BARBITURATES

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BARBITURATES

• DENNIS STEVENS MSN, CRNA, ARNP
• NOVEMBER 2005
• FLORIDA INTERNATIONAL UNIVERSITY
• PHARMACOLOGY OF ANESTHESIOLOGY NURSING
• NGR 6173

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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.

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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.

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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

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BARBITURATES
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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

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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)

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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

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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

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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
• lt1 of administered thiopental or methohexital is
  excreted unchanged in the urine
• Elimination half-time
• Thiopental - 11.6 hrs
• Methohexital 3.9 hrs

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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

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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

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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

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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

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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

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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