Inhalational Anesthetics

Halothane, Enflurane, Desflurane

and Sevoflurane

Hadia Mruma
OUTLINES
Introduction
Overview of Inhalational anaesthetics uptake
Physical-chemical properties
Systemic effects
Biotransformation and Excretion
References
Introduction
• Nitrous oxide, chloroform, and ether were the first universally
accepted general anesthetics
• Methoxy-flurane and enflurane, two potent halogenated agents, were
used for many years in North American anesthesia practice
• Methoxyflurane was the most potent inhalation agent, but its high
solubility and low vapor pressure yielded longer inductions and
emergences- renal failure
• Enflurane has a nonpungent odor and is nonflammable at clinical
concentrations. It depresses myocardial contractility.
ETHER
Ether is a class of organic compounds that contain an
ether group — an oxygen atom connected to two
alkyl or aryl groups — of general formula R–O–R
A typical example is the solvent and anesthetic
diethyl ether, commonly referred to simply as "ether"
(CH3-CH2-O-CH2-CH3)
History
The first anaesthetic agent to be used
Made from sugar cane
Demonstrated first its effect in Boston(1846 by
William Morton)
Properties
Molecular weight of 74.1
Boiling point of 34.6
Saturated vapour pressure of 44.2
Solubility in blood 12.1
MAC 1.92
Colourless, highly flammabe liquid with pungent
chocking smell
Systemic effects
 Respiratory effects
 Irritant to respiratory tract
 Laryngeal spasms during induction
 Bronchial secretions
 Produce bronchial muscle relaxation ie benefit for
patients with asthma and bronchitis
Cardiovascular effects
 During light planes of ether anaesthesia there are
usually minor changes in blood pressure , cardiac
output and peripheral resistance.

 During deeper anaesthesia, myocardial depression

and paralysis of the vasomotor and other vital
centres may lead to circulatory failure.
CNS
During Induction of Anaesthesia There Is Stimulation
of Sympathetic Nervous System, With Increase in
Circulating catecholamines
Muscular relaxation effects

Depression of nerve impulse transmission at NMJ

Skeletal muscle tone is reduced during deep
anaesthesia
Hence when used with muscle relaxants, small doses
should be given
Biotransformation& Excretion
About 15% of inhaled ether is metabolized in the
liver.
Increased in sympathetic activity potentiate
glycogenolysis leading to hyperglycaemia.
Caution to DM patient.
Because of these concerns, ether, methoxyflurane
and enflurane are no longer used
Introduction
• The course of a general anesthetic can be divided into three phases:
(1) induction, (2) maintenance, and (3) emergence.
• Inhalation anesthetics, such as halothane and sevoflurane, are
particularly useful in the induction of pediatric patients in whom it
may be difficult to start an intravenous line.
• Adults are usually induced with intravenous agents
• Maintanance of anaesthesia with inhalation agents regardless of age.
• Emergence depends primarily upon redistribution from the brain and
pulmonary elimination of these agents
• Five inhalation agents continue to be used in clinical anesthesiology:
nitrous oxide, halothane, isoflurane, desflurane, and sevoflurane
Inhalation anaesthetic uptake
Inspired air to alveolar
Alveolar to Arterial blood
Arterial blood to Tissue
Factors affecting anaesthetic uptake

solubility in the blood,

alveolar blood flow,
The difference in partial pressure between alveolar
gas and venous blood.
solubility
Partition coefficients of volatile
anaesthetics
Alveolar blood flow
• The second factor that affects uptake is alveolar blood flow, which—in
the absence of pulmonary shunting—is essentially equal to cardiac
output.
• If the cardiac output drops to zero, what will anesthetic uptake be?
Drop or rise.
Tissue groups on perfusion and solubility
• The final factor affecting uptake of
anesthetic by the pulmonary circulation
is the partial pressure difference
between alveolar gas and venous blood.
• This gradient 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 coeffi-cient), tissue blood flow,
and the difference in partial pressure
between arterial blood and the tissue.
Elimination
• Recovery from anesthesia depends on lowering the concentration of
anesthetic in brain tissue. Anesthetics can be eliminated by
biotransformation, transcutaneous loss, or exhalation (alveolus)
• Many of the factors that speed induction also speed recovery:
elimination of rebreathing, high fresh gas flows, low anesthetic-circuit
volume, low absorption by the anesthetic circuit, decreased solubility,
high cerebral blood flow (CBF), and increased ventilation
• Redistribution
HALOGENATED ANAESTHETICS
MAC?
Halothane
Halogenated alkane compound.
2-bromo-2-chloro-1,1,1-trifluoroethane
Colourless, pleasant , unstable in light.
Mwt 197.4Da
Boiling point 50.2c
Vapour pressure 243mmHg
carbon–fluoride bonds are responsible for its
nonflammable and nonexplosive nature
Properties continue
• MAC 0.75%
• Blood :gas partition coefficient
2.4
• Poor analgesic
• Induction dose 2-4%
• Maintainance dose o.5-1.5%
Systemic effects
CVS
As for most volatile anaesthetics halothane has a narrow
margin of safety, resulting in severe cardiovascular
depression.
 dose-dependent reduction of arterial blood pressure is
due to direct myocardial depression.
In infants, halothane decreases cardiac output by a
combination of decreased heart rate and depressed
myocardial contractility
Sensitizes the heart to arrythmogenic effects of
epinephrine
CVS
Hypotension is the dominant indicator of anaesthetic
depth.
All halogenated anaesthetics produce a dose
dependent decrease in mean Arterial Blood Pressure.
Halothane unlike other halogenated anaesthetics
decrease mean ABP by decreasing myocardial
contractility and cardiac output.
Desflurane, Isoflurane and Sevoflurane decrease ABP
by their effect on peripheral vasodilatation.
Respiratory system

Rapid and shallow breath

Hence increase in RR but decrease in Tidal volume
Depress hypoxic drive by even low concentrations of
halothane (0.1 MAC) hence PaCO2 may increase
 Potent bronchodilatation
Blunt airway reflexes and relaxes bronchial smooth ms.
Depression of mucociliary function(post op hypoxia and
atelectasis
CNS
Cerebral blood vessels dilates during halothane
anaesthesia, with loss of normal autoregulation.
Increase in CBF and ICP
Muscle
Some degree of muscle relaxation (potentiate NMBA
action)
Uterine smooth muscle
Like others can cause malignant hyperthermia
Renal
A dose of 1MAC decrease RBF and GFR up to 40-50%
and urinary output
The effect may be greater in pre-existing
hypovolaemia
In normovolaemic subjects halothane does not
interfere markedly with autoregulation of the kidney.
There is usually good recovery of kidney function,
Post operatively
Biotransformation.
85% is exhaled unchanged within 24hrs.
15% is metabolized by the liver
Oxidized to trifluoroacetic acid (TFA) by CYP2E1
?Isoniazid, ethanol
Conjugation with N-acetylycysteine via glutathione.
Major metabolites is trifluoroacetic acid.
Liver toxicity
Trifluoroacetyl intermediate play a role in liver toxicity.
However Viral hepatitis remains the most common cause
of postoperative hepatic dysfunction,1:10,000
Usually occurs btn 2-5days post anaesthesia
Characterized by; fever, N/V, rashes and eosinophilia.
Halothane hepatitis” is extremely rare (1 per 35,000
cases). Patients exposed to multiple halothane
anesthetics at short intervals, middle-aged obese women,
and with a familial hx to halothane toxicity or a personal
history of toxicity are considered to be at increased risk.
Enflurane
2-chloro-1,1,2-trichloroethyl-difluoromethyl ether.
MAC 1.68%
Blood gas partition coefficient 1.91
Lipid gas partition coefficient 98
Systemic effects
CVS
Cause myocardial depression
Does not decrease HR and CO as much as halothane
Cardiovascular depression effects exeggerated by
beta-antagonists
RS
Assisted ventilation should nearly always be used due
to significant respiratory depression.
CNS
In small proportion of subjects cause seizures
Other CNS manifestation similar to halothane.
Muscle relaxation-more potentiated than halothane

RENAL
Cause dose dependent reduction of GFR, RBF and
urine production.
Safe for renal disease pt provided the depth and
duration is not prolonged.
Biotransformation
2-5% is metabolized in the liver by oxidation.
Low % of metabolism is explained by
.the absence of bromine
. Presence of ether bond
 Isoflurane
Colourless, pungent ethereal odor, non flammable,
stable to light and sodalime
Chemical structure 2,2,2-trifluoro-1-chloroethyl-
difluoromethyl ether.
MAC 1.15%
Blood gas partition coefficient 1.4
Lipid gas partition coefficient 99
Saturated vapour pressure 250mmHg
Boiling point 48.5
Induction 4%, maintenance 1-1.5%
Systemic effects
• CVS
• Produce a dose dependent
reduction in BP with
maintainance of cardiac
output( rise of HR is maintained)
• Do not sensitize the heart with
catecholamine.
• Unlike enflurane do not cause
seizures.
• Dilates coronary artery
systemic
• Respiratory
• Tachypnea less pronounced
• Blunt normal ventilator response to hypoxia and hypercapnia
• Irritate upper airway reflexes
• CNS
• Increases CBF and ICP less compared to halothane
• Reduces cerebral metabolic oxygen demand
• Renal
• Decreases RBF, GFR and urinary output
Biotransformation
Metabolized to trifluoroacetic acid
Only 0.2% of isoflurane is metabolized in the liver
No evidence of renal impairement
This can be explained by
.the absence of bromine
.the presence of the ether bond
Hepatic failure has not been reported with isoflurane
because of its limited oxidative metabolism
 Sevoflurane
Halogenated with flourine
Colourless liquid nonpungent and rapid rise in
alveolar anaesthetic concentration
BP 58.9C, VP 170mmHg. MWt200Da
Non flammable, relative stable. Hydrolysed on
prolonged contact with Hydroxide or exposure to soda
lime and baralyme
Blood:gas part coeff 0.65, MAC 1.8%
Best choice for induction in peadiatric
Indn 4-6%. Maintenance 1-3%
Low solubility- rapid emergence
Systemic effects
• 1trifluoro2,2,2trifluoroethyl
monofluoromethyl ether
• CVS
• Mild depress myocardial
contractility
• Decrease in systemic vascular
resistance and arterial BP slightly
less compared to isoflurane and
desflurane
• Little rise in HR, CO not maintained
Systemic effects
respiratory
 Respiratory depressant similar to other volatile anaesthetics
CNS
 Slight increase in CBF and ICP

 Decrease in cerebral metabolic oxygen demand

 No seizures activities

 Does not sensitize the heart to catecholamines

Neuromascular
 Muscle relaxation
Biotransformation and toxicity
• Metabolized by the liver microsomal enzyme P450
• Can be induced with ethanol/ phenobarbital pretreatment
• No evidence of renal dysnfunction
• Can be degraded by alkali such as barium hydroxide lime or soda lime producing
compound A (nephrotoxic)
• Also degraded into hydrogen fluoride by metal and environmental impurities
present in manufacturing equipment, glass bottle packaging, and anesthesia
equipment.
• Hydrogen fluoride can produce an acid burn on contact with respiratory mucosa
• Can trigger MH
Desflurane
2,2,2-trifluoro-1-fluoroethyl-difluoromethyl ether
MAC 6
Blood gas partition coefficient 0.42
Saturated vapour pressure 663mmHg
Special systemic effects
• Similar to those of isoflurane
.potentiate action of deporalizing and non-deporalizing
muscle relaxants
.rapid induction due to very small blood solubility.
Systemic effect
• Pungency and airway irritation
during induction
• Airway resistance increase in
children with reactive airway risk
• Poor choice of inhalation
induction
• Vasodilates cerebral vessels,
increasing CBF
• Decrease in cerebral oxygen
demands
 Summary
• Halothane hepatitis is extremely rare (1 per 35,000 cases). Patients exposed 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 are considered to be at increased risk. Desflurane and
isoflurane undergo much less metabolism than halothane, resulting in fewer of
the metabolite protein adducts that lead to immunologically mediated hepatic
injury .

• The low solubility of desflurane in blood and body tissues causes a very rapid
induction of and emergence from anesthesia .
• Prolonged exposure to anesthetic concentrations of nitrous oxide can
result in bone marrow depression (megaloblastic anemia) and even
neurological deficiencies (peripheral neuropathies) .
• Isoflurane dilates coronary arteries, but is not nearly as potent a
dilator as nitroglycerin or adenosine. Dilation of normal coronary
arteries could theoretically divert blood away from fixed stenotic
lesions .
References
• Principles and practices of Phamacology for
Anaesthetists.. T.N Calvey.
• Anaesthesia by Ronard miller
• Pharmacology and physiology in anaesthesia by
Robert k stoeling(lippincott)
• Textbook of anaesthesia by Graham smith