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Pharm Test 2 > Sedative-Hypnotics > Flashcards

Sedative-Hypnotics Flashcards

1
Q

What is chemical formula for propofol?

A

2,6-di-isopropophenol

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2
Q

What is composition of propofol?

A
  • 1.2% egg
  • 10% soybean oil
  • glycerol base
  • 2.25% solution
  • Supports bacterial growth
  • Can increase plasma glycerides with prolonged infusion
    • Egg yolk allergy
    • Anaphylactoid rections reported
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3
Q

What is problem with egg yolk allergies with propofol?

A

Usually people are allergic to egg white, so they are able to tolerate the egg yolk in propofol

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4
Q

What are some alternate brands/formulations of propofol

A
  • Diprivan-EDTA (disodium edetate)
  • Propofol (generic)
  • Ampofol- low lipid formulation
  • Aquavan
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5
Q

What can generic propofol cause?

A

Bronchospasms (sodium metabisulfite)

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6
Q

What is diprivan?

A

EDTA preservative- Disodium edetate

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7
Q

What is ampofol?

A
  • Low lipid forumulation
    • `5% soy, 0.6% egg lecithin
  • Does not need preservative
  • Higher incidence of pain with injection
  • Very expensive, not a lot of facilities
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8
Q

What is aquavan?

A

Prodrug- adding groups to parent drug (ie : phosphate monoesters)

  • hydrolysis in plasma, can be unpredictable
    • hasn’t taken off in market
  • slower onset
  • higher vd
  • higher potency
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9
Q

What is main mechanism of action of propofol?

A

GABA (major)

(glycine minor only)

  • Decreases rate of dissociation of GABA from GABAa
  • No spinal cord depression
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10
Q

Pharmackokinetics of propofol?

Vd?

Clearance vs perfusion dependent?

T1/2 elimination?

What effects pharmacokinetics?

A
  • Vd 3.5-4.5 L/kg
    • Huge
  • clearance exceeds hepatic blood flow.
    • Capacitance dependent (enzyme dependent)
  • 2-3 comparatment mode of distribution
  • Weight, co-existing disease, age, co-admin of other drugs affect pharmacokinetics
  • t 1/2 elim 0.5-1.5 hours
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11
Q

T 1/2 elim of propofol? Vd?

A

T1/2= 0.5-1.5 hours

Vd 3.5-4.5 L/kg

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12
Q

What do you need to consider about patient when dosing propofol?

A
  • Weight
    • i.e.-obese, propofol is stored in fat, takes longer to leave body
  • co-existing disease
  • age
    • i.e. younger, muscular person would need more
  • co-admin of other drugs
    • move through similar enzymatic breakdown
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13
Q

CNS effects of propofol?

A
  • Chloride channel activation of B1 subunit of GABA receptor and NMDA inhibition
  • Rapid onset, one arm-brain circulation
  • Decreases CBF, ICP, CMRO2, CPP = cerebral protective
  • EEG burst suppression
  • Age affects ED95
    • ED 95- Highest in toddlers, decreases with age
      • elderly need to reduce dose
  • Hiccoughing, muscle twitching can occue
  • hallucinations opisthotonis (spasm of muscles on back of neck, causing head to arch back)
  • decreases IOP
  • Antioxidant effect resembles Vit E–> cerebral protection
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14
Q

Respiratory effects of propofol?

A
  • Apnea following induction dose
  • Decreases TV, RR
  • Decreases vnetilatory response to CO2 and hypoxia
  • PaCO2 rises, pH decreases
  • bronchodilation in COPD patients
  • Hypoxia vasoconstriction remains intact
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15
Q

CV effects of propofol?

A
  • 25-40% decrease in BP
    • Greater than STP (sodium thiopental)
  • Dose dependent myocardial depression and vasodilation
  • Similar decreases in SV, CO, SVR
  • Heart rate unchanged (Baroreceptor inhibition?)
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16
Q

Other effects of propofol?

A
  • Does not potentiate muscle relaxants!
  • Myoclonus
    • higher than with TPL but less than with etomidate and brevital
  • Pain on injection
  • Antiemetic and antipruritic at sub-hypnotic doses, 10 mg
    • mechanism of anti emetic/pruritic effect unknown
  • Amnestic at doses >30 mcg/kg/min
  • Crosses placenta, rapidly removed from fetal circulation
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17
Q

Propofol induction dose? Maintenance? Sedation?

A
  • Induction 1-2.5 mg/kg
    • as high as 3 mg/kg in toddlers d/t pharmacokinetics
  • GA maintenance 100-300 mcg/kg/min
  • Sedation infusion 25-100 mcg/kg/min
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18
Q

Metabolism of propofol?

A
  • Conjugated in liver to water soluble compounds
    • CP-450 system
    • Liver function does not affect rate of metabolism
      • still reduce doses if patient has liver dx
  • Metabolites mostly inactive
    • 4-hydroxypropofol is 1/3 potent
  • Renal excretion
    • CRF doesn’t affect clearance
  • Highly metabolized, less than 3% excreted unchanged
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19
Q

Etomidate composition?

A
  • Carboxylated imidazole derivative
  • Imidazole refers to parent compound C3H4N2
  • Propylene glycol solvent<— painful
  • pH 6.90- water soluble in solution
    • at physiologic pH becomes highly lipid soluble
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20
Q

Etomidate MOA?

A
  • Selective GABA
  • binds to specific site on receptor
  • Increases affinity of GABA to GABAa
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21
Q

Pharmacokinetics etomidate?

A
  • Onset of action rapid, one arm to brain
  • Highly lipid soluble, weak base pH8.2
  • Vd- 2.5-4.5 L/kg
  • Redistribution terminates hypnotic effect
  • 3 compartment model
  • elimination half life 3-5 hours
  • High hepatic extraction ratio and clearnace
    • changes in liver blood flow or function will prolong effect
  • 75% protein bound
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22
Q

Vd and elim 1/2 life of etomidate?

A

Vd 2.5-4.5 L/kg

T1/2 elim= 3-5 hours

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23
Q

Protein bound etomidate?

A

75%

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24
Q

CNS effects of etomidate?

A
  • Rapid loss of consciousness after single dose
  • No analgesia
  • Direct cerebral vasoconstriction results in decreaesd CBF, ICP, CMRO
  • Reduces IOP
  • Increases EEG activity in epileptogenic focci
    • Rare association with grand mal sz
    • higher risk in pt with sz hx
  • Produces myoclonic movmenet
  • also possess anticonvulsant properties
25
Q

Respiratory effect?

A
  • Ventilatory response to CO2 depressed minimally
  • Decrease in TV, increase in RR
  • Hiccups or coughing
26
Q

CV effects of etomidate?

A
  • MINIMAL effects on cardiovascular function due to lack of effect on SNS baroreceptors
  • HR, ABP, PAP, CO, SVR, PVR unchanged!
    • this is what sets this drug apart
27
Q

Endocrine effects of etomidate?

A
  • Dose dependent reversible inhibition of 2 enzymes in biosynthesis of cortisol/aldosterone
    • major: 11-beta-hydroxylase
    • minor: 17-alpha-hydoxylase
  • Results in adrenocortical suppression for 4-8 hours reduces mineralcorticoid and corticosteroid production
  • Not too much clinical significant for us
    • we don’t know full implications long term dosing but one shot deal not a big deal
28
Q

Etomidate induction dose? Maintenance? Sedation? Rectal?

A
  • Induction
    • 0.2-0.6 mg/kg **0.3 mg/kg<< this is the most cardiac stable dose.
  • Maintenance
    • infusion 10 mcg/kg/min with n2o and opioid
  • Sedation
    • 5-8 mcg/kg/min for short procedure
  • Rectal
    • 6.5 mg/kg used in peds
29
Q

Other effects etomidate?

A
  • High incidence of N/V (30-40%)
  • Myoclonic movement (30-60%)
    • due to disinhibiting extrapyramidal system
  • Enhances NDMR activity
30
Q

Metabolism of etomidate?

A
  • Liver, ester hydrolysis or N-dealkylation to carboxylic acid
  • Biotransformation 5x faster than TPL
  • 85% Renal, 13% biliary excretion
  • 2% excreted unchanged
  • NO ACTIVE METABOLITE
31
Q

Composition of ketamine?

A
  • Phencyclidine derivative
    • PCP derivative
  • Lipid soluble
  • prepared in acidic solution
  • Racemic mixture of equal parts R and S enantiomer
    • S enantiomer more potent analgesic, undergoes faster metabolism and has lower incidence of emergence delirium
      • nasal spray is example s enantiomer
32
Q

Mechanism of action for ketamine?

A
  • NMDA (n-methyl d-aspartate) ionotropic receptor for glutamate most potent activity
    • ​Why people become unconscious
      • glutamate= excitatory. If you inhibit it, then you’ll lose consciousness
  • Opioid Mu, Delta, Kappa, Sigma(dont’ think of sigma as opioid receptor anymore)
  • Monoaminergic- involves descending inhibitory pathways- for antinociception
  • Muscarinic- antagonist
  • calcium channels
33
Q

How do NMDA receptors work?

A
  • Activation of NMDA receptors results in opening of an ion channel which is nonselective to cations
    • allows flow of Na and small amounts of Ca into cell and K out of cell
  • Calcium flux through NMDAr is thought to play critical role in synaptic plasticity, cellular mechanism for learning and memory
  • NMDA receptor is intersting becaues it is both ligand and voltage dependent
34
Q

Metabolism of Ketamine?

A
  • First pass effect
  • hepatic microsomal enzymes
  • N-demethylation followed by hydroxylation
    • norketamine (metabolite 1- only 20-25 % activity of parent cmpd
    • hydroxylated to hydroxynorketamine
  • Conjugation water soluble
  • urinary excretion
  • total body clearance is roughly equal to liver blood flow
  • Changes in liver blood flow affect clearance
    • perfusion dependent (blood flow dependent)
35
Q

Pharmacokinetics of ketamine?

Lipid solubility? VD, Elim 1/2 time?

A
  • 2 compartment model
  • High lipid solubility–> large Vd
  • Rapid onset, short duration
  • VD 3L/kg (large)
  • Elimination 1/2 time 2-3 hours
36
Q

Pharmacologic CNS effects ketamine?

A
  • Crosses BBB
  • Depresses neuronal function in association area of cerebral cortex and thalamus
    • stimulates the hippocampus (limbic) causing “dissociative state”
  • Amnesia not as prominent as benzos
  • Onset 30 seconds max effect 1 min
  • Termination of effect if rapid after single bolus (15 min) due to redistribution
    *
37
Q

CNS effects ketamine?

A
  • Nystagmus, pupil dilation
  • Salivation, lacrimation
  • Increased skeletal muscle tone, non purposeful movement
  • Myoclonic activity
  • increases ICP, CBF, Metabolic rate, ICP
  • Increases IOP
  • Emergence reactions
  • dreming, out of body sense of floating, excitement, illusion
    • relatively common (10-30%) of pt who received ketamine as part of anesthetic
38
Q

Spinal anesthesia with ketamine?

A
  • Dose 0.2-0.5 mg/kg IV
  • Mu receptor activity
    • s enantiomer has some mu activity
  • NMDA antagonism
    • S isomer has high affinity for excitatory NMDA receptor in dorsal horn
39
Q

Respiratory effects of ketamine?

A
  • Minimal effects
  • no alteration CO2 response
  • bronchial smooth muscle relaxation
    • sns activity
  • Increases PVR
  • Increases in salivation
40
Q

CV effects of ketamine?

A
  • Sympathomimetic-NMDA effect
    • not a peripheral effect
    • probably occurs because of NMDA receptor activity in nucleus tractus solitarus
  • Increases BP, HR, CO
  • Inhibits reuptake of NE
  • Increases myocardial work and o2 consumption
    • however, ketamine is direct myocardial depressant, especially in critically ill pt with minimal NE stores
      • only reason it is not a depressant is because of the SNS response!
41
Q

Doses ketamine? Premed, induction, mainenance, po/iv/im?

A
  • Premedication:
    • sedative/analgesic 0.2-0.5 mg/kg
  • Induction: 1-2 mg/kg IV, 4-8 mg/kg IM
  • Maintenance 1-2 mg/kg/hr
  • Can be administered PO, IV, IM, nasally
    • PO and internasal dose: 6 mg/kg
42
Q

Contraindications for ketamine?

A
  • Increased ICP (with normocapnia?)
  • Open eye injury
  • CAD (as sole anesthetic) (Increases work in heart)
  • Vascular aneurysms (increase in BP)
  • Uncontrolled systemic or pulmonary HTN
  • Certain psych diseases
    • schizophrenia
    • personaility d/o
43
Q

Composition and MOA of dexmedetomidine?

A
  • Water soluble
  • Selective alpha-2 adrenergic agonist
    • 1620:1 alpha 2: alpha 1
  • Of all anesthetics it produces sedation that most closely mimics physiological sleep
    • locus ceruleus (hypnosis)<– main impact. produces
    • spinal cord (analgesia)
44
Q

CNS effects dexmedetomidine

A
  • Decrease CBF
  • NO CHANGE IN ICP or CMRO2
  • Decrease MAC of volatile agents and opioid requirement
  • Depresses thermoregulation (hypotehermia, depresses shivering)
45
Q

CV effects of precedex?

A
  • CV effects
    • Decreased HR, SVR, BP
    • Bolus can cause transient increase BP and decrease HR
    • Potential for severe bradycardia
    • heart block, asystole
    • attenuates CV response to noxious stimuli- decreases catecholamine levels during GA
46
Q

Respiratory effects of dexmedetomidine?

A
  • Minimal change in RR, moderate decrease in TV
  • No change CO2 responsiveness
  • Upper airway obstruction possible
47
Q

Metabolism of dexmedetomidine?

A
  • Rapid metabolism
    • conjugation
    • n-methylation
    • hydroxylation
  • Metabolites cleared urine and bile
  • 90% protein bound
  • E 1/2t= 2-3 hours
  • inhibit CYP 450- interfere with clearance of other drugs? i.e. opioids?
48
Q

Dose precedex?

A
  • adjunct to GA
    • 1mcg/kg bolus over 10-15 minutes; followed by 0.2-1 mcg/kg/hr infusion
49
Q

Dexmedetomidine antagonist?

A
  • Atipamezole- specific and selctive antagonist that rapidly and effectively reverses sedative and CV effects of dex
  • Researched in humans as a potential anti-parkinson’s drug
50
Q

Which drugs (benzos and sedatives) cause pain on injection?

A

Propofol, Etomidate, Diazepam, Lorazepam

51
Q

Which drugs cause myoclonus ( all classes we’ve learned)

A

Propofol

Etomidate (30-60%)

Ketamine

Methohexital (Brevital)

52
Q

Drugs that have active metabolites?

A

Ropivicaine

lidocaine

midazolam

diazepam

ketamine

propofol

53
Q

Drugs that decrease IOP

A

Barbiturates, propofol, etomidate

54
Q

Which drugs induce hepatic enzymes?

A

Barbituates

55
Q

Which drugs are impacted by hepatic blood flow?

A

Etomidate

Ketamine

means they have high hepatic extraction ratio!

56
Q

Which drugs release histamine?

A

Barbituates

57
Q

Which drugs are water soluble?

A

Midazolam

Precedex

Etomidate

58
Q

How is precedex’s CNS activity different from other sedation meds?

A

Decreases CBF with NO change in ICP/CMRO2

Pharm Test 2 (3 decks)

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