UPTAKE AND DISTRIBUTION OF INHALATIONAL ANAESTHETIC AGENTS

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

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 & thyrotoxicosiswhere 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

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 inspconc…… not so during recovery as inspconc cannot be reduced below 0 • Tissue partial pressures during recovery are variable unlike equal tissue partial pressue , which is 0 , during induction!!

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