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

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

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.

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

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

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

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 )

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

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

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

Anaesthetic delivery

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

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

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

Concentrating effect

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

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

Second gas effect

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

Effect on ventilation on alveolar conc. of AA

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

Negative feedback

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……

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

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

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

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

Rate of rise of alveolar concentration & Solubility

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

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

Cardiac output

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

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

Concomitant changes in ventilation & perfusion

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..

Faster induction in children…

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….

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…..

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……

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

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

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

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

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

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

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

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…

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!!

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.)

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

Diffusion hypoxia

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……

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

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