Pharmacology of therapeutic gases and inhalational anesthetics 07-07-2013

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Pharmacology of therapeutic gases and inhalational anesthetics
Presentation Transcript
Drug metabolism
1. Pharmacology of Therapeutic Gases and Inhalational Anesthetics 14489 views

www.freelivedoctor.com
Drug metabolism
2. OUTLINE Therapeutic gases Introduction and historical perspective 3 views
Mechanisms of action Potency and pharmacokinetics www.freelivedoctor.com

3. OBJECTIVES To understand the indications for and uses of common Neuro muscular blockers
2109 views
therapeutic gases. To be familiar with the mechanisms of action (or major
theories) of general anesthetics. To grasp the role of solubility and
pharmacokinetics in inhaled anesthetic action. www.freelivedoctor.com Neuro muscular blockers
2817 views

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Pharmacology of therapeutic gases and inhalational anesthetics 07-07-2013

4. THERAPEUTIC GASES: Oxygen Hypoxia can result from: Ineffective uptake

Inadequate delivery to tissues Impaired utilization Administered to prevent
Neuro muscular blockers
hypoxic injury Can have toxic effects www.freelivedoctor.com 1 views

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 Anxyolitics& hypnotics
2422 views
Simple Facemask 56 0.40 67 0.50 78 0.60 Mask w/ Reservoir Bag 6 0.60 7
0.70 8 0.80 9 0.80 10 0.80
Inhalant anaesthetics
6. Hemoglobin O 2 Saturation Curve www.freelivedoctor.com 2419 views

7. THERAPEUTIC GASES: Nitric Oxide Important cell signaling molecule,

activates sGC Can preferentially dilate pulmonary vasculature Administered to 13236530 Anesthesia
Pharmacology
newborns with persistent pulmonary hypertension Under investigation for 2463 views
numerous disease states Can have toxic effects due to NO 2 or MetHb
www.freelivedoctor.com GA Class drdhriti
1339 views
8. THERAPEUTIC GASES: Helium Pulmonary Function Testing Imaging studies
Laser surgery on airway www.freelivedoctor.com
Usage of glucocorticoids in
bronchial asthma
9. THERAPEUTIC GASES: CO CO is produced endogenously by Heme Oxygenase 2487 views
Therapeutic and toxic properties mediated by binding to metalloproteins
www.freelivedoctor.com The pathway of heme metabolism Drug actions
8100 views

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
The umbilical cord
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11. What Is General Anesthesia? Generalized reversible depression of the

central nervous system such that perception of all senses is ablated Reversible The placenta

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 The foetal membranes

12. Desirable Components of Anesthesia Immobility in response to noxious

stimulus Amnesia Analgesia Unconsciousness Muscle relaxation Loss of
Physiology of reproduction
autonomic reflexes Anxiolysis www.freelivedoctor.com

13. Effects of General Anesthesia Low Dose Effects Amnesia Euphoria Analgesia
Hypnosis Excitation Hyperreflexia High Dose Effects Deep sedation Muscle Minor complaints during
pregnancy
relaxation Diminished motor responses Diminished autonomic responses
Myocardial protection from ischemia Cardiovascular/respiratory depression
Hypothermia www.freelivedoctor.com Diagnosis of pregnancy

14. Before Anesthetics Surgery uncommon Surgical pain relief alcohol, opium
physical methods (ice, ischemia) unconsciousness (blow to head, strangulation) Antenatal care
simple restraint most common www.freelivedoctor.com

15. HISTORY OF ANESTHESIA 1540 Paracelsus, a Swiss physician and

Postpartum mood disorders
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. 1790 Humphry Davy uses nitrous oxide to relieve his headache and tooth Normal and abnormal
puerperium
pain 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 Version

probable utility in surgical operations on human subjects 1830s Crawford Long

and others engage in ether frolics. Insensibility to pain is noted 1844 Nitrous
oxide is used by Horace Wells for tooth extraction 1846 TG Morton: First public Vacuum extraction (ventouse)

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Pharmacology of therapeutic gases and inhalational anesthetics 07-07-2013

demonstration of ether administration for excision of neck mass 1850s

Chloroform begins to be used in England for surgery and childbirth
www.freelivedoctor.com Symphysiotomy

16. Gentlemen, this is no humbug. www.freelivedoctor.com

17. HISTORY OF ANESTHESIA 1929 Waters introduces cyclopropane into clinical Forceps delivery

practice at Wisconsin explosive! 1951 Halothane synthesized to be

nonflammable, but causes cardiac dysrhythmias 1973 Enflurane convulsant at
high concentrations 1981 Isoflurane little toxicity, oldest volatile agent in Episiotomy

common use today 1990 Sevoflurane introduced into clinical practice 1993
Desflurane introduced www.freelivedoctor.com
Caesarean section
18. Rapid and pleasant induction Rapid changes in the depth of anesthesia
Adequate muscle relaxation Wide margin of safety Absence of toxic/adverse
effects CHARACTERISTICS OF AN IDEAL ANESTHETIC No single agent yet
Normal labour
identified is an ideal anesthetic www.freelivedoctor.com

19. CLASSIFICATION OF GENERAL ANESTHETICS Intravenous agents primarily

used for induction Barbiturates Benzodiazepines Etomidate Ketamine Propofol Anatomy of the foetal skull

www.freelivedoctor.com

20. INTRAVENOUS ANESTHETICS Rapid onset (seconds) Rapid awakening Anatomy of the female pelvis
(minutes) Redistribution determines duration of action www.freelivedoctor.com

21. CLASSIFICATION OF GENERAL ANESTHETICS Inhalational agents primarily

Active management of normal
used for maintenance Volatile agents Isoflurane Sevoflurane Desflurane
labour
Halothane, Enflurane Anesthetic gases Nitrous Oxide - currently used Xenon - in
the future? www.freelivedoctor.com
Thyrotoxicosis in pregnancy
22. Measures of Anesthetic Potency MAC: m inimum a lveolar c oncentration
MAC is the concentration of anesthetic that produces immobility in 50% of
patients exposed to a noxious stimulus. MAC awake : MAC at which response to
commands are lost amnesia, loss of awareness MAC BAR : b lunt a utonomic r
esponse MAC intubation : response to intubation www.freelivedoctor.com

23. MAC values are useful Allows comparison of anesthetics Important clinical
endpoints Consistent and reproducible www.freelivedoctor.com

24. Therapeutic Index Margin of safety very small TI: 2-4 dose that produces
circulatory failure may be 2-4X that for anesthetic dose Some of the most
dangerous drugs in common clinical use www.freelivedoctor.com

25. Unitary Hypothesis General anesthesia can be caused by a remarkable

number of structurally diverse molecules www.freelivedoctor.com

26. Meyer-Overton Correlation 1903: Meyer and Overton note very strong
correlation between solubility in olive oil and anesthetic potency
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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. Nonspecific Theory Unitary hypothesis + Myer-Overton Rule = Anesthetics

act nonspecifically on hydrophobic lipid components of cells
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Pharmacology of therapeutic gases and inhalational anesthetics 07-07-2013

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. Protein Theory of General Anesthesia www.freelivedoctor.com

31. Molecular Sites of Action Ligand-gated ion channels GABA A receptor

Activity is enhanced by intravenous and volatile agents Glycine receptor Activity
is enhanced by volatile agents NMDA receptor Blocked by nitrous oxide, xenon,
cyclopropane, volatile agents nACh receptor Blocked by volatile agents Voltage-
gated ion channels Calcium channels synaptic function impaired by volatile
agents Sodium channels impaired function Background channels Tandem
pore-domain potassium channels Activated by volatile agents
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32. Molecular Mechanism(s) of General Anesthesia www.freelivedoctor.com Xe

Isoflurane Halothane ...... Cellular (synapses) Molecular (lipids & receptors)

33. A Working Hypothesis Anesthetics enhance inhibitory postsynaptic channel

activity (GABA A and glycine receptors) Anesthetics inhibit excitatory synaptic
channel activity (nicotinic acetylcholine and glutamate receptors)
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34. MACROSCOPIC SITES OF ACTION Anesthetic induced ablation of movement

in response to pain is mediated primarily by spinal cord. Cervical transection or
decerebration does not alter MAC Selective administration to cord causes
immobility Anesthetic induced amnesia is mediated by higher brain structures
(e.g., hippocampus) Anesthetic induced sedation mediated by
tuberomammillary nucleus of hypothalamus www.freelivedoctor.com

35. Inhaled Anesthetics - Pharmacokinetics Partial pressure vs. Concentration

Partial pressure in a mixture of gases is the portion of the total pressure
supplied by gas Amount of gas in blood or tissue is dependent on the solubility
of the gas in that solvent. Solvent/gas partition coefficient
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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. Induction Speed Determined by rate that alveolar partial pressure

equilibrates with inspired partial pressure Solubility (less soluble, faster)
Ventilation rate (increased rate, faster) Cardiac output (decreased output,
faster) Inspired concentration (higher concentration, faster)
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38. Induction Speed www.freelivedoctor.com

39. Anesthetic Uptake and Distribution Vessel Rich Group (VRG) CNS and
visceral organs High blood flow (75%) and low capacity Muscle Group (MG) Skin
and muscle Moderate flow and high capacity Fat Group (FG) Low flow and high
capacity Vessel Poor Group Bone, cartilage, ligaments Low flow and low
capacity www.freelivedoctor.com

40. Anesthetic of the Future: Xenon Rare gas extracted from air Very expensive

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Pharmacology of therapeutic gases and inhalational anesthetics 07-07-2013

to produce Close to ideal anesthetic Low blood and tissue solubility (rapid
induction/recovery) Potent Not metabolized Nonflammable Minimal side effects
www.freelivedoctor.com

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