general anaesthetics Flashcards
three main categories of anaesthetic
local, regional and general
what is anaesthesia
the reversible loss of awareness in pain
local anaesthesia
small area has sensation blocked, patient remains conscious
regional anaesthesia
pain sensation in region of body are blocked.
Allows more extensive procedures to take plain but maintains the advantage that patients are conscious. Is safer than general anaesthesia
general anaesthesia
general: patient is given a drug that causes them to loose consciousness (and enter a state or altered consciousness)
Can essentially be viewed as a medically induced coma
Allows major surgery to take place
-that may be too painful or traumatic for the patient (or too difficult for the surgeon) if the patient were conscious
historical general anaesthetics
nitrous oxide, chloroform, ether
the first ‘modern’ anaesthetic
haloethane
problems with ether
highly flammable
problems with chloroform
hepatoxic and causes cardiac dysrhythmias
problems with haloethane
It causes liver damage with repeated use because (unlike other inhlaed agents) a substantial fraction (20%) is metabolised in the liver.
The product of this metabolism is trifluroacetic acid, which causes hepatitis.
This is a problem not just for patients, but for operating theatre staff who breathe in “waste” halothane.
stage 1: induction/ analgesia
patient is conscious but drowsy
they have reduced response to pain
stage 2: excitement
patient may become delirious and hypersensitive to pain (pain responses preserved)
may have increased gag reflex making intubation difficult
concerns in this phase: choking, breath holding, movement and vomiting
-important to limit the amount of time patient is in stage 2
stage 3: surgical anaesthesia
desired stage for surgery
there are 4 substages (‘planes’) in stage 3
as you move through the phases there is progressive shallowing of breathing and loss of muscle tone and reflex
plane 3 is said to be the ideal state for surgery, because there is relaxation of the thoracic and abdominal muscles
stage 4 results in apnea due to diaphragm paralysis
stage 4: anaesthetic overdose
in this stage there is medullary paralysis, cessation of respiration and loss of vasomotor control
without rapid intervention, the patient will die
goals of an anaesthetist
Achieve a pleasant, rapid induction
Spend as little time in stage II as possible
Get the patient into stage III as quickly as possible
Make this surgery as easy as possible for the surgeon
Stay out of stage IV
Achieve a rapid recovery from anaesthesia, with minimal post operative pain
pre-operative/ sedative anxiolytic
midazolam
induction of anaesthesia
propofol (IV)
maintenance of anaesthesia
isoflourane/ nitrous oxide mixture (inhaled)
relax tracheal muscles to facilitate intubation
suxamethonium
post operative analgesia
fentanyl
overton and myer
reported that the potency of the general anaesthetic is directly proportional to the lipophilicity
lipid theories
fluidizaition
volume expansion
These changes were presumed to affect the behaviour of the ion channels and receptors in the membrane.
However, the lipid theories explain drug action in terms of the AMOUNT of anaesthetic that accumulates in the membrane (which is related to the drug’s lipid solubility).
fluidization
Anaesthetic causes the membrane to become more fluid. As normal operation of the channel depends on its interactions with the solvent it is dissolved in (the membrane), its function is altered and it closes
volume expansion
The general anaesthetic causes the membrane to thicken. This alters interactions between the membrane and the channels/ receptors within it, causing their function to change
problems with lipid theories
The potency of alkyl alcohols increases up to around 13 carbons in length, but this is the cut off point
-suggests binding to a pocket of a defined size within a protein
Stereoisomers of anaesthetics have identical effects on membrane but can differ in their anaesthetic potency
Temperature changes fluidise membranes, but do not produce effects similar to general anaesthetics
Not all lipophilic molecules are general anaesthetics
current view of how anaesthetics work
protein theories
seems more likely that anaesthetics alter the way the protein moves between different conformational states.
-For example, an ion channel might have a higher likelihood of opening in the presence of a general anaesthetic.
Protein theories explain the lipophilic nature of general anaesthetics by proposing that:
the binding sites on target proteins are located in their membrane regions.
Thus, the drug would have to dissolve in the bilayer to be able to access its target site
how can the myer-overton correlation be explained in terms if we hypothesise actions of GA are protein dependent
that anaesthetics have to cross the blood brain barrier in order to exert their actions, and this depends on lipophilicity.
GA target proteins
Potentiating GABAA receptors and strychnine-sensitive glycine receptors
-extrasynaptic GABAA receptors may be particularly important targets of general anaesthetics
Potentiating two-pore-domain potassium channels
Inhibiting ionotropic glutamate receptors
two pore-domain potassium channels
Potassium channels that are open at resting membrane potential
-determine the resting membrane potential
Have two pore-forming domains in each subunit (and 4 transmembrane domains)
Assemble as dimer with 2 pore forming domains from each subunit contributing to the lining of the channel
Compounds that potentiate the function of these channels (more potassium moves out of cell) will produce neuronal inhibition
types of anaesthesia
inhalation
intravenous
neurolept
dissociative
inhalation
Requires use of volatile agent, that can be mixed with air or oxygen and delivered to patient via a mask
advantages of inhalation
by adjusting the mixture of anaesthetic drug reaching the patient, its relatively easy to maintain a certain level of anaesthesia
there will be rapid equilibration between the inhaled gas and the patient’s tissues
Most general anaesthetics undergo only limited metabolism in the patient’s body, and they will leave by the same route that they entered: the patient’s lungs. This can give rapid emergence from anaesthesia
potency of general anaecthetics
For an injected or orally administered drug, we would normally express potency as an ED 50 with units of mg/kg.
-we cannot do this for an inhaled drug.
inhaled anaesthetic potency is expressed as its minimum alveolar concentration (MAC).
minimum alveolar concentration
This is the minimum concentration of the anaesthetic at 1 atm pressure that is needed to prevent movement in 50% of subjects in response to an incision.
oil-gas partition coefficient
This is a measurement and anaesthetics lipid solubility and we have already met the idea that high lipid solubility confers high potency (probably due to needing to cross the blood-brain barrier).
the oil gas partition coefficient can also impact on pharmacokinetics.
If our anaesthetic is highly soluble in fat, lots of the anaesthetic will partition into fatty tissues. Because fat has a poor blood supply, the anaesthetic will take a long time to leave this tissue.
Our patients will have a slowly resolving “hangover” as the anaesthetic gradually leaks back into their blood and leaves the body via the lungs.
This will be worse the fatter the patient and the more fat-soluble the drug. Again, we have a short animation to help with this concept (no sound
blood gas partition coefficient
The blood gas partition coefficient of an anaesthetic is one of the determinants of induction and recovery speed.
This parameter is essentially a measure of how well the drug dissolves in blood compared with gas
a drug with a low blood gas partition coefficient will give rapid induction and rapid recovery
disadvantages of inhalation
Longer induction and marked stage II
-slower compared to intravenous agents
-risk patient will spend more time in dangerous, excitation stage II
Equipment factors and psychological distress
-require complex, expensive, bulky equipment -patient can become stresses from experience of having mass placed over face
Metabolism, toxicity and environmental damage
-Although inhaled general anaesthetic metabolism is unimportant for elimination, metabolites can be a significant source of toxicity both for the patient and operating theatre staff.
flurane metabolism problem
Flurane general anaesthetics generate fluoride when they are metabolised which can cause renal toxicity.
halothane metabolism problems
is converted to bromide and trifluoroacetic acid which can cause liver toxicity, leukaemia, spontaneous abortions and birth defects
problem in operating theatres with staff who were repeatedly exposed to halothane
why are most inhaled general anaesthetics damaging to the environment
because they have up to 2000x the green house gas effect of CO2
two most common inhalation anaesthetics in the UK
nitrous oxide and isoflurane
desflurane and sevoflurane are becoming more popular but are considerably more expensive
haloether compounds
halothane, isoflurane, desflurane, sevoflurane
what are haloether compounds thought to act on?
potentiate GABA A receptors leading to increased inhibitory transmission
inhibit NMDA receptors leading to decreases in excitatory transmission
potentiate two pore domain potassium channels leading to increased neuronal inhibition
isoflurane effects
Can produce hypotension through two different mechanisms
-it is a negative inotropic (decreases force of contraction)
-can decrease peripheral vascular resistance
most commonly used general anaesthetic
isoflurane
what is a suggested outcome of the coronary vasodilatory properties if isoflurane
may worsen ischaemia in parts of the heart that are supplied by vessels with atherosclerosis
phenomenon known as coronary steal and occurs because blood is diverted away from the ischemic areas into the dilated blood vessel
toxicity of isoflurane
low toxicity
it is not significantly metabolised
concerns with isoflurane?
Have been some concerns it can induce neurodegeneration
-has been shown experimentally in neonatal animal models
-appears to have a greater tendency to promote neurodegeneration than sevoflurane
why does sevoflurane have rapid induction?
due to its low blood: gas coefficient
however this recovery can be so rapid that post-operative pain relief is frequently needed
high oil gas partition
lots of the anaesthetic will partition into fatty tissues. Because fat has a poor blood supply, the anaesthetic will take a long time to leave this tissue.
Our patients will have a slowly resolving “hangover” as the anaesthetic gradually leaks back into their blood and leaves the body via the lungs.
This will be worse the fatter the patient
toxicity of sevoflurane
some metabolism to release fluoride but this is not significant
doesn’t produce respiratory tract irritation
evidence for some neurodegeneration being caused, but this is less than with isoflurane
toxicity of desflurane
Although there is very little metabolism, can produce significant irritation of the respiratory tract, can lead to coughing
causes high levels of sympathetic activity, which is dangerous in patients whose cardiac function is compromised
blood gas partition of desflurane
Low blood: gas partition coefficient
less soluble in blood than sevoflurane
makes it particularly suitable for use on obese patients
-however has a rather low potency
mechanism of nitrous oxide
It is a moderately potent blocker of MNDA receptors and this probably underlies its anaesthetic actions
It may have some additional but weaker potentiating actions at GABAA receptors and other targets that mediate its anxiolytic and analgesic effects
potency of nitrous oxide
Has a very low potencyits potency is so low that it cannot be used to produce a surgical anaesthesia on its own
even an 80% mixture with oxygen does not produce a loss of consciousness
ethanox
50/50 mix of nitrogen oxide and oxygen
commonly used in trauma and obstetrics
mechanisms of nitrous oxide
It is a moderately potent blocker of NMDA receptors and this probably underlies its anaesthetic actions
It may have some additional but weaker potentiating actions at GABAA receptors and other targets that mediate its anxiolytic and analgesic effects
why does nitrous oxide have low potency
due to its low oil : gas partition coefficient and this caused other problems
when the patient stops receiving nitrous oxide, the anaesthetic can transfer very rapidly from the blood into the lungs, reducing the partial pressure of oxygen in the lungs
also a problem if the has recently been scuba diving
-scuba divers can have tiny bubbles of nitrogen in their blood which doesn’t usually cause a problem. However, Nitrous oxide can transfer from the liquid phase of the blood into these bubbles and expand them to cause gas emboli
problems with nitrous oxide drug abuse
N2O is relatively safe but is contraindicated in early pregnancy as it can produce foetal abnormalities
it can also cause or exacerbate vitamin B12 deficiency, which has been a problem in some recreational users
advantages of intravenous anaesthesia over inhalation methods
rapid induction
Very limited stage II anaesthesia
Simple apparatus (syringe/ infusion system)
Relatively pleasant induction (no mask)
No atmospheric pollution
disadvantages of anaesthesia
‘once its in, its in’: the level of anaesthesia can be difficult to control
Recovery can be slow due to redistribution metabolism
Vein damage van occur e.g. thrombophlebitis
what are intravenous anaesthetics used for
largely avoid stage II anaesthesia (the excitation phase), they often used to induce anaesthesia in a balanced anaesthesia protocol
once patient has reached stage III, an inhalation anaesthetic can then be used to maintain anaesthesia during surgery
however for a short surgeries intravenous anaesthetics may be suitable for the entire procedure
what type of drug is sodium thiopental
barbiturate
effect of sodium thiopental being very lipid soluble
so crosses the blood-brain barrier very quickly which makes induction dependent only on blood flow i.e. very rapid.
However, it is rapidly redistributed into tissues and accumulates in fat.
-This means that it has the same problems with a hangover effect that are seen with inhalational agents with a high oil: blood partition coefficient. This issue precludes thiopental being used via continuous infusion and it is only used as an induction agent.
what is sodium thiopental increasingly being replaced by?
It is being increasingly replaced by propofol and etomidate.
mechanism of sodium thiopental
The mechanism of the barbiturates anaesthetics is thought largely to be by positive allosteric modulation of GABAA receptors.
-At higher doses, barbiturates are able to directly activate the GABAA receptor and this makes them particularly dangerous in overdose.
Some studies have also found that barbiturates also act as inhibitors of AMPA type glutamate receptors.
effects of sodium thiopental
Thiopental can produce respiratory and cardiac depression.
it is used as one of the agents in lethal injections and in euthanasia, partly because of these properties.
It can also induce arrhythmias as a side effect.
how is propofol thought to act?
Propofol, also named Divipram, is thought to act largely by allosterically potentiating GABAA receptors
although at higher doses may be able to directly activate the receptor and is somewhat similar to the barbiturates in this respect.
how is propofol administered?
as an emulsion
as a single does or as via continuous infusion
how is propofol used?
become very widely used as an induction agent and is used as a sole agent in short surgeries.
advantages of propofol
It is rapidly metabolised giving a rapid recovery compared to other IV agents.
It produces little or no hangover effect and has lower rates of post-operative nausea and vomiting than thiopental or etomidate.
disadvantages of propofol
The most common side effect of propofol is pain when it is injected but this can be managed with analgesic agents.
It can also cause hypotension due to its cardiovascular effects and it can decrease respiratory drive
Propofol has been widely abused by medical personnel for its amnesic, euphoric and hypnotic properties.
it has a steep dose response curve and this has led to accidental overdose in some cases.
etomidate shares many characteristic with what drug
propofol
uses of etomidate
generally used for induction or short surgeries, and is rapidly metabolised, so recovery is fast
side effects of etomidate
It has a good cardiovascular profile but can cause post-operative nausea and vomiting and like propofol can caue pain at the injection site.
One additional side-effect is that it can suppress the production of steroids by the adrenal cortex.
what type of anaesthesia is ketamine
dissociative anaesthesia
mechanism of ketamine
none competitive antagonist at NMDA receptors
what doses of ketamine produce loss of consciousness? what drug is this similar to?
high doses of ketamine, similar effects to nitrous oxide
serious side effect of haloether inhalation agents
malignant hyperthermia
what anaesthetics do not trigger malignant hyperthermia
intravenous anaesthetics and non-depolarising neuromuscular blocker
what is malignant hyperthermia characterised by?
muscle rigidity and increase in body temperature
what can malignant hyperthermia lead to
kidney failure
genetic factor of people at risk of MH
usually have either a mutation in an L type calcium channel subunit or a mutation in the ryanodine receptor
-these mutations make the system sensitive to inhalational anaesthetics and suxamethonium
what happens if someone with an MH mutation is given a trigger drug?
calcium floods out of the SR triggering sustained muscle contraction.
This generates large amounts of heat - hence the hyperthermia part of the name.
what is the mortality rate of MH? how is this reduced?
mortality rate of 80% but this is reduced to 5% if patients are treated with a muscle relaxant called dantrolene.
how does dantrolene work?
blocks the ryanodine receptor, preventing the release of calcium from the SR
what doe neurolept anaesthesia involve
the use of an antipsychotic and an opioid
Many antipsychotics produce profound sedation when combined with an opioid, this can produce a rapid acting anaesthesia with similar effects to ketamine
etorphine
is an opioid around 2000x more potent than morphine
one drop is sufficient to kill an adult human within a few minutes
the tranquiliser darts are always supplied with an antidote (revivon) in case of accidental human exposure
