
what are some disadvantages of Xenon ?
- extremeley expensive, even with recycling systems
- not listed in BNF
83
what are the advantages of intravenous anaesthesia over inhalational methods ?
- rapid induction
- very limited Stage II anaesthesia
- simple apparatus (syringe/infusion system)
- relatively pleasant induction (no mask)
- no atmospheric pollution
84
what are some disadvantages of intravenous anaesthetics ?
- "once it's in, it's in": the level of anaesthesia can be difficult to control
- recovery can be slow due to redistribution metabolism
- anaesthesia has a finite duration (infusion can get round this problem)
- vein damage can occur e.g. thrombophlebitis
85
why are intravenous anaesthetics often used to induce anesthesia in a balanced anaesthetic protocol and what happens after this?
- IV GA's largely avoid stage II
- once patient at stage III, inhalation can then be used to maintain during surgery (if long procedure)
## Footnote
IV GA's alone may be more suitable for short procedure
86
what are 3 individual intravenous agents ?
- sodium thiopental
- propofol
- etomidate
87
what is sodium thipental ?
only barbiturate still commonly used in surgery
88
what is an advantage and disadvantage of sodum thiopental being very lipid soluble ?
advantage:
- crosses BBB easily
- induction dependent only on blood flow; very rapid
disadvantage:
- rapidly redistrbuted into tissues and accumulates in fat
- 'hangover effect' (same as inhalation agents with high OBPC)
- means cannot be used via continuous infusion, only as an induction agent
89
what is the genral mechanism of barbiturates anaesthetics such as sodium thiopental ?
- positive allosteric modulation at GABA-A
## Footnote
some studies have alos found they act as inhibitors of AMPA type glutamate receptors
90
what happens with barbiturates anaesthetics, such as sodium thiopental, at high doses ?
directly activate GABA-A receptors, making them dangerous in overdose
91
what are some side effects of thiopental, and when can these be used ?
- respiratory and cardiac depression
- arrhythmias
as an agent in lethal injections and euthanasia
92
what is the mechanism of propofol ?
## Footnote
or 'DIVIPRAM'
allosteric potentiation of GABA-A receptors
## Footnote
similar to barbiturates as at higher doses can directly activate
93
how is propofol administered ?
as an emulsion
- either as a single doze or via continous infusions (different to thiopental)
## Footnote
nicknamed: 'the milk of amnesia'
94
when is propofol used ?
- inudction agent
- sole agent in short surgeries
-
95
what are some advantages of propofol ?
- rapidly metabolised: rapid recovery compared to other IV agents
- little or no hangover effect
- lower rates of post-op nausea and vomiting (than thiopental or etomidate)
96
what is a common side effects/ disadvantages of propofol ?
- pain during injection
(can be managed with analgesic agents)
- hypotension due to cardiovascular effects as it can decrease respiratory drive
- has as steep dose response curve which means can lead to accidental overdose
97
what are the properties of propofol ?
## Footnote
as a barbiturate
amnesic, euphoric, hypnotic
98
what are the mechanisms of action of etomidate ?
allosterically potentiates GABA-A receptors (and can directly activate at higher doses)
## Footnote
same as propofol
99
when is propofol used and why ?
- induction and short surgergies
- rapidly metabolised and fast recovery rate
100
what are some side effects of etomidate ?
- post-op nausea and vomititing
- pain at injection site
- suppresses the production of steroids by the adrenal cortex
101
what is the mechanism of action of ketamine ?
non-competitive antagonist at NMDA receptors
## Footnote
similar to PCP and MK801
102
What can ketamine be used for at low doses ?
- rapidly acting antidepressant
- to produce human (animal) models of schizophrenia
- as an adjunct medication to opiiods
103
why can ketmaine be used at low doses as an adjunct medication for opioids ?
it acts synergistically with opioids to potentiate their action, allowing for a lower (safer) dose of opioid to be used
104
what can ketamine be used for at moderate-higher doses ?
- higher: produce analgesia (and loss of consciousness)
- moderate: dissociated state (conscious but loss of sensory percetion, amnesia, sedation and immobility)
105
what can nitrous oxide and ketamine both be classed as ?
dissociative anaesthetics
106
what are the main advantages of ketamine ?
- little effect on respiration and blood pressure
- may inc. HR
## Footnote
makes it safe for emeregency situations where full extent of px injurys is unkown
107
what are the main side effects of ketamine (as an IV anaesthetic) ?
- bizarre behaviour during recovery e.g. hallucination and delusions
108
when NMDA receptor antagonsits, like ketamine, are abuse, what can happen ?
- potential for neurodegeneration
- or bladder damage
## Footnote
unkown of neural damage is a problem if used surgically
109
what can cause malignant hyperthermia ?
- many haloether inhalation agents
- or suxamethonium
## Footnote
IV anaesthetics and non-depolarising neuromuscular blockers do NOT cause MH
110
what is suxamethonium ?
depolarizing neuromuscular blocking agent
111
what is an example of a non-depolarising neuromuscular blocker ?
atracurium
112
what is malignant hyperthermia characterised by and what can it lead to?
- muscle rigidity
- increase body temperature
which can lead to....
- rhabdomyolysis
- which can turn into kidney failure
113
In skeletal muscle, explain how calcium channels are linked to MH ?
- in skeletal muscle, AP down t tubulues, triggers release of Ca from SR to initate muscle contraction
- 'sensor' for AP is L type Ca channel (or DHP receptor)
- L type CaV is mechanically linked to ryanodine channel on SR
- people at risk of MH either have a mutation in an L type CaV subunit or in ryanodine receptor
- makes system more sensitive to inhalation anaesthetics and suxamethonium
- if px has mutation and given one of the drugs, Ca floods out of SR triggering sustained muscle contraction
- generates large amounts of heat (hyperthermia part)
114
what is another name for L type calcium channels ?
dihydropyridine or DHP receptors
115
what is the mortality rate of MH ?
- 80% if untreated
- 5% if treated with muscle relaxant dantrolene
116
what is dantrolene used for and how does this work?
- can be used as a muscle relaxant to treat MH
- blocks ryanodine receptor, preventing Ca release from SR
117
what is neuolept anaesthesia ?
involves the use of an antipsychotic and an opioid, as this combination produces profound sedation and can act as a rapid acting anaesthesia with similar effects to ketamine
118
what was the old term for antipsychotic drugs ?
neuroleptic agents
119
when was neuroleptic anaesthesia used ?
- in humans until 1980s
- now only for large animals
120
what is a large animal immobilon (neuroleptic anaesthesia) a mixture of ?
the antipsychotic acepromazine and the opioid etorphine
## Footnote
these are non-GABA-A non NMDA mechanisms
121
what is the potency of etorphine ?
2000x that of morphine, one drop can kill an adult in minutes
## Footnote
darts often have antidote incase of accidental human exposure
122
what is the antidote for etophine ?
Revivon, an opioid antagonist
