General Anaesthetics For Post-Graduates Inhalational anesthetics are either volatile liquids (e.g. halothane, isoflurane) or gaseous (e.g. nitrous oxide, xenon) that are inhaled to induce anesthesia. They work primarily by potentiating the inhibitory neurotransmitter GABA at GABAA receptors in the brain, though some like nitrous oxide also impact NMDA receptors. Their uptake in the lungs and distribution in tissues depends on factors like solubility and cardiac output. While they depress brain and cardiovascular function in a dose-dependent manner, individual agents have different organ effects. The most commonly used inhalational anesthetics today have low acute toxicity

1. General Anaesthetics
For Post-Graduates

2. QUESTION
• INHALATIONAL ANAESTHETICS (20MARKS)

3. • They are of mainly 2 types
Volatile anesthetics (diethyl ether, halothane,
enflurane, isoflurane, desflurane, sevoflurane)
• They have low vapor pressures and high boiling
points .
• liquids at room temperature (20 deg C)
Gaseous anesthetics (nitrous oxide, xenon)
• They Have high vapor pressures and low boiling
points

4. History
• The use of nitrous oxide to relieve the pain of
surgery was suggested by Humphrey Davy in
1800.
• Crawford Long, a physician in rural Georgia,
first used ether anesthesia in 1842.
• In 1846 James Simpson, used chloroform to
relieve the pain of childbirth.

5. Mechanism of action
• Not properly understood.
• Primary focus (of research) has been on the
synapse.
GABAA receptors
• Almost all anaesthetics (with the exceptions of
cyclopropane, ketamine and xenon) potentiate
the action of GABA at the GABAA receptor.
(GABAA receptors are ligand-gated Cl- channels
made up of five subunits (generally comprising
two α, two β and one γ or δ subunit).

6. • volatile anaesthetics (may) bind at the
interface between α and β subunits.
Two-pore domain K+ channels
(These belong to a family of 'background' K+
channels that modulate neuronal excitability.)
Channels made up of TREK1, TREK2, TASK1,
TASK3 or TRESK subunits (can be) directly
activated by low concentrations of volatile
and gaseous anaesthetics.
• Thus reducing membrane excitability.

7. NMDA receptors
• (Glutamate the major excitatory neurotransmitter
in the CNS, activates three main classes of
ionotropic receptor-AMPA, kainate and NMDA
receptors.)
• Nitrous oxide, xenon apppear to reduce NMDA
receptor-mediated responses.
• Xenon appears to inhibit NMDA receptors by
competing with glycine.
• Other inhalation anaesthetics may also exert
effects on the NMDA receptor in addition to their
effects on other proteins such as the GABAA
receptor

8. PHARMACOKINETICS
• Inhaled anesthetics are taken up through gas
exchange in the alveoli.
Uptake & Distribution
A. Inspired Concentration and Ventilation
• The driving force for uptake is the alveolar
concentration.
• Two determinants :
(controlled by the anesthesiologist)
(1) inspired concentration or partial pressure
(2) alveolar ventilation .

9. • Increases in the inspired partial pressure
increase the rate of rise in the alveoli and thus
accelerate induction.
• The increase of partial pressure in the alveoli
is expressed as
a ratio of alveolar concentration (F A ) over
inspired concentration (F 1 );
• The faster F A /F 1 approaches 1
(1 representing the equilibrium), the faster is
the induction.

11. • The other parameter by which FA/F1
approaches to 1 is alveolar ventilation.
• However The magnitude of the effect varies
according to the blood:gas partition
coefficient.
Factors Controlling Uptake
1. Solubility
2. Cardiac output
3. Alveolar-venous partial pressure difference

12. Solubility :
• The blood:gas partition coefficient is a useful
index of solubility.
• Defines the relative affinity of an anesthetic
for the blood compared with that of inspired
gas.
• The partition coefficients for desflurane and
nitrous oxide, which are relatively insoluble in
blood, are extremely low.

13. • When an anesthetic with low blood solubility
diffuses from the lung into the arterial blood,
relatively few molecules are required to raise
its partial pressure
• Therefore, the arterial tension of gas rises
rapidly.

14. • Conversely, for anesthetics with moderate to
high solubility ( halothane, isoflurane), more
molecules dissolve before partial pressure
changes significantly, and arterial tension of
the gas increases less rapidly.
• A blood: gas partition coefficient of 0.47 for
nitrous oxide means that - At equilibrium, the
concentration in blood is 0.47 times the
concentration in the alveolar space (gas).

16. Cardiac output—
• An increase in pulmonary blood flow (ie,
increased cardiac output) will increase the uptake
of anesthetic.
• But anesthetic taken up will be distributed in all
tissues, not just the CNS.
• Cerebral blood flow is well regulated and the
increased cardiac output will therefore increase
delivery of anesthetic to other tissues and not the
brain.

17. Alveolar-venous partial pressure difference—
• The anesthetic partial pressure difference
between alveolar and mixed venous blood is
dependent mainly on uptake of the anesthetic
by the tissues, including non-neural tissues.
• The greater this difference in anesthetic gas
tensions, the more time it will take to achieve
equilibrium with brain tissue.

18. Elimination
• Recovery from inhalation anesthesia follows
some of the same principles in reverse that
are important during induction.
• One of the most important factors governing
rate of recovery is the
• Blood : gas partition coefficient of the
anesthetic agent. Lesser the value faster is the
recovery.
• nitrous oxide, desflurane, and sevoflurane
occurs at a rapid rate.

19. • Recovery also depends on
1. Alveolar Ventilation (controlled by
Anaesthesiologist)
2. Metabolism of anaesthetic.
• Modern inhaled anesthetics are eliminated
mainly by ventilation and are only metabolized
to a very small extent.
• However , metabolism have important
implications for their toxicity.

20. • In terms of the extent of hepatic metabolism,
the rank order for the inhaled anesthetics is
• halothane > enflurane > sevoflurane
>isoflurane > desflurane > nitrous oxide

21. PHARMACODYNAMICS
A. Cerebral Effects
• Anesthetic potency is currently described by
the minimal alveolar concentration (MAC)
required to prevent a response to a surgical
incision.
• Inhaled anesthetics decreases the metabolic
activity of the brain.
• Decreased cerebral metabolic rate (CMR)
generally reduces blood flow within the brain.

22. • However, volatile anesthetics also cause
cerebral vasodilation, which can increase
cerebral blood flow.
• The net effect on cerebral blood flow
(increase, decrease, or no change) depends on
the concentration of anesthetic delivered.
• Clinical importance : An increase in cerebral
blood flow is undesirable in patients who have
increased intracranial pressure because of
brain tumor, intracranial hemorrhage, or head
injury.

23. • Anesthetic effects on the brain produce four
stages or levels of increasing depth of CNS
depression
(Guedel’s signs, derived from observations of the
effects of inhaled diethyl ether):
• Stage I—analgesia: The patient initially
experiences analgesia without amnesia. Later in
stage I, both analgesia and amnesia are
produced.
• Stage II—excitement: During this stage, the
patient appears delirious, may vocalize but is
completely amnesic.
Respiration is rapid, and heart rate and blood
pressure increase.

24. Stage III—surgical anesthesia:
• This stage begins with slowing of respiration
and heart rate and extends to complete
cessation of spontaneous respiration (apnea).
• Four planes of stage III are described based on
changes in ocular movements, eye reflexes,
and pupil size, indicating increasing depth of
anesthesia.

25. Stage IV—medullary depression:
• Severe depression of the CNS, including the
vasomotor center and respiratory center in
the brainstem.
• Without circulatory and respiratory support,
death would rapidly ensue.

26. B. Cardiovascular Effects
• All depress normal cardiac contractility
(halothane and enflurane more so than
isoflurane, desflurane, and sevoflurane).
• So they tend to decrease mean arterial
pressure in direct proportion to their alveolar
concentration.

27. • In halothane and enflurane, the reduced
arterial pressure is caused primarily by
myocardial depression (reduced cardiac
output) and there is little change in systemic
vascular resistance.

28. • In contrast, isoflurane, desflurane, and
sevoflurane produce greater vasodilation with
minimal effect on cardiac output.
• Clinical importance : These differences may
have important implications for patients with
heart failure.

29. C. Respiratory Effects
• All volatile anesthetics possess varying
degrees of bronchodilating properties.
• The control of breathing is significantly
affected by inhaled anesthetics.
• With the exception of nitrous oxide, all
inhaled anesthetics cause a dose-dependent
decrease in tidal volume
increase in respiratory rate (rapid shallow
breathing pattern).

30. • All volatile anesthetics are respiratory
depressants (reduced ventilatory response to
increased levels of carbon dioxide in the
blood)
D. Renal Effects
• Inhaled anesthetics tend to decrease
glomerular filtration rate (GFR) and urine flow.

31. Effects on Uterine Smooth Muscle
• Nitrous oxide appears to have little effect on
uterine musculature.
• However, the halogenated anesthetics are
potent uterine muscle relaxants
(concentration-dependent)

32. • Toxicity of inhaled Anesthetics
A. Acute Toxicity
1. Nephrotoxicity—
• Metabolism of enflurane and sevoflurane may
generate compounds that are potentially
nephrotoxic. (liberate fluoride ions)
2. Hematotoxicity—
• Prolonged exposure to nitrous oxide
decreases methionine synthase activity, which
could cause megaloblastic anemia

33. • All inhaled anesthetics can produce some
carbon monoxide (CO) from their interaction
with strong bases in dry carbon dioxide
absorbers. (desflurane)
3. Malignant hyperthermia—
is a heritable genetic disorder of skeletal
muscle that occurs in susceptible individuals
exposed to volatile anesthetics while
undergoing general anesthesia. ( Halothane)

34. 4. Hepatotoxicity (halothane hepatitis)—
Hepatic dysfunction
• a small subset of individuals previously
exposed to halothane has developed
fulminant hepatic failure.
• Cases of hepatitis of others have rarely been
reported.

35. B. Chronic Toxicity
Mutagenicity, teratogenicity.
• Under normal conditions, inhaled anesthetics
including nitrous oxide are neither mutagens
nor carcinogens in patients.
• Nitrous oxide can be directly teratogenic in
animals under conditions of extremely high
exposure.
• Halogenated agents may be teratogenic in
rodents.

36. Nitrous oxide
Important features.
• Nitrous oxide is completely eliminated by the
lungs.
• Non toxic to liver , kidney and brain. No much
adverse effects on CVS , RS.
• Probably the safest with 30% oxygen

37. • N2O is a weak, low potency anesthetic agent.
• Action is quick and smooth .
• Recovery is rapid. Rarely exceeds 4 min.
• It is a poor muscle Relaxant.
• It has significant analgesic effects.
• Nitrous oxide is used primarily as an adjunct to
other inhalational or intravenous anesthetics
mainly during maitenance phase.
• 70% N2O +25-30% oxy + 0.2-2% potent
anaesthetic

38. Adverse effects
 Pneumothorax.
Megaloblastic anemia
peripheral neuropathy (because of
methionine synthetase inactivation

39. Halothane
• Induction is relatively slow.
• Halothane is soluble in fat and other body tissues,
it will accumulate during prolonged
administration.
• Halothane can sensitize the myocardium to the
arrhythmogenic effects of Adrenaline.
Uses : Induction and maintenance anaesthesia
in pediatric age group.
Maintenance anaesthesia in adults

40. • Adverse Effects :
Shivering during recovery
Malignant hyperthermia
Fulminant hepatic necrosis

41. Enflurane
• Induction of anesthesia and recovery from
enflurane are relatively slow.
• It is primarily utilized for maintenance rather
than induction of anesthesia.
• Enflurane provokes seizure attacks in
susceptible patients.
• Enflurane produces significant skeletal muscle
relaxation

42. Isoflurane
• Induction with isoflurane and recovery from
isoflurane are faster than with halothane.
• It is typically used for maintenance of
anesthesia after induction with other agents
because of its pungent odor. Another e.g,
Desflurane.

43. Sevoflurane
• Eventhough non-explosive in mixtures of air or
oxygen.
sevoflurane can undergo an exothermic
reaction with desiccated CO2 to produce airway
burns. So it should be used in open system airway
ventilation.
• Effects on CVS and RS is modest.
• It is well-suited for inhalation induction of
anesthesia (particularly in children)