Inhalational agents

Question 1

define critical temperature

Answer 1

The temperature at which a gas cannot be liquified regardles of the pressure applied.

below this it exists as a vapour and above as a gas.

Question 2

describe the concept of saturated vapour pressure

Answer 2

if a liquid is in a closed container, molecules within the liquid will evapourate and fill the gaseous phase of the container. some molecules in the gaseous phase will condense
at equilibrium there is a equal rate of vapourisation and condensation.

the pressure of the vapour phase is known as the saturated vapour pressure. this is temperature and substance specific

Question 3

describe the relationship between SVP and temperature

Answer 3

as temp increases, molecules have more kinetic energy and more energy for intermolecular bonds to break and hence vapourise.
more of the substance exists in the vapour phase
hence increase in SVP
non linear relationship

Question 4

define critical pressure

Answer 4

the pressure at which is required to liquify a vapour at or just below its critical temp.

Question 5

define the boiling point…

Answer 5

the boiling point of an agent is rhe temperature at which the SVP is equal to the atmospheric pressure

therefore by reducing atmospheric pressure will reduce boiling point

increasing temp will increase SVP until it is equal to atmospheric pressure and all liquid vapourises into gaseous phase.

Question 6

what are the groups of inhalational agents?

Answer 6

halogenated hydrocarbons e..g halothane and chloroform

halogenated ethers e.g. sevoflurane, isoflurane etc

inorganic molecules - xenon and N20

Question 7

describe the common themes of physiochemical properties of inhalational agents?

Answer 7

all very volatile - low boiling points, high SVP especialy desflurane. this means that they have the convienence of being a liquid at room temp but easily vapourising

all lipid soluble - hence cross BBB to exert pharmacodynamic effects

mostly low blood gas partition - gives them faster onset of action. especially desflurane

chemical stability - all stable in light. some dissolve in rubber e.g. sevoflurane

Question 8

what is a partition coefficient. Which ones are commonly discussed with inhalational agents?

Answer 8

partition coefficient is the ratio of the amount of substance present in one phase compared to another, when the two phases are of equal volumes, temp and pressure and in equilibrium. it is a dimensionless number.

oil gas - how much dissolves in oil vs gas phase
blood gas - how much dissolves in blood vs gas phase

Question 9

define oil gas partition coefficient ?

Answer 9

a ratio of the amount of substance dissolved in oil phase compared to gas phase when the two phases are of equal volume, temp, pressure and in equilibrium

it is a measure of lipid solubility and correlates with potency and MAC of inhalational agent.

Question 10

define the blood gas partition coefficient

Answer 10

a ratio of the amount of substance dissolved in blood phase compared to gas phase when the two phases are of equal volume, temp, pressure and in equilibrium

relates to speed of onset, i.e. the higher the blood:gas , the slower the speed of onset of inhalation agent.

Question 11

what is the relationship between oil gas partition coefficient and MAC?

Answer 11

the higher the oil:gas, the more lipid soluble, the potent and hence the lower the MAC i.e. the less agent needed to anaesthetise 50% of population.

therefore inverse relationship
found to be a straight line when log MAC is plotted against log O:G

Question 12

what is the O:G for isoflurane and enflurane, what is their MAC values. what is significant about this…

Answer 12

enflurane and isoflurane are structural isomer differing in position of their chloride group.

MAC of isoflurane is 1.17
MAC of enflurane 1.7

O:G of iso is 90
O:G of en is 98

you would expect enflurane to have a lower MAC. this suggests, potency is not only determined by lipid solubility. must be to do with molecular interactions.

Question 13

how does the metabolism of iso and enflurane compare?

Answer 13

structural isomers, however slight difference in metabolised which must be governed by position of Cl.

enflurane is 2% metabolised whilst iso is only 0.2%
this is because isoflurane is less water soluble.

Question 14

iso and enflurane are structural isomers, however have different properites, can you highlight these?

Answer 14

Question 15

Draw a graph to compare the speed of onset of inhalation agents…

Answer 15

this can be demonstrated by plotting the FA/FI vs time
where FA = fraction of agent in alveolus
and FI = fraction of agent in air

all substances will eventually reach a FA/FI of 1 but at different rates.
the quicker the alveolar fraction equals fraction in air, the quicker the speed of onset - this relates to B:G partition.

Question 16

what factors affect speed of onset of inhaled agent?

Answer 16

an inhalation agent exerts its effects via crossing alveolar membrane and then BBB. It is the partial pressure of the agent that exerts its effects on the brain. The alveolar PP is in equilibrium with the brain and the quicker this builds up, the quicker the conc in brain builds up.

agent factors
* blood:gas solubility - the lower the quicker the onset as more remains in alveolus to reach the FI. the alveolar PP is in equilbrium with PP in the brain which is having its effects
* higher SVP - the more volatile an agent, the higher its SVP and hence PP at brain, quicker the onset

Equiptment factors
* the % inspired in inspired FGF
* the flow rate of FGF
* the dead space of the equiptment - less deadspace the quicker.
* the use of second gas e.g. 70% N20

patient factors
* FRC - the smaller the volume, the higher the conc of anaesthetic agent in alveolus
* CO - the slower, less is removed from alvelous
* minute volume - the quicker , the quicker FA=FI
* cerebral blood flow - increased blood flow, the quicker the effect

Question 17

explain the relationship between B:G and speed of onset

Answer 17

it is the partial pressure of an agent that exerts its effects at the brain
the more soluble in blood, the lower the partial
blood is acting as a sink
it will be removed from alveolus, reducing PP here and hence also PP at brain

Question 18

what determines the speed of offset at the end of an operation?

Answer 18

patient factors
- MV - quicker, the quicker offset
- obesity - agent dissolved into lipid compartments

drug factors:
* low B:G partition coefficient
* low lipid solibility - less likely to accumulate

other
* operation time - longer to accumulate in tissues
* FGF rate

Question 19

tell me about the metabolism of inhaled agents…

Answer 19

small proportion of inhaled agents are metabolised by liver CYP2E1
to varying degrees

e.g.
halothane 20%
isoflurane 0.2%
enflurane 2%
sevo 3-5%
desflurane = 0.02%
xenon = 0
N20 = 0.01%

otherwise clearance is through exhalation.

most agents are oxidised to trifluroacetic acid + halogen ions. except sevo.

Question 20

what induces the CYP2E1

Answer 20

alcohol
ketones - DKA

Question 21

draw the washout curve for inhaled agents..

Answer 21

the FA/FAE is plotted against time, eventually this will be 0
where FA= fraction in alveolus
FAE = fraction in alveolus at point when vapour is first turned off.

relates to B:G solubility i.e. desflurane is quickest offset, then sevo etc

wash out curve = negative exponential

Question 22

describe the theories for the mechanisms for inhalation anaesthesia

Answer 22

meyer overton hypothesis = found MAC related to O:G i.e. the more lipid soluble, the more potent an agent and thus hypothesised they work through dissolving in lipid membranes of neurons

development from this = lipid bilayer expansion theroyr (critical volume hypothesis)
* not just related to lipid solubility but also size
* therefore likely to dissolve, take up volume and disrupt protein functions

current models
* likely to do with molecular interactions
* need to be lipid soluble to access membrane proteins , then interact with receptors/ ion channels through lipophilic domains.
* overall potentiate GABA and glycine, inhibit glutamate / nAChR to reduce neuronal excitability.

Question 23

how does xenon and N20 work

Answer 23

thought to work through non competitive NMDA antagonism

Question 24

how is sevoflurane thought to work?

Answer 24

increases activity of 2 pore K+ channels - hyperpolarises

positive allosteric modulator of GABA - hyperpolarises

Question 25

what are the flaws in the theories of mechanisms for inhaled anaesthetic agents?

Answer 25

increase in temp would increase fluidity of membranes and disrupt functioning of proteins - however doesnt cause anaesthesia

some drugs are very lipid soluble bit doesnt have anaesthetic effect

enflurane and isoflurane - structural isomers.
isoflurane has a lower MAC (1.17 vs 1.7) but a lower O:G (90 vs 98). these are the same size - goes against both meyer overton and lipid bilayer expansion theory - ehnce suggests must have differences in receptor activity

Question 26

How is the MAC calculated when multiple agents are used?

Answer 26

MAC is addititive
hence 0.5 MAC of sevo + 0.5 MAC N20 = 1 MAC

Question 27

how does MAC vary with age, can you list some things that increase/ decrease MAC…

Answer 27

MAC is low in neonates,
peaks around 1 yrs,
gradually drops with age

Question 28

can you list some things that increase/ decrease MAC…

Answer 28

Question 29

can you give examples of things that dont effect MAC?

Answer 29

Gender
anaemia

Question 30

Give an overview of the pharmacodynamics of inhaled agents…

Answer 30

CNS - hypnosis, amnesia, algesia. depression of sympatheic NS. Reduce cerebral metabolic rate + consumption, increase BF (uncoupling).

CVS - all drop SVR and hence MAP (except N20). isoflurane and desflurane increase HR and hence CO maintained. isoflurane has significant vasodilatory effects hence can cause coronary steel. sevoflurane causes mild myocardial depression.

Resp - desflurane and isoflurane are irritant and can cause bronchoconstriciton. sevoflurane causes bronchodilation - hence can increase dead space. all increase RR (esp des) but drop TV and overall drop MV. reduce sensitivity of brain to PaCO2 for increasing ventilatory response.

other
halothane is hepatotoxic
sevo can produce compound A theoretical risk of renal toxicity

Question 31

what are the properties of an ideal inhalation agents?

Answer 31

physiochemical
- liquid at room temp
- easily vapourises
- stable in light at room temp, long shelf life
- compatible with equiptment

pharmacodynamic
* quick onset - i.e. low B:G
* potent i.e. high O:G
* minimal side effects i.e. cardiovascularly stable, no resp depression, bronchodilation and non irritant, non epileptogenic
* additional benefits - analgesic, no N&V/ antiemetic

pharmacokinetic
* minimal metabolised
* fully exhaled
* no toxic products

environment
* cheap to make
* not a green house gas

Question 32

SVP and boiling point of desflurane

Answer 32

BP = 23.5
SVP = 89 kpa

Question 33

what is the concentration effect?

Answer 33

this is seen with N20 because it is inhaled in larger concentrations and is more water soluble than N2

therefore N20 will leave the alveolus, quicker than N2 returns. the volume of alveolus reduces, increasing the concentration of remaining N2 and hence speed of onset.

hence there is a disproportionate increase in speed of onset with 70% N20 compared to 20% N20

Question 34

what is the second gas effect?

Answer 34

this is the same as the concentration effect except for other agents…

volume of alveolus is reduced, increasing alveolar conc of other anaesthetic agent and hence its speed of onset.

this is why N20 is good for gas induction

Question 35

what is diffusion hypoxia

Answer 35

this is the reverse of the concentration effect except at the end of anaesthesia

for example…
at the end of anaesthesia, N20 will enter the alveolus rapidly (low B:G value). this dilutes O2 within alveolus. only clinically significant if breathing room air.
unlikely if 100% O2

Question 36

what is ether?

Answer 36

an ether is a chemical with carbon -oxygn - carbon bond
R-O-R

inhalation agents are often ethers.

the older anaesthetic agent called ether is Diethyl ether is still used in some remote areas of the world.

Question 37

what are the pros and cons of diethyl ether?

Answer 37

old inhalation ether
good for trauma - maintains MAP and RR and acts as analgesia. used in remote places

however is pungent, irritant and causes a cough, has high PONV incidence and slow onset/ofset and is more flammable

Question 38

discuss the environmental impact of inhaled agents..

Answer 38

all agents and equiptment used in anaesthesia uses resources and energy to produce.

inhaled agents have an added environemntal risk and risk to staff locally

environemntally
* greeenhouse gases - global warming
* some deplete ozone - N20

the most significant of these is desflurane due to its prolonged lifespan.

Question 39

what is meant by the global warming potential of an inhalation agent?

Answer 39

GWP - allows comparison of environmental impact of agents

the global warming effect of an agent depends on its infrared absorption band and its life span.
The inhalation agents are compared to the GWP of CO2 over 100 years where the GWP of CO2 over 100 years = 1

desflurane is 2500 becuase of its long life span (also des used in higher quantities due to high MAC)
sevo is 130
N20 is 300

Question 40

what methods can be used to reduce environemntal impact of inhalation agents?

Answer 40

low flow anaesthesia - circle system
agent selection - avoid N20 and des where possible
regional anaeshtesia / TIVA where possible
use of BIS to use lowest effective amount of agent

Question 41

what is low flow anaesthesia..

Answer 41

using a circle system, flows can be turned down and gases recycled as long as CO2 is absorbed using soda lime.
this limits the amount of new anaesthetic agent added to circuit to reduce waste and pollution

can use flows as low as 0.5L/min as long as adequate FiO2 (this is the limiting factor)

the advantage of this is that it is more environemntally friendly , plus lower costs

however
- slower changes can be seen so not ideal if want to quickly increase depth of anaesthetisa or at beggining / end of anaesthesia.
- slower flow means more likely for toxic compounds to devleop e.g. compound A
- soda lime needs changing more frequently
- risk of hypoxic mixture.

Question 42

what is malignant hyperthermia?

Answer 42

life threatening anaesthetic emergency
precipitated by inhalation agents and succinylcholine
it is autosomal dominant mutation in the ryanodine receptor

results in activation of ryanodine and uncontrolled Ca release, muscle contraction, tetany

this results in CO2 production, lactic acid, hyperthermia

break down of muscles - rhabdo, K+
sepsis picture / DIC

Question 43

how is MH tested for?

Answer 43

muscle biopsy - in vitro testing against halothane / caffeine.
genetic testing

Question 44

tell me about halothane hepatitis…

Answer 44

2 types of hepatic injury with halothane
mostly due to the fact that it is 20% metabolised so more metabolites build up in comparison to other inhaled agents…

type 1 = mild transient rise in liver enzymes due to production of free radicals from halothane metabolism

type 2 = autoimmune reaction to trifluroacetic acid. rare but has a mortality of 50% due to fulminant hepatitis. Ab made against trifluroacetic acid / hepatocyte complex and destruction of zone 3 (centrolobular necrosis)

Question 45

what are guedels stages of anaesthesia..

Answer 45

guedel was a physian who postulated 4 stages of anaesthesia ranging from being awake to deep brain stem anaesthesia

stage 1 = analgesia and amnesia
stage 2 = excitement phenomena and delirium
stage 3 = surgical anaesthesia - 4 planes ranging from loss airway reflexes, corneal refexes, loss of eye movmenet to relaxation and then apnoea.
stage 4 = deep brain stem anaesthesia

Question 46

at the beginning of anaesthesia, why may the MAC be 1.2 but the patient moves?

Answer 46

the MAC is measured by end tidal inhalation conc.
at the begining the end tidal PP is not equivalent to brain PP as equilibrium has not yet been reached.

can increase the conc and flow rate to overcome this.

Question 47

tell me about sevoflurane

Answer 47

commonly used halogenated ether inhaled anaesthetic agent
for both induction and maintainance

physical properities..
liquid at room temp, stored in polyethelene bottles and used by plenum vapourisers.
it has..
BP = 59 degrees.
SVP = 22.5
MAC = 2

pharmacokinetics
* A: via inhalation route - B:G 0.67 - relatively fast onset
* D: lipid soluble - transfers to most compartments
* M: minimal 3-5% . some fluride ions made.
* E: mostly exhaled

pharmacodynamics
- hypnosis
- CNS: increased blood flow, reduces demand (uncoupling)
- CVS: vasodilation, reduces HR and mild myocardial depression
- resp: sweet smell, bronchodilation, non irritatant. increase RR , drop TV, reduces CO2 sensitivity
- can trigger MH
- can produce compound A to E. A potentially nephrotoxic

Question 48

tell me about desflurane..

Answer 48

halogenated ether
inhalation anaesthetic, not commonly used anymore due to environmental impacts.

chemical properties
BP 23.5, liquid at room temp
SVP 89 - particularly volatile
needs a special Tec6 vapouriser

pharmacodynamics:
MAC 6.6
rapid onset = B:G 0.47
CNS - hypnosis, uncoupling
CVS - drops SVR and MAP. increase HR
resp - irritant, bronchospasm, breathholding. increase RR, drops TV, less sensitive to CO2

pharmacokinetics
A - inhalation, fast
0.02% metabolised
exhaled

Question 49

tell me about isoflurane…

Answer 49

halogenated ether, anaesthesia, particularly for cardiac bypass surfery

chemical properties
liquid at room temp
BP = 49, SVP 33

pharmacodynamics
CNS - hypnosis, uncoupling , MAC 1.17
onset - slower than sevo/des - B:G 1.4
CVS - drop SVR and hence MAP, increase HR. has significant vasodilatory effects hence can cause coronary steel.
Resp - irritant increase RR but drop TV

pharmacokinetics
0.2% metabolism

Question 50

tell me about halothane

Answer 50

halogenated hydrocarbon inhalation agent. no longer used due to problems with hepatitis.

physiochemical properties
liquid at room temp, SVP 32, BP 50
broken down by light so stored in dark bottle.

pharmacodynamics
- very potent with MAC 0.75 (O:G 225)
- slower in onset B:G 2.5
- causes hypnosis and anaesthesia..
- CNS - increased BF, drop in O2comsp, uncoupling
- CVS - drop in MAP / SVR , reduced contractility, sensitises catecholamines and can result in arrhythmias
- Resp - increase RR , drop in TV, reduced sensitivities to CO2. non irritant, sweat smell but too slow for induction. bronchodilator
- hepatitis
- MH risk

pharmacokinetics
- inhaled, uses plenum vapouriser
- 20% metabolism CYP2E1 - trifluroacetic acid

Question 51

what are the risk factors for halothane hepatitis

Answer 51

female
obesity
previous exposure
middle aged

Question 52

tell me about Xenon

Answer 52

inert inorganic nobel gas
causes anaesthesia with MAC 70%
has a safe profile with minimal CVS/ resp effects and no greenhouse effects
howeever is hard to obtain and therefore expensive.

presented as a colourless gas at room temp with no odour.
BP -108 degrees, SVP High , critical temp 16.5

works via NMDA antagonism
hypnosis and analgesia
less potent - MAC 70, O:G 1.9
rapid onset - B:G 0.14
increases CBF and is thought to be neuroprotective
minimal CVS effects
reduces RR and increases TV
increases density of gas - turbulent - increased work of breathing.

pharmacokinetics
inhaled , exhaled, not metabolised.

Question 53

can you tell me about N20..

Answer 53

inorganic gas that can be used as analgesic and anaesthetic agent in adjunct with others.
often used in laboour or for short painful proceedures or as a carrier gas for induction anaesthesia due to second gas effect.

physical properties
Stored under pressure in french blue cylinders as liquid in equilibirum with vapour phase
or as a gas in pipelines.
it has a BP of -88 degrees , critical temp 36.5 degrees and SVP of 5200. critical presure 72bar

works via inhibition of NMDA hence both as anaesthetic and analgesic agent
pharmacodynamics
- rapid onset but not so potent
- B:G 0.47, MAC 103, O:G 1.4
CNS: increase BF, reduced O2, uncoupling, proconvulsant
CVS - mild effects
Resp - reduced RV, increased RR, non irritant, can cause diffusion hypoxia.
GI - N&V
pressure - increases pressure of air spaced cavities e.g. increases size of pneumothorax, increases bowel cavity and inner ear.
long term - megaloblastic anaemia and subacutr combined degen of cord through inhibition of B12

pharmacokinetics
- inhaled, exhaled minimal metabolism

Question 54

what is entanox

Answer 54

50:50 mixture of N20 and O2 produced by poynting effect.
stored in checked french blue and white cylinders as a gas mixture at 137 bar or in pipeline 4bar.

useful in labour and short painful proceedures

uses a mouth piece and a 2 part presure regulator (demand valve) to allow user to apply suction for delivery.

Question 55

what is the poynting effect?

Answer 55

describes the bubbling of gaseous O2 through liquid N20 to create a gas mixture of N20 and O2 which has its own properties which are different to that of individual gases.
e.g. pseudocritical temp -7 degrees
below this, the gases will separate and liquify

Question 56

what are the advantages and disadvantages of entanox?

Answer 56

pros - quick onset, offset, minimal resp depression, CVS instabiltiy. since N20 MAC is very high, unlikely to cause anaesthesia / sedation. patient led - they can suck on the mouth piece when required

cons - N&V, short term analgesic effects, requires patient to understand how to use (e.g. not good in learning disability), dangers in pneumothorax etc. long term problems with B12.
plus environmental harm.

Question 57

how does nitrous oxide effect DNA synthesis…

Answer 57

oxidises colbolt ion in B12
such that becomes inaffective as a cofactor for methione synthase
reduces DNA replication

needed for RBC
needed for myelin

Question 58

what happens if an entanox cylinder is stored below -7 degrees…

Answer 58

O2 and N20 can separate
liquid N20 at bottom
gaseous O2 at top - initially delivered to patient
after hypoxic mixture when O2 used.

Question 59

why is N20 an issue environmentally

Answer 59

depletes ozone
has a global warming potential of 300
stays around in atmosphere for 100yrs and also is often used in large quantities due to low potency

Question 60

compare 2 inhalation agents..

Answer 60

draw a table
physical
pharmacodynamic
pharmacokinetics