Inhalational Anesthetics

Patigas, Requinta, Resuello

Key Concepts
• Pharmacokinetics – relationship
between a dose, tissue
concentration, and elapsed time
• Pharmacodynamics – drug action
Key Concepts
• Factors that affect anesthetic
uptake:
– solubility in the blood
– alveolar blood flow
– difference in partial pressure between
alveolar gas and venous blood
Key Concepts
• Low output states predispose
patients to overdosage with soluble
agents, as the rate of rise in alveolar
concentrations will be markedly
increased
Key Concepts
• General anesthesia – altered
physiological state characterized by
reversible loss of consciousness,
analgesia of the entire body,
amnesia, and some degree of
muscle relaxation
Key Concepts
• Unitary Hypothesis: All inhalation
agents share a common mechanism
of action at the molecular level
• Meyer-Overton Rule: Anesthetic
potency of inhalation agents
correlates directly with their lipid
solubility
Key Concepts
• Minimum Alveolar Concentration
(MAC) – alveolar concentration of an
inhaled anesthetic that prevents
movement in 50% of patients in
response to a standardized stimulus
Key Concepts
• Nitrous oxide – bone marrow
depression and neurologic
deficiencies
• Halothane – hepatitis
• Isoflurane – dilates coronary arteries
• Desflurane – low solubility;
elevations in heart rate, blood
pressure, catecholamines
Key Concepts
• Sevoflurane – nonpungent, causes
rapid increases in alveolar
anesthetic concentration
INTRODUCTION
• Nitrous oxide, chloroform, and ether
were the first universally accepted
general anesthetics
• Ethyl chloride, ethylene, and
cyclopropane were also used
• Cyclopropane – fast induction;
notable recovery (rapid effect with
no delirium)
Methoxyflurane
• Most potent inhalation agent
• High solubility and low vapor pressure
limited rate of induction and
emergence
• 50% is metabolized by cytochrome
P450 to free fluoride (F-), oxalic acid
and other nephrotoxic compounds
• Vasopressin-resistant, high-output
renal failure
Enflurane
• Depresses myocardial contractility
and sensitizes myocardium to
epinephrine
• Increases secretion of CSF and
resistance to CSF outflow
• Tonic-clonic seizures
• Inhalational Agents:
– Nitrous oxide
– Halothane
– Isoflurane
– Desflurane
– Sevoflurane
• Phases of General Anesthesia:
– Induction
– Maintenance
– Emergence
 PHARMACOKINETICS OF
INHALATION ANESTHETICS
 
• Pharmacokinetics- study of relationship
between drug dose, tissue concentration and
elapsed time

• “ How body affects a drug”

• Pharmacodynamics- study of drug action
including toxic response

• “How drugs affect body”

• The ultimate effect of inhalational
anesthetics depends on attainment
of a therapeutic tissue concentration
in the central nervous system.

• Inhalation anesthetic agents must

pass through many barriers between
the anesthesia machine and the
brain.
igure 7–1. 

Inhalation anesthetic agents must pass through many barriers between the anesthesia machine and the
brain
 FACTORS AFFECTING INSPIRATORY
CONCENTRATION (FI)
• fresh gas flow rate
• the volume of the breathing system
• any absorption by the machine or breathing
circuit
The higher the fresh gas flow rate, the smaller
the breathing system volume, and the lower
the circuit absorption, the closer the inspired
gas concentration will be to the fresh gas
concentration.
Thus there would be faster induction and recovery
times.
FACTORS AFFECTING ALVEOLAR
CONCENTRATION (FA)
• Uptake
• Ventilation
• Concentration
 A. UPTAKE
• Because anesthetic agents are taken
up by the pulmonary circulation during
induction, alveolar concentrations lag
behind inspired concentrations (FA/FI
< 1.0).
• The greater the uptake, the slower the
rate of rise of the alveolar concentration
and the lower the FA:FI ratio.
• Concentration of a gas is directly
proportional to its partial pressure

• Alveolar partial pressure determines

the partial pressure of anesthetic in the
blood and brain.

• Partial pressure of the anesthetic in

the brain is directly proportional to its
brain tissue concentration, which
determines clinical effect.
effect
 Factors affect anesthetic uptake:
• Solubility in the blood
– Partition coefficient-
coefficient ratio of the concentrations of the
anesthetic gas in each of two phases at equilibrium

– The higher the blood/gas coefficient, the greater the

anesthetic's solubility and the greater its uptake by the
pulmonary circulation. As a consequence of this high
solubility,
solubility alveolar partial pressure rises more slowly, and
induction is prolonged.
prolonged

– Blood/gas solubility is increased by postprandial lipidemia

and is decreased by anemia.
 
Table 7–1. Partition Coefficients of Volatile Anesthetics
at 37°c.1

Agent Blood/Gas Brain/Bloo Muscle/Blo Fat/Blood

d od

Nitrous oxide 0.47 1.1 1.2 2.3

Halothane 2.4 2.9 3.5 60

Isoflurane 1.4 2.6 4.0 45

Desflurane 0.42 1.3 2.0 27

Sevoflurane 0.65 1.7 3.1 48

• Alveolar blood flow
– Essentially equal to cardiac output
– As cardiac output increases,
increases anesthetic uptake
increases, the rise in alveolar partial pressure slows,
and induction is delayed.
delayed
– Less pronounced for insoluble anesthetics
– Low-output states predispose patients to overdosage
with soluble agents, as the rate of rise in alveolar
concentrations will be markedly increased
– Halothane may create a positive feedback loop by
lowering cardiac output
• Difference in partial pressure
between alveolar gas and venous
blood.
– Depends on tissue uptake
– The transfer of anesthetic from blood to
tissues is determined by three factors
analogous to systemic uptake:
• tissue solubility of the agent (tissue/blood
partition coefficient
• tissue blood flow
• difference in partial pressure between arterial blood
and the tissue.
 4 GROUPS OF TISSUE
• highly perfused vessel-rich group
(brain, heart, liver, kidney, and
endocrine organs)
• muscle group (skin and muscle)
• fat group
• vessel-poor group (bones, ligaments,
teeth, hair, and cartilage)
 B. VENTILATION

• Increase in ventilation will increase

alveolar partial pressure.
• Most obvious in raising the FA/FI for
anesthetics as they are more
soluble anesthetics,
subject to uptake
• Anesthetics that depress ventilation (eg,
halothane)
halothane will decrease the rate of rise in
alveolar concentration and create a
negative feedback loop.
 C.CONCENTRATION
• Concentration effect- increase in the
inspired concentration increases the alveolar
concentration and the rate of rise FA/FI
• 2 phenomena:
– concentrating effect
– augmented inflow effect
• Second gas effect
 FACTORS AFFECTING ARTERIAL
CONCENTRATION (FA)
A. Ventilation/Perfusion Mismatch
• EFFECT: Increase in the alveolar partial pressure
(particularly for highly soluble agents) and a
decrease in the arterial partial pressure
(particularly for poorly soluble agents).

• Thus, a bronchial intubation or a right-to-left

intracardiac shunt will slow the rate of induction
with nitrous oxide more than with halothane.
 FACTORS AFFECTING
ELIMINATION
• Anesthetics can be eliminated by:
1. biotransformation
– Soluble anesthetics
– CYP 2EI
2.transcutaneous loss
3. exhalation
– diffusion hypoxia
• Factors that speed induction also
speed recovery:
1.elimination of rebreathing
2.high fresh gas flows
3. low anesthetic-circuit volume
4. low absorption by the anesthetic
circuit
5.decreased solubility
6. high cerebral blood flow (CBF)
7. increased ventilation
 PHARMACODYNAMICS OF
INHALATION ANESTHETICS
• General anesthesia is an altered
physiological state characterized by:
1. reversible loss of consciousness
2.analgesia of the entire body
3. amnesia
4.degree of muscle relaxation.
• Specific brain areas affected by various
anesthetics include :
1.the reticular activating system
2. the cerebral cortex
3.the cuneate nucleus
4. the olfactory cortex
5. hippocampus.
• Anesthetics have also been shown to
depress excitatory transmission in the
spinal cord, particularly at the level of the
dorsal horn interneurons that are involved in
pain transmission
• Meyer–Overton rule:proposes that all
inhalation agents share a common
mechanism of action at the molecular
level. Anesthetic potency of inhalation
agents correlates directly with their
lipid solubility
 MINIMUM ALVEOLAR
CONCENTRATION (MAC)
• The alveolar concentration that prevents
movement in 50% of patients in response to
a standardized stimulus (eg, surgical
incision).

• MAC is a useful measure because it mirrors

brain partial pressure, allows comparisons of
potency between agents
• Equivalent of a median effective dose (ED50).
 Table 7–3. Properties of Modern Inhalation Anesthetics.

Agent Structure MAC%1 Vapor Pressure

  (mm Hg at
20°C)

Nitrous oxide 1052 —

 

Halothane (Fluothane) 0.75 243

Isoflurane (Forane) 1.2 240

Desflurane (Suprane) 6.0 681

Sevoflurane (Ultane) 2.0 160

 FACTORS AFFECTING MAC

FACTORS COMMENTS
Temperature Decreased
Age Young: Inc;
Elderly:Dec

Alcohol Acute:Decrease;
Chronic:Increase

Anemia Decrease
PaO2 Decrease
Blood pressure Decreased if MAP is
<40

Local anesthetics Decreaaed

Coccaine Increased
Clinical Pharmacology of
Inhalational Anesthetics
NITROUS OXIDE
Physical Properties
• the only inorganic anesthetic gas in
clinical use
• colorless and essentially odorless
• nonexplosive and nonflammable
• a gas at room temperature and
ambient pressure
• relatively inexpensive
Effects on Organ Systems
• Cardiovascular
– has a tendency to stimulate the
sympathetic nervous system
– arterial blood pressure, cardiac output,
and heart rate are essentially
unchanged or slightly elevated
– may be associated with a higher
incidence of epinephrine-induced
arrhythmias
Effects on Organ Systems
• Respiratory
– increases respiratory rate (tachypnea)
and decreases tidal volume
– Hypoxic Drive (ventilatory response to
arterial hypoxia that is mediated by
peripheral chemoreceptors in the
carotid bodies) is markedly depressed
Effects on Organ Systems
• Cerebral
– increases CBF and cerebral blood
volume = mild elevation of intracranial
pressure

• Neuromuscular
– does not provide significant muscle
relaxation
Effects on Organ Systems
• Renal
– decrease renal blood flow by increasing
renal vascular resistance = drop in GFR
and UO

• Hepatic
– Hepatic blood flow falls

• Gastrointestinal
– postoperative nausea and vomiting
Biotransformation and
Toxicity
• eliminated by exhalation
• less than 0.01% undergoes reductive
metabolism in the gastrointestinal tract
by anaerobic bacteria
• inhibits enzymes that are vitamin B12
dependent (methionine synthetase and
thymidilate synthetase) 
megaloblastic anemia, peripheral
neuropathies, pernicious anemia
Biotransformation and
Toxicity
• Has possible teratogenic effects 
avoided in pregnant patients
• alter the immunological response to
infection
Contraindications
• air embolism
• Pneumothorax
• acute intestinal obstruction
• intracranial air
• pulmonary air cysts
• intraocular air bubbles
• tympanic membrane grafting
Drug Interactions
• used in combination with the more
potent volatile agents
• decreases the requirements of other
agents
• attenuate the circulatory and
respiratory effects of volatile
anesthetics in adults
• potentiates neuromuscular blockade
HALOTHANE
Physical Properties
• a halogenated alkane
• nonflammable and nonexplosive
• the least expensive volatile
anesthetic
Effects on Organ Systems
• Cardiovascular
– dose-dependent reduction of arterial
blood pressure
– sensitizes the heart to the
arrhythmogenic effects of epinephrine
Effects on Organ Systems
• Respiratory
– causes rapid, shallow breathing
– alveolar ventilation drops and resting
PaCO2 is elevated
– Hypoxic drive is severely depressed
– a potent bronchodilator
– depresses clearance of mucus from
the respiratory tract
Effects on Organ Systems
• Cerebral
– Dilates cerebral vessels  lowers cerebral
vascular resistance and increases CBF
– Autoregulation is blunted
– Cerebral activity is decreased

• Neuromuscular
– relaxes skeletal muscle
– potentiates nondepolarizing neuromuscular-
blocking agents
– A triggering agent of malignant hyperthermia
Effects on Organ Systems
• Renal
– reduces renal blood flow, glomerular
filtration rate, and urinary output

• Hepatic
– Decreased hepatic blood flow
– Impaired metabolism and clearance of
some drugs (eg, fentanyl, phenytoin,
verapamil)
Biotransformation and
Toxicity
• oxidized in the liver by a particular
isozyme of cytochrome P-450 (2EI)
to its principal metabolite,
trifluoroacetic acid
– can be inhibited by pretreatment with
disulfiram
Biotransformation and
Toxicity
• Halothane Hepatitis
– Risk factors: exposure to multiple
halothane anesthetics at short intervals,
middle-aged obese women, and persons
with a familial predisposition to halothane
toxicity or a personal history of toxicity
– Signs: increased serum alanine and
aspartate transferase, elevated bilirubin
(leading to jaundice), and encephalopathy
Contraindications
• patients with unexplained liver
dysfunction following previous
exposure
• patients with intracranial mass
lesions
• Hypovolemic patients
• some patients with severe cardiac
disease (aortic stenosis)
Drug Interactions
• β-adrenergic-blocking agents (eg,
propranolol) and calcium channel-
blocking agents (eg, verapamil)
exacerbates myocardial depression
• TCAs and MAOIs have been
associated with fluctuations in blood
pressure and arrhythmias
• Halothane + aminophylline has
resulted in serious ventricular
arrhythmias
ISOFLURANE
Physical Properties
• nonflammable volatile anesthetic
with a pungent ethereal odor
• chemical isomer of enflurane
Effects on Organ Systems
• Cardiovascular
– minimal cardiac depression

• Respiratory
– Respiratory depression resembles that
of other volatile anesthetics
– Tachypnea is less pronounced
– more pronounced fall in minute
ventilation
Effects on Organ Systems
• Cerebral
– At concentrations greater than 1 MAC,
isoflurane increases CBF and
intracranial pressure.
– reduces cerebral metabolic oxygen
requirements, and at 2 MAC it
produces an electrically silent
electroencephalogram (EEG).

• Neuromuscular
– relaxes skeletal muscle.
Effects on Organ Systems
• Renal
– decreases renal blood flow, glomerular
filtration rate, and urinary output

• Hepatic
– Total hepatic blood flow (hepatic artery
and portal vein flow) is reduced
Biotransformation and
Toxicity
• metabolized to trifluoroacetic acid
• nephrotoxicity is extremely unlikely
• limited metabolism minimizes any
possible risk of significant hepatic
dysfunction
Contraindications
• severe hypovolemia
Drug Interactions
• Epinephrine can be safely
administered in doses up to 4.5 g/kg.
• Nondepolarizing NMBAs are
potentiated by isoflurane.
DESFLURANE
Physical Properties
• substitution of a fluorine atom for
isoflurane's chlorine atom
• high vapor pressure
• ultrashort duration of action
• moderate potency
Effects on Organ Systems
• Increasing the dose is associated with
a decline in systemic vascular
resistance that leads to a fall in arterial
blood pressure.
• Cardiac output remains relatively
unchanged or slightly depressed
• moderate rise in heart rate, central
venous pressure, and pulmonary artery
pressure
• does not increase coronary artery
blood flow
Effects on Organ Systems
• Respiratory
– decrease in tidal volume
– increase in respiratory rate
– overall decrease in alveolar ventilation
 rise in resting PaCO2
– depresses the ventilatory response to
increasing PaCO2
– Pungency and airway irritation 
salivation, breath-holding, coughing,
and laryngospasm
Effects on Organ Systems
• Cerebral
– directly vasodilates the cerebral
vasculature  increasing CBF and
intracranial pressure at normotension
and normocapnia
– cerebral oxygen consumption is
decreased
Effects on Organ Systems
• Neuromuscular
– dose-dependent decrease in the response to
train-of-four and tetanic peripheral nerve
stimulation

• Renal
– no evidence of any nephrotoxic effects

• Hepatic
– Hepatic function tests are unaffected
– no evidence of hepatic injury following
desflurane anesthesia
Biotransformation and
Toxicity
• degraded by desiccated carbon
dioxide absorbent (particularly
barium hydroxide lime, but also
sodium and potassium hydroxide)
into potentially clinically significant
levels of carbon monoxide
Contraindications
• severe hypovolemia
• malignant hyperthermia
• intracranial hypertension
Drug Interactions
• potentiates nondepolarizing
neuromuscular blocking agents
• does not sensitize the myocardium
to the arrhythmogenic effects of
epinephrine
SEVOFLURANE
Physical Properties
• halogenated with fluorine
• Nonpungent
• Rapidly increases alveolar
anesthetic concentration
• low blood solubility
• modest vapor pressure
Effects on Organ Systems
• Cardiovascular
– mildly depresses myocardial
contractility
– Systemic vascular resistance and
arterial blood pressure decline slightly
– causes little, if any, rise in heart rate
– may prolong the QT interval
Effects on Organ Systems
• Respiratory
– depresses respiration
– reverses bronchospasm

• Cerebral
– slight increases in CBF and intracranial
pressure at normocarbia
– may impair autoregulation of CBF
– cerebral metabolic oxygen requirements
decrease
Effects on Organ Systems
• Neuromuscular
– produces adequate muscle relaxation

• Renal
– slightly decreases renal blood flow

• Hepatic
– decreases portal vein blood flow
– increases hepatic artery blood flow
Biotransformation and
Toxicity
• potentially nephrotoxic because of
the resulting rise in inorganic fluoride
(F–)
• barium hydroxide lime or soda lime
can degrade sevoflurane, producing
another proven (at least in rats)
nephrotoxic end product (compound
A, fluoromethyl-2,2-difluoro-1-
[trifluoromethyl]vinyl ether).
Contraindications
• severe hypovolemia
• susceptibility to malignant
hyperthermia
• intracranial hypertension
Drug Interactions
• potentiates NMBAs
• does not sensitize the heart to
catecholamine-induced arrhythmias