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 levelsProduction 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

AdvantagesLower costHumidificationReduced heat lossLess environment pollutionDisadvantagesLack of controlHypoxic mixture can be deliveredFd/FA ratio governed by uptake

Low flow anaesthetic deliveryMitigates 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 concentrationConcentration 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 effectA 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

HyperventilationIncreases alveolar conc directlyDecreases 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 SolubilityThe 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 outputQ = 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 outputLower 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 & perfusionTrue 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 mismatchIncreases 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 intubationHyperventilation in intubated lungShunting 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 solubilityTissue blood flowPa - 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 tissuesTissue 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

Characteristic Vessel Rich Muscle Fat Vessel

Poor

Percent Body Mass

10 50 20 20

Percent Cardiac Output 75 19 6 0

Perfusion (ml/min/100g

m)

75 3 3 0

Tissue Group CharacteristicsVRG 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: washoutFactors 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…

Why different from induction?

1. 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

2. Tissue partial pressures during recovery are variable unlike equal tissue partial pressue , which is 0 , during induction!!

Recovery from anaesthesia: waking up

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 editionWylie and Churchill : practice of

anaesthesia – 5th editionClinical anesthesiology by

Morgan et al - 4th editionClinical anesthesia by Barash et

al- 5th edition

Thank you..