• Pharmacokinetics: Relationship between a drug's •
dose tissue concentration and elapsed time. Pharmacodynamics: Drug action including toxic responses.

• • 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

 hepatic function and pulmonary gas exchange

• Principal objective of inhalational anesthesia

is to achieve a constant and optimal brain partial pressure of inhaled anesthetic PA Pa  Pbr PA is an indirect measurement of anesthetic partial 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 inspiratory
  

concentration (Fi) -Fresh gas flow rate, -volume of breathing system, -absorption by machine or breathing circuit.

• • Factors affecting alveolar
  

concentration (FA) -Uptake -Ventilation

• 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 venous blood Q = Cardiac output

• • Anesthetic agents are taken by pulmonary
circulation during induction. Therefore alveolar 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 in blood 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 volatile Agent N 2O Halot hane Isoflurane Desflurane Sevofluran e anesthetics at 37oC Blood/Gas Brain/Blood Fat /Blood 0.47 2.4 1.4 0.42 0.65 1.1 2.9 2.6 1.3 1.7 2.3 60 45 27 48

• Higher b/g  induction is prolonged. • Blood/gas solubility is increased by post prandial lipidemia
and is decreased by anaemia.

(b) Alveolar blood flow
• • In absence of pulmonary shunting alveolar blood flow is
equal to cardiac output

• •  cardiac output   anesthetic uptake  slower induction • • Effect of cardiac output is more pronounced for more blood
soluble 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 greater proportion of cardiac output, increasing the effect of inhaled anesthetic.

(c) Partial pressure difference between alveolar gas and venous 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 on solubility's and blood flow.

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

endocrine organ) (moderate solubility and small volumes), 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,

• Ventilation: Lowering of alveolar partial • • Anesthetic that depress ventilation (e.g.

pressure by uptake can be countered by increasing alveolar ventilation.

halothane) will create a negative feed back protective effect. This effect is lost in mechanical ventilation.

• • Concentrations : Effect of uptake can also
be reduced by increasing inspired concentration.

Concentration effect

It include concentrating effect and augmentation of tracheal inflow.

• • Concentrating effect reflects

concentration of inhaled anesthetic in 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 19% O2

1.7%second gas O

1%second gas inspiration o2 19%


80% sec g

N2O 50% of N2O taken up



containing 80% N2O 19% O2 1% second gas


40% 0.4%

    



7.6 32%

• Concentration effect is more significant for nitrous

• • Second gas effect:

Reflect the ability of high volume uptake of one gas (first gas) to accelerate the rate of increase of alveolar partial pressure of a second concurrently administered 'Companion gas' (Second gas) Factors affecting arterial concentration (Fa)

• • Ideally, alveolar and arterial anesthetic partial

pressure are assumed to be equal, but in reality arterial partial pressure are consistently less than alveolar due to venous admixture, alveolar, dead space, ventilation perfusion mismatching.

• • Overall effect is an increase in alveolar partial

Factors affecting elimination

• 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 soluble anesthetic, cytochrome P-450 group of isozymes (CYP2E1) appears to important for some volatile anesthetic. Ex. it accounts for halothane faster elimination than isoflurance. -Transcutaneous loss. -Exhalation: The most important route for elimination is alveolar factors that speed induction also favour recovery that is elimination of rebreathing, high fresh gas flow, low anaesthetic circuit 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 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) is defined as

concentration at 1 atm that prevents skeletal muscle movement in response to a supramaximal painful stimulus (surgical incision) in 50% of patients. Immobility measured by MAC is medicated principally by effects on spinal cord only. MAC mirrors brain partial pressure, allows comparison of patency, standard for experimental evaluation.

Ag e n t
N 2O


V a p or p r e ssur e ( m m H g a t 2 0 oC)

105 0.75 1.2 6 2 243 240 664 160

Halot hane Isoflurane Desflurane Sevoflurane

• • • • • • •

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 been found 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.


Effect on MAC
decrease decrease increase decrease decrease increase decrease decrease decrease no change decrease decrease increase decrease decrease decrease

Com m ent s
increase if > 42 0 C

• 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 GABA receptors. 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

Mechanism of anesthesia induced

unconsciousness • • 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 anesthetic

• • 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 proteins rather than by pertubing lipid bilayers. Stereoselectively suggest existence of specific binding sites on membrane protein. Ex. levoisomer of isoflurane is more potent. There is accumulating evidence the GABA and glycine receptors provide molecular binding sites for inhaled anesthetics.


volume hypothesis) Unitary hypothesis – All inhalational agents share a common mechanism of action at molecular level.

• According to this theory, there is correlation between
lipid solubility (oil gas partition coefficient) and anesthetic potency.

• • When a sufficient number of molecules dissolve

(critical concentration) in crucial hydrophobic sites such as lipid cell membrane, there is distortion of channel necessary foreign flux, likewise changes in lipid matrix produced by dissolved anesthetic molecules could alter the function of protein in cell membrane.

• • 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 lipid soluble drugs are anesthetic infact, some