Pharmacology 2 Flashcards
(185 cards)
1
Q
Describe the component of the neuron and their function
A
2
Q
What is conduction velocity, and how it it affected by myelination and axon diameter?
A
Conduction velocity is a measure of how fast an axon transmits the action potential.
CV is increased by:
* Myelination- the action potential skips along the nodes of Ranvier (saltatory conduction)
* Large fiber diameter
3
Q
List the 3 different nerve fiber types. Compare and contrast them in terms of myelination, function, diameter, conduction velocity, and block onset
A
A- autonomic: B fibers (preganglionic), C fibers (post ganglionic)
T- Touch: C fibers and Beta
P- Pain: Slow: C fibers, Fast: Delta
T- Temperature: C fibers, Delta
P- Pressure: A-beta
M- motor: A-alpha…muscle tone- A- gamma
V- vibration:
P- Proprioception: A-alpha
1st blocked: B fibers
2nd blocked: C fibers
3rd blocked: Delta and gamma
4th blocked : Beta and alpha
4
Q
Discuss differential blockade using epidural bupivacaine as an example
A
Differential blockade is the idea that some fiber types are blocked sooner (easier) than others.
Epidural bupivacaine serves as an excellent example of this:
* at lower concentrations, epidural bupivacaine provides analgesia while sparing motor function
* As the concentration is increased, it anesthetizes more resistant nerve types, such as those that control motor function and proprioception
* This is the basis for a “walking” epidural with a low concentration of bupivacaine
5
Q
What concept is analogous to ED50 for local anesthetics?
A
Minimum effective concentration (Cm) is a units of measure that quantifies the concentration of local anesthetic that is required to block conduction. It’s analogous to ED50 for IV drugs and MAC for volatile anesthetics
- Fibers that are more easily blocked have a lower Cm.
- Fibers that are more resistant to blockade have a higher CM
6
Q
Rank the nerve fiber types according to their sensitivity to local anesthetics in vivo (most to least sensitive)
A
B fibers> C fibers> Small diameter a fibers (gamma and delta)> Large diameter (alpha and beta)
7
Q
What are the 3 possible configurations of the voltage-gated sodium channel
A
The sodium channel can exist in 3 possible states
* Resting: The channel is closed and able to be opened if the neuron depolarizes
* Active: The channel is open, and Na+ is moving along its concentration gradient into the neuron
* Inactive: The channel is closed and unable to be opened (it is refractory)
As its name suggests, the voltage near the channel determines the state of the channel
8
Q
How and when do local anesthetics bind to the voltage-gated sodium channel?
A
the guarded receptor hypothesis states that local anesthetics can only bind to sodium channels in their active (open) and inactive ( closed refractory) states. Local anesthetics do NOT bind to sodium channels in their resting states.
Local anesthetics are more likely to bind to axons conducting action potentials and less likely to bind to those that are not conducting action potentials. The more frequently the nerve is depolarized and the voltage-gated sodium channel opens, the more time available for local anesthetic binding to occur. The nerve will become blocked faster. This is called a use-dependent or phasic blockade.
9
Q
What is an action potential, and how does it depolarize a nerve?
A
An action potential is a temporary change in the transmembrane potential followed by a return to transmembrane potential
* For a neuron to depolarize, sodium or calcium must enter the cell (this makes the inside more positive)
* once the threshold potential occurs, the cell depolarizes and propagates an action potential
* The action potential only travels in one direction. This is because Na+ channels in the upstream portion of the neuron in the close/inactive state.
10
Q
what happens when a nerve repolarizes?
A
If depolarization is the accumulation of positive charge (Na+) inside the neuron, then repolarization is the removal of positive charges from inside the cell. Repolarization is accompanied by removing potassium.
11
Q
How do local anesthetics affect neuronal depolarization?
A
Local anesthetics bind to alpha-subunit on the inside of the sodium channel when it’s in either the active or inactive state
- When a critical number of sodium channels are blocked, there aren’t enough open channels for sodium to enter the cell in sufficient quantitiy
- the cell can’t depolarize, and the action potential can’t propagate. Whatever modality that nerve services (pain, movement, etc.) is blocked.
Local anesthetics do NOT affect resting membrane potential or threshold potential
12
Q
Discuss the role of ionization with respect to local anesthetics
A
Since local anesthetics are weak bases with pKa values higher than 7.4, we can predict that >50% of the local anesthetics will exist as the ionized, conjugate acid after injection
The non-ionized fraction diffuses into the nerve through the lipid-rich axolemma. Once inside the neuron, the law of mass action promotes re-equilibration of charged and uncharged species. The charged species binds to the alpha-subunit on the interior of the voltage-gated sodium channel.
learn the language, here are other ways to say the same thing:
Ionized fraction
Conjugate acid
Protonated species
Cation
13
Q
what are the 3 building blocks of the local anesthetic molecule? how does each one affect the PK/PD profile of the molecule?
A
Benzene ring: Lipophilic, permits diffusion through lipid bilayers
Intermediate chain: Ester- CO-O-C or Amide NH-CO-C-C-C , class- metabolism and allergic potential
Tertiary amine: NH-R-R: hydrophilic, accepts proton, makes molecule a weak base
14
Q
How can you use the drug name to determine if it’s an ester or amide? List examples from each class.
A
Ester: Benzocaine, cocaine, chloroprocaine, procaine, tetracaine
Amide: I before suffix: Articaine, bupivacaine, dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, ropivacaine
15
Q
Contrast the metabolism of ester and amide local anesthetics. Which local anesthetic participates in both metabolic pathways?
A
Ester metabolism: Pseudocholinesterase
Amide metabolism: Hepatic carboxylesterase/P450
Cocaine is an exception- it is an ester, but it is metabolized by pseudocholinesterase and the liver
16
Q
Discuss the local anesthetic allergy and cross sensitivity.
A
Although true allergy to local anesthetics is rare, it is more common with the esters. The ester-type local anesthetics are derivatives of para-aminobenzoic acid (PABA). PABA is an immunogenic molecule capable of causing an allergic reaction. This is why there is cross-sensitivity within this class.
The incidence of allergy to amides is incredibly rare. Some multi-dose vials contain methylparaben as a preservative. This compound is similar to PABA and can also precipitate and allergic reaction.
If a pt has experienced a true allergy with an ester, avoid administering all other esters. Since there is no cross-sensitivity between the esters and amides, it is safe to select an amide that does not contain methylparaben. Conversely, a pt who’s allergic to an amide may safely receive an ester-type local anesthetic
17
Q
What determines local anesthetic onset of action? which drug disobeys this rule and why?
A
pKa determines the onset of action
* If the pKa is closer to pH, the onset is faster
* If pKa is further from pH, the onset is slower
Chloroprocaine disobeys this rule. here’ why…
*It has a high pKa, which suggests a slower onset
* At the same time, chloroprocaine is not very potent, so we have to give it in a higher concentration (usually a 3% solution)
* Giving more molecules creates a mass effect that explains why chloroprocaine has a rapid onset of action even though it has a high pKa
18
Q
What determines local anesthetic potency?
A
Lipid solubility is the primary determinant of potency
* the more lipid soluble a local anesthetic, the easier it is for the molecule to traverse the neuronal membrane.
* Because more drug enters the neuron, there will be more available to bind to the alpha-subunit of the voltage-gated sodium channel
An intrinsic vasodilating effect is a secondary determinant of potency
* Vasodilation increases uptake into the systemic circulation, and this reduces the amount of local anesthetic available to anesthetize the nerve
19
Q
what factors determine local anesthetic duration of action?
A
Protein binding is the primary determinant of the duration of action
- After local anesthetic injection, some of the molecules penetrate the epineurium, some diffuse away into the systemic circulation, and some bind to tissue proteins. The molecules that bind to proteins serve as a reservoir that extends the duration of action
ProteinLA + <-> Protein + LA+ <-> LA + H+
Lipid solubility and intrinsic vasodilating activity are secondary determinants of duration of action.
* A higher degree of lipid solubility also correlates with a longer duration of action
* A drug with intrinsic vasodilating activity will increase its rate of vascular uptake and shorten its duration of action
20
Q
Discuss the intrinsic vasodilating effects of local anesthetics. Which local anesthetic has the opposite effect?
A
For most of the drugs we administer, absorption into the bloodstream 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.
Most local anesthetics cause some degree of vasodilation in clinically used doses. Those with a greater degree of intrinsic vasodilating effects (lidocaine) undergo a faster rate of vascular uptake, preventing some of the administered dose from accessing the nerve. The addition of a vasoconstrictor can prolong the duration of action, and this benefit is realized when used with LAs that produce the greatest amount of vasodilation.
Cocaine is unique. It always causes vasoconstriction, because it inhibits NE reuptake in sympathetic nerve endings in vascular smooth muscle.
21
Q
Rank the amide local aneathetics according to pKa.
A
- as pKA gets further away from physiologic pH, the degree of ionization increases
22
Q
Rank the ester local anesthetica to pKa
A
Notice that chloroprocaine does NOT bind to plasma proteins in a meaningful way
23
Q
list 5 factors that govern the uptake and plasma concentration of local anesthetics
A
Factors that influence vascular uptake and Cp:
* Site of injection
* Tissue blood flow
* physiochemical properties of local anesthetic
* Metabolism
* addition of vasoconstrictor
24
Q
Rank injection sites to the corresponding plasma concentrations of local anesthetic
A
most vascular and highest Cp-> least vascular and lowest Cp
IV
Tracheal
Interpleural
Intercostal
Caudal
Paravertebral
Epidural
Brachial plexus
Spinal
Sciatic/Femoral
Subcutaneous
In Time I Can Please Everyone But Susie and Sally
or
I I I Can’t Possibly Enjoy Slow Sloppy Sex
Think about this in terms of local anesthetic toxicity
25
What is the maximum dose for each amide local anesthetic (weight based and max total dose)
26
What is the maximum dose for each ester local anesthetic (weight based and max total dose)?
ester-type Max dose (mg/kg) Max total
Procaine 7 350-600
Chloroprocaine 11 800
Chloroprocaine/epi 14 1000
27
what is the most common sign of local anesthetic systemic toxicity
The most common sign is seizure
Bupivacaine is the exception- a cardiac arrest can occur before a seizure
28
Liste the effects of lidocaine toxicity according to plasma concentration
29
What conditions increase the risk of CNS toxicity in LAST?
Factors that increase the risk of CNS toxicity in LAST: hypercarbia, hyperkalemia, and metabolic acidosis
* Hypercarbia- increases cerebral blood flow and increases drug delivery to the brain. It also decreases protein binding and increases the free fraction available to enter the brain
* Hyperkalemia- Raises resting membrane potential, making neurons more likely to depolarize
* Metabolic acidosis- decreases the convulsion threshold and favors ion trapping inside the brain
* If you were thinking that acidosis should increase the fraction of the conjugate acid and decrease the amount of uncharged base that is available to pass through the blood-brain barrier, then you were right! Unfortunately, this alone is not enough to decrease the risk of CNS toxicity
30
Why is the risk of cardiac morbidity higher with bupivacaine than with lidocaine?
Two features determine the extent of cardiotoxicity of any local anesthetic:
1. Affinity for the voltage-gated sodium channel in the active and inactive state.
2. Rate of dissociation from the receptor during diastole
Compared to lidocaine, bupivacaine has a greater affinity for the voltage-gated sodium channel and a slower rate of dissociation from the receptor during diastole. This result is that more bupivacaine remains at the receptor for a longer period of time. This explains why cardiac morbidity is higher with bupivacaine and why resuscitation is so difficult.
Difficulty of cardiac resuscitation: Bupivacaine> Levobupivacaine> ropivacaine> lidocaine
31
Discuss the modifications to the ACLS tx protocol when applied to LAST.
Epi can hinder resuscitation from LAST, and it also reduces the effectiveness of lipid emulsion therapy. If epi must be used give it in doses of < 1mcg/kg
Amiodarone is the agent of choice for ventricular arrhythmias
Avoid vasopressin, lidocaine and procainamide
32
Discuss the use of lipid emulsion for the tx of LAST.
Lipid emulsion acts as a lipid sink- an intravascular reservoir that sequesters local anesthetic and reduces the plasma concentration of local anesthetic.
Tx for LAST:
Pt is over 70kg:
* Bolus = 100mL over 2 - 3 minutes
* Infusion= 250mL over 15-20 minutes
* if the pt remains unstable -> repeat bolus and/or double the infusion
Pt is under 70kg:
* bolus: 1.5mL/kg of LBW over 2-3 min
* Infusion= 0.25 mL/kg/min
* if the pt remains unstable-> repeat bolus and/or double the infusion
Continue the infusion for a minimum of 15 minutes after the pt regains cardiovascular stability
The maximum recommended dose = 12mL/kg
33
you are providing anesthesia for a 90 kg pt undergoing liposuction. The plastic surgeon wants to use tumescent lidocaine 0.1% and asks you to calculate the maximum dose. How much tumescent lidocaine can this pt receive? (answer in 1mL of tumescent solution)
the max dose of lidocaine for tumescent anesthesia is 55mg/kg (Nagelhout says 50mg/kg)
90 x 50= 4500mg
90 x 55= 4950mg
a 0.1% lidocaine solution contains 1mg/mL. This makes the math pretty easy. the pt can receive 4500-4950 mL of tumescent solution.
34
in addition to local anesthetic toxicity, what are other potential complications of a large volume of tumescent anesthesia?
Pulmonary edema may occur as a result of volume overload. If a pt experiences CV collapse, first calculate the max dose of lidocaine received. If this dose is within the acceptable range, then think of other complications, such as volume overload (calculate fluid balance) or pulmonary embolism
General anesthesia is recommended if >2-3L of tumescent solution is injected
35
Name the two local anesthetics that are most likely to produce a leftward shift of the oxyhemoglobin dissociation curve. Why does this happen?
Prilocaine and benzocaine can cause methemoglobinemia. Here's what you need to know...
* the oxygen binding site of the heme portion of the hgb molecule contains an iron molecule in its ferrous form (Fe+2)
* Oxidation of the iron molecule to its ferric form (Fe +3) creates methemoglobin
* methemoglobin impairs O2 binding and unbinding from the Hgb molecule, shifting the oxyhemoglobin dissociation curve to the left. This creates a physiologic anemia
36
What drugs are capable of causing methemoglobinemia
Local anesthetics:
Benzocaine, cetacaine (contains benzocaine), prilocaine, EMLA (prilocaine + lidocaine)
Other drugs:
Nitroprusside, nitroglycerine, sulfonamides, phenytoin
37
S/Sx of methemoglobinemia
Hypoxia
cyanosis (slate-grey pseudocyanosis)
chocolate colored blood
tachycardia
tachypnea
mental status changes
coma and death
* Cyanosis in the presence of a normal PaO2 is highly suggestive of methemoglobinemia
38
What is the tx for methemoglobinemia? How does it work?
Methylene blue 1-2mg/kg over 5 minutes up to a maximum dose of 7-8 mg/kg
Methemoglobin reductase metabolizes methylene blue to form leucomethylene blue. This metabolite functions as an electron donor and reduces methemoglobin (Fe+3) back to hgb (Fe+2)
39
Name two pt populations who are at increased risk for developing methemoglobinemia
1. Pts with glucose-6-phosphate reductase deficiency do not possess methemoglobin reductase, so that an exchange transfusion may be required
2. Fetal Hgb is relatively deficient in methemoglobin reductase, making it susceptible to oxidation. Therefore, neonates are at higher risk for toxicity.
40
What are the constituents of EMLA cream?
5% EMLA cream is a 50/50 combination of 2.5% lidocaine and 2.5% prilocaine.
* Prilocaine metabolizes to O-toluidine, which oxidizes hgb to methemooglobin. Infants and small children are more likely to become toxic
41
What is the max does of EMLA cream
42
How does sodium bicarbonate affect local anesthetic onset of action? Are there any other benefits?
Sodium bicarbonate shortens local anesthetic onset time.
* Alkalization increases the number of lipid soluble molecules, which speeds up the onset of action. In practice, however, there is a limit to how much a local anesthetic solution can be alkalized before it precipitates, so this technique only produces a modest benefit.
* you can alkalize local anesthetic by mixing 1 mL of 8.4% sodium bicarbonate with 10mL of local anesthetic.
* the addition of sodium bicarbonate also reduces pain during injection
43
how does adding epi affect the duration of action of a local anesthetic?
Epi extends local anesthetic duration.
* The alpha-1 agonist effect of epi makes it a potent vasoconstrictor. It can decreases systemic uptake of local anesthetic, prolong block duration, and enhance block quality
44
What drugs can be added to local anesthetics to provide supplemental analgesia? what is the mechanism of action for each one?
clonidine (alpha 2 agonist)
Epi (alpha 1 agonist)
opioids (mu agonist)
* chloroprocaine is an exception, as it reduces the effectiveness of opioids in the epidural space
45
What are the 2 types of nictoninc receptors present at the neuromuacula junction? What is the function of each?
Prejunctional Nn receptor:
* present om the presynaptic nerve
* regluates Ach release
Postsynaptic Nm receptor:
* present at the motor endplate on the muscle cell
* responds to Ach (depolarizes muscle)
46
Describe the structure of the post-synaptic, nicotinic receptor at the neuromuscular junction
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.
* the normal receptor contains 2 alpha, 1 beta, 1 delta, and 1 epsilon subunits
47
What happens when Ach activates the post-synaptic, nicotinic receptor at the neuromuscular junction?
Ach binds to the alpha units of the receptor (1 Ach at each of the 2 alpha subunits). Binding prompts the channel to open. Na+ and Ca+2 enter the cell, and K+ exits the cell
At rest, the inside of the muscle cell is negative relative to the outside of the cell. When Nm receptor is activated, Na+ flows down its concentration gradient and enters the cell. This makes the cell interior more positive, activates voltage-gated sodium channels, depolarizes the muscle, and initiates an action potential
Depolarization of the myocyte instructs the endoplasmic reticulum to release Ca+2 into the cytoplasm where it engages with the myofilaments and initiates muscle contraction
48
How is the Ach signal "turned off" at the neuromuscular junction.
Acetylcholinesterase is strategically positioned around the pre- and postsynaptic nicotinic receptors; it hydrolyzes Ach almost immediately after activating these receptors
49
why are extrajunctional receptors sometimes called fetal receptors?
There are two pathologic variants of the nicotinic receptor.
* the alpha2beta1delta1gamma1 subtype has a gamma subunit instead of an epsilon subunit
* the alpha 7 consists of 5 alpha subunits
Extrajunctional receptors resemble those that are present early in fetal development. ONce innervation takes place, adult alpha2beta1delta1epsilon1 subtype receptors replace the fetal nicotinic receptors
Denervation later in life allows for the return of both types of extrajunctional receptors. Notice how they're distributed at the NMJ and also throughout the sarcolemma.
50
What conditions allow extrajunctional receptors to populate the myocyte?
Upper and lower motor neuron injury
spinal cord injury
burns
skeletal muscle trauma
cerebrovascular accident
prolonged chemical denervation (magnesium, long term NMB infusion, clostridial toxin)
Tetanus
severe sepsis
muscular dystrophy
51
what is the risk of using succ's in a pt with upregulation of extrajunctional receptors?
In the absence of extrajunctional receptors, succ's can transiently increase serum potassium by 0.5-1 mEq/L for up to 10-15 minutes
Extrajunctional receptors are much more sensitive to succ's; they remain open for a longer period of time. This augments the potassium leak and may precipitate life-threatening hyperkalemia
52
How do extrajunctional receptors affect the clinical use of non-depolarizing neuromuscular blockers?
Pt's with upregulation of extrajunctional receptors are resistant to nondepolarizers (reduced potency). As a result, the dose may need to be increased
53
Discuss fade in the context of succ's and non-depolarizing neuromuscular blockers.
There are two supplies of Ach vesicles:
* Ach that is available for immediate release
* Ach that must be mobilized before it can be available for immediate release
Nondepolarizing neuromuscular blockers competitively antagonize the presynaptic Nn receptors. This impairs the mobilization process, so now only the vesicles available for immediate release can be used. Since this is a limited quantity, nerve stimulation can quickly exhaust this supply. With each successive stimulation, less Ach is released. Clinically this manifests as fade with TOF, double burst, and tetanus.
Succ's stimulates the prejunctional receptors- it has the same effect as Ach. When succ's binds to the presynaptic Nn receptor, it facilitates the mobilization process. So, there is always Ach available for immediate release. This explains why fade is not observed with a depolarizing neuromuscular blocker.
54
what is the difference between a phase 1 and phase 2 block? What risk factors increase the likelihood of a phase 2 block with succinylcholine?
the presence or absence of fade distinguishes between a phase 1 and phase 2 block
* Phase 1 = no fade
* phase 2= fade present
The only time succ's causes fade is when it produces a phase 2 block- otherwise, succs does not produce fade! there will be 4 twitches or 0 twitches. As the block gets deeper, the quality of each twitch will decrease until all of them go away.
Two situations favor the development of a phase 2 block with succs:
*dose >7-10mg/kg
* 30-60 minutes of continuous exposure (IV infusion)
If you get a phase 2 block with succs, you have to wait it out. Do not reverse it.
55
compare and contrast phase 1 and phase 2 block in terms of TOF, tetany, double burst stimulation, and post-tetanic potentiation.
this chart compares the phase 1 and phase 2 blocks as observed by a nerve stimulator. We want you to notice a few things:
* the phase 1 response to stimulation are diminished but equal= no fade
* the phase 2 response to stimulation is characterized by fade
* there is no post-tetanic potentiation with a phase 1 block, but it is present with a phase 2 block
56
What TOF ratio correlates with full recovery from neuromuscular blockade?
TOF ratio of >0.9
historically, we believed that TOF ratio of 0.7 correlated with a full recovery from neuromuscular blockade. More recent evidence suggests that normal upper airway and respiratory muscle function does not return until a TOF ratio of >0.9 is achieved at the adductor pollicis
57
what is the best location to assess the onset of neuromuscular blockade? how bout recovery?
Onset is best measured at the orbicularis oculi muscle with the facial nerve
Recovery is best measured at the adductor pollicis muscle with the ulnar nerve
58
List all the tests of recovery from neuomuscular blockade. What values suggest recovery and to what degree?
59
How does succ's affect heart rate? Why?
Succ's can cause bradycardia or tachycardia:
Bradycardia:
* Succ's can cause bradycardia or asystole by stimulating the M2 receptor on the SA node
* A second dose of succ's increases the risk (particularly in children <5 yrs old)
* Succinylmonocholine (primary metabolite of succ's) is probably responsible for the effect
* Antimuscarinics may prevent or reverse the bradyarhythmias
Tachycardia:
* succ's can cause tachycardia and HTN by mimicking the action of Ach at the sympathetic ganglia
* in adults, tachycardia is more common than bradycardia
60
Is Succ's safe to give to a pt with renal failure?
Succ's can increase serum potassium by 0.5-1 mEq/L for up to 10-15 min
* succ's is safe in the pt with renal failure who has a normal potassium
* Renal failure pts with elevated potassium do not have an increased release, however, the normal response to succ's may increase serum potassium to a dangerous level
61
how does succs affect IOP?
Succ's transiently increases intraocular pressure by 5-15 mmHg for up to 10 min
* this is a concern if the pt has an open globe injury
* balance this concern against the need to rapidly secure the airway
* Rocuronium 1.2 mg/kg is alternative if an RSI is indicated
While some argue that pretreatment with a non-depolarizing NMB attenuates the rise in IOP, the texts say that it's controversial and/or provides little to no benefit.
62
How does succ's affect intragastric pressure?
Contraction of the abdominal muscles increases intragastric pressure. A the same time, succ's raises lower esophageal sphincter tone. These processes cancel each other out, so barrier pressure at the gastroesophageal junction is unchanged. The risk of aspiration is not increased.
63
List 5 enzymes that metabolizes Ach. List 5 names for the enzyme that metabolizes succ's.
Metabolizes Ach: primary location Neuromuscular junction:
Names: Acetycholinesterase, genuine cholinesterase, Type 1 cholinesterase, True cholinesterase, specific cholinesterase
Metabolizes succ's, mivacurium, ester LAs
Primary location: Plasma
Names: Butyrylcholinesterase, pseudocholinesterase, type 2 cholinesterase, False cholinesterase, plasma cholinesterase
64
List all the drugs and conditions that reduce pseudocholinesterase activity
Drugs: Metoclopramide, esmolol, neostigmine ( not edrophonium), echothiopate, oral contraceptives/ estrogen, cyclophosphamide, monoamine oxidase inhibitors, nitrogen mustard
Co-existing diseases: Atypical PChe, severe liver dx, chronic renal dx, organophosphate poisoning, burns, neoplasm, advanced age, malnutrition, pregnancy (late stage)
65
How do you interpret the results of the dibucaine test?
Normal test
* A normal dibucaine number is 80. This means dibucaine has inhibited 80% of the pseudocholinesterase in the sample and suggests that the normal enzyme is present . Typical Homozygotes
Abnormal test:
* Dibucaine does not inhibit atypical plasma choliseterase. If the pt has a dibucaine number of 20, this means that dibucaine did not inhibit the pt's PChE and atypical variant is present
40-50- Atypical heterozygote
20 or less- atypical homozygote
66
What are the 3 variants of pseudocholinesterase, and what is the duration of action of succ's for each one?
67
why does succ's have a black box warning?
Succ's has a black box warning detailing the risk of cardiac arrest and sudden death. These catastrophic events are secondary to hyperkalemia in children with undiagnosed skeletal muscle myopathy
* this is caused by an MH-like syndrome characterized by rhadomyolysis
* These events are not due to malignant hyperthermia!
68
Why is calcium used to treat hyperkalemic cardiac arrest caused by succ's?
Hyperkalemia raises resting membrane potential, so excitable tissues are closer to threshold potential and depolarization.
Administration of IV calcium increases threshold potential, which helps re-establish the normal difference between transmembrane potentials (the distance between RMP and TP increases)
69
How do you treat a pt who has become hyperkalemic in response to succ's?
70
Who is at the highest risk of myalgia following succ's? who is at the lowest risk?
Those with the highest 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 pts seem to have the lowest rate of occurrence
71
how can the risk of succ's induces myalgia be reduced?
Myalgia can be minimized, but not entirely eliminated, by pretreatment with a nondepolarizing neuromuscular blocker
Other methods that may reduce the risk of myalgia include:
* NSAIDs
* Lidocaine 1.5mg/kg
* the use of a higher dose rather than a lower dose of succinylcholine
Opioids do not reduce the incidence of myalgia
72
Which pt populations should not receive a defasciculation dose of a nondeploraizing neuromuscular blocker?
the use of this technique should be carefully balance against potential complications.
Pts may experience muscle weakness, dyspnea, dysphagia, and diplopia. Those with pre-existing skeletal muscle weakness, such a myasthenia gravis, should probably not receive a defasciculation dose.
73
What pt populations are at risk for developing Hyperkalemia following succinylcholine?
* Amyotrophic lateral sclerosis
* Charcot-Marie-tooth
* Duchenne's muscular dystrophy
* Guillain-Barre
* Hyperkalemic periodic paralysis (not the hypokalemic variant)
* multiple sclerosis
* upregulation of extrajuctional receptors (burns, denervation injury)
74
Rank the nondepolarizing neuromuscular blockers in terms of ED 95 (lowest to highest)
The ED 95 is the dose at which there is a 95% decrease in twitch height.
order from smallest ED 95 to largest ED95:
* Cisatracurium
* Vecuronium
* mivacurium= pancuronium
*atracurium
* rocuronium
the dose required to provide optimal conditions for tracheal intubation is around 2-3 times the ED95
75
what are the 2 classes of nondepolarizing neuromuscular blockers? which drugs belong in each?
Benzylisoquinolinium compound
* atracurium
* cisatracurium
* mivacurium
Aminosteroid compounds:
* rocuronium
* Vecuronium
* pancuronium
76
Discuss the metabolism of the benzylisoquinolinium neuromuscular blockers
All end in -curium, undergo sponataneous degradation in the plasma. They are not dependent on hepatic or renal function for metabolism and elimination
Atracurium is hydrolyzed by hofmann elimination (33%) and non-specific esterases (66%). These are the same enzymes that degrade esmolol and remifentanil. Remember that non-specific plasma esterases are NOT the same as pseudocholinesterase. Therefore, the pts with pseudocholinesterase deficiency do not experience a prolonged block with atracurium
Cisatracurium breakdown is dependent on Hofmann elimination only.
Mivacurium is metabolized by pseudocholinesterase (same as succinylcholine). This explains why it has a relatively short duration of action.
77
what factors impact Hofmann elimination?
Hofmann elimination is a base-catalyzed reaction that is dependent on normal blood pH and temperature.
* the reaction is faster with alkalosis and hyperthermia (duration of action is shorter)
* The reaction is slower with acidosis and hypothermia (duration of action is longer)
Therefore, a cold and/or hypercarbic patient is more difficult to reverse
78
What is the active metabolite of atracurium and cisatracurium? What is the clinical significance?
Laudanosine is a metabolite of both atracurium and cisatracurium, although atracurium produces more.
* As a CNS stimulant, laudanosine is capable of producing seizures
* this is not a problem during routine administration of these drugs in the OR. However, it may be valid with a prolonged infusion in the ICU
* laudanosine has no muscle relaxant properties
Mivacurium does not produce and active metabolite.
79
Discuss the metabolism, elimination, and active metabolites of the aminosteroid neuromuscular blockers
Rocuronium: metabolism: >70% eliminated by liver, 10-25% renal elimination, no metabolites
Vecuronium: Metabolism: Liver (30-40%), liver elimination 40-50%, Renal elimination 50-60%, metabolite: 3-OH vecuronium
Pancuronium: Metabolism: liver (10-20%), Liver elimination 15%, Renal elimination 85%, metabolite 3-OH pancuronium
80
what drugs can potentiate the effects of neuromuscular blockers?
Volatile anesthetics
Antibiotics
* examples: aminoglycosides, clindamycin, tetracycline
Antidysrhythmic
* examples: verapamil (CCB), amlodipine (CCB), quinidine (Antiarrhythmic)
Local anesthetics
* examples: probably most
Diuretics
* examples: furosemide
Other
* examples: dantrolene, tamoxifen, cyclosporine
81
What electrolyte disturbances can potentiate the effects of neuromuscular blockers?
Increased concentration of:
*Lithium
*Magnesium
Decreased concentration of:
* calcium
* potassium
82
Compare and contrast cardiovascular effects of neuromuscular blockers
Succs- histamine release, autonomic ganglia: stimulation (tachycardia), Heart M2 receptor: stimulation (bradycardia)
Pancuronium: moderate M2 receptor blockade
rocuronium: 0- Slight blockade of heart M2 receptors (vagolytic effect)
atracurium and mivacurium have histamine release as well
83
which neuromuscular blocker has a vagolytic effect?
Pancuronium is unique in that it has a vagolytic effect. Pancuronium inhibits M2 receptors at the SA node, stimulates the release of catecholamines, and inhibits catecholamine reuptake in adrenergic nerves. This increases heart rate and cardiac output with no or minimal effect on the systemic vascular resistance. This drug is sometimes used to mitigate opioid-induced bradycardia in cardiac surgery.
Pancuronium doe not release histamine.
84
Which neuromuscular blocker should be avoided in the pt with hypertrophic cardiomyopathy
* pancuronium (vagolytic effect)
* Atracurium (histamine release)
* Mivacurium (histamine release)
In this disease process, there is a hypertrophied ventricular septum and systolic anterior motion of the anterior leaflet of the mitral valve.
* when the ventricle contracts forcefully or quickly, there is a greater tendency for the anterior leaflet to occlude the LVOT, which reduces flow through the aortic valve
* this reduces cardiac output and blood pressure
85
Which NMB is most likely to cause anaphylaxis?
succinylcholine
86
How does cholinesterase inhibitors reverse paralysis caused by a nondepolarizing neuromuscular blocker?
Acetylcholinesterase hydrolyzes Ach into choline and acetate. This enzyme is concentrated around the nicotinic.
Drugs as edrophonium, neostigmine, and pyridostigmine reversibly inhibit AchE, which indirectly increases concentration of Ach at the neuromuscular junction. Since more Ach is present, it is better able to compete for the alpha binding sites on the nicotinic receptor and antagonize the block.
87
list 3 ways to inhibit acetylcholinesterase. Give examples of each
1. Electrostatic attachment
* competitive inhibition
ex: edrophonium
2. Formation of carbamyl esters
* competitive inhibition
ex: neostigmine, pyridostigmine, physostigimine
3. Phosphorylation:
* Non-competitive inhibition
Ex: organophosphates and echothiophate
88
regarding edrophonium, what is the dose, onset, duration, metabolism, and best antimuscarinic pairing?
Dose: 0.5-1mg/kg
onset: 1-2 min
duration: 30-60 min
Metabolism: 75% renal + 25% hepatic
Best pairing: Atropine
89
Regarding neostigmine, what is the dose, onset, duration, metabolism, and best antimuscarinic pairing?
Dose: 0.02-0.07mg/kg
Onset 5-15 min
Duration 45-90 min
metabolism: 50% renal + 50% hepatic
Best pairing: glycopyrrolate
90
Regarding pyridostigmine what is the dose, onset, duration, metabolism, and best antimuscarinic pairing?
Dose: 0.1-0.3 mg/kg
Onset: 10-20 min
Duration: 60-120 min
Metabolism: 75% renal + 25% hepatic
Best Pairing: glycopyrrolate
91
How does renal failure affect the dosing of acetylcholinesterase inhibitors after an aminosteroid neuromuscular blocker is administered?
renal failure prolongs the duration of action for both AchE inhibitors and aminosteroid neuromuscular blockers.
Since both drugs will remain in the body for a longer time, there is no need to adjust the dose of the AchE inhibitor or re-dose it
92
Contrast neostigmine reversal in adults and children.
When compared to adults, antagonism with neostigmine is faster in infants and children
93
Which acetylcholinesterase inhibitors pass through the blood brain barrier? which do not? why?
Physostigmine is a tertiary amine- it passes through the BBB
Edrophonium, neostigmine, and pyridostigmine are quaternary amines- they carry a positive charge preventing them form passing through the BBB
94
List the side effects common to acetylcholinesterase inhibitors
By increasing the concentration of Ach at the muscarinic receptor, AchE inhibitors cause a predictable set of parasympathetic side effects
Mnemonic: DUMBBELLS
* Diarrhea
* urination
* miosis
* bradycardia
* Bronchoconstriction
* Emesis
* Lacrimation (increased tear production)
* Laxation (elimination of fecal waste)
* Salivation
95
Compare and contrast the side effects of atropine, scopalamine, and glycopyrrolate
can't spit, can't shit, can't sweat
96
Which antimuscarinics pass through the BBB? which do not? why?
Atropine and scopalamine are natrually occuring tertiary amines. Because they are lipophillic, they easily cross the lipid membranes including the BBB, Gi tract, and placenta.
Glycopyrrolate is different. As a quaternary ammonium derivative, it is ionized. This limits its ability to cross cell membranes. Therefore, it does not possess CNS activity or cross the placenta
97
In what situation can atropine cause a paradoxical bradycardia?
small doses of atropine (<0.5 mg IV in adult) can causes a paradoxical bradycardia
This is probably due to the inhibition of presynaptic M1 receptor on vagal nerve endings. This receptor's job is to reduce Ach release via a negative feedback loop. Blockade of the presynaptic M1 receptor "turns off" this negative feedback loop and allows for continued Ach release and bradycardia
98
Do patients with a history of heart transplantation require an antimuscarinic for reversal of a nondepolarizing block?
A heart transplant denervates the heart. Said in another way, the ANS influence has been removed. The intrinsic firing rate of the SA node now solely determines the heart rate.
For this reason, muscarinic antagonist do not affect the heart rate of the pt with a previous heart transplant. Even so, these pts will still experience cholinergic effects from AchE inhibitors. So they should receive a muscarinic antagonist with AchE inhibitor
99
what is the MOA of sugammadex?
Sugammadex is a gamma-cyclodextrin made of 8 sugars assembled in a ring. The ring encapsulates the neuromuscular blocker, rendering it inactive and unable to engage with the nicotinic receptor. It's like febreeze aminosteroid neuromuscular blockers.
100
What neuromuscular blockers can be reversed by sugammadex?
Rocuronium> vecuronium> pancuronium
It has no effect on succ's or the benzylisoquinolines (atracurium, cisatracurium, and mivacurium)
101
How does sugammadex improve safety?
Safety improve in 3 ways:
* Rocuronium can be used for difficult intubation without the drawbacks of succ's
* it can reverse a dense neuromuscular block quickly, thus greatly reducing the risk of residual paralysis
* It allows for a dense block until the very end of the surgical procedure without the concerns of a delayed extubation
102
how do you dose sugammadex?
Roc or Vec
TOF 2/4 or better = 2mg/kg
TOF 0/4 + 2 PTC or better= 4mg/kg
Roc only- you may reverse 3 minutes after rocuronium administration at 1.2mg/kg (or less) = 16mg/kg
103
How is sugammadex metabolized?
Unlike rocuronium, which is primarly excreted by the biliary system, sugammadex and the sugammadex-rocuronium complex are excreted unchanged by the kidneys
104
What are the three most significant risks associated with sugammadex?
1 anaphylaxis- occurs in 0.3% of pts
2. CV changes- bradycardia and cardiac arrest have been reported. Anticholinergics may be useful in this context
3. Unplanned pregnancy- sugammadex reduces the effectiveness of hormonal contraceptives for up to 7 days. Females of childbearing age should be instructed to continue their hormonal contraceptives during this time, but they should also use a backup birth control method for 7days
105
Discuss the process of pain transduction.
The experience of pain can be divided into four steps: transduction, transmission, modulation, and perception. We'll begin with transduction...
Injured tissues release various chemicals that activate peripheral nerves and/or cause immune cells to release proinflammatory compound. The peripheral nerves transduce this chemical soup into an action potential, so the extent of tissue injury can be interpreted by the brain.
106
What type of nerve fibers transmit pain?
A-delta fibers transmit "fast pain" that is sharp and well localized
C-fibers transmit "slow pain" that is dull and poorly localized
107
What is the role of inflammation in pain transduction?
Inflammation contributes to
* reduced threshold to pain stimulus (allodynia)
* increased response to pain stimulus (hyperalgesia)
108
discuss the process of pain transmission.
the pain signal is relayed through the three- neuron afferent pain pathway along the spinothalamic tract
* first-order neuron: periphery -> dorsal horn (cell body in the dorsal root ganglion)
* Second-order neuron: dorsal horn-> thalamus (cell body in the dorsal horn)
* third-order neuron: Thalamus-> cerebral cortex (cell body in the thalamus)
109
What is the process of pain modulation?
The pain signal is modified ( inhibited or augmented) as it advances towards the cerebral cortex
the most important modulation site is the substantia gelatinosa in the dorsal horn (rexed lamina II and III)
* the descending inhibitory pain pathway begins with the periaquaductal gray and rostroventral medulla. It projects to the substantia gelatinosa
the inhibition of pain occurs when:
* spinal neurons release GABA and glycine (inhibitory transmitters)
* the descending pain pathway releases NE, 5-HT, and endorphins.
Pain is augmented by:
* central sensitization
* wind-up
110
discuss the process of pain perception.
Perception describes the processing of afferent pain signals in the cerebral cortex and limbic system
* How we "feel" about pain
111
MOA of opioids.
Each opioid receptor links to a G protein, and agonism of the receptor instructs the G protein to "turn off" adenylate cycalse. This reduces the intracellular concentration of cAMP (second messenger), which alters ionic currents and reduces neuronal function
112
What are the precursors of the endogenous opioids?
Pre-proopiomelanocortin -> endorphins (mu receptor)
Pre-enkephalin -> enkephalins (delta receptor)
Pre-dynorphin -> dynorphins (kappa receptor)
113
Pretend for a moment mu receptor subtypes exist. What are their physiologic effects of mu-1, mu-2, and mu-3 receptor stimulation
The existence of mu receptor subtypes in humans has yet to be proven. Most newer texts don't delineate between the physiologic effects of mu 1, 2, and 3 stimulation. But some do, for this reason, mu receptor subtypes are fair game on the NCE, and we think you should learn them, the most important to know are starred
Mu 1: Analgesia*, Bradycardia*, euphoria, low abuse potential, miosis, hypothermia, urinary retention
Mu 2: Analgesia*, Bradycardia*, respiratory depression*, constipation*, physical dependence*
Mu-3: Immune suppression*
Flood states Mu-1 is responsible for bradycardia in a table, but then states Mu-2 is responsible for bradycardia in the text
114
what are the unique effects of kappa stimulation
The kappa receptor is unique because it can cause:
* Antishivering effect
* Diuresis
*dysphoria
* delirium
* Hallucination
115
How do opioid affect heart rate, blood pressure, and myocardial function?
Heart rate:
* bradycardia from mu stimulation (if you are given a choice of mu-1 or mu-2, then choose mu-2)
* meperidine can cause increase heart rate (atropine-like ring in chemical structure produces anticholinergic effects: Tachycardia, mydriasis, and dry mouth)
Blood pressure:
* there is minimal effect on BP in healthy pts
* hypotension with morphine or meperidine is likely to result of histamine release.
Myocardial function:
* contractility is not affected
* Myocardial depression can occur if combined with N2O
116
How do opioids affect ventilation?
Opioid stimulate the mu and delta receptors (and possibly kappa) to produce their ventilatory effects
* Decreased ventilatory response to CO2 (CO2 response curve shifted to the right)
* Decreased RR and compensatory increased Vt (partial compensation)
117
how do opioid affect the pupil?
Edinger Westphal nucleus stimulation -> Increased PNS stimulation of ciliary ganglion and oculomotor nerve (CN 3)-> pupil constriction
118
How do opioids produce N/V?
By mu receptor stimulation:
* chemoreceptor trigger zone stimulation (are postrema of medulla). Remember, the BBB does not protect the CTZ
* possible interaction with the vestibular apparatus
119
How do opioids affect biliary pressure, gastric emptying, and peristalsis?
Opioids produce their GI effects through mu receptor stimulation.
Biliary pressure:
* contraction of the sphincter of Oddi-> increased biliary pressure
* Reversed by naloxone or glucagon
* meperidine causes the lowest incidence of this side effect
Gastric emptying is prolonged
Peristalsis is slowed-> constipation
120
How do opioids contribute to urinary retention?
Opioids produce their GU effects through mu and delta receptor stimulation
* Detrusor relaxation (contraction is needed to pass urine into the urethra)
* Urinary sphincter contraction (relaxation is needed to void)
121
what are the immunologic effects of opioids?
* Histamine release (morphine, meperidine, codeine)
* inhibition of cellular and humoral immune function
* Suppression of natural killer cell function
122
How do opioids affect thermoregulation?
Opioids reset the hypothalamic temperature set point -> decreases core body temperature
123
Rank IV opioids in terms of potency.
Sufentanil > fentanyl = remifentanil> alfentanil > hydromorphone > Morphine > meperidine
124
Compare the equianalgesic doses relative to 10mg of morphine
125
What opioids produce an active metabolite?
Morphine and meperidine
Except remifentanil, all of the opioids undergo hepatic biotransformation.
Of these, only morphine and meperidine produce active metabolites
Morphine:
* morphine conjugates to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active)
* impaired renal function -> decreases MP6 excretion -> increases accumulation -> respiratory depression
Meperidine:
* Normeperdine is one half as potent as its parent compound
* it reduces the seizure threshold and increases CNS toxicity
* impaired renal function -> decreased normeperidine excretion -> Increased accumulation-> seizures
126
Discuss the co-administration of meperidine and MAO inhibitors
Meperidine + MAO inhibitors can cause serotonin syndrome.
* meperidine is a week serotonin reuptake inhibitor
* Since MAO deaminates serotonin in the synaptic cleft, co-administration of meperidine and an MAO inhibitor can cause serotonin syndrome.
* S/sx include: hyperthermia, mental status changes, hyperreflexia, seizures, and death
* MAO inhibitors: phenelzine, isocarboxide, tranylcypromine
127
How does the ionization characteristics of alfentanil influence its onset of action?
Of all the opioids, afentanil has the fastest onset of action. Here's why...
* Alfentanil's pKa is 6.5, which is less than physiologic pH
* it is around 90% unionized and 10% ionized ( remember that unionized passes through the BBB)
* it also has a low Vd and a high degree of plasma protein binding (alpha-1-glycoprotein)
(Since it's highly unionized and doesn't have a large Vd, more of the drug is available to enter the brain
128
Which opioid has the largest volume of distribution? Which is the smallest?
Largest Vd: Fentanyl (4L/kg)
Smallest Vd: Remifentanil (0.39L/kg)
* remifentanil doesn't distribute to the fat, because it's metabolized so quickly in the plasma
129
Discuss the PK/PD profile of remifentanil
Remifentanil is a rapid-on and rapid-off mu agonist.
* the context-sensitve half-time is about 4 minutes regardless of infusion duration.
* remifentanil contains an ester linkage. This renders it susceptible to hydrolysis by erythrocyte and tissue esterases
* even though it is highly liphophilic, it behaves as though it has a small Vd. This is do to a very fast rate of clearance in the plasma
*Potency is similar to fentanyl
* Maintenance infusion is 0.1-1mcg/kg/min
* in the obese pt, the remifentanil infusion rate is calculated with lean body weight ( it does not distribute throughout the body fat it is metabolized so quickly)
130
Discuss the relationship between remifentanil and opioid induced hyperalgesia. What drugs can prevent this phenomenon?
Remifentanil causes acute opioid-induced hyperalgesia following discontinuation
* postoperative opioid requirements are particularly high in these pts
* Ketamine or magnesium sulfate can prevent OIH
131
Can remifentanil be used for neuraxial anesthesia? Why or why not?
Remi powder is mixed with a free base and glycine to provide a buffered solution following reconstitution.
* glycine is an inhibitory neurotransmitter
*it can cause skeletal muscle weakness, so don't administer in the epidural or intrathecal space
132
How does methadone reduce pain?
Methadone decreases pain by 3 mechanisms
* Mu receptor agonist
* NMDA receptor antagonist (the only opioid that has this effect)
* Inhibits reuptake of monoamines in the synaptic cleft
133
which opioid is most likely to cause QT prolongation?
Although a rate event, methadone can potentially increase the QT interval. This can lead to torsades de pointes
134
What is the etiology of opioid induced skeletal muscle rigidity?
Rapid IV administration of the potent IV opioids can cause skeletal muscle rigidity (mu receptor stimulation in the CNS). Historically, this complication has been described as chest wall rigidity or stiff chest syndrome. However, current evidence suggest that the greatest resistance to ventilation occurs at the larynx
135
What is the tx of opioid induced skeletal muscle rigidity?
Tx:
* the best tx is paralysis and intubation
* Naloxone can also reverse rigidity, but giving this just before surgery seems counterproductive given that there is better alternative
136
What are the common characteristics of the opioid partial agonists?
Opioid partial agonists (agonist-antagonists) function just as their name suggests. They can never achieve the same intensity of effect at a specific receptor as a full agonist.
Common characteristics:
* produce analgesia with a reduced risk of resp depression
* have a ceiling effect beyond which additional analgesia is not possible
* reduce the efficacy of previously administered opioids
* Can cause acute opioid withdrawal in the opioid-dependent pt
* carry a low risk of dependence
* are used in pt's who cannot tolerate a full opioid agonist
ex: buprenorphone, nalbuphine, butorphanol
137
Compare and contrast buprenorphine, nalbuphine, and butorphanol.
138
Discuss the potential complications pf opioid reversal with naloxone.
Short duration:
* Naloxone's duration (30-45 min) may be shorter than the opioid your trying to reverse. Consider an infusion if a long-acting opioid is the cause of resp depression
SNS stimulation
* this is the mechanism by which naloxone causes tachycardia, cardiac dysrhythmias, pulmonary edema, and sudden death
* slow titration minimizes these effects
N/V
* slow titration over 2-3 minutes causes less N/V
Fetal withdrawal:
* Naloxone crosses the placenta. If given to an opioid abusing mother, it can precipitate acute opioid withdrawal in the neonate
139
Which opioid antagonist is least likely to reverse resp depression? why?
Methylnatrexone has a quaternary amino group that prohibits its passage across the BBB
* Since it doesn't enter the brain, it doesn't reverse resp depression
* It's useful for mitigating the peripheral effects of opioids, such as opioid- induced bowel dysfunction
140
What is the maximum dose of cocaine that can be used as a topical vasoconstrictor?
150-200mg
1.5 - 3mg/kg
141
general rule for onset of action, potency, and duration of action
onset of action= pKa
Potency= Lipid solubility
Duration of action= protein binding (receptor)
142
which local anesthetic is unionized at physiologic pH?
Benzocaine
it's the only clinically available local anesthetic with a pKa below physiologic pH pka of 3.5
greatest risk for methemoglobinemia is when total dose exceeds 200-300mg
143
ED95 of all clinically used NMBs Most potent to least:
Cisatracurium = 0.04mg/kg
vecuronium= 0.043 mg/kg
mivacurium= 0.067mg/kg
pancuronium= 0.067mg/kg
atracurium= 0.21 mg/kg
succinylcholine = 0.3 mg/kg
rocuronium= 0.305mg/kg
144
what is the BEST intraoperative test to confirm the diagnosis of an anaphylactic response cause by a neuromuscular blocker?
tryptase
Anaphylaxis is the result of mas 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
145
muscles of the eye and thumb
corrugator supercilii= moves the eyebrow- facial nerve
orbicularis oculi= closes the eyelid- facial nerve
medial rectus= adducts the eyeball- oculomotor nerve
adductor pollicis= adducts the thumb- ulnar nerve
146
which is the BEST acetylcholinesterase inhibitor to antagonize a block with 90% twitch suppression?
Neostigmine
147
onset of action edrophonium, pyridostigmine, neostigmine
edrophonium- 1 minute
pyridostigmine- 15 minutes
neostigmine- 10 minutes
148
Naturally occurring, semisynthetic, and synthetic opioid agonists and antagonists
naturally occurring:
* phenanthrene derivatives= Morphine, codeine (codeine is a prodrug that produces morphine)
Semisynthetic:
* Morphine derivatives= Hydromorphone, heroin, naloxone, naltrexone
* Thebaine derivatives= oxycodone
Synthetic:
* Piperidines= Meperidine
* Phenylpiperidines= Fentanyl, sufentanil, remifentanil, alfentanil
diphenylpropylamine= methadone
149
which opioid side effects are most resistant to tolerance?
Miosis and constipation
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.
150
A pt becomes hypotensive after 10 mg of IV morphine. What is the LEAST likely explanation for this finding?
myocardial depression
decreases SNS tone -> venous pooling -> decreased preload -> decreased CO -> Decreased BP
Decreased SNS tone -> orthostatic HoTN
Histamine release -> decreased BP (only morphine and meperidine)
151
In women, morphine is associated with a:
greater analgesic potency
As well as
* slower onset of action
* longer duration of action
* lower post-operative opioid consumption
152
An opioid dependent pt is experiencing intense signs of withdrawal 8 hrs after his last dose. Which of the following drugs is the pr MOST likely abusing?
Fentanyl
Pt who are physically dependent on opioid agonists will experience s/sx of withdrawal upon disconinuation 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 2-6hrs - 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 - 48hrs - peak 3-21 days - Duration 6-7 weeks
153
which opioid inhibits nerve conduction?
Meperidine
It exhibits 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
154
What is Kava-Kava used for?
as an anxiolytic and analgesic. Its anticipated drug interaction includes the potentiation of opioids and benzos. It has no known effect upon coagulation or MAOI therapy and is not known to produce HTN.
155
Match the drug and its path of metabolism
Midazolam- CYP3A
Diazepam- Cyp2C19
Codeine- CYP2D6
Methadone- CYP2B6
40-50% of all anesthetic drugs are metabolized by CYP3A4: Midazolam, acetaminophen, fentanyl, statins
Diazepam and warfarin CYP2C19 and CYP3A
Codeine and oxycodone are metabolized by CYP2D6, and methadone and propofol are metabolized by CYP2B6
156
The pharmacokinetics of benzodiazepines in obese pts are characterized by
Increased volume of distribution and prolonged elimination half-life
Increased volume of distribution due to the movement of the drug from the plasma into the adipose tissue. Clearance is not altered; however, the elimination half-life is increased as a result of the increased volume of distribution. This creates an extended movement of the drug from the excess adipose tissue into the plasma for elimination
157
When a dose of fentanyl has a volume of distribution larger than total body water, what are the possible locations of the drug?
Bound to peripheral tissue
Fist-pass pulmonary uptake
Drugs that have a higher volume of distribution are typically those with high solubility in tissue. Initial redistribution out of the central compartment is directly to the peripheral tissue beds. In the case of fentanyl (along with sufentanil, alfentanil, meperidine, lidocaine, propranolol, and propofol), first-pass pulmonary uptake also occurs at rates exceeding 60% of the injected dose
First-pass pulmonary uptake and elimination is an example of extrahepatic clearance of drugs.
158
the plasma half-life of diazepam may be prolonged with the concurrent administration of:
Ciprofloxacin
Cytochrome P450 enzymes are responsible for much of the metabolism in the body during phase 1 reactions. 20-50% of all anesthetic drugs are metabolized by CYP-mediated drug metabolism, specifically CYP3A4.
There are subsets of CYP enzymes. Diazepam is metabolized by CYP2C19 and CYP3A4. Ciprofloxacin is a known inhibitor of CYP2C19, and the administration of diazepam to the individual taking cipro will result in a prolonged duration of action. Grapefruit juice is an inhibitor of CYP3A have minimal effect on diazepam metabolism
Midazolam is metabolized by CYP3A4. They CYP3A4 enzyme is inhibited by antifungal agents and grapefruit juice, increasing the duration of action of midazolam.
Inhalation agents do not inhibit P450 enzyme activity and do not affect the duration of action of diazepam.
159
Midazolam induced respiratory depression is the result of:
Midazolam produces respiratory depression via a decrease in hypoxic ventilatory drive. This may be exaggerated as a result of synergism when midazolam is combined with an opioid. Individuals with COPD may have exaggerated respiratory depression following the administration of a benzo.
160
Which conditions may produce hyperkalemia with the administration of succinylcholine?
Immobilization, sepsis, hemiplegia
Conditions that increase the proliferation of extrajunctional (immature or fetal) nicotinic acetylcholine receptors increase the risk of hyperkalemia following administration of succinylcholine. This is a classic example of receptor up-regulation which is elicited by a lack of stimulation of ACh receptors at the NMJ. Up-regulation of ACh receptors may occur following stroke, hemiplegia or paraplegia, burn injury, upper or lower motor neuron denervation, sepsis, and chronic immobilization (individuals following extended hospitalization or ICU stay).
Fatal hyperkalemia has been reported in individuals receiving succs with underlying metabolic acidosis and hypovolemia and in pts with certain muscle myopathies
Succs administration is safe in individuals with renal failure who have normal serum potassium levels. Healthy individuals experience increases in K of approximately 0.5 mEq/L. Individuals with myasthenia gravis and Eaton-Lambert syndrome affect succs duration but do not increase the risk of hyperkalemia.
161
Edrophonium dosing
PNS result
TOF < 1= not indicated
TOF 1-2 - 1000-1500mcg/kg
TOF 3-4 with fade= 500 mcg/kg
TOF 4 without fade= 500mcg/kg
a low does of edrophonium can be given (0.5mg/kg) for TOF 3
162
What side effects persist into the postoperative period following anticholinergic drugs given in conjunction with anticholinesterases of NMBA reversal?
Attenuated heart rate variability
decreased baroreceptor sensitivity
both will be restored 2 hours post op
163
Neostigmine dosing
PSN result
TOF <1 - not indicated
TOF 1-2= 0.07mg/kg
TOF 3-4 with fade= 0.04-0.05 mg/kg
TOF 4 without fade= 0.02 mg/kg
164
Pyridostigmine dosing
PNS result:
TOF ,1 - not indicated
TOF 1-2= .35 mg/kg
TOF 3-4 with fade= .2 mg/kg
TOF 4 without fade= .2 mg/kg
165
What is the duration in minutes of an intubating does of 1mg/kg of succs when measured at the adductor pollicis?
7-13 min
The ED95 of succs is clinically about 0.3 mg/kg. A dose of 1mg/kg succs typically results in complete suppression of neuromuscular function in 60-90 seconds. Full recovery of (TOFR 0.9) requires 7-12 minutes or 9 to 13 minutes.
166
what factor may lead to an excessive depth of anesthesia when using an inhalation agent?
Mechanical ventilation
Because anesthetics have dose-dependent effects upon respiration, spontaneous breathing acts as a negative feedback loop during uptake. When ventilation is depressed by anesthesia, the delivery of inhaled agents is reduced, thus limiting anesthetic uptake. This protective mechanism with spontaneous ventilation decreases the incidence of anesthetic overdose.
Mechanical ventilation permits constant alveolar ventilation, in which delivery of an anesthetic continues regardless of the depth of anesthesia, increasing anesthetic uptake and the possibility of anesthetic overdose.
167
Which inhalation agents are the MOST effective in reducing the resistive work of breathing?
Iso and sevo
Isoflurane, sevoflurane, and halothane all exhibit bronchodilating effects as early as 5 minutes after administration. Neither des or nitrous oxide reduces respiratory resistance. Des is pungent and produces airway irritation
168
What increases the suceptibility of N2O toxicity?
Vit B12 deficiency
Methotrexate administration
Chronic nitrous oxide administration results in the irreversible binding of the cobalt atom on vit B12 (cobalamin) and inhibits methionine synthase, resulting in an increase in homocysteine concentrations.
Factors that increase the susceptibility to toxicity include pernicious anemia (decreased vit B12), extremes of age, alcoholism, malnutrition, inhibitors of folate metabolism that occurs with methotrexate administration, and inborn errors in cobalamin or folate metabolism.
169
what are the clinical benefits of nitrous oxide administration?
prominent analgesic effect
enhances catecholamine release
170
what conditions can alter the blood:gas partition coefficients of inhales anesthetics?
Decreased Hct and fatty meal ingestion
Blood:gas partition coefficients are decreased 20% with a Hct of 21% compared with 43%, and are increased about 20% following the ingestion of a fatty meal. Erythrocytes provide a source of lipid-dissolving sites, while after a fatty meal, the chylomicron content of the circulating blood rises. Chylomicrons are composed largely of triglycerides but also contain cholesterol and phospholipids, all of which provides sites for anesthetic binding.
Although the percutaneous loss of inhalation anesthetic does occur, it is very small, and increased BSA is unlikely to make a significant difference. This event does not influence the blood:gas solubility coefficient. Body fat content also does not influence the blood:gas solubility coefficient.
171
Which opioid subtypes elicit respiratory depression?
Delta and Mu2
172
which opioid antagonist is MOST appropriate for treating severe constipation in the postoperative patient ready for discharge?
Naloxegol
Oral peripherally acting mu-receptor antagonist used to treat opioid-induced constipation
Methylnaltrexone (quaternary ammonium opioid receptor antagonist) does not cross the BBB but acts peripherally to reduce opioid-induced delayed gastric emptying and constipation. However, it must be given subcutaneously and is not ideal for home use.
Naltrexone is an oral long-acting antagonist at mu, delta and K opioid receptors. It can be used to treat opioid induced pruritus and vomiting
Naloxone is a short-acting IV or intrathecal agent used to reverse opioid-induced respiratory depression
173
Benzodiazepines will reliably produce all of the following effects except:
Mitigating the stress of intubation
Despite hemodynamic effects of modestly decreased MAP and SVR with the maintenance of HR and CO, benzos do not mitigate the stress of ETT placement or surgery
Benzos suppress upper airway muscle tone and depress the ventilatory response to CO2. Sedative doses of midazolam also depress hypoxic ventilatory response. These drugs provide for anterograde amnesia but not retrograde amnesia.
174
Sedative-hypnotic effects in the CNS are elicited by agonism at which receptor types?
Alpha 2- adrenergic and gamma-aminobutyric acid
propofol, barbiturates, benzos, and etomidate all AGONIZE gamma-aminobutyric acid, subtype A, receptors. Dexmedetomidine agonizes alpha2 adrenergic receptors.
Droperidol fully INHIBITS alpha2 acetylcholine nicotinic receptors as well as partially INHIBITING GABA-A, Beta 1, and gamma2 acetylcholine receptors.
Ketamine ANTAGONIZES excitatory N-methyl-D-aspartate receptors, producing dissociative anesthesia
175
What are the beneficial features of opioid agonist- antagonists?
Lower potential for physical dependence, and ceiling effect for respiratory depression
Opioid agonist-antagonists decrease MAC less effectively than pure opioid agonists. They can also provoke withdrawal symptoms when used in patients on chronic opioid therapy
176
Which opioids produce active metabolites?
Tramadol (O-desmethyl tramadol)
meperidine (normeperidine)
morphine (morphine-6-glucuronide)
177
An induction dose of methohexital may produce:
Hiccups
Tremors
Garlic taste (40% of pts)
can also produce cough and twitching
178
Under which condition is epidural analgesia considered the gold standard for pain control?
Thoracotomy
not- discectomy, end of life cancer pain, or abdominal surgery
Thoracic epidural analgesia is the gold standard for postoperative pain management following thoracic surgery and is the pain management technique against which all other techniques are compared. The most effective approach includes low-dose local anesthetics combined with opioids. The advantage of epidurally administered opioids includes effective analgesia without sympathetic or motor blockade. Thoracic epidural analgesia improves coronary blood flow and reduces pulmonary complications.
179
Which local anesthetics used for an epidural block are prolonged with the addition of epinephrine?
Lidocaine and chloroprocaine
not ropivicaine or bupivicaine
180
single blood patch has what success rate?
75-90%
181
what are the two most important factors for spread and duration of subarachnoid anesthesia?
local anesthetic dose and local anesthetic density
182
transient neurological symptoms following spinal anesthesia are MOST commonly associated with:
5% lidocaine, and injection through a small continuous spinal catheter
additional factors include the administration of non-preservative free 2-cholorprocaine, lithotomy positioning, and the use of spinal anesthesia in individuals with spinal stenosis. These expose the cauda equina to pooled concentrations of the local anesthetic
183
which molecular feature of local anesthetics confers the ability to be rapidly metabolized?
ester bond
ester= hydrolyzed in the plasma by pseudocholinesterase
Amide= metabolized in the liver by carboxylesterases, and their metabolites are excreted via the kidney
tertiary amide confers the acid-base status of a molecule (pKa), while various substitutions on the amide (hydrophilic) and the aromatic ring (lipophilic) determine the lipid solubility.
184
what are the initial steps in treating a pt with local anesthetic systemic toxicity.
Call for help
ventilate with oxygen
suppress seizures with benzodiazepine
Infuse 20% lipid emulsion
185
life-threatening ventricular dysrhythmias and cardiovascular collapse due to bupivacaine overdose are BEST treated with:
Amiodarone and chest compressions
not aggressive epi (small doses are okay) or CCBs and BBs can worsen myocardial depression, vasopressin and lidocaine should also be avoided
