IV Sedatives Flashcards
Define sedative
a drug that induces a state of calm or sleep
Define hypnotic
a drug that induces hypnosis or sleep
Define anxiolytic
any agent that reduces anxiety
Define sedative-hypnotics
drugs that reversible depress the activity of the central nervous system
Describe the mechanism of action of barbiturates
GABA-A agonist (GABA is the primary inhibitory NT in the brain)
- increase the DURATION of opening of chloride channels
What substance are barbiturates derived from?
barbituric acid
What effect does substituting a sulfur molecule to the 2nd position of a barbiturate have on PK/PD? What are 2 examples?
increases lipid solubility and potency
- thiobarbiturates -
Ex: thiopental, thiamylal
What effect does substituting an oxygen molecule on the second position of a barbiturate have on PK/PD? What are 2 examples?
effect unknown..
- oxybarbiturates -
Ex: methohexital, pentobarbital
Adding a methyl group to a nitrogen of a barbiturate has what effect?
lowers the seizure threshold and increases potency
(ex: methohexital)
What effect does adding a phenyl group the 5th carbon of a barbiturate have?
increases anticonvulsant effect
(ex: phenobarbital)
Describe the effects of low/normal dose versus high-dose thiopental
low/normal: increase affinity of GABA for its binding site
high: directly stimulates GABA-A receptor
What is the typical dose of thiopental for adults? Peds?
adult: 2.5-5mg/kg
peds: 5-6mg/kg
Give the onset and duration of thiopental
onset = 30-60 seconds
duration = 5-10 minutes
How is thiopental metabolized?
liver via P450 enzymes
*awakening is determined by redistribution (not metab)
What effect does repeated doses of thiopental have on wake-up?
repeated doses leads to tissue accumulation which results in prolonged wake-up time and hangover effect
Thiopental cardiovascular effects:
- hypotension d/t venodilation, decreased preload, and histamine release
- baroreceptor reflex is preserved
- less hypotension than propofol
Thiopental respiratory effects:
- respiratory depression (shifts CO2 response curve to the right)
- bronchoconstriction d/t histamine release
Thiopental CNS effects:
- decreased CMRO2
- decreased cerebral BF
- decreased ICP
- decreased EEG activity
- NO analgesia
- neuroprotective in focal ischemia (not global)
Does thiopental have an active metabolite?
after high dose = pentobarbital
Describe acute intermittent porphyria
- caused by a defect in heme synthesis resulting in the accumulation of heme precursors
- most common and dangerous type of inducible porphyria
What factors worsen acute intermittent porphyria?
- stimulation of ALA synthase
- emotional stress
- prolonged NPO status
- CYP450 induction
List the signs and symptoms of acute intermittent porphyria
GI: severe abdominal pain, NV
CNS: anxiety, confusion, sz, psychosis, coma
PNS: skeletal muscle weakness, bulbar weakness
Which drugs should be avoided in patients with acute intermittent porphyria?
-barbiturates
-etomidate
-ketamine
-ketorolac
-amiodarone
-many CCBs
-birth control pills
How does anesthesia manage acute intermittent porphyria?
- HYDRATION
- glucose supplementation to dec. ALA synthase activity
- heme arginate (same)
- prevent hypothermia
- regional anesthesia
List the medications that are safe for patients with acute intermittent porphyria
- volatile anesthetics
- N2O
- NMBs
- NMB reversal agents
- narcotics
- midazolam
- ondansetron
- vasopressors
- beta-blockers
What happens if thiopental is injected interarterially? How is it treated?
vasoconstriction, crystal formation, inflammation, tissue necrosis
treatment= inject vasodilator (phentolamine or phenoxybenzamine), or sympathectomy via stellate ganglion block or brachial plexus block
Which medication is the gold-standard for ECT?
Methohexital (induction dose 1-1.5mg/kg)
What is unique about phenobarbital when compared to other barbiturates?
phenobarb is excreted unchanged in the urine
(the rest are metabolized by the CYP450 system)
What is the mechanism of action of propofol?
- direct GABA-A agonist
- activity at the glycine receptors, too
- increases transmembrane Cl- conductance
- hyperpolarizes postsynaptic membrane
- inhibition of postsynaptic neuron
What is the chemical name for propofol?
2,6-diisopropylphenol
What is the typical induction dose of propofol? infusion dose?
induction: 1.5-2.5mg/kg
infusion: 25-200 mcg/kg/min
What is the onset and duration of propofol?
onset: 30-60 seconds
duration: 5-10 minutes
How is propofol metabolized?
via the liver (P450) + extrahepatic clearance in the lungs
What effect does renal impairment have on propofol metabolism/elimination? liver impairment?
renal: none
liver: none
What subset of patients have a decreased rate of plasma clearance of propofol?
patients >60
What is propofol’s effect on the cardiovascular system?
- decreased BP d/t decreased SNS tone, vasodilation
- decreased SVR
- decreased venous tone –> decreased preload
- decreased myocardial activity
What effect does propofol have on the respiratory system?
- shifts CO2 response curve down and to the R
- respiratory depression
- inhibits hypoxic ventilatory drive
What effect does propofol have on the CNS?
- decreased CMRO2
- decreased cerebral BF
- decreased ICP
- decreased IOP
NO analgesia - some anticonvulsant properties
- myoclonus possible
- seizures?
What effect can propofol have on the urine?
green –> phenol excretion
cloudy –> increased uric acid excretion
List three beneficial effects of propofol?
antioxidant properties
antipruritic effect
antiemetic effect
What are the risk factors for propofol infusion syndrome?
- dose > 4mcg/kg/hr
- duration >48 hours
- sepsis
- continuous catecholamine infusions
- high-dose steroids
- significant cerebral injury
Describe the clinical presentation of PIS
*acute refractory bradycardia –> asystole
one of the following:
- metabolic acidosis
- rhabdo
- enlarged fatty liver
- renal failure
- hyperlipidemia
- lipemia
How do you treat PIS?
- d/c propofol
- maximize gas exchange
- cardiac pacing
- phosphodiesterase inhibitors
- glucagon
- ECMO
- CRRT
Propofol syringe is good for _ hours
Propofol tubing is good for _ hours
syringe = 6
tubing = 12
Which propofol preservative can cause issues?
generic formulation: metabisulfite can cause bronchospasm, benzyl alcohol is avoided in infants
What is the MOA of fospropofol?
it is a prodrug; metabolized to propofol by alkaline phosphatase in the blood
What is the chemical name of fospropofol?
phosphono-O-methyl-2,6-diisopropylphenol
What is the onset and duration of fospropofol?
onset: 5-13 minutes
duration: 15-45 minutes
What is the active metabolite of fospropofol?
propofol
formaldehyde is metabolized to formate (excreted in the urine)
What is a major side effect of fospropofol?
genital and anal burning
What is the most commonly used IV anesthetic for induction and sedation?
propofol
What is the MOA of etomidate?
- direct GABA-A agonist
- increased transmembrane Cl- conductance
- hyperpolarization of postsynaptic cell membrane
- inhibition of postsynaptic neuron
What is the chemical name of etomidate?
R-1-methyl-1-(a-methylbenzyl) imidazole-5-carboxylate
What drug class is etomidate part of?
imidazoles
Describe how etomidate acts at normal pH and acidic pH
normal pH: imidazole ring closes, increased lipid solubility
acidic pH; imidazole ring opens, increased water solubility
What are the 2 formulations of etomidate and what is the important difference?
1) 35% propylene glycol (painful to inject)
2) lipid emulsion (less pain on injection)
What is the onset and duration of etomidate?
onset: 30-60 seconds
duration: 5-15 minutes
How is etomidate metabolized?
liver (P450) and plasma esterases
Rapid awakening after etomidate can be attributed to what?
redistribution (not metabolism)
Etomidate cardiovascular effects:
- minimal change in HR, SV, or CO
- decreased SVR causes a small reduction in BP
- does NOT block SNS response to laryngoscopy
Etomidate respiratory effects:
mild respiratory depression (less than propofol or barbiturates)
Etomidate CNS effects:
- decreased CMRO2
- decreased cerebral blood flow
- decreased ICP
- stable CPP
NO analgesia
Which IV sedative can increase the risk of seizures?
etomidate – if the patient has a history of seizures
How does etomidate affect the adrenal system?
inhibits 11-beta-hydroxylase and 17-alpha-hydroxylase (needed for cortisol and aldosterone synthesis) for 5-8 hours
What is the MOA of benzodiazepines?
- GABA-A agonist
- increases frequency of channel opening
- neuronal hyperpolarization
What are the most common side effects of benzos?
fatigue and drowsiness
What side effects can occur when benzos are used in combination with CNS depressants or opioids?
- decreased motor coordination
- impaired cognitive functions
- increased ventilatory depression
- anterograde amnesia
What effect do benzos have on the hypothalamic-pituitary-adrenal axis?
suppression of cortisol levels
How long does dependence on benzos take to develop?
- therapeutic doses may cause physical dependence
- > 6 months of use
What are the risks of giving benzos to an aging adult?
- increased sensitivity
- gait instability, falls, fractures
- accelerated cognitive decline with long-term use
- confusion with withdrawal
What chemical structure describes midazolam?
imidazole ring
Give the dose ranges for midazolam:
IV sedation: 0.01-0.1 mg/kg
IV induction: 0.1-0.5mg/kg
PO sedation (peds): 0.5-1.0 mg/kg (50% bioavail d/t first pass metab)
What is the onset and duration of midazolam?
onset: 30-60 seconds
duration: 20-60 minutes
How is midazolam metabolized?
liver (P450)
intestines (P450)
What is the active metabolite of midazolam?
1-hydroxymidazolam
- 1/2 the potency of midaz
- rapidly conjugated to an inactive compound
- renal failure prolongs the effects
Respiratory effects of midazolam:
- sedation dose: minimal
- induction dose: respiratory depression
- effects are potentiated by opioids
- pts with COPD are more sensitive
Cardiovascular effects of midazolam:
- sedation dose: minimal
- induction dose: decreased BP and SVR
CNS effects of midazolam:
- decreased CMRO2
- decreased CBF
- anterograde amnesia
- anticonvulsant
- anxiolysis
- skeletal muscle relaxation at spinal neurons
NO analgesia
Why is diazepam not frequently used in surgery?
undergoes hepatic recirculation making its elimination half-time 43 hours
What are 3 beneficial features of diazepam?
- anticonvulsant properties
- prevents emergence delirium following ketamine
- antispasmodic agent
Lorazepam is (more/less) potent than midaz and diazepam?
more (side effects remain consistent)
What is the onset of lorazepam?
1-2 minutes (peak effect at 20-30 minutes) which limits its usefulness as an anticonvulsant
Key features of oxazepam:
- active metabolite of diazepam
- shorter DOA than diazepam
- elim half-time 5-15 hours
Key features of alprazolam:
more prominent inhibition of adrenocorticotrophic hormone and cortisol secretion than other benzos
Key feature of clonazepam:
effective in controlling and preventing seizures
Key features of flurazepam:
- used exclusively to treat insomnia
- has an active metabolite that can cause daytime sedation
Key feature of temazepam:
- used exclusively to treat insomnia
- daytime drowsiness is unlikely
Key features of triazolam:
- effective in treating insomnia (difficulty in falling asleep)
- shortest acting (1.7 hours)
- daytime drowsiness unlikely
- decreased dose by 50% in elderly
What is the MOA of flumazenil?
competitive antagonist of GABA-A receptor (high affinity)
What is the duration of flumazenil?
30-60 minutes (may need to re-dose)
What is the dose of flumazenil?
initial: 0.2mg
titrated in 0.1 mg Q1min
Describe the effects of flumazenil:
- does not increase SNS tone, anxiety, or stress
- may cause withdrawal symptoms including sz in dependent patients
- reverses sedative effects better than amnestic effects
What is the MOA of ketamine?
NMDA receptor antagonist (antagonizes glutamate)
- dissociates the thalamus from the limbic system
*also targets opioid, MAO, serotonin, NE, muscarinic, and Na+ channels/receptors
Ketamine belongs to which class of drugs?
arylcyclohexylamine
What are the doses for ketamine?
induction: 1-2mg/kg
maintenance: 1-3mg/min
analgesia: 0.1-0.5mg/kg
IM: 4-8mg/kg
PO: 10mg/kg
What is the onset of ketamine?
IV: 30-60 seconds
IM: 2-4 minutes
PO: varies
What is the duration of ketamine?
10-20 minutes; 60-90 to return to “normal”
How is ketamine metabolized?
liver (P450)
What is the active metabolite of ketamine?
norketamine
1/3-1/5 the potency of ketamine
Cardiovascular effects of ketamine
- increase SNS tone
- increase CO, HR, SVR, PVR
- myocardial depressant
Respiratory effects of ketamine:
- bronchodilation
- maintain respiratory drive
- no significant effect on CO2
- increase oral and pulmonary secretions
CNS effects of ketamine:
- increased CMRO2, CBP, ICP, IOP, EEG activity
- nystagmus
- emergence delirium (esp in Peds)
Ketamine is better at relieving (somatic/visceral) pain
somatic
Which IV sedative is a good adjunct for patients with chronic pain?
ketamine
List 3 other facts about ketamine:
- treatment for depression
- chronic use can cause ulcerative colitis
- avoid in patients with acute intermittent porphyria
Which IV sedative undergoes the least plasma binding?
ketamine = 12%
etomidate = 75%
lorazepam = 90%
dexmedetomidine & midaz = 94%
propofol & diazepam = 98%
What is the MOA of dexmedetomidine?
- alpha-2 agonist
- decreases cAMP
- inhibits locus coeruleus in the pons causing sedation
What is the loading dose of dex? maintenance dose?
loading: 1mcg/kg over 10 minutes
maintenance: 0.4-0.7 mcg/kg/hr
What is the onset and duration of dex?
onset with loading dose: 10-20 minutes
duration after infusion is stopped: 10-30 minutes
How is dex metabolized?
liver (P450)
What is the active metabolite of dex?
none
Cardiovascular effects of dex:
- bradycardia
- hypotension
- transient hyPERtension if given rapidly
Respiratory effects of dex:
- no respiratory depression
- no change in oxygenation
- no change in blood pH
- no change in CO2 response curve
CNS effects of dex:
- decrease CBF
- no change in CMRO2
- no change in ICP
- sedation caused by decreased SNS tone
- unreliable amnesia
- patients easily aroused
Dex provides analgesia through what mechanism?
alpha-2 stimulation in the dorsal horn of the spinal cord (decreases substance P and glutamate release)
List some other effects of dex:
- impairs thermoregulatory response (anti-shivering)
- reduces emergence delirium in peds
- NO impairment of evoked potentials
- used for “wake-up” test in scoliosis surgery
- nasal and buccal routes have high bioavailability
What is the MOA of scopalamine?
- anticholinergic
- binds to muscarinic cholinergic receptors
- decreases the activity of the RAS
- lipid-soluble tertiary amine
- crosses BBB
How is scopolamine eliminated?
hepatic and renal pathways
What is the elimination half-life of scopolamine?
4.5 hours
Scopolamine belongs to which class of drugs?
anticholinergic
What are some beneficial side effects of scopolamine?
- amnesia
- antisialagogue
- antiemetic
What is the dose of scopolamine for sedation?
0.3-0.5mg IM or IV
also available via transdermal patch
What is the reversal agent for scopolamine?
physostigmine 2mg IV
What are two negative side effects of scopolamine?
- mydriasis and cycloplegia (caution in patients with glaucoma)
- central anticholinergic syndrome
What are the symptoms of central anticholinergic syndrome? What is the treatment?
symptoms: restless, hallucinations, somnolence, unconsciousness
treatment: physostigmine 15-60mcg/kg IV every 1-2 hours until symptoms improve
