Pharmacology - Inhaled Anaesthetic Agents Flashcards
R_BK_27 Volatile and gaseous anaesthetic agents: Structure of available agents. MAC. Clinical effects: CNS [including ICP], CVS, RS. Unwanted effects of individual agents. MH susceptibility; hepatitis risks. Factors affecting onset and offset time. Oil/gas partition coefficient (17 cards)
Explain theories as to how inhaled general anaesthetic agents work.
IMAGE on lipid solubility
Inhaled agents induce a loss of consciousness and response to painful stimuli in a reversible manner, with the site of action believed to be in the brain & spinal cord.
Meyer-Overton hypothesis describes relationship between lipid solubility & potency - the greater the solubility, the lower dose to induce deep anaesthesia, suggesting that any lipid soluble drug could induce anaesthesia as a result.
However this doesn’t explain how the S & R enantimers of etomidate are equally lipid soluble, but only R-etomidate induces anaesthesia.
A subsequent theory involved the highly lipid-soluble drugs infiltrating the phospholipid bilayer & increasing its thickness, disrupting signal transmission. However, thickness also increases with temperature, without the same effect - conversely, increasing temperature increases anaesthetic agent requirement.
Nowadays, it is accepted that there are specific protein targets, with lipophilic binding sites, explaining the correlation with potency.
What are Guedel’s Stages of Anaesthesia
Chart devised by Arthur Guedel in 1917 to teach nurses & orderlies how to monitor depth of anaeshesia, to enable safe administration to wounded soldiers.
Stage 1
From induction to loss of consciousness
Analgaesia and amnesia, but conversational
Stage 2
Excitement or delirium, with disinhibition & uncontrolled movements.
Loss of eyelash reflex, hypertension & tachycardia
Airway reflexes intact & hypersensitive, with risk of laryngospasm, vomiting, and irregular respiration
Stage 3
Surgical anaesthesia, no eye movement, respiratory depression, and airway manipulation now safe.
Divided into 4 planes
Plane 1
Regular, spontaneous breathing, with central gaze & constricted pupils.
Eyelid, conjunctival & swallow reflexes disappear
Plane 2
Pauses in breathing, increased lacrimation.
Loss of corneal & laryngeal reflexes, reduced ocular movements
Plane 3
True surgical anaesthesia, complete relaxation of intercostal & abdominal muscles
Loss of pupillary light reflex
Plane 4
Irregular respiration, full diaphragm paralysis, apnoea
Stage 4
Deep brainstem anaesthesia & death
Guedel was using diethyl ether as the sole agent - some patients premedicated with morphine or atropine, but no muscle relaxation, benzodiazepines, or other induction agents.
These stages & planes are less reliable in context of balanced anaesthesia, as some parameters are disproportionately affected by the other drugs.
Discuss the advantages & disadvantages of diethyl ether
Advantages
Excellent analgaesia and amnesia
Stimulates respiratory system
Cardiostable, with depression of heart rate & blood pressure reflexes
Dose-dependent muscle relaxation, affecting abdominal wall before the respiratory muscles
Disadvantages
Irritant with pungent smell, causing coughing & breath holding
Emetogenic
Highly flammable & explosive in the presence of oxygen
High blood:gas partition coefficient (12:1), with very slow onset & offset.
Unlikely to come up in exams
Explain Blood:Gas and Oil:Gas partition coefficients, and saturated vapour pressure
Blood:Gas partition coefficient
The ratio of partial pressure of an anaesthetic agent in the blood vs the gas, when both phases are at equilibrium
This assumes that both blood & gas phases are of equal volume, and at the same pressure, at 37ºC
This coefficient corresponds to the speed of onset of the anaesthetic agent, as the partial pressure of an agent determines depth of anaesthesia, rather than the total number of molecules
More soluble agents exert lower partial pressure - Desflurane has a B:G coefficient of 0.42, and is much faster onset than isoflurane (B:G coefficient 1.4)
Oil:Gas partition coefficient
The ratio of partial pressure of an anaesthetic agent in oil or fat vs a gas at equilibrium.
This relates to the potency of an agent, and therefore the MAC.
Isoflurane has an O:G coefficient of 98, being much more potent than desflurane (O:G coefficient of 19)
Saturated vapour pressure
Determines the volatility of a drug and therefore its boiling point - with implications as to the type of vapouriser it will need
What are the characteristics of an ideal inhalational anaesthetic agent?
Physicochemical
Easy & cheap to manufacture
Environmentally friendly during production & use
Non-flammable, non-explosive
Safe to store & transport at room temperature
Stable on exposure to light
Compatible with existing equipment - non-reactive with metal, rubber & soda lime
Inert in air, glass and plastic
Pharmacological
Pleasant odour & non-toxic
High O:G partition coefficient (high potency)
Low B:G partition coefficient (fast onset-offset)
Minimal metabolism, excreted by the lungs
Non-immunogenic, with no effect on other body systems
Predictable pharmacokinetics
Easily measurable in real-time using existing equipment - such as IR spectrometry
Sufficient dose-dependent respiratory depression to prevent oversedation when spontaneously breathing
Analgaesic and bronchodilatory effects
For instance - Enflurane demonstrates epileptiform activity on EEG
All currently used volatile agents cause a decrease in uterine tone
What factors determine the rate at which inhaled anaesthetic agent is taken up into the blood?
Inhaled concentration of the agent
Minute ventilation - A larger FRC will dilute the agent, and slow uptake (one of the reasons why uptake is faster in the elderly, neonates, and pregnant woman)
VQ matching - Anatomical & alveolar dead-space, lung pathology will decrease diffusion
Cardiac output - Higher CO washes away the agent before partial pressure builds up in the lungs, and allows the agent to distribute around the body
B:G partition coefficient - A lower coefficient means that less agent will cross into the blood for each kPa of partial pressure in the alveolus - and the partial pressure will climb faster in the lungs
Second gas effect - NO dissolves rapidly into the blood, reducing alveolar pressure, and increasing the partial pressure of the agent more rapidly than if administered with oxygen alone
What is MAC?
The Minimum alveolar concentration of anaesthetic agent at sea level, in 100% oxygen, at which 50% of un-premedicated experimental subjects will not respond to a standard 1cm surgical abdominal midline incision. Expressed as a percentage concentration.
Technically this is known as the MAC50, with the MAC90 being for 90% of subjects
A higher MAC indicates low potency, as concentrations in the brain and lungs are very similar at steady state.
MAC values for commonly used agents:
Sevoflurane 2.1
Desflurane 6.6
Isoflurane 1.15
Nitrous oxide 103 - Possible at hyperbaric pressures in order to ensure that there was enough oxygen present to prevent hypoxia - MAC is a %, but it is the partial pressure of an agent that matters, so 103kPa in this case.
When MAC is shown on an anaesthetic machine, it reflects the end-tidal concentration of agent relative to 1 MAC of that agent - so 4.2% Sevoflurane is equivalent to 2x MAC
What are the different levels of MAC?
MAC-Amnesia The level of anaesthesia needed to prevent explicit memory of noxious stimulus. Thought to be due to agent action on the amygdala and hippocampus.
Occurs at approx 0.25 of the MAC50 (FeSevo of 0.4kPa)
MAC-Unconscious Occurs at approximately 0.5 of the MAC50 (0.8kPa for Sevoflurane)
MAC-BAR Blockade of Autonomic Response - no tachycardia, pupil dilation or HTN in response to painful stimulus - around 1.5 MAC50
MAC-EI Endotracheal intubation - the MAC required for successful intubation in 50% of subjects without muscle relaxants or opioids. More frequently used in children (1.3 MAC), as in adults it is 3 MAC, which would result in significant cardiovascular instability).
What factors affect MAC requirement?
Increase MAC requirement
Patient factors
Anxiety
Hyperthermia (Apart from N2O)
Hyperthyroidism
Hypernatraemia
Red hair (decreased sensitivity to anaesthetic agents, possibly due to melanocortin 1 receptor gene)
Pharmacological factors
Recreational drug usage (cocaine & catecholamines, acute amphetamine usage, chronic EtOH and amphetamine usage)
Co-administered medications (Adrenaline & thyroxine)
Decrease MAC requirement
Patient factors
Increasing age (peaks at 6 months, dropping by 6% per decade)MAC40 x 10^(-0.00269x(Age-40))
Hypothermia (MAC drops by 5% for every 1ºC drop in core body temperature - theoretically no anaesthetic required at 20ºC
Hypothyroidism
Pregnancy (up to 30% reduction)
Critical illness (Hypoxia, hypercapnoea, acidosis, severe anaemia, hypotension, hyponatraemia, head injury & low GCS, some neurological diseases)
Pharmacological factors
Other drugs:
A second inhalational agent is additive
IV agents
α2 adrenergic antagonists
GABA potentiators
Lithium
Verapamil (Calcium channel inhibition)
Regional & local anaesthesia
Factors that do not affect MAC
Sex
Duration of anaesthesia
Species
Magnesium
Haemoglobin concentration
CO2 tension in the blood
Categorise into increase/decrease requirement, then within each, classify into patient and pharmacological factors.
Explain coronary steal
If a drug induces vasodilation, but areas of the myocardium already have maximally dilated vessels (due to stenosis or atherosclerosis), then resistance cannot be lowered any further to these areas.
As other areas vasodilate, blood flows to these now lower resistance areas, leading to a reduction in flow to the stenosed area, and therefore potentially precipitates ischaemia.
Discuss Sevoflurane as an inhaled anaesthetic agent
Polyfluorinated ether, with a sweet odour. Stored in polyethylene naphthalate bottles (glass is a source of lewis acids, which can cause sevoflurane breakdown to hydrofluoric acid)
B:G Coefficient 0.7 (Intermediate)
O:G Coefficient 53 (Intermediate)
MAC 2.0
Effects
Cardiovascular - Reduces SVR, often without compensatory tachycardia - drop in BP
Respiratory - Dose dependent respiratory depression, some bronchodilation
Neurological - Hypnosis & reduced CMRO₂
Metabolism
Less than 5% metabolised by CYP2E1, but fluoride ions may cause nephropathy.
Produces compounds A, B, C, D, E when interacting with soda lime - compount A toxic in rat models
Risk factors: high temperature or sevoflurane concentraction, baralyme, and low gas flow
Discuss Desflurane as an inhaled anaesthetic agent
Boiling point of 23.5°C makes it too volatile for normal variable bypass vaporisers - TEC6 vaporiser heats it to 39°C at 2atm, injecting the vapour directly into the fresh gas flow using a differential pressure transducer
B:G Coefficient 0.4 (fast onset)
O:G Coefficient 19 (low potency)
MAC 6.6
Effects
Cardiovascular - a high doses, paradoxical tachycardia, and reduces SVR
Respiratory - Dose dependent respiratory depression, pungent smell can trigger laryngospasm & breath holding
Neurological - Hypnosis with MAC of 6.6, increased CBF, but reduces cerebral metabolic oxygen consumption
Metabolism
0.02% metabolised by hepatic CYP450 enzymes to trifluoroacetic acid
Reacts with soda lime to form carbon monoxide at low flow rates
Discuss Isoflurane as an anaesthetic agent
Halogenated ethyl-methyl-ether, pungent smell makes it inappropriate for volatile induction.
B:G coefficient 1.4 (Slow onset)
O:G coefficient 98 (High potency)
MAC 1.1
Effects
Cardiovascular - reduces SVR and BP, without reflex tachycardia
Coronary steal is unlikely to be clinically significant
Respiratory - Respiratory depression
Breath holding and laryngospasm if used for volatile induction
Neurological - Reduced CMRO₂, stable cerebral blood flow, autoregulation maintained up to 1 MAC.
Metabolism
0.2% by CYP2E1
May react with dry soda or baralyme to produce carbon monoxide
Enflurane is a structural isomer of isoflurane, with similar properties
Discuss Halothane as an inhaled anaesthetic agent
No longer routinely used
Halogenated hydrocarbon, unstable in light and leaches into rubber & breathing circuits. Stored in thymol to prevent release of bromine. Boiling point 50°C
Effects
Cardiovascular - increased vagal stimulation & bradycardia, myocardial depression, and sensitisation to catecholamines
Respiratory - Bronchodilator, potent and sweet smelling - good for gas induction, but slow onset
Neurological = Increases cerebral blood flow (and therefore ICP) above 0.6 MAC, and reduces CMRO₂
Metabolism
20% metabolised in liver
Halothane hepatitis
Initially reversible & likely due to hypoxia
May progress to fulminant necrosis - mortality over 50%
Risk factors: Obesity, middle age, female, repeated exposure
Discuss Xenon as an inhaled anaesthetic agent
Inert halogen gas with no environmental impact
MAC 71
B:G Coefficient of 0.14 results in rapid onset & offset, but costs 2000x more to produce compared with nitrous oxide.
Effects
Reduced RR, increased TV (opposite to other agents)
Minor bradycardia
Increased cerebral blood flow
Excellent analgaesic properties
Metabolism
Not metabolised, excreted by lungs
To what extent does each inhaled anaesthetic agent undergo metabolism in the body?
Vast majority unchanged by the lungs, with differing levels of hepatic metabolism through CYP2E1.
C-Br bond much easier to break down than C-Cl, which is easier than C-F.
Halothane 20%
Trifluoroacetic acid, chloride & bromine
Isoflurane 0.2%
Trifluoroacetic acid & fluoride
Enflurane 2%
Inorganic & organic fluorides
Sevoflurane 3.5%
Compound A if soda lime & heat present, also B, C, D, E
Desflurane 0.02%
Trifluoroacetic acid
Nitrous < 0.01%
Nitrogen
List the boiling points & the saturated vapour pressures (At 20°C) for each of the inhaled anaesthetic agents
Desflurane 23°C, 89kPa (very close to atmospheric pressure, hence the need for a dedicated vaporiser, rather than the standard TEC5)
Sevoflurane 59°C, 21kPa
Isoflurane 49°C, 32kPa
Halothane 50°C, 33kPa
Enflurane 57°C, 23.3kPa
Nitrous Oxide -88°C, 5200kPa (nitrous is a vapour at this temperature, and if heated to 36.5°C, it will exceed critical temperature, and is therefore a gas)
Xenon -108°C
