hands administering med   Barbiturates

Overview

  • Thiopental (2.5%), Thiamylal and Methohexital (1-2%) have been commonly used in the past for induction of anesthesia
    • became popular due to their rapid onset and short duration
  • Prepared as sodium salts in an alkaline solution (thus cannot be reconstituted with LR)
    • if alkalinity is reduced, for example by mixing barbiturates with acidic solutions like vecuronium, pancuronium, atracurium, alfentanil, sufentanil, or midazolam, then barbiturate may precipitate (causing occlusion of IV line or even the vessel)

  • Barbiturates provide reliable loss of consciousness (LOC), and fairly good amnesia, BUT beware!
    • Barbiturates do NOT provide analgesia, and in fact can be antianalgesic

    • Analgesics MUST be used with barbiturates

  • Barbiturates can be used for induction and maintenance of anesthesia, as well as the hypnotic component of anesthesia premedication

  • Major side effects include:

    • mild pain on injection (less than propofol)

    • respiratory depression

    • cardiovascular depression (direct vascular and cardiac effects)

    • prolonged sedation with continuous infusion

    • excitatory symptoms with induction    

Pharmacokinetics

  • Barbiturates' pharmacokinetic profile is best described using compartmental models

  • Important Pharmacokinetic Variables

    • Thiopental
      • Vdss = 1.5-3 L/kg
      •  Clearance = 3-4 mL/kg/min
      • Alpha Eliminination Half-life = 2-4 min
      • Beta Elimination Half-life = 7-17 hours
      •  85% protein bound
    • Methohexital
      • § Vdss = 1.5-3 L/kg
      • Clearance = 10-15 mL/kg/min.
      • Alpha Elimination Half-life = 5-6 min 
      •  Beta Eliiminiation Half-life = 4 hours
      • 85% protein bound
  • Metabolism

    • Barbiturates are hepatically metabolized (except Phenobarbital), and these metabolites are mostly inactive, water-soluble and excreted in the urine. Only very small amounts of barbiturates are excreted unchanged by the kidney

      • Oxidation is the most significant metabolic pathway - oxidative metabolites are readily excreted in the urine or conjugated with gluconuride and excreted in bile

      • Long-term administration of barbiturates induces oxidative microsomes - thus DO NOT administer barbiturates to patients with Acute Intermittent Porphyria since g-aminolevulinic acid synthetase will be induced, and may precipitate an attack

      • Methohexital has a shorter elimination half-time than thiopental, due to more rapid clearance by the liver

  • Barbiturates, like propofol, quickly distribute to highly perfused tissues and cross the BBB due to their high lipid solubility and preference for their nonionized form (high pKa). These properties account for their rapid onset of action. However, they also undergo rapid redistribution to well-perfused, but inactive tissues (skeletal muscle), which terminates the action of a single bolus (induction dose) typically within 5-10 minutes.

  • Barbiturates have increased context-sensitive half-times as compared to propofol (tend to wear off slower with continued administration), since propofol has the unique property of undergoing extrahepatic metabolism, and barbiturates (especially thiopental) have high affinities for fat, large volumes of distribution, and relatively low hepatic clearances → tissue accumulation, especially with large doses over a prolonged period.

  • Barbiturates are highly protein bound (to albumin and other plasma proteins). Only unbound drug may enter CNS. Disease states and pH will affect how much drug is bound, and therefore how much drug enters the CNS

  • Interestingly, clearance of barbiturates is not affected by cirrhosis (except end-stage cirrhosis) since an adequate amount of enzyme is still available even at advanced stages of disease

Pharmacodynamics

  • CNS

  • o Barbiturates seem to work by two different pathways producing sedation and sleep (LOC and amnesia < benzodiazepines)

  • § enhancement of inhibitory neurotransmission

  • Barbiturates bind to GABAA receptor ® enhances (at low dose) and mimics (at higher doses) action of GABA and seems to account for sedative-hypnotic effects of barbiturates

  • § blockade of excitatory neurotransmission (glutamate and acetylcholine)

  • o barbiturates seem to be antianalgesic (decrease the pain threshold, especially at low doses)

  • o Awakening may be delayed in the elderly due to increased CNS sensitivity, alterations in metabolism, and decreased central volume of distribution

  • o Peds patients have a more rapid rate of total clearance, which means they may awaken earlier, especially with prolonged infusions or multiple doses

  • o Effects on cerebral metabolism

  • § dose related depression of cerebral oxygen consumption (CMRO2), and protection from incomplete cerebral ischemia

  • § decrease in ICP due to decrease in cerebral perfusion (from cerebrovascular vasoconstriction and decreased CMRO2)

  • § ratio of CBF to CMRO2 is unchanged

  • § Cerebral perfusion pressure (CPP) is not compromised

  • Respiratory System

  • o Dose related central respiratory depression ® peak respiratory depression for thiopental is 1 - 1.5 minutes after bolus
  • o 20% of cases experience apnea with thiopental, but duration is usually only about 25 sec long; characterized by "double apnea"
  • § transient apnea after induction lasts a few sec and is followed by a few breaths with adequate tidal volume
  • § then followed by longer apneic period, thus patients induced with thiopental require assisted ventilation
  • o

    BE WARNED ®

    After a single dose of a barbiturate, patients will gain consciousness before respiratory effects have worn off

  • Cardiovascular System

  • o Cardiovascular depression results from direct vascular and cardiac effects
  • § peripheral vasodilation of capacitance vessels ® decrease in BP and preload
  • § increase in HR (10-36%), due to activation of the baroreceptor reflex to hypotension (can be deleterious in patients with CAD due to increased myocardial O2 consumption)
  • § decrease in CO due to
  • negative inotropy
  • decreased preload
  • transiently decreased sympathetic outflow from CNS

Uses

  • Induction and maintenance of anesthesia
  • o Thiopental ® induction has prompt onset (15-30 sec), and generally "smooth", but there is rapid emergence with a single dose
  • o Thiopental can be used to maintain anesthesia since it reliably sustains unconsciousness and contributes to amnesia. HOWEVER, awakening can be quite delayed due to tissue saturation
  • o Methohexital ® induction and emergence are swift using a dose of 1-2 mg/kg. ALSO, since methohexital has a more rapid clearance than thiopental, it is generally considered a superior choice for the maintenance of anesthesia
  • o Recovery from methohexital infusion (<60 min. in duration) is similar to propofol
  • Dosing

  • o Thiopental

  • § Induction ® 3-4 mg/kg over 5-15 sec with an onset of 10-30 sec (Beware of significant interpatient variability in required dose)
  • § IV maintenance ® 50-100 mg every 10-12 min.
  • o Methohexital
  • § Induction 1-1.5 mg/kg over 5-15 sec ® an onset of 10-30 sec (Beware of significant interpatient variability)
  • § IV maintenance ® 20-40 mg every 4-7 min.

Side Effects/Contraindications

  • Respiratory and Cardiovascular depressants
  • o Thiopental should be avoided in hypovolemia due to reduction in CO and BP
  • Garlic or onion taste in 40% of patients
  • local tissue irritation and rarely necrosis (more common with thiopental)
  • urticarial rash on head, neck or trunk lasting a few minutes
  • Induction excitatory symptoms ® 5X more common with methohexital ® cough, hiccough, tremors and twitching
  • pain on injection: methohexital > thiopental
  • Intra-arterial injection can result in severe pain and thrombosis
  • o Treatment ® dilution, heparinization, and brachial plexus block

  • Contraindications

  • o Respiratory obstruction or inadequate airway (thiopental may worsen respiratory depression
  • o Severe cardiovascular instability or shock
  • o Status asthmaticus
  • o Acute Intermittent Porphyria
  • o Barbiturates should not be administered without proper airway equipment available (since assisted ventilation is required)
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