inhalational anaesthetics pharmacokinetics & pharmacodynamics, uptake & distribution

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  • 1. Inhalational Anaesthetics Dr. Swadheen kumar Rout 2nd year P.G Dept. of Anaesthesiology M.K.C.G College & hospital

2. HISTORY:- Surgery Before Anesthesia 3. HISTORY:- Surgical pain relief Alcohol Opium Unconsciousness (blow to head, strangulation) 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. 1830s 1840s 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 Mortons demonstration but Important lesson learned if you dont publish it, it didnt 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. 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. 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. 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. 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. 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 (MeyerOverton 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Olea