Pharmacology 2 Flashcards
Describe the component of the neuron and their function
What is conduction velocity, and how it it affected by myelination and axon diameter?
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
List the 3 different nerve fiber types. Compare and contrast them in terms of myelination, function, diameter, conduction velocity, and block onset
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
Discuss differential blockade using epidural bupivacaine as an example
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
What concept is analogous to ED50 for local anesthetics?
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
Rank the nerve fiber types according to their sensitivity to local anesthetics in vivo (most to least sensitive)
B fibers> C fibers> Small diameter a fibers (gamma and delta)> Large diameter (alpha and beta)
What are the 3 possible configurations of the voltage-gated sodium channel
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
How and when do local anesthetics bind to the voltage-gated sodium channel?
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.
What is an action potential, and how does it depolarize a nerve?
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.
what happens when a nerve repolarizes?
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.
How do local anesthetics affect neuronal depolarization?
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
Discuss the role of ionization with respect to local anesthetics
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
what are the 3 building blocks of the local anesthetic molecule? how does each one affect the PK/PD profile of the molecule?
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
How can you use the drug name to determine if it’s an ester or amide? List examples from each class.
Ester: Benzocaine, cocaine, chloroprocaine, procaine, tetracaine
Amide: I before suffix: Articaine, bupivacaine, dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, ropivacaine
Contrast the metabolism of ester and amide local anesthetics. Which local anesthetic participates in both metabolic pathways?
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
Discuss the local anesthetic allergy and cross sensitivity.
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
What determines local anesthetic onset of action? which drug disobeys this rule and why?
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
What determines local anesthetic potency?
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
what factors determine local anesthetic duration of action?
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
Discuss the intrinsic vasodilating effects of local anesthetics. Which local anesthetic has the opposite effect?
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.
Rank the amide local aneathetics according to pKa.
- as pKA gets further away from physiologic pH, the degree of ionization increases
Rank the ester local anesthetica to pKa
Notice that chloroprocaine does NOT bind to plasma proteins in a meaningful way
list 5 factors that govern the uptake and plasma concentration of local anesthetics
Factors that influence vascular uptake and Cp:
* Site of injection
* Tissue blood flow
* physiochemical properties of local anesthetic
* Metabolism
* addition of vasoconstrictor
Rank injection sites to the corresponding plasma concentrations of local anesthetic
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
What is the maximum dose for each amide local anesthetic (weight based and max total dose)
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
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
Liste the effects of lidocaine toxicity according to plasma concentration
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
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
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
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
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.
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
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
What drugs are capable of causing methemoglobinemia
Local anesthetics:
Benzocaine, cetacaine (contains benzocaine), prilocaine, EMLA (prilocaine + lidocaine)
Other drugs:
Nitroprusside, nitroglycerine, sulfonamides, phenytoin
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
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)
Name two pt populations who are at increased risk for developing methemoglobinemia
- Pts with glucose-6-phosphate reductase deficiency do not possess methemoglobin reductase, so that an exchange transfusion may be required
- Fetal Hgb is relatively deficient in methemoglobin reductase, making it susceptible to oxidation. Therefore, neonates are at higher risk for toxicity.
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
What is the max does of EMLA cream
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
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
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
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)
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
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
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
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.
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
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
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
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.
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.
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
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
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
List all the tests of recovery from neuomuscular blockade. What values suggest recovery and to what degree?
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
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
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.
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.
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
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)
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
What are the 3 variants of pseudocholinesterase, and what is the duration of action of succ’s for each one?
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!
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)
How do you treat a pt who has become hyperkalemic in response to succ’s?
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
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
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.
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)
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
list 3 ways to inhibit acetylcholinesterase. Give examples of each
- Electrostatic attachment
* competitive inhibition
ex: edrophonium - Formation of carbamyl esters
* competitive inhibition
ex: neostigmine, pyridostigmine, physostigimine - Phosphorylation:
* Non-competitive inhibition
Ex: organophosphates and echothiophate
Compare and contrast the side effects of atropine, scopalamine, and glycopyrrolate
can’t spit, can’t shit, can’t sweat
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
Compare the equianalgesic doses relative to 10mg of morphine
Compare and contrast buprenorphine, nalbuphine, and butorphanol.
