Transcript INHALED ANESTHETICS

INHALED ANESTHETICS AND
GASES
HISTORY
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Horace Wells administered N2O for dental
extraction in 1844
William Green Morton demonstrated use of
ether for surgical anesthesia on October 16,
1846 at MGH
“ Inventor and revealer of anesthetic inhalation
Before whom in all time, surgery was agony.
By whom pain in surgery was averted and
annulled.
Since whom science has control of pain”
KEY TOPICS
Potency or MAC
 Factors affecting uptake and distribution
 Effects on various organ systems
 Metabolism and toxic effects
 N2O and Xenon
 Mechanisms of action
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STRUCTURE OF DIETHYL ETHER
F
H
F – C – C* – Br
N=N=O
F
Nitrous Oxide
H
F
F– C – C* – O – C – H
F
Cl
F
F
F
F
F
H H
F
C O
F
Enflurane
C
C F
C
F
Isoflurane
H
Halothane
F
F
Cl – C* – C – O – C – H
Cl
F
F
F
H
H
F
F – C – C* – O – C – H
F
F
F
F
Sevoflurane
Desflurane
ANESTHETIC POTENCY
MAC
 MAC awake: 0.3 MAC
 MAC BAR: 1.5XMAC
 MAC intubation: 2XMAC
 Alveolar concentration represents brain
concentration after a short period of
equilibration
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FACTORS AFFECTING MAC
Temperature: ↓ 2%-5% for 1 0C ↓ temp.
Age: Maximum at 6 months;↓6%/decade
CNS catecholamine stimulation:↑ MAC
Benzodiazepine, opiates,alpha-2 agonists:↓MAC
Inhaled anesthetics: additive effect
1% N2O decreases MAC by 1%
 Pregnancy: ↓ MAC
 Ethanol: acute ↓MAC, chronic ↑ MAC
 Metabolic acidosis, hypoxia, hypotension:↓ MAC
 Hypernatremia:↑MAC
 Hyponatremia, hypermagnesemia: ↓MAC
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MAC, BP,VAPOR PRESSURE
Halothane
Enflurane
Isoflurane
mmHg
Sevoflurane
Desflurane
mmHg
N2O
Xenon
MAC
0.77
1.7
1.15
BP(0C) VP (200C)
50.2
241 mmHg
56.2
175 mmHg
48.5
238
2.0
6.0
58.5
23
104
71
160 mmHg
664
UPTAKE AND DISTRIBUTION
Goal: To develop and maintain a satisfactory
partial pressure or tension of anesthetic at the
site of anesthetic action in brain
 Delivered>Inspired>Alveolar>Arterial>Brain
 Concentration= Partial pressure/barometric
pressurex100
 Brain with its high perfusion per gram rapidly
equilibrates with anesthetic partial pressure in
blood
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Nitrous oxide
1.0
Desflurane
Sevoflurane
FA/F1
Isoflurane
Halothane
0.5
0
0
10
20
Anesthesia administration (min)
30
Human Blood/Gas and Tissue/Blood Partition Coefficients (Mean±SD)1-4
Tissue
Desflurane
Sevoflurane
Isoflurane
Halothane
Blood
0.42±0.02
0.69±0.05
1.46±0.09
2.54±0.18
Brain
1.3±0.1
1.7±0.1
1.6±0.1
1.9±0.2
Heart
1.3±0.2
1.8±0.2
1.6±0.2
1.8±0.3
Liver
1.3±0.1
1.8±0.2
1.8±0.2
2.1±0.3
Kidney
1.0±0.1
1.2±0.2
1.2±0.2
1.0±0.2
Muscle
2.0±0.6
3.1±1.0
2.9±1.0
3.4±1.4
Fat
27±3
48±6
45±6
51±10
UPTAKE AND DISTRIBUTION
Balance between the delivery of anesthetic and
its removal by uptake or metabolism
determines FA/FI ratio at any given time after
administration of inhaled anesthetic
 The rate of rise of alveolar concentration (FA)
toward inspired concentration (FI) or FA/FI ratio
determines speed of induction of anesthesia
1. Alveolar ventilation
2. The inspired concentration (concentration
effect)
3. Second gas effect
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Ventilation lit/min
8
4
2
1.0
Nitrous oxide
8
Halothane
4
8
0.5
2
Diethyl ether
4
2
00
0
20
40
Anesthesia administration (min)
60
UPTAKE AND DISTRIBUTION
Concentration Effect: The inspired
anesthetic concentration also determines
the rate of rise of alveolar concentration
toward inspired concentration (FA/FI)
ratio. The greater the inspired
concentration, the more rapid is the rate
of rise in FA/FI ratio. It results from two
factors:
1. A concentrating of the residual gases
2. Increase in inspired ventilation
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UPTAKE AND DISTRIBUTION
Second Gas Effect: Factors governing
concentration effect also influence
concentration of any gas given concomitantly
with N2O (Second gas effect). It results from
two factors:
1. The loss of volume associated with N2O uptake
concentrates the second gas
2. Replacement of the gas taken up by an increase
in inspired ventilation augments the amount of
second gas in the lung.
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C
1% of
second gas
B
1.7 % of
second gas
A
1% of
second gas
31.7 % O2
19 % O2
Uptake of
half of
the N2O
Absorbed
gases
replaced by
added
ventilation
66.7 % N2O
19 % O2
40% N2O
80% N2O
0.4% of second gas
7.6% O2
32% N2O
Anesthesia administration (min)
1.0
65% N2O
Desflurane in
65% N2O
0.9
FA/F1
5% N2O
0.8
Desflurane in
5% N2O
0
0
10
20
UPTAKE AND DISTRIBUTION
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Anesthetic Uptake Factors: Solubility x Cardiac
output x Alveolar to venous partial pressure
difference.
Solubility: Primary factor that determines FA/FI
ratio
Blood/gas partition coefficient: Relative affinity
or partitioning of an anesthetic between two
phases at equilibrium.
Larger blood/gas partition coefficient→ more
solubility→greater uptake→↓ FA/FI ratio
Cardiac output: ↓ Cardiac output→ ↑FA/FI ratio
PARTITION COEFFICIENT OF NITROUS
OXIDE
UPTAKE AND DISTRIBUTION
Alveolar to venous anesthetic gradient
depends on tissue uptake.
 Tissue uptake:
1. Tissue solubility (tissue/blood partition
coefficient)
2. Tissue blood flow
3. Arterial to tissue anesthetic partial
pressure difference
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Tissue group characteristics
Tissue Group
Characteristic
Vessel-Rich
Muscle
Fat
Vessel-Poor
Percentage of body mass
10
50
20
20
Perfusion as percentage of cardiac output
75
19
6
0
UPTAKE AND DISTRIBUTION
Tissue Groups:Three tissue groups form depots for
anesthetic within the body.
 Vessel rich group (VRG) : Brain, heart, splanchnic bed,
liver, kidney and endocrine
 Equilibrates with blood in 4-8 minutes
 Muscle group (MG) : Muscle and skin
 Equilibrates with blood in 2-4 hours
 Fat group (FG) : Equilibration: 70-80 min for N2O
30 hours for sevoflurane
 Vessel poor group (VPG)) : Bone , cartilage, ligaments,
tendons-no uptake
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RECOVERY FROM ANESTHESIA
Recovery correlates with fall in alveolar concentration
 Solubility: Low solubility→Rapid recovery
 Desflurane>Sevoflurane>Isoflurane
 Duration of anesthesia
 MAC awake:Varies with different anesthetics
 MAC awake of N2O> Inhlaled anesthetics
 Lower MAC awake: More amnestic the agent
 Metabolism:Alveolar washout of halothane more rapid
than enflurane
 Residual gases in the anesthetic circuit.
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CARDIOVASCULAR EFFECTS
Systolic and Diastolic Function:
 Dose related negative inotropic effect
 Halothane=Enflurane>Isoflurane=Desflura
ne=Sevoflurane
 Dose related prolongation of isovolemic
relaxation, early LV filling and filling
associated with atrial systole
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CARDIOVASCULAR EFFECTS
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Systemic Hemodynamics:
Depress baroreceptors.
No change in CI except halothane (↓CI)
Desflurane 1 MAC→1.5 - 2 MAC ↑ HR and
BP
Sevoflurane 1 MAC→1.5 - 2 MAC ↓ HR or no
change
Isoflurane –Intermediate effect
All cause concentration related decreases in BP
Sevoflurane, desflurane, isoflurane→↓ SVR
Halothane, enflurane→ Myocardial depression
CARDIOVASCULAR EFFECTS
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Epinephrine induced arrhythmias:
Halothane arrythmogenic
Other agents safer
Coronary Steal:
Coronary vasodilataion with isoflurane may
cause detrimental redistribution of coronary
blood flow away from ischemic myocardium
with hypotension leading to coronary steal
No coronary steal if hypotension avoided
CARDIOVASCULAR EFFECTS
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Myocardial Protection:
Protect against reversible and irreversible
ischemia
Reduce the infarct size
Decrease myocardial reperfusion injury and
improve functional recovery after global
ischemia
Activation of intracellular transduction
pathways involving A1 receptors, PKC, G
proteins and mitochondrial or sarcolemmal
KATP Channels
PULMONARY EFFECTS
Respiratory depression leading to ↓ MV and
↑pCO2: : Desflurane>Isoflurane>Sevoflurane
 Depress ventilatory responses to hypercarbia
and hypoxia in a dose dependent manner
 Respiratory Irritation:
2 MAC Desflurane
75%
2 MAC Isoflurane
50%
2 MAC Sevoflurane 0%
1 MAC –No respiratory irritation
 Sevoflurane agent of choice for inhalation
induction
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PULMONARY EFFECTS
Potent bronchodilators in animals and
human
 Halothane probably the most potent
bronchodilator
 Preferential dilatation of distal airways as
compared to proximal airways
 Action mediated through several complex
mechanisms leading to ↓ intracellular
Ca++
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PULMONARY EFEFCTS
Depress mucociliary clearance and
function of type II alveolar cells
 Attenuate hypoxic pulmonary
vasoconstriction (HPV) in vitro
 Modest inhibitory effects on HPV in vivo
leading to shunting and decreased
oxygenation.
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CENTRAL NERVOUS SYSTEM
↓ EEG wave frequency and ↑ amplitude
 Higher conc. (2 MAC): Isoelectric EEG
and burst suppression
 Protect against ischemia by ↓ CMRO2
 Cerebral vasodilation leading to ↑ ICP
 Enflurane and sevoflurane to a lesser
extent can cause convulsions
 Dose related ↓ amplitude and ↑ latency of
evoked potentials
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UTERINE AND FETAL EFFECTS
Dose dependent relaxation of uterus
 Increased blood loss during CD
 Lower concentrations (=0.5MAC safer)
 Inhaled anesthetics cross placenta
 Higher concentration: Fetal cardiovascular
depression
 Reduction of CBF and O2 delivery to
brain
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NEUROMUSCULAR SYSTEM
Dose dependent muscle relaxation
 Can cause sufficient relaxation to permit
endotracheal intubation and facilitate intra
abdominal procedures
 Potentiate the action of muscle relaxants
 Non depolarizers > Depolarizers
 All trigger MH; Halothane worse
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NITROUS OXIDE
Clear, colorless and odorless gas
 Supplied in pressurized cylinders
 Elimination through exhalation
 No biotransformation
 Uptake and elimination rapid due to low
blood/gas partition coefficient (0.47)
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NITROUS OXIDE
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Analgesia in a dose dependent manner
>60% produce amnesia
Can’t be used as sole anesthetic (MAC 104%)
Direct negative inotropic effect
Mild sympathetic nervous system agonist
Modest increases in PAP and PVR
Mild respiratory depression
Cerebral vasodilation leading to ↑ ICP
↑ CMRO2
NITROUS OXIDE
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Expansion of closed gas spaces
N2O 31 times more soluble than nitrogen
(nitrogen blood gas partition coefficient:0.015)
Moves faster into spaces than nitrogen can move
out
Contraindicated in pneumothorax, air embolism,
posterior fossa surgery, laparoscopy and
tympanoplasty
Diffusion hypoxia or Fink effect:
Significant for 5-10 min after discontinuation of
anesthesia during recovery
1. Large amounts of released N2O displace O2
2. Reduced alveolar ventilation due to fall in CO2
METABOLISM
Halothane: 20%
 Enflurane: 2.5%
 Isoflurane: 0.2%
 Desflurane: 0.01-0.02%
 Sevoflurane:5%
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HEPATOTOXICITY
Correlates with extent of oxidative
metabolism
 Halothane>Enflurane>Isoflurane>Desflura
ne
 50 case reports with enflurane
 Fewer case reports with isoflurane
 One case report with desflurane
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HALOTHANE HEPATITIS
Trifluoroacetic acid, chlorine and bromine
Major metabolite: Trifluoracetic acid
Intermediate reactive metabolite: TFA-Cl
Trifluoracetylated proteins→formation of antitrifluoracetylated protein antibodies
 Subsequent exposures lead to massive hepatic
necrosis
 Sevoflurane metabolism different from other
inhaled anesthetics
 Sevoflurane: Inorganic fluoride and
hexafluoroisopropanol
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CLINICAL FEATURES
MILD FORM:
 Incidence: 1:5
 Repeat exposure not necessary
 Mild elevation of ALT, AST
 Focal necrosis
 Self limited
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CLINICAL FEATURES
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FULMINANT FORM:
Incidence: 1:10,000
Multiple exposures
Marked elevation of ALT, AST, bilirubin and
alkaline phosphatase
Massive hepatic necrosis
Mortality: 50%
Antibodies to halothane altered protein antigen
NEPHROTOXICITY
Methoxyflurane:Vasopressin resistant high
output renal failure
 Related to inorganic fluoride
 Subclinical nephrotoxicity: 50-80 uM/lit
 Overt nephrotoxicity: 80-175 uM/lit
 2-4 MAC-hr enflurane: 20-30 uM/lit
 2-4 MAC-hr isoflurane: 3-8 uM/lit
 Desflurane: Unchanged
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NEPHROTOXICITY
1-2 MAC-hr sevoflurane: 10-20 uM/lit
 2-7 MAC-hr sevoflurane: 20-40 uM/lit
 15% sevoflurane anesthetics→>50 uM/lit
 Absence of sevoflurane nephrotoxicity
contradicts classical fluoride hypothesis of
50 uM toxic threshold
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COMPOUND A
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Sevoflurane decomposes to compound A in
presence of CO2 absorbents (alkali)
Higher compound A formation:
Low FGF
Higher absorbent temperature
↑ CO2 production
Greater sevoflurane concentrations
Baralyme > soda lime
Compound A renal injury:
Dose and time dependent, transient, 150 ppmhr
CO2 Flow vs COMPOUND A and
Temperature
FGF vs COMPOUND A
COMPOUND A
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Toxic threshold reached after prolonged
sevoflurane anesthesia
Compound A nephrotoxicity more of
theoretical concern
Patients with preexisting renal disease should
not be exposed to sevoflurane
Sevoflurane should not be used with FGF < 1
lit/min
For exposure greater than 2 MAC hr, FGF
should be increased to 2 lit/min or above
CARBON MONOXIDE
 CO
formation occurs in presence of
desiccated CO2 absorbents
 Desflurane>Isoflurane>Enflurane
 Common scenario-First case Monday
morning
 Intraoperative detection difficult
 Pulse oxymeters can’t distinguish
between carboxyhemoglobin and
oxyhemoglobin
CARBON MONOXIDE
Factors influencing CO production:
Choice of anesthetic agent
Inspired anesthetic concentration
Temperature and degree of dryness of CO2
absorbent
 Type of absorbent: Baralyme > Soda lime
 Precautions: Use of fresh absorbent, use of soda
lime instead of baralyme and avoiding
techniques drying CO2 absorber
 CO toxicity: Undetected in great proportion of
cases
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HEMATOPOIETIC AND
NEUROLOGIC EFFECTS OF N2O
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N2O by oxidation of vit B12 inhibits methionine
synthetase preventing conversion of
methyltetrahydrofolate to tetrahydrofolate
Reduced synthesis of thymidine
50% N2O for 12 hrs-mild megaloblastic changes
Marked changes after exposure for 24 hrs
Complete bone marrow failure after exposure
for several days
Subacute combined degeneration of spinal cord
after exposure for several months
Should not be used in vit B12 deficient patients
XENON
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Not approved for clinical use in humans yet
Inert gas with anesthetic properties
Obtained by fractional distillation of air
Expensive to manufacture
Minimal hemodynamic side effects
↑ Pulmonary airway resistance (high density)
Not metabolized
Doesn’t trigger MH in animals
Positive environmental effects
MECHANISMS OF ACTION
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KEY POINTS:
The structural diversity of inhaled anesthetics
suggests that they all do not interact with single
receptor site (multisite theory).
Physical or biochemical changes important to
mechanism occur within seconds and are
rapidly reversible
Inhaled anesthetics have inhibitory synaptic
>axonal effects in the brain and spinal cord.
Immobility occurs by action on the spinal cord
Amnesia is achieved by action on the brain.
MECHANISMS OF ACTION
Many excitatory (e.g. glutamate) and inhibitory
(GABA, glycine) neurotransmitters alter the
anesthetic requirement.
 Gaseous agents ( N2O and xenon) exert their
effect by inhibition of excitatory glutamate
(NMDA) receptors
 Volatile agents exert their greater effect by
enhancing inhibitory GABA or glycine
transmission
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MECHANISMS OF ACTION
Meyer Overton Hypothesis describes the
correlation between lipid solubility and
anesthetic potency (unitary theory of narcosis)
 MAC X Oil/gas partition coefficient:1.84 atm
for conventional anesthetics
 Additive effect of inhaled anesthetics
 However some volatile halogenated
compounds like non-immobilizers, transitional
compounds and alcohols don’t obey Meyer
Overton hypothesis
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Ca2+
Action potential entry
Neurotransmitter
release
(GABA, glycine)
Postsynaptic
membrane
Inhibitory postsynaptic
potential
Voltage
CICICI-
Time
B
A
a
B
Extracellular
B
a
B
Critical
amino acids
1
Intracellular
C
+ Anesthetic
Channel
Putative
pore anesthetic site
D
2
3
4
SUGGESTED READINGS
Inhaled Anesthetics in Miller’s Anesthesia
(Vol 1), Editor Ronald D Miller, Churchill
Livingstone.
 The Pharmacology of Inhaled Anesthetics
by Edmond I Eger II, James B Eisenkraft,
Richard B Weiskopf.
 Basic Physics and Measurement in
Anaesthesia, Editor Paul D Davis and
Gavin NC Kenny.
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