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BARBITURATES. DENNIS STEVENS MSN, CRNA, ARNP NOVEMBER 2005 FLORIDA INTERNATIONAL UNIVERSITY PHARMACOLOGY OF ANESTHESIOLOGY NURSING NGR 6173. OBJECTIVES. Discuss the preparation of barbiturates regarding expiration times following reconstitution.
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BARBITURATES DENNIS STEVENS MSN, CRNA, ARNP NOVEMBER 2005 FLORIDA INTERNATIONAL UNIVERSITY PHARMACOLOGY OF ANESTHESIOLOGY NURSING NGR 6173
OBJECTIVES • Discuss the preparation of barbiturates regarding expiration times following reconstitution. • Compare the structure-activity relationships of oxybarbiturates and thiobarbiturates. • Explain mechanism of action associated with barbiturates and involvement with neurotransmitters. • Discuss the pharmacokinetic properties specific to barbiturates. • Explain the effects that barbiturates have on organ systems. • State potential drug interactions with barbiturates.
REFERENCES Morgan, G.E., Mikhail, M.S., and Murray, M.J. (2002). Clinical Anesthesiology. (3rd Ed.) New York, NY: McGraw-Hill. Nagelhout, J.J. and Zaglaniczny, K.L. (2005). Nurse Anesthesia. (3rd Ed.) St. Louis, MO: Elsevier- Saunders. Stoelting, R.K. (1999). Pharmacology & Physiology in Anesthesia Practice. (3rd Ed.) Philadelphia, PA: J.B. Lippincott Company.
COMMERCIAL PREPARATIONS • Barbiturates are prepared commercially as sodium salts readily soluble in water or saline • These highly alkaline solutions are incompatible for mixture with many medications which are acidic • Thiopental usually prepared in 2.5% solution • Methohexital usually prepared in 1% solution • Powder form of thiopental stable indefinitely • Refrigerated solutions: • Thiobarbiturates stable up to two weeks • Methohexital stable up to six weeks • Room temperature reconstituted solutions of thiopental remain stable and sterile for at least 6 days
STRUCTURE ACTIVITY RELATIONSHIPS • Barbiturates are barbituric acid derivatives • Barbiturates with sedative-hypnotic properties result from substitutions at the number 2 and 5 carbon atoms of barbituric acid • Substitutions determine hypnotic potency, lipid solubility, anticonvulsant properties, onset, and duration of action • Barbiturates that retain: • An oxygen atom on number two carbon are designated as oxybarbiturates • A sulfur atom on number two carbon results in thiobarbiturates
MECHANISM OF ACTION • Barbiturates depress the RAS (reticular activating system) • Preferentially affect the function of nerve synapses rather than axons • Suppress transmission of excitatory neurotransmitters • Enhance transmission of inhibitory neurotransmitters • Interferes with transmitter release (presynaptic) and stereoselectively interacting with receptors (postsynaptic)
PHARMACOKINETICSCLINICAL CONSIDERATIONS • Prompt awakening after a single dose of thiopental or methohexital reflects redistribution of these drugs from brain to inactive tissues • Elimination from the body depends almost entirely on metabolism
PHARMACOKINETICSABSORPTION AND DISTRIBUTION • Barbiturates are most frequently administered intravenously for induction of general anesthesia in adults and children with an established IV • Exceptions: • Rectal methohexital for induction in children • Distribution of barbiturates in the body is determined by lipid solubility, protein binding, and degree of ionization • Tissue blood flow is major determinant in delivery of barbiturates to tissues • Duration of action of highly lipid-soluble barbiturates determined by redistribution
PHARMACOKINETICSBIOTRANSFORMATION AND EXCRETION • Metabolism of barbiturates principally involves hepatic oxidation to inactive water-soluble metabolites • Thiobarbiturates also break down to a small extent in extrahepatic sites • Hepatic dysfunction • Renal excretion is limited to water-soluble end products of hepatic biotransformation • <1% of administered thiopental or methohexital is excreted unchanged in the urine • Elimination half-time: • Thiopental - 11.6 hrs • Methohexital – 3.9 hrs
CLINICAL INDICATIONS • Principal clinical uses of barbiturates: • Induction of anesthesia • Treatment of increased intracranial pressure • Barbiturates have been replaced by benzodiazepines for preanesthetic medication • Rapid onset of action of barbiturates renders these drugs useful for treatment of grand mal seizures, but benzodiazepines are probably superior
CLINICAL INDICATIONS • Thiopental: • Induction dose: 3-5 mg/Kg IV • Metabolism and redistribution to inactive tissue sites are important determinants of early awakening • Metabolized in the liver to metabolites that are more water soluble and have little CNS activity • Methohexital: • Induction dose: 1-1.5 mg/Kg IV or 25 mg/Kg PR • Metabolized more rapidly than thiopental reflecting lesser lipid solubility • Redistribution to inactive tissue sites
EFFECTS ON ORGAN SYSTEMS • Cardiovascular: • IV induction dose causes a fall in BP and a rise in HR • CO often maintained by a rise in HR and increased myocardial contractility • CV effects of barbiturates vary markedly, depending on volume status, baseline autonomic tone, and preexisting cardiovascular disease • Consider slow rate of injection and adequate preoperative hydration • Respiratory: • Decreased response to hypercapnia and hypoxia • Leads to upper airway obstruction and apnea • During awakening TV and RR decreased
EFFECTS ON ORGAN SYSTEMS • Cerebral: • Decreases cerebral blood flow and ICP • Cerebral perfusion pressure usually increased • Cerebral oxygen consumption decreased • EEG activity changes: Low-voltage fast activity- small dose High-voltage slow activity to electrical silence- large dose • Taste sensation during induction with thiopental • Barbiturates appear to have an antianalgesic effect • Grand mal seizures: • Thiopental 50-100 mg IV
EFFECTS ON ORGAN SYSTEMS • Renal: • Reduce RBF and GFR in proportion to fall in BP • Hepatic: • Hepatic blood flow is modestly decreased • Induction doses do not alter postoperative LFTs • Placental Transfer: • Maternal doses of thiopental up to 4 mg/Kg IV probably do not result in excessive concentrations of barbiturates in fetal brain • Immunologic: • Anaphylactic and anaphylactoid reactions are rare • Treatment of allergic reaction • Some evoke mast cell histamine release
MEDICATION INTERACTIONS • Contrast media, sulfonamides, and other drugs that occupy the same protein-binding sites as thiopental will increase the amount of free drug available • ETOH, narcotics, antihistamines, and other CNS depressants potentiate the sedative effects of barbiturates • Chronic ETOH abuse