Pentothal, Brevital, Etomidate, & Dexmedetomidine Flashcards
Define “intravenous anesthetic agent.”
Typically, a drug injected IV to induce unconsciousness at the beginning of general anesthesia, but allows rapid recovery after the end of its effect.
By which MOAs does an intravenous anesthetic agent typically work?
It changes level of consciousness by depressing the reticular activating system either by enhancing inhibition properties of GABA or inhibiting the NMDA excitatory synapses.
Which IV anesthetic agent is the “gold standard” to which all other agents are compared?
Thiopental (Sodium Pentothal)
What is the primary mechanism for terminating the central effect of IV induction agents?
Their redistribution from the central, highly-perfused compartment to the larger and less-well perfused “peripheral” compartments (skeletal muscles)
What is the alpha phase of pharmacokinetics?
Redistribution - plasma concentration declines so drug moves out of vessel-rich central group and to peripheral group
What is the beta phase of pharmacokinetics?
Elimination - metabolism and excretion
Describe the “ideal” IV anesthetic.
Water soluble/chemically stable/IV fluid compatible
Rapid onset w/o myoclonus or unpredictable CV or CNS SE
Anticonvulsant/antiemetic/analgesic/amnestic
Rapid onset (lipid soluble) and predictable recovery
No impairment of renal/hepatic function, steroid synthesis, or teratogenicity
No pain on injection
Low potential for histamine release/anaphylaxis
Rapidly metabolize to inactive substances/minimal accumulation
“Dialable”/rapidly responsive to titration
Cerebroprotective - dec metabolism in proportion to dec CBF, no inc in ICP
No hangover/HA
What drug class is thiopental?
Barbiturate - Thiobarbiturate (sulfur)
Describe the 2.5% preparation of thiopental
2.5% sodium salt (25 mg/ml) is water-soluble but highly alkaline pH 10.5 therefore bacteriostatic
How long will thiopental stay stable after reconstituted from a powder?
6 days at room temperature, 2 weeks in the refrigerator
What can occur when thiopental is mixed with opioids, catecholamines, NMB, and LR, which are more acidic? If injected intraarterially?
Precipitation!!
Is thiopental (2.5%) painful upon injection?
Minimally; irritating if extravascular but NOT necrotic
What is the MOA of thiopental?
Increases duration of GABA on its receptor (Cl- channels open longer –> hyperpolarization) AND mimics GABA on its receptor (directly causing Cl- channels to open)
Also activates glutamate, adenosine, and nACh receptors (SNS causes hemodynamic depression & desensitizes nACh receptors to depolarizing effects of ACh (large doses)
How do the hemodynamic effects of thiopental compare to propofol?
They are minimal in magnitude
What are the cardiovascular effects of thiopental?
Transient decrease in BP (arterial AND venous); increase in HR (carotid sinus baroreceptor - can be absent with beta blockade or hypovolemia); peripheral vasodilation (venous pooling, decreased venous return/CO) usually offset by sympathetic activation; HISTAMINE RELEASE.
Can you decrease CV effects of thiopental through SLOW administration?
No
How do myocardial depressant effects of thiopental compare with volatile agents?
Less; no direct myocardial depressant effect.
What are the respiratory effects of thiopental?
Decreases sensitivity of medullary ventilatory center to CO2 stimulation; respiration returns with small TV and slow RR; AW reflexes intact
Apnea potentiated with opioids, benzos, and other depressant drugs
Why might thiopental require concurrent administration of propofol for a general anesthetic?
Because airway reflexes remain intact, allowing the possibility of a laryngospasm
What are the CNS effects of thiopental?
Decreased ICP by cerebral vasoconstriction; decrease CMRO2 by 55%
Hypotension with large doses can decrease CPP below adequate
How much does thiopental decrease CMRO2?
55%
By what mechanism and under what conditions does thiopental provide cerebral protection?
Mechanism: reduction of CMRO2 is greater than decrease in CBF (demand less than supply)
Conditions: Successful in incomplete cerebral ischemia (CBP, hypotension, circ. arrest); NO protection for global ischemia (cardiac arrest)
Doses adequate to provide cerebral protection cause vasodilation/myocardial depression; hypothermia does same thing without these SE.
Does thiopental cause liver and kidney damage?
No; slight decrease in flow d/t reduction in BP, but no damage
What blood condition contraindicates use of methohexital and thiopental?
Porphyria; stimulates/increases production of heme
Does thiopental cross the placenta? If so, is it safe for the fetus?
Yes; maternal doses up to 4 mg/kg are safe for fetus
Dr. Cahoon knew of a resident who died in the call room from an overdose of which drug?
Thiopental; can cause tolerance and physical dependence
Thiopental can cause _________ and __________ reactions. (negative)
anaphylactoid; anaphylaxis
What is thiopental’s redistribution 1/2 life?
2-4 minutes
What is thiopental’s elimination 1/2 life?
10-12 hours (long beta phase!)
Thiopental (is/is not) highly lipid soluble and (non/ionized) at physiologic pH.
is lipid soluble; nonionized
Thiopental is __% protein bound.
85; protein binding effects the diffusion rate of the drug - the more bound, the slower the diffusion
What is the dose of thiopental?
3-5 mg/kg (less for elderly and early pregnancy)
What is the onset of thiopental?
30 seconds
What is the duration of thiopental?
5-10 minutes
How many redistribution 1/2 lives are required for termination of effect?
3-4
Summarize the properties of thiopental as an IV anesthetic.
“Gold standard,” minimal CV effects, good cerebral protection, minimal pain on injection, hangover, moderate emetic, precipitation
What is the drug class of methohexital?
Barbiturate - oxybarbiturate (less lipid soluble than thiopental)
What is the advantage of 1% methohexital over 2% methohexital?
Decreased risk of venous thrombosis
How long is refrigerated methohexital stable after reconstitution?
6 weeks
What is the MOA of methohexital?
Increases duration of GABA on its receptor (Cl- channels open longer –> hyperpolarization) AND mimics GABA on its receptor (directly causing Cl- channels to open)
Also activates glutamate, adenosine, and nACh receptors (SNS causes hemodynamic depression & desensitizes nACh receptors to depolarizing effects of ACh (large doses)
What limits the central effects of methohexital and thiopental?
Redistribution to the peripheral compartment
Methohexital is metabolized _-_x faster than thiopental due to ______ ______ __________ which causes _________ VOD and keeps ____ methohexital in the plasma.
3; 4; decreased lipid solubility; smaller; more
Since methohexital is metabolized faster than thiopental, this results in…
Less hangover and more rapid awakening after repeated doses
What is the elimination 1/2 time for methohexital?
~4 hours (much shorter than thiopental ~12 hours)
What is the advantage of methohexital over pentothal?
More rapid recovery
What is the disadvantage of methohexital compared to pentothal?
More excitatory activity - myoclonus, hiccoughs; infusions associated with postop seizures!!!
How can you prevent the excitatory nervous activity associated with methohexital?
Small doses (up to 1.0-1.5 mg/kg?), pretreat with opioids
Methohexital is ___x more potent than thiopental due to _______ nonionized at blood pH.
2.5; higher percentage
How do CV effects of methohexital differ from pentothal?
Similar but perhaps less hypotension due to better preserved HR; NO HISTAMINE RELEASE
How do CNS effects of methohexital compare to pentothal?
Slightly less cerebral protection; increased excitatory activity
Methohexital and thiopental can exacerbate acute intermittent _______.
porphyria
Induction dose of methohexital
1-2 mg/kg (less in elderly)
Sedation dose of methohexital
0.2-0.4 mg/kg
Onset of methohexital
30 seconds
Duration of methohexital
5-10 minutes
Distribution 1/2 time of methohexital
5.6 minutes
Elimination 1/2 time of methohexital
2-5 hours (much faster than thiopental!)
Summarize how methohexital compares to thiopental
More rapid recovery, more excitatory activity (hiccoughs), moderate emetic (same as pentothal)
Chemical structure of etomidate?
Carboxylated imidazole [ring]-containing compound; water soluble at acidic pH and lipid soluble at physiologic pH
Etomidate is sometimes dissolved in _______ ________ at what pH? Causes what? Concentration? Alternative preparation?
propylene glycol; 6.9; pain on injection; 0.2%; fat emulsion (minimal pain on injection)
What is the MOA of etomidate?
Mimics inhibitory effects of GABA by increasing receptor affinity to GABA, depressing RAS
How do neuromotor effects compare with etomidate vs. thiopental?
Etomidate has excitatory activity causing myoclonus in 30-60% of patients (50-80% without benzos, opioids, or SMALL etomidate dose); MOA - disinhibition of subcortical structures that usually suppress extrapyramidal motor activity
What is the cardiovascular SE profile like for etomidate?
Most minimal SEs of all IV anesthetic agents! Slight decrease in MAP, SVR, least inotropic depression, no decrease in renal BF, NO HISTAMINE
What are the respiratory effects of etomidate?
Less than barbiturates
Decrease TV, increase RR (opposite of opioids); airway reflexes maintained, can maintain spontaneous ventilation.
Increased depression with rapid injection or combo with volatile or opioids.
What are the CNS side effects of etomidate?
Only decrease CMRO2 35-45% (thiopental 55%); CPP well maintained; excitatory (avoid in seizure patients - some myoclonus does have EEG seizure activity with etomidate).
Prevent myoclonus with opioid premedication.
What is the major disadvantage of etomidate?
Causes adrenocortical suppression! :(
What is the MOA of etomidate adrenocortical suppression?
Inhibits conversion of cholesterol to cortisol (11-beta-hydroyxlation reaction)
How long does it take cortisol and aldosterone levels to decrease after etomidate injection?
30 minutes
How long does adrenocortical suppression last with etomidate?
4-8 hours (up to 48 hours???)
What patients need to have an appropriate stress response that could theoretically be prevented by etomidate?
Septic and bleeding patients
What pharmacokinetic characteristics cause etomidate’s fast onset?
High lipid solubility, large nonionized percentage
What limits etomidate’s duration of action?
Redistribution (like barbiturates)
How does etomidate’s rate of clearance compare to thiopental? What causes this difference?
It is 5 times faster than thiopental. Metabolism is by hepatic microsomal enzymes and plasma esterases.
What is the dose of etomidate?
0.3 mg/kg
What is the onset of etomidate?
14-45 seconds (similar to barbiturates ~30 sec)
What is the duration of etomidate?
3-12 minutes
What is the distribution 1/2 time of etomidate?
2-4 minutes (same as thiopental)
Elimination 1/2 time of etomidate?
2-5 hours (like methohexitol)
Summarize the characteristics of etomidate as an IV anesthetic.
Pain on injection, emetic, adrenocortical suppression, GOOD CV support, excitatory CNS activity (myoclonus, seizures)
What is the drug class of dexmedetomidine?
Alpha2-adrenergic agonist
How does dexmedetomidine compare to its cousin clonidine?
8x more selective for alpha2 receptors
What is the MOA of dexmedetomidine?
In spinal cord and pontine locus ceruleus:
Hyperpolarization with efflux of K+
Reduce NE release due to prevention of Ca+ release in presynaptic area
Decrease cAMP concentration by inhibiting adenylyl cyclase
What may happen with a dexmedetomidine loading dose due to its effect on both alpha2Beta and alpha2Alpha receptors?
Hypertension
What other CV effects may occur with an infusion of dexmedetomidine?
Decrease HR (be careful with heart block!), BP (hypotension more common with infusion vs bolus and in those with high sympathetic tone such as diabetic, elderly, hypovolemic)
Describe the sedation provided by dexmedetomidine.
Sedation similar to physiologic sleep, easily rousable; NOT approved for GA.
Little depression of ventilation, can use to wean patient off vent.
Less delirium than benzos, less grogginess.
Amnesia not reliable.
What effect does dexmedetomidine have on MAC?
Greater than 905 reduction with halothane; 35-48% with isoflurane
What factor makes dexmedetomidine an appealing sedative for use in MRI?
Does not cause apnea which is good because you can’t be in the room with the patient in MRI.
However, requires longer recovery than propofol and requires a higher dose for MRI (2 mcg/kg/hr vs normal 1)
What medication is appropriate for an awake fiberoptic intubation during which you need the patient cooperative and sedated but not apneic?
dexmedetomidine
What is dexmedetomidine’s effect on secretions?
Antisialagogue
What is the redistribution 1/2 life of dexmedetomidine?
6-8 minutes
What is the loading dose of dexmedetomidine? Infusion dose?
0.5-1 mcg/kg over 10 minutes; 0.2-1.4 mcg/kg/hr
What property of dexmedetomidine allows it to serve as an adjunct to spinal and supraspinal anesthesia or in multimodal analgesia?
The analgesic effect
What is the effect of dexmedetomidine on thermoregulation?
Reduces shivering through alpha2 effects; inhibits central thermoregulatory control and vasoconstriction, making patient more susceptible to hypothermia
What effect does dexmedetomidine have on PONV? Emergence delirium?
Decreases; prophylactic
