Inhalants Flashcards
% Anesthetic = ?
% anesthetic = flow of anesthetic from vaporizing chamber/total gas flow
Anesthetic Uptake = ?
Anesthetic Uptake = S x CO x (PA-Pv/Pbar) where Pv = mixed venous blood, PA = alveolar concentration, Pbar = atmospheric pressure in mm Hg
Clearance
% clearance = 100 x VA /(agent blood/gas PC x CO + VA)
Panes ?
Panes = fractional anesthetic concentration x total ambient pressure
STP
0*C (273K), 760mm Hg (1atm)
1 atm = barr, mm Hg, Torr?
1 atm = 1 barr, 760mm Hg, 760 Torr
1 atm = psi, kPa, cmH20?
1atm = 14.7psi, 101.325kPa, 1030 cmH2O
1atm = ? dynes/cm^2
1atm = 1.013x10^6 dynes/cm^2
Saturated vapor concentration of a gas
= SVP/barometric pressure x 100%
Gas
agent that in gaseous form at room temp/ambient pressure (ambient conditions)
Vapor
gaseous state of an agent that is a LIQUID at ambient temperature
Critical Temperature
temperature above which substance cannot be liquified no matter how much pressure applied
Pseudocritical temperature
specific critical temperature at which a mixture will split into components
Vapor Pressure
pressure that vapor molecules exert when liquid/vapor phases in equilibrium
SVP
maximum concentration of molecules in vapor state for each liquid at each temperature, depends only on temperature
Saturated Vapor Concentration
max concentration of inhalant you can obtain at ambient conditions
o Calculation: SVP/Pressure of air x 100%
Boiling Point
temperature at which vapor pressure = atm pressure
Solubility
ability of an agent to dissolve in liquids, solids; application of Henry’s Law S=V*P
Partition Coefficient
concentration ratio that describes how inhalant ax will partition itself btw two phases at equilibrium
Avogardo’s Principle
equal vol of gas under same temp/pressure contain 6.02x10*23 molecules
Partial Pressure
individual pressure that each gas exerts in mixture of gases, application of Dalton’s Law
Blood Gas Partition Coefficient
predicts speed of induction, recovery, change in depth
Lower BG PC: less soluble in blood, faster induction/recovery/depth change
Higher BG PC: blood acts like a sink, increased solubility in blood, slower induction/recovery/depth change
Oil Gas Partition Coefficient
predicts potency
o Higher number potency, lower MAC
Which agents contain preservatives?
Sevo, halothane, methyoxyflurane
MW - desflurane
168g
MW - enflurane
185g
MW - Halothane
197g
MW - isoflurane
Same as enflur, 185g
MW - methyoxyflurane
165g
MW - N2O
44g
MW - sevo
200g
Specific gravity (20*C) (g/mL)- des
1.47
Specific gravity (20*C) (g/mL) - enflurane
1.52
Specific gravity (20*C) (g/mL) - halothane
1.86g/mL
Specific gravity (20*C) (g/mL) - isoflurane
1.49
Specific gravity (20*C) (g/mL) - methyoxyflurane
1.42
Specific gravity (20*C) (g/mL) - N2O
1.42
Specific gravity (20*C) (g/mL) - sevo
1.52
BP (*C) - des
23
BP (*C) - enflur
57
BP (*C) - halothane
50
BP (*C) - iso
48.5
BP (*C) - Methyoxyflurane
105
BP (*C) - N2O
-89
BP (*C) - sevo
59
VP mmHg at 20*C - des
700
VP mmHg at 20*C - enflur
172
VP mmHg at 20*C - halo
243
VP mmHg at 20*C - iso
240
VP mmHg at 20*C - methoxyflurane
23
VP mmHg at 20*C - sevo
160
VP mmHg at 24*C - des
804
VP mmHg at 24*C - enf
207
VP mmHg at 24*C - halo
288
VP mmHg at 24*C - iso
286
VP mmHg at 24*C - methoxyflurane
28
VP mmHg at 24*C - sevo
183
mL vapor/mL liquid at 20*C - des
209.7
mL vapor/mL liquid at 20*C - enflur
197.5
mL vapor/mL liquid at 20*C - halo
227
mL vapor/mL liquid at 20*C - iso
194.7
mL vapor/mL liquid at 20*C - methoxy
206.9
mL vapor/mL liquid at 20*C - sevo
182.7
Which agents are unstable in Sodalime?
Halo, sevo, methoxy
General MAC - des
6.5-8.5
General MAC - N2O
> 200
General MAC - Enf
1.6
General MAC - iso
1.3-1.6
General MAC - halothane
0.9-1.2
General MAC - methoxy
0.16-0.2
General MAC - ether
3-3.2
General MAC - sevo
2.3-2.6
VP Ether
425
BP ether
34.5
% metabolized - des
0.02
% metabolized - N2O
0.004
% metabolized - enfl
2-8
% metabolized - sevo
2-5
% metabolized - iso
0.2
% metabolized - methoxy
50
% metabolized - halothane
40-45
Inorganic inhalants
N2O, cyclopropane, xenon
Structure of most inhalants
= organic compounds
o Aliphatic – straight or branch chained hydrocarbons or ethers - 2 organic radicals attached to atom of oxygen with general structure ROR’
Why halogenation?
Addition of halogens - gas at room temp, R side of periodic table - Fl, Br, Cl
Less reactive, more potent, nonflammable
Cl, Br convert many compounds of low potency into more potent drugs
Fluorine
atomic # 9, weight 19
Bromine
atomic #35, weight 80
Chlorine
atomic # 17, weight 35
Atomic # vs atomic weight
Atomic # = # of protons
Atomic weight = # protons + # neutrons
Challenges with addition of fluorine atom
improves stability, but lowers potency, solubility
* Reduced solubility = lower potency, rapid equilibration
Halothane Structure
halogenated aliphatic ethane
o Halothane + catecholamines increased cardiac arrhythmias
o Incidence of arrhythmias reduced by ester linkage – chemical structure preserved across all inhalants developed since
Halothane Decomposition
decomposition, addition of thymol
Problem: thymol less volatile, accumulated in vaporizers, malfunction
Fl now used in place of Br, Cl - +shelf life, stability, can go without thymol
Fluorine ion: toxic to organs (kidneys) – only problematic if metabolized
Density
amt of matter or mass percent per unit vol
d=m/V
Dalton’s law
Partial pressure exerted by a gas is proportional to its fractional contents
Henry’s Law
Amt of gas dissolved in a liquid proportional to partial pressure of that gas at equilibrium with that liquid (blood gases)
Rauolt’s Law
Partial vapor pressure of each component in an ideal mixture of liquids = vapor pressure of each component x mole fraction in the liquid
Ideal Gas Law, principles
- Ideal gas molecules do not attract, repel each other - only interaction is elastic collision upon impact with each other or an elastic collision within walls of container
- Ideal gas molecules themselves take up no vol - gas takes up vol since molecules expand into a large space, but ideal gas molecules approximated as point particles that have no vol in and of themselves
Ideal Gas Law
PV = nRT
Boyle’s Law
At constant temp, vol of fixed amount of gas varies inversely with its pressure
PV=K –> P1V1=P2V2
Charle’s Law
At constant pressure, the vol of fixed gas varies directly with its absolute temperature
V/T = K –> V1/T1=V2/T2
TEMP IS IN KELVIN!!!
Gay Lussac’s Law
At constant vol, pressure of fixed amt of gas varies in proportion with absolute temperature
P/T = K –> P1/T1 = P2/T2
Partial Pressure
Individual pressure of each gas in a mixture of gas, absolute value
* Partial pressure of agent same in different compartments that in equilibrium with each other
Mole
relates number of molecules, quantity of a substance containing same number of particles as there are atoms in 0.012kg of carbon 12, Avogardo’s number 6.0226x1023 per gram molecular weight
Under STP…
number of gas molecules in 1gm of molecular weight = 22.4L
Specific Gravity
relative value, ratio of weight of unit vol of one substance to similar vol of water for liquids, vol of air for gases/vapors under similar conditions
Vapor Pressure
pressure exerted by vapor molecules when liquid, vapor phases in equilibrium
Some in surface layer gain sufficient velocity to overcome attractive forces btw neighboring molecules, escape from surface enter gas phase
Vaporization/evaporation: change in state from liquid to gas
Dynamic, in closed container at constant temp will reach equilibrium: # of molecules leaving = # of molecules entering
* Gas phase saturated
Saturated VP Concentration
Relates VP to ambient pressure
- Example: iso – max concentration at 20*C at sea level= 240/760 * 100 = 32%, 760 is sea level pressure
- If in Denver at 20*C, 635mm Hg: 240/635 = 37.8%
Saturated VP
maximum concentration of molecules in vapor state that exist for a given liquid at each temperature
unique to each agent, depends only on temperature – not ambient pressure
MOA Temperature Changes within a Vaporizer
o If temp of liquid increases: more molecules escape, enter gas phase–> greater number of molecules in vapor phase = greater VP, concentration
o If temp of liquid decrease: fewer molecules escape/more return to liquid phase = less VP, concentration
o Liquid cooling = natural consequence of vaporization process
‘Fastest molecules escape first, avg kinetic energy of those left behind decrease so temp decreases
As temp decreases, VP and vapor concentration decreases
Latent Heat of Vaporization
amount of energy consumed for a liquid to be converted to vapor, calories to convert 1g liquid to vapor without change in temperature
Specific Heat
calories required to increase 1g of liquid 1oC
Thermal Conductivity
measure of ability to conduct heat
o Copper, aluminum, brass»_space;> steel
Boiling Point
temperature of liquid at which VP = Patm (760 mmHg)
o Boiling point decreases at increased altitude, no change in vapor pressure but have change in barometric pressure
Critical Temperature
temperature above which substance cannot be liquefied no matter how much pressure applied
Molecular Weight
(aka molecular mass): mass of a molecule of a substance based on 12 as the atomic weight of carbon, summing anatomic weights of atoms in molecular formula
o Ex: H2O = H – atomic weight of 1, oxygen = 16 so MW of oxygen = 16
Triple Point
temperature, pressure at which solid, liquid, vapor phase all coexist in equilibrium
Ax solubility in blood, tissues
primary factor for rate of uptake, distribution within body –> primary determinant of speed of ax induction, recovery
Also influences how they dissolve in rubber goods on machine
Henry’s Law
total number of molecules of given gas dissolving in solvent depends on chemical nature of gas, partial pressure of gas, nature of solvent, temperature
Vol of gas (V) = partial pressure of gas (P) x Solubility coefficient (S)
* S = solubility coefficient for gas in solvent at given T(temperature)
* Applies to gases that do not combine with solvents to form compounds
Solubility in lipid
relationship to anesthetic potency
Low solubility = more rapid equilibration – determines speed of induction
Uptake = solubility x CO x [(PA-Pv)/Pbar]
solvent made up of mixture of gases
each gas dissolves in solvent in proportion to partial pressure of individual gases
o Total pressure exerted by all molecules
Three compartment model
Passive gradient from gas phase to oil: gas molecules move into oil compartment gradient develops for gas molecules in oil to move into water
At given temperature, when no more gas dissolves into oil (solvent) = fully saturated (equilibrium)
At equilibrium, pressures of gas in all three compartments will be the same
BUT # of molecules or volume of gas partitioned between two liquids will vary with nature of liquid and gas
What is the key about the three compartment model?
at equilibrium at given temperature, PRESSURE of gas in all compartments the same but actual # of molecules in compartments different
Less gas dissolves in a solvent as temp increases, more gas taken up as solvent temp decreases
* Ex: Gases become more soluble in blood when patient hypothermic
Solubility Coefficient
extent to which gas will dissolve in a solvent
Inhalants: usually expressed as partition coefficient (PC), concentration ratio of anesthetic in solvent and gas phases or btw two tissue solvents
* Describes capacity of given solvent to dissolve anesthetic gas
* Eg how anesthetic will partition itself btw gas and liquid solvent phases after equilibrium established
Movement of anesthetic gas
occurs bc partial pressure difference in gas, liquid solvent phases –> no partial pressure difference (equilibrium), no net movement
Blood Gas Coefficients Order
Nice dogs serve icy enchiladas (every) holiday meal BUT since blooD, des is actually first then nitrous - order of increasing BG coefficients
BG PC
predicts speed of anesthetic induction, recovery, change of ax depth
o Lower BG, faster onset
SOLUBILITY: inversely proportional to BG
Sevo is LESS soluble in blood than iso
OG PC
predicts potency
o Lower OG, higher potency
Nice dogs serve icy enchiladas (every) holiday meal
removal of ax from blood/tissues and solubility
- Solubility of tissue determines in part quantity of anesthetic removed from blood by tissue to which exposed
o Higher tissue solubility, longer it will take to saturate tissues with anesthetic
o All things equal: anesthetics that are very soluble in tissues require LONGER period for induction, recovery
Coefficients of Rubber, Plastic
- If amt of rubber goods used in apparatus used to deliver ax to patient is substantial/anesthetic agent very soluble in rubber, amt of uptake of agent by rubber may be significant less important with current equipment
What does ax depth directly vary with?
with Panes in brain tissue
Pharmacokinetics of anesthetics
o Move down a series of pp gradients from higher to lower tension until equilibrium
Vapor pressure in vaporizer patient breathing circuit –> lungs –> arterial blood –> tissues
* At induction, Panes at vaporizer is high, progressively decreases as go down chain
PA(anes)
is pivotal: usually GE at alveolar level efficient such that PAanes = Paanes
Brain = highly vascular, rapidly equilibrates with Pa anes
* By controlling PAanes, reliable indirect control of Pbrain anes
Essentially: PAanes = Paanes = Pbrainanes
Panes = fractional anesthetic concentration x total ambient pressure with fractional anesthetic concentration Canes/100
* In blood or tissues, actual quantity of anesthetic depends on: Panes, anesthetic solubility as determined by PC within solvent (blood or oil)
* At equilibrium, partial pressure of gas in alveoli and among tissue compartments will be equal BUT concentrations will vary among tissues
Factors that Determine PA of anesthetic
- Increased alveolar delivery via increased ax concentration, increased alveolar ventilation
- Decreased removal from alveoli
Ax: uptake - increased alveolar delivery from increased inspired ax concentration
- increased vaporization of agent
- increased vaporizer dial setting
- increased FGF
- Decreased gas vol of patient BC
Ax update - increased alveolar ventilation
- increased minute ventilation
- decreased dead space ventilation
Ax update - decreased removal from alveoli
- decreased blood solubility of ax
- decreased CO
- decreased alveolar-venous ax gradient
Delivery to alveoli
Balance btw anesthetic input (alveolar delivery), loss (uptake by blood/tissue)
Inspired Concentration
Upper limit dictated by SVP, dependent on temperature
Characteristics of patient BS also important: volume, amt of rubber/plastic, position of vaporizer (VIC vs VOC), FGI
Characteristics of patient breathing system (volume, material (i.e. rubber, plastic etc), position of vaporizer (inside or outside of circuit), fresh gas inflow
Vol of Circuit and Effect on Inspired Concentration
- BC contains gas vol that must be replaced with gas containing desired anesthetic concentration buffer that delays rise of anesthetic concentration
o Small animals with NRB: high FGF should not differ from vaporizer setting
o Larger animals on circle – volume may be large compared to FGF – marked delays/must wash out, rebreathing expired gas with less anesthetic than FGF, expired gas contains less anesthetic than FG, inspired gas concentration will be less than FG leaving the vaporizer
Horses, cattle, closed circuit FGF (FGI low vs circuit vol)
Equipment
High solubility of some anesthetics (methoxyflurane) in rubber, plastic delays development of appropriate inspired anesthetic concentration
* Loss of anesthetic to these equipment ‘sinks’ s apparent vol of circuit, clinically important
* No longer relevant with current inhalants used
VIC, Inspired Concentration of Inhalants
VIC: increased FGF into circuit decreases Fi (no flow compensation, decreased SA
VOC, Inspired concentration of inhalants
increased FGF will increase Fi (technically increases RATE of delivery) so reaches equilibrium with FA faster
Effect of hypoventilation on ax induction
decreased rate at which alveolar concentration changess over time vs Fi – slower induction, slower changes
Second Gas Effect
administration of potent inhalant eg N2O can speed uptake of concurrently administered inhalant agent
Increases rate of rise of alveolar concentration
Removal from alveoli/uptake by blood
Eger: anesthetic uptake product of 3 factors – solubility (S; BG PC), cardiac output (CO), difference in anesthetic partial pressure btw alveolus, venous blood returning to lungs (PA-Pv/Pbar) where Pbar = barometric pressure (mm Hg)
Effect of Solubility on removal
Solubility of inhalation anesthetic in blood, tissues characterized by partition coefficient (PC)
* How inhalation agent distributes btw two phases or two solvents eg quantity of agent in blood and alveoli, or btw blood and muscle once equilibrium established
Agents with low blood solubility…
more rapid equilibration, smaller amount of anesthetic must be dissolved in blood before equilibrium reached with gas phase
Agents with high blood solubility…
blood acts like large sink into which anesthetic is poured, reluctant to give up to other tissues including brain
* Pharmacologically inactive reservoir interposed btw lungs, brain
Effect of CO
Greater CO more blood passing through lungs carrying anesthetic away from alveoli delays rise of PA anes
* With greater CO, such as with excitement, delay onset
* Inhalant cleared away faster
Decreased CO, PA anes will rise more quickly
Remember, gas movement is all about pressure gradients
Alveolar to venous anesthetic partial pressure difference
Magnitude of difference in anesthetic partial pressure btw alveoli, mixed venous blood returning to lungs related to amt of uptake of ax by tissues
Largest gradient during induction
Once equilibrium reached, tissues no longer absorb anesthetic/no longer tissue uptake from lungs mixed venous blood returning to lungs contains as much anesthetic as when left lungs - Pv=PA
Distribution of CO
- Brain, heart, hepatoportal system, kidneys receive ~75% total blood flow per minute –> rapidly equilibrate with Pa anes compared to other body tissues
- Skin, muscle = 50% body in humans, at rest receive 15-20% CO – saturation of tissues takes hours to accomplish
- Fat = poorly perfused, saturation is slow, anesthetics more soluble in fat than other tissues
Clearance
% clearance = 100 x VA (agent blood/gas PC x CO + VA)
o Affected by alveolar ventilation, CO, agent sol***
Wash out of less solub agents high at first DT lung FRC then rapidly declines to lower output level, continues to decrease but at slower rate
Wash out of more solub agents also high at first but magnitude of decrease less, decreases more gradually with time
Other Important Factors in Elimination
Percutaneous loss
Intertissue diffusion of agents
* Limited clinical important
Metabolism
* Methoxy, maybe halothane
Transcutaneous movement of inhalation agent
* Small amt
What is the most important factor in wash out?
DURATION OF AX
o Rebreathing circuits: circuit may reduce rate of recovery bc need to wash out inhalant, can reduce via high FGF of O2 only
Essentially use RBC as NRB
Other names for diffusion hypoxia?
Fink Effect, Third Gas Effect
Diffusion Hypoxia
at end of giving N2O, patient goes to room air – lrg vols N2O return from blood to lung, displace other gases in lung esp oxygen
If on room air (21% oxygen), N2O will dilute alveolar oxygen: decreased PaO2 from levels found in room air life threatening hypoxia
Mitigate by 100% oxygen for 5-10min after discontinuation if N2O
Biotransformation
o Most inhalation anesthetics not chemically inert, varying degrees of metabolism
Primarily liver, lesser in lung, kidney, GIT
o Metabolism: may facilitate in recovery of anesthesia, may result in acute/chronic toxicities from intermediate or end metabolites
Magnitude: by chemical structure, hepatic enzyme activity (cytochrome P450 in ER of hepatocyte), blood concentration of anesthetic, disease states, genetic factors.
Metabolism
Least N2O, most methoxy
Never deny iguanas sunny eateries (that) have mangos.
Factors that Favor Elimination
- Increased alveolar ventilation
- Decreased CO
- Decreased BG PC
- Decreased Duration of GA
Factors that Increase Ax Uptake
Agent Vaporization
Vaporizer Setting
Increased FGF
Increased MV
Factors that Decrease Ax Uptake
Increased vol of breathing circuit
Increased dead space volume
Lower BG PC
Lower CO
Lower arterial-venous anesthetic gradient
MAC
- 1963 Merkel and Eger made the standard index of anesthetic potency: MAC
o Minimum alveolar concentration of an anesthetic at 1 atm that produces immobility in 50% of subjects exposed to a supramaximal noxious stimuli
o Corresponds to the effective dose50 (ED50)
o ED95 (humans) 20-40% > MAC
How is MAC related to potency?
- Anesthetic potency = 1 / MAC
o MAC is inversely related to oil/gas PC
o Very potent anesthetic like methoxy (high oil/gas PC) has a low MAC
o Agent with low oil/gas PS = high MAC
How MAC determined?
Healthy patients without any other influence of drugs
MAC determination - people
initial noxious stimulus = skin incision
MAC determination - SA
o SA (mice to dogs, pigs): forceps or other surgical instrument to tail base or base of dewclaw
In dogs, ovarian/ovarian ligament traction sevoflurane MAC vs tail clamp
MAC(awake)
humans on emergence, MAC in which humans open eyes after verbal stimulus (coined by Stoelting)
o Verbal stimulus less intense than surgical incision, response occurs at lower concentration of ax than movement following incision
MAC - BAR
MAC required to not have increases in catecholamines when skin incision made
MAC of N2O
o Because nitrous MAC > 100%, cannot be used by itself at one atmosphere pressure in any species and still provide adequate amounts of O2
o Usually administered with another mower potent agent to reduce concentration of that more potent agent necessary for anesthesia
MAC Reduction of dogs vs humans
o Significantly less MAC reduction in dogs vs humans: 60% N2O with halothane = 55% decrease in healthy humans vs 20-30% in dogs
ED50
1MAC, light plane of ax
MAC-awake
voluntary responses, awareness
MAC 0.3-0.5
MAC 1
Prevent movement to sx stimulus in 50% of population, ED50
MAC1.3
Prevents movement in 95% of individuals, prevents response to tracheal intubation - ED95
MAC1.7-2.0
MAC-BAR: blunts autonomic response to sx stimulus
MAC and Apneic Index
Apneic Index = 1.5-3MAC
CV collapse
2.7-3MAC
Factors that Increase MAC
Drugs that cause MAC: amphetamine, ephedrine, morphine (horses), laudanosine, physostigmine
Hyperthermia
Hypernatremia
No change in MAC
ABP >50mmHg
Atropine, glycol, scopolamine
Duration of ax
Gender
Hyper/hypokalemia
Metabolic AB change
PaO2 >40mmHg
PaCO2 15-95mmHg
CNS
o Reversible, dose-related state of CNS depression (somatic, motor)
o Hemodynamic, endocrine unresponsiveness to noxious stimuli
o Exact MOA unknown
Influence electrical activity of brain, cerebral metabolism, cerebral perfusion, ICP, analgesia
Molecular Mechanism
- Meyer-Overton
- Cantor
Meyer-Overton/Critical Vol Hypothesis
strength of inhalants based on lipid vs water affinity: oil:water partition coefficient
Cell lipid membrane = site of action
Limitations: does not explain effect of differences btw stereoisomers, ax cut off effect or non-immobilizers
Cantor Hypothesis
may alter molecular composition, forces within bilayer plane –> change within lateral pressure profile exerted upon proteins in lipid membrane
Non-immobilizers: may not access interfacial regions of membrane critical to modulation of embedded protein R
Ion channels/membrane lipids: chiral centers that may interact differently with anesthetic stereoisomers
Fills in gaps of Meyer-Overton
protein theories
Inhaled anesthetics bind proteins, modulate function in absence of lipid environment
Potentiate inhibitory target cells: GABAA, glycine, two pore domain K channels
Inhibit excitatory cell targets: NMDA, AMPA, nicotinic R, VG Na channels
Inability to identify R for anesthetic action –> multiple cell R, ion channel target modulation
Site of action in brain
cerebral cortex, amygdala, and hippocampus hypnosis, amnesia
* Amnesia= amygdala and hippocampus
* EEG: hippocampal-dependent -rhythm frequency slows to amnestic effects with subanesthetic doses of iso
* alpha4, beta3 subunits of GABA partly responsible for iso depression
* Mice: antagonism of 5 subunit-containing GABAA R restores hippocampal-dependent memory during sevo
* GABAA vs TREK-1 K+ channels
Spinal Cord
critical site for suppressing noxious-evoked movement (immobility)
* Principally responsible for preventing movement during surgery with inhaled anesthetics
* NMDA, glycine receptor antagonism
* Depression of locomotor neuronal networks located in ventral horn
Analgesia assoc with xenon, n2O:
Supraspinally DH of SC
analgesia via glutamatergic R inhibition, inhibit NMDA receptors and K2P/TREK1 receptors
o Additional modulation of noradrenergic opioid R pathways
o Ca channels: decrease Ca available and responsiveness – BP and negative inotropic effects (not true with xenon
N2O, xenon: 0.8-1MAC…
decreased but do NOT prevent wind-up/central sensitization
o No benefit of higher concentrations
N2O, Xenon: 0.4-0.8MAC…
decreases withdrawal responses to noxious stimuli, but can actually cause hyperalgesia
o Peak effect at 0.1MAC
o Potent nicotinic cholinergic R inhibition
5HT3
Autonomic effects
EEG Effects
No parameter has sensitivity/specificity to justify use of EEG alone as reliable index of ax depth
* Improvements in technology: Bispectral index
As depth of ax increases, cerebral cortex becomes desynchronized - decreased in frequency, increase in EEG activity
EEG Effects and MAC
increased frequency of EEG activity ~0.4MAC
wave amplitude increases then progressively declines ~1MAC
Burst suppression ~1.5MAC
Isoelectric activity (flat late) at ~2.0MAC iso, servo, des; 3.5 halothane
Enflurane and EEG
spontaneous or noise-initiated sz in dogs, people
o Substantial increases in cerebral blood flow, CMO2
Cerebral Metabolism
all decrease cerebral metabolic rate (CMR), least with halo
CBF
–Either no change or increase - dose-related VD from ax, decreased CMO2
Halothane (greatest) > N2O > enf, iso, des > sevo (least)
* N2O: severe vasodilation
* increased CBF –> increase blood brain vol, ICP
* Most likely DT time-dependent increase in NO synthase inhibition
Horses: regional CBF constant over wide range of CPPs despite changes in ICP
Loss of Cerebrovascular Autogregulation
uncoupling of CP from CMO2
o 0.5MAC: diminished, obtunded
o High MACs: cerebrovascular autoregulation very diminished –> CBF simply function of CPP
o Effects on CBF = duration-dependent
Sevo: best at maintaining cerebral autoregulation
CO2 Tension and Autoregulation
- Autoregulation lost, CBF increases at lower MAC when patients hypoventilate
- Interaction greater with iso + CO2 than sevo + CO2
ICP
Increases DT increased CBF
* Regardless of species, cerebrovascular autoregulation better preserved at MAC-multiple of halothane ax when hyperventilation maintained, PaCO2 decreased
Respiratory Effects
–Decreased SpV as dose increases: VT>RR
–Decreased minute ventilation, increased dead space ventilation (increased VD/VT >0.3-0.5)
–Hypercapnia DT depression of alveolar minute ventilation, stimulation of ventilation by central and chemoR blunted
–Bronchospasm
–Respiratory depression worsened with concurrent drugs
Bronchospasm and Inhalants
–BD DT decreased cholinergic transmission
–iso, +/- enflurane, sevo, des: relaxation of constricted bronchial SmM least equal to or exceeds that caused by halothane via inhibition of M3
–Airway irritation: desflurane at >7%, lesser extent with iso
Factors Influencing Respiratory Effects
- Ventilation - assisted not usually effective in substantially lowering PaCO2, CMV best
- Duration of ax: higher MAC for prolonged periods = significant temporal increase in PaCO2
- Respiratory depression blunted by sx, noxious stimulus - effect diminishes at increased deoth
Cardiac Effects
Myocardial depression (interference with Ca), decreased symapthoadrenal activity
Decreased CO = dose dependent, DT decrease in SV from decreased myocardial contraction HALOTHANE
–Also affected ABP
Variable effects on HR
Cardiac Dysrhythmias, Catecholamines
Increased automaticity of myocardium, increased likelihood of propagated impulses from ectopic sites (especially ventricle)
* Newer ether-derived agents: do not predispose heart to extrasysoles
Spontaneous dysrhythmias- halothane
* Markedly decreases amount of epi necessary to cause VPCs
Halothane > Enflurane, methoxy > des, sevo iso
ALL agents exaggerate adrenergic agonist associated dysrhythmias
Factors Influencing Circulatory Effects
- Mode of Ventilation/PaCO2 - CV usually depressed during IPPV
- Noxious Stimulation - blocked at MACbar/MAC1.5-2.0
How IPPV Depresses CV Activity
Direct mechanical action (increase intrathoracic pressure, resultant decrease in venous return to heart)
Indirect (pharmacologic action of PaCO2)
o Increase PaCO2 = direct depression of heart, SmM of peripheral blood vessels (dilation)
Indirect (via sympathetic activity) stimulation of circulatory function
CV Effects of Other Drugs
MAC reduction –> decreased CV effects
N2O may directly depress myocardium, counterbalanced by sympathomimetic effect - net improvement of CV function
Kidneys
All useful agents: similar, mild, reversible dose-related decrease in renal BF, GFR –> anesthesia-related decrease in CO
Smaller vol concentrated urine vs awake
increased BUN, creatinine, inorganic phosphate may accompany prolonged ax
Renal function reduction highly influenced by hydration, hemodynamics during GA
Mitigated by IVF, prevention of marked reduction in renal BF
Methoyxflurane and Nephrotoxicity
Renal failure characterized by polyuria unresponsive to VP n
MOA: biotransformation of methoxyflurane, large release of free fluoride ions
* Peak levels, prolonged exposure DT high adipose accumulation during ax
Free fluoride ions cause direct damage to renal tubules
Reported in dogs in conjunction with tetracycline, banamine
Enflurane: also able to produce fluoride ions, above nephrotoxic threshold in humans but not seen
Sevoflurane and Fluorine Ion Induced Nephrotoxicity
–Production of FI ions in humans > nephrotoxic threshold
–Histological, clinical, biochemical evidence of injury rare
Why Sevoflurane Lacks Nephrotoxicity vs Methoxy
Area under serum fluoride concentration vs time curve may more important determinant of nephrotoxicity than peak serum fluoride concentrations
o Sevo = poorly soluble, rapidly eliminated by lungs
o Duration of availability for biotransformation limited
Hepatic metabolism vs methoxy = hepatic, renal
o Lack of intrarenal ax defluorination may markedly reduce nephrotoxic potential
o Horse: increase serum fluorine, magnitude/time course of increase similar to humans, no evidence untoward renal effects
Compound A Production
degradation of sevoflurane by CO2 absorbents
Nephrotoxic = renal injury, death in rats
Proposed MOA: species-specific metabolic degradation to directly nephrotoxic compounds
most commercially available absorbents in US no longer contain KOH, NaOH
Baralyme>Sodalime, not Amsorb
Hepatic Effects of Inhalant
–hepatocellular injury DT decreased HBF, DO2
Isoflurane better maintains O2 delivery, agent less likely to cause hepatocellular injury
–Iso >/~ Sevo, Des»_space;> Halothane
Cofounding factors: N2O, concurrent hypoxia, prior induction of hepatic drug-metabolizing enzymes, mode of ventilation, PEEP
* May worsen conditions, likelihood of hepatocellular damage
Halothane Hepatic Effects
- Inhibition of drug metabolizing capacity
- Mild, self-limiting hepatocellular damage
- Halothane hepatitis - fatal immune-meditated toxicity
Malignant Hyperthermia
Pharmacogenetic myopathy via activation of RYR1 – swine, horses, dogs, humans
Halothane = most potent triggering agent, can be any volatile anesthetic
o Rapid rise in cellular metabolic activity, death if not treated quickly
o Monitoring of temp, CO2 production, other signs of metabolic imbalance IE ABG warranted and susceptible, suspected patients
Avoid triggering agents, prophylactic tx with dantrolene
Pigs Most Susceptible to MH
Pietrain, Landrace, Poland China Pigs
Clinical Signs MH
muscle rigidity, hyperthermia with 1*C increase Q5min, tachyarrhythmias, tachypnea
ABG Changes Assoc with MH
metabolic acidosis, hypercapnia, base deficit >8mEq/L, hyperlactatemia, hyperkalemia
Treatment for MH
active cooling, CMV, TURN OFF VAPORIZER, HCO3 PRN (0.3kgsdesired change), switch circuits, TIVA or xenon, dantrolene 5mg/kg IV or 10mg/kg PO via stomach tube
N2O
low blood solubility, limited CV/resp system depression, minimal toxicity
o Not potent – MAC humans 100%, dogs 188%, cats 255%- will not anesthetize healthy individual as solo agent
Main benefit: allow reduction of primary more potent inject/inhal
As concentrations of N2O increases, change in proportion, partial pressure of other constituents of inspired breath esp O2
No more than 75% N2O to avoid hypoxemia (usually 66%)
>sea level, lower N2O to ensure adequate PIO2
Nitrous Second Gas Effect
Very low blood solubility = rapid onset
Large vol of N2O leaves alveoli, allowing for concentrating effect of second gas to create faster induction
High concentration of N2O administered concurrently in mixture with inhalation agent, alveolar concentration of simultaneously administered anesthetic increases more rapidly than when ‘second’ gas administered without N2O
Contraindications for N2O Use
ruminants/horses, pneumothorax, GDV, FB, air embolism, cavotomy , esophageal FBs
Systemic Effects of Nitrous
-Direct myocardial depression, counteracted by SNS stimulation - increased BP, arrhythmias
-Little effects on resp, kidney, liver
Elimination N2O
rapid, exhaled breath
Biotransformation to molecule N2 very small, mainly by intestinal flora
Effect of Inhalants on Uterine Tissue
o Decreases uterine SmM contractility, BF
SE N2O
- Prolonged exposure = megaloblastic hematopoiesis DT interference with RBC/WBC production by BM
- Polyneuropathy
- Vascular inflammation
- Induced inactivation of vit B12-dependent enzyme methionine synthase via oxidation of cobalt from B12 - interruptions of folic acid metabolism
- Abuse potential
- Interference with some respiratory monitoring
N2O Transfer to Closed Spaces
When N2O introduced into inspired breath, re-equilibration of gases in gas spaces
N2O quickly enters, N2 slowly leaves
–N2O = 30x more soluble in blood (BG PC 0.47): vol of N2O that can be transported to closed gas space many times vol of N2 can be carried away (BG PC 0.015)
Result: net transfer of gas to gas space as increased in vol with gut, pneumothorax, blood embolus; increased pressure; pneumocephalogram,
Where does N2O go in the body?
ETT
Gut
Middle Ear
Sinuses
Diffusion Hypoxia
Lrg vol N2O stored in body during ax, unequal exchange of N2O for N2, deficiency in blood oxygenation may occur at end of ax if abrupt substitution of air for N2O
Rapid outpouring of N2O from blood into lung = transient but marked decrease in PAO2
Diffusion Hypoxia
Lrg vol N2O stored in body during ax, unequal exchange of N2O for N2, deficiency in blood oxygenation may occur at end of ax if abrupt substitution of air for N2O
Rapid outpouring of N2O from blood into lung = transient but marked decrease in PAO2
What is the NIOSH limit for inhalant exposure?
2.0ppm
What is the NIOSH limit for N2O?
25ppm
Role of Contemporary volatile anesthetics as green house gases
Stratospheric ozone layer known to be damaged by rapid, widespread global usage and subsequent atmosphere presence of volatile, synthetic, long lived organochlorine and bromine containing compounds = chlorofluorohydrocarbons, CFCs
All contemporary volatile anesthetics = potentially destructive to ozone layer as halogenated compounds
In effect only chlorine containing halothane, isoflurane (less so)
* Relative contribution of these two volatile agents estimated at most 0.01% of annual global release of CFC’s
Substances that contain only fluorine do not harm the ozone layer
N2O Environmental Effects
Emission highlighted as single most important ozone depleting emission, expected to remain largest throughout 21st century
Long atmospheric lifetime so contributes to warming as well as ozone depletion
Which two inhalants have the most significant environmental effects?
Des, N2O
Desflurane Environmental Effects
has highest heat trapping effects, now removed from markets in some countries
MAC Basis: desflurane»_space;> iso > sevo
Ozone depleting potential of inhalants
o Iso, halothane = chloroflurocarbon, ozone depleting capacity
Des, sevo = hydrofluorocarbons, no ozone depleting potential
N2O: ozone depleting potential
Xenon
–Inert noble gas, MAC 71%
–No compounds, no biotransformation - requires prolonged denitrogenation
–BG PC 0.14 –> rapid induction
–CV safe, no potential to induce MH
–Used for contrast imaging, neuroprotectivity
–Not FDA approved - research only
Xenon MOA
post synaptic NMDA R blockade at K2P - decreases in excitatory neurotransmission
