Apex Unit 5 Pharm II Flashcards
Match each type of peripheral nerve with its function. A Alpha A delta B C
A alpha + Motor
A delta + Fast pain
B + Preganglionic SNS
C + Slow pain
Local anesthetics can bind to the voltage-gated sodium channel when it is in the: active state only. active and inactive states. resting and inactive states. resting and active states.
Active and inactive states
The sodium channel can exist in three states: resting, active, and inactive.
Local anesthetics preferentially bind to the alpha-subunit of the sodium channel in the active and inactive states.
Local anesthetics: (Select 2.)
increase threshold potential.
decrease resting membrane potential.
have no effect on threshold potential.
have no effect on resting membrane potential.
Have no effect on threshold potential
Have no effect on resting membrane potential
When a critical number of sodium channels are blocked by local anesthetic, sodium is unable to enter the neuron in sufficient quantity. This means the neuron can’t depolarize and the action potential can’t be propagated.
Local anesthetics do NOT affect resting membrane potential or threshold potential, but you should know what does:
Potassium regulates resting membrane potential.
Calcium regulates threshold potential.
Select the true statement regarding the primary mechanism of action of local anesthetics.
The uncharged base binds to the intracellular portion of the sodium channel.
The uncharged base binds to the extracellular portion of the sodium channel.
The conjugate acid binds to the intracellular portion of the sodium channel.
The conjugate acid binds to the extracellular portion of the sodium channel.
The conjugate acid binds to the intracellular portion of the sodium channel.
Local anesthetics are weak bases. When they are placed into solution, they dissociate into an uncharged base and its conjugate acid.
You may have been tempted to select the uncharged base. This form of the drug is required for it to gain entry inside the cell. Once inside, however, it’s actually the conjugate acid that binds to the sodium channel.
A patient states she experienced hypotension, tachycardia, and shortness of breath after receiving tetracaine during a previous surgery. Which drugs should be avoided in this patient? (Select 3.)
Chloroprocaine Mepivacaine Cocaine Articaine Benzocaine EMLA cream
Cocaine
Benzocaine
Chloroprocaine
There are two classes of local anesthetics: esters and amides.
Because there is no cross sensitivity between these classes, a patient with an ester allergy may safely receive an amide (and vice versa). Since the preservatives are often the cause of an alleged allergic reaction, a preservative free anesthetic should be selected.
Which characteristics correlate BEST with local anesthetic duration of action?
Protein binding
Lipid solubility
Concentration
pKa
Protein binding
For testing purposes, you should equate: Onset of action + pKa Potency + lipid solubility Duration of action + protein binding In real life, however, it's not this cut and dry. We hope the NCE isn't so picky as to ask you about the secondary variables that influence onset, potency, and duration of action. Just to be safe, we have a handy chart for you on the next page.
Match each local anesthetic with its pKa. Mepivacaine Lidocaine Ropivacaine Chloroprocaine
Mepivacaine + 7.6
Lidocaine + 7.9
Ropivacaine + 8.1
Chloroprocaine + 8.7
The pKa correlates with onset of action. The closer the pKa is to the pH of the blood, the faster the local anesthetic begins to take effect.
As you’ll see on the next page, chloroprocaine has a high pKa and a fast onset of action. Why is this?
Rank the speed of local anesthetic uptake after injection into each location. Intercostal Caudal Brachial plexus Sciatic
Intercostal + 1
Caudal + 2
Brachial plexus + 3
Sciatic + 4
The blood flow to the area where local anesthetic is injected affects duration of action. Furthermore, it affects the concentration of LA in the blood and the risk of systemic toxicity.
Match each local anesthetic with its MAXIMUM allowable dose in the adult. Bupivacaine Ropivacaine Lidocaine Mepivacaine
bupivacaine 175mg
ropivacaine 200mg
lidocaine 300mg
mepivacaine 400mg
At what plasma concentration would you expect lidocaine to produce seizures?
(Enter your answer as a whole number in mcg/mL)
10 – 15 mcg/mL
Lidocaine can cause cardiac and neurologic toxicity. Seizures are most likely to begin when Cp = 10 – 15 mcg/mL.
One minute following an interscalene block, a 62 kg patient has a seizure. How much 20 percent lipid emulsion should you administer?
(Enter your answer as a whole number in mL)
93 mL
Local anesthetic systemic toxicity (LAST) is treated with 20% lipid emulsion at an initial dose of 1.5 mL/kg.
62 kg x 1.5 mL/kg = 93 mL
What is the MAXIMUM recommended dose for lidocaine during tumescent anesthesia?
5 mg/kg
7 mg/kg
55 mg/kg
75 mg/kg
55 mg/kg
When used for tumescent anesthesia, the maximum dose of lidocaine should not exceed 55 mg/kg.
For all other applications, the maximum dose of lidocaine is:
4.5 mg/kg (some texts say 5 mg/kg)
7 mg/kg when epinephrine is added
Which local anesthetics are MOST likely to produce methemoglobinemia? (Select 3.) Ropivacaine Cetacaine Mepivacaine Benzocaine EMLA cream Etidocaine
Benzocaine
Cetacaine
EMLA cream
Methemoglobin is formed when the iron on the hemoglobin molecule becomes oxidized to its ferric form (Fe+3). It decreases oxygen carrying capacity and shifts the oxyhemoglobin dissociation curve to the left.
Benzocaine, cetacaine, and EMLA cream can induce methemoglobinemia.
What is the MAXIMUM dose of EMLA cream for a nine month old infant who weighs 8-kg?
(Enter your answer as a whole number in grams)
Two
EMLA cream contains a 50/50 percent mixture of lidocaine and prilocaine.
The max dose in this patient is 2 g.
All of the following additives prolong the duration of local anesthetics EXCEPT: hyaluronidase. dexamethasone. dextran. epinephrine.
Hyaluronidase
Hyaluronic acid is present in the interstitial matrix and basement membrane. It hinders the spread of substances through tissue.
Hyaluronidase hydrolyzes hyaluronic acid, which facilities diffusion of substances in the tissues.
All of the other answer choices prolong the duration of local anesthetics. These include dexamethasone, dextran, and epinephrine.
Which subunits MUST be occupied to open the nicotinic receptor at the motor end plate? Alpha and gamma Alpha and epsilon Alpha and alpha Alpha and delta
Alpha and alpha
The postsynaptic nicotinic receptor (Nm) is a pentameric ligand-gated ion channel located in the motor endplate at the neuromuscular junction. It is comprised of 5 subunits that align circumferentially around an ion conducting pore.
There are two alpha subunits on this receptor, and both must be occupied by an agonist (Ach or succinylcholine) for the channel to open.
All of the following statements regarding extrajunctional nicotinic receptors are true EXCEPT:
an epsilon subunit replaces a gamma subunit.
it opens for a longer period of time.
denervation allows for its proliferation.
it is opened by choline.
An epsilon subunit replaces a gamma subunit
The extrajunctional nicotinic receptor has a gamma subunit in lieu of an epsilon subunit (not the other way around). This structural change impacts how it responds to succinylcholine.
Fade during train-of-four stimulation is caused by:
impaired presynaptic acetylcholine reuptake.
agonism of presynaptic nicotinic receptors.
antagonism of presynaptic nicotinic receptors.
decreased acetylcholine synthesis.
Antagonism of presynaptic nicotinic receptors
Antagonism of the presynaptic Nn receptor produces fade during train-of-four stimulation. Indeed, this is how nondepolarizers produce fade.
By contrast, agonism of the presynaptic nicotinic receptor prevents fade. This explains why succinylcholine does not produce fade.
Identify the statements that BEST characterize a phase II block following succinylcholine. (Select 2.)
Fade with tetany
Post-tetanic potentiation is absent
Constant but diminished response to double burst stimulation
Prolonged duration
Fade with tetany
Prolonged duration
A phase I block is a normal response to succinylcholine. It is characterized by the absence of post-tetanic potentiation and demonstrates a constant but diminished response to double burst stimulation.
A phase II block occurs with an excessive dose of succinylcholine. It is characterized by fade with tetany as well as a prolonged duration.
Identify the MOST sensitive indicator of recovery from neuromuscular blockade.
Nerve stimulator shows 4/4 twitches with no fade
Tidal volume 6 mL/kg
Vital capacity > 20 mL/kg
Inspiratory force better than – 40 cm H20
Inspiratory force better than – 40 cm H2O
You should be able to match the bedside test of recovery to the maximum percentage of post junctional nAChRs that can remain occupied by the NMB.
A tidal volume of 6 mL/kg is possible when no more than 80% of the receptors are blocked.
A vital capacity that exceeds 20 mL/kg is possible when no more than 70% of the receptors are blocked.
4/4 twitches without fade is possible when no more than 70 – 75% of the receptors are blocked.
An inspiratory force better than – 40 cm H20 is possible when no more than 50% of the receptors are blocked.
Identify the statement that demonstrates the MOST accurate understanding of succinylcholine. (Select 2.)
It is an absolute contraindication with an open globe injury.
Masseter spasm warrants cancellation of the planned procedure.
Severe sepsis increases the risk of hyperkalemia.
Hypertension is a normal side effect.
Hypertension is a normal side effect
Severe sepsis increases the risk of hyperkalemia
Why where the other answers wrong?
Succinylcholine is not absolutely contraindicated with an open globe injury. The risk of eye injury in this context is low, and securing the airway is the top priority.
Masseter spasm may be a warning sign of malignant hyperthermia. It is also a normal effect of succinylcholin
Which enzymes hydrolyze succinylcholine? (Select 3.) True cholinesterase Pseudocholinesterase Type 1 cholinesterase Butyrylcholinesterase Acetylcholinesterase Plasma cholinesterase
Pseudocholinesterase
Butyrylcholinesterase
Plasma cholinesterase
Succinylcholine is metabolized by one enzyme that happens to go by several different names. type 2, butrl, false, plasma and pseudo cholinesterase
Acetylcholine is metabolized by one enzyme that also goes by several different names.Type 1, acetylcholinestersa, true, spcific, genuine
Which factors are associated with a reduction in pseudocholinesterase activity? (Select 3.)
Obesity Myasthenia gravis Esmolol Metoclopramide Edrophonium Late stage pregnancy
Esmolol
Metoclopramide
Late stage pregnancy
You should be familiar with the drugs that reduce pseudocholinesterase activity. Some examples include: metoclopramide, esmolol, echothiophate, oral contraceptives, cyclophosphamide, and neostigmine (not edrophonium).
Late stage pregnancy reduces PChE activity.
Obesity increases PChE activity.
Myasthenia gravis is associated with a resistance to succinylcholine, but this is a pharmacodynamic effect related to a reduced number of nicotinic receptors at the neuromuscular junction (not PChE activity).
A patient with a dibucaine number of 20 received succinylcholine. This patient:
fails to produce pseudocholinesterase in sufficient quantity.
is heterozygous for pseudocholinesterase.
should receive fresh frozen plasma.
will be paralyzed for eight hours.
Will be paralyzed for eight hours
Atypical PChE is a qualitative defect. Pseudocholinesterase is produced in sufficient quantity, however the enzyme that is produced is not functional.
This patient is homozygous (not hetero) for atypical PChE, so he’ll remain paralyzed for 4 – 8 hours.
Although whole blood, fresh frozen plasma, or purified human cholinesterase will restore plasma pseudocholinesterase levels in a patient with an atypical variant, postoperative mechanical ventilation and sedation is the treatment of choice. It is the safest and least expensive option.
The routine administration of succinylcholine is contraindicated in young children because of the possibility of: bradycardia. malignant hyperthermia. trismus. hyperkalemic rhabdomyolysis.
Hyperkalemic rhabdomyolysis
Succinylcholine is contraindicated in young children because of the possibility of hyperkalemic rhabdomyolysis in patients with undiagnosed muscular dystrophy.
Although the rest of the answer choices are troubling events that can occur with the use of succinylcholine, they are not the origin of the black box warning.
Identify the patient at the HIGHEST risk for developing postoperative myalgia following succinylcholine.
6 year old boy for strabismus correction
24 year old female for umbilical hernia repair
86 year old male for total hip arthroplasty
35 year old pregnant patient for appendectomy
24 year old female for umbilical hernia repair
Muscle pain is a side effect of succinylcholine. Young adults (women > men) undergoing ambulatory surgery have the highest incidence of myalgia, while children, the elderly, and pregnant patients seem to have the lowest incidence.
Which diseases are associated with hyperkalemia following succinylcholine administration? (Select 3.) Guillain-Barre Hypokalemic periodic paralysis Myotonic Dystrophy Multiple sclerosis Hyperkalemic periodic paralysis Huntington chorea
Guillain-Barre
Multiple sclerosis
Hyperkalemic periodic paralysis
Succinylcholine can cause hyperkalemia in patients with Guillain-Barre, multiple sclerosis, and hyperkalemic (not hypokalemic) periodic paralysis.
In patients with myotonic dystrophy, succinylcholine can cause muscle contractures that may interfere with ventilation and intubation. There is no risk of hyperkalemia.
Patients with Huntington chorea are sensitive to succinylcholine. There is no risk of hyperkalemia.
Rank the nondepolarizing neuromuscular blockers in terms of potency.
(One is the most potent and four is the least potent) Cisatracurium Rocuronium Atracurium Pancuronium
Cisatracurium + 1
Pancuronium + 2
Atracurium + 3
Rocuronium + 4
Match each drug with the primary event that terminates its effect. Rocuronium Pancuronium Atracurium Cisatracurium
Rocuronium + Biliary excretion
Pancuronium + Renal excretion
Atracurium + Non-specific ester hydrolysis
Cisatracurium + Hofmann elimination
Which drugs potentiate neuromuscular blockade? (Select 3.)
Gentamycin Hydrocortisone Phenytoin Mannitol Desflurane Dantrolene
Desflurane
Gentamycin
Dantrolene
You should know how other drugs affect the duration of action of neuromuscular blockers.
Duration can be prolonged by: volatile anesthetics, aminoglycosides, and dantrolene
Duration can be shorted by: phenytoin
Duration is unaffected by: mannitol and hydrocortisone
Which condition precludes the use of pancuronium? Aortic regurgitation Hypertrophic cardiomyopathy Bradycardia First degree AV block
Hypertrophic cardiomyopathy
Pancuronium is a vagolytic (it increases heart rate). Depending on the patient’s co-morbidities, this can be helpful or harmful.
The vagolytic effect is beneficial in the patient with aortic regurgitation and bradycardia.
In the patient with hypertrophic cardiomyopathy, tachycardia reduces blood flow through the left ventricular outflow tract, ultimately reducing cardiac output.
Which neuromuscular blocker is MOST likely to cause anaphylaxis? Rocuronium Succinylcholine Cisatracurium Atracurium
Succinylcholine
Contrary to some teachings, anaphylaxis is most common with succinylcholine (when compared to the other neuromuscular blockers). Read on for our analysis of this controversial subject…
What type of bond is formed when edrophonium binds to the anionic site on acetylcholinesterase?
Ester
Covalent
Hydrogen
Electrostatic
Electrostatic
Acetylcholinesterase hydrolyzes Ach into choline and acetate. This enzyme can be inhibited at the anionic site and/or the esteratic site, and the type of bond that is formed at these sites determines the drug’s duration of action.
Edrophonium forms an electrostatic bond at the anionic site and a hydrogen bond at the esteratic site. These are weak bonds, which explains its short duration of action.
Neostigmine, pyridostigmine, and physostigmine form a carbamyl ester at the esteratic site. These are stronger bonds, which explains why these drugs have a longer duration of action.
Which statements regarding anticholinesterase drugs are true? (Select 2.)
50 percent of neostigmine is metabolized by the liver.
Renal failure necessitates a second dose.
Edrophonium + neostigmine has a synergistic effect.
Neostigmine is more potent than pyridostigmine.
Neostigmine is more potent than pyridostigmine.
50 percent of neostigmine is metabolized by the liver.
Why were the other answers wrong?
Mixing AchE inhibitors yields an additive (not synergistic) effect.
Renal failure prolongs the duration of action for both AchE inhibitors and NMBs. Since both drugs remain in the body for a longer period of time, there is no need to adjust the dose of the AchE inhibitor or to re-dose it.
Which side effect is LEAST likely to occur following administration of neostigmine? Mydriasis Nausea Bronchospasm Prolonged QT interval
Mydriasis
If you already understand the autonomic nervous system (and you should if you’ve been through our tutorials), you quickly identified that neostigmine causes miosis – not mydriasis.
Compared to atropine, glycopyrrolate is MORE likely to cause: sedation. mydriasis. xerostomia. tachycardia.
Xerostomia
Compared to atropine, glycopyrrolate is more likely to cause xerostomia (dry mouth). This makes it particularly useful for awake fiberoptic intubation as well as oral surgery.
Additionally, glycopyrrolate is a quaternary ammonium and this prevents it from crossing the blood brain barrier.
By contrast, atropine is a tertiary ammonium (it crosses the BBB), so it produces sedation and mydriasis. It’s also associated with a more significant tachycardia
Which neuromuscular blocker is MOST effectively antagonized by sugammadex? Pancuronium Rocuronium Succinylcholine Cisatracurium
Rocuronium
Sugammadex is a gamma-cyclodextrin that encapsulates the aminosteroid neuromuscular blockers in the bloodstream. It has the greatest affinity for rocuronium.
Molecular mechanisms of opioid receptor stimulation include: (Select 2.) increased adenylate cyclase activity. increased potassium conductance. increased calcium conductance. decreased cAMP production.
Increased potassium conductance
Decreased cAMP production
Opioid receptors are linked to G proteins. When an opioid binds to its receptor, several events transpire:
Adenylate cyclase activity is decreased (not increased).
cAMP production is decreased.
Calcium conductance is decreased (not increased). This reduces neurotransmitter release.
Potassium conductance is increased. This hyperpolarizes the nerve, so it’s less responsive to stimulation.
Mu receptor stimulation contributes to all of the following EXCEPT: antishivering effect. bradycardia. miosis. increased biliary pressure.
Antishivering effect
There are three types of opioid receptors: mu, delta, and kappa
From this question, the mu receptor mediates bradycardia, miosis, and increased biliary pressure by constricting the sphincter of Oddi.
An antishivering effect is mediated by kappa stimulation. This explains why meperidine is the only clinically used opioid that is used to reduce shivering.
You’ll absolutely want to know which receptors mediate which side effects.
Match each drug to its potency relative to morphine. Remifentanil Alfentanil Meperidine Sufentanil
Meperidine + 0.1 times
Alfentanil + 10 times
Remifentanil + 100 times
Sufentanil + 1000 times
Which opioid produces an active metabolite? (Select 2.)
Remifentanil
Morphine
Meperidine
Alfentanil
Morphine
Meperidine
In the liver, morphine is conjugated to morphine-3- and morphine-6-glucuronide. M6G is an active metabolite that accumulates with renal failure and chronic morphine administration.
Meperidine is demethylated in the liver to its active metabolite - normeperidine. This metabolite is half as potent as its parent compound and accumulation in patients with renal failure or the elderly increases the risk of seizures.
Remifentanil and alfentanil do not produce active metabolites.
Which drug is associated with anticholinergic side effects?
meperidine.
methadone.
naloxone.
remifentanil.
Meperidine
Meperidine is unique in that is constructed from an atropine-like ring. This explains why meperidine causes mydriasis and elevates heart rate.
The rest of the opioids tend to cause bradycardia and miosis. Miosis is the result of stimulation of the Edinger-Westphal nucleus, which increases PNS tone to the oculomotor nerve and constricts the pupil.
Which pharmacological characteristic accounts for the rapid onset-of-action of alfentanil?
High lipid solubility
Low protein binding
High potency
Low degree of ionization
Low degree of ionization
Alfentanil achieves effect site equilibration in ~ 1.4 min (compared to 6.8 min for fentanyl).
You might be tempted to think that a higher degree of lipid solubility accounts for this, but you’d be mistaken. Instead, it’s all about the pKa.
Alfentanil’s pKa is 6.5, which is less than physiologic pH. This makes it 89% unionized at physiologic pH. This means that there are more molecules in the lipid soluble, non-ionized form to enter the CNS.
Alfentanil’s potency is about 10 times morphine, 1/10th of fentanyl, 1/10th of remifentanil, and 1/100th of sufentanil.
Which agents can be used to attenuate opioid induced hyperalgesia? (Select 2.) Magnesium sulfate Morphine Ketamine Clonidine
Ketamine
Magnesium sulfate
Remifentanil is associated with opioid induced hyperalgesia. This response can be attenuated by ketamine (NMDA receptor antagonist) or magnesium sulfate.
At resting membrane potential, the NMDA receptor is plugged by Mg+2. It should make sense that increasing Mg+2 concentration near the receptor limits receptor activation.
Methadone provides analgesia by all of the following ways EXCEPT:
NMDA receptor antagonism.
mu receptor agonism.
cholinergic receptor antagonism.
monoamine reuptake inhibition.
Cholinergic receptor antagonism
Among the opioids, methadone’s mechanisms of action are unique. It works via three distinct mechanisms:
Mu receptor agonism
NMDA receptor antagonism
Monoamine reuptake inhibition
Which of the following are expected to increase during an episode of opioid induced muscle rigidity? (Select 3.) Thoracic compliance Functional residual capacity Intracranial pressure Oxygen consumption Pulmonary vascular resistance Mixed venous oxygen saturation
Oxygen consumption
Pulmonary vascular resistance
Intracranial pressure
Opioid induced skeletal muscle rigidity causes sustained muscular contraction of the muscles in the abdomen, thorax, and throat. Contraction is an ATP-dependent process, so oxygen consumption is increased. Increased VO2 reduces (not increases) mixed venous oxygen saturation.
Decreased (not increased) chest wall compliance increases intrathoracic pressure. This can elevate ICP.
An opioid dependent patient is scheduled for a cesarean section. Side effects of naloxone administration in this patient include all of the following EXCEPT: bradycardia. neonatal opioid withdrawal syndrome. pulmonary edema. nausea.
Bradycardia
Naloxone is the prototype opioid antagonist. Acute reversal of analgesia activates the SNS (tachycardia and hypertension). A significant rise in afterload can precipitate cardiac failure and pulmonary edema. Naloxone also causes nausea and vomiting.
Opioids cross the placenta, so the fetus of an opioid dependent mother is also dependent. Naloxone also crosses the placenta. It can cause a state of acute withdrawal in both mother and baby.
Rank the sensitivity of each nerve fiber type to the physiologic effects of local anesthetics in vivo.
(One is the most sensitive and four is the least sensitive)
1 + B fibers
2 + C fibers
3 + A delta fibers
4 + A alpha fibers
Differential blockade refers to how susceptible nerve fibers are to local anesthetic conduction block. Laboratory findings often differ from clinical experience.
In vivo, local anesthetics inhibit peripheral nerves in the following order (first to last):
B fibers
C fibers
A fibers (smaller diameter)
A fibers (larger diameter)
As a general rule, the fibers that are blocked first are the slowest to recover.
The primary mechanism of action for local anesthetics blockade is: G-protein coupled sodium channels. voltage-gated sodium channels. metabotropic calcium channels. voltage-gated potassium channels.
Voltage-gated sodium channels
Local anesthetics reversibly bind to the alpha subunit of the voltage-gated sodium channel. Plugging the channel reduces sodium conductance and interrupts the creation and propagation of action potentials in the axon.
The voltage-gated sodium channel contains 1 alpha subunit and several beta subunits. The alpha subunit forms the entire ion conduction pore.
Saltatory conduction occurs in all of the following nerve types EXCEPT:
A gamma fibers.
A delta fibers.
B fibers.
C fibers.
C fibers
Axons in the peripheral nerves differ in their size, structure, speed of conduction, myelination, and sensitivity to local anesthetic blockade. For example, conduction velocity is faster in axons with a wider diameter as well as those with myelination. Myelin insulates the axon and allows the electrical current to skip along only the uninsulated regions, known as the nodes of Ranvier. This process is called saltatory conduction.
Critical to answering this question was also knowing which type of nerve fiber lacks myelination. It looks like you got this one right, so nice job!
Regarding the structure of local anesthetics, match each molecular component with its medicinal chemistry.
Regarding the structure of local anesthetics, match each molecular component with its medicinal chemistry.
The local anesthetic molecule is constructed from 3 key components:
1. Benzene Ring: Lipophilic (permits diffusion through lipid bilayers) 2. Intermediate Chain: Class - ester or amide Metabolism Allergic potential
- Tertiary Amine:
Hydrophilic
Accepts proton
Makes molecule a weak base
*Nagelhout says it’s a quaternary amine, but this isn’t right.
Local anesthetic potency BEST correlates with:
pKa.
lipid solubility.
concentration.
duration of action.
Lipid solubility
As a general rule:
Onset of action = pKa
Potency = Lipid solubility
Duration of action = Protein binding (receptor)
Although this is a bit of an oversimplification, it is essential that you know this!
Rank the local anesthetics according to their degrees of ionization at physiologic pH.
(One is the most ionized and four is the least ionized) Chloroprocaine Tetracaine Bupivacaine Lidocaine
1 + Chloroprocaine
2 + Tetracaine
3 + Bupivacaine
4 + Lidocaine
Remember that the pKa is the pH where 50% of a drug exists as the uncharged base (unionized) and 50% of the drug exists as the conjugate acid (ionized).
Acid in acid = unionized Base in base = unionized Acid in base = ionized Base in acid = ionized Since we are putting a base (local anesthetic) in a relatively acidic medium (blood), then the drugs with the highest pKa tend to ionize the most and the drugs with the lowest pKa tend to ionize the least. Let's look at those listed in the question.
Chloroprocaine pKa = 8.7-9.1 (most ionized)
Tetracaine pKa = 8.4
Bupivacaine pKa = 8.1
Lidocaine pKa = 7.8 (least ionized)
*Understand that pKa values are a little different in each book, however the ranking of agents is usually the same.
Which local anesthetic is unionized at physiologic pH?
Dibucaine
Ropivacaine
Cocaine
Benzocaine
Benzocaine
You already know that local anesthetics are weak bases that are ionized (charged) at physiologic pH, but did you also know that benzocaine is the odd man out? It’s the only clinically available local anesthetic with a pKa well below physiologic pH (benzocaine pKa = 3.5).
What’s the significance of this? Benzocaine is unionized at physiologic pH, yet it possesses anesthetic activity. For all other local anesthetics, the charged species is required to produce the anesthetic effect.
Benzocaine is useful for topical anesthesia of the mucus membranes during endoscopy, TEE placement, and bronchoscopy.
Methemoglobinemia is a side effect of benzocaine. This risk greatly increases when the total dose exceeds 200-300 mg.
Select the BEST local anesthetic to use for a subarachnoid block in the patient who has a sensitivity to bupivacaine. Lidocaine Etidocaine Chloroprocaine Tetracaine
Tetracaine
There are two parts to this question.
- ) This patient has a sensitivity to bupivacaine, so you had to choose an ester. This narrowed your choices to tetracaine and chloroprocaine. Remember that the “i-caine” drugs belong to the class of amide agents.
- ) You also had to know that chloroprocaine is NOT used for spinal anesthesia. Although the literature is unclear, neurotoxicity may be directly related to chloroprocaine or its preservative (bisulfite). Other data suggest that bisulfite may actually be protective! While you don’t need to know these minutiae, you must know that subarachnoid chloroprocaine is associated with neurotoxicity.
Which local anesthetic is the LEAST protein bound in the plasma? Lidocaine Prilocaine Chloroprocaine Bupivacaine
Chloroprocaine
Chloroprocaine is an ester local anesthetic that is rapidly metabolized from the plasma. Because of this, plasma protein binding with this drug is assumed to be nil.
We’ve ranked the degree of plasma protein binding below:
Levo-bupivacaine = 98% Bupivacaine = 96% Ropivacaine = 94% Mepivacaine = 78% Tetracaine = 76% Lidocaine = 65% Prilocaine = 55% Procaine = 6% Chloroprocaine = 0%
Rank the speed of local anesthetic uptake after injection into the following sites.
(One is the fastest and four is the slowest)
1 + Intrapleural
2 + Intercostal
3 + Caudal
4 + Epidural
For most drugs we administer, systemic absorption begins the process of delivering a drug to its site of action. Local anesthetics are different. We administer these drugs directly to their site of action. Absorption into the systemic circulation removes the LA from its site of action and contributes to the termination of its effect. At the same time, a higher amount of vascular uptake contributes to a higher plasma concentration. This may result in toxicity.
You must know how fast LAs are transferred into the systemic circulation from a variety of sites. The most vascular site (fastest uptake) is listed first.
Interpleural Intercostal Caudal Epidural Brachial plexus Femoral Sciatic Subcutaneous The takeaway is that local anesthetic toxicity is greater after an interpleural block than with a sciatic block.
One minute following an axillary block, a 36 kg patient has a seizure. How much 20% lipid emulsion should you administer?
(Enter your answer as a whole number in mL)
54 mL
Local anesthetic systemic toxicity (LAST) is treated with 20 percent lipid emulsion at a dose of 1.5 mL/kg (lean body mass) over one minute. Follow with an infusion of 0.25 mL/kg/min.
This patient weighed 36 kg, so the initial dose is 54 mL (36 kg x 1.5 mL/kg).
If symptoms are slow to resolve, repeat bolus up to two more times and increase infusion to 0.5 mL/kg/min.
Continue infusion for 10 minutes after achieving hemodynamic stability.
The maximum recommended dose is 10 mL/kg in the first 30 minutes.
Propofol is NOT a substitution for lipid emulsion therapy!
This question could’ve asked you to calculate the dose in mg to be administered. Remember that this is a 20 percent lipid emulsion. Pay attention to what the question asks of you.
How many mL of a 0.5 percent bupivacaine solution can be safely injected into a child weighing 35 kg?
17.5 mL
The maximum weight based dose for bupivacaine is 2.5 mg/kg. If epinephrine is added, then the dose can be increased to 3 mg/kg.
35 kg x 2.5 mg/kg = 87.5 mg
Then you have to cross multiply…
5 mg / 1 mL = 87.5 mg / ? mL
Maximum allowable volume of 0.5% bupivacaine = 17.5 mL
Identify the factors that increase the risk of local anesthetic systemic toxicity. (Select 2.) Hypercarbia Local anesthetic potency Alkalosis Hypokalemia
Local anesthetic potency
Hypercarbia
Higher potency local anesthetics are more likely to produce CNS toxicity.
Hypercarbia/Acidosis:
Increases cerebral blood flow, which increases drug delivery to the brain. Reduces protein binding, and this increases the free fraction available to the brain.
Promotes ion trapping inside the brain.
Lowers the seizure threshold.
The clinical implications of this cannot be overemphasized!
Seizures → hypoventilation → respiratory acidosis → ↑ CNS toxicity.
Hyperkalemia:
Raises resting membrane potential, making neurons more likely to fire.
What metabolite of ester-type local anesthetics is MOST likely to cause a type I hypersensitivity reaction?
O-toluidine
Para-aminobenzoic acid
Methylparaben
Metabisulfite
Para-aminobenzoic acid
A type I hypersensitivity reaction is another name for anaphylaxis. Although rare, this can occur in response to local anesthetic exposure. It is more common with ester-based local anesthetics.
Ester-type local anesthetics undergo hydrolysis in the plasma, producing para-aminobenzoic acid (PABA). This compound is antigenic.
Although true allergy to the amide-based local anesthetics is incredibly rare, many of these agents are prepared with methylparaben as a preservative. This compound is similar to PABA and can also precipitate an allergic response. Metabisulfite is another presevative that can cause an allergic response.
There is no cross sensitivity between esters and amides, however it is best practice to give a preservative free amide to a patient with an ester allergy.
Choose the statements that MOST accurately describe EMLA cream. (Select 2.)
Analgesia is achieved within 15 minutes.
Compared to adults, infants are more susceptible to methemoglobinemia.
A dressing should be applied after EMLA is applied to the patient.
Procaine is metabolized to o-toluidine.
Compared to adults, infants are more susceptible to methemoglobinemia
A dressing should be applied after EMLA is applied to the patient
5 percent EMLA cream is a 50/50 combination of 2.5 percent lidocaine and 2.5 percent prilocaine.
It produces analgesia within 1 hour (not 15 minutes) and achieves maximum effect after 2-3 hours.
A dressing should be applied after EMLA is applied to the patient.
Prilocaine (not procaine) is metabolized to o-toluidine, which oxidizes hemoglobin to methemoglobin. Infants and small children are more likely to become toxic.
What is the MAXIMUM dose of cocaine that can be used as a topical vasoconstrictor?
(Enter your answer in mg)
150 mg or 200 mg
Barash says that the dose range for cocaine is 1.5 – 3.0 mg/kg, not to exceed 200 mg. Stoelting says that the maximum dose is 150 mg. We accepted both answers.
Cocaine (an ester) is the only local anesthetic with vasoconstrictive properties. It inhibits NE reuptake into the presynaptic nerve terminal - it does NOT cause the release of endogenous NE.
Cocaine should be avoided with MAOIs, TCAs, or sympathomimetic drugs. Beta-blockade in the setting of cocaine overdose is a questionable practice that allows for unopposed alpha-1 stimulation. High SVR (alpha-1 stimulation) and reduced inotropy (beta-1 antagonism) set the stage for cardiovascular collapse. A vasodilator such as nitroglycerine is best, but if you are given a list of beta-blockers, then labetalol (or another mixed alpha and beta antagonist) is the correct choice.
Which of the following illustrations BEST represents the mechanism of action of a local anesthetic?
Which of the following illustrations best represents the mechanism of action of a local anesthetic?
After you inject local anesthetic around a nerve, the local anesthetic rapidly dissociates into an uncharged base (LA) and an ionized, conjugate acid (LA+).
The uncharged base (LA) enters the axon, and once inside the nerve, a new equilibrium is established
Only the ionized, conjugate acid (LA+) binds to the local anesthetic binding site (alpha-subunit) on the inside of the voltage-gated sodium channel.
The sodium channel remains in the closed, inactivated state until enough local anesthetic diffuses away.
All of the following ions pass through the nicotinic receptor at the neuromuscular junction EXCEPT:
sodium.
calcium.
chloride.
potassium.
Chloride
The neuromuscular junction is populated by M-type nicotinic receptors (M = muscle). After two acetylcholine molecules bind to the two alpha subunits of the nicotinic receptor, the receptor opens allowing Na+ and Ca+2 to flow into the cell and K+ to flow out of the cell.
Anions, such as Cl-, can’t pass through the nicotinic receptor. They are repelled by the strong negative charge inside the channel.
Succinylcholine is metabolized by: (Select 2.)
acetylcholinesterase.
plasma cholinesterase.
butyrylcholinesterase.
type 1 cholinesterase.
Butyrylcholinesterase
Plasma cholinesterase
We hope you’re already familiar with acetylcholinesterase and plasma cholinesterase, but each one has a bunch of synonyms.
Enzymes that metabolize succinylcholine and mivacurium:
Type 2 cholinesterase False cholinesterase Butyrylcholinesterase Plasma cholinesterase Pseudocholinesterase Enzymes that metabolize acetylcholine:
Type 1 cholinesterase Genuine cholinesterase Specific cholinesterase True cholinesterase Acetylcholinesterase
Which antiemetic can prolong succinylcholine's duration of action? Scopolamine Metoclopramide Droperidol Ondansetron
Metoclopramide
Pseudocholinesterase is synthesized by the liver.
Elimination half-time = 8 - 16 hours
Succinylcholine is prolonged when serum concentration is less than 75 percent of normal
Anything that impairs the ability of pseudocholinesterase to hydrolyze succinylcholine will increase the duration of action for succinylcholine. Of course this assumes that all other factors remain unchanged. Examples include:
PChE inhibitors (echothiopate, neostigmine, pyridostigmine) Metoclopramide Monoamine oxidase inhibitors Cyclophosphamide Esmolol (this is very short lived) Severe liver disease Malnutrition Although pregnancy is associated with increased estrogen, succinylcholine’s duration of action is not prolonged. This is best explained by an increased Vd.
Interpret each dibucaine number
80 + Homozygous typical plasma cholinesterase
50 + Heterozygous atypical plasma cholinesterase
20 + Homozygous atypical plasma cholinesterase
Dibucaine is an amide local anesthetic that inhibits normal plasma cholinesterase. It has no effect on atypical PChE. The number reflects the percentage of normal enzyme that is inhibited by dibucaine.
Homozygous typical = 70 - 80%
Heterozygous atypical = 50 - 60%
Homozygous atypical = 20 - 30%
Duration of action for succinylcholine:
Homozygous typical = 5 - 10 minutes
Heterozygous atypical = 20 - 30 minutes
Homozygous atypical = 4 - 8 hours
All of the following have been shown to reduce the incidence of postoperative myalgia following the administration of succinylcholine EXCEPT:
lidocaine.
ketorolac.
fentanyl.
use of a higher dose rather than a lower dose of succinylcholine.
Fentanyl
The incidence of myalgia can be minimized, but not entirely eliminated, by pretreatment with a nondepolarizing neuromuscular blocker. The dose is 1/10th of the ED95.
Other methods that may reduce the risk of myalgia include:
NSAIDs
Lidocaine 1.5 mg/kg
Use of a higher dose rather than a lower dose of succinylcholine
Opioids do not decrease the incidence of myalgia.
Patients at the greatest risk of myalgia include young adults undergoing ambulatory surgery (women > men) and those that do not routinely engage in strenuous activity. Children, the elderly, and pregnant patients seem to have the lowest rate of occurrence.
Which neuromuscular blocking agents are aminosteroid compounds? (Select 2.)
Pancuronium
Mivacurium
Atracurium
Vecuronium
Vecuronium
Pancuronium
Neuromuscular blockers are classified as depolarizing or non-depolarizing.
Succinylcholine is the only clinically used depolarizing NMB.
Non-depolarizing NMBs are classified as aminosteroid or benzylisoquinolinium compounds.
Aminosteroids = rocuronium, vecuronium, pancuronium
Benzylisoquinoliniums = atracurium, cisatracurium, mivacurium
Match each neuromuscular blocker with its ED95.
Succinylcholine + 0.30 mg/kg
Atracurium + 0.21 mg/kg
Vecuronium + 0.04 mg/kg
When thinking about the potency of any drug, all you have to do is compare the dosages. The higher the dose you have to give to achieve a given effect, the lower its potency.
The ED95 is a Measure of Potency - They are inversely related
In the context of neuromuscular blockers, the ED95 is the dose at which there is a 95% decrease in twitch height. This is different than the intubating dose!
The dose required to provide optimal conditions for tracheal intubation is ~ 2 – 3 times the ED95. ED95 of all of the clinically used NMBs (most potent to least potent): Cisatracurium = 0.04 mg/kg Vecuronium = 0.043 mg/kg Mivacurium = 0.067 mg/kg Pancuronium = 0.067 mg/kg Atracurium = 0.21 mg/kg Succinylcholine = 0.30 mg/kg Rocuronium = 0.305 mg/kg
The duration of action of cisatracurium is prolonged by:
hypothermia.
metabolic alkalosis.
hepatic failure.
homozygous atypical pseudocholinesterase.
Hypothermia
Atracurium and cisatracurium undergo organ independent elimination.
Atracurium = non-specific plasma esterases > Hofmann elimination Cisatracurium = Hofmann elimination
Hoffman elimination is dependent on pH and temperature.
Hypothermia and metabolic acidosis prolong duration of action.
Hyperthermia and metabolic alkalosis shorten duration of action.
Both produce laudanosine as a metabolite (atracurium produces more). Laudanosine is a CNS stimulant that can theoretically produces seizures. This is not a problem with routine dosing in the OR.
Choose the BEST neuromuscular blockers to administer to a patient with hypertrophic cardiomyopathy. (Select 2.)
Pancuronium
Cisatracurium
Atracurium
Vecuronium
Cisatracurium
Vecuronium
Obstructive cardiomyopathy (idiopathic hypertrophic subaortic stenosis) causes left ventricular outflow tract obstruction. This is the result of:
Congenital hypertrophy of the intraventricular septum.
Systolic anterior motion (SAM) of the anterior leaflet of the mitral valve.
The obstruction is made worse by any condition that causes narrowing of the LVOT. This includes a/an: Increased heart rate Increased contractility Decreased preload Decreased aortic pressure Decreased afterload
Pancuronium is a vagolytic that increases heart rate.
Atracurium and mivacurium release histamine, which increases heart rate and reduces afterload.
- Hines p. 137 states incorrectly that a reduced afterload improves LVOT obstruction.
Which inhaled anesthetic potentiates the neuromuscular blocking effect of nondepolarizing neuromuscular blockers the MOST
Sevoflurane
Isoflurane
Nitrous oxide
Desflurane
Desflurane
Inhalation anesthetics work in the ventral horn of the spinal cord to produce immobility. Therefore, it should make sense that the inhaled agents potentiate the neuromuscular blocking effects of nondepolarizing NMBs. This means that, in the presence of an inhaled anesthetic, the level of blockade is deeper and duration of action is longer for a given dose of NMB.
The inhaled anesthetics are ordered from most potentiation to least potentiation (propofol is added for comparison):
Des > Sevo > Iso > N2O > Propofol
There are several possible explanations for this including:
A central effect on alpha motor neurons and their synaptic connections.
Inhibition of postjunctional nicotinic receptors at the NMJ.
Increased NMB affinity at the postjunctional nicotinic receptors at the NMJ.
Which antibiotics prolong the duration of action of vecuronium? (Select 2.)
Penicillin G
Clindamycin
Gentamycin
Cefazolin
Gentamycin
Clindamycin
Some antibiotics potentiate neuromuscular blockade.
Agents that inhibit Ach release and reduce the sensitivity of the postjunctional nicotinic receptor to the effect of Ach:
Aminoglycosides (gentamycin, streptomycin)
Clindamycin
Lincomycin
Polymyxins
Agents that reduce the sensitivity of the postjunctional nicotinic receptor to the effect of Ach:
Tetracycline
Which of the following neuromuscular blockers is MOST likely to increase airway resistance?
Cisatracurium
Pancuronium
Mivacurium
Rocuronium
Mivacurium
Atracurium and mivacurium stimulate histamine release from mast cells.
Physiologic effects of histamine release include:
Increased airway resistance Increased heart rate Decreased systemic vascular resistance Decreased blood pressure Skin flushing It is best to avoid atracurium or mivacurium in patients who are sensitive to a/an:
Increased heart rate (hypertrophic cardiomyopathy)
Decreased afterload (aortic stenosis)
Increased airway resistance (asthma)
Select the BEST intraoperative test to confirm the diagnosis of an anaphylactic response caused by a neuromuscular blocker. White blood cell count with differential Tryptase Intradermal skin test Homocysteine
Tryptase
Anaphylaxis is the result of mast cell activation.
An elevated tryptase level is consistent with mast cell degranulation. The serum tryptase concentration peaks between 15 – 120 minutes.
An elevated serum histamine concentration peaks at 60 – 90 minutes.
Intradermal skin testing is used to diagnose the allergic potential of a given drug in a particular patient, however it isn’t helpful in determining if a reaction has already occurred.
An elevated homocysteine level is associated with vascular inflammation and may increase the risk of cardiovascular disease.
Select the BEST location to monitor the onset of neuromuscular blockade.
Trigeminal nerve
Oculomotor nerve
Facial nerve
Ulnar nerve
Facial nerve
When using a nerve stimulator, observe the following rules:
Best location to monitor onset:
Nerve = facial Muscle = orbicularis oculi or corrugator supercilii
Best location to monitor recovery:
Nerve = ulnar
Muscle = adductor pollicis
Match each muscle with its mechanical action.
Corrugator supercilii + Moves the eyebrow
Orbicularis oculi + Closes the eyelid
Medial rectus + Adducts the eyeball
Adductor pollicis + Adducts the thumb
The corrugator supercilii moves the eyebrow. It is innervated by the facial nerve (CN VII).
The orbicularis oculi closes the eyelid. It is innervated by the facial nerve (CN VII).
The adductor pollicis adducts the thumb. It is innervated by the ulnar nerve.
The medial rectus adducts the eyeball. It is innervated by the oculomotor nerve (CN III).
The adductor pollicis muscle can be stimulated by placing the negative electrode at points: (Select 2.) A. B. C D.
B
C
Stimulation of the ulnar nerve results in contraction of the adductor pollicis muscle. Visually this appears as thumb ADDuction; not pinky finger ADDuction or flexion.
The adductor pollicis recovers later than the diaphragm, laryngeal adductors, and abdominal muscles, however it recovers at the same time as the geniohyoid. The take away is that if the adductor pollicis is not recovered, then the geniohyoid probably isn’t either and this increases the risk of upper airway obstruction.
Stimulation of the ulnar nerve at the wrist:
Negative electrode = C
Positive electrode = D
Stimulation over the adductor pollicis muscle:
Negative electrode = B
Positive electrode = A
Remember the red wire of the nerve stimulator is Positive and placed Proximal. The black wire is distal and black.
The risk of pulmonary aspiration increases when the train-of-four ratio measured at the adductor pollicis is less than:
- 9.
- 8
- 7
- 6
0.9
A train-of-four ratio less than 0.9 at the adductor pollicis is associated with:
Impaired pharyngeal function and swallowing
Decreased upper esophageal sphincter tone
Taken together, these consequences increase the risk of pulmonary aspiration.
The patient may appear to be strong enough to maintain ventilation, however once the endotracheal tube is removed, the upper airway and pharyngeal musculature may not be strong enough to maintain upper airway patency or protect the airway.
Which finding is MOST consistent with recovery from neuromuscular blockade in a 70 kg patient?
Vital capacity = 1,400 mL
Tidal volume = 350 mL
Train-of-four monitor reveals 4 equal twitches
Patient holds tongue blade in mouth against force
Patient holds tongue blade in mouth against force
The upper airway is the most sensitive component of the respiratory system. Indeed, upper airway tone is impaired and aspiration is a risk when the TOF ratio is < 0.9.
Most sensitive bedside assessments of recovery:
Head lift > 5 seconds
Leg lift > 5 seconds
Holding tongue depressor between teeth against force (of these, Barash thinks this is the best)
Select the BEST acetylcholinesterase inhibitor to antagonize a block with 90 percent twitch suppression.
Physostigmine
Edrophonium
Pyridostigmine
Neostigmine
Neostigmine
Many books say that neostigmine adequately reverses a block with 90 percent twitch suppression, however this is a function of how we define full recovery.
Older data suggests that full respiratory recovery occurs at a TOF ratio of 0.6 at the adductor pollicis. Newer data suggests that upper airway dilator tone and hypoxic ventilatory drive are impaired up to a TOF ratio of 0.9! For this reason, we recommend that you wait to reverse until you have a minimum of two twitches.
Although edrophonium is as effective as neostigmine in reversing mild to moderate neuromuscular blockade (2 – 4 twitches), it fails to adequately reverse profound relaxation (90 percent twitch depression or one twitch).
Physostigmine has a prolonged onset, making it less attractive. Also, it is the only acetylcholinesterase inhibitor that diffuses across the blood-brain barrier. CNS side effects limit its utility as a reversal agent.
Neostigmine antagonizes rocuronium by:
reversibly binding to butyrylcholinesterase.
decreasing acetylcholine hydrolysis.
potentiating acetylcholinesterase activity.
competing with rocuronium at the nicotinic receptor.
Decreasing acetylcholine hydrolysis
Neostigmine is a cholinesterase inhibitor that reversibly binds to the enzyme acetylcholinesterase at the NMJ. This process inhibits acetylcholine hydrolysis, thus allowing more acetylcholine to compete with the NMBA at the nicotinic receptors. This is an example of competitive antagonism.
The offset of NMBAs is also influenced by its diffusion away from the NMJ, redistribution, metabolism, and excretion.
Butyrylcholinesterase, (another name for plasma cholinesterase or pseudocholinesterase) is concentrated in the plasma. It, too, is inhibited by neostigmine. Butyrylcholinesterase metabolizes succinylcholine, mivacurium, and local anesthetics.
Match the acetylcholinesterase inhibitor to its dose.
Neostigmine + 0.05 mg/kg
Edrophonium + 1 mg/kg
Pyridostigmine + 0.3 mg/kg
If you were asked to line these up according to potency, the drug with the smallest dose (neostigmine) is the most potent and the one with the largest dose is the least potent (edrophonium).
In the PACU, an 85-year-old female who received scopolamine is agitated and confused. What is the BEST intervention at this time? Midazolam Physostigmine Pyridostigmine Reduce environmental stimuli
Physostigmine
Scopolamine crosses the BBB and may cause central anticholinergic syndrome. The elderly are particularly vulnerable. Symptoms include confusion, agitation, hallucinations, somnolence, and unconsciousness.
Physostigmine (15 - 60 mcg/kg) is the only AchE inhibitor that crosses the BBB. It is the antidote for antimuscarinic overdose. It is dosed q1-2 hr. Central anticholinergic syndrome is often mistaken for slow emergence from anesthesia.
Pyridostigmine does not cross the BBB, so it won’t benefit this patient. Midazolam does not reverse the etiology of this patient’s confusion, so it’s not the best choice. Reducing environmental stimuli can also be useful, but again it doesn’t reverse the cause of confusion, so it’s not the best option.
Which acetylcholinesterase inhibitors in clinical use prolong the duration of succinylcholine? (Select 2.)
Pyridostigmine
Edrophonium
Neostigmine
Physostigmine
Neostigmine
Pyridostigmine
Succinylcholine is hydrolyzed by pseudocholinesterase in the plasma. AchE inhibitors inhibit acetylcholinesterase at the NMJ and neostigmine and pyridostigmine (not edrophonium) inhibit pseudocholinesterase in the plasma.
If succinylcholine is administered shortly after neostigmine or pyridostigmine, then succinylcholine’s duration of action will be prolonged.
Physostigmine crosses the BBB, so its CNS side effects limit its utility as a reversal agent.
Match the drug to its onset of action. Assume that there is a steady state concentration of nondepolarizing neuromuscular blocker in the plasma.
Edrophonium + 1 minutes
Neostigmine + 10 minutes
Pyridostigmine + 15 minutes
At a steady state concentration of NMBA in the plasma, the onset of action for the AchE inhibitors is:
Edrophonium: 1 min
Neostigmine: 7 - 11 min
Pyridostigmine: Up to 16 min
Select the BEST statement regarding the use of an anticholinergic agent and edrophonium when used to antagonize neuromuscular blockade.
Glycopyrrolate should be mixed in the same syringe as edrophonium.
Atropine should be avoided because of CNS side effects.
Atropine is given after edrophonium.
Atropine pairs better than glycopyrrolate.
Atropine pairs better than glycopyrolate
This question deals with the pharmacokinetics of antimuscarinics. Since the onsets and durations are similar, atropine can be mixed with edrophonium and glycopyrrolate can be mixed with neostigmine. This explains why atropine is “better” than glycopyrrolate when edrophonium is selected. You should’ve been able to exclude the rest of the answer choices to arrive at this answer.
Mixing glycopyrrolate and edrophonium in the same syringe will cause profound bradycardia. The same complication can occur if you administer atropine after edrophonium.
While atropine does cross the BBB, it remains an acceptable choice when it is paired with edrophonium.
Correct Answer:
Edrophonium + 1 minutes
Neostigmine + 10 minutes
Pyridostigmine + 15 minutes
At a steady state concentration of NMBA in the plasma, the onset of action for the AchE inhibitors is:
Edrophonium: 1 min
Neostigmine: 7 - 11 min
Pyridostigmine: Up to 16 min
All of the following are well absorbed from the gastrointestinal tract EXCEPT:
atropine.
pyridostigmine.
scopolamine
glycopyrrolate.
Glycopyrrolate
Atropine and scopolamine are naturally occurring tertiary amines, which makes them lipophilic. These drugs easily diffuse through lipid membranes like the blood-brain barrier, GI tract, and placenta.
Pyridostigmine is the longest acting AchE inhibitor. It’s a first-line medical therapy for myasthenia gravis.
Glycopyrrolate is different. It has a quaternary ammonium that ionizes in the plasma. This limits its ability to cross cell membranes, which explains why it doesn’t pass through the BBB, GI tract, or placenta.
Rank the following drugs according to their tendency to cause cycloplegia.
(+++ is most likely and 0 is least likely)
Scopolamine +++
Atropine ++
Glycopyrolate 0
Cycloplegia is paralysis of the ciliary muscle in the eye, resulting in loss of accommodation. Remember the comparison list we gave you in the corresponding tutorial? You’d be wise to memorize it.
Sugammadex antagonizes a nondepolarizing neuromuscular blockade by encapsulating:
rocuronium only.
benzylisoquinolines.
aminosteroids.
benzylisoquinolines and aminosteroids.
Aminosteroids
Sugammadex is a cyclodextrin that encapsulates all aminosteroids, however it is most selective for rocuronium. Its affinity for the aminosteroids is:
rocuronium > vecuronium > pancuronium
Sugammadex does not reverse benzylisoquinolines or succinylcholine.
Match each opioid agonist with its respective drug class.
Fentanyl + Phenylpiperidine
Morphine + Phenanthrene
Methadone + Diphenylpropylamine
Opioid agonists and antagonists are classified as naturally occurring, semisynthetic, and synthetic.
Naturally Occurring:
Phenanthrene derivatives (morphine, codeine)
Semisynthetic:
Morphine derivatives (hydromorphone, heroin, naloxone, naltrexone)
Thebaine derivatives (oxycodone)
Synthetic:
Phenylpiperidines (meperidine, fentanyl, sufentanil, remifentanil, alfentanil)
Phenylheptylamines (methadone)
Identify the physiologic effects commonly associated with mu receptor stimulation. (Select 3.)
Diuresis Antishivering effect Respiratory depression Bradycardia Dysphoria Pruritis
Bradycardia
Respiratory depression
Pruritus
Opioid receptors are divided into three categories: Mu, Delta, and Kappa.
Mu Receptor:
There is no evidence to support the existence of separate mu1 and mu-2 receptors.
Key effects of mu stimulation include supraspinal and spinal anesthesia, euphoria, sedation, respiratory depression, bradycardia, pruritus, miosis, constipation, N/V, increased biliary pressure, and urinary retention.
Kappa Receptor:
Key effects of kappa stimulation include dysphoria, antishivering effect, and diuresis.
Delta Receptor
If you understand mu and kappa effects, then you can probably get by not knowing much about the delta receptor.
Know that delta receptors do not mediate bradycardia or sedation.
Which opioid side effects are most resistant to tolerance? (Select 2.) Miosis Respiratory depression Constipation Emetic effects
Miosis
Constipation
Tolerance occurs when a patient requires higher doses of a drug to achieve a given effect. It can occur without physical dependence, however the opposite isn’t usually true.
Tolerance and physical dependence are most likely due to receptor desensitization and increased synthesis of cAMP. These phenomena are not due to enzyme induction. There is cross-tolerance among the opioid antagonists.
The time table for tolerance is dependent on the particular drug; it tends to occur faster with the more potent agents.
Tolerance develops to nearly all of the side effects associated with opioids. This includes analgesia, sedation, euphoria, respiratory depression, and emetic effects. There are 2 exceptions to this rule. Tolerance does NOT develop to miosis and constipation.
A patient becomes hypotensive after 10 mg of intravenous morphine. What is the LEAST likely explanation for this finding?
Decreased preload
Histamine release
Myocardial depression
Decreased sympathetic tone
Myocardial depression
As a general rule, opioids don’t cause myocardial depression. Meperidine is the exception to the rule (usually with higher doses).
Cardiovascular side effects of opioids include:
↓ SNS tone → venous pooling → ↓ preload → ↓ CO → ↓ BP
↓ SNS tone → orthostatic hypotension
Histamine release → ↓ BP (only morphine and meperidine)
In women, morphine is associated with a:
shorter duration of action.
greater analgesic potency.
higher post-operative opioid consumption.
faster onset of action.
Morphine has a greater analgesic potency
Gender plays a role in the PK/PD differences among opioid agonists.
In women, morphine is associated with a:
Greater analgesic potency Slower onset of action Longer duration of action Lower post-operative opioid consumption
Anesthesia is induced in a healthy 35 year-old male with propofol 160 mg, sufentanil 150 mcg, and succinylcholine 120 mg. After 1 minute he becomes impossible to ventilate. What is the MOST likely explanation for this situation?
Skeletal muscle rigidity
Bronchospasm
Pulmonary embolism
Malignant hyperthermia
Bronchospasm
Be careful with questions that try to lead you down a particular path.
Rapid IV administration of opioids can cause skeletal muscle rigidity. This condition is more common with the potent (lipophilic) compounds, such as sufentanil, fentanyl remifentanil, and alfentanil. Historically, this complication has been described as chest wall rigidity or stiff chest syndrome, however current evidence suggests that the greatest resistance to ventilation occurs at the larynx.
This patient became difficult to ventilate after receiving succinylcholine. If skeletal muscle rigidity was the cause, then succinylcholine would’ve improved ventilation. Indeed, NMBs are the primary treatment for opioid-induced skeletal muscle rigidity, although naloxone works as well.
What else could’ve caused this situation? Succinylcholine releases histamine. This can cause bronchospasm, making mask ventilation difficult or even impossible. As an aside, don’t forget that NMBs only relax skeletal muscle and not smooth muscle – they do not treat bronchospasm!
Pulmonary embolism causes hypoxemia, however ventilation would remain possible. Malignant hyperthermia does not make sense in this context.
Match each opioid agonist to its unique characteristic. Methadone Codeine Sufentanil Alfentanil
Methadone + QT interval prolongation
Codeine + Metabolized to morphine
Sufentanil + Most potent opioid
Alfentanil + pKa is less than physiologic pH
Codeine is metabolized to morphine by CYP2D6. Asians tend to have lower CYP2D6 activity, making this population resistant to codeine therapy. Conversely, Ethiopians have significant CYP2D6 activity, making this population sensitive to codeine therapy.
Sufentanil is the most potent opioid agonist. It is 1000 times the potency of morphine and 10 times the potency of fentanyl.
Alfentanil is the only opioid with a pKa (6.5) that is lower than physiologic pH (7.4). Because most of the drug exists in the nonionized form (~90%), more of it is available to penetrate the blood-brain-barrier. This explains why it is the fastest acting opioid agonist.
Methadone delays the inward K+ rectifier, and this can prolong the QT interval and increase the risk of Torsades de pointes.
Which drugs are MOST effective at reducing opioid-induced hyperalgesia after the administration of remifentanil? (Select 2.)
Magnesium
Dexmedetomidine
Ketamine
Ketorolac
Ketamine
Magnesium
Remifentanil is associated with acute opioid-induced hyperalgesia (OIH) following discontinuation. This phenomenon can be thought of as acute opioid tolerance that develops early in the post-operative period. These patients tend to consume more opioids during this time.
The most likely explanation for OIH involves the NMDA receptor and its second messenger systems. NMDA receptor antagonists, such as ketamine and magnesium, have been shown to reduce or eliminate OIH after remifentanil.
An opioid dependent patient is experiencing intense signs of withdrawal 8 hours after his last dose. Which of the following drugs is the patient MOST likely abusing?
Methadone
Heroin
Morphine
Fentanyl
Fentanyl
Patients who are physically dependent on opioid agonists will experience s/sx of withdrawal upon discontinuation of these drugs.
Early s/sx: diaphoresis, insomnia, restlessness
Later s/sx: abdominal cramping and N/V
The time course of opioid withdrawal is a function of the drug’s half-life. Withdrawal s/sx occur as follows:
Fentanyl and meperidine:
Onset 2-6 hrs - Peak 6-12 hrs - Duration 4-5 days
Morphine and heroin:
Onset 6-18 hrs - Peak 36-72 hrs - Duration 7-10 days
Methadone:
Onset 24-48 hrs - Peak 3-21 days - Duration 6-7 weeks
Which opioid inhibits nerve conduction? Hydromorphone Morphine Meperidine Sufentanil
Meperidine
Meperidine exhibits a structural resemblance to local anesthetics as well as atropine.
By inhibiting sodium channels in the axon, it inhibits nerve conduction. This can be useful for spinal anesthesia.
Meperidine also resembles atropine. This explains why it increases heart rate and causes mydriasis.
The endogenous pain modulation pathway terminates in the:
rostroventral medulla.
ventral root ganglion.
periaqueductal grey.
substantia gelatinosa.
Substantia gelatinosa
The endogenous pain modulation pathway (descending inhibitory pain pathway) is a critical component of pain modulation.
The periaqueductal grey communicates with the ventrolateral medulla to indirectly influence pain transmission in the substantia gelatinosa (Rexed lamina II and III) in the dorsal horn of the spinal cord.
Periaqueductal grey → Rostroventral medulla → Substantia gelatinosa
Which agent is associated with the GREATEST amount of rostral spread when injected into the intrathecal space?
Morphine
Fentanyl
Hydromorphone
Meperidine
Morphine
Rostral spread describes the cephalad migration of a drug after injection into the CSF. This concept helps us understand why some opioids produce a late respiratory depression. Indeed, respiratory depression is the most common serious complication of intrathecal opioids. As an aside, pruritus is the most common side effect.
Morphine is the least lipophilic opioid that is used for spinal anesthesia. Since morphine is less likely to diffuse out of the intrathecal space, more of the drug is available to ascend towards the brain.
Early phase respiratory depression results from systemic absorption. This occurs at < 6 hours.
Late phase respiratory depression results from rostral spread and inhibition of the respiratory center in the brainstem. This occurs between 6 and 12 hours
Which route of morphine administration is associated with reactivation of herpes simplex labialis virus?
Intravenous
Intramuscular
Epidural
Oral
Epidural
Epidural morphine can reactivate herpes simplex labialis virus, usually in obstetric patients. It tends to occur 2-5 days after the dose is administered.
External symptoms tend to occur along the same dermatome as the initial infection. This is usually along the trigeminal nerve distribution on the face (cold sores).
Butorphanol reduces post-operative shivering by:
kappa receptor agonism.
alpha-1 receptor antagonism.
acetylcholine receptor antagonism.
mu receptor agonism.
Kappa receptor agonism
Shivering increases whole body oxygen consumption, and this can lead to myocardial ischemia in susceptible patients. Stimulation of the kappa opioid receptor as well as the alpha-2 receptor reduces post-operative shivering.
There are three drugs that are used to treat post-operative shivering:
Meperidine: kappa and alpha-2 stimulation
Butorphanol: kappa stimulation
Clonidine: alpha-2 stimulation
Cardiovascular side effects of naloxone include all of the following EXCEPT: bradycardia. cardiac dysrhythmias. hypertension. myocardial ischemia.
Bradycardia
Naloxone is an opioid antagonist used to treat opioid overdose. It reverses respiratory depression at the expense of reversing analgesia. It should be titrated slowly in increments of 1-4 mcg/kg q 2-3 minutes. In our experience, titrating 40 mcg at a time effectively reverses respiratory depression without significantly reversing analgesia.
Acute analgesic reversal activates the sympathetic nervous system, which can manifest as tachycardia and hypertension. These sequelae can precipitate myocardial ischemia and pulmonary edema.
Naloxone can also increase the incidence of N/V. Slower titration reduces the incidence.
