2. Sedative, Hypnotics, IV Anesthetics Flashcards
sedation
calming and drowsiness
decreases activity
moderates excitement
calms pt
hypnosis
produces drowsiness
facilitates the onset/mx of sleep
anesthesia
global but reversible CNS depression results in loss of response to and perception of external stimuli
“deafferentation”
changes in behavior and perception
anesthetic effects
amnesia
decreased/diminished pain response
immobility to noxious stimuli
analgesia
unconsciousness
anesthetic drugs can
enhance inhibitory synaptic activity
(GABA/Glycine)
or
diminish excitatory activity
(Glutamate)
glutamate anatomy
relay neurons all levels and some interneurons
glutamate receptors
NMDA
AMPA
Kainate
metabotropic
NMDA (gultamate)
excitatory
increase cation conductance
(esp Ca++)
AMPA (glutamate)
excitatory
increase cation conductance
Kainate (glutamate)
excitatory
increase cation conductance
metabotropic (glutamate)
inhibitory (presynaptic)
- decrease Ca conductance
- decrease cAMP
excitatory
- decrease K+ conductance
- increase IP3
- increase DAG
glycine anatomy
spinal interneurons and some brainstem interneurons
glycine receptors
glycine
glycine receptor MOA
inhibitory
increase Cl conductance
GABA anatomy
spuraspinal and spinal interneurons
pre and postsynaptic
GABA receptors
GABAa
GABAb
GABAa
inhibitory
increase Cl conductance
GABAb
inhibitory
presynaptic:
- decrease Ca conductance
postsynaptic:
- increase K conductance
drug catetogies
sedatives
hypnotics
anesthetics
potential drug effects
amnesia
analgesia
anticonvulsant
muscle relaxation
respiratory
depression
drug classes
benzodiazepines
non-bz sedative hypnotics (Z drugs)
barbituates
melatonin congeners
IV anesthetics
inhaled anesthetics
balanced anesthesia
combination of agents to limit dose and toxicity of each agent
triad of general anesthesia
unconsciousness
analgesia
muscle relaxation
IV agent uses:
- sedation-based
- monitored anesthesia care
- regional anesthesia
- conscious sedation
- deep sedation
- light general anesthesia
monitored anesthesia care (MAC)
regional or local anesthesia delivered with supplemental sedation
conscious sedation
small doses
pt mxs airway
pt responds to commands
ICU for prolonged mechanical ventil
light state of general anesthesia
loss of protective reflexes
inability to mx airway
lack responsiveness to sx stimuli
IV induction side effects
(non-anesthetic)
CV (?)
pain at injection site
movement
hiccups
apnea
IV recovery side effects
(non-anesthetic)
restlessness
nausea
vomiting
GABA type
inhibitory CNS neurotransmitter
GABAa receptor
pentameric structure
- subunits: aby
major isoform has
- 2 alpha 1
- 2 beta 2
- 1 gamma 2
GABA binding site (GABAa)
2 sites (one on each lobe)
located between a1 and b2
BZ binding site (GABAa)
between a1 and y2
BZ binding is
allosteric modulation
BZ effects GABAa by
attracting more GABA to the receptor to bind
barbituates effect GABAa by
increasing the duration the channel is open
allosteric agonist
different binding site
enhance effect
allosteric antagnoist
different binding site
inhibit effect
onset time
how quickly the drug takes to get from blood to tgt organ
(brain/viscera)
continuous infusion half life
pt may take longer to recover from a continuous infusion compared to a single dose due to a prolonged half life
barbiturates
methohexital (Brevital)
thiopental (Pentothal)
thiamylal
barbituates MOA
-allosteric modulation
-enhance Cl conductance
-increased duration of GABA-gated Cl channel opening
barbituates structure
derived from barbituric acid
methohexital will elicit
epilectiform activity
used in electroconvulsive therapy or surgeries where seizures are desired
barbituates admin
- IV
- rectally (peds)
barbituates lipid solubility
high
barbituates distribution
plasma:brain equilibrium rapidly
- onset within 30 sec
rapid diffusion to other tissues
- limited duration of induction
(20 min)
barbituates and elderly
reduce induction dose
slower redistribution
longer duration of action
barbituates repeated doses
(or continuous infusion)
saturates peripheral compartments
minimize redistribution effect
increases duration of action
barbituates metabolism
metabolized by CYP enzymes
no active metabolites
barbituates elimination
some renal elim of metabolites
some excretion in feces
methohexital cleared rapidly by liver
barbituates formulations
alkaline solution for solubility
will precipitate when mixed w/weak bases
- roc, lidocane, labetalol, morphine
barbituates site of action
CNS
barbituates CNS onset
10-20 sec
bolus lasts 8-20 min
half life: 3-12 hrs
barbituates CNS impacts
constrict cerebral vasculature
-decrease BF/ICP
-decrease cerebral O2 consumption
anticonvulsant (except methohexital)
-decreases EEG
decrease pain threshold
involuntary muscle movements
-hiccups, myoclonus
barbituates cardiovascular impacts
peripheral vasodilation: BP decreas
neg ionotropic effects (CO decrease) venous vasodilation
- (decrease BP/CO)
vagolytic compensatory responses
- HR and contractility
barbituates contraindications
Pt w/o adequate baroreceptor response
- hypovolemia
- beta blocker therapy
- congestive heart failure
asthma pt (histamine response)
acute intermittent porphyria
barbituates respiratory impacts
dose related respiratory depression
incomplete suppress of airway reflex
apnea
bronchospasm
hiccup
laryngospasm
barbituates histamine release
may cause hypotension/tachycardia
rare allergic reactions
barbituates pharmacodynamics
no muscle relaxation
injection pain
no analgesia
no renal/hepatic toxicity
induce ALA-S (may trigger porphyrins)
acute intermittent porphyria
neurological disease cause by inadequate porphyrin metabolism
porphyrins
highly reactive oxudants
cause toxic neurological seueqlae
porphyrias symptoms
nausea
vomiting
abdominal pain
psychosis
lower motor neuron palsies
barbituates status
being replaced by propofol
methohexital used for ECT
thiopental not used in US
barbituates interactions req dose reduction
opioid
alpha 2 adrenergic agonist
benzodiazepine
acute ethanol
barbituate dose reduction for pts w/
anemia
low protein
decreased cardiac output
shock
elderly
benzodiazepines (BZ)
diazepam
lorazepam
midazolam
BZ mechanism of action
potentiate GABA inhibition
increase efficiency of GABA
increase freq of Cl channel openings
GABA must be present
binds to BZ receptor
flumazenil
BZ receptor antagonist
BZ structure
3 ring structure
water soluble
- affects parenteral prep
BZ lipid solubility
high
speeds up CNS onset
diazepam absorption/admin
oral
- 1-2 hr onset
IM
- painful/erratic absorption
lorazepam absoprtion/admin
oral
- 1-2 hr onset
IM
- well absorbed
- 90 min peak
midazolam absorption/admin
oral
IM
- well absorbed
- 30 min peak
IV
- short onset (minutes)
BZ lipid solubility
M>D>L
BZ distibution to brain
time to onset:
M<D<L
BZ redistribution
rapid
3-10 min
short duration of effect
BZ protein bound
high
>= 90%
BZ metabolism
hepatic
phase 1 oxidation
active metabolites (D/M)
Phase 2 rxns = metabolite
conjugation for elimination
BZ half life
D>L>M
BZ excretion
renal
enterohepatic recirculation
- Diazepam
enterohepatic recirculation
the process by which biliary excreted drug is reabsorbed in the intestine instead of being removed from the body
high dose midazolam accumulation
accumulation of active metabolite in pts w/kidney failure
high lipid solubility =
high volume of distribution
volume of distribution
the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma
BZ Vd
L<D<M
BZ hepatic extraction
Low: D/L
High: M
BZ CNS effects
sedation
hypnosis
anesthesia
amnesia
anticonvulsant
muscle relaxation (not paralysis)
tolerance
dependence
decreased CBF/O2 consumpt/ICP
muscle relaxation at spinal cord
anterograde amnesia
antianxiety
stupor/unconsciousness (induction)
control seizure activity
no analgesia
BZ cardiovascular impacts
minimal
lg doses may decrease BP
w/opioids may decrease BP
possible increase HR
BZ respiratory impacts
minimal respiratory depression
decrease ventilatory resp to CO2
induction apnea
thrombophlebitis
(D>M»L)
BZ drug interaction
drugs that induce/inhibit CYP P450
opioids - decrease SVR = hypotension
decrease MAC (incr potency of IA)
additive effects w/sedative/resp dep.B
BZ status
perioperative period
sedation-hypnosis
procedure not req analgesia/full anes
seizure control
ICU sedation
BZ receptor antagonist
flumazenil
reversal agent for midazolam
competitive antagonist
no impact to BZ elimination/conc
half-life: 54 min
duration of action: 20 min
re-sedation may occur
Ketamine MOA
inhibit NMDA receptor complex
NMDA complex
glutamate receptor
affects CNS/spinal cord
dissocaitive anesthesia
- dissociates thalmus to limbic
appears awake but unable to respond to stimuli
no global CNS depression (some stimulation)
Ketamine potency
0.1
some psychotomimetic effects
Ketamine isomers
S+: potent anesthetic w/o psychotomimetic effects
- greater affinity for NMDA = greater potency
Ketamine absorption
IV
or
IM
Ketamine distribution
lipophilic
fast onset
short duration (10-15min)
Ketamine metabolism
induction of CYP enzymes
extensive hepatic extraction (oral)
Ketamine active metabolite
Norketamine
(less potent)
Ketamine excretion
renal elimination of metabolites
(aka renal elimination of norketamine)
Ketamine analgesic
excellent analgesic at subanesthetic doses (2.5-15 mcg/kg/min)
Which drug can be a complete anesthetic?
ketamine
analgesia
amnesia
unconsciousness
“complete” anesthetic
analgesia
amnesia
unconcsciousness
Ketamine CNS effects
cerebral vasodilator
- increase blood flow
- increase ICP
does not lower seizure threshold
anticonvulsant alt for status epilepticus
Ketamine onset
15-30s
Ketamine duration
10-15 min
analgesia/amnesia onset/duration
immediate onset
duration: 40 min
Ketamine emergenc reactions
occur in 10-30% of adults
- delirium, excitement, confusion, euphoria, fear, vivid dreaming, hallucinations
- 1st hour of emergence
- lower rate in peds
how to minimize ketamine emergence reactions
benzodiazepine
Ketamine cardiovascular reactions
central sympathetic stimulation
- inhibits NE
- increase NE in synaptic cleft
- increase HR, BP, CO
Ketamine contraindications
coronary artery disease
uncontrolled hypertension
congestive heart failure
arterial aneurysms
Ketamine CV exceptions
may see direct myocardial depression in pts w/ depleted catecholamines/spinal cord transection
w/ very lg doses
(Ca++ channel blocker)
Ketamine respiratory effects
minimal effect on RR
minimal effect on ventilatory drive (CO2)
bronchodilator (racemic)
increase salivary/trachiobronchial secretions
Ketamine muscular effects
myoclonic activity (uncontrollable twitching)
stimulates uterine muscle contract
no risk for malignant hyperthermia
Ketamine drug interactions
a/b adrenergic receptor antagonists
- block ketamine sympa effects
- direct myocardial depress. effects
Ketamine drug additives
inhaled anesthetics
propofol
BZ
GABA acting agents
Ketamine status
used w/BZ in emergent/trauma situations
severe depression
Propofol MOA
interacts w/GABAa receptor
- binds to beta subunit
allosterically increases binding
affinity of GABA for GABAa receptor
- hyperpolarization of membrane
binds to multiple ion channels
- glutamate related
Propofol formulation
Not water soluble
1% solution oil/water emulsion
lipophilic (10% fat emulsion)
Propofol absorptions
IV only
Propofol distribution
rapid onset
short duration
Propofol initial distribution half life
2-8 min
Propofol metabolism
hepatic &
extra hepatic clearance
hepatic conjugation to inactive metabolites –> renal clearance
Propofol Cerebral/CNS effects
decrease cerebral BF, BV, ICP
antiemetic
antipruritic
no analgesic effects
Propofol contraindications
pts w/elevated ICP
- can cause critical reduction in ICP unless steps are taken to support BP
pts w/porphyrias
Propofol CNS effects
dystonic movements
- excitatory mvmt w/induct/emerg
seizures
- some anticonvulsant properties
- epileptogenic in pts w/seizure diag
Propofol tolerance
does not occur w/repeated doses
Propofol addiction
not common
Propofol cardiovascular effects
decrease BP by 15-40%
- decreased SVR/cardiac filling
- effects contractility
- inhibits baroreceptor response
(HR unchanged w/BP decrease)
Propofol BP impacts are greater in
pts w/
hypovolemia
elderly
LV dysfunction
beta blockers
Propofol respiratory effects
respriatory depression
decreased CO2 response
30-60 sec apneic period post-induct
inhibits airway reflexes
minimal histamine release
lees impacts to asthmatics
Propofol muscle effects
NO muscle relaxation
Propofol pain w/injection
burning/stinging
can give lidocaine before/with
opioid before
Propofol other effects
sedative/anxiolytic
antiemetic (subanesthetic doses)
antipruritic
OB/GYN safe
Propofol porphyrinogenic
increases ALA reductase activity
Hypertriglyceridemia
high blood lipids
can be caused by prolonged/continuous propofol
critical care/peds at higher risk
Propofol infusion syndrome
metabolic acidosis
lipemic plasma
myocardial failure
hepatomegaly
rhabdomyolysis
Propofol status
induction
anesthetic mx
ICU
Propofol onset
10-20 seconds
Propofol awakening
2-8 min
Propofol induction
use w/midazolam
additive effect w/midazolam/opioids
- decrease propofol by 10%+
Propofol TIVA
use w/remifentanil and ketamine
Propofol and fentanyl
increase concentrations of fentanyl/alfentanil
may be able to decrease propofol dose
Propofol dosing (elderly)
smaller induction dose
Fospropofol formulation
water soluble prodrug
(no lipid emulsion)
sterile aqueous clear solution
Fospropofol metabolism
metabolizes to:
- propofol
- phosphate
- formaldehyde
Fospropofol onset/recovery
slower onset than propofol
longer duration than propofol
Fospropofol uses
monitored anesthesia care
w/O2
Etomidate MOA
enhances GABA
- binds to GABAa (increase affinity)
- increase Cl- conductance
Etomidate absorption
IV only
Etomidate distribution
high-protein binding
high lipid solubility
large non-ionized fraction
rapid onset
Etomidate metabolism
metabolized by:
plasma esterases
hepatic CYP enzymes
Etomidate clearance
renal clearance
Etomidate CNS/Cerebral effects
potent
hypnotic
decrease cerebral metabolic rate
decrease CBF/ICP
well mx cerebral perfusion
EEG changes
- no seizures during ECT
- seizures in pts w/epilepsy
involuntary muscle movements
Etomidate onset
20-30 sec
Etomidate duration
5 min
Etomidate cardiovascular effects
reduced sympa/barorecept response
decline in SVR
no histamine release
low rate incidence of hypersensitivity
Etomidate indication
pts w/
impaired LV function
cardiac tamponade
hypovolemia
emergent tracheal intubation
high risk CV pts
Etomidate respiratory effects
less depression
no apnea (unless +opioids)
Etomidate endocrine effects
suppress adrenal cortical function
- inhibit 11-b-hydroxylase
(enzyme needed for steroid biosynt - cortisol
- body cant make cortisol 4-8 hrs post sedation
Etomidate analgesia
None
Etomidate contraindication
not used in ICU sedation
- cortisol not produced 4-8hrs post
Etomidate status
typically used w/BZ for induction
- neurosurgical case
- CV risk pts
Dexmedetomidine
Alpha 2 receptor agonist
greatest affinity for Alpha 2 in CNS
Alpha 2 receptor
stops stimulating NE
Dexmedetomidine FDA indications
- sedation of intubated and ventilated pt in ICU
- sedation prior to and/or during surgical procedures of non-intubated pts
Dexmedetomidine MOA
selective alpha 2 adrenergic agonist
<24 hr sedation (prolonged use can cause withdrawl)
Dexmedetomidine Uses
- presedation
- procedural sedation
- GA supplementation
- ICU sedation
- withdrawl treatment/prevention
- Epidural regional
** No amnesia
Dexmedetomidine CV effects
hypotension (25-50% pts)
bradycardia (5-15% pts)
withdrawal effects > 24 hrs
nausea
Dexmedetomidine withdrawal effects
BP
nervousness
agitation
headache
Dexmedetomidine respiratory effects
little effect on ventilation
Dexmedetomidine dosing
loading dose: 1 mcg/kg over 10 min
infusion: 0.2-0.7 mcg/kg/hr
Dexmedetomidine onset/duration
rapid onset
half-life: 2 hrs
Dexmedetomidine drug interaction
vasodilators
cardiac depressants
drugs that decrease HR
hypnotics
Dexmedetomidine reduce dose for
combo w/hypnotics/volatile agents
- offsets hypotensive effects
renal/hepatic insufficiency
Dexmedetomidine other uses
post-op shivering
premed for Ketamine/intubation
Dexmedetomidine pt candidates
drug/alcohol withdrawal
chronic pain
unwilling/able to take opioids
hypertension
if you need hypotension for sx
ophthalmic surgery
ketamine anesthesia
doxapam
respiratory/CNS stimulant
given for respiratory depression
doxapam MOA
selective activation of carotid chemoreceptors by low doses
- stimulates hypoxic drive (low PO2)
doxapam adverse effects
seizures
muscle fasciculation
HA
dizzy
tachycardia
arrythmia
nausea/vomiting
doxapam contraindictions
epilepsy
cerebrovascular and CAD
acute head injury
hypertension
asthma
doxapam dosing
IV bolus
0.5-1 mg/kg
doxapam onset
1 min
doxapam duration
5-10 min
doxapam continuous infusion
1-3 mg/min
Max: 4mg/kg
malignant hyperthermia
rare (1:15000 peds, 1:40000 adults)
acute hypermetabolic state
mostly on induction
malignant hyperthermia signs
profound MMR
tachycardia
hypercarbia
hyperthermia
malignant hyperthermia MOA
uncontrolled release of intracellular Ca++ in skeletal muscle
VA or Succ bind to nAChR causing depolarization
depolarization is prolonged in MHR
malignant hyperthermia treatment
stop VA/Succinycholine
hyperventilate
bicarbonate
dantrolene
cooling measures
dantrolene MOA
binds to Ryr1 receptor of Ca channel
inhibits Ca release from SR
dantrolene dosing
20 mg/60mL water
initial dose: 2.5mg/kg every 5 min until episode terminated
Max: up to 10 mg/kg
