Unit 5: Pharmacology 2 Flashcards
What is conduction velocity, and how is it affected by myelination and axon diameter?
Conduction velocity = measure of HOW FAST an axon transmits the AP
Increased by:
- myelination (AP 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 onet
Discuss differential blockade using epidural bupivacaine as an example
Differential blockade is the idea that some fiber types are blocked sooner (easier) than others
- at lower concentrations, epidural bupivacaine provides analgesia while sparing motor function – as concentration is increases, it anesthetizes more resistant nerve types such as those that control motor function and proprioception
- this is the basis for “walking” epidural w/ a low concentration of bupivacaine
What concept is the equivalent of an ED50 for local anesthetics?
Minimum effective concentration (Cm) – measure that quantifies the concentration of LA that is required to block conduction
- 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 local anesthetics in vivo (most to least sensitive)
B-fibers > C fibers > Small diameter A fibers (gamma & delta) > Large diameter A fibers (alpha & beta)
What are the 3 possible configurations of the voltage-gated sodium channel?
Resting: channel is closed and able to be opened if neuron depolarizes
Active: channel is open, Na+ is moving along its concentration gradient into the neuron
Inactive: channel is closed and unable to be opened (it is refractory)
How and when do local anesthetics bind to voltage-gated sodium channel?
They can only bind in their ACTIVE (open) and INACTIVE (closed refractory)
- DO NOT bind in resting state
- Use dependent or phasic blockade = the more frequently the nerve is depolarized and the voltage-gated sodium channels open, the more time available for LA binding to occur
What is an action potential and how does it depolarize a nerve?
AP = a temporary change in transmembrane potential followed by a return to transmembrane potential
- for a neuron to depolarize, sodium or calcium must enter the cell (makes inside more positive)
- once the threshold potential occurs, the cell depolarizes and propagates and AP
- depolarization is an all or none phenomenon – it either depolarizes or doesn’t
- AP only travels one direction – because Na+ open in the upstream portion of the neuron are in the closed/inactive state
What happens when a nerve repolarizes?
Repolarization is the removal of positive charges from inside the cell – accomplished by removing potassium
How do local anesthetics affect neuronal depolarization?
LA 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 isn’t enough open channels for sodium to enter the cell in sufficient quantity
- cell can’t depolarize and the AP can’t propagate – whatever modality that nerve services (pain, movement, etc) is blocked
**LA do NOT affect resting membrane potential or threshold potential
Discuss the role of ionization with respect to local anesthetics
Since LA are weak bases with pKa values higher than 7.4 – >50% of the LA 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 – charged species binds to the alpha-subunit on the interior of the voltage gated sodium channel
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 or amide
- metabolism
- allergic potential
Tertiary amine:
- hydrophilic
- accepts proton
- makes molecule a weak base
How can you use the drug name to determine if it’s an ester or amide?
Ester = only has one “i” in the name
(Benzocaine, Cocaine, Chloroprocaine, Procaine, Tetracaine)
Amide = has two “i” in the name
(Bupivacaine, Lidocaine, Mepivacaine, Ropivacaine)
How are ester and amide local anesthetics metabolized? 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 is metabolized by pseudocholinesterase & the liver
Discuss local anesthetic allergy and cross sensitivity
True allergy is rare – more common with esters
-esters are derivatives of PABA which is an immunogenic molecule capable of causing an allergic reaction (reason there is cross-sensitivity within the class)
Allergy to amides is incredibly rare
*no cross-sensitivity between esters and amides
What determines local anesthetic onset of action? Which drug disobeys this rule and why?
pKa determines the onset of action
- if pKa is closer to pH, onset is faster
- if pKa is further from pH, onset is slower
Chloroprocaine disobeys this rule:
- it has a high pKa which suggests slow onset
- at the same time it is not very potent so we give it in a higher concentration (usually 3% solution)
- giving more molecules creates a mass effect that explains why chloroprocaine has a rapid onset of action even with its high pKa
What determines local anesthetic potency?
Lipid solubility = primary determinant of potency
- the more lipid soluble, the easier it is to traverse the neuronal membrane
- because more drug enters the neuron, there will be more available to bind to the receptor
An intrinsic vasodilating effect = secondary determinant of potency
- vasodilation increases uptake into systemic circulation (reduces amount of LA available to anesthetize the nerve)
What factors determine local anesthetic duration of action?
Protein Binding = primary determinant of duration of action
- some molecules penetrate epineurium after injection, some diffuse away into the systemic circulation, and some bind to tissue proteins
- molecules that bind to proteins serve as a reservoir that extends the DOA
Lipid Solubility and Intrinsic Vasodilating Activity = secondary determinants of duration of action
- higher degree of lipid solubility also correlates w/ 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 one has the opposite effect?
Most LA cause some degree of vasodilation – those with greater degree of intrinsic vasodilating effects (lidocaine) undergo a faster rate of vascular uptake preventing some of the administered dose from accessing the nerve
-addition of vasoconstrictor can prolong the DOA
**Cocaine is unique – it always causes vasoconstriction because it inhibits NE reuptake in the sympathetic nerve endings in vascular smooth muscle
Rank the amide local anesthetics according to pKa (highest to lowest)
Bupivacaine = 8.1 Levo-Bupivacaine = 8.1 Ropivacaine = 8.1 Lidocaine = 7.9 Prilocaine = 7.9 Mepivacaine = 7.6
*as pKa gets further away from physiologic pH – the degree of ionization increases
Rank the ester local anesthetics according to pKa (highest to lowest)
Procaine = 8.9 Chloroprocaine = 8.7 Tetracaine = 8.5
What five factors govern the uptake and plasma concentration of local anesthetics?
- Site of injection
- Tissue blood flow
- Physiochemical properties of local anesthetics
- Metabolism
- Addition of vasoconstrictor
Rank injection sites to the corresponding plasma concentrations of local anesthetics
Most Vascular & Highest Cp
- IV
- Tracheal
- Interpleural
- Intercostal
- Caudal
- Epidural
- Brachial plexus
- Femoral
- Sciatic
- Subcutaneous
Least Vascular & Lowest Cp
What is the maximum dose for each amide local anesthetic? (weight based and max total dose)
- Levobupivacaine
- Bupivacaine
- Bupivacaine + Epi
- Ropivacaine
- Lidocaine
- Lidocaine + Epi
- Mepivacaine
- Prilocaine
- Levobupivacaine = 2 mg/kg or 150 mg
- Bupivacaine = 2.5 mg/kg or 175 mg
- Bupivacaine + Epi = 3 mg/kg or 200 mg
- Ropivacaine = 3 mg/kg or 200 mg
- Lidocaine = 4.5 mg/kg or 300 mg
- Lidocaine + Epi = 7 mg/kg or 500 mg
- Mepivacaine = 7 mg/kg or 400 mg
- Prilocaine = 8 mg/kg or 500 mg if <70kg or 600 mg if >70kg
What is the max dose for each ester local anesthetic? (weight based and max total dose)
- Procaine
- Chloroprocaine
- Chloroprocaine + Epi
- Procaine = 7 mg/kg or 350-600 mg
- Chloroprocaine = 11 mg/kg or 800 mg
- Chloroprocaine+ Epi = 14 mg/kg or 1000 mg
What is the most common sign of LAST?
Seizure
-bupivacaine is the exception (cardiac arrest can occur before seizure
What are the CNS effects of lidocaine toxicity according to plasma concentration?
Cp 1-5 = Analgesia
Cp 5-10 = Tinnitus, Skeletal muscle twitching, Numbness of lips and tongue, Restlessness, Vertigo, Blurred vision
Cp 10-15 = Seizures, Loss of Conciousness
Cp 15-25 = Coma
What are the Cardiopulmonary effects of lidocaine toxicity according to plasma concentration?
Cp 5-10 = Hypotension, Myocardial depression
Cp 15-25 = Respiratory arrest
Cp >25 = Cardiovascular collapse
What conditions increase the risk of CNS toxicity in LAST?
Hypercarbia: increases cerebral blood flow (increasing drug delivery to the brain), decreases protein binding, and increases free fraction available to enter the brain
Hyperkalemia: raises resting membrane potential, making neurons more likely to depolarize
Metabolic Acidosis: decreases convulsion threshold and favors ion trapping inside the brain
Why is the risk of cardiac morbidity higher with bupivacaine than with lidocaine?
Two features determine the extent of cardiotoxicity:
- affinity for voltage-gated sodium channel in the active and inactive state
- rate of dissociation from the receptor during diastole
Bupivacaine has a greater affinity for the sodium channel and a slower rate of dissociation from the receptor during diastole – bupivacaine remains at the receptor for a longer period of time
Rank the difficulty of cardiac resuscitation of local anesthetics
Bupivacaine > Levobupivacaine > Ropivacaine > Lidocaine
What are the modifications to the ACLS treatment protocol when applied to LAST?
Epi can hinder resuscitation from LAST – it reduces the effectiveness of lipid emulsion therapy (if epi must be used, give in doses of < 1 mcg/kg)
Amiodarone is the agent of choice for ventricular arrhythmias
Avoid vasopressin, lidocaine, and procainamide
Discuss the use of lipid emulsion for the treatment of LAST
Lipid emulsion acts as a lipid sink – an intravascular reservoir that sequesters LA and reduces the plasma concentration of LA
Treatment of LAST:
- bolus 20% 1.5 mL/kg (lean body mass) over 1 min
- infusion 0.25 mL/kg/min
- if symptoms are slow to resolve, repeat bolus up to 2 more times and increase infusion rate to 0.5 mL/kg/min
- continue infusion for 10 min after achieving hemodynamic stability
- max recommended dose is 10 mL/kg in the first 30 min
You are providing anesthesia for a 90kg patient undergoing liposuction. The plastic surgeon wants to use tumescent lidocaine 0.1% and asks you to calculate the max dose. How much tumescent lidocaine can this patient receive?
Max dose of lidocaine for tumescent anesthesia is 55 mg/kg (Nagelhous says 50 mg/kg)
90 kg x 50 mg/kg = 4500 mg
90 kg x 55 mg/kg = 4950 mg
A 0.1% lidocaine solution contains 1 mg/mL – Patient 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 – due to volume overload
- if a pt experiences CV collapse, first calculate the max dose of lidocaine received – if the dose is within acceptable range, then think of other complications such as volume overload or PE
- General anesthesia is recommended if >2-3 L 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 – they can cause methemoglobinemia
- O2 binding site on the heme portion of the Hgb molecule contains an iron molecule in tis ferrous form – oxidation of the iron molecule to its ferric form creates methemoglobin – methemoglobin impairs O2 binding and unbinding from the Hgb molecule shifting the curve left
- creates a physiologic anemia
What drugs are capable of causing methemoglobinemia? (8)
- Benzocaine
- Cetacaine (contains benzocaine)
- Prilocaine
- EMLA (prilocaine + lidocaine)
- Nitroprusside
- Nitroglycerine
- Sulfonamides
- Phenytoin
What are the signs & symptoms of methemoglobinemia?
- Hypoxia
- Cyanosis (in the presence of a normal PaO2 is highly suggestive of it)
- Chocolate colored blood
- Tachycardia
- Tachypnea
- Mental status changes
- Coma and death
What is the treatment for methemoglobinemia? How does it work?
Methylene blue 1-2 mg/kg over 5 min up to a max dose of 7-8 mg/kg
-methemoglobin reductase metabolize methylene blue to form leucomethylene blue – this metabolite functions as an electron donor and reduces methemoglobin (Fe+3) back to hemoglobin (Fe+2)
Name two patient 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 hemoglobin is relatively deficient in methemoglobin reductase, making it susceptible to oxidation – neonates are at higher risk for toxicity
What are the constituents of EMLA cream?
5% EMLA crease is a 50/50 combination of 2.5% lidocaine and 2.5% prilocaine
- prilocaine metabolizes to o-toluidine, which oxidizes hemoglobin to methemoglobin
- infants and small children more likely to become toxic
What is the max dose and surface area for EMLA cream?
0-3 months or <5 kg = 1g over 10 cm2 area
3-12 months and >5 kg = 2g over 20 cm2 area
1-6 years and >10 kg = 10g over 100 cm2 area
7-12 years and >20 kg = 20g over 200 cm2 area
How does sodium bicarb affect local anesthetic onset of action? Are there any other benefits?
It shortens local anesthetic onset time
- alkalization increases the number of lipid soluble molecules, which speeds up the onset of action (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 bicarb with 10 mL of local
Addition of sodium bicarb also reduces pain during injection
How does adding epinephrine affect local anesthetics?
It extends local anesthetic duration
-alpha-1 agonist effect of epi makes it a potent vasoconstrictor – can decrease systemic uptake of LA, prolong block duration, and enhance block quality
What drugs can be added to LA to provide supplemental analgesia? What is the mechanism of action for each one?
Clonidine (alpha-2 agonist)
Epinephrine (alpha-2 agonist)
Opioids (mu agonist)
-chloroprocaine is an exception (it reduces the effectiveness of opioids in the epidural space)
What drug can be used to improve LA diffusion through tissue?
Hyaluronidase
- hyaluronic acid is present in the interstitial matrix and basement membrane – it hinders the spread of substances through tissue
- hyaluronidase hydrolyzes hyaluronic acid – facilitates the diffusion of substances through tissues
- commonly used in ophthalmic blocks to increase the speed of onset, enhance block quality, and mitigate a rise in intraocular pressure
What are the 2 types of nicotinic receptors present at the neuromuscular junction? What is the function of each?
Prejunctional Nn Receptor:
- present on presynaptic nerve (n = nerve)
- regulates ACh release
Postsynaptic Nm Receptor:
- present at the motor endplate on the muscle cell (m = muscle)
- responds to ACh (depolarizes muscle)
Describe the structure of the post-synaptic, nicotinic receptor at the neuromuscular junction
Postsynaptic nicotinic receptor (Nm) is 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 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 (makes cell interior more positive, activates voltage-gated Na channel, depolarizes the muscle cell, and initiates an AP)
- depolarization of the myocyte instructs the endoplasmic reticulum to release Ca into the cytoplasm, where it engages with the myofilaments and initiates muscle contraction
How is the ACh signal “turned off” at the neuromuscular junction?
AChE is strategically positioned around the pre- and postsynaptic nicotinic receptors – it hydrolyzes ACh almost immediately after activating the receptors
Why are extrajunctional receptors sometimes called fetal receptors?
There are 2 pathologic variants of the nicotinic receptor:
-the α2β1δ1γ1 subtype has a gamma subunit instead of an epsilon subunit
the α7 subtype consists of 5 alpha subunits
Extrajunctional receptors resemble those that are present early in fetal development – once innervation takes place, adult α2β1δ1Ɛ1 subtype receptors replace fetal nicotinic receptors
Denervation later in life allows for the return of both types of extrajunctional receptors
What conditions allow extrajunctional receptors to populate the myocyte?
- Upper and lower motor neuron injury
- Spinal cord injury
- Burns
- Skeletal muscle trauma
- CVA
- Prolonged chemical denervation (magnesium, long term NMB infusion, clostridial toxin)
- Tetanus
- Severe sepsis
- Muscular dystrophy
What is the risk of using SUX in a ptt with upregulation of extrajunctional receptors?
Extrajunctional receptors are much more sensitive to SUX – 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?
Pts with upregulation of extrajunctional receptors are resistant to NMDRs (reduced potency)
-dose may need to be increased
Discuss fade in the context of SUX and NMDRs
There are two supplies of ACh vesicles:
- ACh that is available for immediate release
- ACh that must be mobilized before it can be made available for immediate releas
NMDRs competitively antagonize the presynaptic Nn receptor – this impairs the mobilization process so only vesicles available for immediate release can be used
- Since this is a limited supply, nerve stimulation can quickly exhaust the supply – with each successive stimulation less ACh is released (manifests as fade)
SUX stimulates the prejunctional receptors – when it binds it facilitates the mobilization process so there is always ACh available for immediate release (why fade doesn’t occur)
What is the difference between a phase 1 and phase 2 block? What risk factors increase the likelihood of a phase 2 block with SUX?
Phase 1 Block = No Fade
Phase 2 Block = Fade Present
The only time SUX causes fade is when it produces a phase 2 block - 2 situations favor the development of the phase 2 block:
- Dose >7-10 mg/kg
- 30-60 min of continuous exposure
Compare and contrast the phase 1 and phase 2 block in terms of TOF, tetany, double burst stimulation, and post-tetanic potentiation
- Phase 1 responses to stimulation are diminished but equal (no fade)
- Phase 2 response to stimulation is characterized by fade
- 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
What is the best location to assess the onset of neuromuscular blockade? How about 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
What is the acceptable clinical endpoint and what percent of receptors are still occupied for the following tests that show recovery from neuromuscular blockade?
- Tidal Volume
- TOF
- Vital Capacity
- Sustained Tetanus
- Double Burst Stimulation
- Inspiratory Force
- Head Lift
- Hand Grip
- Holding Tongue Blade
- Tidal Volume: >5 mL/kg – 80% receptors occupied
- TOF: No fade – 70% receptors occupied
- Vital Capacity: >20 mL/kg – 70% receptors occupied
- Sustained Tetanus (50Hz): No fade – 60% receptors occupied
- Double Burst Stimulation: No fade – 60% receptors occupied
- Inspiratory Force: better than -40 cmH2O (more negative = better) – 50% receptors occupied
- Head Lift: Sustained for 5 seconds – 50% receptors occupied
- Hand Grip Same as Preinduction: Sustained for 5 seconds – 50% receptors occupied
- Holding Tongue Blade in Mouth Against Force: Can’t move tongue blade – 50% receptors occupied
How does SUX affect HR? Why?
Bradycardia:
- by stimulating the M2 receptor on the SA node
- second dose increases the risk (particularly in kids <5yo)
- succinylmonocholine (primary metabolite) is probably responsible for this effect
- antimuscarinics may prevent or reverse these bradyarrhythmias
Tachycardia:
- tachy + HTN by mimicking the action of ACh at the sympathetic ganglia
- in adults tachy is more common than brady
Is SUX safe to give to a patient with renal failure?
It can increase K+ by 0.5-1.0 mEq/L for up to 10-15 min
- safe in pts with renal failure who have a normal potassium level
- pts w/ elevated K+ don’t have an increased release, however, the normal response to SUX may increase K+ to a dangerous level
How does SUX affect intraocular pressure?
Transiently increases it by 5-15 mmHg for up to 10min
- concern if pt has an open globe injury
- balance this concern against the need to rapidly secure the airway
- Roc 1.2 mg/kg is an alternative if RSI is indicated
How does SUX affect intragastric pressure?
Contraction of abdominal muscles increases it – At the same time, SUX raises LES tone
These processes cancel each other out, so barrier pressure at the gastroesophageal junction is unchanged
*risk of aspiration is NOT increased
What are the five names for the enzyme that metabolizes ACh? Where is the primary location metabolism occurs?
Primary Location = Neuromuscular junction
- Acetylcholinesterase
- Genuine Cholinesterase
- Type 1 Cholinesterase
- True Cholinesterase
- Specific Cholinesterase
What are the five names for the enzyme that metabolizes SUX? Where is the primary location metabolism occurs?
Primary Location = Plasma
- Butyrylcholinesterase
- Pseudocholinesterase
- Type 2 Cholinesterase
- False Cholinesterase
- Plasma Cholinesterase
What drugs reduce pseudocholinesterase activity?
- Metoclopramide
- Esmolol
- Neostigmine (not edrophonium)
- Echothiopate
- Oral Contraceptives/Estrogen
- Cyclophosphamide
- MAOIs
- Nitrogen Mustard
What conditions reduce pseudocholinesterase activity? (9)
- Atypical PChE
- Severe liver disease
- Chronic renal disease
- Organophosphate poisoning
- Burns
- Neoplasm
- Advanced Age
- Malnutrition
- Pregnancy (late stage)
How do you interpret the results of the dibucaine test?
Normal = 80
-means dibucaine has inhibited 80% of the pseudocholinesterase in the sample (normal enzyme present)
Abnormal = 20
-means dibucaine doesn’t inhibit atypical plasma cholinesterase (atypical variant is present)
What are the 3 variants of pseudocholinesterase, and what is the duration of action of SUX for each one?
Typical Homozygous (UU):
- dibucaine number = 70 - 80
- SUX duration = 5 - 10 min
Heterozygous (UA):
- dibucaine number = 50 - 60
- SUX duration = 20 - 30 min
Atypical Homozygous (AA):
- dibucaine number = 20 - 30
- SUX duration = 4 - 8 hrs
Why does SUX have a black box warning?
Black box warning detailing the risk of cardiac arrest and sudden death
-these events are secondary to hyperkalemia in children with undiagnosed skeletal muscle myopathy
- caused by an MH-like syndrome characterized by rhabdomyolysis
- not due to MH
Why is calcium used to treat hyperkalemic cardiac arrest caused by SUX?
Hyperkalemia raises resting membrane potential, so excitable tissues are closer to threshold potential and depolarization
Admin of IV calcium increases threshold potential, which helps re-establish the normal difference between transmembrane potentials
How do you treat a patient who’s become hyperkalemic in response to SUX?
- Stabilize the Myocardium
- calcium chloride 20 mg/kg
- calcium gluconate 60 mg/kg - Shift K+ Into Cells
- hyperventilation
- glucose + insulin (0.3-0.5 g/kg glucose solution + 1 unit insulin per 4-5 g IV glucose)
- sodium bicarb 1-2 mmol/kg
- albuterol nebulizer - Enhance K+ Elimination
- furosemide 1mg/kg
- volume resuscitation
- hemodialysis
- hemofiltration
Who is at the highest risk of myalgia following SUX? Who is at lowest risk?
Highest Risk
- young adults undergoing ambulatory surgery (women > men)
- those that don’t routinely engage in strenuous activity
Lowest Risk
- elderly
- children
- pregnant
How can the risk of SUX induced myalgia be reduced?
With pretreatment with a NDMR
Other methods include:
- NSAIDs
- Lidocaine 1.5 mg/kg
- Use of higher dose rather than a lower dose of SUX
*Opioids don’t reduce the incidence of myalgia
Which patient populations should not receive a defasciculating dose of NDMRs?
Those with pre-existing skeletal muscle weakness (i.e. myasthenia gravis)
What patient populations are at risk for developing hyperkalemia following SUX?
- ALS
- Charcot-Marie-Tooth
- Duchenne’s muscular dystrophy
- Guillain-Barre
- Hyperkalemic periodic paralysis (not the hypokalemic variant)
- Multiple Sclerosis
- Upregulation of extrajunctional receptors (burns, denervation injury)
Rank the NDMRs in terms of ED95 lowest to highest
LOWEST -Cisatracurium -Vecuronium -Mivacurium = Pancuronium -Atracurium -Rocuronium HIGHEST
*ED95 = dose at which there is 95% decrease in twitch height
What are the 2 classes of NDMRs? Which drugs belong in each?
Benzylisoquinolinium Compounds: -curium
-atracurium, cisatracurium, mivacurium
Aminosteroid Compounds: -onium
-rocuronium, vecuronium, pancuronium
How are the benzylisoquinolinium neuromuscular blockers metabolized?
Undergo spontaneous degradation in the plasma
-not dependent on hepatic or renal function for metabolism and elimination
- Atracurium: hydrolyzed by Hofmann elimination (33%) and non-specific plasma esterases (66%)
- Cisatracurium: dependent on Hofmann elimination only
- Mivacurium: pseudocholinesterase (same as SUX)
What factors impact Hofmann elimination?
It is a base-catalyzed reaction that is dependent on normal blood pH and temp
- reaction is faster w/ alkalosis and hyperthermia (DOA = shorter)
- reaction is slower w/ acidosis and hypothermia (DOA = longer)
*cold and/or hypercarbic pt is more difficult to reverse
What is the active metabolite of atracurium and cisatracurium? What is the clinical significance?
Metabolite = Laudanosine – atracurium produces more
- it is a CNS stimulant, thus is capable of producing seizures
- not a problem during routine administration of these drugs in the OR – only if a prolonged infusion in the ICU
- Laudanosine has no muscle relaxant properties
What is the metabolism, elimination, and active metabolites of the aminosteroid neuromuscular blockers?
Rocuronium:
- metabolism = none
- elimination = liver (>70%) and renal (10-25%)
- metabolites = none
Vecuronium:
- metabolism = liver (30-40%)
- elimination = liver (40-50%) and renal (50-60%)
- metabolites = 3-OH vecuronium
Pancuronium:
- metabolism = liver (10-20%)
- elimination = liver (15%) and renal (85%)
- metabolites = 3-OH pancuronium
What drugs can potentiate the effects of neuromuscular blockers? (8)
- Volatile Anesthetics
- Antibiotics (aminoglycosides, clindamycin, tetracycline)
- Antidysrhythmics (verapamil, amlodipine, quinidine)
- Local Anesthetics
- Diuretics (furosemide)
- Dantrolene
- Tamoxifen
- Cyclosporine
What electrolyte disturbances can potentiate the effects of neuromuscular blockers?
Increased Concentration of:
- lithium
- magnesium
Decreased Concentration of:
- calcium
- potassium
Which neuromuscular blockers cause histamine release? (3)
SUX
Atracurium
Mivacurium
Which neuromuscular blockers stimulate the autonomic ganglia?
SUX = stimulation (tachycardia)
*NDMRs have no autonomic ganglia stimulation
Which neuromuscular blockers affect the heart M2 receptor?
SUX = stimulation of M2 receptor (bradycardia)
Pancuronium = moderate blockade of M2 receptor
Rocuronium = slight blockade of M2 receptor (or no effect)
Which neuromuscular blocker has a vagolytic effect?
Pancuronium
- inhibits M2 receptor at the SA node – stimulates release of catecholamines, and inhibits catecholamine reuptake in adrenergic nerves
- increases HR and CO w/ no or minimal effect on SVR
Which neuromuscular blockers should be avoided in the patient with hypertrophic cardiomyopathy (idiopathic hypertrophic subaortic stenosis)?
- Pancuronium (vagolytic effect)
- Atracurium (histamine release)
- Mivacurium (histamine release)
Which NMB is most likely to cause anaphylaxis?
SUX
How do cholinesterase inhibitors reverse paralysis caused by a NDMR?
AChE hydrolyzes ACh into choline and acetate – this enzyme is concentrated around the nicotinic receptors at the neuromuscular junction
Drugs such as edrophonium, neostigmine, and pyridostigmine reversibly inhibit AChE – increases the concentration of ACh at the NMJ (more ACh to compete for the alpha binding site)
What are the 3 ways to inhibit acetylcholinesterase? Give an example of each
- Electrostatic Attachment (competitive inhibition)
- ex) Edrophonium - Formation of Carbamyl Esters (competitive inhibition)
- ex) Neostigmine, Pyridostigmine, Physostigmine - Phosphorylation (non-competitive inhibition)
- ex) Organophosphatase and Echotiophate
What is the dose, onset, duration, metabolism, and best antimuscarinic pairing for edrophonium?
Dose: 0.5 - 1 mg/kg Onset: 1 - 2 min Duration: 30 - 60 min Metabolism: 75% renal + 25% hepatic Best Pairing: Atropine
What is the dose, onset, duration, metabolism, and best antimuscarinic pairing for Neostigmine?
Dose: 0.02 - 0.07 mg/kg Onset: 5 - 15 min Duration: 45 - 90 min Metabolism: 50% renal + 50% hepatic Best Pairing: Glycopyrrolate
What is the dose, onset, duration, metabolism, and best antimuscarinic pairing for Pryidostigmine?
Dose: 0.1 - 0.3 mg/kg Onset: 10 - 20 min Duration: 60 - 120 min Metabolism: 75% renal + 25% hepatic Best Pairing: Glycopyrrolate
How does renal failure affect the dosing of AChE inhibitors after an aminosteroid NMB is administered?
Renal failure prolongs the DOA for both AChE inhibitors AND aminosteroid neuromuscular blockers
-since both remain in the body for a longer time, there is no need to adjust the dose of the AChE inhibitor or re-dose it
How does neostigmine reversal differ in children vs adults?
Antagonism with neostigmine is faster in infants and children when compared to adults
Which AChE 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 from passing through the BBB
What are the side effects common to AChE inhibitors?
They cause a predictable set of parasympathetic side effects: DUMBBELLS
- Diarrhea
- Urination
- Miosis
- Bradycardia
- Bronchoconstriction
- Emesis
- Lacrimation (increased tears)
- Laxation (elimination of fecal waste)
- Salivation
Compare and contrast the side effects of atropine, scopolamine, and glycopyrrolate
Which antimuscarinics pass through the BBB? Which do not? Why?
Atropine and Scopolamine are naturally occurring tertiary amines – because they are lipophilic they easily cross BBB, GI tract, and placenta
Glycopyrrolate is a quaternary ammonium derivative and is ionized – limits the ability to cross cell membranes (doesn’t cross BBB)
In what situation can atropine cause a paradoxical bradycardia?
Small doses of atropine (<0.5 mg IV in an adult) can cause paradoxical bradycardia
-probably due to the inhibition of the presynaptic M1 receptor on vagal nerve endings
Do patients with a history of heart transplantation require an antimuscarinic for reversal of a NDMR?
Heart transplant denervates the heart – ANS influence has been removed – intrinsic firing of SA node now solely determines the HR
- because of this muscarinic antagonists don’t affect the HR
- however, should still receive a muscarinic antagonist with AChE inhibitor due to the other cholinergic effects
What is the mechanism of action of sugammadex?
Gamma-cyclodextrin made of 8 sugars assembled in a ring – the ring encapsulates the neuromuscular blocker, rendering it inactive and unable to engage w/ the nicotinic receptor
What neuromuscular blockers can be reversed by sugammadex?
It selectively encapsulates the aminosteroid nondepolarizing neuromuscular blockers
-rocuronium > vecuronium > pancuronium
What three ways does sugammadex improve safety?
- Rocuronium can be used for difficult intubation without the drawbacks of SUX
- 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
How do you dose sugammadex?
For Roc or Vec:
- TOF 2/4 or better = 2 mg/kg
- TOF 0/4 + 2 PTC or better = 4 mg/kg
For Roc Only:
- you may reverse 3 min after roc administration at 1.2 mg/kg (or less) = 16 mg/kg
How is sugammadex metabolized?
Sugammadex and the sugammadex-rocuronium complex are excreted unchanged by the kidneys
What are the three most significant risks associated with sugammadex?
- Anaphylaxis (occurs in 0.3% of pts)
- CV Changes (bradycardia and cardiac arrest have been reported – anticholinergics may be useful in this context)
- Unplanned Pregnancy (reduces the effectiveness of hormonal contraceptives for up to 7 days)
What are the four steps of pain pathway?
- Transduction
- Transmission
- Modulation
- Perception
Discuss the process of pain transduction
Injured tissues release various chemicals that activate peripheral nerves and/or cause immune cells to release proinflammatory compounds
Peripheral nerves transduce this chemical soup into an AP, so the extent of tissue injury can be interpreted by the brain
What type of nerve fibers transmit pain?
A-delta fibers transmit “fast pain” (sharp and well localized)
C-fibers transmit “slow pain” (dull and poorly localized)
What is the role of inflammation in pain transduction?
it contributes to:
- reduced threshold to pain stimulus (allodynia)
- increased response to pain stimulus (hyperalgesia)
Discuss the process of pain transmission
Pain signal is relayed through the three-neuron afferent pain pathway along the spinothalamic tract
- 1st order neuron: periphery –> dorsal horn (cell body in dorsal root ganglion)
- 2nd order neuron: dorsal horn –> thalamus (cell body in the dorsal horn)
- 3rd order neuron: thalamus –> cerebral cortex (cell body in the thalamus)
Discuss the process of pain modulation. Where is the most important modulation site?
- Pain signal is modified (inhibited or augmented) as it advances towards the cerebral cortex
- Most important modulation site is the substantia gelatinosa in the dorsal horn (Rexed lamina II & III) –descending inhibitory pain pathway begins in the periaqueductal gray and rostroventral medulla and projects to the substantia gelatinosa
- Inhibition of pain occurs when spinal neurons release GABA and glycine (inhibitory neurotransmitters) and the descending pain pathway releases NE, 5-HT, and endorphins
- Pain is augmented by central sensitization and wind-up
Where does the process of pain perception occur?
Perception describes the process of afferent pain signals in the cerebral cortex and limbic system
How we “feel” about pain
What is the mechanism of action of opioids?
Each opioid receptor links to a G protein
Agonism of the receptor instructs the G protein to “turn off” adenylate cyclase
This reduces the intracellular concentration of cAMP (second messenger) – alters ionic currents and reduces neuronal function
What are the precursors of the endogenous opioids?
Pre-proopiomelanocortin –> Endorphins (Mu receptor)
Pre-enkephalin –> Enkephalins (Delta receptor)
Pre-dynorphin –> Dynorphins (Kappa receptor)
What are the physiologic effects of the Mu-1 receptor?
- ANALGESIA (supraspinal and spinal)
- BRADYCARDIA
- Euphoria
- Low abuse potential
- Miosis
- Hypothermia
- Urinary retention
What are the physiologic effects of the Mu-2 receptor?
- Analgesic (spinal only)
- Bradycardia
- Respiratory depression
- Constipation
- Physical dependence
What are the physiologic effects of the Mu-3 receptor?
Immune suppression
What are the unique effects of kappa stimulation?
- Antishivering effect
- Diuresis
- Dysphoria
- Delirium
- Hallucinations
How do opioids affect HR, BP, and myocardial function?
HR:
- bradycardia results from mu stimulation
- Meperidine can increase HR (atropine-like ring in chemical structures produces anticholinergic effects)
BP:
- minimal effect in healthy pts
- hypotension w/ morphine or meperidine is likely result of histamine release
Myocardial Function:
- contractility is not affected
- myocardial depression can occur if combined with N2O
How do opioids affect ventilation?
They stimulate the Mu and Delta receptors (and possibly kappa) to produce their ventilator effects:
- decreased ventilatory response to CO2 (CO2 curve shifted to the right)
- decreased RR and compensatory increase in tidal volume (partial compensation)
- increased PaCO2 –> increased ICP if ventilation is not maintained
How do opioids affect the pupil?
Edinger Westphal nucleus stimulation –> increase PNS stimulation of ciliary ganglion and oculomotor nerve (CN III) –> pupil constriction
How do opioids produce nausea and vomiting?
By Mu receptor stimulation:
- chemoreceptor trigger zone stimulation (area of postrema of medulla)
- possible interaction with the vestibular apparatus
How do opioids affect biliary pressure, gastric emptying, and peristalsis?
Produce GI effects through Mu receptor stimulation
- Biliary pressure: contraction of the sphincter of Oddi increases pressure, reversed by naloxone or glucagon – meperidine causes the lowest incidence
- Gastric emptying = prolonged
- Peristalsis = slowed –> constipation
How do opioids contribute to urinary retention?
Produce GU effects through mu and delta receptor stimulation
- Detrusor relaxation (contraction is needed to pass urine)
- Urinary sphincter contraction (relaxation is needed to void)
What are the immunologic effects of opioids?
- Histamine release (morphine, meperidine, codeine)
- Inhibition of cellular and humoral immune function
- Suppression of natural killer function
How do opioids affect thermoregulation?
Opioids reset the hypothalamic temperature set point –> Decrease core body temperature
Rank the IV opioids in terms of potency from most to least potent
Sufentanil > Fentanyl = Remifentanil > Alfentanil > Hydromorphone > Morphine > Meperidine
What is the equianalgesic opioid dose relative to 10mg of morphine for the following:
- Meperidine
- Hydromorphone
- Alfentanil
- Remifentanil
- Fentanyl
- Sufentanil
- Meperidine: 100 mg (0.1 relative potency)
- Hydromorphone: 1.4 mg (7 relative potency)
- Alfentanil: 1000 mcg (10 relative potency)
- Remifentanil: 100 mcg (100 relative potency)
- Fentanyl: 100 mcg (100 relative potency)
- Sufentanil: 10 mcg (1000 relative potency)
What opioids produce an active metabolite?
Morphine and Meperidine
-except for remifentanil, all opioids undergo hepatic biotransformation
What is the active metabolite of morphine, and why is it a problem?
Morphine conjugates to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active)
Impaired renal function –> decreased MP6 excretion –> increased accumulation –> respiratory depression
What is the active metabolite of meperidine, and why is it a problem?
Normeperidine is 1/2 as potent as meperidine – It reduces the seizure threshold and increases CNS excitability
Impaired renal function –> decreased normeperidine excretion –> increased accumulation –> seizures
What happens with the co-administration of meperidine and MAO inhibitors?
Meperidine + MAOIs can cause serotonin syndrome
- meperidine is a weak serotonin reuptake inhibitor and since MAO deaminates serotonin in the synaptic cleft, co-admin can cause serotonin syndrome
- S/Sx: hyperthermia, mental status changes, hyperreflexia, seizures, and death
MAOI examples: Phenelzine, Isocarboxazid, Tranylcypromine
How does the ionization characteristics of alfentanil influence its onset of action?
Alfentanil = Fastest onset of action of all opioids – this is due to:
- pKa of 6.5 (less than physiologic pH)
- it is ~90% unionized and 10% ionized (unionized fraction passes through BBB)
- has a low Vd and high degree of plasma protein binding (alpha-1-acid glycoprotein)
*since it is highly unionized and doesn’t have a large Vd, more of the drug is available to enter the brain
Which opioid has the largest volume of distribution? Which has thee smallest?
Largest Vd = Fentanyl (4 L/kg)
Smallest Vd = Remifentanil (0.39 L/kg)
-remi doesn’t distribute to the fat because it’s metabolized so quickly in the plasma
What is the pharmacokinetic and pharmacodynamic profile of remifentanil?
Remifentanil = rapid-on and rapid-off mu agonist
- context-sensitive half-time is about 4 min regardless of infusion duration
- contains an ester linkage – renders it susceptible to hydrolysis by erythrocyte and tissue esterases
- even though it is highly lipophilic, it behaves as though it has a small Vd – due to very fast rate of clearance in the plasma
- potency is similar to fentanyl
- maintenance infusion is 0.1 - 1.0 mcg/kg/min
- in the obese pt, infusion rate is calculated with lean body weight
What is the relationship between remifentanil and opioid induced hyperalgesia? What drugs can prevent this phenomenon?
Remifentanil causes acute opioid-induced hyperalgesia following discontinuation
- postop opioid requirements are particularly high in these patients
- Ketamine or Magnesium sulfate can prevent it
Can remifentanil be used for neuraxial anesthesia? why or why not?
Remifentanil 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
How does methadone reduce pain?
- Mu receptor agonist
- NMDA receptor antagonist (the only opioid with this effect)
- Inhibits reuptake of monoamines in the synaptic cleft
Which opioid is most likely to cause QT prolongation?
Methadone
-rare but can potentially increase QT interval – can lead to Torsades de Pointes
What is the etiology of opioid induced skeletal muscle rigidity?
Rapid IV admin of the potent IV opioids can cause skeletal muscle rigidity (Mu receptor stimulation in the CNS)
Historically it has been described as chest wall rigidity or stiff chest syndrome – however current evidence suggests the greatest resistance to ventilation occurs at the larynx
What is the treatment of opioid induced skeletal muscle rigidity?
Best treatment = Paralysis and Intubation
-naloxone can also reverse rigidity, but giving this just before surgery seems counterproductive given that there is a better alternative
What are the common characteristics of the opioid partial agonists?
- Produce analgesia with a reduced risk of respiratory 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 patient
- Can cause dysphoric reactions
- Carry a low risk of dependence
- Are used in pts who cannot tolerate a full opioid agonist
Compare and contrast buprenorphine, nalbuphine, and butorphanol
Buprenorphine:
- partial Mu agonist
- greater analgesia compared to morphine
- difficult to be reversed by naloxone due to high affinity for mu receptor
- long duration (8hrs)
- available via transdermal route
Nalbuphine:
- kappa agonist and mu agonist
- similar analgesia compared to morphine
- can be reversed by naloxone
- doesn’t increase BP, PAP, HR, or RAP
- useful with h/o heart disease
Butorphanol:
- kappa agonist and weak mu antagonist
- greater analgesia compared to morphine
- can be reversed by naloxone
- useful for postop shivering
- available via intranasal route
What are the potential complications of opioid reversal with naloxone?
- Short Duration (naloxone duration of 30-45 min may be shorter than the opioid being reversed) – consider infusion
- SNS Stimulation (mechanism by which naloxone causes tachycardia, cardiac dysrhythmias, pulmonary edema, and sudden death) – slow titration minimizes these
- Nausea and Vomiting (slow titration over 2-3 min causes less)
- Fetal Withdrawal (naloxone crosses the placenta - if given to opioid abusing mother it can precipitate acute opioid withdrawal in the neonate
Which opioid antagonist is least likely to reverse respiratory depression? Why?
Methylnaltrexone – it has a quaternary amino group that prohibits its passage across the BBB
- since it doesn’t enter the brain, it doesn’t reverse respiratory depression
- it’s useful for mitigating the peripheral effects of opioids, such as opioid-induced bowel dysfunction
Which opioid antagonist has the longest duration of action?
Naltrexone – it doesn’t undergo significant first-pass metabolism
- can be given orally and has a duration of up to 24 hours
- an extended-release formulation may be used for alcohol withdrawal treatment
- it can also be used to maintain recovering opioid abusers
