Apex Unit 4 Flashcards
Define volume of distribution, and recite the equation.
The volume of distribution (Vd) describes the relationship between a drug’s plasma concentration following a specific dose. It is a theoretical measure of how a drug distributes throughout the body.
Vd assumes two things:
The drug distributes instantaneously (full equilibration occurs at t = 0).
The drug is not subjected to biotransformation or elimination before it fully distributes.
What are the implications when a drug’s Vd exceeds TBW? What if Vd is less than TBW?
If Vd > TBW, the drug is assumed to be lipophilic:
It distributes into TBW + fat.
It will require a higher dose to achieve a given plasma concentration.
Examples: propofol, fentanyl
If Vd < TBW, the drug is assumed to be hydrophilic:
It distributes into some or all of the body water, but it does not distribute into fat.
It will require a lower dose to achieve a given plasma concentration.
Examples: NMBs (ECF), albumin (plasma)
How do you calculate the loading dose for an IV medication?
How about a PO medication?
For an IV drug, the bioavailability is always 1. This is because all of the drug enters the bloodstream.
A drug administered by any other route may not be absorbed completely and/or it may be subjected to first pass metabolism in the liver. These conditions reduce bioavailability and explain why the dose that achieves a giv
What is clearance? What factors increase/decrease it?
Clearance is the volume of plasma that is cleared of drug per unit time.
What is steady state?
Steady state occurs when the amount of drug entering the body is equivalent to the amount of drug being eliminated from the body – there is a stable plasma concentration. Each of the compartments has equilibrated, although the total amount of drug may be different in different compartments.
(SS) Rate of Administration = Rate of Elimination
Steady state is achieved after 5 half-times.
Compare and contrast the alpha- and beta distribution phases on the plasma concentration curve.
The plasma concentration curve graphically depicts the biphasic decrease of a drug’s plasma concentration following a rapid IV bolus.
Alpha distribution phase:
Describes drug distribution from the plasma to the tissues.
Beta distribution phase:
Begins as plasma concentration falls below tissue concentration.
The concentration gradient reverses, which causes the drug to re-enter the plasma.
The beta phase describes drug elimination from the plasma by the clearing organs.
You have administered 30 mg of esmolol to a patient after a sudden (and profound) elevation in heart rate. After three half-lives, what percentage of your initial dose remains in the patient’s bloodstream?
12.5% of the drug remains in the patient’s bloodstream.
The half-time is the amount of time required for the drug concentration to decrease by 50%. You must know this chart!
What is context sensitive half-time?
The problem with half-times is that they do NOT consider time.
The context sensitive half-time solves this problem. It is the time required for the plasma concentration to decline by 50% after discontinuing the drug.
Discuss the context sensitive half-times of fentanyl, alfentanil, sufentanil, and remifentanil. Which has the longest? Which has the shortest? Why?
The context-sensitive half-time for a fentanyl infusion increases as a function of how long it was infused. A longer infusion had more time to fill up the peripheral compartments, therefore more fentanyl has to be eliminated and it will have a longer elimination half-time. This is also true for alfentanil and sufentanil to lesser degrees.
Remifentanil is an exception. Even though it is highly lipophilic, it is quickly metabolized by plasma esterases and has a similar context-sensitive half-time regardless of how long it is infused.
What is the difference between a strong and weak acid or base?
what is the equation?
The difference is the degree of ionization:
If you put a strong acid or a strong base in water, it will ionize completely.
If you put a weak acid or a weak base in water, a fraction of it will be ionized and the remaining fraction will be unionized.
What is ionization? What 2 factors determine how much a molecule will ionize?
Ionization describes the process where a molecule gains a positive or negative charge.
The amount of ionization is dependent on two things:
The pH of the solution
The pKa of the drug
Finish this sentence: When pKa and pH are the same, _______________________________.
50% of the drug will be ionized and 50% will be unionized.
How does ionization affect solubility, pharmacologic effect, hepatic biotransformation, renal elimination, and diffusion across lipid bilayers?
What happens when you put an acid in a basic solution?
How about an acidic solution?
Remember that “like dissolves like”
An Acid in a Basic Solution:
An acidic drug will be highly ionized in a basic pH.
The acidic drug wants to donate protons and the basic solution wants to accept protons.
The acidic drug happily donates its protons and will become ionized.
An Acid in an Acidic Solution:
An acidic drug will be highly unionized in an acidic pH.
The acidic drug wants to donate protons and the acidic solution wants to do the same.
Since there are no proton acceptors, the acidic drug retains its proton and will remain unionized.
Can you tell if a drug is an acid or a base by looking at its name? If yes, how?
Most drugs are weak acids or weak bases. They are usually prepared as a salt that dissociates in solution.
A weak acid is paired with a positive ion such as sodium, calcium, or magnesium.
Example: Sodium thiopental
A weak base is paired with a negative ion such as chloride or sulfate.
Example: Lidocaine hydrochloride, morphine sulfate
Name the 3 key plasma proteins. Does each bind acidic drugs, basic drugs, or both?
Albumin primarily binds to acidic drugs, however it also binds to some neutral and basic drugs.
α1-acid glycoprotein binds to basic drugs.
Beta-globulin binds to basic drugs.
What conditions reduce albumin concentration?
Liver disease
Renal disease
Old age
Malnutrition
Pregnancy
What conditions affect α1-acid glycoprotein concentration?
Increased α1-acid glycoprotein concentration:
Surgical stress
Myocardial infarction
Chronic pain
Rheumatoid arthritis
Advanced age
Decreased α1-acid glycoprotein concentration:
Neonates
Pregnancy
How do changes in plasma protein binding affect plasma drug concentration?
Decreased PP binding → Increased Cp
Increased PP binding → Decreased Cp
How do you calculate changes in plasma protein binding?
[Free drug] + [Unbound protein binding sites] ↔ [Bound drug]
If a drug is 98% bound and the bound fraction is reduced to 96%, the unbound or free fraction has increased by 100%! Said another way, if the free fraction is 2% and it increases to 4%, then the free fraction has increased by 100%.
***You must calculate the percent change to complete this calculation***
A new anesthetic drug is cleared from the body at a rate proportional to its plasma concentration. What kinetic model best describes the elimination of this drug?
First-order kinetics: A constant fraction of drug is eliminated per unit time.
Most drugs follow this model.
Alcohol is cleared from the body via zero-order kinetics. How will this drug’s rate of elimination change as plasma drug concentration changes?
Under zero-order kinetics, a constant amount of drug is eliminated per unit time. Said another way, the rate of elimination is independent of plasma drug concentration.
Other examples: aspirin, phenytoin, warfarin, heparin, and theophylline
What is the function of a phase 1 reaction? List 3 examples.
Phase 1 reactions result in small molecular changes that increase the polarity (water solubility) of a molecule to prepare it for a phase 2 reaction – it creates a location on the molecule that will allow the phase 2 reaction to take place. Most phase I biotransformations are carried out by the P450 system.
There are 3 phase I reactions that you should understand:
Oxidation – adds an oxygen molecule to a compound
Reduction – adds electrons to a compound
Hydrolysis – adds water to a compound to split it apart (usually an ester)
What is the function of a phase 2 reaction? List 5 common substrates.
The phase 2 reaction conjugates (adds on) an endogenous, highly polar, water soluble substrate to the molecule. This results in a water soluble, biologically inactive molecule ready for excretion.
Common substrates for conjugation reactions include: glucuronic acid, glycine, acetic acid, sulfuric acid, or a methyl group.
Some drugs do not require preparation by phase I reactions and may proceed directly to phase II reactions.
Discuss enterohepatic circulation, and list 1 drug example.
Enterohepatic circulation - Some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation.
Example: Diazepam
What is the extraction ratio?
The extraction ratio is a measure of how much drug is delivered to a clearing organ vs. how much drug is removed by that organ.
ER of 1.0 means that 100% of the drug delivered to the clearing organ is removed.
ER of 0.5 means that 50% of the drug delivered to the clearing organ is removed.
Regarding hepatic clearance, what is flow limited elimination?
Flow Limited Elimination (ER > 0.7)
For a drug with a high hepatic extraction ratio (> 0.7), clearance is dependent on liver blood flow.
Hepatic blood flow greatly exceeds enzymatic activity, so alterations in hepatic enzyme activity has little effect.
↑ liver blood flow → ↑ clearance
↓ liver blood flow → ↓ clearance
Regarding hepatic clearance, what is capacity limited elimination?
Capacity Limited Elimination (ER < 0.3)
For a drug with a low hepatic extraction ratio (< 0.3), clearance is dependent on the ability of the liver to extract drug from the blood. Changes in hepatic enzyme activity or protein binding have a profound impact on clearance of these drugs.
Changes in the liver’s intrinsic ability to remove drug from the blood is influenced by the amount of enzyme present.
Enzyme induction → ↑ clearance
Enzyme inhibition → ↓ clearance
Theophylline has a low hepatic extraction ratio. Which will have a greater effect on its metabolism: prolonged hypotension or CYP inhibition?
CYP inhibition.
Because theophylline has a low hepatic ratio, prolonged hypotension will not impact its rate of metabolism to the same degree that CYP inhibition will.
What’s the difference between a hepatic enzyme inducer and enzyme inhibitor? List examples of each.
The P450 system is the most important mechanism of drug biotransformation in the body. In the liver, these enzymes reside in the smooth endoplasmic reticulum.
A unique feature of the P450 system is that exogenous chemicals can influence the expression of these enzymes. This can be a significant source of drug interactions.
List 2 drug classes and 7 drugs that are metabolized by pseudocholinesterase.
Some neuromuscular blockers:
Succinylcholine (depolarizer)
Mivacurium (nondepolarizer)
Ester-type local anesthetics:
Chloroprocaine
Tetracaine
Procaine
Benzocaine
Cocaine (also metabolized by the liver)
List 6 drugs that are metabolized by non-specific plasma esterases.
Esmolol
Remifentanil
Aspirin
Clevidipine
Atracurium (and Hofmann elimination)
Etomidate (and hepatic)
List 1 drug that is biotransformed by alkaline phosphatase hydrolysis
Fospropofol (propofol prodrug under the trade name Lusedra)
Define pharmacokinetics, pharmacobiophysics, and pharmacodynamics.
How do they relate to each other?
Pharmacokinetics can be thought of as “what the body does to the drug.” It explains the relationship between the dose that you administer and the drug’s plasma concentration over time. This relationship is affected by absorption, distribution, metabolism, and elimination.
Pharmacobiophysics considers the drug’s concentration in the plasma and the effect site (biophase).
Pharmacodynamics can be thought of as “what the drug does to the body.” It explains the relationship between the effect site concentration and the clinical effect.
What is potency, and how is it measured?
Potency is the dose required to achieve a given clinical effect (x-axis of the dose response curve).
The ED50 and ED90 are measures of potency. They represent the dose required to achieve a given effect in 50% and 90% of the population respectively.
How is potency measured on the dose-response curve?
Drug A is more potent than Drug B.
Drug A: The curve shifts left with → increased affinity for receptor → higher potency → lower dose required
Drug B: The curve shifts right with → decreased affinity for receptor → lower potency → higher dose required
What is efficacy, and how is it measured on the dose-response curve?
Efficacy is a measure of the intrinsic ability of a drug to produce a clinical effect.
The height of the plateau on the y-axis represents efficacy.
Higher plateau = greater efficacy
Lower plateau = lower efficacy
Once the plateau phase is reached, additional drug does NOT produce additional effect. Additional drug will only increase the risk of toxicity.
Go back to the last question, and notice that drug A and drug B share the same efficacy. This means that drug A and drug B can achieve the same clinical effect, however you’ll need to give a larger dose of drug B to accomplish this.
What does the slope of the dose-response curve tell you?
The slope tells us how many of the receptors must be occupied to elicit a clinical effect.
Steeper slope = Small increase in dose can have a profound clinical effect
Flatter slope = Higher doses are required to increase the clinical effect
What are the differences between a full agonist, partial agonist, antagonist, and inverse agonist?
Full agonist: Binds to a receptor and turns on a specific cellular response.
Partial agonist: Binds to a receptor, but it is only capable of partially turning on a cellular response. It is less efficacious than a full agonist.
Antagonist: Occupies the receptor and prevents an agonist from binding to it. It does not tell the cell to do anything. By definition, it does not have efficacy.
Inverse Agonist: Binds to the receptor and causes an opposite effect to that of a full agonist. It has negative efficacy.
What is competitive antagonism? Give an example.
Competitive Antagonism
Competitive antagonism is reversible.
Increasing the concentration of the agonist can overcome competitive antagonism.
Examples: atropine, vecuronium, rocuronium
What is noncompetitive antagonism? Give an example.
Noncompetitive Antagonism
Noncompetitive antagonism is not reversible. The drug binds to a receptor (usually through covalent bonds) and its effect cannot be overcome by increasing the concentration of agonist.
The effect of a noncompetitive agonist can only be reversed by producing new receptors. This explains why these drugs have long durations of action.
Examples: aspirin and phenoxybenzamine
Define ED50.
Effective dose 50 is the dose that produces the expected clinical response in 50% of the population. It is a measure of potency.
Define LD50.
Lethal dose 50 is the dose that will produce death in 50% of the population.
Define therapeutic index.
Therapeutic index helps us determine the safety margin for a desired clinical effect.
Therapeutic Index = Lethal Dose 50 / Effective Dose 50
A drug with a narrow TI has a narrow margin of safety.
A drug with a wide TI has a wide margin of safety.
What is chirality?
Chirality is a division of stereochemistry. It deals with molecules that have a center of three-dimensional asymmetry. In biologic systems, this type of asymmetry generally stems from the tetrahedral bonding of carbon – carbon binds to 4 different atoms.
A molecule with 1 chiral carbon will exist as 2 enantiomers. The more chiral carbons in a molecule, the more enantiomers that are created.
What is an enantiomer?
What is the clinical relevance?
Enantiomers are chiral molecules that are non-superimposable mirror images of one another.
Different enantiomers can produce different clinical effects. For example, the side effect profile of one enantiomer of a drug can be different from another enantiomer of the same drug.
What is a racemic mixture? List some commonly used examples.
A racemic mixture contains 2 enantiomers in equal amounts.
About one third of the drugs we administer are enantiomers, and just about all of these are prepared as racemic mixtures. Common examples include: bupivacaine, ketamine, isoflurane, and desflurane (not sevo).
What is the mechanism of action of propofol?
Direct GABA-A agonist → ↑ Cl- conductance → neuronal hyperpolarization
What is the dose, onset, duration, and clearance mechanism for propofol?
Dose:
Induction: 1.5 - 2.5 mg/kg IV
Infusion: 25 - 200 mcg/kg/min
Onset: 30 - 60 seconds
Duration: 5 - 10 minutes
Clearance: Liver (P450 enzymes) + extrahepatic metabolism (lungs)
What are the cardiovascular and respiratory effects of propofol?
Cardiovascular effects:
Decreased BP (due to ↓SNS tone and vasodilation)
Decreased SVR
Decreased venous tone → decreased preload
Decreased myocardial contractility
Respiratory effects:
Shifts CO2 response curve down and to the right (less sensitive to CO2) → respiratory depression and/or apnea
Inhibits hypoxic ventilatory drive
What are the CNS effects of propofol?
CNS effects:
↓ Cerebral oxygen consumption (CMRO2)
↓ Cerebral blood flow
↓ Intracranial pressure
↓ Intraocular pressure
No analgesia
Anticonvulsant properties
What is the formulation of propofol? Is there a patient population where this is a problem?
Propofol is prepared as a 1% solution in an emulsion of egg lecithin, soybean oil, and glycerol.
Despite concerns that propofol might precipitate anaphylaxis in patients allergic to egg, soy, and/or peanuts, there is a gross lack of evidence to justify these fears.
Most people with egg allergy are allergic to the albumin in egg whites. Egg lecithin is derived from the yolk. There is no good evidence to support cross-sensitivity in egg allergic patients, and propofol is probably safe to administer to patients with egg allergies.
There is no cross sensitivity between propofol and soy or peanuts.
What is propofol infusion syndrome?
Propofol contains long chain triglycerides, and an increased LCT load impairs oxidative phosphorylation and fatty acid metabolism. This starves cells of oxygen, particularly in cardiac and skeletal muscle. Propofol infusion syndrome is associated with a high mortality rate.
What are the risk factors for propofol infusion syndrome?
Risk factors:
Propofol dose > 4 mg/kg/hr (67 mcg/kg/min)
Propofol infusion duration > 48 hours
Children > adults
Inadequate oxygen delivery
Sepsis
Significant cerebral injury
What is the clinical presentation of propofol infusion syndrome?
Clinical presentation includes acute refractory bradycardia → asystole + at least one of the following:
Metabolic acidosis (base deficit > 10 mmol/L)
Rhabdomyolysis
Enlarged or fatty liver
Renal failure
Hyperlipidemia
Lipemia (cloudy plasma or blood) may be an early sign
When must a propofol syringe be discarded? How about an infusion?
Propofol supports bacterial and fungal growth, therefore strict attention to asepsis must be observed while withdrawing the drug from the vial. Additionally, the vial and rubber stopper must be cleansed with 70% isopropyl alcohol before removing the drug.
Syringe (drug removed from vial) = must be discarded within 6 hours
Infusion (drug remains in vial after rubber stopper is violated) = must be discarded within 12 hours (this includes the tubing)
What preservatives are used in brand and generic propofol? What patient populations are at risk?
Diprivan (branded propofol), contains EDTA (disodium ethylenediamine tetraacetic acid) as a preservative. It’s not a problem for any specific patient population.
Generic propofol formulations contain different preservatives, and these can cause unique problems of their own.
Metabisulfite can precipitate bronchospasm in asthmatic patients.
Benzyl alcohol should be avoided in infants. There are a few case reports of toxicity and death attributed to the benzyl alcohol preservative when used in other medications.
How can propofol injection pain be minimized?
Propofol injection pain can be minimized or eliminated by:
Injecting into a larger and more proximal vein
Lidocaine (before propofol injection or mixed with propofol)
Giving an opioid prior to the propofol
Discuss the antipruritic effects of propofol.
Propofol (10 mg IV) can reduce itching caused by spinal opioids and cholestasis.
Discuss the antipruritic and antiemetic effects of propofol.
Propofol (10 - 20 mg IV) can be used to treat PONV. An infusion of 10 mcg/kg/min can also be used.
How is fospropofol converted to its active form?
Fospropofol is a prodrug, and propofol is the active metabolite. Alkaline phosphatase converts fospropofol to propofol.
This mechanism of action explains why it has a slower onset (5 - 13 min) and longer duration (15 - 45 min).
What is the mechanism of action for ketamine?
Ketamine is an NMDA receptor antagonist (antagonizes glutamate)
Secondary receptor targets: opioid, MAO, serotonin, NE, muscarinic, Na+ channels
Ketamine dissociates the thalamus (sensory) from the limbic system (awareness)
What are the potential routes of administration for ketamine? Include the doses for each.
IV:
Induction = 1 - 2 mg/kg
Analgesia = 0.1 - 0.5 mg/kg
IM: 4 - 8 mg/kg
PO: 10 mg/kg
What is the onset, duration, and clearance mechanism for ketamine?
Onset:
IV = 30 - 60 sec
IM = 2 - 4 min
PO = variable
Duration: 10 - 20 min (may require 60 - 90 min to return to full orientation)
Clearance: Liver (P450 enzymes)
It produces an active metabolite - norketamine (1/3 - 1/5 the potency of ketamine)
Chronic ketamine use induces liver enzymes (ex: burn patients)
What are the cardiovascular effects of ketamine?
Cardiovascular effects:
↑ SNS tone (useful if the patient is hemodynamically unstable, but harmful if severe CAD)
↑ Cardiac output
↑ Heart rate
↑ Systemic vascular resistance
↑ Pulmonary vascular resistance (caution if severe RV failure)
Subhypnotic doses (< 0.5 mg/kg) usually don’t activate the SNS
It’s important to understand that ketamine is actually a myocardial depressant. The cardiovascular effects discussed above require an intact SNS. The myocardial depressant effects will be unmasked in patients with depleted catecholamine stores (sepsis) or sympathectomy.
What are the respiratory effects of ketamine?
Respiratory effects:
Bronchodilation (great choice if the patient is actively wheezing)
Upper airway muscle tone and airway reflexes remain intact
Maintains respiratory drive, although a brief period of apnea may occur following induction
Does not significantly shift the CO2 response curve
↑ Oral and pulmonary secretions → ↑ risk of laryngospasm (glycopyrrolate helps reduce secretions)
What are the CNS effects of ketamine?
CNS effects:
↑ Cerebral oxygen consumption (CMRO2)
↑ Cerebral blood flow
↑ Intracranial pressure
↑ Intraocular pressure
↑ EEG activity (caution if hx of seizures)
Nystagmus (caution during ocular surgery that requires a still eye)
Emergence delirium
Discuss ketamine and emergence delirium (presentation, treatment, risk factors).
Emergence delirium:
Presents as nightmares and hallucinations (risk persists for up to 24 hours)
Benzodiazepines are the most effective way to prevent emergence delirium (midazolam is better than diazepam)
Risk factors: age > 15 years, female gender, ketamine dose > 2 mg/kg, hx of personality disorder
Discuss the analgesic properties of ketamine.
Ketamine:
Provides good analgesia & opioid-sparing effect (the only induction agent that does this).
Relieves somatic pain > visceral pain.
Blocks central sensitization and wind-up in the dorsal horn of the spinal cord.
Prevents opioid induced hyperalgesia (after remifentanil infusion).
Is good for burn patients (frequent dressing changes) and those with pre-existing chronic pain syndromes.
What is the dose, onset, duration, and clearance mechanism for etomidate?
Dose: 0.2 - 0.4 mg/kg IV
Onset: 30 - 60 seconds
Duration: 5 - 15 min
Clearance: Hepatic P450 enzymes + plasma esterases
What are the cardiovascular and respiratory effects of etomidate?
Cardiovascular effects:
Etomidate’s key benefit is hemodynamic stability (minimal change in HR, SV, or CO).
SVR is decreased, which accounts for a small reduction in BP.
It does not block the SNS response to laryngoscopy. An opioid or esmolol will help.
Respiratory effects:
Mild respiratory depression (less than propofol and barbiturates)
What are the CNS effects of etomidate?
CNS effects:
↓ Cerebral oxygen consumption (CMRO2)
↓ Cerebral blood flow (cerebral vasoconstriction)
↓ Intracranial pressure
Cerebral perfusion pressure remains stable
No analgesia
What is the relationship between etomidate and myoclonus?
Myoclonus is described as involuntary skeletal muscle contractions, dystonia, or tremor.
Although the exact mechanism of myoclonus is unclear, it is likely due to an imbalance between excitatory and inhibitory pathways in the thalamocortical tract. It is NOT a seizure.
What is the relationship between etomidate and seizure activity?
If the patient does not have a history of seizures, then etomidate does not increase the risk of seizures.
If the patient has a history of seizures, then etomidate can increase epileptiform (seizure like) activity and possibly increase the risk of seizures. This property can make it useful for mapping seizure foci.
What is the relationship between adrenocortical suppression and etomidate?
Cortisol and aldosterone synthesis are dependent on the enzyme 11-beta-hydroxylase (located in the adrenal medulla). Some texts also add 17-alpha-hydroxylase.
Etomidate is a known inhibitor of 11-beta-hydroxylase and 17-alpha-hydroxylase.
A single dose of etomidate suppresses adrenocortical function for 5-8 hours (some books say up to 24 hrs).
For this reason, etomidate should be avoided in patients reliant on the intrinsic stress response (sepsis or acute adrenal failure). These patients need all of the cortisol they can muster.
Mortality may be increased by etomidate, particularly in patients with sepsis.
Which induction agent is most likely to cause PONV?
PONV is more common with etomidate than with any other induction agent (incidence may be as high as 30-40%).
What are the 2 sub-classes of barbiturates? List examples of each.
Barbiturates are derived from barbituric acid. Substitutions on the ring can modify the PK/PD profile for each drug.
Thiobarbiturates:
There is a sulfur molecule in the second position (increases lipid solubility and potency)
Examples: thiopental, thiamylal (notice the T’s)
Oxybarbiturates:
There is an oxygen molecule in the second position
Example: methohexital, pentobarbital (notice the O’s)
What is the mechanism of action for thiopental?
GABA-A agonist → Depresses the reticular activating system in the brainstem
Low/normal dose: Increases the affinity of GABA for its binding site
High dose: Directly stimulates the GABA-A receptor
What is the dose, onset, duration, and clearance mechanism for thiopental?
Dose:
Adult = 2.5 - 5 mg/kg
Children = 5 - 6 mg/kg
Onset: 30 - 60 seconds
Duration: 5 - 10 minutes
Clearance: Liver (P450 enzymes)
Awakening is determined by redistribution (not metabolism)
Repeated doses → tissue accumulation → prolonged wake up time + hangover effect
What are the cardiovascular and respiratory effects of thiopental?
Cardiovascular effects:
Hypotension is primarily the result of venodilation and decreased preload; myocardial depression is a secondary cause.
Thiopental causes non-immunogenic histamine release. This can also contribute to hypotension, however this effect is short-lived.
The baroreceptor reflex is preserved, so a reflex tachycardia helps restore cardiac output.
Compared to propofol, thiopental produces less hypotension.
Respiratory effects:
Respiratory depression (shifts the CO2 response curve to the right).
Histamine release can cause bronchoconstriction (caution with asthma).
What are the CNS effects of thiopental?
CNS effects:
↓ Cerebral oxygen consumption (CMRO2)
↓ Cerebral blood flow (cerebral vasoconstriction)
↓ Intracranial pressure (used in the treatment of intracranial hypertension)
↓ EEG activity (can cause burst suppression and/or isoelectric EEG → neuroprotection)
No analgesia (low dose may increase the perception of pain)
In what circumstances can thiopental be used for neuroprotection?
Focal ischemia: Yes (Examples: carotid endarterectomy, temporary occlusion of cerebral arteries)
Global ischemia: No (Example: cardiac arrest)
Discuss the pathophysiology of acute intermittent porphyria.
Heme is a key component of hemoglobin, myoglobin, and the cytochrome P450 enzymes. Porphyria is caused by a defect in heme synthesis that promotes the accumulation of heme precursors (ALA induction).
Succinyl-CoA + Glycine → ALA synthase → Precursors → Heme
The porphyrias can be classified as acute or cutaneous. Acute intermittent porphyria is the most common (and dangerous) type.
What drugs should be avoided in the patient with acute intermittent porphyria? Why?
Any drug or condition that induces ALA synthase will accelerate the production of heme precursors and therefore must be avoided in the patient with acute intermittent porphyria.
Succinyl-CoA + Glycine → ALA synthase → Precursors → Heme
Drugs to avoid: barbiturates, etomidate, glucocorticoids, and hydralazine
Conditions to avoid: emotional stress, prolonged NPO status
What is the treatment for acute intermittent porphyria?
Treatment for acute intermittent porphyria:
Liberal hydration
Glucose supplementation (reduces ALA synthase activity)
Heme arginate (reduces ALA synthase activity)
Prevention of hypothermia
What is the risk of intra-arterial injection of thiopental? What is the treatment?
Intra-arterial injection → intense vasoconstriction + crystal formation (occludes blood flow) + inflammation → tissue necrosis
Treatment:
Injection of vasodilator: phentolamine or phenoxybenzamine
Sympathectomy: stellate ganglion block or brachial plexus block
What induction agent is the gold standard for electroconvulsive therapy? Why?
Methohexital is the gold-standard for electroconvulsive therapy. It decreases the seizure threshold and produces a better quality seizure.
Induction dose = 1-1.5 mg/kg
What is the mechanism of action for dexmedetomidine?
Alpha-2 agonist → ↓ cAMP → Inhibits the locus coeruleus in the pons (sedation)
What is the dose, onset, duration, and clearance mechanism for dexmedetomidine?
Dose:
Loading = 1 mcg/kg over 10 min
Maintenance infusion = 0.4 - 0.7 mcg/kg/hr
Onset: 10 - 20 min
Duration: 10 - 30 min (after infusion stopped)
Clearance: Liver (P450 enzymes)
What are the cardiovascular effects of dexmedetomidine?
The most common side effects are bradycardia and hypotension.
As an aside, rapid administration of dexmedetomidine can cause hypertension (alpha-2 stimulation in the vasculature → temporary vasoconstriction → HTN). This effect is usually short lived.
Why is dexmedetomidine attractive for procedural sedation?
Dexmedetomidine does not cause respiratory depression, and this makes it attractive for procedural sedation and sedation during difficult airway management.
No change in oxygenation
No change in blood pH
No change in the slope of the CO2 response curve
What are the CNS effects of dexmedetomidine?
Dexmedetomidine is unique, because it produces sedation that resembles natural sleep.
Sedation is the result of decreased SNS tone and decreased level of arousal.
Patients are easily aroused.
It does not provide reliable amnesia.
Other CNS effects:
↓ CBF
No change in CMRO2
No change in ICP
How does dexmedetomidine produce analgesia?
Analgesia is produced by alpha-2 stimulation in the dorsal horn of the spinal cord (↓ substance P and ↓ glutamate release).
Aside from IV, what other routes can dexmedetomidine be administered? What is the dose?
The nasal and buccal routes have a high degree of bioavailability. This makes it useful for preoperative sedation in children (3-4 mcg/kg 1 hour prior to surgery).
Midazolam contains an imidazole ring. How does this affect its solubility?
The imidazole ring can assume the open or closed position depending on the environmental pH.
Acidic pH → imidazole ring opens → ↑ water solubility
Physiologic pH → imidazole ring closes → ↑ lipid solubility
Because midazolam is water soluble inside the vial, it does not require a solvent such as propylene glycol (diazepam and lorazepam require it).
What is the mechanism of action for midazolam?
GABA-A agonist → ↑ frequency of channel opening → neuronal hyperpolarization
Most GABA-A agonists ↑ channel open time, but benzos ↑ open frequency
What are the IV and PO doses for midazolam? Why are they different?
IV sedation: 0.01 - 0.1 mg/kg
IV induction: 0.1 - 0.4 mg/kg
PO sedation in children 0.5 - 1 mg/kg
PO bioavailability = 50% due to significant first pass metabolism
Which induction agents produce an active metabolite?
Always think about active metabolites when a patient has kidney or liver dysfunction or with prolonged administration.
Midazolam produces 1-hydroxymidazolam (0.5 potency parent compound)
Ketamine produces norketamine (0.33 - 0.5 potency parent compound)
Fospropofol produces propofol
Propofol, etomidate, and dexmedetomidine do not produce active metabolites
What are the cardiovascular and respiratory effects of midazolam?
Cardiovascular effects:
Sedation dose: Minimal effects
Induction dose: ↓ BP and ↓ SVR
Respiratory effects:
Sedation dose: Minimal effects
Induction dose: Respiratory depression
Opioids potentiate the respiratory depressant effects, even at doses used for sedation
Patients with COPD are more sensitive to the respiratory depressant effects
What are the CNS effects of midazolam?
CNS effects:
Sedation dose: Minimal effects on CMRO2 and CBF
Induction dose: ↓ CMRO2 and ↓ CBF
Cannot produce isoelectric EEG (propofol and barbiturates can)
Anterograde amnesia (not retrograde)
Anticonvulsant
Anxiolysis
Spinally mediated skeletal muscle relaxation (antispasmodic - useful for the patient with cerebral palsy)
No analgesia
What is the reversal agent for benzodiazepines? How does it work?
Flumazenil is a competitive antagonist of the GABA-A receptor.
It has a very high affinity, but it has a short duration of action (30-60 min).
For this reason, repeat dosing may be necessary to prevent resedation.
The initial dose is 0.2 mg IV and titrated in 0.1 mg increments q1min.
What are the potential side effects of flumazenil?
Unlike post-operative opioid reversal with naloxone (which can cause a profound increase in SNS tone), post-operative benzodiazepine reversal with flumazenil does NOT increase SNS tone, anxiety, or neuroendocrine evidence of stress.
In benzodiazepine dependent patients (chronic use), flumazenil reversal can precipitate signs of withdraw, including seizures.
How can you tell the difference between the chemical structures of the halogenated agents?
All you have to do is count the halogens.
Isoflurane has 5 fluorine atoms + 1 chlorine atom
Desflurane has 6 fluorine atoms
Sevoflurane has 7 fluorine atoms (sevo = 7)
How does fluorination affect the physiochemical characteristics of halogenated anesthetics?
As a general rule, adding fluoride ions tends to:
↓ potency
↑ vapor pressure
↑ resistance to biotransformation
Even though sevoflurane is heavily fluorinated, it’s ~ 3 times as potent as desflurane. This is most likely due to the bulky propyl side chain.
What is vapor pressure, and how is it affected by the ambient temperature?
Vapor pressure is the pressure exerted by a vapor in equilibrium with its liquid or solid phase inside of a closed container.
Vapor pressure is directly proportional to temperature (↑ temperature → ↑ vapor pressure)
How is anesthetic delivery affected by altitude?
When does this matter?
For this to make sense, you need to know that the depth of anesthesia is determined by the partial pressure of anesthetic agent in the brain - NOT the volumes percent.
Partial pressure of a gas = Vol% x Total gas pressure
As atmospheric pressure decreases at higher elevations, the vol% of a gas remains the same, however the partial pressure of the gas decreases. The risk is underdosing the anesthetic agent (remember the PP determines depth of anesthesia).
For Sevo or Iso at elevation, underdosing is not a problem. This is because the conventional variable bypass vaporizer automatically compensates for the change in elevation.
For Des at elevation, underdosing is a problem (unless the vaporizer has been calibrated to the lower atmospheric pressure). This is because the injector design of the Tec 6 vaporizer does not compensate for elevation.
6% Des at sea level results in a delivered partial pressure of 45.6 mmHg (0.06 x 760 mmHg = 45.6 mmHg)
6% Des 1 mi. above sea level results in a delivered partial pressure of 37.2 mmHg (0.06 x 620 mmHg = 37.2 mmHg).
This translates into a 18.4% reduction.
What are the vapor pressures Sevo, Des, Iso, and N2O?
Vapor pressures listed as mmHg:
Sevo = 157
Des = 669
Iso = 238
N2O = 38,770
Notice the VPs of the halogenated agents are less than atmospheric pressure. This explains why they exist as liquids. Conversely, the VP of N2O exceeds atmospheric pressure, so it exists as a gas (unless it’s compressed in a cylinder, of course).
Which inhalation anesthetics are stable in soda lime? What byproducts can each agent produce in soda lime?
Sevo: Not stable / Compound A (happens in functional soda lime - worse if soda lime is desiccated)
Des: Not stable / Carbon monoxide (only a problem if soda lime is desiccated)
Iso: Not stable / Carbon monoxide (only a problem if soda lime is desiccated)
N2O: Stable / None
What is solubility, and how do we measure it?
Solubility is the tendency of a solute to dissolve into a solvent. In the case of inhalation anesthetics, it’s the ability of the anesthetic agent to dissolve into the blood and tissues.
The blood : gas partition coefficient (λ) describes the relative solubility of an inhalation anesthetic in the blood vs. in the alveolar gas when the partial pressures between the 2 compartments are equal.
What is the blood : gas solubility for Sevo, Des, Iso, and N2O?
Blood gas solubilities (part dissolved in blood / part in the alveolus).
Sevo = 0.65
Des = 0.42
Iso = 1.45
N2O = 0.46
How do we establish an anesthetic concentration inside the alveolus?
- Turn the vaporizer on. This creates a concentration gradient that pushes anesthetic agent from the vaporizer towards the alveoli. This is FI.
- Ventilation washes the anesthetic agent into the alveoli. This is FA.
- The buildup of anesthetic partial pressure inside the alveoli is opposed by continuous uptake of agent into the blood. This is uptake.
- The cardiac output distributes the anesthetic agent throughout the body. This is distribution.
What does the FA/FI curve tell us? How does anesthetic solubility affect the FA/FI curve for each agent?
The FA/FI curve allows us predict the speed of induction.
Low solubility → less uptake into the blood → ↑ rate of rise → faster equilibration of FA/FI → faster onset
High solubility → more uptake into the blood → ↓ rate of rise → slower equilibration of FA/FI → slower onset
What factors affect agent delivery to and removal from the alveoli?
Determinants of delivery:
Setting on the vaporizer
Time constant of the delivery system
Anatomic dead space
Alveolar ventilation
Functional residual capacity
Determinants of uptake:
Solubility of anesthetic in the blood (blood : gas partition coefficient)
Cardiac output
Partial pressure gradient between the alveolar gas and the mixed venous blood
What conditions increase FA/FI? Which conditions decrease it?
For FA/FI to increase, there must be greater wash in and/or reduced uptake.
For FA/FI to decrease, there must be a reduced wash in and/or an increased uptake.
In which patient will the onset of sevoflurane be the fastest? Patient A has a heart rate of 55 bpm with a stroke volume of 100 mL/beat. Patient B has a heart rate of 60 bpm and a stroke volume of 85 mL/beat (assume all other factors are equal).
Patient B.
We know that anesthetic uptake is directly proportional to cardiac output. Additionally, a high cardiac output removes more anesthetic agent from the alveoli, so it slows the rate of rise of FA/FI (it slows anesthetic induction).
Patient A has a CO of 5.5 L/min, and patient B has a CO of 5.1 L/min. All other factors being equal, the onset of sevoflurane (rate of anesthetic induction) will be faster in patient B (he has a smaller CO).
What are the 4 tissue groups? How much cardiac output does each receive?
We can divide the body into 4 tissue groups. Each group is defined by how much cardiac output it receives relative to its percentage of body weight.
How are inhalation anesthetics removed from the body? For each agent, what percent is attributed to hepatic metabolism?
Inhaled anesthetics are eliminated from the body in 3 ways:
Elimination from the alveoli (most important)
Hepatic biotransformation
Percutaneous loss (minimal)
You should remember this as “the rule of 2’s – (0.02, 0.2, and 2).” Additionally, you should notice that halogenated agents are in alphabetical order from least to greatest metabolism (D – I – S).
Discuss the FDA recommendations for the minimum fresh gas flow requirement for sevoflurane. What is a MAC hour?
Compound A is a halogenated vinylic ether. While it’s associated with renal tubular necrosis in rats, there’s no supporting evidence that this complication occurs in humans. Even so, the FDA recommends a minimum fresh gas flow of 1 L/min for up to 2 MAC hours and 2 L/min after 2 MAC hours.
What is a MAC hour?
1 MAC hour equals:
1% sevoflurane x 2 hours
2% sevoflurane x 1 hour
4% sevoflurane x 30 minutes
Which volatile agents are metabolized to trifluoroacetic acid? What is a potential consequence of this?
Up to 40% of halothane undergoes hepatic biotransformation, and a high concentration of TFA in the liver is the mechanism for halothane hepatitis.
Although desflurane and isoflurane undergo a much smaller degree of hepatic biotransformation, there remains a very minute possibility that TFA could precipitate an immune mediated hepatic dysfunction, especially in a patient with previous TFA exposure.
What are the theoretical consequences of sevoflurane metabolism?
Sevoflurane is not metabolized to TFA, but its biotransformation does result in the liberation of inorganic fluoride ions.
Because sevoflurane has a relatively higher degree of metabolism, there are theoretical concerns of fluoride induced high output renal failure (there is no solid human evidence for this).
Signs of high output renal failure include: polyuria, hypernatremia, hyperosmolarity, increased plasma creatinine, and inability to concentrate the urine.
Remember: Compound A is produced inside the circuit and F- ions are produced by hepatic metabolism. Both can theoretically cause renal problems.
What is the concentration effect?
The concentration effect describes an increased rate of alveolar uptake as the concentration of a gas is increased. This is a function of 2 mechanisms:
Concentrat’ing’ effect: When nitrous oxide is introduced into the lung, the volume of nitrous oxide going from the alveolus to the pulmonary blood is much higher than the amount of nitrogen moving in the opposite direction. This causes the alveolus to shrink and the reduction in alveolar volume causes a relative increase in FA.
Augmented gas inflow: On the subsequent breath, the concentrating effect causes an increased inflow of tracheal gas containing anesthetic agent to replace the lost alveolar volume. This increases alveolar ventilation and augments FA. Alveolar volume is restored quickly, so this is only a very temporary phenomenon.
When compared to nitrous oxide, desflurane has a lower blood-gas partition coefficient. Why does the FA/Fi ratio for N2O rise faster than desflurane?
The concentration effect explains this phenomenon.
Despite a slightly higher blood/gas partition coefficient, the alveolar partial pressure of N2O rises faster than desflurane. This is because we can safely deliver a much higher inspiratory concentration, and this negates the small difference imposed by the slightly higher blood/gas partition coefficient.
Anesthetic overpressure results in a more profound effect for agents with a (higher/lower) blood solubility?
Higher blood solubility
The concentration effect says that an anesthetic’s onset of action is directly proportional to the concentration of inhalation anesthetic delivered to the alveolus.
When applied to the halogenated anesthetics (not N2O), overpressure will have a more profound effect with agents of higher blood solubility. Said another way, we can offset the effects of a higher blood solubility by increasing the inspired concentration on the vaporizer. It helps us reach FA/FI equilibration faster.
How does N2O affect the uptake of a halogenated anesthetic during induction? \What is this called?
The use of nitrous oxide during anesthetic induction will hasten the onset of a second gas. This is called the second gas effect.
Explain diffusion hypoxia.
Diffusion hypoxia is a risk during emergence.
N2O moves from body towards the lungs → Dilutes alveolar O2 and CO2 → Decreased respiratory drive and hypoxia.
Diffusion hypoxia can be prevented by administering 100% O2 for 3 – 5 minutes after the N2O has been turned off.
Which inhalation anesthetics are most greatly affected by a right-to-left shunt?
In the presence of a right-to-left shunt, the FA/FI of an agent with lower solubility (Des) will be more affected than an agent with higher solubility (Iso).
Which inhalation anesthetics are most greatly affected by a left-to-right shunt?
A left-to-right shunt will not have a meaningful effect on anesthetic uptake or induction time.
Why does N2O accumulate in closed air spaces?
Nitrous oxide is 34x more soluble than nitrogen. This means it will enter a space 34 times faster than nitrogen can exit that space.
N2O blood : gas partition coefficient = 0.46
Nitrogen blood : gas partition coefficient = 0.014
This can be problematic, because N2O can accumulate in closed air spaces (middle ear, bowel, pneumothorax).
How does N2O affect a patient with an ocular gas bubble? When can N2O be used in these patients?
During retinal detachment surgery, a gas bubble is placed over the site of the retinal break. This functions as a “splint” to hold the retina in place while healing occurs. Because nitrous oxide can diffuse into the bubble faster than the other gases in the bubble can diffuse out, nitrous oxide can expand the SF6 bubble, compromise retinal perfusion, and cause permanent blindness.
Discontinue N2O 15 minutes before the SF6 bubble is placed.
Avoid N2O for 7-10 days after the SF6 bubble is placed.
Alternatives to SF6 and When to Avoid N2O:
Air: 5 days
Perfluoropropane: 30 days
Silicone oil: No contraindication to N2O
What is the relationship between nitrous oxide and anesthesia equipment?
Nitrous oxide can increase the volume and pressure in a/an:
Endotracheal tube cuff
LMA cuff
Balloon-tipped pulmonary artery catheter
The most reliable way to check the internal pressure of the endotracheal tube or LMA cuff is to attach a manometer to the pilot balloon. Palpation is grossly inaccurate.
How do we quantify anesthetic potency?
What is this value for each inhalation agent?
Minimum alveolar concentration (MAC) is a measure of potency. You can think of it as the same thing as ED50.
What are MAC-bar and MAC-awake?
MAC-bar is the alveolar concentration required to block the autonomic response following a supramaximal painful stimulus. It is ~ 1.5 MAC.
MAC-awake is the alveolar concentration at which a patient opens his or her eyes. This shows hysteresis in that MAC-awake is ~ 0.4 – 0.5 during induction, but during recovery MAC-awake is as low as 0.15 MAC.
What factors increase MAC?
Drugs:
Chronic alcohol consumption
Acute amphetamine intoxication
Acute cocaine intoxication
MAOIs
Ephedrine
Levodopa
Electrolytes:
Hypernatremia
Age:
Increased in infants 1 – 6 months
Sevo is same for neonates & infants
Body Temperature:
Hyperthermia
Other:
Red hair
What factors decrease MAC?
Drugs:
Acute alcohol intoxication
IV anesthetics
N2O
Opioids (IV & neuraxial)
Alpha-2 agonists
Lithium
Lidocaine
Hydroxyzine
Electrolytes:
Hyponatremia
Age:
Older age (↓ 6% per decade after 40)
Prematurity
Body Temperature:
Hypothermia
Other:
Hypotension (MAP < 50 mmHg)
Hypoxia
Anemia (< 4.3 mL O2/dL blood)
Cardiopulmonary bypass
Metabolic acidosis
Hypo-osmolarity
Pregnancy → Postpartum (24 – 72 hrs)
PaCO2 > 95 mmHg
What factors do not affect MAC?
Electrolytes:
Hyper- or hypokalemia
Hyper- or hypomagnesemia
Other:
Hyper- or hypothyroidism
Gender
PaCO2 15 – 95 mmHg
Hypertension
How do hyper- and hypothyroidism affect MAC? Why?
Hyper- and hypothyroidism do NOT directly affect MAC, however changes in cardiac output associated with these conditions may affect anesthetic uptake and subsequent onset of action.
For example, profoundly hypothyroid patients have a reduced CO leading to decreased uptake into the blood and a faster rate of rise of FA/FI. Because of this, these patients are more susceptible to anesthetic overdose.
What is the Meyer-Overton rule?
The Meyer-Overton rule states that lipid solubility is directly proportional to the potency of an inhaled anesthetic. This theory implies that depth of anesthesia is determined by the number of anesthetic molecules that are dissolved in the brain.
What is the unitary hypothesis?
The unitary hypothesis states that all anesthetics share a similar mechanism of action, although each may work at a different site.
What is the most important site of halogenated anesthetic action in the brain?
In the brain, the most important site of volatile anesthetic action is the GABA-A receptor.
The GABA-A receptor is a ligand gated chloride channel.
Stimulation of the GABA-A receptor increases chloride influx and hyperpolarizes neurons. This impairs neurotransmission.
Volatile anesthetics most likely increase the duration that the chloride channel remains open.
How do halogenated anesthetics produce immobility?
In the spinal cord, volatile anesthetics produce immobility in the ventral horn.
Which cerebral receptors are stimulated by nitrous oxide?
Nitrous oxide produces:
NMDA antagonism
Potassium 2P-channel stimulation
Nitrous oxide does not stimulate the GABA-A receptor.
In which regions of the brain do halogenated anesthetics produce unconsciousness?
Cerebral cortex
Thalamus
Reticular activating system
In which regions of the brain do halogenated anesthetics produce amnesia?
Amygdala
Hippocampus
In which regions of the brain do halogenated anesthetics produce autonomic modulation?
Pons
Medulla
How do halogenated agents reduce blood pressure?
The halogenated anesthetics decrease MAP in a dose dependent fashion. At equivalent doses, there is little difference between agents.
Primary Cause: ↓ intracellular Ca+2 in vascular smooth muscle → systemic vasodilation → ↓ SVR and ↓ venous return
Secondary Cause: ↓ intracellular Ca+2 in the myocyte → myocardial depression → ↓ inotropy
How do halogenated anesthetics affect heart rate?
Halogenated anesthetics directly affect cardiac conduction in a dose dependent fashion. They do this in several ways:
↓ SA node automaticity
↓ Conduction velocity through AV node, His-Purkinje system, and ventricular conduction pathways.
↑ Duration of myocardial repolarization by impairing the outward K+ current (prolongs action potential duration and the QT interval)
Altered baroreceptor function
Why do desflurane and isoflurane sometimes increase heart rate?
Desflurane and isoflurane increase heart rate from baseline by 5 – 10%. This is most likely due to SNS activation from respiratory irritation.
Rapid increases in desflurane, and to a lesser degree, isoflurane cause tachycardia. Pulmonary irritation → SNS activation → ↑ norepinephrine release → beta-1 stimulation
Tachycardia can be minimized with opioids, alpha-2 agonists, or beta-1 antagonists.
What is the relationship between isoflurane and coronary steal?
Isoflurane is the most potent coronary artery dilator.
This gave rise to the fear that isoflurane might contribute to coronary steal syndrome. The underlying principal is that atherosclerotic vessels can’t dilate, while normal vessels can. This would preferentially divert blood away from areas of higher resistance, starving those regions of oxygen.
This is more of a textbook thing than a real world problem.
How does nitrous oxide (by itself) affect hemodynamics?
N2O activates the SNS. This increases MAP as a function of increased SVR. CVP and right atrial pressure may increase.
N2O is also a myocardial depressant, but the increased SNS stimulation outweighs the physiologic consequences of this.
Myocardial depression is more likely when N2O is used in combination with an opioid.
How do halogenated anesthetics contribute to hypercarbia?
Volatile anesthetics cause a dose dependent depression of the central chemoreceptor and the respiratory muscles. This contributes to hypercarbia. Mechanisms include:
Altering the respiratory pattern (↓ Vt and compensatory ↑ RR → ↓ Ve and ↑ Vd)
Impairing the response to carbon dioxide (slope CO2 response curve shifts down and right)
Impairing motor neuron output and muscle tone to upper airway and thoracic muscles
How do halogenated anesthetics affect cerebral metabolic rate?
CMRO2 is a function of:
Electrical activity (60%)
Cellular homeostasis (40%)
Volatile anesthetics reduce CMRO2, but only to the extent that they reduce electrical activity. Once the brain is isoelectric, volatile agents cannot reduce CMRO2 any further.
Isoelectricity on EEG occurs at 1.5 - 2 MAC.
Compare and contrast the effects of halogenated anesthetics and N2O on cerebral blood flow
The brain matches its blood flow with its metabolic requirement.
When metabolic demand increases, the blood vessels dilate (cerebrovascular resistance decreases).
When metabolic demand decreases, the blood vessels constrict (cerebrovascular resistance increases).
Volatile anesthetics uncouple this relationship: CMRO2 decreases and CBF increases. This can increase ICP as well.
Nitrous oxide is different. It increases CMRO2 and cerebral blood flow appropriately.
How do halogenated anesthetics affect evoked potentials? How about N2O?
Desflurane, isoflurane, and sevoflurane produce a dose-dependent effect on evoked potentials. They:
Decrease amplitude (signal is not as strong)
Increase latency (signal is slower to conduct)
The addition of nitrous oxide to a halogenated anesthetic agent can lead to a more profound amplitude reduction. Therefore, N2O should not be used during evoked potential monitoring.
Which type of evoked potential is most sensitive to the effects of volatile anesthetics? Which is the most resistant?
Sensitivity ranking:
Visual evoke potentials are the most sensitive to volatile anesthetics.
Brainstem evoked potentials are the most resistant to volatile anesthetics.
SSEPs and MEPs are somewhere in between.
What is the relationship between N2O and bone marrow depression?
Nitrous oxide inhibits methionine synthase and folate metabolism. This can cause megaloblastic anemia.
