Joanna Webb CHEM 5398 Spring 2010 • • • • History of Anesthesia Methods of Administration Mechanisms of Action Companion Animal Drugs • Amnesia – Loss of memory • Immobility – Stay still • Analgesia – Pain relief • Homeostasis Blaze ppt. TCSVM Common: Inhalation Intravenous Intramuscular Less Common: Rectal Oral Nasal Intraperitoneal • Used to think all anesthetics worked the same way • The gas disrupted cell membrane lipids • Flaw: enantiomers of the same anesthetic have unique actions but the same physical properties (i.e. isoflurane) • Therefore, anesthetics must bind to specific proteins • Hyperpolarize neurons • Anticholingeric: suppresses nervous system communication • Alpha-2 adrenergic receptor agonist/antagonist: suppress norepinephrine binding/release to receptor • Cardiovascular depressant • Respiratory depressant •Ach is a main neurotransmitter of the autonomic NS of PNS •In the CNS, excitatory actions http://www.youtube.com/watch?v=VByEDXsRIFI&feature=related • Diethyl ether, nitrous oxide, chloroform • Halothane • Isoflurane • Sevoflurane http://www.dreveterinary.com/catalog/images/coaxial_lg_5.jpg http://www.asbestos.co.za/images/alveoli.jpg • • • • First anesthetic discovered Nontoxic to organs Unpleasant smell Decreases possibility of action potential by decreasing rate of rise to an end-plate potential • Colorless and odorless • Hepatotoxin • Severe CV depressant – Cardiac arrhythemia – Aka Sudden Sniffer’s Death • Blocks flow of K+ out of the cell www.inchem.org/documents/ehc/ehc/ehc163.htm • Binds to GABA receptor: enhances inhibitory synapses – Lets more Cl- into the cell • Competitive glycine inhibitor: agonist for N-methyl-Daspartic acid (NMDA) receptor • Pre-medicate with a barbiturate • Dog: 2.0-2.5% isoflurane concentration (in oxygen) • Horse: 3.0-5.0% isoflurane concentration (in oxygen) • Can keep it on a low concentration throughout the procedure • • • • Newer, more expensive than isoflurane Dogs: Induce with 7.0% sevoflurane Maintenance level is 3.3-3.6% with pre-medication 3.7-4.0% maintenance concentration without premedication • Common pre-meds: benzodiazepine or phenothiazine • Isoflurane is safer because patient does not require as much anesthesia, can be kept lighter – Higher cardiovascular stability Pre-anesthetics • Mild sedative, analgesic • Acepromazine – Combine with NSAID or opiod • Medetomidine • Atipamezole Induction anesthetics • Dissociative – Ketamine – Tiletamine • Benzodiazepines – Diazepam – Zolazepam • Propofol • Barbiturates • Partition into the highly lipophilic tissues of the brain and spinal cord • Produce rapid anesthesia • Immediate low concentrations of anesthetic in blood stream causes the drug to leave the CNS and enter the peripheral tissues via the blood • Effect can wear off in about 10 minutes unless continuously infused • • • • • Ace is provides strong sedation and antiemetic effects Phenothiazine Give with a NSAID or opiod to provide anagesic effects 6-8 hours of activity Anticholinergic, antihistamine, antispasmodic, and alpha-andrenergic blocking • Medetomidine is an NSAID – Strong sedative, strong analgesic – Alpha-2 adrenergic receptor agonist – 45-90 minutes • Atipamezole – Reversal agent – Alpha-2 adrenergic receptor antagonist – Administer a new analgesic after reversal since ALL effects of medetomidine are reversed Norepinephrine Medetomidine Atipamezole • Ketamine inhibits excitatory synapses S (+) – Dissociate: cataleptic state – Eyes open, limb movements involuntary • Serotonin, dopamine – High analgesic effects – Hypnotic state • Increases intracranial pressure and blood flow • Marketed as a racemic mixture • Partially water soluble pKa 7.5 • Highly lipophilic R (-) • Alpha-2 andrenergic receptor agonist • Binds to GABA receptor – Gamma-aminobutyric acid >20%: anxiolysis >30-50%: sedation >50%: unconsciousness • Opens Cl- channel, hyperpolarize membrane, so inhibitory • Given with ketamine to produce better anesthetic effects Diazepam • Pentobarbital • Derivative of barbituric acid (has no CNS activity) – Oxygen or sulfur at 2 position – Adds to CNS depressant activity • Commonly used in rats: research • Marketed as pentobarbital sodium powder – Soluble in water or alcohol, forms clear solution • Inhibits excitatory and enhances inhibitory CNS signals Barbituric acid Pentobarbital • • • • • • • • • • http://www.metrohealthanesthesia.com/edu/ivanes/ketamine2.htm http://www.inchem.org/documents/ehc/ehc/ehc163.htm http://vetmed.duhs.duke.edu/guidelines_for_pentobarbital.htm http://metrohealthanesthesia.com/edu/ivanes/benzos1.htm Blaze, C.A. (2009). Veterinary anesthesia and analgesia introduction. Microsoft Powerpoint. Tufts Cummings School of Veterinary Medicine. Chloroform. 2010). Wikipedia. Retrieved (2010, April 4) from http://en.wikipedia.org/wiki/Chloroform#Production Dickinson, R, Peterson, B.K, Banks, P.B., Similis, C, Martiin, J.C.S., Valenzulela, C.A., Maze, M, Franks, N.P. (2007). Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology. Anesthesiology, 107(5): 756-767. Muir, W.W. (2008): Intravenous anesthetic drugs: dissociative anesthetics. DVM360. Retrieved (2010, April 5) End plate potentials. (2009). Wikipedia. Retrieved (2010, April 4) from http://en.wikipedia.org/wiki/End-plate_potential University of Minnesota. Guidelines for the use of anesthetics, analgesics and tranquilizers in laboratory animals. Accessed 15 February 2010. < http://www.ahc.umn.edu/rar/anesthesia.html#Selection> • Goodman and Gilman’s Pharmacological Basis of Therapeutics, Chapter 13, pp. 341-363 • Draw the structure of propofol, the most commonly used anesthetic in the US. • Propofol is not water soluble, thus has to be constituted in an emulsion-like mixture of soybean oil, glycerol, and egg phosphatide. Circle the structural features responsible for its water insolubility. • Halothane, isoflurane and sevoflurane are commonly used inhalation anesthetics. Draw their structures • Draw and label the R and S stereoisomers of ketamine. • Which stereoisomer of ketamine has more psychic emergence? Which stereoisomer contributes more analgesic and anesthetic effects? • Thiopental (pentobarbital), thiamylal, methohexital are all derivatives of barbituric acid. Draw their structures and that of the parent structure barbituric acid.