1. UPTAKE AND DISTRIBUTION OF INHALATIONAL ANAESTHETIC AGENTS
Dr Neha Gupta
University College of Medical Sciences & GTB Hospital, Delhi

2. Pharmacology
Pharmacokinetics – what body does to the drug like absorption of the drug (uptake), distribution, metabolism, excretion, etc
Pharmacodynamics – what drug does to the body like effect on various organ systems, etc

3. INHALATIONAL AGENTS
Goal of inhalational anaesthesia Development of critical tension of anaesthetic agent in the brain : correlates with depth of anaesthesia and its side effects.

4. Factors controlling the brain levels
Production and delivery of suitable concentration of anaesthetic agent for inhalation ( Fi AA)
Factors effecting the distribution of this agent to the lung
Uptake of the drug by the blood from the lung
Delivery from circulation to the brain

5. Delivery of adequate Fi AA
Depends on
Delivered concentration ( Fd )
Wash in of the circuit : higher inflow rates required initially to wash in the circuit volume with anaesthetic gas mixture
Loss of anaesthetic to plastic and soda lime
Rebreathing

6. Rebreathing
Patient takes up anaesthetic from the inspired gases ; leading to depletion of anaesthetic in the rebreathed gas mixture
Lowering of inspired conc of AA due to rebreathing
This effect can be minimized by increasing the inflow rates to decrease rebreathing : high inflow rates ↑ predictability

7. Anaesthetic circuits High flow (> 5L/m)
Advantages- ↑ predictability
Disadvantages- wasteful, ↑ atmospheric pollution , costly, drying of inspired gas
Low flow ( FGF < half the MV ; 3L/m)
Closed circuit anaesthesia ( flow sufficient to replace the gases removed by the patient )

8. Closed circuit anaesthesia
Advantages
Lower cost
Humidification
Reduced heat loss
Less environment pollution
Disadvantages
Lack of control
Hypoxic mixture can be delivered
Fd/FA ratio governed by uptake

9. Low flow anaesthetic delivery
Mitigates instability of the closed circuit
Constant oxygen and anaesthetic levels
Elimination of CO and other toxic anaesthetic breakdown products

10. Anaesthetic delivery Factors governing Fd/FA
Solubility : higher for more soluble agents
Inflow rate : higher with less inflow rates
Uptake of AA by the circuit

11. Anaesthetic delivery

12. Delivery of anaesthetic agent to lung & alveoli
Partial pressures of AA in alveoli ( PA ) governs the partial pressure of anaesthetic agents in arterial blood ( Pa ) and thence in all body tissues, esp brain

13. Delivery of anaesthetic agent to lung & alveoli
Alveolar levels governed by
Factors promoting delivery to the lung-
a)inspired concentration of the AA
b)alveolar ventilation
Factors promoting uptake of AA by the blood passing thru the lung

14. Effect of inspired concentration
Concentration effect - increasing the inspired concentration not only increases the alveolar conc but also increases the rate of rise of volatile anaesthetic agents in the alveoli
- concentrating effect
- augmentation by inspired flow

15. Concentrating effect

16. Augmented inflow effect
Due to inspiration of additional volume of gas mixture to replace that lost by uptake

17. Second gas effect
A high concentration of N2O augments its own uptake & that of concurrently administered volatile anaesthetic too.
Thus, passive ↑ in inspired ventilation due to rapid uptake of large volumes of N2O ↑ rate of rise of 2nd gas in alveoli regardless of Fi AA

18. Second gas effect

19. Effect on ventilation on alveolar conc. of AA
↑ ventilation accelerates rate of rise of FA/Fi by augmenting the delivery of AA to the lungs
Change more pronounced with more soluble agents : more caution required clinically

20. Effect on ventilation on alveolar conc. of AA

21. Effect on ventilation on alveolar conc. of AA
Negative feedback with AA- Inhalational agents depress ventilation and cause apnea : hence alter their own uptake

22. Negative feedback

23. Hyperventilation Increases alveolar conc directly
Decreases cerebral blood flow : reduces rate of rise of AA conc in brain
Balance depends on the solubility of the AA used……

24. Uptake of the anaesthetic agent by the blood
Organ of uptake is the lungs – large surface area
Uptake =
[(l) x (Q) x (PA-PV)] / Barometric Pres.
l = solubility
Q = cardiac output
PA-PV = alveolar venous partial pressure difference

25. Solubility
Describes how a gas or vapour is distributed between two media at equilibrium. For eg, between blood and gas, between tissue and blood, etc.
Higher B:G partition coefficient means more solubility & greater uptake and vice versa

26. Blood gas coefficients
Anaesthetic agent
B:G coefficient
Desflurane
0.45
Nitrous oxide
0.47
Sevoflurane
0.65
Isoflurane
1.4
Halothane
2.5
Diethyl ether 12

27. Uptake and Solubility
The more soluble the anesthetic agent is in blood the faster the drug goes into the body
The more soluble the anesthetic agent is in blood the slower the patient becomes anesthetized (goes to sleep)
To some degree this can be compensated for by increasing the inhaled concentration but there are limits

28. Rate of rise of alveolar concentration & Solubility

29. Cardiac output
↑ in cardiac output increases uptake and ↓ FA/Fi ratio causing ↓ Pa & Pt
However this low Pt especially in brain is reached rapidly
More soluble agents more effected by the effect of Q on uptake

30. Cardiac output Q = Stroke Volume x rate
amount of AA in each alveolus is fixed between breaths
Increasing the volume of blood improves the amount of AA absorbed, but the concentration of agent in blood is lower
Higher Q creates lower Pv concentrations
Increased Cardiac Output slows the rate at which the patient goes to sleep

31. Cardiac output

32. Cardiac output
Lower Q states (shock) ↑ alveolar conc of more soluble agents : use of less soluble agents like N2O preferred
Positive feedback- AA ↑ their own alveolar conc by depressing the circulation

33. Concomitant changes in ventilation & perfusion
Doubling of both V & Q should produce no net change in the conc of AA in alveoli…. But an inc in Q decreases alveolar to venous partial pressure difference, thus reducing the uptake
Net result is increase in rate of rise in FA/Fi

34. Concomitant changes in ventilation & perfusion

35. Concomitant changes in ventilation & perfusion
True for conditions like hyperthermia & thyrotoxicosis where increased CO is distributed equally to all tissue groups
Children (especially infants) have a greater perfusion of VRG : more rapid development of anaesthesia in young patients..

36. Faster induction in children…

37. Ventilation perfusion mismatch
Increases alveolar end tidal partial pressure of AA (PA)
Decreases arterial pressure (Pa)
Relative change and thus induction of anaesthesia depends on the solubility of the AA….

38. Endobronchial intubation
Hyperventilation in intubated lung
Shunting in unventilated lung
More soluble agents(halothane, ether) rapidly increase FA due to hyperventilation, thus compensating for absence of uptake from unventilated lung.
This compensatory mechanism absent with poorly soluble agents…..

39. The poorly soluble agents like sevoflurane, desflurane would achieve lower Pa ( and hence a delayed induction) than more soluble agents like ether in clinical conditions with VQ mismatch if compared with normal VQ……

40. PA - PV
PA – PV (PAlveolar – PVenous) anesthetic agent partial pressure difference
is the result of uptake of anesthetic agent by the patients tissues
This difference remains until the tissues are saturated and at equilibrium
Tissue/blood solubility
Tissue blood flow
Pa - Pt

41. PA - PV
During induction – rapid removal of AA by the tissues causing increase in alveolar to venous gradient leading to max anaesthetic uptake
With passage of time, ↑ in tissue conc decreases the gradient, thus reducing the uptake

42. Delivery of anaesthetic to the tissues
Uptake by the tissues are governed by-
a) solubility of the agent in the tissues
b) tissue blood flow
c) arterial-tissue partial pressure gradient

43. Delivery of anaesthetic to the tissues
Tissue blood gas partition coefficient vary less than B:G partition coeff.
Rate at which tissue anaesthetic partial pressure reaches arterial level is fairly uniform for all anaesthetic agents and depends on the blood supply to the tissues

44. Tissue Group Characteristics
Vessel Rich
Muscle
Fat
Vessel Poor
Percent Body Mass 10 50 20
Percent Cardiac Output 75 19 6
Perfusion (ml/min/100gm) 3

45. Tissue Group Characteristics
VRG equilibrates with Pa in 8-10 min
MG determines most of tissue uptake after that and require 2-4 hrs to achieve equilibrium
The FG has great affinity for AA which considerably increases the time over which it absorbs anaesthetic: equilibrium is never achieved

46. Recovery from anaesthesia: washout
Factors Affecting Elimination 
Elimination
1. Biotransformation: cytochrome P-450
2. Transcutaneous and visceral loss: insignificant
3. Exhalation: most important

47. Recovery
Factors speeding recovery : identical to those present during induction
increased ventilation
Elimination of rebreathing, high fresh gas flows,
anesthetic washout from the circuit volume,
decreased solubility and uptake,
high cerebral blood flow,
Short duration of exposure…

48. Recovery from anaesthesia: waking up
Why different from induction?
During induction, effect of solubility to hinder ↑ in alveolar conc can be overcome by increasing insp conc…… not so during recovery as insp conc cannot be reduced below 0
Tissue partial pressures during recovery are variable unlike equal tissue partial pressue , which is 0 , during induction!!

49. Both solubility and duration of anesthesia affect the fall of the alveolar concentration (FA) from its value
immediately preceding the cessation of anesthetic administration (FA0 ). A longer anesthetic slows the fall, as does a
greater solubility, and the effects are shown for the increasingly soluble desflurane, sevoflurane, and isoflurane (A to C).
The horizontal lines designated (a), (b), and (c) indicate 80%, 90%, and 95% decreases, respectively, in the alveolar
concentration from the concentration at the end of anesthesia. (Data from Yasuda N, Lockhart SH, Eger EI II, et al:
Kinetics of desflurane, isoflurane, and halothane in humans. Anesthesiology 74:489–498, 1991, and from Yasuda N,
Lockhart SH, Eger EI II, et al: Comparison of kinetics of sevoflurane and isoflurane in humans. Anesth Analg 72:316–
324, 1991.)

50. Diffusion hypoxia
Elimination of nitrous oxide is so rapid that alveolar O2 and CO2 are diluted: max during initial 5-10 min
Oxygenation hampered due to diluted alveolar oxygen tension
Decrease in CO2 leads to dec respiratory drive and hence ventilation

51. Diffusion hypoxia

52. Inhalational anaesthesia may be viewed as development of a series of tension gradients which decrease as we pass from
-cylinder to the anaesthetic circuit
-circuit to alveoli
-alveoli to brain & other tissues
Rational administration of anaesthesia require an understanding of factors governing these gradients so that they may be best controlled or accounted for……

53. References Miller’s anaesthesia – 7th edition
Wylie and Churchill : practice of anaesthesia – 5th edition
Clinical anesthesiology by Morgan et al - 4th edition
Clinical anesthesia by Barash et al- 5th edition

54. Thank you..