Sedative Hypnotics

  1. What receptor do the barbiturates work on?  What cellular effects does this cause?
    • -GABA
    • -Cl- ions enter the cell, postsynaptic membrane becomes hyper-polarized
    • -Barbiturates prevent dissociation of GABA from the receptor, thus prolonging the effect of GABA (more Cl- goes in)
  2. What is the characteristic structure of the barbiturates?
    barbiturate ring, formed by interaction of malonic acid and urea
  3. What structural differences account for the different classification of barbiturates?
    substitutions on carbons 2 and 5
  4. What group of barbiturates has sulfur at C2?  What does this do?
    • Thiobarbiturates, ex: thiopental and thiamylal.
    • Replacing O with S increases lipid solubility.
  5. What substitution in the barbiturate chemical structure determines hypnotic potency and anticonvulsant properties?
  6. What is an example of a methylbarbiturate?  What's characteristic of its structure?
    • methohexital (brevital)
    • O at C2
  7. What factor most influences distribution of the barbiturates?
    • lipid solubility
    • followed by: ionization, protein binding, blood flow
  8. Are the barbiturates acid or basic drugs?
  9. What's the pKa of thiopental?  What form of the drug predominates?
    • 7.6
    • HA (nonionized, protonated form)
  10. Are the barbiturates highly lipid soluble?  What does this mean for us?
    Yes, rapid uptake into the brain.  Fat acts as inactive reservoir.
  11. Protein binding of thiopental and methohexital.
    • Thiopental 80%
    • Methohexital 85%
  12. Do the barbiturates have active metabolites?
    Only thiopental does, it is oxidized to pentobarbital.  However, this is only significant with a long infusion and at high doses.  It's not a good infusion agent anyway since it's so fat soluble, but...
  13. Does thiopental have a long or short CSHT (context sensitive half time)?
  14. How should we dose the barbiturates?
    • According to lean (ideal) body weight.
    • Males 52 + 1.9 kg/in over 5 ft tall
    • Females 49 + 1.7 kg/in over 5 feet tall
  15. Does thiopental or methohexital have a shorter elimination half time?  Why?
    Methohexital has a short elimination half time.  Its clearance is greater than thiopental despite their Vd being almost equal.
  16. Will pedi pts experience longer or shorter elimination half times than adults?  Why?
    Shorter due to more rapid hepatic clearance.
  17. How do the barbiturates affect the CV system?
    • -BP decreased (vasodilation of venous capacitance vessels, pooling of blood, decreased preload).  
    • -HR increases to maintain CO in a healthy pt
    • -Pt with poorly controlled HTN will have labile BP on induction
  18. How do the barbiturates affect the respiratory system?
    • -Depress resp center in medulla
    • -Decrease response to hypercapnea and hypoxia
    • -Upper airway obstruction
  19. How do the barbiturates affect the CNS?
    • -Cause constriction of cerebral vasculature
    • -Decreased CBF, ICP, and O2 consumption
    • -CPP increased (Greater reduction in ICP than in BP)
  20. Do the barbiturates cause analgesia?
    No, they are anti-analgesics and lower the pain threshold.
  21. T or F, small doses of barbiturates can cause excitation and induce involuntary skeletal muscle contractions?
    T, more with methohexital
  22. How do the barbiturates affect the renal system?
    BP is decreased so this decreases renal blood flow and GFR
  23. How do the barbiturates affect the liver?
    • -Decrease hepatic blood flow.  
    • -Enzyme inducers, metabolized by CP450
  24. Which barbiturates can cause histamine release?
    The sulfur containing barbiturates: thiopental and thioamylal
  25. T or F, the pH of thiopental solution is 10.5, so this means it's a basic drug?
    F!  The pH and pKa do NOT tell us if it's an acid or basic drug.
  26. T or F, it's not a big deal if IV barbiturates are injected intrarterially or extravascularly?
    F, they are very basic solutions and local infiltrations need to be treated with phentolamine to inhibit smooth muscle spasm.
  27. What are barbiturates contraindications?
    Porphyria (CP450 induction stimulates porphyrin pathway) and status asthmaticus (histamine release from thiopental)
  28. What's the onset of thiopental (and thiamylal)?
    10-20 sec
  29. What's the peak of thiopental (and thiamylal)?
    30-40 sec
  30. What's the duration of thiopental (and thiamylal)?
    5-15 mins (to awakening)
  31. What's the induction dose of thiopental (and thiamylal)?
    3-5 mg/kg IV
  32. What's the onset of methohexital?
    20-40 sec
  33. What's the peak of methohexital?
    45 sec
  34. What's the duration of methohexital?
    5-10 mins
  35. Can you give methohexital PR?
  36. What's the basic chemical structure of the benzos?
    benzene ring and 7 member diazepine ring
  37. How does the imidazole ring on midaz affect solubility?
    • At low pH (<4) the ring opens and it is water soluble.
    • At physiological pH, the ring closes and it is lipid soluble.
  38. What's the MOA of the benzos?
    • GABA
    • Facilitates binding of GABA to the receptor, doesn't activate the receptor itself but enhances affinity of GABA to the receptor
  39. At what levels of receptor occupancy do the benzos cause anxiolysis, sedation, and unconsciousness?
    • Anxiolysis 20%
    • Sedation 30-50%
    • Uncons >60%
  40. What's the pKa of midaz?  What form predominates?
    • 6.15
    • B
  41. Are the benzos basic or acid drugs?
  42. What's the site equilibration time of midaz?
    1-5.5 mins.  It is very lipid soluble and crosses the BBB quickly, but has slow effect compared to propofol or thiopental.
  43. What percent protein bound are the benzos?
  44. What benzo (out of midaz, valium, and ativan) has the shortest elimination half time?
    • midaz
    • it's hepatic clearance is also much faster than ativan or valium
  45. Do any of the benzos have an active metabolite?
    Valium only.  Metabolized to desmethyldiazapam and oxazepam in phase I
  46. What's the advantage of midaz being water soluble at low pH?
    It doesn't need propylene glycol to make it soluble like ativan and valium do.  Propylene glycol can be irritating to the veins.
  47. How do the benzos affect the CV system?
    • Minimally.  
    • -Autoregulation is preserved.  
    • -BP, CO, and SVR may decrease slightly.  
    • -HR may increase slightly due to vagolysis.
  48. How do the benzos affect the resp system?
    • Depression, more pronounced when used with opiates.  
    • Decreased response to CO2
  49. How do the benzos affect the CNS?
    • -Decreased cerebral O2 consumption, CBF, ICP
    • -Prevent and control seizures
    • -Antegrade amnesia
    • -Muscle relaxation
  50. Are the benzos usually used for induction?
    No, slower induction and emergence so not used.
  51. What is flumenazil?
    Antagonist to the benzos.  Competative antagonist at the GABA receptor.
  52. What's the premedication / sedation dose of midaz?
    0.5-1 mg IV
  53. What's the induction dose of midaz?
    50-350 mcg/kg IV
  54. What's the onset of midaz?
    30 sec to 1 min
  55. What's the peak of midaz?
    3-5 mins
  56. What's the duration of midaz?
    15-80 mins
  57. Are the benzos acid or basic drugs?
  58. What is the pKa of propofol?  What form predominates?
    • 11
    • HA
  59. Is propofol an acid or basic drug?
  60. What's the MOA of propofol?
  61. How is propofol prepared?
    • 1% aqueous solution, oil in water emulsion.
    • 10% soybean oil
    • 2.25% glycerol
    • 1.2% purified egg phos (lecithin)
  62. How long is propofol good for (after opening a vial)?
    6 hours, it supports bacterial growth, so toss it after 6 hrs.
  63. How protein bound is propofol?
  64. What's the Vd of propofol?
    4 l / kg
  65. What's propofol's clearance?  What contributes to this?
    • 30-60 ml/kg/min
    • Extrahepatic mechanism for metabolism that enhances its clearance.  
  66. Does propofol have active metabolites?
  67. Is the effect site equilibration time of propofol short or long?
  68. What's the context sensitive half time of propofol?
    <40 mins for an infusion of up to 8 hours
  69. Why is propofol not used for long term sedation in kids?
    It's associated with lipenia, acidosis, and death in children, it's used for short periods of time in kids.  
  70. How does propofol affect the CV system?
    • -Causes hypotension (more than thiopental) due to decreased SVR, contractility, and preload (vasodilation)
    • -Impairs the normal baroreflex (HR can't increase to compensate for decreased BP, HR actually decreases)
  71. How does propofol affect the resp system?
    • -decreased in TV > decrease in RR
    • -decreased upper airway reflexes
    • -resp depression
  72. How does propofol affect the CNS?
    • -Decreased cerebral O2 consumption, CBF, and ICP
    • -anti-pruritic properties
    • -anti-emetic properties
    • -excitatory activity on induction
    • -anti-convulsant properties
  73. What's propofol infusion syndrome?
    • -Metabolic acidosis, poisoning of the electron transport chain, impaired oxidation of long chain fatty acids in susceptible pts, mimics mitochondrial myopathy
    • -Possibly a genetic component
    • -Uncertain MOA
    • -Increased HR is a sign
    • -This might be what occurs in peds
  74. What's the induction dose of propofol?
    1.5-2.5 mg/kg
  75. What's the maintenance infusion dose of propofol?
    50-200 mcg/kg/min
  76. What's the onset of propofol?
    40 sec
  77. What's the peak of propofol?
    1 min
  78. What's the duration of propofol?
    5-10 mins
  79. What's ketamine's MOA?  What receptor(s) does it work on?
    • -It acts on the NMDA receptor as a noncompetitive antagonist.  NMDA is a member of the glutamate (excitatory NT) family
    • -Also acts on opioid receptors to produce analgesia
  80. What type of anesthesia does ketamine produce?  Describe it.
    • -Sedation, immobility, amnesia, analgesia
    • -Dissociative anesthesia.  Resembles a cataleptic state.  Eyes open with slow nystagmic gaze.  Non-communicative but awake.  Hypertonus and purposeful movement.  Dissociation from the environment.
  81. Why wouldn't you want to give ketamine to a psych pt?
    It produces emergence delirium.
  82. How does ketamine produce dissociative anesthesia?
    • -Produces dissociation between the thalamocortical and limbic systems.
    • -Thalamus relays sensory impulses from RAS to cortex
    • -Limbic cortex involved with awareness of sensation.
    • -Inhibits excitatory NT effects in the brain
  83. What sedative hypnotic produces analgesia?
  84. Is ketamine an acid or basic drug?
    basic (amine)
  85. What's the pKa of ketamine?  What form of the drug predominates?
    • 7.5
    • BH+
  86. How protein bound is ketamine?
  87. Does ketamine have active metabolites?
    Yes, norketamine, 1/3 to 1/5 as potent as ketamine.
  88. What's the Vd of ketamine?
    4 L/ kg
  89. What's the clearance of ketamine?
    17 ml/kg/ min
  90. What type of pain is ketamine best for?
    Somatic pain (skeletal)
  91. What effects does ketamine have on the CV system?
    • -INCREASE BP, HR, CO, mimics the SNS system.  
    • -Increased myocardial O2 consumption
  92. What effects does ketamine have on the respiratory system?
    • -Bronchodilation and increased secretions.
    • -Protective airway reflexes are preserved.
  93. What med would you want to give to treat the increased secretions produced by ketamine?  Why?
    Glycopyrrolate, it can't cross the BBB.  Want to avoid scop. and atropine as they do cross the BBB and could increase the risk of emergence delirium.
  94. How can we attentuate the emergence delirium produced by ketamine?
    With benzos
  95. What effects does ketamine have on the CNS?
    Increased CBF, ICP, CMRO2 
  96. Can you give ketamine to a pregnant woman?
    Yes.  It crosses the placenta, but doses of 0.5 - 1 mg / kg will NOT compromise the fetus.  Effects are dose dependent.
  97. What pts would you NOT want to give ketamine to?
    Pts with uncontrolled HTN, CAD, CHF, aneurysm, space occupying lesions, increased ICP, psych issues.  
  98. What pts would ketamine benefit?
    asthmatic, unstable HD in an otherwise healthy person (intact SNS).  
  99. What's the induction dose of ketamine?
    • 1-2 mg/ kg IV
    • or
    • 5-10 mg/kg IM
  100. What's the onset of ketamine?
    30 sec
  101. What's the peak of ketamine?
    1 min
  102. What's the duration of ketamine?
    • 5-15 mins
    • Short DOA, but time to full orientation is a lot longer due to decreased clearance
  103. How does etomidate work?
    • -GABA
    • -Depresses RAS
  104. What's the characteristic structure of etomidate?  What other drug is it chemically related to?
    • -Carboxylic acid ester
    • -R/t midaz (it has an imidazole containing compound)
  105. Is etomidate an acid or basic drug?
  106. Which form of etomidate is pharmacologically active?
  107. What's the pKa of etomidate?  What form of the drug predominates?
    • 4.2
    • B
  108. How protein bound is etomidate?
  109. How is etomidate metabolized?  Does it have an active metabolite?
    • Hydrolysis of ester side chain.
    • Inactive metabolites.  
  110. Why does etomidate cause pain on injection?
    It's dissolved in propylene glycol (like ativan and valium)
  111. What's the Vd of etomidate?
    2.2-4.5 L/ kg
  112. What's the clearance of etomidate?
    10-20 ml/kg/min
  113. Rank the following from greatest clearance to least clearance: thiopental, propofol, and etomidate.
  114. Rank the following from greatest amount of protein binding to least: etomidate, ketamine, propofol, thiopental
    thiopental and propofol>etomidate>ketamine
  115. How does etomidate effect the CV system?
    Minimally, this is why we use it!
  116. How does etomidate effect the respiratory system?
    -Produces less depression than with barbiturates or benzos
  117. How does etomidate effect the CNS?
    • -Decreased CBF, CMRO2, ICP
    • -CPP is well maintained
  118. Does etomidate produce N/V or analgesia?
    • -Produces N/V.
    • -No analgesic effects.
  119. How does etomidate effect the endocrine system?
    • -Causes transient adrenocortical suppression.
    • -Last about 4-8 hours after an induction dose.
    • -Suppresses beta hydroxylase enzymes responsible for aldosterone and cortisol synthesis in a dose dependent manner. 
  120. In what pts should etomidate be avoided in?
    Adrenal suppression and porphyria
  121. What are examples of pts at risk for adrenocortical suppression?
    • -long term steroid use
    • -septic
    • -hemorrhaging
  122. What's the induction dose of etomidate?
    0.1-0.4 mg /kg IV
  123. What's the onset of etomidate?
    30-60 sec
  124. What's the peak of etomidate?
    1 min
  125. What's the duration of etomidate?
    3-10 mins.
Card Set
Sedative Hypnotics
Sedative Hypnotics