SJ

1. Guided by: Dr. SURENDRA SIR
Dr. MUNIRAM SIR
Presented by: Dr. SHREE JAYANTH

5. UPTAKE OF INHALATIONAL ANAESTHETIC
AGENTS
• Inhalational agents are delivered by vaporizers and mixed
with carier gas (oxygen with nitrous oxide or oxygen alone)
then reaches the patient's alveoli, from where it is taken up
by blood and reaches dilferent tissues. The concentration in
brain determines the effect of inhalational agent.
• FACTORS AFFECTING UPTAKE & DISTRIBUTION-
• 1) Inspired concentration (Fl)
• 2) Alveolar Concentration (FA)
• 3) Blood Gas partition coefficient
• 4) Cardiac Output
• 5) Alveolar to venous partial pressure
• 6) Ventilation

6. Factors affecting Anaesthetic Uptake

7. FACTORS AFFECTING INSPIRED GAS
CONCENTRATION(Fi)
1)fresh gas flow
↑ FGF1 →↑speed of induction &
recovery(If pt awakes in the middle of
surgery on low flow→↑FGF)
2)volume of breathing circuit
if ↑volume→slower
induction due to dilution of anaesthetic
gases (Eg. MRI breathing circuits,
circuit priming for pacdiatrics, circuit
priming for single breath technique for
sevoflurane)

8. 3) Absorption by the breathing circuit
rubber tubing absorbs more when compared to plastic &
silicon,this delays induction & recovery. Not
used for pt with suspected malignant
hyperthermia (release of trace
anaesthetic gases)

9. FACTORS AFFECTING ALVEOLAR
CONCENTRATION
Ventilation: ↑minute ventilation→↑ delivery (Eg. child crying)
uptake : ↑uptake →slower rate of induction due to Slower build up
of Alveolar Partial Pressure.
1 Blood/gas solubility coefficient:
↑solubility →↓rate of induction (Blood & tissues act like a sponge)

10. 2.PULMONARY BLOOD FLOW:(CARDIAC OUTPUT)
↑Alveolar blood flow→↑ uptakes→lower build up of alveolar
partial pressure, thus slower induction.
This effect is greater with soluble agents (E.g. halothane)> insoluble
agents (N20)
Children with TOF→Rapid induction due to ↓ pulmonary blood flow.
3) Tissue Uptake:
↑ Tissue uptake→ lower partial pressure of venous blood→↑
uptake→slower rate of induction
(a) Tissue solubility of anaesthetic agent
(b) Tissue blood flow
(c) Partial pressure difterence between Arterial blood and tissues.

11. ALVEOLAR VENTILATION
• Increase in Minute alveolar ventilation→Increases FA/FI
• The change is greatest for more soluble
anaesthetics.
• Halothane depress alveolar ventilation and limit the
rise of alveolar concentration.
● Nitrous ovide and Halothane-slows induction.
Ether-faster induction.

12. PARTIAL COEFFICIENTS OF VOLATILE
ANAESTHETICS AY 37 DEG C

13. FACTORS AFFECTING ARTERIAL
CONCENTRATION (Fa)
depends on ventilation perfusion mismatch
(a) Ventilated non perfused areas: [dead space]→ ↓arterial
concentration.
(b) Perfused non ventilated areas: [intrapulmonary shunting]→
↓arterial concentration.

14. SUMMARY
1. Factors affecting Inspiratory Concentrations ( Fi ):
• Fresh gas flow rate
• Breathing circuit volume
• Circuit absorption
2.Factors affecting Alveolar Concentrations ( FA ):
Uptake: 3 factors
1.Solubility in blood
2. Alveolar blood flow
3.tissue uptake
Delivery:
1.concentration
2.minute ventilation

15. 3.Factors affecting Arterial Concentration ( Fa ):
• Ventilation perfusion mismatch
• Alveolar deadspace
• Nonuniform alveolar gas distribution
4.Factors affecting Elimination
• Exhalation- most important route of elimination
• Biotransformation (cyto P450)
• Transcutaneous- insignificant

18. Summary of co-relations
1. B/G coeflicient ∝ 1/time of induction and recovery
2 Cardiac output ∝uptake ∝ 1/Alveolar Conc∝ 1/Time of Induction
3 Ventilation ∝ Alveolar conc. Of High B/G coeff

19. DISTRIBUTION
• Brain rapidly equilibrate with arterial blood.
• Time constant (2-4 minutes) is brain blood partition coeficient
divided by brain blood low.
• Blood brain partition coefficients vary relatively little between
anesthetic agents.
• After one time constant, brain partial pressure is at 63% of
arterial partial pressure.
• Brain uptake follows alveolar uptake within 5-10 minutes.
• Speed of equilibration inversely proportional to brain blood
partition coefficient.
• BBPCs do not vary much between agents.

20. METABOLISM
• All inhalational agents undergoes oxidation (dealkylation or
dehalogenation) in liver (halothane also undergoes reduction) by
cytochrome P450 enzymes in phase I reactions and by
conjugation in phase II reactions.
• All enzyme inducers like isoniazid, phemytoin phenobarbitone,
ethanol, diazepam increase the metabolism of inhalational
agents.
• Among the agents available today maximum metabolism is seen
with halothane (20%). Desflurane is negligibly metabolized (<1%)
and Nitrous oxide does not undergo any metabolism in human
body.

21. ELIMINATION OF INHALATIONAL AGENT
• Recovery from any anesthesia depends on lowering the brain
anaesthetic concentration, indirectly rate at which the alveolar
anaesthetic partial pressure declines. This elimination can
happen secondary to-
• Biotransformation(more with soluble agents)-Halothane
• Transcutaneous loss (minimal)
• Exhalation (Most important)

22. • Thus, the fall in the alveolar partial pressure of methoxyflurane
is slower than the fall with halothane, and the latter in turn, is
less rapid than the fall with nitrous oxide.
• The rate at which recovery occurs is similarly affected:
It is rapid with nitrous oxide and may be slow with
methoxyflurane.
• The rapidity of recovery thus largely depends on the
solubility of the anaesthetic.

23. ELIMINATION ROUTES OF DIFFERENT
VOLATILE AGENTS

24. IDEAL PHYSICAL PROPERTIES OF
INHALATIONAL AGENTS
• 1.Stable over range of temperatures.
• 2.Not degraded by light.
• 3.Does not require the presence of preservatives.
• 4.Non-explosive and does not support combustion.
• 5.0dourless or has a pleasant smell.
• 6.Environmentally safe.
• 7.Does not reacts with other compounds(e.g.-soda lime)
• 8.Has a boiling point well above room temperature.

25. IDEAL PHARMACOKINETIC PROPERTIES OF
INHALATIONAL AGENTS
• 1.Low blood: gas solubility coefficient.
• 2.Low oil: gas solubility coefficient.
• 3.Not metabolised or no active metabolites.
• 4.Is excrected completely by the respiratory system

26. IDEAL PHARMACODYNAMIC PROPERTIES OF
INHALATIONAL AGENTS
• 1.Predictable dose related CNS depression.
• 2.Analgesic anti-emetic and muscle relaxation properties.
• 3.Minimal respiratory depression, does not cause coughing or
bronchospasm.
• 4.Minimal cardiovascular effects.
• 5.No increase in cerebral blood flow(and therefore intracranial
• pressure)
• 6.Not epileptogenic.
• 7.Does not impair renal or hepatic function.
• 8.No effect on uterine smooth muscles.
• 9.Does not trigger malignant hyperthermia.

27. PHARMACODYNAMICS
OF INHALATIONAL
AGENTS

28. SITE OF ACTION OF INHALATIONAL
ANAESTHETICS
• These agents mainly acts on CNS producing amnesia, muscle
relaxation and unconsciousness.
• Dorsal horn cells of spinal cord producing analgesia.
• Mainly acts on synapses, can bock axonal transmission
at high doses.
• Acts at both pre and post synaptic levels.
• At molecular level all inhalational agents have a common
lipophilic (lipid soluble) site. This theory is called UNITARY
THEORY OF NARCOSIS.

29. MECHANISM OF ACTION
•The most acceptable mechanism is that they directly bind to
cellular proteins altering their enzymes.
• Theory of Fluidization- they expand cellular membrane,causes
its fluidization to block sodium channels.
*It enhances GABA mediated inhibition of cns
*Decrease the concentration of excitatory neurotransmitters
like adrenaline, nor-adrenaline, acetylcholine and serotonin.
• Increases the concentration of inhibitory neurotransmitters
like GABA and adenosine.
• Opening of inhibitory ion channels (Cl- or K)
• Hyper polarization of nerve cell membrane.
• Diminished propensity to action potential.
• Multiple sites of action.

30. THEORIES OF ANAESTHETIC ACTION
• lipid based
• 1) Lipid Solubility- Overton & Meyer rule
• 2) Alterations to Lipid Bilayers
• a) Lipid perturbation -dimensional change-lipid phase transition,
i.e. gel to liquid crystalline state
• b) lipid-protein interactions
• protein based
• Alteration to Protein Function

31. LIPID SOLUBILITY
• Aesthetie potenty:minimum alveolar concentration MAC)
• Anaesthetic potency of an inhalational agent is directly
proportional to its lipid solubility (Oil:Gas partition coeflicient).
• This is called MEYER OVERTON RULE given by Hans Horst Meyer and
Charles Ernest Overton.
• The potency of a drug is the measure of quantity of drug that must be
administered to achieve a given effect.
• In case of inhalational anaesthetic agents, potency is described by the
MINIMUM ALVEOLAR CONCENTRATION(MAC) defined as minimum
concentration of volatile agent measured as a percentage at I
atmosphere i.e. partial pressure that prevents the movement in
50% subjects in response to a sub maximal stimulus which is skin
incision(surgical stimulus).
• This measurement is done at steady state assuming that this allows an
equilibration between gases in alveoli, brain and blood.

33. • The implication is that anacsthesia results from molecules
dissolving at specific lipophilic sites, when a critical number of
anaesthetic molecules occupy a crucial hydrophobic region
resulting in disturbance of physical properties of cell
membranes in CNS.
• Meyer-0verton rule postulates that it is number of molecules
which are present at the site of action is important and not their
type, thus, this hypothesis supports additive nature of
anaesthetic agents.
• Exceptions to the Meyer-Overton Rule:
• 1) HALOGENATED COMPOUNDS-
• Enflurane and Isoflurane are structural isomers and have similar
oil: gas partition coefficients, however, the MAC for isoflurane is
only-70% of enflurane.
• Complete halogenation of alkanes & ethers results in decreased
• anaesthetic potency as for enfluranes.

34. • 2) CUTOFF EFFECT:
• Increased lipid solubility increases anesthetie potency.
• Increasing homologues alkane series display a cut-off point,
beyond which anaesthetic potency sharply decreases.
• One postulate is that the larger members of a series are too large
to fit into the anaesthetic site.

35. ALTERATIONS TO LIPID BILAYERS
• Biological membranes consist of a cholesterol- phospholipid
bilayer, having a thickness of 4 nm.
• Peripheral proteins are weakly bound to exterior hydrophilic
membrance & integral proteins are deeply imbedded in, or
pass through the lipid bilayer.
• Synaptic membranes are-50:50 lipid bilayer & protein by
weight.

36. LIPID PERTUBATION: Effects on Membrane Dimension
• Anaesthetic binding significantly modify membrane structure,
effect is exerted through some perturbation of the lipid bilayer.
• Several types of bilayer perturbations were proposed to cause
anaesthetic effect
• changes in bilayer thickness
• changes in phase separation
• changes in curvature/elasticity

37. LIMITATIONS OF LIPID SOLUBILITY:
1) Stereo isomers of an anesthetic drug have very different
anesthetic potency whereas their oil/gas partition coeffecients are
similar.
2) Certain drugs that are highly soluble in lipids, and therefore
expected to act as anaesthetics, exert only one constituent of the
anaesthetic action (amnesia) and do not suppress movement (and
therefore were called immobilizers).
3) A small increase in body temperature attects membrane
density and fluidity as much as general anaesthetics, yet it does
not cause anaesthesia.
4) Increasing 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.

38. PROTEIN BASED THEORY OF INHALATIONAL ANESTHESIA : .
• In the early 1980s,Franks and Lieb demonstrated that Meyer-
Overton correlation can be reproduced using a soluble protein.
• These are luciferases and cytochrome P50.
• Remarkably, inhibition of these proteins by general anaesthetics
was directly correlated with their anaesthetic potencies.
• They demonstrated that general anaesthetics may also interact
with hydrophobic protein sites of certain proteins,rather than
affect membrane proteins indirectly through nonspecific
interactions with lipid bilayer as mediator.

40. MAC TYPES
• MAC AWAKE: allowing voluntary response to command in
50% of patients.(0.3 times MAC)
• MAC95 :MAC that prevents movement in 95 % of patients. (1.3
times MAC)
• MAC intubation: MAC that allows intubation without muscle
relaxant, coughing or bucking in 50% of patients(1.3 times
MAC)
• MAC-BAR: (1.7-2.0 times MAC) which is the concentration
required to block autonomic reflexes to nociceptive stimuli.

41. • The substitution of fluorine for chlorine in the conversion of
isoflurane to desflurane decreases potency by 5-folds. Even so, the
potency of desflurane permits the use of nearly 100% oxygen, Nitrous
Oxide decreases the MAC requirement for all inhaled agents, but the
decrease is consistent (proportionately the same) for all.
• MAC AWAKE is the alveolar concentration at which 50% of subjects
respond appropriately to command. For all potent inhaled anesthetic
agents, the ratio of MAC-awake to MAC is between 0.3 and 0.5.
• The importance of the ratio of MAC-awake to MAC lies in the
connection between MAC-awake and amnesia. The modern inhaled
anesthetics are much more potent amnestic agents than nitrous
oxide.
• MAC-BAR is the concentration of an inhaled anesthetic that blocks
the sympathetic response (increased blood pressure and/or heart
rate) to a noxious stimulus, such as skin incision in 50% of subjects of
the modern inhaled agents, sevoflurane has the highest MAC-BAR.

43. PHYSIOLOGIC & PHARMACOLOGIC
FACTORS AFFECTING MAC
Increase in MAC:-
Hyperthermia
Hypernatraemia
Drug induced elevation of CNS catecholamine stores
Chronic alcohol abuse & chronic opioid abuse
Increases in ambient pressure (experimental)
Cyclosporine
Excess pheomelanin production(red hair)

44. Decrease in MAC:-
Hypothermia & Hyperthermia (if >42◦ C)
Hyponatraemia
Drug induced decrease in CNS catecholamine level
Increasing age (6% decrease/decade)
Preoperative medication
Hypoxaemia (PaO2< 38mmHg)
Hypotension(<40 mm hg- MAP)
Anaemia (Haematocrit<10%)
Pregnancy ( progesterone)
Postpartum(returns to normal in 24-72 hrs)
CNS depressant drugs – Opioids,Benzodiazepines TCA's etc.
other drugs–lithium, Lidocaine,Magnesium
acute alcohol abuse
Cardiopulmonary bypass

45. • No Change in MAC
Gender
Duration of anaesthesia
Anaesthetic metabolism
Hypo/ Hyperkalaemia
Thyroid gland dysfuction
PaCO2 ~ 15-95 mmHg
PaO2 > 38 mmHg
MAP > 40 mmHg