2. History
âą Inhaled anesthetics introduced
into clinical practice with the
successful use of nitrous oxide
in 1844 for dental anesthesia
followed by recognition of the
anesthetic properties of ether
in 1846 and of chloroform in
1847.
âą Modern anesthetics, beginning
with halothane, differ from
prior anesthetics in being
fluorinated and nonflammable
4. Determinants of Alveolar Partial Pressure
âȘ PA and ultimately the PBRAIN of inhaled anesthetics
determined by
âȘ Input (delivery) into alveoli minus uptake
(loss) of the drug from alveoli into arterial
blood
5. Input of anesthetics
Input of anesthetics into alveoli depends on
1. Inhaled partial pressure (PI)
2. Alveolar ventilation
3. Characteristics of the anesthetic breathing
6. 1 Inhaled partial pressure (PI)
âȘ High PI delivered from anesthetic machine is required
during initial administration of the anesthetic.
âȘ A high initial input offsets the impact of uptake,
accelerating induction of anesthesia as reflected by the rate
of rise in the Pa and thus the PBRAIN.
âȘ With time, as uptake into the blood decreases, PI should be
decreased to match the decreased anesthetic uptake and
therefore maintain a constant and optimal PBRAIN.
7. Concentration effect
âȘ Impact of PI on the rate of rise of the Pa of an inhaled anesthetic
âȘ Impact of the inhaled concentration of an anesthetic on the rate at
which the alveolar concentration increases toward the inspired
âȘ Higher the PI, the more rapidly the PA approaches the PI
âȘ Results from concentrating effect & augmentation of tracheal inflow
âȘ Concentrating effect: reflects concentration of the inhaled anesthetic in
a smaller lung volume due to uptake of all gases in the lung
âȘ Anesthetic input via tracheal inflow is increased to fill the space (void)
produced by uptake of gases
8. 2L 2L
2L
1L
50% O2
50% N2O
66 %O2
33 % N2O
2.5L
1.5L
62.5 %O2
37.5 % N2O
500 ml N2O + 500 ml O2
Augmentation of
tracheal inflow
Concentrating
effect
Inspired
After
diffusion
of N2O
If 10% N2O and 90% O2â the rise in alveolar concentration of N2O will be very low
5.3% by concentrating effect 5X
5.5. % by augmented inflow effect 6.8X compared to the 50:50 mixture
9. Second-Gas Effect
âȘ The ability of high-volume uptake of one gas (first gas) to accelerate
the rate of increase of the Pa of a concurrently administered
âcompanionâ gas (second gas)
âȘ Initial large-volume uptake of nitrous oxide accelerates the uptake of
companion (second) gases such as oxygen and volatile anesthetics.
âȘ Increased uptake of second gas reflects increased tracheal inflow of all
inhaled gases (first and second gases) and higher concentration of
second gas or gases in a smaller lung volume (concentrating effect) due
to high-volume uptake of first gas
10. âą Concentrating effect: Half of nitrous oxide diffuses quickly to blood, alveolar volume reduces to 3000 ml.
The new alveolar concentration of isoflurane is 40/3000 ~ 1.33%.
âą Augmented inflow or ventilation effect: Due to subatmospheric pressure created in alveoli, further 1 l of
mixture gas is inhaled, i.e. 10 ml isoflurane, 490 ml oxygen and 500 ml nitrous oxide. So, the new alveolar
concentration is (40+10)/4000 ~ 1.25%.
50% N2O
40 ml
1.96 L
2L
500 ml N2O + 490 ml O2+ 10ml Isoflurane
Inspired
After
diffusion
of N2O
49% O2
1% Isoflurane
33.3 % N2O
40 ml
1.96 L
1L
65.3 %O2
1.3 % Isoflurane
37.5 % N2O
61.25 % O2
1.25% Isoflurane
4 L 4 L
3 L
11. 2 Alveolar Ventilation
âȘ Increased alveolar ventilation, like PI, promotes input of
anesthetics to offset uptake
âȘ More rapid rate of increase in the Pa toward the PI and
thus induction of anesthesia
âȘ In neonates, this ratio is approximately 5:1 compared with
only 1.5:1 in adults, reflecting the greater metabolic rate in
neonates compared with adults.
âȘ Rate of increase of Pa toward the PI and thus the induction
of anesthesia is more rapid in neonates than in adults
12. Spontaneous vs Mechanical Ventilation
âȘ Inhaled anesthetics influence their own uptake by virtue of dose-
dependent depressant effects on alveolar ventilation.
âȘ As anesthetic input decreases in parallel with decreased ventilation,
anesthetic present in tissues is redistributed from tissues in which it is
present in high concentrations (brain) to other tissues in which it is
present in low concentrations (skeletal muscles).
âȘ When the concentration (partial pressure) in the brain decreases to a
certain threshold, ventilation increases and delivery of the anesthetic
to the lungs increases.
âȘ A protective mechanism, which is not seen in mechanical ventilation
13. 3 Anesthetic Breathing System
âȘ Induction can be accelerated with the use of high inflow
rates
âȘ Smaller the circuit volume, closer the inspired gas
concentration will be to the fresh gas concentration
âȘ Lower the circuit absorption, closer the inspired gas
concentration will be to the fresh gas concentration.
âȘ In rebreathing the inspired gas mixtures may be diluted
by residual gases in the system . Lower the rebreathing,
closer the inspired gas concentration will be to the fresh
gas concentration
14. Uptake of inhaled anesthetics
Uptake of inhaled anesthetics from alveoli into the pulmonary
capillary blood depends on
âȘ Solubility of the anesthetic in body tissues
âȘ Cardiac output
âȘ Alveolar-to- venous partial pressure differences
15. Solubility
âȘ Partition coefficient is a distribution ratio describing how
the inhaled anesthetic distributes itself between two
phases at equilibrium (partial pressures equal in both
phases).
âȘ Ostwaldâs blood:gas partition coefficient of 0.5 means that
the concentration of inhaled anesthetic in the blood is half
that present in the alveolar gases when the partial
pressures of the anesthetic in these two phases is identical
16. Blood:Gas Partition Coefficients
âȘ When blood solubility is low, minimal amounts of inhaled anesthetic must be
dissolved before equilibration is achieved; therefore, the rate of increase of Pa
and Pa, and thus onset-of-drug effects such as the induction of anesthesia, are
rapid.
âȘ overpressure technique and may be used to speed the induction of anesthesia:
increasing the PI above that required for maintenance of anesthesia
âȘ Blood:gas partition coefficients are altered by individual variations in water,
lipid, and protein content and by the hematocrit of whole blood
âȘ blood:gas partition coefficients are about 20% less in blood with a hematocrit
of 21% compared with blood with a hematocrit of 43%. Presumably, this
decreased solubility reflects the decrease in lipid-dissolving sites normally
provided by erythrocytes.
âȘ Ingestion of a fatty meal alters the composition of blood, resulting in an
approximately 20% increase in the solubility of volatile anesthetics in blood
17. Tissue: blood partition coefficients
âȘ Tissue: blood partition coefficients determine uptake of
anesthetic into tissues and the time necessary for
equilibration of tissues with the Pa.
18. Oil: gas partition coefficients
âȘ Oil: gas partition coefficients parallel anesthetic
requirements
âȘ Estimated MAC= 150 divided by the oil: gas partition
coefficient
âȘ 150, is the average value of the product of oil: gas solubility
and MAC for several inhaled anesthetics with widely
divergent lipid solubilities
19. Cardiac output
âȘ Cardiac output (pulmonary blood flow) influences uptake
âȘ And PA by carrying away either more or less anesthetic
from the alveoli
âȘ An increased cardiac output results in more rapid uptake,
ârate of increase in the PA âslow induction of anesthesia
20. Alveolarâvenous partial pressure gradient
âȘ The difference between alveolar and venous partial
pressures is due to tissue uptake of inhalation agents.
âȘ Brain tissue equilibrates quickly because it is highly
perfused with blood. Lean tissue (muscle) has roughly the
same affinity for anaesthetic agents as blood (blood tissue
coefficient 1:1), but perfusion is much lower than brain
tissue; therefore, equilibration is slower. Fatâblood
coefficients are significantly >1.
âȘ Such high affinity of fat tissue for anaesthetic and its low
perfusion levels result in a very long equilibration time.
21. Pharmacodynamics
âȘ MAC of an inhaled anesthetic is defined as that concentration at 1
atmosphere that prevents skeletal muscle movement in response to a
supramaximal painful stimulus (surgical skin incision) in 50% of
patients
âȘ MACawake, the concentration of anesthetic that prevents consciousness
in 50% of persons, - about half of MAC.
âȘ MACmemory, the concentration of anesthetic that is associated with
amnesia in 50% of patients, 0.25 MAC
âȘ MAC bar, to prevent adrenergic response to noxious stimuli-1.5 MAC
âȘ MAC intubation 1.3 MAC
23. Increase in MAC
âȘ Hyperthermia
âȘ Excess pheomelanin production (red hair)
âȘ Drug-induced increases in central nervous system
catecholamine levels
âȘ Cyclosporine
âȘ Hypernatremia
24. Decrease in MAC
âȘ Hypothermia
âȘ Increasing age
âȘ Preoperative medication
âȘ Drug-induced decreases in
central nervous system
catecholamine levels
âȘ a-2 agonists
âȘ Acute alcohol ingestion
âȘ Pregnancy
âȘ Postpartum (till 24â72 hours)
âȘ Lithium
âȘ Lidocaine
âȘ Neuraxial opioids (?)
âȘ PaO2 <38 mm Hg
âȘ Mean blood pressure<40
mmHg
âȘ Cardiopulmonary bypass
âȘ Hyponatremia
25. Mechanisms of Anesthetic Action
Meyer-Overton Theory
(Hans Horst Meyer 1899, Charles Ernest Overton1901)
âȘ Correlation between the lipid solubility of inhaled
anesthetics (olive oil:gas partition coefficient) and
anesthetic potency
âȘ Greater the lipid solubilityâ greater its anaesthetic
potency
âȘ Inhaled anesthetics disrupts the structure or dynamic
properties of the lipid portions of nerve membranes.
26. âȘ Linear relationship
between potency and
partition coefficient for
many types of
anaesthetics
âȘ Anaesthetic concentration
required to induce
anaesthesia in 50% of a
population of animals (the
EC50) was independent of
the means by which the
anaesthetic was delivered,
i.e., the gas or aqueous
phase
27. Critical volume hypothesis (Miller & Smith 1973)
âȘ Anesthetic binding to hydrophobic/lipophilic sites
in the phospholipid bilayer
âȘ Expand the bilayer beyond a critical amount,
altering membrane function
âȘ Distortion of channels necessary for ion flux and the
subsequent development of action potentials
needed for synaptic transmission
28. Bulky and hydrophobic
anaesthetic molecules
accumulate inside the
neuronal cell membrane
causing its distortion and
expansion (thickening) due
to volume displacement.
Membrane thickening reversibly alters function of membrane ion channels thus
providing anaesthetic effect.
Actual chemical structure of the anaesthetic agent per se was not important.
But its molecular volume plays the major role: the more space within membrane
is occupied by anaesthetic - the greater is the anaesthetic effect.
29. âȘ Stereoisomers of an anaesthetic drug have very different anaesthetic
potency whereas their oil/gas partition coefficients are similar
âȘ Certain drugs that are highly soluble in lipids, and therefore expected
to act as anaesthetics, exert convulsive effect instead
(called nonimmobilizers. [Flurothyl (Indoklon) volatile liquid drug
from halogenated ether family]
âȘ A small increase in body temperature affects membrane density and
fluidity as much as general anaesthetics, yet it does not cause
anaesthesia.
âȘ Increasing the chain length in a homologous series of straight-chain
alcohols or alkanes increases their lipid solubility, but their anaesthetic
potency stops increasing beyond a certain cutoff length.
Objections to lipid hypotheses
30. Macroscopic
âȘ At the spinal cord level, inhalation anaesthetics decrease transmission of noxious
afferent information ascending from the spinal cord to the cerebral cortex via the
thalamus, thereby decreasing supraspinal arousal.
âȘ There is also inhibition of spinal efferent neuronal activity reducing movement response
to pain.
âȘ Hypnosis and amnesia, on the other hand, are mediated at the supraspinal level.
âȘ Inhalation agents globally depress cerebral blood flow and glucose metabolism.
âȘ Tomographic assessment of regional uptake of glucose in anaesthetized volunteers
indicates that the thalamus and midbrain reticular formations are more depressed
than other regions.
âȘ Electroencephalographic changes including generalized slowing, increased amplitude,
and uncoupling of coherent anteroposterior and interhemispherical activity occur during
anaesthetic-induced unconsciousness
31. Synaptic
âȘ The actions of inhalation agents on ion channels of neuronal
tissue can influence either the presynaptic release of
neurotransmitters, alter the post-synaptic response threshold to
neurotransmitters, or both.
âȘ Inhaled anaesthetics are believed to inhibit excitatory
presynaptic channel activity mediated by neuronal nicotinic,
serotonergic, and glutaminergic receptors, while also
augmenting the inhibitory post-synaptic channel activity
mediated by GABAA and glycine receptors.
âȘ The combined effect is to reduce neuronal and synaptic
transmission.
32. Molecular
âȘ Effects of inhalation agents on a-subunits of the GABAA
transmembrane receptor complex are likely to be important.
âȘ GABA binding to its receptor leads to opening of a chloride
channel leading to increased Cl2- ion conductance and
hyperpolarization of the cell membrane, thereby increasing the
depolarization threshold.
âȘ Inhalation anaesthetics prolong the GABAA receptor-mediated
inhibitory Cl2- current, thereby inhibiting post-synaptic neuronal
excitability
âȘ N2O and xenon are NMDA antagonists
33. Effects on Respiratory system
âȘ Depress ventilation by reducing tidal volume
âȘ Increase in respiratory rate does not compensate for the reduced alveolar ventilation, as it primarily
results in increased dead-space ventilation.
âȘ Consequently, PaCO2 increases
âȘ Increase the threshold (⏠sensitivity) of respiratory centres to CO2
âȘ Hypoxic drive (the ventilatory response to arterial hypoxia) that is mediated by peripheral
chemoreceptors in the carotid bodies: depressed by N2O, Halothane
âȘ Halothane: a potent bronchodilator, reverses asthma-induced bronchospasm
âȘ Halothane attenuates airway reflexes and relaxes bronchial smooth muscle by inhibiting intracellular
calcium mobilization. Halothane also depresses clearance of mucus from the respiratory tract
(mucociliary function), promoting postoperative hypoxia and atelectasis
âȘ Isoflurane and sevoflurane decrease airway resistance.
âȘ Desflurane: pungent, airway irritation- manifested by salivation, breath-holding, coughing, and
laryngospasm. Airway resistance may increase in children with reactive airway susceptibility. â poor
choice for inhalation induction.
35. CVS
âȘ N2O stimulates Sympathetic NSâ catecholamine stimulation
âȘ So, even though N2O causes myocardial depression, BP, CO, HR unchanged
âȘ Reduction of arterial BP mainly due to myocardial depression
âȘ Reduction in mean arterial pressure by desflurane, sevoflurane, and isoflurane is primarily
determined by the reduction in systemic vascular resistance.
âȘ Normally, hypotension inhibits baroreceptors in the aortic arch and carotid bifurcation, causing a
decrease in vagal stimulation and a compensatory rise in heart rate. Halothane blunts this reflex.
âȘ Cardiac output maintained with isoflurane due to preservation of carotid baroreflexes.
âȘ Halothane sensitizes heart to arrthymogenic effects of epinephrineâdose above 1.5mcg/kg avoided
âȘ Isoflurane: Dilation of normal coronary arteries can divert blood away from fixed stenotic lesions
(Coronary steal)
âȘ Sevoflurane may prolong the QT interval, manifest 60 min following emergence in infants
âą Ischaemic preconditioning with inhalation anaesthetics may reduce perioperative myocardial
injury: KATP channel activity increasedâ decrease in the voltage gradient, decrease in calcium ion
accumulation, the cardiac action potential shortens, negative inotropic action and remarkable
protection against subsequentmsustained ischemic
39. Neuromuscular
âȘ N2O does not provide significant muscle relaxation. At high
concentrations â skeletal muscle rigidity
âȘ Halothane relaxes skeletal muscle and potentiates non-
depolarizing neuromuscular-blocking agents.
âȘ Volatile anesthetics: triggering agent of malignant
hyperthermia
âȘ Desflurane is associated with a dose-dependent decrease
in the response to train-of-four and tetanic peripheral
nerve stimulation.
40. Renal
âȘ Production of inorganic fluoride by the metabolism of
halogenated agents may cause direct nephrotoxicity.
âȘ âŹBlood flow, GFR, urine output âŹ
(due to âŹRenal vascular resistance, âŹarterial BP and CO)
âȘ Isoflurane is more resistant to defluorination and can be
used for prolonged periods without significant increases in
serum fluoride levels
âȘ Preoperative hydration limits these changes in renal
function
41. Gastrointestinal
âȘ N2O increases the risk of postoperative nausea and vomiting
âȘ Activation of chemoreceptor trigger zone and vomiting center in the
medulla
42. Metabolism and toxicity
âȘ N2O: eliminated by exhalation
âȘ Small amount diffuses out through skin
âȘ <0.01% undergoes reductive metabolism in GI tract by anaerobic bacteria
âȘ Oxidizes cobalt (vitamin B 12)â inhibits vitamin B-12 dependent enzymes
âȘ Methionine synthetase (myelin formation)â peripheral neuropathies,
neurotoxicity
âȘ Thymidylate synthetase (DNA synthesis)â teratogenecity
âȘ Bone marrow depression (megaloblastic anemia)
âȘ Alter immunological response to infection by affecting chemotaxis and motility
of polymorphonuclear leukocytes
43. âȘ Extremely rare (1 per 35,000 cases)
â Halothane oxidized in the liver by CYP 2EIâprincipal metabolite, trifluoroacetic acid
â This metabolism can be inhibited by pretreatment with disulfiram
âȘ Exposure to multiple halothane anesthetics at short intervals
âȘ Middle-aged obese women
âȘ Familial predisposition to halothane toxicity
âȘ Personal history of toxicity
âȘ Signs (are mostly related to hepatic injury)
âȘ increased serum alanine and aspartate transferase, elevated bilirubin (leading to
jaundice), and encephalopathy
âȘ Centrilobular necrosis
âȘ Signs indicating an allergic reaction (eosinophilia, rash, fever) and do not
appear until a few days after exposure
Halothane hepatitis
44. Carbon monoxide poisoning
âą Desflurane is degraded by desiccated CO2
absorbent (barium hydroxide lime, but also
sodium and potassium hydroxide) into carbon
monoxide
âą Difficult to diagnose under GA
âą Carboxyhemoglobin may be detectable by ABG
analysis, lower than expected SpO2
45. Compound A
âą Soda lime or barium hydroxide lime (but not calcium
hydroxide) can degrade sevofluraneâ Compound A
âą Fluoromethyl-2,2-difluoro-1-[trifluoromethyl] vinyl ether
âą Nephrotoxic
âą Accumulation increases with increased respiratory gas
temperature, low flow anesthesia, dry barium hydroxide
absorbent, high sevoflurane concentrations, and
anesthetics of long duration.
46. Xenon
âȘ Inert (probably nontoxic with no metabolism)
âȘ Minimal CVS effects
âȘ TV increase, RR decrese
âȘ Low blood solubility (B:G coeff 0.115)
âȘ Rapid induction and recovery
âȘ Does not trigger malignant hyperthermia
âȘ Environmentally friendly
âȘ Nonexplosive
âȘ High cost, Low potency (MAC = 70%)
47. References
âȘ Morgan & Mikhailâs Clinical Anesthesiology,
5th edn
âȘ Stoeltingâs Pharmacology and Physiology in
Anesthetic Practice, 5th edn
âȘ Khan KS, Hayes I, Buggy DJ. Pharmacology of
anaesthetic agents II: inhalation anaesthetic
agents. Continuing Education in Anaesthesia
Critical Care & Pain. 2014;14(3):106-11.