Pharmacology of therapeutic gases and inhalational anesthetics

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  • -focus on inhaled anesthetics -lung is ideal for delivering gases to blood
  • -one of the greatest discoveries in medicine of all time -made modern surgery possible -rare to go through life without being anesthetized at least once -scary: low TI, unknown mechanism of action
  • Most anesthetic procedures today involve the combination of different anesthetic drugs which are being used in concentrations that are considerably smaller than those needed if the drug were to be used all by itself. Halogenated anesthetics: (1) rapid and pleasant induction of, and recovery from, anesthesia; (2) rapid changes in the depth of anesthesia; (3) adequate relaxation of skeletal muscles; (4) the absence of toxic effects or other adverse properties in normal doses; (5) a wide margin of safety. Advantages of using intravenous drugs: (1)high potency and rapid reversibility (2) adds flexibility and permits the administration of lower doses of inhalational agents; (3) permit more precise control of the effect required.
  • Most anesthetic procedures today involve the combination of different anesthetic drugs which are being used in concentrations that are considerably smaller than those needed if the drug were to be used all by itself. Halogenated anesthetics: (1) rapid and pleasant induction of, and recovery from, anesthesia; (2) rapid changes in the depth of anesthesia; (3) adequate relaxation of skeletal muscles; (4) the absence of toxic effects or other adverse properties in normal doses; (5) a wide margin of safety. Advantages of using intravenous drugs: (1)high potency and rapid reversibility (2) adds flexibility and permits the administration of lower doses of inhalational agents; (3) permit more precise control of the effect required.
  • Besides conventional EC50 for the drug potency measurement, MAC is more popularly used in the field.
  • Different size, different chemical properties. Suggests single site, common mechanism.
  • This famous plot demonstrates an amazing correlation between gA potency and their solubility in lipid. The more…the more. The correlation lasts 6 order of magnitudes.
  • The difficulty to determine the site of action in the CNS for GA: we have no consensus of opinion regarding the region or regions of the brain responsible for the maintenance of consciousness. the brain area responsible for the control of consciousness: cerebral cortex? No. Large regions of the cortex could be ablated without loss of consciousness brainstem? No. Although much data exist on anesthetic effects in various brain regions, no set is sufficiently complete or consistent to allow one to conclude that exert their actions through one specific effect in one CNS region. Since it’s difficult to define gA comprehensively and quantitatively, there has been from the beginning a search for in-vivo and in-vitro model systems capable to either reflect gA completely, to describe partial aspects of it or to measure it indirectly.
  • What this means is that at 1MAC the concentration of anesthetic in brain is nearly the same for all anesthetics.
  • Pharmacology of therapeutic gases and inhalational anesthetics

    1. 1. Pharmacology of Therapeutic Gases and Inhalational Anesthetics www.freelivedoctor.com
    2. 2. OUTLINE <ul><li>Therapeutic gases </li></ul><ul><li>Introduction and historical perspective </li></ul><ul><li>Mechanisms of action </li></ul><ul><li>Potency and pharmacokinetics </li></ul>www.freelivedoctor.com
    3. 3. OBJECTIVES <ul><li>To understand the indications for and uses of common therapeutic gases. </li></ul><ul><li>To be familiar with the mechanisms of action (or major theories) of general anesthetics. </li></ul><ul><li>To grasp the role of solubility and pharmacokinetics in inhaled anesthetic action. </li></ul>www.freelivedoctor.com
    4. 4. THERAPEUTIC GASES: Oxygen <ul><li>Hypoxia can result from: </li></ul><ul><ul><ul><ul><li>Ineffective uptake </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Inadequate delivery to tissues </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Impaired utilization </li></ul></ul></ul></ul><ul><ul><ul><li>Administered to prevent hypoxic injury </li></ul></ul></ul><ul><ul><ul><li>Can have toxic effects </li></ul></ul></ul>www.freelivedoctor.com
    5. 5. O 2 Delivery Devices www.freelivedoctor.com 100% O 2 Flow Rate (L/min)      Estimated FiO 2 Nasal Cannulae 1 0.24 2 0.28 3 0.32 4 0.36 5 0.40 6 0.44 Simple Facemask 5–6 0.40 6–7 0.50 7–8 0.60 Mask w/ Reservoir Bag 6 0.60 7 0.70 8 0.80 9 ≥ 0.80 10 ≥ 0.80
    6. 6. Hemoglobin O 2 Saturation Curve www.freelivedoctor.com
    7. 7. THERAPEUTIC GASES: Nitric Oxide <ul><ul><ul><li>Important cell signaling molecule, activates sGC </li></ul></ul></ul><ul><ul><ul><li>Can preferentially dilate pulmonary vasculature </li></ul></ul></ul><ul><ul><ul><li>Administered to newborns with persistent pulmonary hypertension </li></ul></ul></ul><ul><ul><ul><li>Under investigation for numerous disease states </li></ul></ul></ul><ul><ul><ul><li>Can have toxic effects due to NO 2 or MetHb </li></ul></ul></ul>www.freelivedoctor.com
    8. 8. THERAPEUTIC GASES: Helium <ul><ul><ul><ul><li>Pulmonary Function Testing </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Imaging studies </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Laser surgery on airway </li></ul></ul></ul></ul>www.freelivedoctor.com
    9. 9. THERAPEUTIC GASES: CO <ul><li>CO is produced endogenously by Heme Oxygenase </li></ul><ul><li>Therapeutic and toxic properties mediated by binding to metalloproteins </li></ul>www.freelivedoctor.com The pathway of heme metabolism
    10. 10. THERAPEUTIC GASES: CO Potential signaling pathways activated by CO leading to tissue protection Ryter, S. W. et al. Physiol. Rev. 86: 583-650 2006 www.freelivedoctor.com
    11. 11. What Is General Anesthesia? <ul><li>Generalized reversible depression of the central nervous system such that perception of all senses is ablated </li></ul>Reversible condition of comfort, quiescence, and physiological stability in a patient before, during, and after performance of a procedure that otherwise would be painful, frightening, or hazardous www.freelivedoctor.com
    12. 12. Desirable Components of Anesthesia <ul><ul><ul><li>Immobility in response to noxious stimulus </li></ul></ul></ul><ul><ul><ul><li>Amnesia </li></ul></ul></ul><ul><ul><ul><li>Analgesia </li></ul></ul></ul><ul><ul><ul><li>Unconsciousness </li></ul></ul></ul><ul><ul><ul><li>Muscle relaxation </li></ul></ul></ul><ul><ul><ul><li>Loss of autonomic reflexes </li></ul></ul></ul><ul><ul><ul><li>Anxiolysis </li></ul></ul></ul>www.freelivedoctor.com
    13. 13. Effects of General Anesthesia <ul><li>Low Dose Effects </li></ul><ul><ul><li>Amnesia </li></ul></ul><ul><ul><li>Euphoria </li></ul></ul><ul><ul><li>Analgesia </li></ul></ul><ul><ul><li>Hypnosis </li></ul></ul><ul><ul><li>Excitation </li></ul></ul><ul><ul><li>Hyperreflexia </li></ul></ul><ul><li>High Dose Effects </li></ul><ul><ul><li>Deep sedation </li></ul></ul><ul><ul><li>Muscle relaxation </li></ul></ul><ul><ul><li>Diminished motor responses </li></ul></ul><ul><ul><li>Diminished autonomic responses </li></ul></ul><ul><ul><li>Myocardial protection from ischemia </li></ul></ul><ul><ul><li>Cardiovascular/respiratory depression </li></ul></ul><ul><ul><li>Hypothermia </li></ul></ul>www.freelivedoctor.com
    14. 14. Before Anesthetics <ul><li>Surgery uncommon </li></ul><ul><li>Surgical pain relief </li></ul><ul><ul><li>alcohol, opium </li></ul></ul><ul><ul><li>physical methods (ice, ischemia) </li></ul></ul><ul><ul><li>unconsciousness (blow to head, strangulation) </li></ul></ul><ul><ul><li>simple restraint most common </li></ul></ul>www.freelivedoctor.com
    15. 15. HISTORY OF ANESTHESIA <ul><li>1540 Paracelsus, a Swiss physician and alchemist, sweetens the feed of fowl with “sweet oil of vitriol” (diethyl ether) “and besides, it has associated with it such sweetness that it is taken even by chickens and they fall asleep from it for a while but awaken later without harm.” </li></ul><ul><li>1790 Humphry Davy uses nitrous oxide to relieve his headache and tooth pain </li></ul><ul><li>1824 Henry Hill Hickman uses carbon dioxide to partially asphyxiate to the point of insensibility several animal species. Delivers an address to the Royal Society: “Letter on suspended animation – with the view to ascertaining its probable utility in surgical operations on human subjects” </li></ul><ul><li>1830s Crawford Long and others engage in ether frolics. Insensibility to pain is noted </li></ul><ul><li>1844 Nitrous oxide is used by Horace Wells for tooth extraction </li></ul><ul><li>1846 TG Morton: First public demonstration of ether administration for excision of neck mass </li></ul><ul><li>1850s Chloroform begins to be used in England for surgery and childbirth </li></ul>www.freelivedoctor.com
    16. 16. “ Gentlemen, this is no humbug.” www.freelivedoctor.com
    17. 17. HISTORY OF ANESTHESIA <ul><ul><ul><li>1929 Waters introduces cyclopropane into clinical practice at Wisconsin – explosive! </li></ul></ul></ul><ul><ul><ul><li>1951 Halothane synthesized to be nonflammable, but causes cardiac dysrhythmias </li></ul></ul></ul><ul><ul><ul><li>1973 Enflurane – convulsant at high concentrations </li></ul></ul></ul><ul><ul><ul><li>1981 Isoflurane – little toxicity, oldest volatile agent in common use today </li></ul></ul></ul><ul><ul><ul><li>1990 Sevoflurane introduced into clinical practice </li></ul></ul></ul><ul><ul><ul><li>1993 Desflurane introduced </li></ul></ul></ul>www.freelivedoctor.com
    18. 18. <ul><li>  </li></ul><ul><li>Rapid and pleasant induction </li></ul><ul><li>Rapid changes in the depth of anesthesia </li></ul><ul><li>Adequate muscle relaxation </li></ul><ul><li>Wide margin of safety </li></ul><ul><li>Absence of toxic/adverse effects </li></ul><ul><li>  </li></ul>CHARACTERISTICS OF AN IDEAL ANESTHETIC No single agent yet identified is an ideal anesthetic www.freelivedoctor.com
    19. 19. CLASSIFICATION OF GENERAL ANESTHETICS <ul><li>Intravenous agents </li></ul><ul><ul><ul><li>primarily used for induction </li></ul></ul></ul><ul><ul><ul><ul><li>Barbiturates </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Benzodiazepines </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Etomidate </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Ketamine </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Propofol </li></ul></ul></ul></ul>www.freelivedoctor.com
    20. 20. INTRAVENOUS ANESTHETICS <ul><li>Rapid onset (seconds) </li></ul><ul><li>Rapid awakening (minutes) </li></ul><ul><li>Redistribution determines duration of action </li></ul>www.freelivedoctor.com
    21. 21. CLASSIFICATION OF GENERAL ANESTHETICS <ul><li>Inhalational agents </li></ul><ul><ul><ul><li>primarily used for maintenance </li></ul></ul></ul><ul><ul><li>Volatile agents </li></ul></ul><ul><ul><ul><ul><ul><li>Isoflurane </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Sevoflurane </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Desflurane </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Halothane, Enflurane </li></ul></ul></ul></ul></ul><ul><ul><li>Anesthetic gases </li></ul></ul><ul><ul><ul><ul><ul><li>Nitrous Oxide - currently used </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Xenon - in the future? </li></ul></ul></ul></ul></ul>www.freelivedoctor.com
    22. 22. Measures of Anesthetic Potency <ul><li>MAC: m inimum a lveolar c oncentration </li></ul><ul><ul><ul><li>MAC is the concentration of anesthetic that produces immobility in 50% of patients exposed to a noxious stimulus. </li></ul></ul></ul><ul><li>MAC awake : MAC at which response to commands are lost </li></ul><ul><ul><ul><li>amnesia, loss of awareness </li></ul></ul></ul><ul><li>MAC BAR : b lunt a utonomic r esponse </li></ul><ul><li>MAC intubation : response to intubation </li></ul>www.freelivedoctor.com
    23. 23. MAC values are useful <ul><li>Allows comparison of anesthetics </li></ul><ul><li>Important clinical endpoints </li></ul><ul><li>Consistent and reproducible </li></ul>www.freelivedoctor.com
    24. 24. Therapeutic Index <ul><li>Margin of safety very small </li></ul><ul><li>TI: 2-4 </li></ul><ul><ul><li>dose that produces circulatory failure may be 2-4X that for anesthetic dose </li></ul></ul><ul><li>Some of the most dangerous drugs in common clinical use </li></ul>www.freelivedoctor.com
    25. 25. Unitary Hypothesis General anesthesia can be caused by a remarkable number of structurally diverse molecules www.freelivedoctor.com
    26. 26. Meyer-Overton Correlation 1903: Meyer and Overton note very strong correlation between solubility in olive oil and anesthetic potency www.freelivedoctor.com
    27. 27. Meyer-Overton rule The correlation of anesthetic potency with lipid solubility provides a means of predicting anesthetic potency. This correlation has traditionally been interpreted as meaning that primary anesthetic action sites are lipid portions of nerve membranes . Molecular Actions of General Anesthetics www.freelivedoctor.com
    28. 28. Nonspecific Theory Unitary hypothesis + Myer-Overton Rule = Anesthetics act nonspecifically on hydrophobic lipid components of cells www.freelivedoctor.com
    29. 29. General anesthetic potencies in animals can be correlated well with their ability to inhibit the activity of certain soluble enzymes, such as firefly luciferase. The finding shook the foundation of lipid theory, and opened a new chapter for protein theory. Proteins: molecular targets of general anesthetics Franks & Lieb 1984 Nature. 310:599-601 www.freelivedoctor.com
    30. 30. Protein Theory of General Anesthesia www.freelivedoctor.com
    31. 31. Molecular Sites of Action <ul><ul><ul><li>Ligand-gated ion channels </li></ul></ul></ul><ul><ul><ul><ul><li>GABA A receptor </li></ul></ul></ul></ul><ul><ul><ul><li>Activity is enhanced by intravenous and volatile agents </li></ul></ul></ul><ul><ul><ul><ul><li>Glycine receptor </li></ul></ul></ul></ul><ul><ul><ul><li>Activity is enhanced by volatile agents </li></ul></ul></ul><ul><ul><ul><ul><li>NMDA receptor </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Blocked by nitrous oxide, xenon, cyclopropane, volatile agents </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>nACh receptor </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Blocked by volatile agents </li></ul></ul></ul></ul></ul><ul><ul><ul><li>Voltage-gated ion channels </li></ul></ul></ul><ul><ul><ul><ul><li>Calcium channels – synaptic function impaired by volatile agents </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Sodium channels – impaired function </li></ul></ul></ul></ul><ul><ul><ul><li>Background channels </li></ul></ul></ul><ul><ul><ul><ul><li>Tandem pore-domain potassium channels </li></ul></ul></ul></ul><ul><ul><ul><li>Activated by volatile agents </li></ul></ul></ul>www.freelivedoctor.com
    32. 32. Molecular Mechanism(s) of General Anesthesia www.freelivedoctor.com Xe Isoflurane Halothane ...... Cellular (synapses) Molecular (lipids & receptors)
    33. 33. A Working Hypothesis <ul><li>Anesthetics enhance inhibitory postsynaptic channel activity (GABA A and glycine receptors) </li></ul><ul><li>Anesthetics inhibit excitatory synaptic channel activity (nicotinic acetylcholine and glutamate receptors) </li></ul>www.freelivedoctor.com
    34. 34. MACROSCOPIC SITES OF ACTION <ul><li>Anesthetic induced ablation of movement in response to pain is mediated primarily by spinal cord. </li></ul><ul><ul><li>Cervical transection or decerebration does not alter MAC </li></ul></ul><ul><ul><li>Selective administration to cord causes immobility </li></ul></ul><ul><li>Anesthetic induced amnesia is mediated by higher brain structures (e.g., hippocampus) </li></ul><ul><li>Anesthetic induced sedation mediated by tuberomammillary nucleus of hypothalamus </li></ul>www.freelivedoctor.com
    35. 35. Inhaled Anesthetics - Pharmacokinetics <ul><ul><ul><li>Partial pressure vs. Concentration </li></ul></ul></ul><ul><ul><ul><ul><li>Partial pressure in a mixture of gases is the portion of the total pressure supplied by gas </li></ul></ul></ul></ul><ul><ul><ul><li>Amount of gas in blood or tissue is dependent on the solubility of the gas in that solvent. </li></ul></ul></ul><ul><ul><ul><li>Solvent/gas partition coefficient </li></ul></ul></ul>www.freelivedoctor.com
    36. 36. Properties of Inhaled Anesthetics Less potent More potent www.freelivedoctor.com ANESTHETIC MAC(atm)  (oil/gas)  (oil/gas) x MAC Nitrous oxide 1.01 1.4 1.4 Desflurane 0.06 19 1.1 Sevoflurane 0.02 51 1.0 Ether 0.019 65 1.2 Enflurane 0.0168 98 1.6 Isoflurane 0.0114 98 1.1 Halothane 0.0077 224 1.7
    37. 37. Induction Speed <ul><ul><ul><li>Determined by rate that alveolar partial pressure equilibrates with inspired partial pressure </li></ul></ul></ul><ul><ul><ul><ul><li>Solubility (less soluble, faster) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Ventilation rate (increased rate, faster) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cardiac output (decreased output, faster) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Inspired concentration (higher concentration, faster) </li></ul></ul></ul></ul>www.freelivedoctor.com
    38. 38. Induction Speed www.freelivedoctor.com
    39. 39. Anesthetic Uptake and Distribution <ul><ul><ul><li>Vessel Rich Group (VRG) </li></ul></ul></ul><ul><ul><ul><ul><li>CNS and visceral organs </li></ul></ul></ul></ul><ul><ul><ul><ul><li>High blood flow (75%) and low capacity </li></ul></ul></ul></ul><ul><ul><ul><li>Muscle Group (MG) </li></ul></ul></ul><ul><ul><ul><ul><li>Skin and muscle </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Moderate flow and high capacity </li></ul></ul></ul></ul><ul><ul><ul><li>Fat Group (FG) </li></ul></ul></ul><ul><ul><ul><ul><li>Low flow and high capacity </li></ul></ul></ul></ul><ul><ul><ul><li>Vessel Poor Group </li></ul></ul></ul><ul><ul><ul><ul><li>Bone, cartilage, ligaments </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Low flow and low capacity </li></ul></ul></ul></ul>www.freelivedoctor.com
    40. 40. Anesthetic of the Future: Xenon <ul><ul><ul><li>Rare gas extracted from air </li></ul></ul></ul><ul><ul><ul><ul><li>Very expensive to produce </li></ul></ul></ul></ul><ul><ul><ul><li>Close to ideal anesthetic </li></ul></ul></ul><ul><ul><ul><ul><li>Low blood and tissue solubility </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>(rapid induction/recovery) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>Potent </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Not metabolized </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Nonflammable </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Minimal side effects </li></ul></ul></ul></ul>www.freelivedoctor.com

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