Induction Drugs (Barbiturates/Propofol) (2) Flashcards
Sedative:
A drug that induces a state of calm or sleep
Hypnotic:
A drug that induces hypnosis or sleep
Anxiolytic:
A drug that reduced anxiety and that has sedation as a side effect
Sedative-Hypnotic:
A drug that reversible depresses the activity of the CNS
General Anesthesia:
State of drug induced unconsciousness
What other terms can be used for conscious sedation?
Procedural sedation
MAC (monitored anesthesia care)
What is the definition of procedural sedation (MAC/conscious sedation)?
The administration of a combination of sedatives and analgesics to induce a depressed level of consciousness, allowing patients to tolerate unpleasant procedures and enabling clinicians to perform procedures
What is indicated by each arrow? What % of cardiac output goes to each group?
Red: vessel rich group (75% CO)
Orange: muscle group (18% CO)
Yellow: fat (5% CO)
Vessel Poor group: 2% CO
What organs are part of the vessel rich group?
Brain
Heart
Kidneys
Liver
What makes up the vessel poor group?
Bone
Tendon
Cartilage
What is the main organ target for IV anesthestics?
Brain
What would you expect from a patient that is hypovolemic being anesthetized with IV anesthesia?
Not enough blood volume to dilute the drug→ drug goes into compartments faster
Explain how to compartment of the body work as reservoirs for IV medication:
Med can continue to cause sedation flowing back to vessel rich group from vessel poor groups
What are the 5 components of general anesthesia?
Hypnosis
Analgesia
Muscle relaxation
Sympatholysis
Amnesia
What drugs is the best at producing sympatholysis and amnesia?
Propofol
Short hand way to categorize the stages of anesthesia:
Stage 1: analgesia
Stage 2: delirium
Stage 3: surgical anesthesia
Stage 4: medullary paralysis
What is the last sensory experience the patient goes through in stage 1?
Hearing→keep environment calm/quiet
What are the 4 main protective airway reflexes?
Cough
Gag
Swallow
Sneeze
What stage are airway reflexes completely gone?
Stage 3
What happens during stage 2 when the patient is stimulated?
Response to stimulation is exaggerated and violent
What is the most dangerous stage of anesthesia and how long should this stage last?
Stage 2→should pass through in 5-15 seconds (max 30 sec)
When does the excitatory stage occur and what is it a response to?
Stage 2 Increase pulse rate after paralytic→ when HR goes back to baseline or brady they are into stage 3
What stage do you intubate in?
Stage 3
What are common vital changes that occur with over anesthetizing a patient (approaching stage 4)?
Hypotension and bradycardia
How is stage 2 different with emergence compared to induction?
Stage 2 is prolonged with emergence compared to induction
What is the gold standard barbiturate used to compare with other drugs?
Thiopental
When was thiopental introduced? What is it derived from?
1934-not used in US anymore
Derived from barbituric acid
What is the MOA for barbiturates?
Potentiate GABA(A) channel activity→ directly mimics GABA and promotes hypnosis
Also acts on glutamate. adenosine, and neuronal nicotinic acetylcholine receptors
How do Barbiturates affect cerebral blood flow?
Cerebral vasoconstrictors→decrease CBF and decrease CMRO2 55%
Do barbiturates provide any analgesia?
No, need multimodal agents/opioids
Most IV anesthetic agents couple the effects of CBF/CMRO2. What anesthetics decouple CBF/CMRO2?
Volatile anesthetics→ inverse CBF/CMRO2
Explain the pharmacokinetics of thiopental after IV injection (blood, brain, lean tissue, and fat):
When does thiopental peak in the brain?
Rapid decrease in blood
Peak level time is directly associated with tissue blood flow
Initially taken up in vessel rich group→ drug then redistributed to skeletal muscle → then to lesser extent to the fat (redistribution)
What is the onset of barbiturates?
Rapid onset: 30 seconds and rapid awakening d/t rapid uptake
How does redistribution of thiopental affect the concentration at 5min and 30 minutes?
Rapid redistribution
5 min: 1/2 total dose
30min: 10% total dose
Prolonged infusion of thiopental is associated with _______ context-sensitive half-time.
Lengthy
When is perfusion decreased from vessel rich group to skeletal muscle?
Perfusion decrease in shock
Mass decrease in elderly
**decrease skeletal muscle mass in elderly= more fat
Explain how fat becomes a reservoir for drugs?
Induction agents are highly fat soluble→ fat becomes a reservoir for drug (redosing from the fat)
need to dose from ideal body weight/lean body weight
How are barbiturates metabolized and excreted?
99% hepatic metabolism
Renal excretion
How does the E1/2 time for barbiturates differ in pediatric population?
Half time is shorter in kids
Are barbiturates protein bound?
Yes 70-85% albumin bound
What is the effect on redistribution if the drug has a high protein binding capacity?
Longer duration of action
What are clinical applications for barbiturates (thiopental)?
Non-ionized drug
→More lipid soluble
→Favors acidosis
Ionized drug
→Less lipid soluble
→Favors alkalosis
Previous Uses
→Premedication?
→Treat grand mal seizures
→Uncooperative/young patients
→Increased ICP, cerebral protection, and induction.
___ isomer is much more potent than ___ but barbiturates are marketed only as _________ _________.
S(-), R(+), Racemic mixture
What are examples of Oxybarbiturates?
Methohexital (ECT)
Phenobarbital
Pentobarbital
What are examples of Thiobarbiturates?
Thiopental
Thiamylal
What is the dosing for Thiopental?
4 - 5 mg/kg IV
How does thiopental half time compare to methohexital?
Thiopental stays longer in the fat (longer half time)
What is the fat/blood partition coefficient for thiopental?
11
Which patient would need decreased doses of thiopental?
Hypovolemic patients (shock)
Elderly patients (decrease skeletal muscle)
What is a partition coefficient?
Describes the distribution of a given agent at equilibrium between 2 substances at the same temp, pressure, and volume
What is blood-gas coefficient?
Describes the distribution of an anesthetic between blood and gas at the same partial pressure
What does a higher blood-gas coefficient correlate with?
Higher solubility of anesthetic in blood= slowing the rate of induction
____ can be considered a pharmacologically inactive reservoir
Blood
Why is ideal body weight used?
The greater the ratio of fat to body weight= the less the blood volume
Why is it that “the greater the ratio of fat to body weight= the less is the blood volume?
Adipose tissue has decreased blood supply
Methohexital is associated with excitatory phenomena. What does this include?
Myoclonus
Hiccups
What is the dose for methohexital (Brevital)?
1.5 mg/kg IV (IBW)
When would a continuous infusion of methohexital be used?
For postop seizure activity
What is the rectal dose of Brevital?
20-30mg/kg
How would methohexital induce seizures in patients undergoing temporal lobe resection?
It lowers seizure threshold (increases chance of having seizure)
Why is Methohexital preferred over Etomidate?
Methohexital associated with decreased seizure duration 35-45% in ECT
Etomidate can produce seizures that last longer than Methohexital
What are potential CV side effects of barbiturates?
Caution with lack of baroreceptor response→ hypovolemia, CHF, beta blocker
What potentially causes hypotension with barbiturates?
Histamine release→ usually asymptomatic
Thiopental associated with anaphylaxis with previous exposure
What is a common vital sign change in response to 5mg/kg IV Thiopental in normovolemic patient?
Transient decrease (10-20) in SBP
Transient HR Increase (15-20bpm)
What is the graph depicting and what barbiturate is it associated with?
In normovolemic patients→ rapid IVP of thiopental causes decrease in BP but it compensated by increase in HR
How do barbiturates effect ventilation?
Dose dependent depression of vent centers in Medulla and Pontine (makes them less sensitive to CO2)
Slower return to spontaneous ventilation (Slower rate and lower VT)
What happens if a barbiturate gets injected intra-arterial?
Causes immediate intense vasoconstriction and excruciating pain that radiates along artery
Obscure distal arterial pulses, blanching of extremity followed by cyanosis, gangrene and permanent nerve damage
What is the treatment for intra-arterial barbiturate injection?
Inject vasodilators: Lidocaine of Papaverine
Need to sustain adequate blood flow
What monitoring is required when using barbiturates?
Somatosensory Evoked Potential (SSEP)
Why is a continue infusion of barbiturates not the best idea long term?
Causes enzyme induction around 2-7 days of infusion
Accelerated metabolism of Anticoags, Phenytoin, TCAs, Dig, steroids, Vit K, bile salts
What side effect of barbiturates may require infusion of crystalloids?
Can cause modest transient decreases in renal blood flow and GFR
10-30mL/kg crystalloids
What class of drug is propofol?
Gamma aminobutyric acid (GABA) agonist
What is the induction dose for Propfol?
1.5-2.5mg/kg IV
What is the conscious sedation dose for propofol?
25-100mcg/kg/min
What is the maintenance dose for propofol?
100-300mcg/kg/min
How fast is unconsciousness achieved with rapid injection of propofol?
unconscious within 30 seconds
What is the lipid component of Propofol? What is the emulsifier and stabilizer?
Lipid component: 10% soybean oil
Emulsifier: 2.25% Glycerol
Stabilizer/emulsifier: 1.2% purified egg phosphatide (lecithin)
What are disadvantages of propofol?
Support bacterial growth: 6hrs to use IV
Causes increased plasma triglyceride concentrations (in prolonged IV infusions).
Pain on injection from soybean oil
Dont give propofol if patient has a ______ allergy
Egg Yolk
What is the purpose of the glycerol in propofol?
Makes the propofol closer to isotonic level of the blood to try to decrease pain with injection
What are other form of propofol and their “benefits”?
Ampofol
→Low-lipid emulsion with no preservative.
→Higher incidence of pain on injection.
Aquavan
→Pro-drug that lessens pain on injection.
→By-product : unpleasant dysesthia (burning sensation genital area esp with females)
→Slower onset, larger Vd, and higher potency.
What types of propofol derivative is still in clinical trials and claims to not cause pain on injection?
Nonlipid with cyclodextrins (probably still causes pain based off study)
What is Propofol MOA?
A relatively selective modulator of gamma-aminobutyric acid (GABA) Type A receptors
Transmembrane CHLORIDE conductance increases
-hyperpolarization of the postsynaptic cell membrane and functional inhibition of the postsynaptic neuron
Potentiate activity at glycine receptors
-partially contributes to hypnosis effect
Primary inhibitory neurotransmitter in the brain:
GABA
Does propofol cause spinal cord depression?
No–would take a long time to reach spinal cord
How is propofol metabolized and cleared?
Plasma→pulm/lung uptake (1st pass)→tissue uptake→Hepatic metabolism (CYP450)
Excreted by kidneys
Does propofol produce metabolites?
Water soluble sulfate and glucuronic acid metabolites
What is responsible for most of the 1st pass uptake of propofol?
Pulmonary first pass metabolism (hits lungs before liver)
What is the E1/2 time for propofol?
0.5-1.5 hours
What is the context-sensitive 1/2 time for propofol?
40 minutes (8 hour infusions)
Which CYP enzyme is responsible for individual variability of propofol hydroxylation by the liver?
CYP2B6
Major metabolic pathway for propofol
What is the Vd for propofol, etomidate, and ketamine?
Prop: 3.5-4.5 L/kg
Etomidate: 2.2-4.5 L/kg
Ketamine: 2.5-3.5 L/kg
Compare E1/2 time, Vd, Clearance, SBP effect, and HR effects of Propofol, Etomidate, and Ketamine:
Is there concern when giving propofol to liver, renal, or pregnant patients?
Not really an issue–potential ion trapping with pregnancy
What is the induction agent of choice/
Propofol
What is used for continuous IV infusion in TIVA?
Propofol with other anesthetic drugs
What is the pediatric dose of propofol?
2.5-3.5mg/kg IV
Kids require higher doses–(larger central distribution volume and clearance rate d/t increased HR)
How would you adjust induction dose of propofol for elderly patients?
Decrease dose by 25-50%
What plasma propofol levels correlate with unconsciousness on induction vs awakening?
Unconsciousness: 2-6mcg/mL
Awakening: 1-1.5mcg/mL
What is the MOA of propofol for anti-emetic effects?
Depresses subcortical pathways and has a direct depressant effect on vomiting center
What is the sub-hypnotic dose for propofol?
10-15mg IV followed by 10mcg/kg/min
What are other benefits of Propofol?
Anti-pruritic: 10mg IV
Anti-convulsant: 1mg/kg IV
Bronchodilator
Can propofol trigger Malignant hyperthermia?
No
Potent antioxidant
What are triggers for malignant hyperthermia?
Volatile anesthetics, Caffeine, succinylcholine
NO audible wheezing associated with propofol induction compared to induction with thiopental/etomidate (solid squares)
Propofol CNS side effects:
Decreases CMRO2 and CBF and ICP
Autoregulation of CBF and paCO2 maintained
Why is propofol a good drug for neuro cases?
Decreases ICP, No SSEP suppression, does not produce seizures
What can happen in regards to movement with propofol induction?
Excitatory movement on induction:N Myoclonus (involuntary skeletal muscle movement)
Anesthetic-induced burst suppression EEG requires __________ mediated excitatory synaptic transmission
Glutamate
Delta: deep sleep—what we want for surgical anesthesia
Theta: sleep
Alpha: awake
Beta: concentrating (“studying”)
Gamma: “testing”
What are CV side effects of propofol?
Decreases SBP/HR
inhibition of SNS (vascular smooth muscle relaxation)→decrease SVR, decreases intracellular calcium→ profound bradycardia (reduced vagal tone/depress baroreceptors)
exaggerated in hypovolemia and elderly
How does thiopental compare to propofol in regards to reduced SVR?
Propofol (solid blue) decreases SVR more than thiopental (open red)
What is the black box warning for propofol in peds? What is a big adverse effect of propofol in healthy adults?
Profound bradycardia: give glyco before prop
Profound bradycardia and asystole in health adults
What are pulmonary side effects of propofol?
Dose dependent resp depression
synergistic with opioids
Intact hypoxic pulm vasoconstriction response (vital functions preserved)
Can depressed ventilation from propofol be counter acted?
Yes, by painful surgical stimulation
What are hepatic/renal side effects of propofol?
Prolonged infusion associated with:
→hepatocellular injury
→propofol infusion syndrome (lactic acidosis)
→no renal function alteration
What is the green urine associated with prolonged propofol infusion from? What about cloudy urine?
Phenols–green urine
Uric acid crystallization–cloudy urine
What are effects of propofol on IOP, Coags, etc?
What causes propofol infusion syndrome?
High dose infusions (>75mcg/kg/min) for longer than 24hours
What are S/S of propofol infusion syndrome?
Severe refractory and fatal bradycardia in kids
Lactic acidosis, brady-dysrhythmias, rhabdomylosis
How is propofol infusion syndrome diagnosed? Is it reversible?
ABG, serum lactate
Reversible in the early stage→leads to cardiogenic shock if not caught (ECMO)
Why does Methohexital have a lower lipid solubility then thiopental if more of methohexital is non-ionized?
Oxybarbiturates (Methohexital) have O2 at the second position. Replacement of the O2 with a sulfur atom results in the corresponding Thiobarbiturates (thiopental) which are much more lipid soluble and have greater hypnotic potency
**Structure matters just as much as percent ionization
