uptake of inhalational anaesthetics

8/6/2019 Uptake of Inhalational anaesthetics

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P T A K E O F I N H A L A T I O N A L P T A K E O F I N H A L A T I O N A LA N E S T H E T I C SN E S T H E T I C S

DR.DEEPAK SOLANKIM.D. [email protected]



• Pharmacokinetics: Relationship between a drug'sdose tissue concentration and elapsed time.

• Pharmacodynamics: Drug action including toxicresponses.

•• Pharmacokinetics of inhaled anesthetic involves : 1.Absorption (uptake) from alveoli into pulmonary

capillary blood. 2.Distribution in the body 3.Metabolism 4.Elimination (lungs)

•• Aging : in lean body mass, in body fat apparent

VD hepatic function and pulmonary gas exchange



• Principal objective of inhalational anesthesiais to achieve a constant and optimal brainpartial pressure of inhaled anesthetic

PA Pa Pbr

• PA is an indirect measurement of anestheticpartial pressure at brain.

•• There are three steps: 1.Transfer of inhaled anestetic from

machine to alveoli 2.Transfer from alveoli to arterial blood 3.Transfer from arterial blood to brain

•

• These steps are influenced by various factors.



• Factors affecting inspiratoryconcentration (Fi)

-Fresh gas flow rate, -volume of breathing system, -absorption by machine or breathing

circuit.

•

•Factors affecting alveolar

concentration (FA) -Uptake -Ventilation -



UptakeUptake

• Uptake by pulmonary circulation = b/g ×

C(A–V)×Q b/g = blood gas partition coefficient C(A–V)= difference of concentration of

anesthetic between alveolar and venousblood Q = Cardiac output

•

• Anesthetic agents are taken by pulmonarycirculation during induction. Thereforealveolar conc. lag behind inspiratory

concentration



• Greater uptake Slower rate of rise

of FA and alveolar partial pressure of

anesthetic slower the rate of

induction (Concentration of a gas partial

pressure)•

• The alveolar partial pressure determine

the partial pressure of anesthetic inblood and ultimately in brain.

•

• Concentration of anesthetic in brain



• Factors affecting anesthetic uptake A. Solubility in blood B. Alveolar blood flow C. Partial pressure difference between alveolar gas

and venous blood

•• Solubility in blood : Insoluble agents like N2O which

are taken up by blood less avidly has faster rate of induction than soluble agents like halothane.

•• The relative solubility's of anesthetic in air, blood and

tissue expressed as partition coefficient.•• Each coefficient is ratio of concentration of anesthetic

gas in each of two phases at equilibrium (equal

partial pressures) b /g = 0.47 for nitrous oxide.



Partition coefficients of volatilePartition coefficients of volatile

anesthetics at 37oCanesthetics at 37oC

• Higher b/g induction is prolonged.

• Blood/gas solubility is increased by post prandial lipidemia

and is decreased by anaemia.

AgentAgent Blood/GasBlood/Gas Brain/BloodBrain/Blood Fat/BloodFat/Blood

NN2OO 0.470.47 1.11.1 2.32.3

HalothaneHalothane 2.42.4 2.92.9 6060

IsofluraneIsoflurane 1.41.4 2.62.6 4545

DesfluraneDesflurane 0.420.42 1.31.3 2727

SevofluranSevofluranee 0.650.65 1.71.7 4848



(b) Alveolar blood flow(b) Alveolar blood flow•

• In absence of pulmonary shunting alveolar blood flow isequal to cardiac output

•• cardiac output anesthetic uptake slower induction

•

• Effect of cardiac output is more pronounced for more bloodsoluble anesthetic

•• Low output states predispose patients to over dosage with

soluble agents like halothane

•• Halothane may create a positive feed back loop.

•• Cerebral blood flow: It is maintained even in shock up to

moribund stage (BP<40 mmHg) and takes a greaterproportion of cardiac output, increasing the effect of inhaled anesthetic.



(c) Partial pressure difference(c) Partial pressure differencebetween alveolar gas andbetween alveolar gas and

venous bloodvenous blood•• This depends on tissue uptake

•• Transfer of anesthetic from blood to

tissue is determined by

(1) Tissue solubility of agent, (2) Tissue blood flow, (3) Partial pressure difference

between arterial blood and tissues



Tissue can be divided into 4 groups based ontheir

solubility's and blood flow.

•• Vessel rich group: (brain, heart, liver, kidney,

endocrine organ) (moderate solubility and smallvolumes), first to take up appreciable amount of

anesthetic and first to fill.•• Muscle group: (skin and muscle) (great capacity):

uptake slower and sustained for hours.

•• Fat group: tremendous solubility of anesthetic leads

to total capacity that would take days to fill.

•

• Vessel poor group: (bones, ligament, teeth, hair,



Concentration effectConcentration effect

• It include concentrating effect

and augmentation of trachealinflow.

•

• Concentrating effect reflectsconcentration of inhaled anestheticin a smaller lung volume due to

uptake of all gases in lung.

•

• At the same time, anesthetic input

via tracheal inflow is increased to



1% second gas 1.7%second gas 1%second gas

19% O2 O 2 31.7% inspiration o2 19%

80% N2O N2O 66.7% containing N2O 40%

50% of 80% N2O 0.4%sec g

N2O taken 19% O2 O 2 7.6

up 1% second

gas N2O 32%



• Concentration effect is more significant for nitrousoxide.

•

• Second gas effect: Reflect the ability of highvolume uptake of one gas (first gas) to acceleratethe rate of increase of alveolar partial pressure of a second concurrently administered 'Companiongas' (Second gas)

• Factors affecting arterial concentration (Fa)

•• Ideally, alveolar and arterial anesthetic partial

pressure are assumed to be equal, but in realityarterial partial pressure are consistently less thanalveolar due to venous admixture, alveolar, deadspace, ventilation perfusion mismatching.

•

• Overall effect is an increase in alveolar partial

F ff iF t ff ti



Factors affectingFactors affectingeliminationelimination

• Recovery depends on lowering the concentration of anesthetic in

brain tissue.

•• Elimination comprises : -Biotransformation: accounts for minimal decrease in rate of

decline of alveolar partial pressure. More important for solubleanesthetic, cytochrome P-450 group of isozymes (CYP2E1)

appears to important for some volatile anesthetic. Ex. it accountsfor halothane faster elimination than isoflurance.

- Transcutaneous loss.

-Exhalation: The most important route for elimination is alveolarfactors that speed induction also favour recovery that iselimination of rebreathing, high fresh gas flow, low anaestheticcircuit volume, high cerebral blood flow, increased ventilation.

• Elimination of N2O is so rapid that it leads to diffusion hypoxia.

– – The rate of recovery is usually faster than induction

••



Clinical applicationClinical application

•

• Factors that increased the speed of induction

- Greater inhaled concentration - Hyperventilation

- Poor circulation to nonvital organs- shock,dehydration old age, wasting of body tissue

- High gas flow system

• Factors that decrease speed of induction

- Respiratory obstruction, laryngospasm,bronchial secretions, lug disease. - Respiratory depression due to premedication iv

induction agent inhalational agent itself. - Increased circulation to non vital organs: in

anxiety, thyrotoxicosis, obesity, robust subjects.



MAC (Minimum alveolar concentration)MAC (Minimum alveolar concentration) is defined asis defined as

concentration at 1 atm that prevents skeletal muscle movement inconcentration at 1 atm that prevents skeletal muscle movement inresponse to a supramaximal painful stimulus (surgical incision) inresponse to a supramaximal painful stimulus (surgical incision) in50% of patients. Immobility measured by MAC is medicated50% of patients. Immobility measured by MAC is medicatedprincipally by effects on spinal cord only.principally by effects on spinal cord only.

MAC mirrors brain partial pressure, allows comparison of patency,MAC mirrors brain partial pressure, allows comparison of patency,

standard for experimental evaluation.standard for experimental evaluation. AgentAgent MAC%MAC% Vapor pr essureVapor pr essure

(mm Hg at 20 oC)(mm Hg at 2 0oC) NN2OO 105105

HalothaneHalothane 0.750.75 243243

IsofluraneIsoflurane 1.21.2 240240

DesfluraneDesflurane 66 664664

SevofluraneSevoflurane 22 160160



• MAC are roughly additive for CNS depression.

•• CVS effect may not be equivalent at same MAC.

•• MAC is equivalent to median effect dose.

•

• Roughly 1.3 MAC of any volatile anesthetic has beenfound prevent movement in about 95% of patients(ED95)

•

• MAC awake: 0.3-0.4 MAC•• MAC-BAR: blockade of adrenergic response in 50% of

subjects due to surgical stimulus.

•



VariableVariable Effect on MACEffect on MAC CommentsCommentsHYPOTHERMIAHYPOTHERMIAHYPERTHERMIAHYPERTHERMIA

decreasedecreasedecreasedecrease

increase if > 42increase if > 42 0 CC

YOUNG AGEYOUNG AGEELDERLYELDERLY

increaseincreasedecreasedecrease

ACUTE ALCOHOL INTOXACUTE ALCOHOL INTOXCHRONIC ALCOHOL ABUSECHRONIC ALCOHOL ABUSE

decreasedecreaseincreaseincrease

ANAEMIAANAEMIAHEMATOCRIT <10%HEMATOCRIT <10%

decreasedecrease

Pao2 < 40 mmHgPao2 < 40 mmHg decreasedecrease

PaCO2 > 95 mmHgPaCO2 > 95 mmHg decreasedecrease

THYROID DISEASETHYROID DISEASE no changeno change

B.P.B.P.MAP < 40 mmHgMAP < 40 mmHg

decreasedecrease

HYPERCALCEMIAHYPERCALCEMIAHYPERNATREMIAHYPERNATREMIAHYPONATREMIAHYPONATREMIA

decreasedecreaseincreaseincreasedecreasedecrease

PREGNANCYPREGNANCYI.V. ANESTH. DRUGSI.V. ANESTH. DRUGS

decreasedecreasedecreasedecrease



• Among the most striking is 6% decrease in MAC per decade of age

• MAC is relatively unaffected by species, sex or duration of anesthesia

• 150

• Estimated MAC = --------------------------------------

• oil gas partition coefficient Theories of anesthetic action

• General anesthesia: loss of consciousness, analgesia, amnesia,muscle relaxation.

• Variety of substances capable of producing general anesthesia.

• Various agents probably prevalence anesthesia by different methods(agent specific theory)

• Mechanism of immobility: - due to action on spinal cord.

• Drug induced depression of excitation and enhancement of inhibition.

• Excitatory alpha amino 3AMPA and NMDA receptors and inhibitory.

• GABA and glycine receptors involved, Na ion channel also important

• Ionotropic and metabotrapic receptors Ionctropic (ligand gated ion channels) – neurestransmitter GABAreceptors.

Metabotropic receptors – Neutrotransmitter acetyl choline –activation of G protein lead to second messenger pathway.

• Glumatate (NMDA, AMPA and kainate receptors)

• Glutamate is principal excitatory neurotransmitter and - important role in immobility



unconsciousnessunconsciousness•• Inhaled anesthetics must act through specific interactions with target

molecule (presumably protein) in CNS

•• Unconsciousness results from action at higher centre.

•• Correlation between ability to hyperpolarize neurons and anestheticpotency.

•• Volatile anesthetic enhance inhibitory synaptic transmission especially

at synapses where GABA is major neurotransmitter in brain(especially reticular activating system)

•• Glycine is another important inhibitory neurotransmitter in spinal cord

and brain stem.

•• Presynaptic sodium ion channels and voltage gated calcium channel

also effected.•



• Molecular and cellular mechanism

• At molecular level, anesthetics almost

certainly ct by binding directly to proteinsrather than by pertubing lipid bilayers.

• Stereoselectively suggest existence of specificbinding sites on membrane protein. Ex.levoisomer of isoflurane is more potent.

• There is accumulating evidence the GABA andglycine receptors provide molecular bindingsites for inhaled anesthetics.

•• MAYER OVERTON THEORY (Critical

volume hypothesis)

• Unitary hypothesis – All inhalational agentsshare a common mechanism of action at

molecular level.



• According to this theory, there is correlation betweenlipid solubility (oil gas partition coefficient) andanesthetic potency.

•• When a sufficient number of molecules dissolve

(critical concentration) in crucial hydrophobic sitessuch as lipid cell membrane, there is distortion of channel necessary foreign flux, likewise changes in

lipid matrix produced by dissolved anestheticmolecules could alter the function of protein in cellmembrane.

•• This is supported by reversal of anesthetic effects by

high pressure (40-100 atm.)

•• Evidence against theory include:

• Effect on lipid bilayers are implausibly small and can

produced by temperature change of 1oC• Not all li id soluble dru s are anesthetic infact, some



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uptake of inhalational anaesthetics

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