Induction Drugs (Barbs & Propofol) (Exam II) Flashcards
What organs utilize the most blood supply?
What organs utilize the least?
What organs are in between these two groups?
- Vessel-rich group = 75% CP (brain, heart, liver, kidneys)
- Skeletal muscles & skin = 18% CO
- Fat = 5% CO
- Bone, tendons, & cartilage = 2% CO
What are the one-word (ish) summaries of the four stages of anesthesia?
- Analgesia
- Delirium
- Surgical Anesthesia
- Medullary paralysis (death)
What reflexes are we suppressing during stage 1 anesthesia?
If stage 1 anesthesia is maintained, what is it called?
- Coughing, swallowing, and gagging reflexes (lower airway reflexes)
- Conscious sedation
During induction, when would one most likely see laryngospasm?
- Stage 2
During emergence, when would one most likely need to be re-intubated?
- Stage 2
What is the mechanism of action of barbiturates?
- Direct mimic of GABA (GABA A Potentiation) causing Cl⁻ influx & cellular hyperpolarization.
Hyperpolarization in the brain = sedation
What do barbiturates do to CBF & CMRO₂ ?
How is this accomplished?
- ↓ CBF & ↓ CMRO₂ (by 55%) via cerebral vasoconstriction
Congruent changes (up or down) in CBF and CMRO₂ are considered coupled. If one changes independently from the other (inhalation agents and Ketamine) it is considered uncoupled.
What drug class is represented by the figure below? How do you know this?
- Barbiturates
- Rapid redistribution & lengthy context-sensitive half-time (noted by fat build-up over time)
At nomal pH Thiopental is more lipid soluble than methohexital even though methohexital concentration is more non-ionized than thiopental (Methohex:76% vs Thiopent:61%). Weird fact right?
Where is the site of initial redistribution for barbiturates?
When is equilibrium between plasma concentrations & muscle concentrations reached?
- Skeletal muscles
- 15 min
Rapid redistribution from brain to other tissues
- after 5 min 1/2 dose available
- at 30 minute, 10% of original dose available in brain
Keyword is REDISTRIBUTION. This refers to AFTER the barb has distributed itself to VRGs like the brain and viscera. It continues into the fat and hangs out there to redose the patient later. That’s why we need to dose off of IBW!
Where is the main reservoir for barbiturates?
What does this mean clinically?
- Adipose tissue (fat)
- Dose on lean body weight and note cumulative effects of barbiturates.
Patient can be redosed after initial dose if enough has stored in the fat, causing sedation hours after expected recovery
What is the metabolism and excretion of barbiturates?
- Hepatic metabolism; Renal excretion
Methohexital is metabolized faster than Thiopental, thus the patient recovers more quickly.
How protein bound (in a percentage) are barbiturates?
- 70 - 85% protein bound
Caution in elderly as their albumin amount may be low.
What are the characteristics of a non-ionized barbiturate?
- Lipophillic
- Acidotic environment is favored.
Non-ionized substance WANT to cross barriers
What are the characteristics of an ionized barbiturate?
- Lipophobic/Hydrophilic
- Alkalotic-favored
Ionized substances DO NOT want to cross barriers
Why might barbiturates be considered cerebro-protective?
- Barbs = ↓CBF & ↓CMRO₂
Coupled responses are good.
Regarding barbiturates, are S-isomers or R-isomers more potent?
Which isomer is used clinically?
- S-isomer barbiturates are more potent
- Trick question. Racemic mixtures are the only ones used.
How would one differentiate thiobarbiturates vs oxybarbiturates?
- Thiobarbiturates: thiopental, thiamylal.
- Oxybarbiturates: methohexital, phenobarbital, pentobarbital.
Remember thio means sulfur so other namings much mean oxygen.
What is the dose for Thiopental?
How much is in the brain 30 minutes post-administration? Why?
- 4mg/kg iV
- 10% in the braine after admin. Rapid redistribution to skeletal muscles occurs.
Rapid redistribution from brain to other tissues
‣after 5 min 1/2 dose available
‣ at 30 minute, 10% of original dose available in brain
What is the fat/blood partition coefficient of thiopental?
What does this mean?
- 11
- Dosing needs to be calculated on Ideal Body Weight.
What does a partition coefficient describe?
- Distribution of a drug between two substances that have the same temp, pressure, and volume.
Partition coefficient describes the distribution ratio of a given agent AT EQUILIBRIUM.
What is the blood-gas coefficient?
- Number that describes the distribution of an anesthetic between blood and gas at the same partial pressure.
What would a high blood-gas coefficient indicate?
- Slower Induction time
Essentially, drug is taken up into the blood and wants to stay in the blood rather than going to tissues like the brain.
Which is more lipid soluble, thiopental or methohexital?
- Thiopental (Trade Name: Sodium Pentothal)
At a normal pH _____% of methohexital is non-ionized.
At a normal pH ____% of sodium pentothal is non-ionized.
What does this mean in regards to induction for comparing these drugs?
- 76% (more unionized molecules than pentothal)
- 61% (still more lipid-soluble than brevital)
- Methohexital for induction has a faster metabolism and recovery even though thiopental (pentothal) is more lipid soluble.
Which barbiturate causes excitatory symptoms like myoclonus and hiccups?
Methohexital
M in metho for myoclonus and H in hexital for hiccups?
How would methohexital infusions differ from induction?
Very lipid-soluble so:
- Drug persists from infusion but clears quickly from induction due to its rapid metabolism (faster than thiopental).
Est 1/2 time of Thiopental > Methohexital
Peds: generally shorter half-time d/t ↑ metabolism
What is the IV methohexital dose?
What if it needs to be given rectally?
- 1.5 mg/kg IV
- 20 - 30 mg/kg PR
What is the seizure profile of methohexital?
Can induce seizures but is better than etomidate or when used with ECT.
- Continuous infusions induce post-op seizures in ⅓ of patients.
- Seizures are induced in patients undergoing temporal lobe resection.
- Seizure duration REDUCED 35-45% in ECT patients vs etomidate.
What cardiovascular side effects would occur with thiopental administration in a normovolemic patient?
- Transient sBP decrease of 10-20mmHg
- Transient HR increase of 15-20 bpm
Decrease in BP is rapidly offset by increase in HR
Caution with lack of baroreceptor response: Hypovolemia, CHF, Beta blockade
‣in shock (↓perfusion)
‣ elderly & women ( ↓ muscle mass)
What patient conditions could result in poor baroreceptor response after barbiturate administration?
- Hypovolemia, CHF, & β-blockade
Thiopental can have a(n) __________ type response due to __________ release coupled with previous exposure to the drug.
anaphylactic ; histamine
What are the respiratory effects of barbiturates?
Dose-dependent medullary & pontine respiratory depression.
- Less sensitivity to CO₂ levels (may need CO2 increased to initiate spontaneous respiration)
- Slow frequency and decreased Vt
What would occur with accidental arterial administration of a barbiturate?
What is the treatment?
- Immediate, limb-threatening vasoconstriction with pain radiating along the distribution of the artery.
- Lidocaine or papaverine injection as well as any other vasodilatory method (must sustain adequate bloodflow!)
Patient can have obscure distal arterial pulses, blanching of the extremity followed by cyanosis, and possible gangrene with permanent nerve damage
Why are barbiturates desired when needing to monitor Somato-Sensory Evoked Potentials (SSEPs)?
Barbs do not affect neuron transmission, thus, they DON’T effect SSEPs
When would CYP450 enzyme induction be seen with a barbiturate infusion?
How long could it last?
- CYP450 induction can be seen if infusion persists for 2-7 days and can last up to 30 days after the infusion is D/C!
- Enzyme induction when on prolonged gtt increases metabolism of: anticoagulants, phenytoin, TCA’s, digoxin, corticosteroids, bile salts, vitmain K
Special caution in coagulation. Induction of CYP450 can cause additional clotting in patients on warfarin (drug metabolized faster) and bleeding with plavix (more of prodrug is metabolized so more effective)
What renal effects would one expect to see after barbiturate administration?
- Modest, but transient ↓RBF and ↓GFR
Remember the transient decrease in BP?
For Propofol, what are the doses for:
1. Induction
2. Maintenance
3. Conscious sedation
- Induction = 1.5 - 2.5 mg/kg IV
- Maintenance = 100 - 300 μg/kg/min
- Conscious sedation = 25 - 100 μg/kg/min
Induction dose has to be higher for rapid onset (dose in mg/kg) and because we are giving a one-time IVP. Maintenance infusion can be lower (dose in μg/kg/min) to keep adequate blood concentration and conscious sedation must be even lower than maintenance so we don’t snow or patients.
What is the most common concentration of a 1% solution?
- 10mg/mL
General rule for % concentration dictates you move the decimal to the right 1 place and that tells you how many grams/L you have. i.e. 0.9%NS=9g of salt/liter. 1.0% lido means 10g/L→10,000mg/L→10mg/mL
What are the inactive ingredients in propofol? Why is one particularly important?
- 1.2% Lecithin (from egg yolks) can cause anaphylaxis with egg allergies.
- 2.25% glycerol (causes pain on injection)
- 10% soybean oil
Both lecithin and soybean oil are factors that contribute to bacterial growth
What are the disadvantages of propofol’s inactive ingredient composition?
- ↑ bacterial growth
- ↑ plasma triglycerides with prolonged infusions
- Pain on injection
Differentiate Ampofol and Aquavan.
- Ampofol - low-lipid, no preservative that burns on injection more often.
- Aquavan - prodrug with less injection pain but causes unpleasant dysesthesias (sensations). Slower onset, larger Vd, and high potency.
What is the mechanism of action of propofol?
- GABA A receptor modulator (Agonist) that increases Cl⁻ conductance.
This causes hyperpolarization of the postsynaptic cell membrane and functional inhibition of the postsynaptic neuron
How does propofol cause immobility through spinal cord-depression?
- Trick question. Immobility from propofol is not from drug-induced spinal cord depression.
What are the clearance characteristics of propofol?
- Plasma (pulmonary/lungs uptake) > hepatic blood flow (Note: Lungs do NOT metabolize the propofol)
- Tissue uptake > Cytochrome P450
The elimination of propofol is primarily through hepatic metabolism, and excretion by the kidneys. However, about 30% of a propofol bolus is taken up by the lungs (lung first-pass) and is eventually (usually quickly) released back into circulation.
What metabolizes propofol?
- 24-60% CYP450 (in the liver) and 40-76% UGT1A9 (liver, kidney, colon, esophagus, and small intestine)
What is the E ½ time of propofol?
- 30 - 90 minutes
What is the context-sensitive half-time of propofol? Is this a relatively low or high context half-time?
- 40 minutes (for an 8 hours infusion)
- Low CS ½ time.
What are the following characteristics of propofol:
1. Elimination ½ time.
2. Volume of distribution
3. Clearance (mL/kg/min)
- E ½ time = 30 - 90 minutes
- Vd = 3.5 - 4.5L
- Clearance = 30 - 60 mL/kg/min
Differentiate blood pressure and heart rate changes that occur with propofol vs thiopental.
- Propofol: ↓BP (greater than Thiopental) & ↓HR (Direct SNS inhibition)
- Thiopental: ↓BP & ↑HR (Both transient)
Profound brady and asystole even in healthy patients!!! Consider pre-treatment with glyco (FDA Black box warning in Pedi<2yrs)
Does propofol cross the placenta? What are the consequences of this?
- Yes but is rapidly cleared from neonatal circulation.
Although unlikely, still consider ion-trapping
Do cirrhosis and renal dysfunction have significant effects on propofol metabolism?
No
While primarily metabolized in liver, UGT1A9 that exists in the liver, kidney, colon, esophagus, and small intestine can pick up slack if liver is impaired.
What drug is the induction drug of choice?
Propofol
Quick on, quick off, and can be metabolized in multiple tissues so it still works well in liver impairment
What is the induction dose of propofol in adults? Children?
- Adults: 1.5-2.5 mg/kg IV
- Pediatrics: higher doses due to larger central volume and clearance rate.
What is the induction dose of propofol in the elderly?
- 1 mg/kg IV (25 - 50% lower than regular adult)
General concensus is that elderly are more sensitive to propofol, don’t know why. Maybe aging organs reduce efficiency of CYP450 and UGT1A9?
What plasma propofol levels would correlate with unconsciousness?
What about awakening?
- Unconscious: 2 - 6 μg/mL
- Awake: 1 - 1.5 μg/mL
What is the conscious sedation dose of propofol?
- 25 - 100 μg/kg/min
What are the characteristics of propofol in the context of conscious sedation?
- Minimal analgesia but has anti-convulsive and amnestic properties.
- Prompt recovery w/ low residual sedation
- ↓ risk of PONV
- Midazolam or opioids as adjuncts.
What are the anti-emetic properties of propofol?
Why is this thought to occur?
- Very anti-emetic (more effective than Zofran)
- Depresses sub-cortical pathways and has a direct depressant effect on the vomiting center)
What is the sub-hypnotic dosing for propofol?
- 10 - 15 mg IV, followed by 10 mcg/kg/min
What is the anti-pruritic dosing of propofol?
- 10 mg IV
What is the anti-convulsant dosing of propofol?
1mg/kg IV
What are “other” category benefits of propofol?
- Bronchodilation
- Anti-emetic (better than Zofran)
- Anti-pruritic
- Anti-convulsant
- Analgesia at low doses
- Potent Antioxidant
- Does not trigger MH
What are propofol’s effects on CMRO₂, CBF, and ICP?
- ↓ CMRO₂, CBF, and ICP (Coupled response)
Large doses of propofol may ______ cerebral perfusion pressure.
decrease
Though propofol will not produce seizures, it will produce _______.
myoclonus (This is normal)
Note: Myclonus is involuntary, sudden, and brief muscle contractions that can affect one or multiple muscles. This can initially look like a seziure but is transient.
Between thiopental, propofol, and isoflurane, which is the least EEG suppressive?
- Propofol
Which would decrease blood pressure more, thiopental or propofol?
Propofol
Thiopental is transient and is mitigated by a reflexive HR increase. Propofol has direct cardiac-suppressive effects!
What is the mechanism for propofol-induced hypotension?
What conditions will exaggerate this effect?
- SNS inhibition causing ↓SVR and ↓ ICF Ca⁺⁺.
- Hypovolemia, elderly, and LV compromise
Can cause profound brady and asystole even in healthy patients!!! Consider pre-treatment with glyco (FDA Black box warning in Pedi<2yrs)
How is propofol-induced hypotension from induction usually counteracted?
- Intubation (from laryngeal stimulation).
Cold blade=SNS Stimulation
Why is bradycardia seen with propofol?
What would occur with propofol overdose?
- ↓SNS response & baroreceptor reflex
depression. - Profound bradycardia & eventual asystole.
What are the pulmonary effects of propofol?
How does this change with opioids?
- Dose-dependent depression of respiratory drive.
- Synergistic resp depression with opioids
What severe condition(s) can occur with prolonged propofol infusions?
- Hepatocellular injury or Propofol Infusion Syndrome.
What is Propofol Infusion Syndrome?
- Metabolic acidosis thought to occur from poisoning of electron transport chain and impaired oxidation of fatty acids.
- S/sx: Lactic acidosis, Brady-dysrhthmias, Rhabdo.
PIS expected to occure in gtt’s > 75 mcg/mg/min for > 24 hrs.
Is reversible in early stages but may require ECMO if cardiogenic shock occurs.
What relatively benign condition(s) can occur from prolonged propofol infusions?
Why does this happen?
Green and cloudy urine from phenols and uric acid crystals.
Neither alters renal function.
What sort of infusion dosing can result in propofol infusion syndrome?
- > 75 μg/kg/min for longer than 24 hours
What is the worst side effect in children who have propofol infusion syndrome?
- Severe, refractory, fatal bradycardia
FDA blackbox to not use propofol in children but we still do because anesthesia knows best…seriously though, consider glyco or some other alternative to keep HR normal, especially in kids because nobody wants the smoke.
What are the symptoms of propofol infusion syndrome?
How is propofol infusion syndrome diagnosed?
- Urine changes, lactic acidosis, brady-dysrhythmias, and rhabdomyolysis.
- ABG & serum lactate concentrations.
What are the “other” organ system effects of propofol?
- Injection pain (lido before)
- ↓ IOP (great for galucom patients)
- Plt aggregation inhibition (slight bleeding risk?)
- Allergic reactions (lecithin)
- Prolonged myoclonus
- Abuse/misuse (“Hee hee”)
Obvious homage to MJ
