Pharm Lecture 4: Sedative Hypnotics

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  1. Define hypnosis
    considered an altered state of consciousness characterized by a heighten suggestibility and receptivity to suggestion, also a sleep like condition
  2. How do barbituates work? (what do they depress)
    Depression of reticular activating system in brainstem
  3. What effect does GABA have?
    • Causes ↑ conduction of chloride ions into the cell 
    • Results in hyperpolarization of postsynaptic membrane
    • So functional inhibition of postsynaptic neuron
  4. How do barbiturates effect GABA?
    • Barbiturates prevent dissociation of GABA from
    • receptor & prolong the effect of GABA

    • Barbiturates also mimic the action of GABA &
    • directly activate the receptor
  5. how do barbiturates effect the SNS?
    Barbiturates selectively depress transmission in SNS ganglia which may contribute to ↓ BP
  6. According to Barash, barbiturates are also a competitive inhibitor of what?
    of nicotinic Ach receptor in CNS.
  7. How is the barbiturate structure formed?
    Formed via the interaction of malonic acid & urea forming the barbiturate ring structure
  8. Name the four classifications of barbiturates
    • Thiobarbiturates
    • Methylbarbiturates
    • Oxybarbiturates
    • Methylthiobarbiturates
  9. Where are the substitutions on the barbiturates?
    at carbon 2 and 5
  10. Tell me about thiobarbiturates
    • Sulfur at C-2
    • Thiopental (Pentothal)
    • Thiamylal (Surital)
  11. What is the importance of replacing the oxygen with sulfur at C2
    • by replacing that oxygen w/a sulfur, this
    • will increase lipid solubility.
  12. What is the importance of C5 substitutions?
    C5 carbon substitutions, determine hypnotic potency and the anti-convulsant properties.
  13. Tell me about Methylbarbiturates
    • Methyl group
    • Methohexital (Brevital)
    • Methylbarbituates have the oxygen at C2.
  14. Tell me about Oxybarbiturates
    • Oxygen at C-2
    • Phenobarbital
    • Pentobarbital
    • Secobarbital
  15. Why aren't Methylthiobarbiturates used clinically?
    very potent but marked excitatory properties so not used
  16. Describe the pharmacokinetics of barbiturates
    • Absorption & (Re)Distribution: 
    •   1. lipid solubility *Most important
    •   2. ionization (HA)
    •   3. protein binding
    •   4. blood flow
    • Lipid solubility most influences distribution. Distribution itself can be influenced by differences in tissue blood flow (which might mean alterations in blood volume). Talking about Vd, if pt is hypovolemic, when we initially give a drug (barbiturate) will have high concentration in central compartment (tank smaller same amount of drug). Higher plasma level of the drug after administration and that will be significant because the patient will have a more profound effect.

    • Ionization is important. pKa of thiopental is 7.6 so it’s close to physiologic pH. Its an acid drug. HA <-> H+ + A
    • HA<- if acidoic pt, so we’ll see more exaggerated effect because more will be in non-ionized form.
  17. Descrbe the Lipid solubility & Ionization of barbiturates
    • Fat:blood partition coefficient high
    • High non-ionized fraction at physiologic pH (Thiopental 60%; pKa =7.6)
    • Rapid uptake in the brain
    • Uptake in the fat continues long after injection
    • Fat is inactive reservoir
  18. What is the the equation to dose according to lean (ideal) body weight?
    • Males: 52 + 1.9 kg/inch over 5 feet tall
    • Females: 49 + 1.7 kg/inch over 5 feet tall
  19. When a patient is awakening after a dose of barbiturates is this due to biotransformation and excretion?
    • NO. It's due to uptake in the fat.
    • There will be continued uptake in the fat for prolonged period of time after injection, fat is really inactive reservoir, the apparent duration of action (the reawakening we see after the induction dose  of say Thiopental, the patient would be asleep in 1min, they would be awakening (not completely wide awake) in 5min if we gave NOTHING else. It's not gone, its in the fat and will have its effect again.
  20. Why is thiopental not satisfactory as an entire anesthetic?
    Not satisfactory to be given as an infusion because when we look at context sensitive ½ times, a drug like thiopental will have a forever context sensitive ½ time, it’s going into fat and it’s clearance is not as high as propofol.
  21. Why is protein binding important?
    What percent of thiopental and methohexital are protein bound?
    Duration of action

    • Thiopental = 80%
    • Methohexital = 85%
  22. Why do we want to give a lower dose of barbiturates in the elderly?
    • Give lower induction doses in elderly as well. Elderly tend to have a smaller volume in central compartment. Broad generalization (healthy elders are pretty healthy, have reasonable physiologic reserve but as they age, and many times have co-morbidities, on edge of slope, doesn’t take much to diminish their functional reserve.
    • Even healthy elders tend to loose their thirst sensation. Don’t necessarily stay euvolemic.
    • Smaller plasma volume, so concentrating the drug. Give smaller dose.
  23. Describe the biotransformation of barbiturates
    • Oxidation in the liver to inactive, water-soluble metabolites
    • Oxidation in liver will replace sulfur with oxygen on that C2. So mostly the metabolites are inactive but thiopental will initially be oxidized to pentobarbital, (which is an active metabolite) thought to be only relevant if given for long period of time in high doses.

    Methohexital metabolized to inactive metabolites.
  24. Which is more lipid soluble, Methohexital or Thiopental? What does this effect?
    • Thiopental is more lipid soluble. Consequently
    • slightly lower Vd and shorter elimination ½ time.

    Vd isn’t everything when we talk about elimination ½ time. Methohexital’s clearance is 3x that of thiopental.
  25. For Thiopental and Methohexital...
    What is the rapid distribrution 1/2 time (mins)?
    What is the slow distribution 1/2 time (mins)?
    What is the elimination 1/2 time (hours)?
    • Thiopental:
    • 8.5 (rapid)
    • 62.7 (intermediate)
    • 11.6 (elimination)
    • Methohexital:
    • 5.6 (rapid)
    • 58.3 (intermediate)
    • 3.9 (elimination)
  26. What is the clearance (ml/kg/min) of Thiopental and Methohexital?
    Thiopental: 3.4

    Methohexital: 10.9
  27. What is the volume of distribution (L/kg) for Thiopental & Methohexital?
    • Thiopental: 2.5
    • Methohexital: 2.2
    • Some drugs exceed VD (exceed total body water) this is another example that Vd is theoretical, not an actual volume.
  28. Why is elimination 1/2 time of thiopental prolonged in obese patients?
    increased Vd with increased fat storage.
  29. Why do pediatric patients have shorter elimination 1/2 times of barbiturates?
    Pediatric patients have a more rapid hepatic clearance so a shorter elimination ½ time.
  30. Recovery to awakening occurs pretty quickly with barbiturates, what % of thiopental, methohexital, and propofol will be metabolized?
    • 18% of Thiopental
    • 38% of Methohexital
    • 70% of Propofol (has high clearance)
  31. What effect do barbiturates have on the CV system?
    ↓ BP 2° vasodilation of venous capacitance vessels → pooling of blood → ↓ venous return

    ­ ↑ HR 2° vagolysis (Baroreceptor intact!)

    • CO maintained by HR (healthy patient only)
    • Pt with poorly controlled HTN is prone to BP swings on induction (see a lot!)
    • Volume status dictates ability to compensate
  32. When would you not see an increase in HR after giving a barbiturate?
    • If Baroreceptor is not intact or functional.
    • (hypovolemia, CHF pt, betablocked) then no longer healthy pt and would see substantial decreases in BP.
  33. Why are patients with poorly controlled HTN prone to swings in BP?
    HTN pt has increased SVR chronically, they’re hypovolemic when they come (even without being NPO) and get roller coaster ride on induction. How well we manage the volume status will help that. If you have a patient that’s hypotensive and has a decreased EF, can’t flood w/volume but in general volume helps us to increase preload  (IV volume) to attenuate that. Increased preload to compensate for HoTN on induction. Better off titrating induction drugs carefully
  34. Why can't the diabetic compensate for hypotension on induction?
    has neuropathy including the ANS so they don’t have ability to compensate easily.
  35. What effect do barbiturates have on the Respiratory system?
    • Depression of respiratory center in medulla
    • ↓ response to hypercapnia & hypoxia
    • Upper airway obstruction
    • As they’re going off to sleep develop upper airway obstruction. Still breathing but relaxation (not neuromuscular blockade) of laryngeal muscles, soft tissues will get in way, snore and develop upper airway obstruction. If trying to ventilate them still, we’ll often put in oral airway but reflexes aren’t completely obliterated. If put in too soon could cause the patient to go into laryngospasm
  36. What effect do barbiturates have on the CNS system?
    • Constriction of cerebral vasculature
    • ↓CBF ↓ICP (Reduction in ICP is > reduction in BP so CPP is usually ↑’d)
    • CPP = cerebral artery pressure - cerebral
    • venous pressure (ICP)

    Cerebral O2 consumption ↓ up to 50% of normal so ↓ CBF isn’t detrimental (benefits of barbitautes)

    • Small doses may cause excitation (Methohexital)
    • Some induce involuntary skeletal muscle contractions
  37. Are barbiturates good for pain control?
    NO! Anti-analgesic– lower the pain threshold
  38. When do barbiturates protect the brain?
    Brain protection from transient episodes of focal ischemia but not global ischemia in cardiac arrest.
  39. How do barbiturates effect the kidneys?
    • ↓ renal blood flow
    • ↓ glomerular filtration
  40. How do barbiturates effect the liver?
    • ↓ hepatic blood flow
    • Enzyme induction
    • Metabolized by CYP450, so if on barbituates chronically (seizure disorder) need more thiopental for induction because enzyme induced (same way the chronic alcohol user is)
  41. What effect do barbiturates have on the immunologic system?
    • Sulfur-containing barbiturates (thiopental and thioamyal) cause histamine release from mast cells
    • See flush from sleep dose of thiopental.
  42. Tell me about Thiopental (Sodium pentothal) and Thiamylal (Surital).
    • Prototype
    • 2.5% solution
    • Sodium salt readily soluble in water
    • Highly alkaline solutions (pH = 10.5)
    • Racemic mixture of levo- & dextro-isomers
    • with levo-isomer twice as potent as dextro
  43. Tell me about Methohexital (Brevital)
    • -1% solution
    • -Levo-isomer 4-5 times as potent as dextro but
    • only available as racemic mixture
    • -Clearance is faster than thiopental (makes
    • elimination ½ time shorter, 3.5x quicker than thiopental)
    • -Myoclonus & other excitatory activity like hiccoughs may occur
    • -Epileptiform activity may be seen on EEG but clinical seizure is rare (odd, think of barbs to tx
    • seizures but some are excitatory)
    • -Pain on injection (5% incidence)
    • -Metabolite is inactive
  44. What are the indications for barbiturates?
    • Induction of anesthesia
    • Unchallenged as induction agent from 1934-1989
  45. What are some special precautions we need to take with barbiturates?
    • (Very alkaline)
    • Intrarterial or extravascular injection treated with local infiltration of phentolamine (alpha blocker), a dilute solution of papaverine, or procaine to inhibit smooth muscle spasm
  46. What are some contraindications of barbiturates?
    • Status asthmaticus (Particularly Thiobarbitautes
    • contraindicated because of histamine release)
    • Porphyria (CYP 450 enzyme induction and precipitates an attack)
  47. What is the induction dose, onset, peak and duration of Thiopental and Thioamylal?
    • Induction 3-5 mg/kg IV
    • Onset: 10-20 sec
    • Peak: 30-40 sec
    • Duration: 5-15 min (awakening)
  48. What is the induction dose, onset, peak, and duration of action of Methohexital?
    • Induction 1-2 mg/kg IV or 25-30 mg/kg PR
    • Onset: 20-40 sec IV (< 5 min PR)
    • Peak: 45 sec IV 9 ( 5-10 min PR)
    • Duration: 5-10 min IV (30-90 min PR)
    • Can be given rectally, advantage, for pedi
    • induction
    • Used for ECT tx (now propfol is used)
  49. Why can't we mix thiopental with other medications?
    • Because it is a highly alkaline solution
    • (pH= 10.5)
  50. Methohexital is a 1% solution so how many mg/ml?
  51. Thiopental is a 2.5% solution so how many mg/ml?
  52. What is the structure/activity relationship of Benzos?
    • Benzene ring
    • 7 member diazepine ring
    • Substitutions alter potency & biotransformation
    • Imidazole ring of midazolam & solubility
  53. What are the effects of Benzos?
    • Anxiolysis
    • Sedation
    • Anterograde amnesia
    • Spinal cord mediated muscle relaxation (GABA-mediated
  54. When were benzos introduced?
    • 1950s
    • Has lots of uses!
  55. Is the kind of muscle relaxation from Benzos good for surgery? Does it add to neuromuscular blockers?
    • Muscle relaxation isn’t the kind for surgical relaxation. Not additive to neuromuscular blockers.
    • More spinal cord mediated, not at NMJ, more GABA mediated.
  56. Tell me about the imidazole ring of midazolam and why that's important
    Versed is different because it has imidazole ring: contributes to water solubility at low pH and lipid solubility at physiologic pH
  57. What makes diazepam irritating and painful when injected?
    Diazepam is insoluble in water, needs to be prepared to propylene glycol which is painful and irritating on injection.
  58. How do Benzo's work (MOA)?
    Benzo binding site located at interface between alpha & gamma subunits of GABAa receptor

    Facilitates binding of GABA to receptor so don’t activate the receptors by themselves but modulate response to GABA by enhancing affinity

    Benzos have ceiling effect = built in limitation on GABAergic transmission = low toxicity**APNEA IS STILL A PROBLEM
  59. For Benzos, Stoelting says  ____% of receptor occupancy produces anxiolysis, ____% is associated w/sedation & greater than ___% is needed to have pt unconscious
    • 20%
    • 30-50%
    • 60%
  60. Tell me about the pH dependent ring-opening phenomenon for midazolam.
    permits ring opening at a pH of less than 4, maintaining water solubility. (in the vial)

    When the drug is exposed to physiologic pH greater than 4 the ring closes and midazolam is converted to a lipid soluble drug
  61. What is the advantage to having Midazolam as a water soluble drug?
    It doesn’t need propylene glycol to make it soluble as propylene glycol is irritating to veins causes discomfort with injections.
  62. Tell me about the pharmacokinetics of Midazolam
    • Midazolam prepared as HCl salt (Basic drug)
    • pka = 6.15
    • pH of solution = 3.5
    • @ physiologic pH, pH > pKa
    • so non-pronated, non-ionized form predominates
  63. All benzos are basic or acidic?
    • basic. 
    • Less active as pt gets more acidoic.

    Solution as it’s prepared has pH of 3.5. so  can’t make inferences to acid base nature of drug based on prepared pH.
  64. Does versed have a quick onset of action like propofol?
    NO. Versed is highly lipid soluble, crosses BBB quickly, but its considered to have a slow effect w/equilibration time (effect site equilibration time is anywhere from 1-5.5min which is pretty slow compared to propofol or thiopental)
  65. TRUE or FALSE. All benzos are highly protein bound.
    TRUE! Highly protein bound (96-98%) higher than thiopental.
  66. What are the equivalent doses of Midazolam, Diazepam, and Lorazepam?
    • Versed 0.15 -0.3 mg
    • Diazepam 0.3- 0.5 mg
    • Lorazepam 0.05 mg
  67. What is the volume of distribution for Midazolam, Diazepam, and  Lorazepam? (in L/kg)
    • Midazolam 1-1.5 
    • Diazepam 1-1.5
    • Lorazepem 0.8-1.3
    • *Midazolam and Diazepam have similar Vd but different elimination 1/2 times...
  68. What is the protein binding for Midazolam, Diazepam, and Lorazepam?
    96-98% for all of them!!!
  69. What is the clearance (ml/kg/min) of Midazolam, Diazepam, and Lorazepam?
    • Midazolam 6-8
    • Diazepam 0.2-0.5
    • Lorazepam 0.7-1.0
  70. What is the elimination 1/2 time (hrs) for Midazolam, Diazepam, and Lorazepam?
    • Midazolam (1-4)
    • Diazepam (21-37)
    • Lorazepam (10-20)
    • *Midazolam has much shorter elimination 1/2 time of all the benzos!
  71. The Vd of benzos is similar, why do the elimination 1/2 times vary?
    Hepatic clearance of midazolam is 5 times greater than lorazepam & 10 times greater than diazepam
  72. Diazepam is metabolized to two active metabolites. what are they?
    desmethyldiazepam & oxazepam in phase I (active) may contribute to the return of drowsiness
  73. What should we remember when giving benzos to the elderly patient?
    elimination ½ time may be prolonged because of body composition changes, deceased blood flow, elderly/geriatric give less. Start low, can always give more.
  74. Will obese patients have a larger or smaller Vd of benzos?
    Larger (more fat)
  75. If our patient has liver disease, what would we expect in regard to benzos?
    • If liver disease, expect there would be impaired clearance or elimination of benzos. 
    • Metabolites by hepatic oxidation and conjugation
  76. Lorazepam may be used in longer infusions for sedation, but what is the problem?
    Also prepared in propylene glycol, Long infusions of Diazepam or Ativan can result in glycerol toxicity.
  77. What are the effects of Benzos on the CV system?
    • Minimal effect (preserves autoregulation)
    • BP, CO, SVR may decrease slightly
    • HR may increase (vagolysis)
  78. What are the effects of Benzos on the resp system?
    • Depression
    • ↓ response to carbon dioxide
    • More pronounced when used with opiates (1+1 =3) **Be careful w/polypharmacy, and let pre-op holding RN know you gave the med**
  79. What are the effects of Benzos on the CNS system?
    • ↓ cerebral oxygen consumption, CBF, ICP
    • Prevent & control seizures
    • Anterograde (not retrograde) amnesia
    • Muscle relaxation (spinal cord level, not at NMJ)
    • Anxiolysis → sedation → loss of consciousness (dose dependent)
    • No analgesia
  80. Why do we worry about aspiration when giving benzos?
    Decrease swallow reflex and also upper airway reflexes. Need to worry about pt at risk for aspiration.(even in MAC cases)
  81. Benzos can be used for induction but not usually used. why?
    induction and recovery are slower than even thiopental
  82. Midax is ___ x as potent (with better sedation/amnesia)
  83. When should we use caution w/Benzos?
    • Elderly
    • Hypovolemia
    • With other respiratory depressants
    • COPD
  84. Tell me about Flumazenil
    • Specific benzo competitive antagonist (drug itself is inert)
    • Concerns with resedation (duration 30-60 minutes)Drug itself has shorter duration of action than the drug you’re trying to block. May
    • need to give supplemental doses to maintain a desired LOC
  85. What is the dosing of Flumazenil?
    0.2 mg IV usually reverses CNS effect in 2 minutes. If more drug is needed, 0.1 mg IV every minute to a total of 1 mg.
  86. Do we give Flumazenil a lot?
    No, We don't give benzos thinking we can just reverse them. (we only plan to reverse our drugs when we use NM blockers)
  87. What is the dosing of Midazolam?
    • Premedication/sedation: 0.5-1.0 mg IV
    • Induction: 50-350 mcg/kg IV
    • Onset: 30 sec-1 minute
    • Peak: 3-5 minute
    • Duration: 15-80 minutes
  88. What is the dosing of Diazepam?
    • Premedication/sedation: 2-10 mg IV
    • Induction: 0.3-0.5 mg/kg IV
    • Onset: < 2 minutes
    • Peak: 3-4 minutes
    • Duration: 15 minutes-1hour
    • (Active metabolites)
  89. What is the dosing for lorazepam?
    • Premedication/sedation: 0.5-2.0 mg IV
    • Onset: 1-5 minutes
    • Peak: 15-20 minutes
    • Duration: 6-10 hours
  90. What is the structure activity relationship of Propfol?
    • 2, 6-diisopropyl phenol
    • Not water soluble but available as 1% aqueous solution, oil-in-water emulsion
    • --10% soybean oil
    • --2.25% glycerol
    • --1.2% purified egg phosphatide (lecithin)
    • ***Sue said we really need to know this***
  91. What is the MOA of propofol?
    GABA mediated
  92. Why can we only use a propofol vial for 6 hrs after opening?
    • Can support bacterial growth! Be very careful
    • Use within 6 hours
    • Contains 0.005% disodium edetate (Diprovan) or 0.025% sodium metabisulfite (Generic)
    • *Helps to retard bacterial growth but don’t meet standard as antimicrobially preserved products under US pharmacy standards.
  93. Is propofol an acid or basic drug? What is it's pKa?
    • acid drug, pKa is 11. So at physiologic pH,
    • non ionizied (protonated HA) form predominates (ph<pKa).
  94. Tell me about the pharmacokinetics of Propofol
    • Highly lipid soluble
    • Very short initial distribution half-time (2-8min) (rapid awakening)
    • Clearance exceeds hepatic blood flow meaning extrahepatic mechanism of metabolism
    • Hepatic metabolism is rapid & extensive to inactive metabolites
    • Unusually high clearance is 10x that of thiopental
  95. Propofol has a slower eye closing than thiopental, what does this mean?
    When going to sleep, want to assess by lid reflex, run finger on eyelashes with thiopental but with propofol is loss of verbal contact.
  96. What is the elimination 1/2 time (hrs) of Propofol, Etomidate,  and Ketamine ?
    • Propofol 1-1.5
    • Etomidate 2-5
    • Ketamine 2-3
  97. What is the Vd of Propofol, Etomidate, and Ketamine? (L/kg)
    • Propofol 3.5-4.5
    • Etomidate 2.2-4.5
    • Ketamine 2.5-3.5
    • *Fairly large Vd
  98. What is the clearance (ml/kg/min) of Propofol, Etomidate, and Ketamine?
    • Propofol 30-60
    • Etomidate 10-20
    • Ketamine 16-18
    • **Clearance of Propofol is much higher, more rapid recovery and less of a hangover
  99. What happens to systemic BP of Propofol, Etomidate, and Ketamine?
    • Propofol = Decreased
    • Etomidate = No change or decreased
    • Ketamine = Increased
  100. What happens to HR w/Propofol, Etomidate, and Ketamine?
    • Propofol = Decreased
    • Etomidate = no change
    • Ketamine = Increased
  101. What % of propfol is protein bound?
    96% or greater, highly protein bound
  102. Do we increase or decrease the dose of propofol in elderly patients
  103. Describe the metabolites of Propofol
    Metabolites are inactive and water soluble that help them get eliminated by the kidneys.
  104. What happens if we give Propfol long term for long term sedation (esp in kids)
    If given for long term sedation for kids in ICU associated with lipemia, metabolic acidosis, & death
  105. Context sensitive ½ time w/propfol is less than ____min for infusions lasting up to 8hrs. Forgiving for that reason.
    40 min
  106. Describe the CV effects of propofol
    • ↓ BP (more than thiopental) 2°
    • --↓ SVR
    • --↓ myocardial contractility (direct myocardial depression)
    • --↓ preload (d/t vasodillation)
    • Impairs normal baroreflex (unlike thiopental)
    • ---Small & transient changes in HR & CO
    • Profound bradycardia & asystole have been reported
    • ---1.4:100,000  (rare, but can happen in healthy adults)
    • ---↓ sympathetic activity > parasympathetic → parasymapthetic predominance (no normal baroreflex to compensate)
  107. When are we more likely to see the CV effects of propofol?
    Effects are seen more w/large doses or pt is hypovolemic, or if we give it rapidly, esp. in geriatrics.
  108. Describe the Resp effects of Propfol
    • Depression (dose dependent)
    • ↓ RR & TV (effect on TV is more prominent than that of RR)
    • ↓ upper airway reflexes
  109. Describe the CNS effects of Propofol
    • ↓ Cerebral oxygen consumption, CBF & ICP
    • Anti-pruritic properties (beneficial)
    • Anti-emetic properties (beneficial, only need to give 10-20mg)
    • Excitatory activities on induction ? 2° subcortical glycine antagonism
    • Anti-convulsant properties
  110. How can we decrease pain on injection w/propofol
    Problem w/propfol. Give 20-50mg of lidocaine. Some people like to give lidocaine 1st then the propofol. Some people mix it w/lidocaine (study says it works better)
  111. Describe Propofol infusion syndrome
    • seen as metabolic acidosis (Mechanism not clear but ?poisoning of electron transport chain, so there is impaired oxygenation of long chain fatty acids, thought to occur in susceptible patients), apparently mimics mitochondrial myopathies.
    • Genetic? If pt becomes tachycardic during propofol, check lactate and blood levels to see if they’re acidotic.
  112. Propofol doses are....
    • Induction: 1.5-2.5 mg/kg
    • Maintenance infusion: 50-200 mcg/kg/min
    • Sedation bolus: 25-50 mg (0.5-1 mg/kg)
    • Sedation infusion: 25-100 mcg/kg/min
  113. What is the onset, peak, and duration of action with propfol?
    • Onset: 40 seconds
    • Peak: 1 minute
    • Duration: 5-10 minutes
  114. All of the induction agents decrease BP except_____
    • Ketamine.
    • (Etomidate and Midaz are no change or decrease)
  115. Which induction agents increase HR?
    • Thiopental and Ketamine
    • Etomidate is unchanged or increased

    Propofol is unchanged or decreased

    Midazolam is unchanged
  116. Which is the only induction agent to INCREASE SVR?
    • Ketamine.
    • Etomidate and Midazolam are unchanged or decreased.
    • Propofol and Thiopental decrease SVR
  117. What is the only induction agent to INCREASE CBF? (and also increase ICP)?
    • Propofol, Thiopental, & Etomidate all DECREASE CBF
    • Midazolam is DECREASED or unchanged CBF
  118. What two induction agents are not know to cause depression of ventilation
    Midazolam and Ketamine.

    (Propofol, Thiopental, and Etomidate will depress ventilation)
  119. Which induction agent is also used for anxiolysis?

    All the others do not! (Propofol, Thiopental, Etomidate, & Ketamine)
  120. What is the only induction agent that can be used for analgesia as well?
    • Ketamine.
    • All the other do not! (Propofol, Thiopental, Etomidate & Midazolam)
  121. What is the only induction agent that causes emergence delirium?
    Ketamine.All the other do not! (Propofol, Thiopental, Etomidate & Midazolam)
  122. What induction agent has increased N/V? Which ones have decreased N/V?
    • Etomidate (increased N/V)
    • Propofol decreases N/V
    • No change w/Thiopental and Ketmaine.
    • No change or decreased w/Midazolam
  123. Which induction agent(s) can cause adrenocortical suppression?
    • Midazolam?
    • Propofol, Thiopental, and Ketamine DO NOT!
  124. Describe the dissociative anesthesia caused by Ketamine.
    • Resembles cataleptic state
    • Eyes open with slow nystamic gaze
    • Non-communicative but awake
    • Hypertonus & purposeful movement
    • Sedation, immobility, amnesia, marked analgesia, & dissociation from the environment
    • Emergence delirium (dreaming, hallucinations, confusion)
  125. What causes the dissociative anesthesia w/Ketamine?
    • Dissociation between thalamocortical & limbic systems
    • Thalamus relays sensory impulses from RAS to cortex
    • Limbic cortex involved with awareness of sensation
    • Inhibits excitatory neurotransmitter effects in the brain
  126. Describe the structure activity relationship of Ketamine
    • Phencyclidine derivative (PCP=angel dust)
    • N=methyl-D-aspartate (NMDA) receptor noncompetitive antagonist
    • Member of the glutamate receptor family
    • Ion channel with excitatory properties
    • Also mu, delta, & kappa opioid receptor interaction *Analgesia*
  127. How does Ketamine exert its effect?
    • Blocks reflexes in spinal cord
    • Inhibiting NT effects in brain
  128. What can partially antagonize Ketamine?
    Ketamine can be partially antagonized by the Anti-cholinesterase drugs.
  129. What causes the increased secretions of Ketamine?
    Can also cause an increases secretions from SNS stimulation.
  130. Describe the pharmacokinetics of Ketamine
    • Basic drug (amine)
    • Water soluble racemic mixture
    • pKa = 7.5 (pH < pKa so protonated, ionized form predominates)
    • Biotransformation to norketamine (1/3 to 1/5 as potent as ketamine)
    • 12-35% protein bound
  131. Ketamine is able to produce intense analgesia at what dose?
    At sub anesthetic doses (0.2 -0.5mg/kg) analgesia is thought to be good for somatic pain (body muscle and skeletons) vs visceral pain (internal organs)
  132. Pt tends to get increased secretions so you want to give what?
    • An antisialagogue like glyccopyrolate is a good idea.
    • As opposed to Atropine and Scolapamine. Don’t want it to cross BBB, already have emergence delirium, don’t want to increase it.
  133. How does Ketamine effect the CV system?
    • ­ ↑ BP, HR, CO (inc. O2 consumption)
    • CO effects mimic SNS stimulation.
    • Increase in systolic BP can be 20-40mmHg occurs in 1st 3-4min after injection, it will decrease to pre-drug levels in about 10-20mins. This is managed though the SNS, if depleted catecholamine stores,then ketamine has direct negative inotropic effect. So we may not always see this but its the typical situation.
  134. How does Ketamine effect the Resp. system?
    • bronchodilation
    • ­ ↑ secretions
    • Protective airway reflexes are well preserved
    • Need to secure airway d/t increased secretions
  135. How does Ketamine effect the CNS?
    ­ ↑ CBF, ICP, CMRO2
  136. Who may you want to avoid Ketamine with?
    • don't want to increase myocardial oxygen demand
    • Avoid ketamine w/someone CAD, uncontrolled HTN, CHF, aneurysm.
  137. Who is ketamine good for?
    • Someone in hypovolemic shock, (ruptured ectopic pregnancy), impact CNS but hypovolemic.
    • *SNS stimulation*
    • Also someone w/Asthma (causes bronchodilation)
  138. When is Ketamine contraindicated (in terms of CNS)?
    Contraindicated in pt w/space occupying lesion.
  139. How can you attenuate the emergence delirium of Ketamine?
    Use a benzo first
  140. What kind of ocular effects does Ketamine have?
    It will increase intraocular pressure, increased muscle tone, & nystagmus
  141. Who should we use caution w/Ketamine (in general)?
    any pt w/increased ICP, CV things, or psychiatric disease (emergence delirium)
  142. Which induction agent is the closest to being a complete anesthetic (besides the volatiles)?
    • Ketamine. 
    • (causes amnesia, analgesia, and unconsciousness)
  143. What about using Ketamine in OB?
    Does cross placenta (lipid soluble) but if low dose then doesn’t compromise status of neonate at delivery. But if doses increases to around 2, then there’s neonatal depression
  144. What is the IV dosing of Ketamine?
    • Induction: 1-2 mg/kg IV 
    • Onset: 30 seconds
    • Peak:  1 minute
    • Duration: 5-15 minutes
  145. What is the IM dosing of Ketamine?
    • Induction: 5-10 mg/kg IM
    • Onset: 3-8 minutes
    • Peak:  5-20 minutes
    • Duration: 12-25 minutes

    *good to give IM for pediatric or mentally impaired*
  146. What is the dose of Ketamine for preemptive analgesia
    10-20mg IV
  147. TRUE or FALSE. We sometimes use Ketamine as an infusion w/propofol.
    TRUE. Not used a lot
  148. For Ketamine, although the duration of action is fairly short, time to full orientation is significantly
    Longer. Just doesn't have same clearance as something like propofol. Time to clearance is longer.
  149. Describe the MOA of Etomidate
    • Depresses RAS
    • Mimics effects of GABA
    • Increases affinity of receptor for GABA
  150. What is the structure activity relationship of Etomidate
    Carboxylic acid ester (imidazole-containing compound) chemically unrelated to any other anesthetic except midazolam

    Imidazole is like midazolam so water-soluble at acid pH and lipid soluble at physiologic pH
  151. Describe the pharmacokinetics of Etomidate
    • Basic drug 
    • Only dextro-isomer is pharmacologically active
    • pKa = 4.2  (pH > pKa so non-protonated, non-ionized form predominates)
    • 75% protein bound (more than ketamine, less than propofol and thiopental)
    • Metabolism due to hydrolysis of ethyl ester side chain results in inactive metabolite (liver & plasma esterases)
    • Clearance is 5 times that of thiopental (not as high as propofol)
    • Etomidate is dissolved in propylene glycol →
    • pain on injection (newer formulations are changed to fat emulsion so less pain)
  152. TRUE or FALSE. Only the levo isomer of etomidate is pharmacologically active
    FALSE. Only the dextro-isomer is active! Formulated as single enantiomer (unlike the other induction drugs we talked about)
  153. Etomidate can have disinhibitory effects on NS, what might you see?
    some myoclonus and muscle twitching in 30-60% of patients.
  154. What effect dose Etomidate have on the CV system?
    minimal **why we use it!
  155. What respiratory effects does Etomidate have?
    < depression than with barbiturates or benzodiazepines
  156. What effects on the CNS does Etomidate have?
    • ↓ CBF, ↓ CMRO2, ↓ ICP
    • CPP well maintained
    • ­N&V (problem w/Etomidate)
    • No analgesia
  157. What effects does Etomidate have on the endocrine system?
    • adrenocortical suppression (transient)
    • lasts 4-8hrs after induction dose. Inhibit betadhyroxylase (enzymes responsible for cortisol and aldosterone synthesis)
    • Dose dependent
    • *it's other problem w/Etomidate besides N/V
  158. What are two contraindications to Etomidate?
    • porphyria
    • adrenal suppression
  159. Why would you not want to do a long term infusion of Etomidate?
    For long term infusions, it could lead to longer term adrenal cortical suppression in patients that are critically ill (increased mortality)

    • At risk pt for adrenal suppresion (are
    • they on steroids for long period of time?) if pt is septic or hemorrhage don’t want to give it. Need intact HPA axis. Good for HD but not for endocrine!
  160. What is the dosing for Etomidate?
    • Induction: 0.1-0.4 mg/kg IV
    • Onset:  30-60 seconds (longer in some, can be a few minutes)
    • Peak: 1 minute
    • Duration: 3-10 minutes (redistribution)
  161. What pharmacodynamic mechanism do barbiturates act by?
    stimulation of the GABA receptor
  162. Which pharmacokinetic parameter most influences absorption and distribution of thiopental
    lipid solubilty
  163. Thiopental's solution pH is _______and the pKa is _____.
    • pH is 10.5.
    • pKa is 7.6
  164. Which has a larger clearance, Methohexital or Thiopental?
  165. What happens to midazolam at physiologic pH?

    a.It becomes more lipid soluble
    b.The imadizole ring closes
    c.The non-ionized non- protonated form predominates
    d.All of the above
    D. all of the above
  166. 6. Compared with thiopental, propofol has ________.

    A. Both A and C
    B. A larger Clearance
    C. Both B and C
    D. A smaller Vd
    E. A larger Vd
    A. Both A & C
    (this multiple choice question has been scrambled)
  167. Which of the following are biotransformed
    to active metabolites?
    D.A & C
    D. A&C
    (this multiple choice question has been scrambled)
  168. Which of the following are biotransformed to active metabolites?
    E.A & C
    E. both A&C
    (this multiple choice question has been scrambled)
  169. Which statement is true concerning Ketamine?
    A.It is available as a single enantiomer
    B.It causes increased systolic and diastolic BP
    C.It acts by stimulation of the GABA receptor
    D.It is an acid drug
    (this multiple choice question has been scrambled)
  170. Which of the following causes adrenal cortical suppression?
    B. Etomidate
    (this multiple choice question has been scrambled)
  171. Which of the induction agents cause involuntary muscle movement?
    D.Both B & C
    D. (and Etomidate)
    (this multiple choice question has been scrambled)
Card Set:
Pharm Lecture 4: Sedative Hypnotics
2013-06-13 02:19:00
BC CRNA Anesthesia Pharm Lecture

sedative hypnotics
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