Inhalational anaesthetics pharmacokinetics & pharmacodynamics, uptake & distribution

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  • Ether, known as "sweet vitriol" until 1730, was discovered in 1275 ether discover by a Spanish chemist named RaymundusLullius. While ethyl ether was first created in a laboratory in 1540 by a German scientist named ValeriusCordusTermed “laughing gas”
  • ho
  • The device consisted of a glass flask with a wooden mouthpiece that could be opened and closed depending on the patient’s state of consciousness. Prevent overdosag
  • Molecular level
  • inert elements ( ex: xenon ) simple inorganic compounds ( ex: nitrous oxide) halogenated hydrocarbons ( ex: halothane ) complex organic structures (ex: barbiturate )Halothane has a MAC of slightly less than 1 while Nitrous oxide has a MAC of around 105, halothane is much more potent and it is because the log of the MAC is plotted on the y axis that halothane has a value of 0.01 and nitrous oxide has a value of 1
  • He & Ne, low lipid solubility gases are not anaesthetics and not all lipid soluble gases were anaesthesic
  • anaesthetic effect is exerted through some perturbation of the lipid bilayer
  • anaesthesia occurring when the volume of the hydrophobic region is caused to expand beyondsome critical volume
  • This anaesthetic-induced fluidization makes membranes less able to facilitate the conformational changes in proteins that may be the basis for such membrane events as ion gating, synaptic transmitter release, and transmitter binding to receptors
  • both the fluidization and lateral phase separation hypotheses suggest that anaesthesia resultsfrom making the membrane more disorganised, or fluid
  • drugs are strikingly similar to potent general anaesthetics and are predicted to be potent anaesthetics based on their lipid solubility, but they exert only one constituent of the anaesthetic action (amnesia) and do not suppress movement (i.e. do not depress spinal cord functions) as all anaesthetics do
  • at general anaesthesia likely involves inhibition of the opening of the ion channel in a postsynaptic ligand-gated membrane protein
  • L
  • Inhaled general anaesthetics frequently do not change structure of their target protein (of Cys-loop receptor here) but change its dynamics especially dynamics in the flexible loops that connect α-helices in a bundle thus disrupting modes of motion essential for the protein function. Snare
  • Inhaled general anaesthetics frequently do not change structure of their target protein (of Cys-loop receptor here) but change its dynamics especially dynamics in the flexible loops that connect α-helices in a bundle thus disrupting modes of motion essential for the protein function.
  • NECESSARY STEP FOR TRANSMISSION OF ACTION POTENTIAL
  • NORMAL TRANSMISSION OF ACTION POTENTIAL
  • Atm. pressure decrease with height, so taking dehradun Atm. Pressure as 600 mm Hg - , %MAC of sevoflurane = 2.8% (16.7 / 600 = 2.8%)
  • Absorption.Distribution.Metabolism.Excretion.
  • For a given partial pressure, a more soluble agent will dissolve more molecules in solution
  • InductionPBLOOD
  • Higher inflow rates accelerate t he rise in inspired concentration
  • In rebreathing the gas mixtures may be diluted by residual gases in the system
  • the slower the rate of rise of the alveolar concentration
  • Each coefficient is the ratio of the concentrations of the anesthetic gas in each of two phases at equilibrium
  • Halothane
  • Low-output states predispose patients to overdosage with soluble agents, as the rate of rise in alveolar concentrations will be markedly increased. Higher than anticipated levels of a volatile anesthetic, which is also a myocardial depressant (eg, halothane), may create a positive feedback loop by lowering cardiac output even further.
  • SOLUBLE AGENT FURTHER REDUCE COSO CONCENTRATION OF INSPIRED AGENT BE DECREASED
  • with equilibration, the alveolar/mixed venous tension difference progressively falls as tissuetensions risesince diffusion is directly proportional to the tension difference, the rate of diffusion into theblood progressively slows
  • is tissue group receives one-quarter the amount of anesthetic delivered to the VRG and initially takes upmuscle has about one-twentieth the perfusion of brain, and thus muscle takes about 20 times as long as brain to equilibrate. Uptake of anesthetic by muscle continues long after uptake by brain has ceased. only approximately one-quarter as much anesthetic.
  • Anesthetic uptake produces a characteristic curve that relates the rise in alveolar concentration to time (Figure 7–2). The shape of this graph is determined by the uptakes of individual tissue groups (Figure 7–3). The initial steep rate of uptake is due to unopposed filling of the alveoli by ventilation. The rate of rise slows as the vessel-rich group—and eventually the muscle group—reach their capacity.
  • acceleratednarrowing of PA-vGas
  • Ptissue
  • No PA-vGas gradient – No uptake
  • The concentrating effect is an effect of uptake on concentration, whereas the concentration effect is an effect of concentration on uptake, that is on the rate of approach to equilibrium
  • alveolar concentration increases from 11% to 12% in 1st case & from 67% to 72% in 2nd case. this is augmented inflow effect
  • The concentration effect of one gas upon another is called the second gas effect
  • more nitrous oxide molecules available for transfer across the alveolar membrane.
  • All that has really happened with a second gas effect is that the probability of alveolar to blood transfer of  nitrous oxide molecules is higher than the probability of alveolar to blood transfer of volatile agent molecules simply because there are more nitrous oxide molecules available for transfer across the alveolar membrane.
  • N20 MORE SOLUBLE, MORE UPTAKE ,LESS ALVEOLAR CONCN.
  • diseases such as emphysema and atelectasis, as well as congenitalincrease the alveolar–arterial difference cardiac dPA-a.Gas gradient, produce substantial deviations from equilibration.
  • Mismatch acts as a restriction to flow: It raises the pressure in front of the restriction, lowers the pressure beyond the restriction,
  • ventilation is absent, as in a segment of atelectatic lung. Blood emerges from that segment with no additional anesthetic. Such anesthetic-deficient blood then mixes with blood from the ventilated segments containing a normal complement of anesthetic. The mixture produces an arterial anesthetic partial pressure that is considerably below normal.
  • Blood from these alveoli has an increased anaesthetic content, the increase being nearly proportional to the increased ventilation. Assuming that overall (total) ventilation remains normal, this increase in the anesthetic contained by blood from the relatively hyperventilated alveoli compensates for the lack of anesthetic uptake in unventilated alveoli. Non ventilated segment
  • Thus, the fall in the alveolar partial pressure of methoxyflurane is slower than the fall with halothane, and the latter, in turn, is less rapid than the fall with nitrous oxide. The rate at which recovery occurs is similarly affected: it is rapid with nitrous oxide and may be slow with methoxyflurane. The rapidity of recovery thus largely depends on the solubility of the anesthetic
  • . In fact, as long as an anesthetic partial pressure gradient exists between arterial blood and tissue blood, that tissue will continue to take up anesthetic. Thus, for the first several hours of recovery from halothane anesthesia, fat continues to take up halothane and by so doing accelerates the rate of recovery. Only after the alveolar (equals arterial) anesthetic partial pressure falls below that in a tissue can the tissue contribute anesthetic to the alveoli.
  • The decline of the partial pressure of a poorly soluble agent such as nitrous oxide is rapid in any case, and thus the acceleration imparted by a less than complete tissue equilibration cannot significantly alter the rate of recovery. The approach to equilibration becomes important with halothane and becomes even more important with methoxyflurane Recovery may be rapid after a short methoxyfluraneanesthetic but may be slow after a prolonged anesthetic. This is one of the reasons why nitrous oxide is usually a component of an inhaled (or for that matter, an injected) anesthetic regimen. The rapid elimination of this component permits at least a portion of recovery to be rapid. The recovery from anesthesia with desflurane and sevoflurane is more rapid than with more soluble agents, such as isoflurane and halothane. 70 
  • Desflurane solubility< sevofluranesolubilitiy
  • HYPOXIA
  • Inhalational anaesthetics pharmacokinetics & pharmacodynamics, uptake & distribution

    1. 1. Inhalational Anaesthetics Dr. Swadheen kumar Rout 2nd year P.G Dept. of Anaesthesiology M.K.C.G College & hospital
    2. 2. HISTORY:- Surgery Before Anesthesia
    3. 3. HISTORY:- Surgical pain relief • Alcohol • Opium • Unconsciousness (blow to head, strangulation)
    4. 4.  No single individual can be said to have discovered anaesthesia.  The speciality of anaesthesia rests on discoveries made from several scientific disciplines. Major discoveries were often made by small groups of curious individuals with diverse backgrounds.  1773 - Joseph Priestly discovers N2O  1798 - Sir Humphrey Davy experimented with N2O, reported loss of pain, euphoria.  Recreational drug  1540 - ethyl ether was first created in a laboratory by a German scientist named Valerius Cordus,  Termed ―laughing gas‖
    5. 5.  1830’s – 1840’s – Gardner Colton & others Involved in Nitrous oxide & ether fun and frolics.  1842 - Crawford W. Long –first used ether for neck surgery. Did not publicize, in part because of concerns about negative fallout from ―frolics‖. Tried to claim credit after Morton‘s demonstration but… Important lesson learned – if you don’t publish it, it didn’t happen.  1844 - Nitrous oxide is used by Horace Wells for tooth extraction - demonstration at The Massachusetts General Hospital - deemed a failure because patient ―reacted‖. -
    6. 6.  1846 – William Morton (apprentice under Horace Wells) First public demonstration of ether administration on October 16.  Dr. john collins warren painlessly removed a tumor from the neck of a Mr. Edward gilbert abbott.  He added a few harmless impurities to the ether to disguise its smell and named it the secret concoction Letheon.  His attempted disguise however failed - a patent was then useless, & no one had a financial claim on the use of ether, within months ether was being used in Europe and all over the United States
    7. 7.  1847 - David Waldie at Edinburgh Medical school England suggested Chloroform as an alternative agent.  1853 – Dr. John Snow administers chloroform to Queen Victoria popularizes anesthesia for childbirth in UK.  1951 - Halothane was synthesised by Suckling and introduced into clinical practice in 1956.  1959 - 1966 - Terrell and colleagues at Ohio medical products synthesised more than 700 products .347th and 469th compounds were Enflurane & Isoflurane  1929 - Cyclopropane was discovered accidentally and was very popular for almost 30 yrs.  1990 - Sevoflurane was introduced into clinical practice initially in Japan.  1993 – Desflurane introduced ,- rapid onset and offset due to its low solubility in blood.
    8. 8. PHARMACODYNAMICS:- the study of drug action, including toxic responses, i.e - how a drug affects a body. Mechanism of action:- still largely unknown • "Anaesthetics have been used for 160 years, and how they work is one of the great mysteries of neuroscience, • The effects of inhaled anaesthetics cannot be explained by a single molecular mechanism. Rather, multiple targets contribute to the effects of each agent. • The immobilizing effect of inhaled anaesthetics involves a site of action in the spinal cord, whereas sedation hypnosis & amnesia involve supraspinal mechanisms. • No comprehensive theory of anaesthesia describes the sequence of events leading from the interaction between an anaesthetic molecule and its targets to the behavioral effects.
    9. 9. Theories of Anaesthetic action:- 1) Lipid Solubility- Overton & Meyer rule 2) Alterations to Lipid Bilayers. i) lipid perturbation – dimensional change - lipid phase transition, i.e: gel to liquid crystalline state ii) lipid-protein interactions LIPID BASED PROTEIN BASED Alteration to Protein Function Molecular level
    10. 10. Lipid Solubility- Unitary Hypothesis:- proposes that all inhalation agents share a common mechanism of action at the molecular level. • Myriad of molecular species - Different size, different chemical properties • This is supported by the observation that the anaesthetic potency of inhalation agents correlates directly with their lipid solubility – olive oil (Meyer–Overton rule).  Oil / gas partition coefficient X MAC = k(Constant) - varies little over ~ a 100,000 fold range MAC • There is a strong linear correlation between lipid solubility and anesthetic potency (MAC) The lesser the MAC the greater the potency i..e -the drug potency increases as the oil:gas solubility increases
    11. 11.  The implication is that anaesthesia results from molecules dissolving at specific lipophilic sites, when a critical number of anaesthetic molecules occupy a crucial hydrophobic region resulting in the disturbance of the physical properties of cell membranes in CNS.  Meyer-Overton rule postulates that it is the number of molecules which are present at the site of action which is important and not their type thus, this hypothesis supports the additive nature of anaesthetic agents. Exceptions to the Meyer-Overton Rule:- 1) HALOGENATED COMPOUNDS- Enflurane and Isoflurane are structural isomers and have similar oil:gas partition coefficients, however, the MAC for isoflurane is only ~ 70% of that for enflurane • Complete halogenation, or complete end-methyl halogenation on alkanes & ethers results in decreased anaesthetic potency
    12. 12. 2) CUTOFF EFFECT- • Increasing homologues of alkane series display a cutoff point, beyond which anaesthetic potency sharply decreases. • one postulate is that the larger members of a series are to large to fit into the "anaesthetic site“. Increased lipid solubility increases anaesthetic potency
    13. 13. Alterations to Lipid Bilayers:- • Biological membranes consist of a cholesterol-phospholipid bilayer, having a thickness of ~ 4 nm. • Peripheral proteins are weakly bound to the exterior hydrophilic membrane & integral proteins are deeply imbedded in, or pass through the lipid bilayer. • Synaptic membranes are ~ 50:50 lipid bilayer & protein by weight.
    14. 14. Lipid perturbation:- Effects on Membrane Dimension • Anaesthetic binding significantly modify membrane structure, effect is exerted through some perturbation of the lipid bilayer. changes in curvature/elasticity • Several types of bilayer perturbations were proposed to cause anaesthetic effect changes in phase separation changes in bilayer thickness
    15. 15. Critical volume hypothesis:-lipid bilayer expansion hypothesis • Bulky and hydrophobic anaesthetic molecules accumulate inside the hydrophobic (or lipophilic) regions of neuronal lipid membrane causing its distortion and expansion (thickening) due to volume displacement. • Accumulation of anaesthetic causes volume of the hydrophobic region to expand beyond some critical volume sufficient to reversibly alter function of membrane ion channels thus providing anaesthetic effect. Changes in bilayer thickness:-
    16. 16. Greater the anaesthetic effect. Actual chemical structure of the anaesthetic agent not important Molecular volume more important More space within membrane is occupied by anaesthetic • Based on this theory, in 1954 Mullins suggested that the Meyer-Overton correlation with potency can be improved if molecular volumes of anaesthetic molecules are taken into account. • This theory was supported by experimental fact that increases in atmospheric pressure reverses anaesthetic effect (pressure reversal effect).
    17. 17. Fluidization theory of anaesthesia- Changes in phase separation:- • Phospholipid membranes undergo a gel-liquid crystalline transition of the lipid matrix with increasing temperature , associated with an increase in the molar volume of the lipid. • Trudell et al. (1973) showed that in the presence of anaesthetic agents this transition occurs at a lower temperature, and over a wider temperature range. An alternative proposal, is the "lateral phase separation hypothesis― • NMR & ESR techniques,show anaesthetic agents cause a local disordering of the phospholipid matrix and reduce the number of molecules which simultaneously alternate between the gel & liquid crystalline states. • Reducing such fluctuations, these agents thereby reduce the magnitude of fluctuations in volume which probably occur in dynamic biological membranes which allow conformational change in ion channels.
    18. 18. • Both the fluidization and lateral phase separation hypotheses suggest that anaesthesia results from making the membrane more disorganised or fluid. • This anaesthetic-induced effect on lipids interacts in the basis of conformational changes in proteins that may be the basis for such membrane events as decreased permeability, ion gating, synaptic transmitter release, and transmitter binding to receptors resulting in anaesthetic action.
    19. 19. 1) Stereoisomers of an anaesthetic drug have very different anaesthetic potency whereas their oil/gas partition coefficients are similar . 2) Certain drugs that are highly soluble in lipids, and therefore expected to act as anaesthetics, exert only one constituent of the anaesthetic action (amnesia) and do not suppress movement (and therefore were called nonimmobilizers).ex-fluorthyl 3) A small increase in body temperature affects membrane density and fluidity as much as general anaesthetics, yet it does not cause anaesthesia. 4) Increasing the chain length in a homologous series of straight-chain alcohols or alkanes increases their lipid solubility, but their anaesthetic potency stops increasing beyond a certain cutoff length .  All these lipid theories generally suffer from four weaknesses
    20. 20. Modern lipid hypothesis:- • States that anaesthetic effect happens if solubilization of general anaesthetic in the bilayer causes a redistribution of membrane lateral pressures. • Each bilayer membrane has a distinct profile of how lateral pressures are distributed within it. Most membrane proteins especially ligand-gated ion channels are sensitive to changes in this lateral pressure distribution profile. • General anaesthesia likely involves inhibition of the opening of the ion channel in a postsynaptic ligand-gated membrane protein. • Oleamide (fatty acid amide of oleic acid) is an endogenous anaesthetic found in vivo (in the cat‘s brain) and it is known to potentiate sleep and lower the temperature of the body by closing the gap junction channel connexion. An example of how bilayer lateral pressure redistribution influences the ion- channel is
    21. 21. • Oleamide (fatty acid amide of oleic acid) is an endogenous anaesthetic found in vivo (in the cat‘s brain) and it is known to potentiate sleep and lower the temperature of the body by closing the gap junction channel connexion.
    22. 22. Theories of Anaesthetic action:- 1) Lipid Solubility- Overton & Meyer rule 2) Alterations to Lipid Bilayers. i) lipid perturbation – dimensional change - lipid phase transition, i.e: gel to liquid crystalline state ii) lipid-protein interactions LIPID BASED PROTEIN BASED Alteration to Protein Function
    23. 23. PROTEIN BASED THEORIES OF ANAESTHESIA:- • In the early 1980s, Franks and Lieb demonstrated that the Meyer-Overton correlation can be reproduced using a soluble protein. • These are luciferases, and cytochrome P450. Remarkably, inhibition of these proteins by general anaesthetics was directly correlated with their anaesthetic potencies. • Demonstrated that general anaesthetics may also interact with hydrophobic protein sites of certain proteins, rather than affect membrane proteins indirectly through nonspecific interactions with lipid bilayer as mediator.
    24. 24. PROTEIN BASED THEORIES OF ANAESTHESIA:-
    25. 25. • Anaesthetics alter the functions of many cytoplasmic signalling proteins, including protein kinase C, however, the proteins considered the most likely molecular targets of anaesthetics are ion channels. • Bind directly only to small number of targets in CNS mostly ligand(neurotransmitter)- gated ion channels in synapse and G-protein coupled receptors altering their ion flux. • Cys-loop receptors are plausible targets for general anaesthetics that bind at the interface between the subunits. Inhibitory receptors (GABA A, GABA C, glycine receptors) Eexcitatory receptors (Ach,5HT3 & glutamate NMDA receptor)
    26. 26. • Anaesthetics alter the functions of many cytoplasmic signalling proteins, including protein kinase C, however, the proteins considered the most likely molecular targets of anaesthetics are ion channels. • Bind directly only to small number of targets in CNS mostly ligand(neurotransmitter)- gated ion channels in synapse and G-protein coupled receptors altering their ion flux. • Cys-loop receptors are plausible targets for general anaesthetics that bind at the interface between the subunits. Inhibitory receptors (GABA A, GABA C, glycine receptors) Excitatory receptors (Ach ,5HT3 & glutamate NMDA receptor) Potentiation Inhibition Effects Of Inhaled Anesthetics
    27. 27. Action of the inhaled agents on synaptic transmission may be due to alteration of either,
    28. 28.  In summary, the predominant effects of the volatile agents cannot at present be explained by depletion, production, or release of a single neurotransmitter.
    29. 29. MACROSCOPIC SITES OF ACTION:-  Anesthetic induced ablation of movement in response to pain is mediated primarily by spinal cord..  Anesthetic induced amnesia is mediated by higher brain structures ( hippocampus).  Anesthetic induced sedation mediated by tuberomammillary nucleus of hypothalamus.
    30. 30. Measures of Anesthetic Potency:- MINIMUM ALVEOLAR CONCENTRATION:- MAC • The minimum alveolar concentration of anaesthetic, at equilibrium, at 1 Atm pressure, which produces immobility in 50% of subjects exposed to a standard noxious stimulus, which, for humans is surgical incision of the skin. • It is used as an index to measure the potency and relate the potency of other agents & provides a standard for experimental evaluations .  Rationale for this measure of anaesthetic potency is, a) Alveolar concentration can be easily measured. b) Near equilibrium, alveolar and brain tensions are virtually equal. c) The high cerebral blood flow produces rapid equilibration.
    31. 31. • MAC represents only one point on the dose–response curve—it is the equivalent of a median effective dose (ED50) for IV drugs. • 1.3 MAC of any of the volatile anesthetics prevent movement in about 95% patients surgical incision( ED95) • The MAC values for different anaesthetics are roughly additive. For example, a mixture of 0.5 MAC of nitrous oxide and 0.5 MAC of halothane approximates the degree of central nervous depression of 1.0 MAC of isoflurane.. • In contrast to CNS depression, the degree of myocardial depression may not be equivalent at the same MAC: 0.5 MAC of halothane causes more myocardial depression than 0.5 MAC of nitrous oxide.
    32. 32. MAC VARIANTS:- • MAC Awake = MAC of anaesthetic that would allow opening of eyes on verbal commands during emergence from anaesthesia (0.3-0.4 MAC ) • MAC Intubation = MAC that would inhibit movement and coughing during endotracheal intubation.(1.3 MAC) • MAC Bar = MAC of anaesthetic necessary to prevent adrenergic response to skin incision, as measured by conc. of catecholamine in venous blood (1.5 MAC) . • When different agents are compared the ratio of MAC skin incision to MAC intubation or MAC awake is relatively constant.
    33. 33. Factors Which Affect MAC:- Increase MAC i) Hyperthermia - if > 42°C ii) Hypernatraemia iii) Drug induced elevation of CNS catecholamine stores. (amphetamine. Cocaine. Ephedrine. MAO inhibitors. Levodopa) iv) Chronic alcohol / opioid abuse
    34. 34. Decrease MAC:- i) Hypothermia – (halothane MAC27°C ~ 50% MAC37°C) ii) Hyponatraemia iii) Increasing age – (6% decrease in MAC per decade of age) iv) Hypoxaemia – (PaO2 < 40 mmHg) v) Hypotension – (MAP < 40 mm Hg) vi) Anaemia – (Hematocrit < 10%) vii) Pregnancy viii) CNS depressant drugs - opioids - benzodiazepines - major tranquilizers - TCA's ix) Other drugs - lithium - lignocaine - magnesium - x) Acute alcohol abuse.
    35. 35. No Change in MAC:- i) Sex, Species ii) Weight, BSA iii) Duration of anaesthesia iv) Hypo/hyperkalaemia v) Hypo/hyperthyroidism
    36. 36. • In Dehradun , the % MAC of sevoflurane will be higher than in puri, but the partial pressure will be the same (2 % X 760 = 15.2 mm Hg) which is constant. • Atm. pressure decrease with altitude, so taking dehradun Atm. Pressure = 600 mm Hg, %MAC of sevoflurane = (15.2/ 600 = 2.5%) • MAC is a concentration expressed as vol % but anaesthetic effect is produced by partial pressures. PP = C * ATM
    37. 37. Pharmacokinetics:- Relationship between a drug‘s dose, tissue concentration, and elapsed time. (i.e- how a body affects a drug ). • Absorption. • Distribution. • Metabolism. • Excretion.  Inhalational anaesthesia ultimate effect depends on attainment of a therapeutic tissue concentration in the central nervous system.  For a better understanding of the factors that govern induction and recovery from anaesthesia.
    38. 38. Some Basic concepts:- Partial Pressure in gaseous phase Partial pressure of a gas in a mixture of gases is the pressure it would have if it alone occupied the entire volume. This pressure is proportional to its fractional mass in the mixture of gases. Partial pressure in Solution Since pressure of a gas can only be measured in gaseous phase, while in solution we measure concentration as an indicator of amount of gas. Partial pressure of a gas in solution, therefore refers to the pressure of the gas in the gas phase (if it were present) in equilibrium with the liquid.Why speak in terms of partial pressure ? Partial pressures assume importance because gases equilibrate based on partial pressures, not concentrations. • A series of partial pressure gradients exists from the anaesthetic machine to brain tissue. • Diffusion occurs from a region of higher concentration to a region of lower concentration (down a concentration gradient). • Concentration of a gas is directly proportional to its partial pressure. Pgas = Cgas x Atm Dalton's law of partial pressures
    39. 39. • FGF = Fresh Gas Flow • FI = Inspired gas Concentration • FA = Alveolar gas Concentration. • Fa = Arterial gas Concentration. 2) Transfer from Inspired Air to Alve 3) Transfer from Alveoli to Arterial B 4) Transfer from Arterial Blood to T 1) Transfer from machine to Inspir
    40. 40. Anaesthetic gases administered via the lungs diffuse into blood until the partial pressures in alveoli and blood are equal. . Transfer of anaesthetic from blood to target tissues also proceeds toward equalizing partial pressures Because gases equilibrate throughout a system based on partial pressures Monitoring the alveolar concentration of inhaled anaesthetic provides an index of their effects in the brain PALVEOLI=PBLOOD=PCNS To put it in another way, faster rise in alveolar concentrations of a given anaesthetic herald a faster induction
    41. 41. PBLOOD < A PALVEOLI= A PBLOOD = A Pulmonary artery Pulmonary vein = arterial blood = Pulmonary capillary P inhaled = 2A Equilibration is complete across AC membrane. Induction
    42. 42. FACTORS AFFECTING INSPIRATORY CONCENTRATION (FI) :- • The patient does not necessarily receive the same concentration set on the vaporizer as there are numerous intervening factors which vary the concentration. 1) Fresh gas flow rate (FGF rate) = Depend on vaporizer & flowmeter settings Higher the rate of FGF, closer the inspired gas concentration will be to fresh gas concentration.(FI =FGC). Induction can be accelerated with the use of high inflow rates 2) Breathing Circuit Volume: (apparatus dead space) Smaller the volume, closer the inspired gas concentration will be to the fresh gas concentration. • Avg. Volume of circle system is 4-5lts. Reservoir bag 2lts. Total vol. to wash out is 6-7lts To wash out this vol. with FGF at 5lts/min may take 5-6minutes. FI =FGC at 5-6mins
    43. 43. FACTORS AFFECTING INSPIRATORY CONCENTRATION (FI) :- 3) Circuit absorption: Rubber tubing absorbs ˃ plastic & silicon • Lower the circuit absorption, closer the inspired gas concentration will be to the fresh gas concentration. 4) The Effect of Rebreathing: Inspired gas is actually fresh gas + exhaled gas • In rebreathing the inspired gas mixtures may be diluted by residual gases in the system • Lower the rebreathing, closer the inspired gas concentration will be to the fresh gas concentration.  Clinically, these attributes translate into faster induction and recovery times.
    44. 44. FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA) :- Anaesthetic Uptake Alveolar ventilation Concentration Of Anaesthetic agent
    45. 45. FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA) :- 1) Uptake:- Alveolar membrane poses no barrier to the transfer of anaesthetic gases to pulmonary circulation. • The FA / alveolar partial pressure determines the partial pressure of anaesthetic in the blood and, ultimately, in the brain which determines clinical effect. Uptake • FA depends on uptake of anaesthetic by pulmonary circulation. If this uptake is poor, whatever anesthetic is inspired is accumulating in the alveoli. thus FA increases rapidly towards FI . i.e. FA / FI =1.0 Greater the uptake Slower the rate of rise FA Lower the FA:FI ratio Slower the rate of induction
    46. 46. • Fick’s equation: VB = ∂b/g x Q x PA-PV / PB VB = Blood uptake ∂b/g = blood / gas partition co-efficient. Q = Cardiac output PA = Alveolar partial pressure Pv = Mixed venous partial pressure PB = Barometric Pressure should any of these components = 0, then uptake will = 0. Anesthetic uptake Solubility in blood (blood/ gas partition coefficient) Alveolar blood flow (Cardiac output) Partial pressure difference between alveolar gas & venous blood.
    47. 47. • The solubility of a gas in liquid is given by its Ostwald solubility coefficient. SOLUBILITY OF THE AGENT:- • Relative solubility of an anaesthetic in air, blood and tissues are expressed as partition co-efficients. • Describes the relative affinity of an anaesthetic for two phases & each coefficient is the ratio of the concentrations of the anesthetic gas in each of two phases when equilibrium has been achieved. • For example, halothane has a blood/gas partition coefficient of 2.4, indicating that at equilibrium, halothane‗s concentration in blood is 2.4 times its concentration in the gas (alveolar) phase. • In another way , a value of 2.4 means that each ML of blood holds 2.4 times as much halothane as a ML of alveolar gas.
    48. 48. Blood has 48 balls of halothane / ml Gas has 20 balls of halothane / ml Halothane blood / gas partition coefficient = 2. No net diffusion when partial pressures are equal.
    49. 49. Partition Coefficients of Volatile Anesthetics at 37°c Greater the co-efficient, more the solubility More the solubility, greater the uptake Greater uptake means longer time required for FA to approach FI More the time required for FA to approach FI, longer it takes for induction to be achieved. N20 Halothane
    50. 50. ALVEOLAR BLOOD FLOW:- • In the absence of pulmonary shunting—is essentially equal to cardiac output. • Determines the rate at which agents pass from gas to blood. Cardiac output increases Greater passage of blood through the lungs removes more anesthetic Uptake increases longer time required for FA to approach FI , Induction is delayed This effect is greater with soluble agents (Eg.halothane) ˃ insoluble agents (N2O).  Children with shunt (F4) → rapid induction due to ↓ pulmonary blood flow. Rt. to lt. shunts - A portion of the pul. blood flow will not come in contact with inspired gas.. Uptake decreases faster FA to approach FI Faster Induction
    51. 51. • Increased CNS anaesthetic concentration leads to reduced cardiac output. Reduced cardiac output as noted above, would be associated with a more rapid rise in FA/FI . • If we decrease blood flow (CO) by 50%, we have the effect of concentrating the anaesthetic in that volume(less). In this case, arterial (in equilibrium with the alveolar anaesthetic), partial pressure would be doubled. • The doubling in alveolar concentration(FA) would mean ultimately that the brain will "see" a double than expected number of anaesthetic molecules transferring in and so there is a greater likelihood of anaesthetic-mediated cardio- respiratory depression. • Patients with shock - agents with relatively low blood: gas solubility might be preferable as the alveolar concentration(FA) of these agents would not be especially sensitive to cardiopulmonary changes. • Nitrous oxide, a sparingly soluble agent, is often used in anaesthetic management in patients with shock. In shock already reduced CO Soluble agent further reduce CO Rapid increase in FA Concentration of inspired agent be decreased in anticipation
    52. 52. Partial pressure difference between alveolar gas and venous blood:- • This gradient depends on tissue uptake. Tissues act like sponge absorbing anaesthetic agent. Movement of agent from blood into tissues is “distribution.” • If no tissue uptake, the venous blood returning to the lungs would contain as much anaesthetic as it had when it left the lungs as arterial blood.( i.e- alveolar which equals arterial partial pressure & venous partial pressure become identical resulting in no uptake. Encouraging greater alveolar uptake. Tissues uptake from blood Partial pressure of the anaesthetic in venous blood decreases relative to alveoli Gradient between the alveoli and blood Pvenous = Parterial = Palveolar when tissues are saturated. Uptake stops when distribution stops, equilibration happens
    53. 53. • The transfer of anaesthetic from blood to tissues is determined by three factors analogous to systemic uptake: 1) Tissue solubility of the agent (tissue/blood partition coefficient), 2) Tissue blood flow, 3) Difference in partial pressure between arterial blood and the tissue.
    54. 54. • Tissues can be divided into four groups based on their solubility and blood flow Highly perfused vessel rich group - Brain, Heart, Liver, Kidney, Endocrine organs - Limitations -moderate solubility, smaller volume - High perfusion -these tissues take up first and get saturated. - Equilibration with arterial pp of anaesthetic is> 90% complete with in 8 mts Muscle Group - Skin, muscle- low perfusion - lower uptake - But due to -larger volumes -greater capacity- sustained uptake for hours. (Equilibration) Fat Group - Final large reservoir of anaesthetic agent -Tremendous solubility of anesthetic leads to a total capacity that would take days to fill. Vessel poor group - Tendons, ligaments, cartilage, teeth and hair. -No pharmacodynamic significance. 19/75=1/4 6/19=1/3
    55. 55. ANAESTHETIC UPTAKE GRAPH • The initial steep rate of uptake is due to unopposed filling of the alveoli by ventilation. • The rate of rise slows as the vessel-rich group—and eventually the muscle group—reach their capacity
    56. 56. FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA) :- Anaesthetic Uptake Alveolar ventilation Concentration Of Anaesthetic agent
    57. 57. Alveolar ventilation:- • Each inspiration delivers some anaesthetic to the lung and, if unopposed by uptake into the blood, normal ventilation would increase FA/FI to 95-98% in 2 minutes. • Greater the FRC, the slower the rise in FA. • FRC is less in supine position, pregnancy and obesity. ↓ FRC → Faster Induction and recovery •The lowering of alveolar partial pressure(FA) by uptake can be countered by increasing alveolar ventilation. Greater the Uptake More needs to be replaced Ventilation has to be increased Increasing ventilation rapidly makes more sense for soluble anaesthetics as their uptake is faster. (is of little consequence if anesthetic is less soluble)
    58. 58. Effect of Concomitant Changes in Ventilation and Perfusion:- If Cardiac output is doubled Uptake (transfer from the alveolar volume to the blood) also be doubled Reduce the rate of rise in FA/ FI by half Ventilation rate were doubled Rate of rise in FA/ FI would be doubled. Effects should cancel each other . No change in FA/FI Doubling anaesthetic delivery to the lungs • This ignores one other factor in the equation that defines uptake. An increase in cardiac output accelerates the narrowing of the alveolar to venous partial pressure difference (PA-vGas) and thereby reduces the impact of the increase in cardiac output on uptake. • Thus, a proportional increase in ventilation and cardiac output increases the rate of rise of FA/FI.
    59. 59. Ultimately reducing uptake. Tissues uptake from blood increased Alveolar/mixed venous tension difference progressively falls as tissue tension rises Narrowing of Gradient between the alveoli and blood (PA-vGas) Cardiac output increased Faster tissue equilibration with blood Increases the rate of rise of FA / FI Diffusion ∝ tension difference, the rate of diffusion SLOWS PA=Pv =Ptissue
    60. 60. VA= ventilation Q= cardiac output • The magnitude of the acceleration of rise in FA/FI depends in part on distribution of the increase in cardiac output. The effect is relatively small if the increase in cardiac output is distributed proportionately to all tissues (i.e., if cardiac output is doubled, all tissue blood flows are doubled) Enhanced cardiac output and ventilation rate might be associated with thyrotoxicosis or hyperthermia. In this situation it is unlikely that a significant change in anaesthesia would be noted as a result of modifying FA/FI Vessel-rich groups preferentially perfused Rapid equilibration Blood returning from the VRG has the same partial pressure as it had when it left lungs PA = Pv No PA-vGas gradient – No uptake Rapid rise in FA/FI
    61. 61. • In children, especially infants there appears to be a greater degree of vessel-rich tissue group perfusion compared to the adults. • So, in children and infants more rapid anesthesia development might be expected. • Additional factor is that there may be relatively higher CNS (brain) perfusion. • Increased perfusion of vessel rich groups and increased ventilation rates will cause a more substantial FA/FI rate of rise. Significant increase in halothane FA/FI rate of rise
    62. 62. FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA) :- Anaesthetic Uptake Alveolar ventilation Concentration Of Anaesthetic agent
    63. 63. Concentration Of Anaesthetic Agent:- • Increased uptake tends to decrease FA. To counter this, Inspired concentration can be increased. (―Over pressurisation‖: analogous to Intravenous bolus) Two consequences of this are:-  Increasing FI increases FA  Increasing FI increases rate of rise of FA / FI Concentration Effect results of two Phenomena: • Concentrating effect • Augmented Inflow effect “Concentration Effect”
    64. 64. N2O :80 O2 :20 N2O : 40 O2 :20 N2O 20 O2 :80 N2O 10 O2 :80 → → Concentrating effect:- 10/90=11% 40/60=67% • The first one represents a lung containing 20% N2O (20 parts per 100 volumes gas)If 50 % of N2O (10 parts) is taken up the pulmonary circulation Remaining 10 parts N20 exist in a total gas of 90 parts, for a concentration of 11%• The 2nd one represents a lung containing 80% N2O (80 parts per 100 volumes gas) 1) 2) Inspired air Alveolar air Alveolar concentration will be 67% (40 parts N2O remaining in total volume of 60 parts gas) • Even though 50% of the anesthetic is taken up in both examples, increasing the inspired concentration 4-fold results in 6-fold increase in alveolar concentration ( disproportionately higher alveolar concentration) • Anesthetic is concentrated following uptake because the remaining gases are ―concentrated‖ in a smaller volume (CONCENTRATING EFFECT) 50% N20 taken up 50% N20 taken up
    65. 65. AUGMENTED INFLOW EFFECT:- N2O 20 O2 :80 N2O 10 O2 :80 Inspired air Alveolar air→ 10/90=11% 50% N20 taken up → Inspiration CONTAINING 20% N2O, 80% O2 N20 10 O2 80 N20 2 02 8 89% 10 parts of absorbed gas(N2O) must be replaced by an equal volume of the 20% mixture to prevent alveolar collapse Thus alveolar concentration becomes 12 % (10 + 2 parts of anesthetic in a total of 100 parts of gas) N20 = 10+2/100 (12%) • In contrast in the 80 % gas mixture, 40 parts of 80 parts N20 must be replaced by an equal volume of the 80% mixture, Replaced by 40 parts gas containing 80 % N20 (80% / 40 parts =32 parts N20) Alveolar concentration becomes 40 parts N20 remaining + 32 parts N20 coming in total 100 parts of gas i.e 72%
    66. 66. • Alveolar concentration increases from 11% to 12% in 1st case & from 67% to 72% in 2nd case. this is augmented inflow effect. Second gas effect:- •The factors that govern the concentration effect also influence the concentration of any gas given concomitantly. The concentration effect of one gas upon another is called the second gas effect. • This second gas effect applies to halothane or enflurane when it is administered with nitrous oxide. • The loss of volume associated with the uptake of nitrous oxide concentrates the halothane or enflurane (2nd gas). • Replacement of the gas taken up by an increase in inspired ventilation augments the amount of halothane or enflurane (2nd gas) present in the lung. • Effect is more significant with nitrous oxide than with the volatile anesthetics, as the former can be used in much higher concentrations.
    67. 67. Second gas effect:- 50 % N20 taken up (40 PARTS) Remaining total gas - 100 -40 = 60 PARTS Concn. N20 = 40PARTS / 60 PARTS (66.7%) SECOND GAS = 1 PART / 60 PARTS (1.7%) Replaced by 40 parts gas Containing N20 : 80% / 40 part = 3 SECOND GAS : 1% / 40 part = 0.4  Uptake of half the N2O does not halve the concentration of N2O, and the reduction in volume thereby increases the concentration of the second gas.  Restoration of the lung volume by addition of gas at the same concentration will increase the N2O concentration & add to the amount of the second gas present in the lung. Because of the large concn of N2O molecules administered, significant alveolar to blood transfer occurs despite relatively low solubility
    68. 68. • The FA/FI for nitrous oxide rose more rapidly when 70 percent nitrous oxide was inspired than when 10 percent was inspired (the concentration effect) • Similarly, the FA/FI ratio for halothane rose more rapidly when 70 percent nitrous oxide was inspired than when 10 percent was inspired (second gas effect).
    69. 69.  On the basis of blood: gas solubility, one might predict that desflurane should exhibit a more rapid rate of rise in FA/FI than N2O. N2O more soluble, more uptake so must be less alveolar concn than desflurane. However, when one takes into account is substantially higher concentration of nitrous oxide delivered, the importance of the concentration effect is clear and is responsible for the rapid increase in FA/FI seen with nitrous oxide.  The clinical consequence of both concentration and second gas effects is to decrease induction time.
    70. 70. Factors Affecting Arterial concentration (Fa):- Ventilation/Perfusion Mismatch:- • General assumption: Partial Pressure alveoli = Partial pressure arterial circulation ( FA = Fa ) • Diseases such as emphysema and atelectasis, as well as congenital cardiac defects, produce substantial deviations from equilibration. 1) Ventilated non-perfused areas: 2) Perfused non-ventilated areas ↓ Parterial gas
    71. 71. i.e: the Alveolar–Arterial difference /gradient (PA-a gas) increases (1) Increases the Alveolar (end-tidal) anaesthetic partial pressure (PAgas). (2) Decreases the Arterial anaesthetic partial pressure.(Pagas) Normal lung PA gas = Pa gas Non-ventilated lung ↑ PAlveoli gas ↓ Parterial gas ↑PAlveoli-arterial gas Ventilation/Perfusion Mismatch:-
    72. 72. Ventilation/Perfusion Mismatch:- • The relative change depends on the solubility of the anesthetic. • With a poorly soluble agent, the end-tidal concentration (PAgas). is slightly increased, but the arterial partial pressure .(Pagas) is significantly reduced. The opposite occurs with a highly soluble anaesthetic. For poorly soluble agents: • Ventilation/perfusion ratio abnormalities increase ventilation relative to perfusion of some alveoli, whereas in other alveoli, the reverse occurs increase in ventilation relative to perfusion does not appreciably increase the alveolar partial pressure issuing from those alveoli . When ventilation is absent(segment of atelectatic lung) Blood from the segment has no additional anaesthetic Anesthetic deficient blood mixes with Normal Anesthetic containing blood from the ventilated segments Mixing leads to dilution Significant reduction of Arterial partial pressure
    73. 73. For highly soluble agents: Initially increased Alveolar Partial Pressure (PAgas). • Alveoli receiving more ventilation relative to perfusion, the Alveolar partial pressure rises to a higher level than usual. Blood from these alveoli has increased anaesthetic content ng with unventilated blood with no anaesthetic to maintain a near normal anaesthetic content in blood Slight reduction of Arterial partial pressure
    74. 74. FACTORS AFFECTING ELIMINATION:- • Recovery from any anesthesia depends on lowering the brain anaesthetic concentration, indirectly rate at which the alveolar anaesthetic partial pressure declines. This elimination can happen secondary to • Biotransformation (more with soluble agents) • Transcutaneous loss (minimal) • Exhalation (Most important) Biotransformation:- Anaesthetic gas undergo metabolism which determins the rate at which the alveolar anesthetic partial pressure declines. • Greatest impact is on the elimination of soluble anaesthetics that undergo extensive metabolism (eg, methoxyflurane). • The greater biotransformation of halothane compared with isoflurane accounts for halothane's faster elimination,even though it is more soluble. • The cytochrome P-450 (CYP) group of isozymes (specifically CYP 2EI) appears to be important in the metabolism of some volatile anesthetics.
    75. 75. Exhalation:- The most important route for elimination of inhalation anesthetics is the alveolus. Many of the factors that speed induction also speed recovery. • Factors affecting the elimination of an anaesthetic agent are identical to those for uptake and distribution Differences Between Induction and Recovery :- • First, on induction, alveolar anaesthetic concentration can be raised by increasing the inspired anaesthetic concentration .No such luxury is available during recovery; the inspired concentration cannot be reduced below zero. • Second, on induction, all the tissues initially have the same anaesthetic partial pressure = zero. On recovery, the tissue partial pressures are variable.
    76. 76. Recovery:- Recovery in general is faster than induction because apart from those compartments (brain) that take up anesthetic agent quickly, there are other compartments (eg: MG & Fat) which take up anesthetics slowly and therefore over a prolonged duration. Implication is that long after administration of Inhalational agent is stopped, these compartments (fat) are still in process of saturating themselves by taking up anesthetic from blood. Results in drop in Arterial partial pressure of anaesthetic To equilibrate partial pressures blood tends to take up more anaesthetic from the alveoli Decrease in partial pressure of anaesthetic in alveoli So with increased uptake, progressive decrease in alveolar partial pressure ensues Hastens Recoverymore rapid than induction
    77. 77. Recovery:- Solubility:- • If it is prolonged anaesthesia (>4 hours), there is enough time to saturate all compartments and consequently the rate of decline in alveolar partial pressures is less i.e. recovery takes a longer time. Conclusion: Recovery depends on duration of anaesthesia influences the rate at which the alveolar anaesthetic partial pressure declines. During recovery exhalation clears anaesthetic from the alveoli lowering alveolar concentration. Opposed by Alveolar – venous partial pressure gradient (drives anaesthetic into alveoli) • A greater reserve exists in blood for the highly soluble agent—that is, far more anaesthetic is available at a given partial pressure for transfer to the alveoli thus opposing the lowering of alveolar concentration.
    78. 78. • Solubility affects the rate of fall in the alveolar partial pressure thereby affecting the rate at which recovery occurs. • Poorly soluble agents( N2O,desflurane,sevoflurane) have a faster recovery compared to soluble agents (halothane, isoflurane) . • This is one of the reasons why nitrous oxide is usually a component of an inhaled anaesthetic regimen. The rapid elimination of this component permits at least a portion of recovery to be rapid. Desflurane solubility< sevoflurane solubilitiy
    79. 79. Diffusion Hypoxia:- • N2O is 30 times more soluble than N2 in the blood. • At the end of anaesthesia after discontinuation of N2O,(first 5-10 mins) N2O diffuses from blood into the alveoli much faster than N2 diffuses from alveoli into the blood. ↑ Total volume of gas in the alveolus Dilutes alveolar oxygen and CO2 Directly affect oxygenation by displacing oxygen Diluting alveolar CO2 decreases respiratory drive & hence ventilation. HYPOXIA. • Advisable to use 100% O2 after discontinuation of N2O (5-10 mins)
    80. 80. The ideal inhalational anaesthetic should have the following properties: a) Rapid and pleasant induction and emergence from anaesthesia. b) Rapid and easily identified changes in the depth of anaesthesia. c) Adequate relaxation of skeletal muscles. d) A wide margin of safety. e) Absence of toxic or other adverse effects at normal doses. f) High degree of specificity of action. g) Technically easy to administer. h) Useful for all age groups.

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