Apex Unit 4 Pharmacology I Flashcards

1
Q

A drug has a volume of distribution of 0.35 L/kg. In a 70-kg patient, what IV loading dose must be administered to achieve a plasma concentration of 8 mg/L?

(Enter your answer as mg and round to the nearest whole number)

A

196 mg

The loading dose is the amount of drug that must be administered to quickly achieve a therapeutic plasma concentration.

Loading dose = (Vd ​ x ​ desired Cp) ​ / ​ Bioavailability

If Vd is 0.35 L/kg and the patient weights 70 kg, the theoretical volume in which this drug will distribute in this patient is 24.5 L. Now we can input this into our equation.

Loading dose ​ = ​ (24.5 L ​ x ​ 8 mg/L) ​ / ​ 1 ​ = ​ 196 mg

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2
Q

Clearance is directly proportional to: ​ (Select 2.)

half-life.
concentration in the central compartment.
extraction ratio.
blood flow to clearing organ.

A

Blood flow to clearing organ
Extraction ratio

Clearance is the volume of plasma that is cleared of drug per unit time.

Cl is directly proportional to blood flow to the clearing organ, extraction ratio, and drug dose.
Cl is inversely proportional to half-life and drug concentration on the central compartment.

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3
Q

Click on the part of the curve that correlates with drug elimination from the plasma.

A

The steepest portion of the curve represents redistribution from the plasma to the tissues. This is called the alpha phase.

The less steep portion of the curve represents elimination from the plasma. This is called the beta phase.

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4
Q

After administering an IV drug that distributes into a 1 compartment model, the patient’s serum contains 6.25 percent of the original dose. How many half-lives have elapsed?

(Enter your answer as a whole number)

A

Four

The elimination half-life (t ½) is the time required for a drug’s plasma concentration to decline by 50 percent.

After four half-lives have elapsed, the patient’s serum will contain 6.25 percent of the original dose.

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5
Q

In which circumstance is a drug more likely to pass through a lipid membrane? ​ (Select 2.))
A weak base where the pH of the solution is < the pKa of the drug
A weak base where the pH of the solution is > the pKa of the drug
A weak acid where the pH of the solution is > the pKa of the drug
A weak acid where the pH of the solution is < the pKa of the drug

A

A weak acid where the pH of the solution is < the pKa of the drug
A weak base where the pH of the solution is > the pKa of the drug

​Ionization describes the process where a molecule gains a positive or negative charge, and this molecular change affects a molecule’s ability to diffuse through lipid membranes.

Remember that like dissolves like, therefore the correct answers are a weak base in a basic solution and a weak acid in an acidic solution.

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6
Q

Which circumstance creates the STRONGEST gradient for passage of local anesthetic from the mother to the fetus?

Maternal acidosis and fetal acidosis
Maternal acidosis and fetal alkalosis
Maternal alkalosis and fetal acidosis
Maternal alkalosis and fetal alkalosis

A

Maternal alkalosis
Fetal acidosis

This question tests your understanding of ion trapping, which happens to be a terrific way to apply what you learned in the last question.

Local anesthetics are weak bases, and the acid-base status of the mother and fetus affects how these drugs transfer across the placenta.

Maternal alkalosis increases the unionized fraction in the maternal circulation; more local anesthetic is available to diffuse across the placenta.

Fetal acidosis increases the ionized fraction inside the fetus. This prevents the local anesthetic from crossing the placenta (back to the mother), thus “trapping” it inside the fetus.

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7
Q

If a drug is usually 98 percent bound by plasma protein and the bound fraction is reduced to 96 percent, the free fraction will increase by: ​

(Enter your answer as a percentage)

A

​100

This question is really a percent change calculation in disguise. The kind of question you probably saw on the GRE. And you thought you could purge all of that from your memory?

We asked about the free fraction, although we gave you values for the bound fraction.

Percent change ​ = ​ [(New value ​ - ​ Old value) ​ / ​ Old value] ​ x ​ 100
Percent change ​ = ​ [(4 ​ - ​ 2) ​ / ​ 2] ​ x ​ 100 ​ = ​ 100%

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8
Q

Which kinetic model describes the process that metabolizes a constant amount of drug per unit time? ​

Zero order
First order
Second order
Third order

A

Zero order

Kinetic models help us predict a drug’s plasma concentration over time.

Zero order kinetics describes a situation where a constant amount of the drug is metabolized per unit time.

First order kinetics describes a situation where a constant fraction of the drug is metabolized per unit time.

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9
Q
Which process is a phase 2 reaction?
Hydrolysis
Reduction
Conjugation
Oxidation
A

Conjugation

Drug metabolism is divided into three phases:
Phase 1 = Modification (oxidation, reduction, hydrolysis)
Phase 2 = Conjugation
Phase 3 = Excretion

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10
Q
Identify the drugs that undergo perfusion-dependent hepatic elimination. ​ (Select 3.)
Remifentanil
Fentanyl
Propofol
Lidocaine
Rocuronium
Diazepam
A

Fentanyl
Propofol
Lidocaine

You’ll need to be able to identify drugs that undergo perfusion-dependent hepatic elimination vs those subject to capacity-dependent hepatic elimination.

​Drugs that undergo perfusion-dependent hepatic elimination include: ​ fentanyl, lidocaine, and propofol.

Drugs that undergo capacity-dependent hepatic elimination include: ​ diazepam and rocuronium.

Remifentanil is metabolized by nonspecific esterases in the plasma (not the liver).

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11
Q
Which drug inhibits codeine metabolism? ​
Fluoxetine
Rifampin
Phenytoin
Diltiazem
A

Fluoxetine

Codeine is biotransformed to its active metabolite (morphine) by CYP 2D6. Therefore, the Cp of its active metabolite is affected by alterations in CYP 2D6 activity.​

Quinidine and selective serotonin reuptake inhibitors (particularly fluoxetine and paroxetine) profoundly inhibit CYP 2D6.

Therefore, codeine, oxycodone, and hydrocodone will not be effectively metabolized to morphine and will fail to provide adequate pain relief. The clinical correlation is that these analgesics are poor choices for patients taking SSRIs or quinidine.

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12
Q

Which statement regarding renal clearance is true?
Acidic urine promotes thiopental excretion.
Organic anion transporters secrete drug into the distal convoluted tubule.
Basic urine enhances morphine reabsorption.
Protein bound drugs are filtered at the glomerulus.

A

Basic urine enhances morphine reabsorption.

This is a complex question that requires a solid understanding of renal physiology, acid/base chemistry, and a bit of pharmacology.

​Morphine is a weak base. As a weak base, the unionized fraction increases in an alkalotic environment. Therefore, basic urine enhances morphine reabsorption.

Thiopental is a weak acid. Acidic urine enhances its reabsorption (not excretion).

Protein bound drugs do not freely pass through the glomerulus – only the free fraction is filtered.
Organic anion transporters are present in the proximal (not distal) convoluted tubule. They actively secrete anions into the urine.

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13
Q
Identify the drugs that are metabolized by nonspecific plasma esterases. ​ (Select 3.)
Remifentanil
Atracurium
Cocaine
Esmolol
Succinylcholine
Fospropofol
A

Esmolol
Remifentanil
Atracurium

Enzymatic drug metabolism in the plasma tends to occur via one of three pathways:

Pseudocholinesterase: ​ succinylcholine, cocaine (+ hepatic)
Nonspecific esterases: ​ esmolol, remifentanil, atracurium (+ Hofmann)
Alkaline phosphatase: ​ fospropofol

For completeness, Hofmann elimination also takes place in the plasma, but is dependent on pH and temperature (not enzymatic function).

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14
Q

Pharmacodynamics is the study of:
plasma concentration and effect site concentration.
drug dose and plasma concentration.
tissue concentration and efficacy.
effect site concentration and clinical effect.

A

Effect site concentration and clinical effect

Pharmacodynamics describes the relationship between the effect site concentration and the clinical effect.​

Pharmacokinetics describes the relationship between drug dose and plasma concentration.

Pharmacobiophasics unites PK and PD by examining the relationship between plasma concentration and effect site concentration.

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15
Q
On the dose response curve, the x-axis correlates with:
percentage of receptors occupied.
individual variability.
efficacy.
potency.
A

Potency

Potency is the dose required to achieve a given clinical effect. It is depicted by the x-axis.

Efficacy is the intrinsic ability of a drug to elicit a given clinical effect. It is depicted by the y-axis.​

The slope tells us how many receptors must be occupied to elicit a clinical effect​

We can compare the dose response curves from multiple patients to learn about the individual variability of each patient.

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16
Q

Click the curve that represents an antagonist.

A

Curve A: ​ An agonist binds to a receptor and turns on a specific cellular response.

Curve B: ​ A partial agonist binds to a receptor, but it is only capable of eliciting a partial cellular response.

Curve C: ​ An antagonist binds to a receptor but does not elicit a clinical response.

Curve D: ​ An inverse agonist binds to a receptor and causes the opposite effect of the agonist.

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17
Q

A new induction agent has a median effective dose of 125 mg and the median lethal dose of 1500 mg. Calculate the therapeutic index for this drug.

(Round your answer to the nearest whole number)

A

12

The therapeutic index is a measure of drug safety.

To calculate TI, you need to divide the LD50 by ED50.
The LD50 was 1500 mg and the ED50 was 125 mg.
TI ​ = ​ 1500 mg / 125 mg ​ = ​ 12

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18
Q

Click on the molecule that is one half of a racemic mixture.

A

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.

A racemic mixture contains 2 enantiomers in equal amounts.

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19
Q

A patient is experiencing a prolonged recovery from midazolam sedation. What is the initial dose of flumazenil?

(Enter your answer as milligrams)

A

0.2 mg

Flumazenil is a competitive antagonist of the GABA-A receptor. It is used to reverse benzodiazepine overdose.

The initial dose is 0.2 mg IV.
It is titrated in 0.1 mg increments until a desired response is achieved.

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20
Q
Propofol infusion syndrome is categorized by the presence of: ​ (Select 2.)
bradycardia.
metabolic acidosis.
hypokalemia.
respiratory failure.
A

Bradycardia
Metabolic acidosis

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 presents with 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

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21
Q
Fospropofol is: ​ (Select 2.)
associated with pain at the injection site.
metabolized by alkaline phosphatase.
a prodrug.
prepared as a lipid emulsion.
A

A prodrug
Metabolized by alkaline phosphatase

Fospropofol (Lusedra) is a prodrug that is metabolized to propofol in the systemic circulation. Alkaline phosphatase is the enzyme that carries out this reaction. Because the drug is activated inside the body, it has a prolonged onset and longer duration of action (it takes time to convert the prodrug to propofol).

Unlike propofol, fospropofol is prepared as an aqueous solution and is not associated with pain at the injection site. Interestingly, fospropofol does cause burning in the genital and anal regions.

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22
Q

Ketamine: ​ (Select 3.)
increases the cerebral metabolic rate of oxygen consumption.
causes emergence delirium.
increases the risk of depression.
relieves somatic pain.
agonizes the N-methyl-D-aspartate receptor.
promotes bronchoconstriction.

A

Relieves somatic pain
Causes emergence delirium
Increases the cerebral metabolic rate of oxygen consumption

Ketamine is an NMDA receptor antagonist (not agonist). Its pharmacologic profile is much different from the other IV induction agents, making it a great topic for boards.

It causes emergence delirium.
It provides good analgesia (somatic pain > visceral pain).
It increases CMRO2.
It promotes bronchodilation (not bronchoconstriction).
It is gaining popularity in the treatment of severe depression (it doesn’t cause it).

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23
Q
Central nervous system effects of etomidate include: ​ (Select 2.)
decreased intracranial pressure.
myoclonus.
cerebral vasodilation.
analgesia.
A

Myoclonus
Decreased intracranial pressure

Central nervous system effects of etomidate include:​
Myoclonus
↓ Cerebral blood flow (cerebral vasoconstriction)
↓ Intracranial pressure

Etomidate does not provide analgesia.

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24
Q
Which anesthetic agent increases mortality in the patient with Addisonian crisis?
Etomidate
Midazolam
Propofol
Dexmedetomidine
A

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 acut

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25
Q

Choose the statements that demonstrate an accurate understanding of thiopental. ​ (Select 2.)

It provides neuroprotection against global ischemia.
There is a sulfur molecule in the second position.
It causes a reflex tachycardia.
Prompt awakening is the result of hepatic metabolism.

A

It causes a reflex tachycardia
There is a sulfur molecule in the second position

Although sodium thiopental isn’t available in the US, its place in anesthetic history makes it fair game on the NCE.

Thiopental is a thiobarbiturate with a sulfur molecule in the second position.

Hypotension is primarily the result of venodilation and decreased preload; myocardial depression is a secondary cause. Because the baroreceptor reflex remains intact, there is a reflex tachycardia. This explains why thiopental tends to cause less hypotension compared to propofol (propofol impairs the baroreceptor reflex).

Although thiopental is metabolized by the hepatic P450 enzymes, rapid awaking following a single IV induction dose is the result of redistribution out of the brain (not metabolism).

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26
Q
Which anesthetic agent produces sedation that MOST closely resembles natural sleep?
Propofol
Dexmedetomidine
Ketamine
Midazolam
A

Dexmedetomidine

Dexmedetomidine is an alpha-2 agonist. Of all of the IV anesthetic agents, it produces sedation that most closely 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.

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27
Q

Rank each benzodiazepine according to its elimination half-life.

​Midazolam ​
Lorazepam ​ ​
Diazepam ​

(One is the shortest and three is the longest)

A

Midazolam ​ + ​ 1
Lorazepam ​ + ​ 2
Diazepam ​ + ​ 3

Comparative elimination half-lives: ​ diazepam > lorazepam > midazolam

Diazepam undergoes enterohepatic recirculation, which explains why it remains in the body for such a long time (elimination t1/2 = 43 hrs).

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28
Q

A patient is experiencing a prolonged recovery from midazolam sedation. What is the initial dose of flumazenil?

(Enter your answer as milligrams)

A

0.2 mg

Flumazenil is a competitive antagonist of the GABA-A receptor. It is used to reverse benzodiazepine overdose.

The initial dose is 0.2 mg IV.
It is titrated in 0.1 mg increments until a desired response is achieved.

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29
Q

Match each inhaled anesthetic with its chemical structure.

A

review nitrous, des 6
iso - cl
sevo 7

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30
Q

Match each inhaled anesthetic with its physiochemical property. ​

A

Isoflurane ​ + ​ Vapor pressure = 240 mmHg
Desflurane ​ + ​ Boiling point = 22 degrees
Sevoflurane ​ + ​ ​ Unstable even in hydrated soda lime
Nitrous oxide ​ + ​ Molecular weight = 44 g

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31
Q

Match each inhalation anesthetic to its blood gas partition coefficient.

A

Desflurane ​ + ​ 0.42
Nitrous oxide ​ + ​ 0.46
Sevoflurane ​ + ​ 0.65
Isoflurane ​ + ​ 1.46

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32
Q

Click on the FA/FI curve that represents nitrous oxide.

A

The FA/FI curves are listed from top to bottom:

Nitrous oxide
Desflurane
Sevoflurane
Isoflurane
​
So if desflurane has the smallest blood:gas partition coefficient, then why is it below nitrous oxide on this graph?
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33
Q

Which factor reduces the rate of rise of FA/FI? ​ (Select 3.)

Increased FRC
Increased cardiac output
Decreased time constant
Decreased fresh gas flow
Increased alveolar ventilation
Decreased anatomic dead space
A

Increased cardiac output
Increased functional residual capacity
Decreased fresh gas flow

A decreased rate of rise of FA/FI means a slower induction. This can be caused by an increased cardiac output, increased FRC, or decreased fresh gas flow.

An increased rate of rise of FA/FI means a faster induction. This can be caused by a decreased time constant, decreased anatomic dead space, or an increased alveolar ventilation.

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34
Q
What percentage of body weight is accounted for by the vessel rich group?
10%
20%
50%
75%
A

10%

when considering the distribution of anesthetics throughout the body, we can conceptualize 4 tissue groups: ​ vessel rich group, muscle group, fat group, and vessel poor group.​

The vessel rich group accounts for only 10% of body weight, yet it receives 75% of the cardiac output!

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35
Q

Match each inhalation anesthetic to its amount of hepatic metabolism.

A

Nitrous oxide ​ + ​ 0.004%
Desflurane + ​ 0.02%
Isoflurane ​ + ​ 0.2%
Sevoflurane + ​ 2% ​ (up to 5%)

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36
Q
Which concept BEST explains why the rate of rise of FA/FI is faster for nitrous oxide than desflurane?
Augmented inflow effect
Concentrating effect
Ventilation effect
Second gas effect
A

Concentrating Effect

Even though desflurane has a lower blood gas partition coefficient than nitrous oxide, the concentrating effect explains why the rate of rise of FA/FI is faster for nitrous oxide than desflurane.

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37
Q

Assuming that the functional residual capacity remains constant, which concept explains a temporary increase in alveolar oxygen concentration when nitrous oxide is turned on during an inhalation induction?

Ventilation effect
Diffusion hypoxia
Concentration effect
Second gas effect

A

Second Gas Effect

Not only does the second gas effect explain how nitrous oxide hastens the onset of a second gas, but it also explains why alveolar oxygen might transiently increase.

We all know that FRC may become smaller during anesthetic induction with a halogenated agent, so in clinical practice the PaO2 may not always increase. This is why we specifically stated that the FRC remained constant.`

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38
Q

A patient has a right-to-left intracardiac shunt. The rate of rise of FA/FI of which drug will be affected MOST?

FA/FI is unaffected by a right-to-left intracardiac shunt
Desflurane
Isoflurane
Sevoflurane

A

Desflurane

This is the kind of question where the rubber meets the road. You need to know something about cardiac shunts as well as how they impact the pharmacokinetics of the inhalation anesthetics.​

A right-to-left cardiac shunt slows the speed of induction with a volatile agent. It takes longer for FA to equilibrate with FI.​

Agents with low solubility (desflurane) are affected the most.
Agents with high solubility (isoflurane) are affected the least.

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39
Q

What is the blood:gas partition coefficient of nitrogen?

  1. 14
  2. 014
  3. 0014
  4. 00014
A

0.014

There will be times where you encounter a question that asks you a fact. Even if you can’t recall that specific fact, try to think of other pieces of information that might be related.

For example, you may not know the blood:gas partition coefficient for nitrogen. While the number may not be important, the relationship between nitrogen and nitrous oxide is very important. You probably know that nitrous oxide is 34x more soluble than nitrogen and you also know that the blood:gas partition coefficient for N2O is 0.46. Now you’re half way home. ​ What is 0.46 divided by 34? You guessed it…it’s the blood:gas partition coefficient of nitrogen.

The correct answer is 0.014.

40
Q

Order the volatile anesthetics from lowest to highest potency. ​

(One is the least potent and four is the most potent)

A

Nitrous oxide ​ + ​ 1 (least potent)
Desflurane ​ + ​ 2
Sevoflurane ​ + ​ 3
Isoflurane ​ + ​ 4 (most potent)

MAC is a measure of potency.​

The higher the MAC value, the lower the potency.
The lower the MAC value, the higher the potency.

41
Q
Volatile anesthetic potency is increased by: ​ (Select 4)
hyponatremia.
old age.
clonidine
chronic alcohol consumption.
red hair.
hypokalemia.
hypothyroidism.
lithium.
A

Old age
Lithium
Clonidine
Hyponatremia

MAC is a measure of anesthetic potency. We could’ve asked what factors reduce MAC, but we wanted to keep you on your toes.

Obviously there is a big list to cover, but for this question…

Potency is increased by hyponatremia, lithium, clonidine, and old age.
Potency is not affected by hypokalemia and hypothyroidism.
Potency is decreased by chronic alcohol consumption and red hair.

42
Q

The Meyer-Overton rule states:
decreased body temperature reduces anesthetic requirements.
all anesthetics share a similar mechanism of action, but each may work at a different site. ​
inhaled anesthetic agents interact with stereoselective receptors.
lipid solubility is directly proportional to potency.

A

Lipid solubility is directly proportional to potency

The Meyer-Overton rule states that lipid solubility is directly proportional to the potency of an inhalation anesthetic. While it is true that decreased body temperature reduces anesthetic requirements, this is not the Meyer-Overton rule.

The unitary hypothesis states that all anesthetics share a similar mechanism of action, but each may work at a different site.

Modern anesthetic theory suggests that inhalation anesthetics interact with stereoselective receptors.

43
Q

Modern theory of anesthetic action suggests inhaled anesthetics: ​ (Select 2)
stimulate the NMDA receptor.
produce immobility by binding in the dorsal horn of the spinal cord.
interact with stereoselective receptors.
facilitate GABA transmission.

A

Facilitate GABA transmission
Interact with stereoselective receptors

Volatile anesthetics most likely exert their effects by stimulating and inhibiting a variety of stereoselective receptors and not simply by disrupting the integrity of the phospholipid bilayer. The primary target of halogenated anesthetics in the brain is facilitation of the GABA-A receptor.

The primary target of volatile anesthetics in the spinal cord is stimulation of glycine channels and inhibition (not stimulation) of NMDA receptors and sodium channels.

Volatile anesthetics produce immobility in the ventral horn of the spinal cord (not dorsal).

44
Q

Match the pharmacodynamic effects of volatile anesthetics to the site of action. ​ ​

A

Unconsciousness ​ + ​ Reticular activating system
Amnesia ​ + ​ Hippocampus
Analgesia ​ + ​ Spinothalamic tract
Immobility ​ + ​ Ventral horn

45
Q
Regarding the modern halogenated anesthetics in the adult at 1 MAC:
systemic vascular resistance increases.
mean arterial blood pressure increases.
heart rate decreases.
QT interval increases.
A

QT interval increases

Volatile anesthetics increase the duration of myocardial repolarization by impairing an outward K+ current. ​ This prolongs the QT interval.

Heart rate increases (des and iso) or stays the same (sevo).

Vasodilation causes a reduction in SVR (not an increase).

MAP decreases (not increases).

46
Q
Regarding the modern halogenated anesthetics in the adult at 1 MAC:
dead space decreases.
airway diameter decreases.
respiratory rate increases.
minute ventilation increases.
A

Respiratory rate increases

Halogenated anesthetics decrease tidal volume and increase respiratory rate, leading to increased dead space ventilation.​

These drugs are bronchodilators, so airway diameter increases (decreased resistance).

Minute ventilation is reduced (Vt gets smaller + partial compensation by increasing RR).

47
Q

Which agent impairs the hypoxic ventilatory response the LEAST?
Desflurane
Sevoflurane
Isoflurane
These drugs produce similar degrees of depression

A

Desflurane

While all anesthetic agents suppress the hypoxic ventilatory response, desflurane affects this response the least.

48
Q
Sevoflurane at 1.5 MAC increases: ​
cerebral vascular resistance.
cerebral metabolic rate of oxygen.
cerebrospinal fluid production.
cerebral blood volume.
A

Cerebral blood volume

Volatile anesthetics uncouple metabolism from cerebral blood flow. Said another way, they supply the brain with more blood flow than it actually needs. Since more blood is delivered to the brain per minute, the cerebral blood volume increases.

CMRO2 is decreased (not increased).
Cerebral vascular resistance decreases (not increases).
CSF production decreases (not increases).

49
Q

Desflurane affects somatosensory evoked potentials by:
decreasing amplitude and increasing latency.
increasing amplitude and increasing latency.
increasing amplitude and decreasing latency.
decreasing amplitude and decreasing latency.

A

Decreasing amplitude and increasing latency

Volatile agents decrease amplitude and increase latency of SSEPs.

50
Q

Use the graph to match each letter with the drug it represents.

A
A ​ + ​ Propofol
B ​ + ​ Nalbuphine
C ​ + ​ Cisatracurium
D ​ + ​ Propranolol
Full Agonist:
Can maximally activate a specific cellular response.
Example: ​ propofol
​
Partial Agonist:
Is only capable of partially activating a cellular response.
Example: ​ nalbuphine
​
Antagonist:
Occupies the receptor binding site and prevents an agonist from binding to it. It does not tell the cell to do anything.
Example: ​ cisatracurium

Inverse agonist:
Causes the opposite effect to that of a full agonist.
Example: ​ propranolol

51
Q

Match each drug interaction with the example that BEST describes it.

A

Addition ​ 1 + 1 = 2
Synergism ​ 1 + 1 = 3
Antagonism ​ 1 + 1 = 0

Addition:
Pharmacologic effects of two drugs given at the same time are added to each other.
1 + 1 = 2

Synergism:
Pharmacologic effects of two drugs given at the same time will be greater than the sum of their individual effects.
1 + 1 = 3

Antagonism:
Simultaneous administration of one drug cancels out the effect of a second drug.
1 + 1 = 0

52
Q

Based on the graph, what assumption can you make about drug A?
It undergoes more plasma protein binding than drug B.
It is more potent than drug C.
It has a smaller volume of distribution than drug C.
It will remain in the central compartment longer than drug D during elimination.

A

It will remain in the central compartment longer than drug D

If you recognized this as the context-sensitive half-time chart for the phenylpiperidines, then pat yourself on the back.

The concept of context-sensitive half-time takes the duration of drug administration into account. It is the time required for a steady-state plasma concentration to decline by 50% after an infusion or repeated drug dosing is stopped (context = time).

A major flaw with this concept is that it only illustrates the time it takes for the concentration to decline by 50% in the central compartment. This means that context-sensitive half-time does NOT necessarily predict the time to wake-up after an infusion is stopped.

Drug A at the top of the graph (fentanyl) had the longest context-sensitive half-time, while drug D at the bottom of the graph (remifentanil) has the shortest context-sensitive half-time.

53
Q

Match each phase of metabolism with its best example.

A

Phase 1 ​ + ​ Modification
Phase 2 ​ + ​ Conjugation
Phase 3 ​ + ​ Elimination

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

Phase 2 reactions conjugate (adds on) an endogenous, highly polar, water-soluble substrate to the molecule. This results in a water-soluble, biologically inactive molecule ready for excretion.

Phase 3 reactions describe elimination via ATP dependent carrier proteins that transport drugs across cell membranes. These are present in the kidney, liver, and GI tract.

54
Q
All of the following enantiomeric drugs are supplied as racemic mixtures EXCEPT:
ropivacaine.
ketamine.
desflurane.
ephedrine.
A

Ropivacaine

A chiral molecule has a center of three-dimensional asymmetry. In biologic systems, this type of asymmetry generally stems from a tetrahedral bonding of carbon, where carbon binds to four different atoms.

Enantiomers are mirror images of the same molecule (they cannot be superimposed on one another). Indeed, the chemical formula is the same, but the difference is how they rotate in polarized light.

Dextrorotatory enantiomers rotate clockwise.
Levorotatory enantiomers rotate counterclockwise.
A racemic mixture contains two enantiomers in equal amounts. About a third of the drugs we administer are enantiomers, and just about all of these are prepared as racemic mixtures. ​

Examples: ​ ephedrine, ketamine, desflurane
There are two exceptions: ​ ropivacaine and levobupivacaine

How is this clinically relevant?
S-bupivacaine (levobupivacaine) is less cardiotoxic than R-bupivacaine or the racemic mixture.
The S enantiomer of ketamine is less likely to cause emergence delirium than the R form. The S form is also more potent.

55
Q

Which drugs are weak acids? ​ (Select 2.)

Thiopental
Methohexital
Ephedrine
Morphine

A

Thiopental
Methohexital

Most drugs that we give are weak acids and bases. Ionization affects a drug’s pharmacologic activity as well as its ability to pass through cell membranes.

A weak base is paired with a negative ion, such as chloride or sulfate.
Examples: ​ ephedrine, morphine

A weak acid is paired with a positive ion, such as sodium, calcium, or magnesium.
Examples: ​ thiopental, methohexital

56
Q
Which route of administration is associated with the LOWEST bioavailability?
Rectal
Intrathecal
Intravenous
Sublingual
A

Intrathecal

The route of administration determines how much of a drug will enter the systemic circulation and ultimately reach its effect-site.

IV administration produces 100% bioavailability.
The lowest amount of bioavailability occurs with intrathecal administration.

It’s not a problem that the intrathecal route has a very low bioavailability. This is because we are administering the drug directly to its effect-site (we don’t need the blood to take it there).

57
Q

Match each tissue group to the percentage of the cardiac output that it receives.

A

Vessel rich ​ + ​ 75%
Muscle ​ + ​ 19%
Fat ​ + ​ 6%
The vessel rich group (heart, lungs, kidney, liver, brain) represents the central compartment, while the other groups represent the peripheral compartments.

The key ideas are these:
The VRG represents only 10% of the total body mass, but it receives 75% of the cardiac output.
All the other tissues (muscle, fat, bone, etc.) represent 90% of the total body mass, but they receive 25% of the cardiac output.
The central compartment equilibrates with Cp long before the peripheral compartment.
Drugs leave the central compartment in two phases: ​ distribution into tissue and biotransformation/excretion.

58
Q
Which process describes the biotransformation of morphine to morphine-6-glucuronide?
Reduction
Conjugation
Oxidation
Hydrolysis
A

Conjugation​

Phase 1 reactions produce small molecular changes that increase a molecule’s polarity (water solubility). The purpose is to prepare the molecule for a phase 2 reaction.​

There are three that you need to know:
Oxidation - removes electrons from a molecule
Reduction - adds electrons to a molecule
Hydrolysis - adds water to a molecule to split it apart
​Example: ​ Morphine undergoes oxidative dealkylation to normorphine (a methyl group is removed).

Phase 2 reactions add on an endogenous, highly polar substrate to the molecule. This makes it highly water-soluble, so that it’s easily excreted in the urine or bile. This process is called conjugation.
There is only one that you need to know:

Glucuronidation - adds glucuronic acid to a molecule

Example: ​ Morphine is glucuronidated to morphine-3-glucuronide and morphine-6-glucuronide. M6G is pharmacologically active and can accumulate in patients with renal failure, producing prolonged respiratory depression.

*Flood incorrectly lists conjugation reactions under phase 1 reactions.

59
Q

Which drugs obey zero order kinetics? ​ (Select 3.)

Rocuronium
Aspirin
Fentanyl
Ethanol
Phenytoin
Propofol
A

Ethanol
Phenytoin
Aspirin

Zero Order Kinetics:
If all the enzymes become saturated, then the enzymatic pathway can only metabolize a constant amount per unit time.
There is more drug than enzyme.
Examples include ethanol, aspirin, phenytoin, heparin, warfarin, and theophylline.

First Order Kinetics:
For most drugs, the clearing organ metabolizes a constant fraction (percentage) per unit time.
There is more enzyme than drug.

Sometimes a drug will follow first order kinetics at low concentrations then change to zero order kinetics when the enzymatic pathway becomes saturated. This is the case with aspirin and phenytoin.

60
Q
Which drug is MOST likely to cause theophylline toxicity?
Tobacco
Ethanol
Erythromycin
Rifampin
A

Erythromycin

Hepatic clearance is the product of:

Liver blood flow - how much drug is delivered to the liver.
Hepatic extraction ratio - how much drug is removed by the liver.

Hepatic clearance can be classified in two ways:

Flow-dependent elimination (ER > 0.7). Clearance is primarily dependent on liver blood flow.
Capacity-dependent elimination (ER < 0.3). Clearance is primarily dependent on liver enzyme activity.

Enzyme inducers increase clearance and decrease Cp.

Common examples: ​ tobacco, ethanol, phenytoin, barbiturates, rifampin

Enzyme inhibitors decrease clearance and increase Cp.
Common examples: ​ grapefruit juice, cimetidine, omeprazole, SSRIs, isoniazid, and erythromycin​

Theophylline has a low hepatic extraction ratio, so its clearance is largely dependent on hepatic enzyme function, specifically CYP1A2.

61
Q

A drug administered via intravenous infusion has achieved steady-state. The infusion was stopped, and 75% of the drug was eliminated from the body. How many half-lives have elapsed?

A

Two

Steady-state occurs when: ​ Drug entering the body = Drug leaving the body ​

Drug elimination usually requires 5 half-lives (Nagelhout says 4-5 half-lives, but 5 is the number you need to know).
​
In this question, we told you that 75% of the drug was eliminated from the body, and we asked how many half-lives this required. So...
​
At Time = 0:
Drug eliminated = 0%
Drug remaining in the plasma = 100%
​
After 1 Half-Life:
Drug eliminated = 50%
Drug remaining in the plasma = 50%
After 2 Half-Lives:
Drug eliminated = 75%
Drug remaining in the plasma = 25%
​
After 3 Half-Lives:
Drug eliminated = 87.5%
Drug remaining in the plasma = 12.5%
​
After 4 Half-Lives:
Drug eliminated = 93.75%
Drug remaining in the plasma = 6.25%
​
After 5 Half-Lives:
Drug eliminated = 96.875%
Drug remaining in the plasma = 3.125%
62
Q

Acetazolamide favors: ​ (Select 2.)

excretion of acidic drugs.
excretion of basic drugs.
reabsorption of basic drugs.
reabsorption of acidic drugs.

A

Reabsorption of basic drugs
Excretion of acidic drugs

Urine pH influences whether drugs are excreted in the urine or reabsorbed into the peritubular capillaries. Remember that “like dissolves like.”
​
Acidic urine favors:
Reabsorption of acidic drugs
Excretion of basic drugs
Basic urine favors:
Reabsorption of basic drugs
Excretion of acidic drugs
​
How to alter urine pH:
Acidify the urine with ammonium chloride or cranberry juice.
Alkalize the urine with acetazolamide.
63
Q

Match each induction agent with its drug class.

A

Propofol ​ + ​ Alkylphenol
Thiopental ​ + ​ Barbiturate
Ketamine ​ + ​ Arylcyclohexylamine
Etomidate ​ + ​ Imidazole

Be able to match each agent with its drug class:
​Alkylphenol: ​ propofol, fospropofol
​Barbiturate: ​ thiopental, methohexital​
Benzodiazepine: ​ midazolam, lorazepam, diazepam​
Arylcyclohexylamine: ​ ketamine
​Imidazole: ​ etomidate, dexmedetomidine
Even though etomidate and dexmedetomidine are in different drug classes, they are both imidazole compounds.

64
Q

Match each drug with its chemical name.

A

Propofol ​ + ​ 2,6-diisopropylphenol
Etomidate ​ + ​ R-1-ethyl-1-(a-methylbenzyl) imidazole-5-carboxylate
Ketamine ​ + ​ 2-(o-Chlorophenyl)-2 (methylamino) cyclohexanone hydrochloride
Thiopental ​ + ​ 5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid

If you’re like most students, this stuff makes your eyes glaze over. We’ll try to give you a few tips to identify each agent easily.

Propofol:
2,6-diisopropylphenol
Remember “prop”

Ketamine:
2-(o-Chlorophenyl)-2 (methylamino) cyclohexanone hydrochloride
The name ketamine is derived from “keto-mine” because it has a ketone group as well as an amine group.

Thiopental:
5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid
All of the barbiturates are derived from barbituric acid.
Thiopental is a thiobarbiturate, with a sulfur in the second position.

Etomidate:
R-1-ethyl-1-(a-methylbenzyl) imidazole-5-carboxylate
Remember “imidazole”

Dexmedetomidine:
(S)-4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole monohydrochloride
Remember “imidazole” and the letter “D.”

65
Q
Identify the anesthetic agents that are MOST likely to cause pain on injection. ​ (Select 3.)
Etomidate
Dexmedetomidine
Ketamine
Fospropofol
Propofol
Diazepam
A

Propofol
Etomidate
Diazepam

The following drugs are associated with pain on injection:
Diazepam ​ +++
Etomidate ​ +++
Propofol ​ ++
Lorazepam +

Propylene glycol is used as a solvent for etomidate, diazepam, and lorazepam formulations. This stuff can be quite irritating, and it can result in venous irritation and phlebitis following injection. Additionally, this explains why we don’t give diazepam or etomidate intramuscularly. Eliminating the propylene glycol carrier in favor of a non-irritating solvent eliminates the pain.

Propofol injection pain can be minimized or eliminated by using a larger, rather than a smaller, vein. Administering lidocaine (before injection or mixed with propofol) or a potent opioid reduces the pain as well.

The following drugs do NOT cause pain on injection:

Dexmedetomidine
Ketamine
Fospropofol
Midazolam… well, at least this is what Nagelhout says. Some of our patients would disagree. Midazolam does not contain propylene glycol.

66
Q

Which generic formulation is MOST likely to precipitate bronchospasm in asthmatic patients?

Midazolam
Ketamine
Propofol
Etomidate

A

Propofol

The key to this question is “generic formulations.” ​

Diprivan, the branded propofol formulation, contains EDTA as a preservative. EDTA stands for disodium ethylenediamine tetraacetic acid. It does not cause bronchial irritation.

Generic formulations of propofol 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.

Ketamine is the only induction agent with bronchodilating properties. This makes it the induction agent of choice in patients experiencing active bronchospasm who require surgery. Bronchodilation is the result of bronchial smooth muscle relaxation and increased catecholamine release.

Midazolam and etomidate do not exhibit clinically significant effects on airway tone.

67
Q

After being withdrawn into a syringe, propofol must be discarded after:

4 hours.
6 hours.
8 hours.
12 hours.

A

Six hours

Propofol supports bacterial and fungal growth, therefore strict attention to asepsis must be observed while withdrawing it from the vial. Additionally, the vial and rubber stopper must be cleansed with 70 percent isopropyl alcohol before removing the drug. Preservatives (discussed in the previous question) are added to minimize the rate of contamination.

You must know how long propofol lasts in a syringe as well as an infusion:

Syringe = must be discarded within 6 hours
Infusion = must be discarded within 12 hours (this includes the tubing)
68
Q
Lecithin is found in all of the following EXCEPT:
peanuts.
egg whites.
egg yolks.
soy products.
A

Egg whites

This can be a confusing subject, so listen up!

Lecithin is used as an emulsifier. It is found in eggs, soy, and peanuts.

Eggs:
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.
Propofol is probably safe to administer to patients with egg allergy.

Soy:
Any soy proteins that are capable of producing an immune response are removed during the refining process.
Propofol is safe to use in patients with a soy allergy.

Peanuts:
Like soy, peanuts are a type of legume. Some have speculated the potential of cross-sensitivity between peanuts and soy, although there is no evidence to support this.
Propofol is safe to use in patients with peanut allergy.

The bottom line is that propofol may be safely administered to patients allergic to soy, peanuts, and probably egg.

69
Q

Click on the curve that represents propofol distribution to the brain.

A

At time = 0, all of the injected propofol is in the blood.​

Cp declines over time.

Propofol is rapidly distributed from the blood and into the vessel rich group.

The brain concentration peaks at ~ 1 min, then propofol redistributes from the VRG to the muscle and adipose. Notice how the drug continues to redistribute to the muscle and fat over time.
Awakening is the result of redistribution away from the brain - NOT metabolism.
Time to awakening is 5 - 15 minutes.

70
Q

In the intensive care unit, a patient receiving a propofol infusion develops acute refractory bradycardia, an increased anion gap metabolic acidosis, and rhabdomyolysis. All of the following increase the risk of this phenomenon EXCEPT:

an infusion time that exceeds 48 hours.
erythrocyte transfusion.
a dose greater than 4 mg/kg/hr.
sepsis.

A

Erythrocyte transfusion

Propofol infusion syndrome is associated with a high mortality rate. 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.

Risk factors include:
Propofol dose > 4 mg/kg/hr
Propofol infusion > 48 hours
Sepsis (Inadequate oxygen delivery)
Continuous catecholamine infusions
High-dose steroids
Significant cerebral injury
​
Clinical presentation includes acute refractory bradycardia leading to asystole and at least one of the following:
Metabolic acidosis (base deficit > 10 mmol/L)
Rhabdomyolysis
Hyperlipidemia
Enlarged or fatty liver
Renal failure
​
Lipemia may be an early sign.

Treatment is supportive and includes discontinuing propofol, maximizing gas exchange, cardiac pacing, PDE inhibitors, glucagon, ECMO, and renal replacement therapy.

71
Q

Which induction agent is MOST likely to cause post-operative nausea and vomiting?

Midazolam
Etomidate
Ketamine
Propofol

A

Etomidate

Among the drugs used for the induction of anesthesia, etomidate is the one that is most likely to cause PONV. The incidence is 30 - 40 percent.

When propofol is a component of the anesthetic plan, the risk of PONV is reduced. It is particularly effective in the PACU, especially when PONV is not vagal in origin.

Bolus = 10 - 20 mg
Infusion = 10 mcg/kg/min

Midazolam also exhibits some antiemetic properties.

Some texts say ketamine has antiemetic properties, while others do not.

72
Q
What is the primary pathway of etomidate metabolism?
Oxidation
Conjugation
Hydrolysis
Reduction
A

Hydrolysis

Etomidate enhances the ease of binding of GABA to the GABA-A receptor in the brain.

​Biotransformation is the result of ester hydrolysis at the ethyl-ester side chain. Plasma esterases and hepatic microsomal enzymes drive the reaction.

Etomidate does not produce an active metabolite.

73
Q
Etomidate causes adrenocortical suppression by inhibiting:
glucose-6-phosphate dehydrogenase.
methionine synthase.
aminolevulinic acid synthase.
11 beta-hydroxylase.
A

11 beta-hydroxylase

A single dose of etomidate suppresses adrenocortical function for 8 - 24 hours.

Etomidate inhibits two enzymes necessary for the conversion of cholesterol to cortisol and aldosterone.
​11 beta-hydroxylase
17 alpha-hydroxylase

For this reason, etomidate should be avoided in patients reliant on the intrinsic stress response (sepsis). This is also why etomidate is not used as a long-term continuous infusion in the ICU. Mortality may be increased by etomidate, particularly in patients with sepsis.

​ALA synthase is a key enzyme in porphyrin metabolism. Etomidate and barbiturates should be avoided in patients with a history of porphyria.
Methionine synthase is inhibited by nitrous oxide, and this increases the risk of impaired B12 metabolism and megaloblastic anemia.

Glucose-6-phosphate dehydrogenase is an enzyme present in red blood cells. G6PD deficiency can lead to hemolysis. Drugs to avoid include aspirin, sulfonamides, and quinidine.

74
Q

Choose the BEST treatments for the patient experiencing an episode of acute intermittent porphyria. ​ (Select 2.)

Induced hypothermia
Glucose
Etomidate
Heme arginate

A

Glucose
Heme arginate
Explanation:

The porphyrias can be classified as acute (inducible) or chronic (non-inducible or cutaneous). The most common (and dangerous) type of inducible porphyria is acute intermittent porphyria.

Porphyria is a defect in heme synthesis leading to the accumulation of heme precursors. Heme is a key component of hemoglobin, myoglobin, and the cytochrome P450 enzymes.

Succinyl-CoA + Glycine ​ → ​ ALA synthase ​ → ​ Precursors ​ → ​ Heme

Triggering agents include:
Barbiturates
Etomidate
Ketamine
Ketorolac
Amiodarone
Calcium channel blockers (many but not all)
Birth control pills
​
Anesthetic management includes liberal hydration, glucose supplementation, and prevention of hypothermia. This condition can be made worse by stimulation of ALA synthase, emotional stress, prolonged NPO status, and CYP450 induction.

An acute exacerbation is treated with glucose and heme arginate. These agents reduce ALA synthase activity.

75
Q
Which anesthetic agent is LEAST affected by alterations in plasma protein binding?
Propofol
Ketamine
Etomidate
Midazolam
A

Ketamine

You can think of plasma proteins as an intravascular drug storage compartment. A drug bound to a protein cannot bind to a receptor, so any bound drug can be considered inert. Only the free fraction can exert a physiologic effect.

Alterations in plasma protein binding can theoretically affect a drug’s therapeutic effect. Drugs that are highly protein-bound are most affected by changes in plasma protein binding.IV Anesthetic Protein Binding Percent:

Propofol ​ = ​ 98%
Diazepam ​ = ​ 98%
Midazolam ​ = ​ 94%
Dexmedetomidine = 94%
Lorazepam ​ = ​ 90%
Etomidate ​ = ​ 75%
Ketamine ​ = ​ 12%
​
You should be able to rank these in a drag-and-drop type question. You should also know that propofol is at the top, and etomidate and ketamine are at the bottom.
76
Q
At the N-methyl-D-aspartate receptor, ketamine is an antagonist of:
magnesium.
gamma aminobutyric acid.
glycine.
glutamate.
A

Glutamate

The N-methyl-D-aspartate (NMDA) receptor is an ion channel that is permeable to sodium, calcium, and potassium. When the channel opens, Na+ and Ca+2 enter the cell and K+ exits the cell. ​

Magnesium acts as a plug inside the channel, which explains how exogenous Mg+2 supplementation can mediate pain transmission.

​NMDA receptor agonist ​ = ​ glutamate
NMDA receptor antagonist ​ = ​ ketamine, nitrous oxide, methadone

The NMDA receptor stimulates the “wind-up” phenomenon, where wide dynamic range neurons increase their firing rate for a given stimulus. This can contribute to hyperalgesia. Ketamine counteracts this process.

77
Q

Side effects of ketamine administration include all of the following EXCEPT:

direct myocardial depression.
nystagmus.
emergence delirium.
xerostomia.

A

Xerostomia

Ketamine has a unique profile that separates it from the other IV anesthetics. Effects include:

Cardiovascular:
SNS stimulation
Direct myocardial depression (only evident if unable to mount SNS response)

Respiratory:
Bronchodilation
Intact pharyngeal and laryngeal reflexes
Spontaneous respiration usually preserved
Increased salivation (reduced by preop antisialagogue)
Central Nervous System:

Dissociative anesthesia
Analgesia
Emergence delirium (treated with benzodiazepine)
Increased cerebral blood flow
Neuroapoptosis in the developing brain (clinical significance unknown)

Eye:
Nystagmus
Increased intraocular pressure (only with high doses)
Increased ocular muscle tone

78
Q

Which anesthetic agent is MOST likely to increase oxygen consumption in the brain?

Midazolam
Propofol
Ketamine
Etomidate

A

Ketamine

​The key to understanding how drugs impact cerebral perfusion is understanding how they affect cerebral metabolism (CMRO2).

As a general rule, drugs that increase CMRO2 also increase CBF - there needs to be a higher blood flow to support the increased oxygen requirement.
Conversely, drugs that decrease CMRO2 also decrease CBF.
A reduction in CBF tends to reduce ICP in patients with intracranial hypertension.
Halogenated agents are a key exception to this rule - CMRO2 is decreased, but CBF increases.

Ketamine:
CMRO2 ​ = ​ Increased
CBF ​ = ​ Increased
ICP ​ = ​ Increased?

Propofol, Etomidate, Benzodiazepines, and Barbiturates:
CMRO2 ​ = ​ Decreased
CBF ​ = ​ Decreased (these drugs are called cerebral vasoconstrictors)
ICP ​ = ​ Decreased

It’s important to note that although these drugs reduce ICP, this assumes that ventilation is controlled. ​ Hypercarbia can increase ICP.

79
Q

A patient requires midazolam reversal in the postanesthesia care unit. What is the initial dose of the drug that is MOST useful in this situation?

0.2 mg
2 mg
20 mg
200 mg

A

0.2 mg

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 minutes). For this reason, repeat dosing may be necessary to prevent resedation.
Initial dose = 0.2 mg IV
Repeat doses = 0.1 mg IV increments q1min

80
Q

How long will an oral dose of lorazepam maintain a therapeutic plasma concentration?

2 - 4 hours
6 - 12 hours
12 - 24 hours
24 - 48 hours

A

24 - 48 hours

PO Lorazepam

Dose = 50 mcg/kg
Cp peak ​ = ​ 2 - 4 hours
Cp therapeutic ​ = ​ 24 - 48 hours
​
IV Lorazepam
Dose ​ = ​ 1 - 4 mg
Cp peak ​ = ​ 20 - 30 minutes
Cp therapeutic ​ = ​ 6 - 10 hours
81
Q

Which anesthetic agents produce an active metabolite? ​ (Select 2.)

Ketamine
Propofol
Etomidate
Midazolam

A

Ketamine
Midazolam
Ketamine:

Primary metabolite ​ = ​ norketamine
Potency ​ = ​ 0.2 - 0.33x ketamine
Metabolic pathway ​ = ​ hepatic P450 enzymes
Chronic ketamine use induces the enzymes that metabolize it. This manifests as a rapid escalation of tolerance (more drug is required to obtain the same effect).

Midazolam:
Primary metabolite ​ = ​ 1-hydroxymidazolam
Potency ​ = ​ 0.5x midazolam
Metabolic pathway ​ = ​ hepatic and small intestine P450 enzymes
The active metabolite is rapidly conjugated to an inactive compound.
Propofol:
Does not produce an active metabolite.
Metabolic pathway ​ = ​ hepatic P450 enzymes
Clearance exceeds tissue uptake, which reflects the role of tissue uptake in its rapid termination of action.

Etomidate:
Does not produce an active metabolite.
Metabolic pathway ​ = ​ ester hydrolysis by plasma esterases and hepatic P450 enzymes

82
Q

Which anesthetic agent is a methyl isopropyl ether?

Isoflurane
Sevoflurane
Desflurane
Nitrous oxide

A

Sevoflurane

All of the potent inhaled anesthetics used today are halogenated, ether-based molecules (ether bond = C-O-C).

There are two classes of ethers you should know:
Methyl isopropyl ether: ​
Example: ​ sevoflurane
​
Methyl ethyl ether:
Examples: ​ desflurane and isoflurane
​
You probably won't be asked, but for completeness, halothane is a halogenated hydrocarbon. It doesn't have an ether bond.
83
Q

Match each agent with its IUPAC chemical name.

A

Desflurane ​ + ​ difluoromethyl 1,2,2,2-tetrafluoroethyl ether
Sevoflurane ​ + ​ fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether
Isoflurane ​ + ​ 1-chloro 2,2,2-trifluoroethyl difluoromethyl ether
Halothane ​ + ​ 2-bromo-2-chloro 1,1,1-trifluoroethane

Counting the halogens is the easiest way to answer a question like this.

Isoflurane:
1-chloro 2,2,2-trifluoroethyl difluoromethyl ether
Fluorine = 5
Chlorine = 1

Desflurane:
difluoromethyl 1,2,2,2-tetrafluoroethyl ether
Fluorine = 6

Sevoflurane:
fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether
Fluorine = 7

Halothane:
2-bromo-2-chloro 1,1,1-trifluoroethane
Bromine = 1
This is the only agent with a bromine atom.

84
Q

Match each volatile agent with its vapor pressure.

A
Nitrous oxide ​ = ​ 38,770
Desflurane ​ = ​ 669
Isoflurane ​ = ​ 238
Sevoflurane ​ = ​ 157
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.
Increased temperature = Increased vapor pressure

Vapor pressure is measured at 20 C by convention:

Nitrous oxide ​ = ​ 38,770 mmHg
Desflurane ​ = ​ 669 mmHg
Isoflurane ​ = ​ 238 mmHg
Sevoflurane ​ = ​ 157 mmHg

85
Q

Match each volatile agent with its oil:gas partition coefficient.

A

Nitrous oxide ​ = ​ 1.4
Desflurane ​ = ​ 19
Sevoflurane ​ = ​ 47
Isoflurane ​ = ​ 91

Volatile anesthetics do not dissolve easily in water, because they do not form hydrogen bonds. This property makes them hydrophobic (lipophilic).

Instead, volatile agents tend to dissolve in non-polar substances, such as oils. The oil:gas partition coefficient is a measure of hydrophobicity.

The larger the number, the greater the tendency to dissolve in a non-polar solvent:

Nitrous oxide ​ = ​ 1.4
Desflurane ​ = ​ 19
Sevoflurane ​ = ​ 47
Isoflurane ​ = ​ 91

86
Q

Which anesthetic agent has the LOWEST boiling point?

Isoflurane
Halothane
Desflurane
Sevoflurane

A

Desflurane

A liquid boils when its vapor pressure exceeds atmospheric pressure (this requires an open container). At high altitudes, a liquid will boil at a lower temperature as a function of the reduction in atmospheric pressure.

Desflurane boils at 24 degrees C (75.2 degrees F). Desflurane does not boil in the bottle, because it’s closed to the atmosphere. The pressure in the bottle continues to rise in proportion to ambient temperature, however. Crack open a bottle of desflurane on a hot day and pour it out of a second story window. It won’t even hit the ground!
A low boiling point also explains why desflurane requires a special heated and pressurized vaporizer (TEC-6 or Drager D-Vapor). The TEC-6 is heated to 39 C and pressurized to 2 atmospheres.

At ambient temperature, nitrous oxide exists as a gas. This is because it boils at the very low temperature of -88 degrees C.

Sevoflurane and isoflurane boil at 59 C and 49 C, respectively.

87
Q

Which factor influences anesthetic uptake the LEAST?

Alveolar-venous partial pressure difference
Cardiac output
Fresh gas flow
Blood/gas solubility

A

Fresh gas flow

You must understand the factors that influence the partial pressure of the anesthetic agent inside the alveoli (FA).

FA is a function of 2 opposing actions:

FI = The rate of delivery TO the alveoli (fills the alveoli)
Uptake = The rate of removal AWAY from the alveoli (empties the alveoli)
​Determinants of delivery to the alveoli (FI):

​Setting on vaporizer (Vol%)
Time constant of delivery system
Anatomic dead space
Alveolar ventilation
Functional residual capacity
​
Determinants of removal from the alveoli (uptake):

Agent solubility (blood:gas partition coefficient)
Cardiac output
Partial pressure gradient between alveolar gas and mixed venous blood

88
Q

Which concept BEST describes how a gas distributes between two compartments at equilibrium?

Second gas effect
Meyer-Overton hypothesis
Charles law
Partition coefficient

A

Partition coefficient

A partition coefficient is a measure of how a gas distributes between two compartments (or phases) at equilibrium.

The blood:gas partition coefficient is critical to your understanding of anesthetic uptake.

Remember, it is the partial pressure of anesthetic agent in the brain that determines the depth of anesthesia, and that a concentration gradient exists from the vaporizer → breathing circuit → patient airway → alveoli → blood → brain/tissue.​

More soluble agents = ​ ↑ Uptake and partial pressure rises slower.
Less soluble agents = ↓ Uptake and partial pressure rises faster.

89
Q

How does endobronchial intubation affect the speed of an inhalation induction?

Induction is faster.
Induction is prolonged.
There is no change in the speed of induction.
There is not enough information to answer this question.

A

Induction is prolonged

Endobronchial intubation creates a situation where only one lung is ventilated, but both lungs are perfused. You guessed it … this is a right-to-left shunt (increased West zone III).

So, how does shunt affect the speed of an inhalation induction? While the texts quickly complicate the matter, this is how we want you to think about it.

When the endotracheal tube is properly positioned (no shunt), nearly all the pulmonary blood picks up anesthetic agent and delivers it to the left heart.
When an endobronchial intubation occurs (shunt), only half of the pulmonary blood picks up anesthetic agent, while the other half of the pulmonary blood can’t pick up agent because it’s not being ventilated.
When the blood from both lungs mixes in the left heart, the final partial pressure of anesthetic agent is diluted by the blood from the non-ventilated lung (it didn’t pick up anesthetic agent).
This effect is more pronounced when less soluble agents are used.

Less soluble agents (des and N2O) undergo very little uptake by the blood, and the effect of dilution is unchecked.
More soluble agents (iso) experience a greater degree of uptake by the blood, which partially offsets the dilution effect.

90
Q

How does increased cardiac output affect the speed of an inhalation induction?

Induction is faster.
Induction is prolonged.
There is no change in the speed of induction.
There is not enough information to answer this question.

A

Induction is prolonged

This question highlights a key distinction between the effects of cardiac output on inhaled and intravenous agents.

Think of the blood as a reservoir that holds volatile anesthetics. An agent that dissolves in the blood doesn’t diffuse into the brain, rather it’s the partial pressure of the agent in the blood that determines the amount of agent that enters the brain.​

As cardiac output increases, there is more blood per unit time in which anesthetic agent can dissolve, so it takes a longer time to achieve an adequate partial pressure.​

Cardiac output influences the removal of inhaled anesthetic from the alveoli.

Increased CO → Increased uptake → Decreased FA (slower induction)
Decreased CO → Decreased uptake → Increased FA (faster induction)
​How is this different from IV agents?
Cardiac output affects the rate of induction of IV agents in the opposite way.

Increased CO → Faster delivery to brain (faster induction)
Decreased CO → Slower delivery to brain → (slower induction)

91
Q
At a given end-tidal partial pressure of volatile anesthetic, which condition is associated with a higher incidence of awareness? ​ (Select 2.)
Methamphetamine intoxication
Increased pheomelanin production
Advanced age
Hyperthyroidism
A

Methamphetamine intoxication
Increased pheomelanin production

MAC is akin to ED50 for IV drugs. Said another way, it’s a measure of anesthetic potency. Conditions that create an apparent reduction in anesthetic potency can be thought to increase the risk of awareness under anesthesia.

MAC is increased by factors that increase central neurotransmitter concentrations, neurotransmission, and cerebral metabolism.

MAC is increased ~ 19% in red heads presumably due to mutations in the melanocyte-stimulating hormone receptor and an increased production of pheomelanin.
Acute methamphetamine intoxication increases CNS neurotransmitters, and this increases MAC.

MAC is decreased by factors that reduce central neurotransmitter concentrations, neurotransmission, and cerebral metabolism.

MAC is decreased by 6% for each decade of life starting at 40 years of age.

Some things don’t affect MAC at all. This is an important one to know!

Hyper- and hypothyroidism do NOT affect MAC. Instead, changes in cardiac output alter anesthetic uptake and subsequent onset of action.
For example, profoundly hypothyroid patients have a depressed CO leading to decreased anesthetic uptake into the blood and a faster rate of rise of FA/FI.

92
Q
MAC is increased by:
hypernatremia.
hyperkalemia.
hyponatremia.
hypokalemia.
A

Hypernatremia
Explanation:
You should understand how electrolyte disorders affect MAC. The only 2 that really make a difference are sodium and lithium.

MAC is increased by: ​ ↑ Na+
MAC is decreased by: ​ ↓ Na+, ↑ Li+
MAC is unchanged by: ​ K+

93
Q

Rank the anesthetics in terms of their degree of metabolism.

1 is the highest and 4 is the lowest

A

1 ​ = ​ Sevoflurane
2 ​ = ​ Isoflurane
3 ​ = ​ Desflurane
4 ​ = ​ Nitrous oxide

Inhaled anesthetics are eliminated from the body in three ways:

Elimination from the alveoli (primary mechanism)
Hepatic biotransformation (secondary mechanism)
Percutaneous loss (not clinically significant)
Hepatic biotransformation of the halogenated agents occurs via CYP 2E1:
Sevoflurane ​ = ​ 2 - 5%
Isoflurane ​ = ​ 0.2%
Desflurane ​ = ​ 0.02%
Nitrous oxide ​ = ​ 0.004%
​
For the halogenated agents, you can remember this with the “rule of 2’s - (0.02, 0.2, 2).

You should also notice that the halogenated agents are in alphabetical order beginning with desflurane undergoing the least amount of biotransformation (D-I-S).

94
Q

Hepatic biotransformation of desflurane produces: ​ (Select 2.)

fluoromethyl-2,2-difluoro-1-[trifluoromethyl] vinyl ether.
inorganic fluoride ions.
carbon monoxide.
Trifluoroacetic acid

A

Inorganic fluoride ions
Trifluoroacetic acid

Hepatic metabolism of desflurane and isoflurane produces inorganic fluoride ions and trifluoroacetic acid (TFA). TFA can bind with liver microsomal proteins, causing an immune-mediated hepatitis.

​Because up to 40% of halothane is metabolized by the liver, this drug was often implicated in hepatitis. Although des and iso are metabolized to a much smaller degree, it’s theoretically possible that they can precipitate an immune-mediated hepatitis as well.

Carbon monoxide is produced when desflurane is exposed to desiccated soda lime. It’s not produced by des metabolism in the body!

Compound A (fluoromethyl-2,2-difluoro-1-[trifluoromethyl] vinyl ether) is produced when sevoflurane is exposed to soda lime (hydrated or desiccated). It’s not produced by sevo metabolism in the body!

95
Q
A patient has a history of halothane hepatitis following cholecystectomy in 1983. Today, she presents for exploratory laparotomy for small bowel obstruction. Select the BEST agent to maintain anesthesia.
Sevoflurane
Desflurane
Isoflurane
Enflurane
A

Sevoflurane

Sevoflurane is metabolized to inorganic fluoride ions but not TFA. For this reason, sevoflurane would be the best choice for a history of halothane hepatitis.

Because sevoflurane undergoes a relatively high degree of hepatic metabolism (2-5%), there are theoretical concerns of fluoride induced high output renal failure. This type of renal failure is characteristically unresponsive to vasopressin.

S/sx include:
Polyuria
Hypernatremia
Hyperosmolarity
Increased plasma creatinine
Inability to concentrate urine
​
To date, these concerns seem unjustified.
While no longer used in the US, enflurane biotransformation (like des and iso) produces TFA and inorganic fluoride ions.
96
Q

How many times more soluble is nitrous oxide than nitrogen?

A

34 ​ ​ (we accepted 32 - 35)

Nitrous oxide is ~ 34 times more soluble than nitrogen. This means that for every 1 molecule of nitrogen that leaves a closed space, 34 molecules of nitrous oxide enter to take its place.

The blood:gas partition coefficient for nitrogen is 0.014. ​
The blood:gas partition coefficient of nitrous oxide is 0.46.

Why does this matter? Think pneumothorax, pulmonary blebs, sodium hexafluoride during retinal attachment surgery, inner ear pressure, and GI surgery.

97
Q
An ophthalmologist placed an intravitreal perfluoropropane bubble during retinal reattachment surgery. How long is nitrous oxide contraindicated in this patient?
10 minutes
30 minutes
10 days
30 days
A

30 days

We will begin our discussion with sulfur hexafluoride then follow with perfluoropropane (the gas from the question).

Sulfur hexafluoride (SF6) is a poorly soluble gas that is placed over the retina during retinal reattachment, vitrectomy, and macular hole repair.

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.

Perfluoropropane (C3F8) can be used instead of SF6. In this case, N2O must be avoided for at least 30 days after the bubble is placed.