GENERAL ANAESTHESIA Flashcards
What is general anaesthesia?
A reversible, drug-induced loss of consciousness.
What are the desirable effects of general anaesthesia?
- Unconsciousness (hypnosis/sedation)
- Analgesia (loss of response to painful stimulation)
- Muscle relaxation / loss of reflexes
- Amnesia
What happened in 1774 regarding nitrous oxide?
Joseph Priestley isolated nitrous oxide
What happened in 1799 regarding nitrous oxide?
Sir Humphrey Davy synthesized and reported the effects of nitrous oxide - analgesia, euphoria and loss of consciousness
What happened in 1844 regarding nitrous oxide?
Horace Wells, a dentist had his own tooth extracted under self-administered nitrous-oxide after observing the effects of gas at a fairground show. This failed when the patient cried out in pain.
What happened in 1847 with chloroform?
After initial attempts with ether, Sir James Young pioneered the use of chloroform in obstetric anaesthesia.
What were three 3 oppositions to chloroform anaesthesia?
Medical - labour pain induced the mother to cry and her cries, “by opening the glottis, takes away all expiratory pressure, and leaves the uterus acting alone”
Religious - “decoy of Satan” - the belief that the pain of childbirth was a divine obligation.
Safety/Ethical - practical medical worries concerning lack of information on safety associated with unwanted drug effect, toxicity etc.
What regulations exist today concerning the introduction of new drugs and medical practice?
- Pre clinical safet and toxicity testing, unwanted effects.
- Clinical trials - to identify efficacy, unwanted effects, adverse reactions.
What new safer compounds have been developed for INHALATIONAL anaesthetics?
What are properties of these drugs?
The most widely used inhalation anaesthetics belong to the flurane series:
- enflurane
- isoflurane
- sevoflurane
- desflurane
- halothane - not widely used because of unwanted effects.
- nitrous oxide - still used often in combination with one of the flurane anaesthetics.
These drugs are non-flammable, have fewer side-effects and improved pharmacokinetic profile compared to older drugs
What are the most widely used intravenous anaesthetics?
- Thiopental (barbiturate)
- Propofol (substituted phenol)
- Etomidate (carboxylated imidazole)
- Ketamine (phencyclidine derivative)
Other agents used include benzodiazepines, diazepam and midazolam but these are slower in onset.
What is the mechanism of arousal and sleep?
Ascending Reticular Activating System (ARAS)
Networks in the reticulum of the brainstem play important roles in inducing sleep and arousal.
ARAS projects to the THALAMUS – a critical relay for sensory and intracerebral
pathways.
In the absence of activity in ARAS the THALAMUS and CORTEX tend towards
“slow wave” activity which underlies sleep/ unconsciousness.
What is pain?
An unpleasant sensory and emotional experience associated with actual, or potential, tissue damage
What is nociception?
- the objective presence of, or potential for, tissue damage
- Experimental correlation of the detection of acute pain with excessive noxious simulation
What pathways mediate ‘nociception’?
- peripheral nociceptive neurones activated by noxious stimuli
- a central mechanism by which the CNS integrates input from the periphery to generate the sensation of pain
Where do Primary nociceptive afferent neurones terminate?
In the dorsal horn of the spinal cord.
Describe A(delta) fibres
fine, myelinated, fast conducting, sharp “focal” pain.
Describe C fibres
non-myelinated, slow conducting, burning “diffuse” pain.
Describe what happens in the spinothalamic tract
The spinothalamic tract conveys slow and fast “pain”, as well as
information from temperature sensors.
Fast pain tends to be the discriminative, whereas slow pain signals evoke the “affective” [arousal-emotional] aspect of the sensation.
Discriminative (fast pain) is
directly “wired” to thalamus.
Affective slow pain reaches the thalamus indirectly and involves various paths. Spinoreticular paths are also
involved in signalling slow pain.
What happens if the thalamus is inhibited?
inhibition in this
region mediates analgesic
effects of general anaesthetics.
What causes muscle relaxation/loss of reflexes?
Primarily due to depression of reflex pathways in spinal cord.
In practice muscle relaxation is produced by co-administration of
neuromuscular blocking drugs.
What part of the brain is important for amnesia?
The case of patient HM suggests that the hippocampus and entorhinal cortex are important brain
structures for short-term memory formation and likely to underlie the amnestic actions of general anaesthetics.
Why are combined drugs used for anaesthetics?
They lower the dose of anaesthetic required to induce unconsciousness.
What are adverse affects of general anaesthetics?
adverse effects on motor control, reflex activity, along with respiratory and autonomic function (the control of homeostatic
mechanisms).
What happens as general anaesthetic concentration is increased?
more brain areas
and functions are affected.
Too high an anaesthetic concentration can lead to widespread CNS
shut-down and death by respiratory failure, unless respiration is maintained artificially.
What is the therapeutic index?
dose of drug that elicits toxic effects/therapeutic dose of drug.
A therapeutic index close to 1 makes a drug difficult to use safely and may require careful monitoring of plasma drug levels during treatment.
Where in the brain does the unconsciousness effect of anaesthesia work?
thalamus, mid-brain and
brainstem reticular activating system
Where in the brain does the analgesia effect of anaesthesia work?
spinal cord,
thalamus, brainstem descending pathways
Where in the brain does the muscle relaxation/loss of reflexes effect of anaesthesia work?
spinal cord, thalamus
Where in the brain does the amnesia effect of anaesthesia work?
hippocampus, entorhinal cortex
What is the Meyer and Overton (1937) lipid theory of general anaesthetic action?
The potency of a general
anaesthetic increases in direct proportion to its solubility in lipid.
The unitary slope of this correlation was widely interpreted as indicating that all general anaesthetic agents acted at the same concentration in the phospholipid bilayer (cell membrane).
What is MAC?
Minimum Alveolar concentration - the amount of anaesthetic required to abolish a surgical incision in 50% of subjects
What is stereo-selectivity?
enantiomers of the same drug have significantly
different anaesthetic potency despite equivalent lipophilicity - this goes against the proposed lipid theory
What is an enantiomer?
A structure with a chiral centre that cannot be superimposed upon its mirror image.
What is the reinterpreted Meyer/Overton relationship
The lipid bilayer is a site that can concentrate anaesthetic molecules closed to their protein sites of action.
What effect does a general anaesthetic have in the CNS?
It promotes a decrease in excitability in the CNS
What are the 2 fundamental mechanisms for communication between neurones (excitability) in the CNS?
- Individual neurones generate and propagate action potentials along
their axons to elicit neurotransmitter release at synapses. - Neurotransmitter release at synapses activates post-synaptic receptors to convey the signal from one neurone to the next – synaptic transmission.
What could achieve a decrease in excitability in the CNS?
Increased inhibitory synaptic transmission
Decreased excitatory synaptic transmission
Or a combination of these
What mediates fast neurotransmission?
Ligand-gated ion channels
What is GABA
gamma-amino butyric acid - the major fast inhibitory neurotransmitter in the mammalian CNS
What is the mechanism for fast neurotransmission?
Ligand-gated ion channels activated by the neurotransmitter GABA (gamma-amino butyric
acid) mediate inhibitory postsynaptic potentials (ipsp).
What does GABA act on
postsynaptic receptors of the ligand-gated ion channel family called GABAa receptors
Describe the structure of a GABAa receptor
they are composed of 5 subunits
The major subunits are called alpha, beta and gamma
The function receptor usually includes 2 alpha, 2 beta and 1 gamma subunit
Describe what happens at the GABA releasing nerve terminal
- The GABAa ion channel is selective for Cl- ions.
- The alpha subunit is believed to posses the GABA binding subunit
- Gaba opens the channel and Cl- flows into the cell causing hyperpolarisation of the membrane potential and inhibition of the cell
What do intravenous anaesthetics (Etomidate, Propofol, Thiopental and Midazolam) do to GABA action?
they enhance it by increasing the Cl- conductance because they bind to the GABAa receptor at a site distinct from the GABA binding site (acting as allosteric modulators) leading to greater inhibition and reduced excitability
Is the identification of the GABAa receptor as a molecular target for
anaesthetic action consistent with the effects of enantiomers?
Yes
the R(+) enantiomer of etomidate is significantly more potent as an anaesthetic than S(-).
This potency ratio is mirrored in their effects on GABAa receptors
where the R(+) enantiomer is more potent.
What do inhalational anaesthetics promote the opening of?
a class of membrane potassium channels called “Two-pore domain” potassium channels.
What forces act on all ions?
concentration gradient and electrical gradient
What happens when an ion channel opens?
A potential is reached when the 2 forces action on the ion (concentration and electrical gradient) cancel each other out resulting in no net flow of the ions through the channel
What are the two most implicated “Two-pore domain” potassium channels and what is there function
The two channel types most implicated are “TREK” and “TASK” channels
These channels are important in maintaining neuronal resting
membrane potential.
What mediates fast EXCITATORY neurotransmission
The neurotransmitter Glutamate
How does glutamate mediate fast excitatory neurotransmission
It acts on postsynaptic receptors of the ligand-gated ion channel
family called AMPA and NMDA glutamate receptors
How does Ketamine inhibit excitatory synaptic transmission
It inhibits NMDA glutamate receptors
It blocks the ion channel once it has been opened by agonist binding
What are NMDA glutamate receptors (NMDAR ) important for in the CNS
they are implicated in many CNS functions particularly mempry formation
They are also implicated in pain pathways in the spinal cord which probably explains the potent analgesic effects of this anaesthetic
What is the direction of blood flow through the heart?
Superior and inferior vena cavae deliver deoxygenated blood to the right atrium
From the right atrium blood
travels to the right ventricle and then into the right and left branches of the pulmonary artery and on to the lungs
Oxygenated blood returns to
the left atrium via the
pulmonary veins from where it travels to the left ventricle and then into the aorta.
How are inhalational anaesthetics distributed and eliminated?
The distribution of an inhalational general anaesthetic follows that of
oxygenated blood. It’s elimination follows the route of deoxygenated blood.
What does the Blood Brain Barrier do?
it prevents large molecules entering the brain interstitual fluid from the blood
What are the structures of the BBB that contribute to low permeability?
tight junctions between
endothelial cells lining the
blood vessel
a basement membrane
processes of astrocyte glial
cells called end-feet that
surround the blood vessel
What does high lipid solubility mean for an anaesthetic
Rapid diffusion across the alveolar membrane in the lungs and into the bloodstream and across the BBB into the brain
What does the inhalational anaesthetics solubility in blood determine?
This is the blood:gas partition coefficient.
It is the main factor determining the rates of induction and recovery from anaesthetic effects
What does the inhalational anaesthetics solubility in fat determine?
This is the oil:gas partition coefficient.
It determines the potency but also the kinetics of distribution - high lipid solubility slows elimination from the body
What is partial pressure?
The driving force that moves the anaesthetic from different compartments. When dissolved in blood or other body tissues the partial pressure is directly proportional to its concentration but inversely proportional to its solubility.
What happens at equilibrium of partial pressure?
the partial pressure of a gas in all body tissues, alveoli and the inspired gas mixture will be equal.
This means the more soluble an anaesthetic in blood the more needs
to be dissolved to reach a partial pressure equivalent to that in the
inspired gas mixture.
What happens when there is a low blood:gas partition coefficient (inhalational)
The lower the solubility in blood, the more rapid the process of equilibrium (and recovery)
This is because less drug has to be absorbed from the inspired air to achieve the required partial pressure for anaesthesia
What are the factors of alveolar ventilation rate?
inhalational
The faster the ventilation rate the more rapid the equilibration of
anaesthetic
Important considerations when co-administering drugs that might suppress respiration
Alveolar dead space also impacts on induction – illness, age-related
What are the factors of cardiac output?
inhalational
Paradoxically increased cardiac output decreases the rate of
induction.
This is because increased pulmonary blood flow means the same volume of anaesthetic dissolves into a greater volume of blood per
unit time.
Thus, blood anaesthetic concentration is initially lower and equilibrium delayed.
Where do general anesthetics distribute to?
- Viscera – highly perfused organs, including the brain - distribution is rapid.
- Muscle – well-perfused, large mass, leading to quick distribution despite low lipid content,
- Fat – despite high-lipid solubility, distribution into this compartment is slow because of poor blood supply.
What are the 3 important factors for transfer of inhalational anaesthetic?
Partial pressure gradient between blood and brain
Solubility of the anaesthetic in brain
Cerebral blood flow.
How does body fat effect the effect of inhalational anaesthetic?
Body fat typically has low blood flow and high anaesthetic solubility
This means as the anaesthetic reaches equilibrium, fat reserves in the body store the drug and have a higher anaesthetic concentration than other
compartments.
This manifests as a slow phase of equilibration during both induction and
recovery.
The larger the proportion of body mass contributed by fat the slower this
equilibration – which can have hazardous, life-threatening consequences.
What are the pharmacokinetic aspects of intravenous anaesthetics?
Blood concentration of anaesthetic rises rapidly, immediately after
administration, followed by a slower decline.
Anaesthesia depends on the rate of transfer from blood to brain
across the blood-brain barrier.
This is largely determined by the lipid solubility of the drug.
High lipid solubility enhances transfer across the blood-brain barrier
into the brain.
What causes recovery of consciousness after anaesthesia?
It is the result of redistribution of anaesthetic in tissues other than the brain.
What happens after an intravenous dose of anaesthetic?
Anaesthetic levels in the blood fall as they
rise rapidly in the viscera (brain) and muscle.
This leads to a fall in blood concentration resulting in diffusion out of the
brain, precipitating a return to consciousness.
What is the hangover effect?
As metabolism is slow and volume of distribution is large, full metabolism and
clearance can take many hours or indeed days
The rate of transfer to the brain is dependent on the availability of (intravenous) drug in the blood. What factors is this subject to?
- Protein Binding
- Cerebral blood flow
- Speed of injection
- Extracellular pH and pKa of the anaesthetic
Why does protein binding affect the rate of transfer of IV anaesthetics?
Only unbound drugs can cross the BBB. Many IV anaesthetics bind to plasma proteins reducing the availability of free drug for transfer into the brain.
Protein levels can be affected by disease and binding of anaesthetic
can be affected by blood pH or the binding of other drugs.
Therefore the anaesthetic effect of a dose may be altered by the state of the patient.
Why does cerebral blood flow affect the rate of transfer of IV anaesthetics?
Low blood flow will ordinarily reduce delivery of anaesthetic to the brain.
but not if it is a result of low cardiac output – this would lead to an initial
higher concentration of anaesthetic. c.f. effects of cardiac output on
equilibration of inhalation anaesthetics.
Low cardiac output might delay anaesthesia but also enhance it.
Why does speed of injection affect the rate of transfer of IV anaesthetics?
Rapid injection promotes high initial anaesthetic concentrations but can also
precipitate unwanted effects.
Can ionised forms of a drug cross the BBB?
No
What is stage 1 of anaesthesia?
Analgesia: Loss of pain; loss of general sensation but consciousness retained.
Stage continues until loss of consciousness.
What is stage 2 of anaesthesia?
Excitement: More commonly seen with inhalational induction; passed rapidly
during iv induction.
Involves erratic respiration, breath holding, can involve irregular heartbeat and raised blood pressure. Hyperactivity may lead to
patient trying to resist treatment.
What is stage 3 of anaesthesia?
Surgical anaesthesia: Skeletal muscles become relaxed and excitement seen in previous stage 2 subsides. Eye movements slow down and patient becomes still. This is the stage for onset of surgery.
There are three / four different levels (planes) depending on
increasing anaesthetic concentration. Pupils are central and gradually
enlarge with depth of anaesthesia
What is stage 4 of anaesthesia?
Overdose: Paralysis of medulla region in the brain responsible for respiratory and cardiovascular control – this paralysis can lead to death so this stage
should be avoided during general anaesthesia.
Reversal by withdrawal of anaesthesia and administration of 100%
oxygen
When is IV induction used for anaesthesia?
It is suitable for most routine surgical purposes
What are the advantages of IV induction?
Fast induction is the major advantage over inhalational induction
Minimises or avoids Stage 2 complications
What are complications/difficulties with IV induction?
Cardiovascular depression – particularly in the elderly or untreated
hypertensive
Respiratory depression – may require assisted ventilation
Histamine release and subsequent allergic response – thiopental in
particular
When is inhalational induction used?
In young childred
If there are upper or lower airway obstructions - inhalational agents dialate bronchii
If there are no accessible veins
What are complications/difficulties with intravenous induction?
-slow rate of induction
-problems associated with stage 2 (excitement)
-bronchospasm – stimulation of airway by inhaled material / associated with asthmatics or smokers. Avoided by co-administration of
bronchodilators
-laryngeal spasm – stimulation of cords by secretions or blood
What is the induction procedure of inhalational anaesthetic?
- Initial 70% nitrous oxide in oxygen
- Anaesthesia deepened by incremental introduction of additional volatile
agent e.g. sevoflurane. - Alternatively more rapid induction is obtained with an initial concentration as high as 8%
- Subsequent maintenance involves lower concentrations of volatile
agents e.g. 1-2% isoflurane, 2-3% sevoflurane.
-The depth of anaesthesia can be controlled by the concentration of
volatile agent and continuous monitoring of patients reaction to
anaesthetic.
What are the aims of maintenance of general anaesthesia
To maintain unconsciousness, muscular relaxation and analgesia
What does maintenance of general anaesthesia involve?
- introduction of an inhalational agent – e.g. sevoflurane, isoflurane
- Continuous infusion of iv anaesthetic agent e.g. propofol
- repeated bolus injection of iv anaesthetic – N.B. danger of increased distribution into fat reserves and delayed reversal.
Describe the use of inhalational anaesthesia with spontantenous ventilation for anaesthesia maintenance
Suitable for minor surgery associated with little reflex or painful stimulation.
The rapid control over the depth of anaesthesia is a major advantage of this method of maintenance.
Partial pressure of volatile agent expired from lungs gives good estimate of partial pressure in brain
Describe the use of total intravenous anaesthesia for maintenance of general anaesthesia
Drugs such as propofol can be used for this method of maintenance
Plasma concentration is subject to biological variability
Rapid assessment of the dose required for each individual patient must be performed by monitoring depth of anaesthesia.
Advantages over inhalational anaesthesia are predominantly to do
with the avoidance of distension of gas-filled spaces and the production of fluoride ions – a potential source of liver toxicity.
What is monitored during emergence and recovery from general anaesthesia and why?
Neuromuscular function to ensure the patient recovers adequate muscle strength.
What can general anaesthetic drugs be combined with?
opioid analgesia
muscle relaxants
regional anaesthesia
What is the neuromuscular junction?
a specialised synapse between a motoneurone, originating in the spinal cord, and skeletal
(voluntary) muscle.
Why are neuromuscular blocking agents used with anaesthetics
The ability to induce muscle relaxation and loss of reflexes is an ideal
property of a general anaesthetic
The concentration at which these effects are elicited may be higher than the dose required for adequate (safe?) anaesthesia
Thus, to allow appropriate anaesthesia with less risk of unwanted effects, co-administration of a neuromuscular blocking agent may be performed.
How is muscle transmission promoted?
The neurotransmitter,
ACETYLCHOLINE, is released
from the terminals of the
motoneurone and this acts on ligand-gated ion channel
receptors called “nicotinic”
acetylcholine receptors.
Activation of nicotinic acetylcholine receptor channels causes sodium ions
to flow into the postsynaptic muscle cell causing a depolarisation – an endplate
potential.
This depolarisation results in the threshold for activation of voltage dependent Na+ channels being attained. This causes the generation of an action potential in the muscle fibre which leads to contraction.
Why are analgesic drugs used with anaesthetics?
not all anaesthetics provide good analgesia at
anaesthetic doses so to improve pain management before, during and after surgery analgesic drugs are co-administered.
What are opioids?
The most frequently used analgesic drugs to treat
moderate to severe pain.
“Opioid” refers to all drugs, synthetic or natural, that act on opioid receptors
What are the 3 main actions relevant to opioid use in anaesthetia
analgesia
sedation
euphoria
What are the different g-protein coupled receptors opioids have their effect through?
mu
kappa
delta
What are the undesirable effects of opioids?
respiratory depression, dysphoria, nausea and vomiting, reduced GI
motility,
physical dependence – not immediately relevant to anaesthetic use.
How are opioid analgesic effects mediated?
by inhibition of the dorsal horn pathway (spinal), activation of descending endogenous analgesic pathways (supraspinal) and inhibition in the periphery
Describe the route of administration of opioid analgesics
- Traditional delivery has been by intramuscular injection but this leads
to variable absorption and often inadequate pain relief. - Intravenous delivery either as a single dose or through continuous infusion leads to high bioavailability of drug and rapid onset of
analgesia. - However, IV does need close monitoring for adverse effects associated
with rapid onset. - Oral delivery of opioids is also common though bioavailability is
reduced and onset slow due to metabolism in the gut and liver
what are the objectives of pre and post medication
- to reduce anxiety and fear
- to enhance hypnotic (sleep-inducing) effect of the general
anaesthetic agent - reduce post-operative nausea and vomiting
- produce amnesia
How is pre-medication used to reduced anxiety and fear
Often achieved non-pharmacologically by effective provision of
information and reassurance pre-operatively.
Where necessary can be achieved through anxiolytic drug administration e.g. a benzodiazepine
How is pre-medication used to enhance hypnotic (sleep-inducing) effect of the general anaesthetic agent
In general it is unnecessary to provide sedation other than in unusual circumstances like those associated with paediatric medicine
Sedation can also be induced using a benzodiazepine though sedative and anxiolytic properties are not always so inter-related.
What causes post operative nausea and vomiting?
Nausea and vomiting are common after general anaesthesia especially
when opioid analgesic drugs have been used (probably through an
action on the chemoreceptor trigger zone (area postrema) in the medulla of the brainstem
What pre medication is used to prevent post operative nausea and vomiting?
Anti-emetic drugs are effective when administered i.v. during anaesthesia
How is amnesia produced throughout the pre and post operative period
Using benzodiazepines
What additional medication is used to reduce volume and increase pH of gastric contents
Where vomiting is a risk (emergency patient with full stomach) should
promote gastric emptying – metoclopramide increases GI tract motility
pH of gastric contents can be raised by sodium citrate
Why and how is medication used to attenuate vagal reflexes?
The vagal nerve controls the heart. Anaesthesia can lead to slowing of the heart (bradycardia), thus, pre-treatment with an anti-cholinergic like atropine may be useful in specific circumstances
What causes unwanted actions of drug that are related to its pharmacological action?
It occurs because their target specificity is not absolute
This may include target organ specificity e.g. a drug delivered by the blood may be absorbed by a number of different organs
Binding site specificity – drugs often bind with lower, but not insignificant affinity, to binding sites other than their desired target.
Describe what can cause and what happens if there are unwanted effects of the drug that are unrelated to its main pharmacological action
It ca be predictable if it has been taken in excessive dose, during pregnancy or if patient has a predisposing disorder.
Unpredictable severe adverse effects can also arise and their frequency of occurrence is important for establishing drug safety.
Unwanted and adverse effects of drugs can be; “Idiosyncratic reactions” often result from the production of a
toxic metabolite leading to direct or immune-mediated damage.
Examples include liver and kidney damage, carcinogenesis, foetal
malformation (teratogenicity).
What are the expected characteristics of an adverse allergic reaction caused by a immunogenic conjugate ?
Delayed onset compared to main action of drug
May only occur on repeated exposure
Doses that induce an allergic response may be small and insufficient to elicit other effects
The response conforms to one of the 4 classes of unwanted inflammatory and immune response
How is a stable immunogenic conjugate formed?
While most drugs are small chemicals and not immunogenic, a drug, or
more commonly a metabolite of the drug, can combine with protein to
form a stable immunogenic conjugate.
Describe the allergic reaction to drugs - Type 1
Immediate or anaphylactic hypersensitivity:
lgE antibody mediated through mase cells and eosinophils. Leads to release of chemical mediators histamine, PAF, eicosanoids and cytokines - triggering response e.g. Hayfever
Describe the allergic reaction to drugs - Type 2
Antibody dependent cytotoxic hypersensitivity:
targeted action against cells recognised as foreign e.g. cells altered by drug treatment
Describe the allergic reaction to drugs - Type 3
Complex mediated hypersensitivity:
Antibodies react with soluble antigens to trigger complement or attatch to mast cells to release chemical mediators of response
Describe the allergic reaction to drugs - Type 4
Cell mediated hypersentivity:
Important in the skin, drugs may have combined with proteins in the skin to evoke a cell mediated immune response
Describe what happens in anaphylactic shock
A life threatening Type 1 hypersensitivity response.
Histamine, leukotriene and other chemical mediators are released triggering rash, swelling of soft tissues, bronchoconstriction and
hypotension
Describe haematological reactions
Type 2, 3 or 4 hypersensitivity can mediate this. Targets are the formed elements of blood including either the circulating blood cells or their bone marrow progenitors.
Describe how Treatment with one drug leads to an increased toxicity risk of a second drug
This can happen through either:
1, Increased plasma levels
2. Increased activity
What causes increased plasma levels of drug X?
- Inhibition of metabolic enzyme activity by Drug Y
- Competition for plasma protein binding with Drug Y
What causes increased activity of drug X?
- Additive actions of Drug Y at same or distinct site
- Allosteric actions of Drug Y at same target
What are the effects of inhalational anaesthetics on the respiratory system?
All inhalational anaesthetics cause dose related respiratory depression.
This leads to a rise in arterial Pco2 which can have effects on heart function as well as tissue hypoxia
What are the effects of inhalational anaesthetics on the cardiovascular system?
All inhalational anaesthetics cause a reduction in arterial pressure by decreasing resistance of blood vessels
Effects on cardiac output vary. Halothane reduces cardiac output by depressing myocardiac contractility and myocardial metabolic activity.
Isoflurane, enflurane and desflurane increase heart rate by increasing
activity in the sympathetic nerve increasing release of the neurotransmitter noradrenaline.
What are the effects of intravenous anaesthetics on the respiratory system?
All intravenous anaesthetics cause rapid dose-related respiratory depression.
This can be prolonged at doses that are only slightly higher than those
required to abolish reflex responses.
Also the effects can be exacerbated if opioid drugs have been used for
pain relief
What are the effects of intravenous anaesthetics on the cardiovascular system?
Thiopental - depresses myocardial contractility and dilates peripheral
blood vessels leading to low blood pressure - hypotension
Importantly for this drug the dose margin between anaesthetic effect
and cardiovascular depression is narrow
Propofol – hypotension due primarily to peripheral blood vessel dilatation
Hypotension is an important consideration in hypovolaemic or shocked
patients
What is the toxic effect of the halogenated flurane series of inhalational anaesthetics?
They produce fluoride which can be toxic.
What led to liver damage when chloroform was used as an anaesthetic?
Free radical formation
What adverse reactions can result from inhalational anaesthetics not related to their main pharmacological action?
- Malignant hypothermia
- Halothane Hepatitis (hepatotoxicity)
- Porphyria - Thiopental
Describe Porphyria
- Porphyria are rare genetic disorders that result in the loss of an enzyme important in haem synthesis
- A build up of haem precursors can result in behavioural and
neurological symptoms - Thiopental (and other barbiturates) induce the production of liver
enzymes that stimulate haem precursor production, thus precipitating an acute attack of the syndrome
Describe Halothane Hepatitis (hepatotoxicity)
Liver metabolism of halothane produces trifluoroacetic acid
This can result in modified liver proteins that initiate an immune response.
Only associated with repeated halothane exposure
Rare but often fatal. One study associated 7 unexplained liver
failure induced deaths with repeated halothane exposure out of
850,000 anaesthetic administrations.
Low incidence makes it difficult to predict and study, therefore, prior
to halothane anaesthesia;
- Anaesthetic history taken
- No repeated exposure within minimum of 3 months
- Unexplained jaundice / pyrexia after previous halothane exposure
absolute contraindication for future use.
Describe malignant hypothermia
Can be triggered by halothane and other halogenated general anaesthetics
Associated with skeletal muscle spasm and rapid temperature increase
Rare inherited disorder due to mutation in Ca2+ release channel (ryanodine receptor) in sarcoplasmic reticulum
Mutation (in unknown way) makes the channel sensitive to halothane etc. causing massive intracellular Ca2+ release
Treatment requires block of Ca2+ release by dantrolene
What factors govern the plasma concentration of a drug when administered and the potential toxicity of a local anaesthetic?
Absorption
Distribution
Metabolism
Elimination
What is the aim of a pre operative assessment
To provide sufficient knowledge concerning the nature of surgery and the necessary anaesthetic management to minimise the risk of an adverse outcome
Risk V benefit
What information is needed in a pre operative assessment?
What is the current condition
Patients medical history
Anaesthetic history
Family history
Drug history
Allergy history
Smoking history
Alcohol history
Why is the patients medical history required in the pre operative assessment?
To highlight co existing disease that might influence the management of anaesthesia
E.g. cardiovascular or respiratory disease
Why is the patients anaesthetic history needed during the pre operative assessment
To identify previous problems. Both patient recollection and anaesthetic record is needed.
Why is the patients family history needed during the pre operative assessment
It is important for first time anaesthesia. Needed to identify potential inherited conditions through related family members experience of anaesthesia
Why is the patients drugs history needed during the pre operative assessment
Full and complete list of concurrent medication needed to identify potential drug interactions and/or potential problems if these drugs are withdrawn prior to anaesthesia
Why is the patients smoking history needed during the pre operative assessment
Chronic deleterious effects of vascular disease.
Acute effects relating to oxygen availability.
Why is the patients alcohol consumption needed during the pre operative assessment
Chronic consumption can have effects on organ function
Why is management of anaesthesia in each patient personalised?
Individual circumstances may influence the effects of anaesthesia like age, disease
The choice of anaesthetic/anaesthetic technique may be influenced
Compensatory responses normally triggered by unwanted anaesthetic actions may be affected
