Sedative Hypnotics

  1. Hypnosis (Definition)
    Artificially induced state of consciousness characterized by heightened suggestibility and receptivity to direction
  2. Mechanism of Action- Barbiturates
    • Depression of reticular activating system in brainstem with GABA mediation
    • -prevent dissociation of GABA from receptor to prolong effect of GABA
    • -mimic action of GABA and directly activate the receptor
  3. How GABA mediation works
    Causes increased conduction of chloride ions into the cell resulting in hyperpolarization of the postsynaptic membrane.  (functional inhibition of postsynaptic neuron)
  4. Why barbiturates cause hypotension
    they selectively depress transmission in SNS ganglia. they are a competitive inhibitor of nicotinic acetylcholine receptors so act like an anti-hypertensive agent
  5. Barbiturate structure
    formed via interaction of malonic acid and urea forming the barbiturate ring structure
  6. 6 types of barbiturates and 3 we focus on
    we focus on methohexital, thiopental, thiamylal, and there's phenobarbital, pentobarbital, secobarbital
  7. What is responsible for identification of barbiturate group?
    Carbons at 2 and 5 and 3rd Nitrogen
  8. 4 main groups of barbiturates, and the 2 we use in anesthesia
    -Thiobarbiturates, Methylbarbiturates, Oxybarbiturates, Methylthiobarbiturates
  9. Thiobarbiturates
    • Sulfur at C-2
    • Thiopental (Pentothal) and Thiamylal (Surital)
  10. Methylbarbiturates
    • Methyl group
    • Methohexital (Brevital)
  11. Oxybarbiturates
    • Oxygen at C-2
    • Phenobarbital, pentobarbital, secobarbital
  12. Methylthiobarbiturates
    • Not used clinically
    • Marked excitatory effects
  13. Sodium salts of barbiturates are...
    _______ soluble but highly ______

    Ex. Thiopental has a ______solution but pH is_____
  14. Absorption and (Re)Distribution of Barbiturates (PKA), and which factor is most important
    • 1. Lipid solubility******
    • 2. Ionization (HA)- acid drugs but prepared in alkaline solution
    • 3. Protein binding 
    • 4. blood flow
  15. Ionization of barbiturates
    (pKa of thiopental)
    • Acid drugs but prepared in alkaline solution
    • pKa of thiopental is 7.6
    • so pH is less than pKA
    • Moves toward non-ionized fraction of drug (HA)
  16. Lipid solubility of thiopental
    • Fat:blood partition coefficient is high! 60% 
    • There is rapid uptake in the brain, and uptake in fat continues long after injection
    • Gives hung-over affect because fat is an inactive reservoir
  17. How should thiopental be dosed
    According to lean body weight (because such high fat-blood coefficient serving as inactive reservoir)
  18. How to determine lean (ideal) body weight
    • Males- 52 +1.9kg/inch over 5 ft
    • Females- 49+ 1.7kg/inch over 5 ft
  19. protein binding of thiopental and methohexital
    • thiopental- 80%
    • methohexital- 85%
  20. biotransformation of barbiturates
    • oxidation in liver to inactive, water-soluble metabolites mostly
    • BUT thiopental oxidizes to pentobarbital (active metabolite) but this only matters at prolonged, high dose administration
  21. Methohexital Vs. Thiopental
    Elimination 1/2 time
    • Methohexital-
    • Elimination 1/2 time = 3.0
    • Clearance= 10.9
    • Vd= 2.2

    • Thiopental
    • Elimination 1/2 time=11.6
    • Clearance= 3.4
    • Vd= 2.5

    • Methohexital is less lipid soluble, has a short Elim 1/2time, more rapid clearance
    • Methohexital has 38% cleared upon awakening, vs thiopental only has 18% cleared
  22. Barbiturates effects on CV system
    • -hypotension (vasodilation, venous pooling, decreased venous return)
    • -Tachycardia (vagolysis, baroreflex intact)
    • -CO maintained in healthy patient! (decreased SV but increased HR)
    • -HTN- prone to BP swings on induction, volume status dictates ability to compensate
  23. bariturates effect on Respiratory system
    • -Apnea: depression of respiratory center in medulla
    • -Decreased response to hypercapnia and hypoxia
    • -upper airway obstruction- may need oral airway, reflexes may not be obliterated and can cause laryngospasm
  24. Barbiturates affect on CNS
    • -Constriction of cerebral vasculature (decreased CBF and ICP)
    • -Reduction in ICP is greater than reduction in BP so CPP increases
    • -Cerebral O2 consumption decreases up to 50% normal so decrease in cerebral blood flow is not detrimental
    • -anti-analgesic, lowers the pain threshold so hyponosis but not an analgesic
    • -small doses might cause excitation
    • -brevital induce involuntary skeletal muscle contraction
    • -protection from some transient episodes of local ischemia (but not against global ischemia like in cardiac arrest)
  25. Barbiturates effect on renal system
    • - decreased GFR
    • -decreased renal blood flow
  26. barbiturate Hepatic effects
    • -decreased hepatic blood flow which may influence biotransformation
    • -enzyme induction (i.e pts on chronic barbs for seizures)
  27. Immunologic effects of barbiturates
    release of histamine from mast cells with sulfur containing barbs (thiopental)
  28. Sodium pentothal
    • Thiopental
    • prototype barbiturate
    • 2.5% solution (25mg/ml)
    • -sodium salt readily soluble in water
    • -highly alkaline solution (ph 10.5)
    • racemic mixture of levo and dextro isomers which the levo isomer twice as potent as the dextro
  29. Methohexital
    • Brevital
    • -1% solution (10mg/ml)
    • -levo isomer 4-5 more potent as dextro but only available as a racemic mixture
    • -clearance faster than thiopental
    • -myoclonus and other excitatory activity occur
    • epileptiform activity on EEG but clinical seizure is rare
    • -pain on injection (5%)
    • inactive metabolite
    • -used for procedure where short sedation was wanted and for ECT treatments
    • -can be given rectally in kids (not used anymore)
  30. Indication for Barbiturates in anesthesia
    induction of GA
  31. special precautions of barbiturates
    • very basic drug so not good to give intraarterial or extravascular
    • intraarterial or extravascular injected treated with local infiltration of pentolamine (a dilute solution of papverine or procaine) to inhibit smooth muscle spasm
  32. Contraindications for barbiturates
    • Status asthmaticus
    • Porphyria (enzyme induction)
  33. Thiopental dosing (for induction)
    • 3-5 mg/kg IV
    • onset within 10-20 seconds and peaks in 30-40 seconds
    • Duration to awakening of 5-15 minutes
  34. Methohexital dosing for induction
    • 1-2mg/kg IV
    • 25-30mg/kg PR
    • onset in 20-40 seconds IV (<5 minutes PR)
    • peaks at 45 seconds IV (or in 5-10 minutes PR)
    • Duration 5-10 minutes IV (30-90 min PR)
    treat a variety of things like anxiety, muscle tension, sleep disorders, panic attacks, status epilepticus
  36. Benzodiazepine Structure
    Benzene ring, 7 member diazepine ring
  37. Imidazole ring of midazolam
    • contributes to water solubility at low pH (<6) as prepared
    • -once administered it becomes lipid soluble
  38. Effects of Benzos (what we use them for in OR)
    • -anxiolysis
    • -sedation
    • -ANTEROGrade amnesia (cant remember what happens after it's given)
    • -spinal cord mediated relaxation (GABA mediated) but different from neuromuscular blockers
  39. Benzo's mechanism of action
    • -benzo binding site located at interface between alpha and gamma subunits of the GABA receptor
    • -Facilitates the binding of GABA to receptor (doesn't actually activate the receptors themselves, just enhances affinity of GABA)
  40. How much Benzo receptor occupany to produce effect
    • -Suggested 20% receptor occupany produces anxiolysis
    • -30-50% occupany associated with sedation
    • >60% for patient to become unconcious
  41. Benzo ceiling effect
    there's a built in limitation on GABAnergic transmission which prevents Benzos from exceeding a max inhibition of GABA so low toxicity
  42. Midazolam pharmacokinetics
    (acid vs base? pka? ph? which way equation moves?)
    • Midazolam prepared as basic drug (HCL salt)
    • -pKa 6.15
    • -pH of solution 3.5
    • -at physiologic pH, pH>pKa- so equation moves toward nonionized B (BH+ --> B + H+)
    • -becomes lipid soluble
  43. Midazolam ring and water/lipid solubility
    • Prepared in pH solution of 3.5 which permits ring opening (ph<4) so it is water soluble
    • When placed in physiologic pH greater than 4, the ring closes so midazolam becomes lipid soluble
    • therefore it doesnt need propylene glycol (irritating to veins) to make it soluble
  44. midazolam protein binding
  45. midazolam onset time
    1-6 minutes  (considered slow, even through it crosses BBB)
  46. elimination 1/2 time of midazolam versus diazepam or lorazepam
    • Midazolam E 1/2 time= 1-4 hours
    • much shorter than others

    • Diazepam = 21-37 hours
    • Lorazepam= 10-20 hours
  47. Elderly and Benzo's
    • Careful! Elimination times often double.
    • Healthy elders may be ok, but decrease in functional reserve, altered body compartment status, hypovolemia causes elders to run into more problems
  48. Vd of midazolam, diazepam, lorazepam
    • Vd of midazolam and diazepam= 1-1.5 L/kg
    • Vd Lorazepam= 0.8-1.3 L/kg
    • similar lipid solubility and protein binding
  49. Clearance of Midazolam, diazepam and Lorazepam
    • Midazolam= 6-8ml/kg/min
    • Diazepam = 0.2-0.5ml/kg/min
    • Lorazepam=0.7-1ml/kg/min

    • Hepatic clearance of midazolam is 5x greater than lorazepam and 10x greater than diazepam
    • hepatic disease would alter clearance but renal disease would not
  50. Metabolism of Diazepam
    • Metabolized to desmethyldiazepam and oxazepam in phase I- (active metabolites)
    • Desmethyldiazepam is only slightly less potent than diazepam so drowsiness persists
  51. Benzo CV effects
    • Minimal effects
    • BP, CO, SV may decrease SLIGHTLY
    • HR may increase
  52. Benzo Respiratory effects
    • -Resp. Depression
    • -decrease response to CO2
    • -More pronounced when used with opiates or propofol
    • -decrease swallowing and upper airway reflexes
  53. Benzo CNS effects
    • -decrease cerebral O2 consumption, CBF and ICP (but not as much as barbiturates)
    • -prevent and controls seizures
    • -anterograde amnesia
    • -muscle relaxation
    • -anxiolysis, sedation, loss of conciousness depending on dose
    • -NO analgesia
  54. Induction with Benzos vs. Barbs
    Induction with benzos not usually done, will be slower than barbs
  55. Caution with Benzo's in...
    • Elderly
    • COPD
    • other respiratory depressants
    • Hypovolemia
  56. Flumazenil
    • -a benzo competitive antagonist given to reverse benzo's
    • -structurally similar to benzos so can bind with GABA receptor and interfere with binding of GABA
    • -metabolized in liver
    • -concerns with resedation because benzos have a longer duration of action so dont want the flumazenil to wear off and then patient be resedated
    • -0.2 mg IV reverses CNS effects in 2 minutes
    • -If more needed, 0.1mg q minute to a total of 1mg
  57. Midazolam dosing
    • Premedication/sedation= 0.5-1mg IV
    • Induction= 50-350mcg/kg IV
    • Onset in 30 seconds- 1 minutes
    • Peak in 3-5 minutes
    • Duration 15-80 minutes
  58. Diazepam dosing
    • premedication/sedation= 2-10 mg IV
    • Induction= 0.3-0.5mg/kg IV
    • Onset in < 2min
    • Peak 3-4 minutes
    • Duration 15 min- 1 hour
  59. Lorazepam dosing
    • Premedication/sedation 0.5-2 mg IV
    • Onset in 1-5 minutes
    • Peak in 15-20 minutes
    • Duration 6-10 hours
  60. Propofol mechanism of action
    GABA mediated
  61. Propofol structure
    • 2, 6-diisopropyl phenol
    • not water soluble, but available as 1% aqueous solution oil-in-water emulsion
  62. Oil-in-water emulsion components
    10% soybean oil, 2.25% glycerol, 1.2% lecithin
  63. Propofol and bacteria
    • Can support bacterial growth, use sterile technique and use within 6 hours
    • Contains 0.005% disodium edetate (diprivan) or 0.025% sosdium metabisulfite which helps to retard bacterial growth but doesnt meet FDA standards
  64. Amprofol
    Newer low-lipid soluble emulsion version of propofol that doesn't require a preservative or microbial growth agent but causes more pain
  65. Propofol pharmacokinetics (solubility, acid vs base, pKa, and which way equation moves)
    • Highly lipid soluble, acid drug, pKa of 11
    • -pH<pKA so equation moves HA nonionized form
  66. Propofol protein binding
  67. Propofol onset of action
    Almsot as fast as thiopental (40 seconds) but slower eye closing, therefore loss of verbal contact is more important than checking lid reflex
  68. Propofol distribution 1/2 time
    2-8 minutes (rapid awakening)
  69. Propofol Elimination 1/2 time, Vd, Clearance
    • Elimination 1/2t= 0.5-1.5 hours
    • Vd= 3.5-4.5 L/kg
    • Clearance= 30-60ml/kg/min
  70. Hepatic metabolism of Propofol
    • Clearance exceeds hepatic blood flow meaning there's an extra-hepatic mechanism of biotransformation
    • Hepatic metabolism is rapid and extensive to inactive metabolites
  71. Propofol clearance compared to Thiopental clearance
    • Propofol clearance is 30-60. thiopental is 3.4
    • Propofol is 10x that of thiopental
  72. Propofol and kids
    long term sedation associated with metabolic acidosis and death
  73. Context sensitive half time for propofol
    • The context-sensitive half-time is the time required for blood or plasma concentrations of a drug to decrease by 50% after discontinuation of drug administration.
    •  It is not substantially different for propofol infusion of up to 8 hours because of rapid clearance of propofol
  74. Propofol CV effects
    • -hypotension (more than thiopental) because of decreased SVR, myocardial contractility and preload
    • -impairs baroreflex
    • -small and transient changes in HR and CO, unable to compensate in the same way
    • -profound bradycardia and systole have been reported but rare
  75. Propofol respiratory effects
    • dose dependent resp depression
    • -decrease RR and tidal volume but decrease in Vt is greater than RR
    • -apnea with induction dose
    • -decrease response to CO2 and hypoxemia
    • -decrease upper airway reflexes
  76. Propofol CNS effects
    • -decreased cerebral O2 consumption, CBF and ICP
    • -anti-pruritic properties
    • -anti-emetic properties (decrease PONV)
    • -excitatory activities on induction possible but rare (d/t subcortical glycine antagonism)
    • -anti-convulsant properties
  77. Propofol infusion syndrome
  78. -poisoning of electron transport chain, impaired oxidation of fatty acids in some susceptible patients leading to metabolic acidosis
    -if patient has unexplained tachycardia, check ABG
  79. Propofol dosing
    • induction: 1.5-2.5mg/kg IV (105-175 for 70kg pt)
    • Maintenance infusion: 50-200 mcg/kg/min
    • Sedation bolus: 25-50 mg (0.5-1mg/kg)
    • Sedation infusion: 25-100mcg/kg/min
  80. Propofol onset, peak, duration
    • onset- 40 seconds
    • peak- 1 minutes
    • duration 5-10 minutes
  81. Ketamine mechanism of action
    • dissociation between thalamocortical and limbic systems
    • -The thalamus relays sensory impulses from RAS to cortex
    • -Limbic cortex invovled with awareness of sensation
    • -Inhibits excitatory NT effects in the brain
  82. Ketamine effects
    • -dissociate anesthesia
    • -resembles cataleptic state
    • -eyes open with slow nystamic gaze
    • -non-communicative but awake
    • -hypertonus and purposeful movement
    • -sedation, immobility, amnesia, marked analgesia, dissociation from the environment
    • -emergence delirium (dreaming, hallucinations, confusion)
  83. Ketamine structure-activity
    • phencyclidine derivative (PCP family)
    • -acts on NMDA receptor, noncompetitiev antagonist
    • -member of glutamate receptor family
    • -ion channel with excitatory properties
    • -also mu, delta, kappa opioid receptor interaction
    • -inhibits acetylcholine receptors (anti-muscarinic atropine like effects)
    • -can produce increased secretions d/t SNS stimulation
  84. Ketamine pharmacokinetics
    (solubility, pKa, which way equation moves)
    • -basic drug (amine)
    • -water soluble racemic mixture
    • -pKa= 7.5
    • -protonated, ionized form predominates (BH+)
  85. biotransformation of ketamine
    to norketamine, an active metabolite 1/3 to 1/5 as potent as ketamine
  86. ketamine protein binding
    12-35% protein bound
  87. Ketamine analgesia
    • Works on mu, kappa, delta opioid receptors
    • -produce significant analgesia in sub-anesthetic doses that are better for the somatic body pain as opposed to internal visceral pain
  88. How to help with hallucinations of ketamine
    Give with a benzo
  89. Ketamine Vd, clearance and Elim 1/2 time
    • elim 1/2 time= 2-3 hours
    • Vd= 2.5-3.5 L/kg
    • Clearance= 16-18 ml/kg/min
  90. Ketamine CV effects
    Increased BP, HR, CO
  91. Ketamine Resp effects
    bronchodilation, increased secretions
  92. Ketamine CNS effects
    • increased CBF, ICP, cerebral O2 consumption
    • -increase intraocular pressure d/t spasms possible
    • -protective reflexes preserved
    • -emergence delerium
  93. Ketamine and fetus
    • crosses placenta d/t lipid solubility but up to 1mg/kg does not compromise fetal status
    • -2mg/kg can cause fetal compromise
  94. IV and IM ketamine dosing, onset, peak, duration
    • IV induction dose 1-2mg/kg IV
    • onset in 30 seconds
    • peak in 1 minutes
    • duration 5-15 minutes

    • IM 5-10mg/kg
    • onset in 3-8 minutes
    • peak in 5-20 minutes
    • duration of 12-25 minutes
    • full orientation takes 60-90 minutes
  95. Etomidate Mechanism of Action
    • depresses reticular activating system 
    • mimics effects of GABA, increases affinity of receptor for GABA
  96. Etomidate structure-activity
    • carboxylic acid ester
    • imidazole containing compound- water soluble at acid pH and lipid soluble at physiologic pH
    • -dextro isomer is active and formulated as a single enantiomer
  97. Etomidate pharmacokinetics (acid vs base, pKa, equation moves to..?)
    • basic drug
    • pKa= 4.2
    • pH >pKa so non-protonated, non-ionized for B predominates
  98. etomidate protein binding
  99. etomidate metabolism
    • -metabolism d/t hydrolysis of ethyl ester side chain results in inactive metabolite 
    • -liver and plasma esterases so rapidly metabolized
  100. etomidate clearance, Vd, elim 1/2 time
    • elim 1/2 time= 2-5 hours
    • Vd 2.2-4.5 L/kg
    • Clearance= 10-20 ml/kg/min (5x that of thiopental)
  101. Etomidate injection
    unstable at physiologic pH so dissolved in propylene glycol which causes pain on injection
  102. Etomidate on CV system
    • minimal! great for the fragile hemodynamic patient
    • mild decrease in SVR
  103. Etomidate Respiratory effects
    less depression than with barbs or benzos
  104. Etomidate CNS effects
    • decreased CBF, O2 consumption and ICP
    • CPP maintained
    • Increased N/V
    • no analgesia
  105. Etomidate Endocine effects
    • adrenocortical suppression lasting 4-8 hours after induction dose
    • -inhibits beta hydroyxlase enzymes responsible for syntehsis of cortisol and aldosterone
  106. Etomidate contraindications
    septic patient because they need the HPA axis intact
  107. Etomidate dosing
    Induction- 0.1-04 mg/kg IV
  108. Etomidate onset, peak, duration
    • onset in 30-60 seconds
    • peak in 1 minute
    • duration 3-10 minutes
Card Set
Sedative Hypnotics
Exam 2