SS25 Induction Drugs (Barbs & Propofol) (Exam 2) Flashcards
What is MAC?
- Monitored Anesthesia Care
- Also known as Conscious sedation or Procedural Sedation
- Combo of sedatives & analgesics to depress LOC for patient’s to be able to tolerate unpleasant procedures & surgeons to perform effectively
What are the 5 components of General Anesthesia (GA)?
(MAASH)
- Hypnosis, analgesia, muscle relaxation, sympatholysis, amnesia
High dose Propofol has all of these
What organs utilize the most blood supply?
What organs utilize the least?
What organs are in between these two groups?
- Vessel-rich group = 75% CO (brain, heart, liver, kidneys)
- Skeletal muscles & skin = 18% CO
- Fat = 5% CO
- Vessel poor group (Bone, tendons, cartilage, skin, hair, nails) = 2% CO
T/F: All anesthetics go to vessel-rich group.
- True (esp. induction)
- A part of 75% CO
When the drug is administered via CVC, does it travel through cardiopulmonary circuit or systemic circuit first?
- cardiopulmonary circuit
What are the stages of general anesthesia (GA)?
- Stage 1: Analgesia
- Stage 2: Delirium
- Stage 3: Surgical Anesthesia
- Stage 4: Medullary paralysis (all of ALL reflexes (CNS/CV), severe hypotension, death)
Describe Stage 1: Anesthesia
- Begins with initiation of an anesthetic agent and ends with LOC
- Lightest level of anesthesia
- sensory and mental depression
- able to open their eyes on command, breathe normal, maintain reflexes, tolerate mild stimuli
If stage 1 anesthesia is maintained, what is it called?
- Conscious sedation
What are the four upper airway reflexes are we suppressing during stage 1 anesthesia?
- Sneezing, Coughing, Swallowing, and Gagging
During induction, when would one most likely see laryngospasm?
- Stage 2
- danger zone; violent/ exaggerated responses
- Starts with LOC to the onset of automatic rhythmicity of VS
-CV instability excitement, dysconjugate ocular movements, emesis - rapid stage!
What population may have a prolonged stage 2 and why?
- Pedis
- Inhaled induction takes longer for LOC and autonomicity
During emergence, when would one most likely need to be re-intubated?
- Stage 2
Which stage would we like to extubate in?
Stage 1: Able to protect airway
Characteristics of Stage 3:
- Absence of response to surgical incision
- depression of all 5 GA components of nervous system (MAASH)
What is the mechanism of action of barbiturates?
- Potentiate GAGA-a channel activity ( directly mimics) causing Cl⁻ influx & cellular hyperpolarization
Do barbiturates have analgesic effects?
- No, will have to add multimodal or opioid
What other receptors do Barbiturates act on?
- Glutamate
- adenosine
- n-Ach
- What do barbiturates do to CBF & CMRO₂ ?
- How is this accomplished?
- ↓ CBF & ↓ CMRO₂ by 55% via cerebral vasoconstriction (coupled)
What drug class is represented by the figure below?
-What is the clinical significance of graph?
- Barbiturates (Thiopental)
- Rapid re-distribution from brain to other tissues
- VRG→ muscle group → fat → VPG
Barbiturates:
- Onset
- Reversal gradient:
- What can cause the drug to re-enter circulation?
- Onset: 30 secs & rapid awakening d/t rapid uptake
- Reversal of gradient
- At 5 mis: 50% total dose gone
- At 30 mins: 10% of total dose remaining
- Lengthy context-sensitive half-time for (d/t fat “reservoir” accumulation)
- What’s the initial site of redistribution from VRG?
- Considerations?
- Skeletal Muscle = Lean tissues (18% CO)
- Considerations: shock patient (decreased perfusion) and elderly (decreased muscle mass)
When is equilibrium between plasma concentrations & skeletal muscle concentrations reached?
- Equilibrium at 15 mins
Where is the main reservoir for barbiturates?
What does this mean clinically?
- Fat (5%): Drug reservoir; can re-dose or cause cumulative effect
- Must dose per IBW or lean body weight
Barbiturates: Thiopental
- Metabolism?
- Excretion?
- Metabolism: Hepatic 99%
- Excretion: Renal
Barbiturates: Protein bound (in a percentage).
- Clinical significance?
- 70 - 85% Albumin bound
- Able to re-bind to Albumin carrier and re-enter VRG (ie: brain) = re-hypnosis
T/F: In pedis, the E1/2 is prolonged with barbiturate use
- False
- shorter
What’s the effect on redistribution if the drug has a high protein binding capacity?
- Longer duration of action d/t context- sensitive half-time
What are the characteristics of a non-ionized barbiturate?
- Favors Fat - Lipophilic
- Favors acidosis
- Readily crosses BBB
What are the characteristics of an ionized barbiturate?
- Hater = Lipophobic
- Favors alkalosis
Why might barbiturates be considered cerebro-protective?
- Barbs = ↓CBF & ↓CMRO₂ 55%
Regarding barbiturates, are S-isomers or R-isomers more potent?
Which is used clinically?
- S-isomer barbiturates are more potent
- Trick question! Racemic mixtures are only ones used
How would one differentiate thiobarbiturates vs oxybarbiturates?
- Thiobarbiturates: thiopental, thiamylal.
- Oxybarbiturates: methohexital (current ECT treatment), phenobarbital, pentobarbital.
Thiobarbiturates result from the replacement of Oxybarbiturate’s oxygen with a _____ atom.
- How does this effect solubility and potency?
- Sulfur atom
- Higher lipid solubility
- greater hypnotic potency
Thiopental (Sodium Pentothal):
- Dose?
- E1/2 compared to methohexital?
- Fat/blood coefficient?
- 4 - 5 mg/kg IV
- E1/2: Longer than methohexital (Thiopental is more lipid soluble)
- 11→ indicates longer duration of action (use IBW)
The greater the ratio of fat to body weight, the less is the blood volume (ml/kg). Why?
- Adipose/fat tissue has reduced blood supply
How much Thiopental is present in the brain 30 mins post-administration?
- Why?
- Only 10%
- Rapid redistribution, skeletal muscles, & decrease doses in shock elderly
What does a partition coefficient describe?
- What are the 2 types?
- The distribution of a drug at equilibrium between two substances that have the same temp, pressure, and volume.
- Blood:gas and Fat:blood
What is the blood-gas coefficient?
- The distribution of an anesthetic between blood and gas at the same partial pressure.
What would a high blood-gas coefficient indicate?
- Correlates with a higher solubility of anesthetic in blood → slower induction time
-The blood basically acts as a pharmacologically inactive reservoir (drug wants to stay in blood) - Inhalant agents
_____ agents have fat to blood coefficients.
- Induction agents
Which is more lipid soluble, Thiopental or Methohexital?
- Why?
- Thiopental
- Sulfur atom → lipid soluble & greater hypnotic potency
At a normal pH, _____% of methohexital is non-ionized.
At a normal pH, ____% of Thiopental is non-ionized.
What does this mean in regards to induction for comparing these drugs?
- 76%
- 61%
- Methohexital for induction has a faster metabolism and recovery due to its increased lipid-solubility.
Which barbiturate causes excitatory phenomena of myoclonus and hiccups?
Methohexital
How would methohexital infusions differ from induction?
Very lipid-soluble so:
- Induction: clears quickly
- Infusion: persists from infusion
Methohexital:
- IV dose?
-Rectal (PR) dose?
- IV Dose: 1.5 mg/kg
- PR dose: 20 - 30 mg/kg
What is the seizure profile of Methohexital?
- Decreases seizure threshold→ induces seizure (ie: 1out 3 patients during temporal lobe resection)
- Decrease duration of seizure by 35 - 45% in ECT therapy compared to Etomidate
What CV side effects would occur with Thiopental 5 mg/kg administration in a normovolemic patient?
- Transient SBP decrease of 10-20mmHg
- Transient HR increase of 15-20 bpm (compensation)
Barbiturates (Thiopental) blunts _____ response.
- CV considerations?
- Baroreceptor response
- Caution for Hypovolemia, CHF, & β-blockade
Thiopental can have a __________ response due to __________ release coupled with previous exposure to the drug.
- anaphylactoid ; histamine
Barbiturates: Ventilation SE
- Dose-dependent medullary & pontine centers respiratory depression
(Less sensitive to CO₂ levels) - Delayed return to spontaneous ventilation (slow frequency (RR) and decreased tidal volume (shallow breathing)
- Stage 4 territory = over anesthetized
What would occur with accidental arterial administration of a barbiturate?
What is the treatment?
- Immediate, limb-threatening vasoconstriction
- obscures distal arterial pulses → permanent nerve damage risk
- Tx: Vasodilators Lido or Papaverine
What type of IntraOp monitoring would prefer barbiturates?
- Why?
- SSEP (Somatosensory Evoked Potential) monitoring
- desired use of barbs over volatiles b/c volatiles suppress sensory output which would cause SSEP not to work
When would CYP450 enzyme induction be seen with a barbiturate infusion?
How long could it last?
- What drugs would be affected?
- 2-7 days post-infusion
- Could last up to 30 days
- Accelerates metabolism of anticoags, phenytoin, TCAs, digoxin, corticosteroids, bile salts and Vit K → may need supplementation
Barbiturates: Renal SE
- Transient ↓RBF and ↓GFR
- May need IV fluids
For Propofol, what are the doses for:
1. Induction
2. Conscious sedation
3. Maintenance
4. Anticonvulsant
5. Sub-hypnotic
6. Anti-pruritic
- Induction = 1.5 - 2.5 mg/kg IV
- Conscious sedation = 25 - 100 mcg/kg/min
- Maintenance = 100 - 300 mcg/kg/min
- Anticonvulsant: 1mg/kg IV
- Sub-hypnotic (N/V): 10 -15 mg/kg, followed by 10 mcg/kg/min
- Anti-pruritic: 10 mg IV
- Tip: maintenance has highest dose range for Prop
Pediatric dose for Propofol?
- Why?
- Require higher dose
- Larger central distribution volume, Higher clearance rate, Higher metabolism
Propofol:
- How long should I push IV injection?
- Onset
- Duration
- E1/2
- Potency compared to barbiturates
- Rapid (<15 secs)
- 30 secs
- Duration: very short acting
- E1/2: 0.5 - 1.5 hrs
- Equipotent to barbs
What is the most common concentration of a 1% solution Propofol?
- 10 mg/mL
What are Propofol clinical uses?
- Induction (1% soln)
- Continuous IV infusion
1. Prop only
2. TIVA - Total/Balanced IV Anesthesia
3. ICU: 2% soln used to ↓ lipid use
4. Status Epileptics
What are the following characteristics of propofol:
- Elimination ½ time.
- Volume of distribution
- Clearance (mL/kg/min)
- E ½ time = 0.5 - 1.5 hrs
- Context sensitive half-time: 40 mins (8- hr infusions)
- Vd = 3.5 - 4.5 L/kg
- Clearance = 30 - 60 mL/kg/min
What are the inactive ingredients in propofol?
- Why is one particularly important? (Think allergies)
- 1.2% Lecithin (from egg yolks) → Anaphylaxis with egg allergy
- 2.25% glycerol
- 10% soybean oil
- Tip: typically if allergy to egg yolk, NOT given; allergy to egg white = OKAY to give
What are the disadvantages of propofol’s inactive ingredient composition?
- ↑ bacterial growth (6 hrs of use from spike; green discoloration)
- ↑ plasma triglycerides with prolonged infusions
- Pain on injection
Differentiate Commercial Prop preps: Ampofol, Aquavan, Non-lipid Cyclodextrins.
- Ampofol: low-lipid, no preservative, high pain on inject
- Aquavan: prodrug with less injection pain but not used often b/c causes dysesthesia (burning sensation esp. women genitals) an slower onset, larger Vd, and high potency
- Non-lipid w/ Cyclodextrins (Solubilizing Agent): in trials; study shows even higher injection pain
Prop MOA (2)
- Selective modulator of GABA-a that increases Cl⁻ conductance → postsynaptichyper polarization
- Potentiates Glycerine → partial hypnotic effect
How does propofol cause immobility through spinal cord-depression?
- Trick question! Immobility from propofol is not from drug-induced spinal cord depression.
- Side bars:
- Volatiles alter spinal motor function
- Spinal motor neuron excitability measured by H reflexes
What are the clearance characteristics of propofol?
- cleared intravascularly NOT from body
- The clearance of propofol from plasma (lung first pass uptake) exceeds hepatic blood flow
- Tissue uptake > CYP450
- What metabolizes propofol?
- What are the metabolites?
- CYP450 and UGT1A9
- Water-soluble sulfate and glucuronic acid metabolites
- What is the context-sensitive half-time of propofol?
- Is this a relatively Low or High context-sensitive (CS) half-time?
- 40 minutes (for an 8 hours infusion)
- Very Low CS ½ time.
Differentiate blood pressure and heart rate changes that occur with propofol vs thiopental.
- Propofol: ↓BP & ↓HR
- Thiopental: ↓BP & ↑HR
Does propofol cross the placenta?
- What are the consequences of this?
- Yes but is rapidly cleared from neonatal circulation.
- Beaware of ion trapping
Do cirrhosis and renal dysfunction have significant effects on propofol metabolism?
- Cirrhosis: No, similar awakening time with alcoholic and normal patient
- Renal dysfunction: No influence on prop clearance via IV
What drug is the induction drug of choice?
Dose?
- Propofol
- 1/5 - 2.5 mg/kg IV
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?
- 25 - 50% lower than regular adult dose
What plasma propofol levels would correlate with unconsciousness on induction?
What about awakening?
- Unconsciousness: 2 - 6 μg/mL
- Awakening: 1 - 1.5 μg/mL
What is the conscious sedation dose of propofol?
- 25 - 100 mcg/kg/min IV
What are the characteristics of propofol in the context of conscious sedation?
- Anticonvulsant use
- DOC for brief GI procedures
- ICU patients on MV postop
- ↓ risk of PONV
- Prompt recovery w/ low residual sedation
- Minimal analgesia and amnestic properties (adjunct opioid or multimodal)
- Midazolam or opioids as adjuncts.
What is the sub-hypnotic dosing for propofol?
- 10 - 15 mg IV, followed by 10 mcg/kg/min
- What are the anti-emetic properties of propofol?
- MOA?
- Which dose would you give?
- More effective than ondansetron; CIMV, PONV
- MOA: Depresses subcortical pathways & direct depression of vomiting center
- Give sub-hypnotic dose (10 - 15 mg IV, followed by 10 mcg/kg/min)
What is the anti-pruritic dosing of propofol?
- 10 mg IV
- Pruritus secondary to neuraxial opioids or cholestasis
What is the anti-convulsant dosing of propofol?
- 1mg/kg IV
List “other” category benefits of propofol?
- Bronchodilator
- Anti-emetic
- Anti-pruritic
- Anti-convulsant
- Low dose analgesia
- Potent Antioxidant
- Does not trigger MH
Explain figure.
Respiratory resistance after tracheal intubation the least after Propofol induction and most with Etomidate
Propofol: CNS effects:
- DECREASED ↓ CMRO₂, ↓CBF, and ↓ICP
- ↓ CPP (support MAP)
- Myoclonus can occur. Does NOT produce seizures tho
T/F: Auto-regulation of CBF and PaCO2 are maintained.
- What term describes the relationship?
- True
- CBF and PaCO2 is coupled
T/F: Propofol EEG changes similar to Isoflurane.
- False; Prop EEG similar to Thiopental
EEG waves one word descriptions per lecture:
Alpha
Beta
Delta
Gamma
Theta
- Alpha: awake
- Beta: Concentration
- Delta: Deep Sleep
- Gamma: Thinking/Testing
- Theta: Light Sleep
Does Propofol cause SSEP suppression?
- No
- Exceptions: Nitrous or volatiles added
Which would decrease blood pressure more, thiopental or propofol?
- Propofol
- Decreased SBP greater than Thiopental
What is the mechanism for propofol-induced hypotension?
* What conditions will these effects be exaggerated?
- SNS inhibition → vascular smooth muscle relaxation = ↓SVR
- ↓ ICF Ca⁺⁺ = ↓ contractility
- Hypovolemia, elderly, and LV compromise
How is propofol-induced hypotension from induction usually counteracted?
- Intubation (laryngoscopy stimulation)
Mechanisms of bradycardia with propofol administration:
- ↓SNS response by direct effect on muscaranic receptors
- Baroreceptor reflex
depression - Profound bradycardia & asystole (documented even in healthy patient)
Propofol black box warning in pediatrics?
- Profound bradycardia (fatal)
- Pre-medicate pedis with Glycopyrolate
Propofol: Pulm effects
How does this change with opioids?
- What intraOp technique can counteract negative effects?
-
Dose-dependent ventilation depression (apnea)
(painful surgical stimulation by surgeon counteracts) - Synergistic with opioids (increased risk)
- Hypoxic pulmonary vasoconstriction reflex remains intact
Propofol: Hepatic/Renal effects
- LFTs/ creatinine are normal
- Hepatocellular injury
- Propofol Infusion Syndrome
What is Propofol Infusion Syndrome?
- What dose is associated w/ syndrome?
- Lactic acidosis thought to occur from poisoning of electron transport chain and impaired oxidation of fatty acids.
- High doses > 75 mcg/kg/min longer than 24 hrs
Propofol infusion syndrome: - - S&S?
- Diagnostics?
- Is it reversible?
- Late stage complication?
- Urine changes, lactic acidosis, brady-dysrhythmias, rhabdomyolysis
- ABG & Lactic
- Reversible in early stages
- Late stage = CV Shock (ECMO)
- severe, refractory bradycardia in KIDS
What relatively benign condition(s) can occur from prolonged propofol infusions?
Why does this happen?
- Urine: Green (phenols) and/or cloudy (uric acid crystals)
- No alterations in renal function
What is the worst side effect in children who have propofol infusion syndrome?
- Severe, refractory, fatal bradycardia
Propofol: Other organ effects
- Injection pain (10% of patients (give Lido prior and/or use larger vein)
- ↓ IOP (benefit for trendelenburg position)
- PLT aggregation inhibition (insignificant clotting risk)
- Allergic reactions (ie: lecithin)
- Prolonged myoclonus (sleep w/ involuntary movement)
- Abuse/misuse (15% in HCWs)
