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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
BARBITURATES

DENNIS STEVENS MSN, CRNA, ARNP

NOVEMBER 2005

FLORIDA INTERNATIONAL UNIVERSITY

PHARMACOLOGY OF ANESTHESIOLOGY NURSING

NGR 6173

objectives
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
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
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
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
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)
pharmacokinetics clinical considerations
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
pharmacokinetics absorption and distribution
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
pharmacokinetics biotransformation and excretion
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
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 indications12
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
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 systems14
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 systems15
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
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