UNIT 5 Pharmacology II Flashcards
Describe the components of the neuron & their functions.
dendrite: receives & processes signal
soma: integrates signal, cellular machinery
axon hillock
axon: sends signal
- contains myelin & nodes of Ranvier
presynaptic terminal: releases neurotransmitters
What is conduction velocity, and how is it affected my myelination & axon diameter?
Conduction velocity is a measure of how fast an axon transmits the action potential
Conduction velocity is increased by:
- myelination: the AP skips along the nodes of Ranvier (saltatory conduction)
- large fiber diameter
So we want it myelinated and a larger diameter = faster velocity
List the 3 different fiber types. Compare & contrast them in terms of myelination, function, diameter, conduction velocity, & block onset.
A-alpha
- heavy myelination
- skeletal muscle (motor) & proprioception
- 12-20mcm
- fastest velocity
- 4th in block onset
A- beta
- heavy myelination
- touch & pressure
- 5-12mcm
- second fastest velocity
- 4th in block onset
A-gamma
- medium myelination
- skeletal muscle (tone)
- 3-6mcm
- middle velocity (3rd)
- 3rd in block onset
A-delta
- medium myelination
- fast pain, temp, touch
- 2-5mcm
- middle velocity (3rd)
- 3rd in block onset
B
- light myelination
- preganglionic ANS
- 3mcm
- 2nd slowest velocity
- 1st in block onset
C-SNS
- no myelination
- postganglionic ANS
- 0.3-1.3mcm
- slowest velocity
- 2nd in block onset
C-dorsal root
- no myelination
- slow pain, temp, touch
- 0.4-1.2mcm
- slowest velocity
- 2nd in block onset.
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 bupi is a good example:
- at lower concentrations, it provides analgesia while sparing motor function
- as concentration increases, it anesthetizes more resistant nerve types, such as those that control motor function & proprioception
- this is the basis for a “walking” epidural w/ a low bupi concentration
What concept is analogous to ED50 for LA?
mimimum effective concentration (Cm) is the concentration of LA that is required to block conduction. It is analagous to ED50 or MAC
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 LA in vivo (most to least sensitive)
B
C
A-gamma & A-delta
A-alpha & A-beta
What are the 3 possible configurations of the voltage gated Na+ channel?
resting: channel is closed & able to be opened if the neuron depolarizes
active: channel is open & Na+ is moving along it’s concentration gradient into the neuron
inactive: the channel is closed & unable to be opened (refractory)
How and when do LA bind to the voltage gated Na+ channel?
guarded receptor hypothesis states that LA can only bind to Na+ channels in their active (open) & inactive (closed refractory) states.
LA do not bind Na+ channels in their resting states.
LA are more likely to bind axons that are conducting AP and less likely to bind those that are not.
This is called a use-dependent or phasic blockade.
What is an AP & how does it depolarize a nerve?
an AP is a temporary change in the transmembrane potential follwed by a return to transmembrane potential
in order for a neuron to depolarize, Na+ must enter the cell (makes the inside more positive)
- once threshold is reached, the cell depolarizes & propogates an AP
- depolarization is an all or none phenomenon; the cell either does or doesn’t
- the AP only travels in one direction. This is because the Na+ channels in upstream portion of the neuron are in the closed/inactive state.
What happens when a nerve repolarizes?
If depolarization is the accumulation of positive charges (Na+) inside
Repolarization is the removal of positive charges from inside the cell= removing K+
How do LA affect neuronal depolarization?
bind to alpha-subunit on the inside of the Na+ channl when it’s in either the active or inactive state.
when a critical # of Na+ channels are blocked, there aren’t enough open channels for Na+ to enter the cell in sufficient quantity; threshold isn’t reached.
LA DO NOT affect resting membrane potential or threshold potential
Discuss the role of ionization w/ respect to LA
Since LA are weak bases w/ pKa values >7.4, we can predict that >50% of the LA will exist as ionized, conjugate acid after injection
The non-ionized fraction diffused into the nerve. Once inside the neuron, the law of mass action promotes re-equilibration of charged & uncharged species. The charged species binds to the alpha subunit on the interior of the voltage gated Na+ channel.
What are the 3 building blocks of the LA molecule? How does each one affect the PK/PD profile of the molecule?
- benzene ring
- lipophilic
- permits diffusion through lipid bilayers - intermediate chain
- class: 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 an amide. List examples from each class.
ester: no “i” before suffix -caine
- benzocaine
- cocaine
- chloroprocaine
- procaine
- tetracaine
amide: has “i” before suffix - caine
- bupivicaine
- dibucaine
- etidocaine
- lidocaine
- mepivacaine
- ropivacaine
contrast the metabolism of ester & amide LA. Which LA participates in both metabolic pathways?
ester: pseudocholinesterase
amide: hepatic carboxylesterase/P450
cocaine is an exception: it is an ester, but is metabolized by pseudocholinesterase & in the liver
Discuss LA allergy & cross sensitivity.
more common w/ the esters since they are derivatives of para-aminobenzoic acid (PABA).
PABA is an immunogenic molecule capable of causing an allergic reaction (cross sensitivty w/in the class)
incidence of allergy to amides is very rare. Some multi-dose vials contain methylparaben as a preservative (similar to PABA and can precipitate an allergic reaction.
if allergy to an ester, avoid all esters, but amides should be ok, and vice versa!!!
What determines LA onset of action? Which drug disobeys this rule and why?
pKa determines onset
- 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 a slow onset
- it’s not very potent, so we have to give a higher concentration (usually 3% solution)
- giving more molecules –> mass effect that explains it’s rapid onset.
What determines LA potency?
1) lipid solubility
- the more lipid soluble a LA, the easier it is for the molecule to traverse the neuronal membrane
- b/c more drug enters the neuron, there will be more of it available to bind the alpha-subunit
2) An intrinsic vasodilating effect is a secondary determinant of potency:
- vasodilation increases uptake into the systemic circulation & this reduces the amount of LA available to anesthetize the nerve.
What factors determine the LA DOA?
1) protein binding
- after 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 the proteins serve as a reservoir that extends the DOA
2) lipid solubility & intrinsic vasodilating activity are secondary determinants of DOA
- higher degree of lipid solubility = longer DOA
- drug w/ instrinsic vasodilatory activity = increase rate of vascular uptake = decreased DOA
Discuss the intrinsic vasodilating effects of LA. Which LA has the opposite effect?
most LA cause some degree of vasodilation in clinically used doses.
Those w/ greater vasodilation (lidocaine) = faster rate of vascular uptake, decreased DOA.
The addition of a vasoconstrictor can prolong the DOA.
Cocaine is unique. It always causes vasoconstriction because it inhibits NE reuptake in sympathetic nerve endings in vascular smooth m.
Rank the amide LA according to pKa
Mepivicaine, bupivicaine, Levo-bupivacaine, lidocaine, ropivicaine, prilocaine
bupivicaine 8.1 levo-bupivicaine 8.1 ropivicaine 8.1 lidocaine 7.9 prilocaine 7.9 mepivicaine 7.6
Rank the ester LA according to pKa
procaine 8.9
chloroprocaine 8.7
tetracaine 8.5
list 5 factors that govern the uptake & plasma concentrations of LA
- site of injection
- tissue blood flow
- physiochemical properties of LA
- metabolism
- addition of a vasoconstrictor
rank injection sites to the corresponding plasma concentrations of LA.
IV Tracheal interpleural intercostal caudal epidural brachial plexus femoral sciatic subcutaneous
Local anesthetic doses and maximum doses
levobupivicaine 2mg/kg (150mg)
bupivicaine 2.5mg/kg (175mg)
bupivicaine w/ epi 3mg/kg (200mg)
lidocaine 4.5mg/kg (300mg)
lido w/ epi 7mg/kg (500mg)
ropivicaine 3mg/kg (200mg)
mepivacaine 7mg/kg (400mg)
prilocaine 8mg/kg (500-600mg, if > or <70kg)
What is the maximum dose for each ester LA (weight based & max total dose)?
procaine 7mg/kg (350-600mg)
chloroprocaine 11mg/kg (800mg)
chloroprocaine w/ epi 14mg/kg (1000mg)
What is the most common sign of LA systemic toxicity?
- seizure
- except in bupivicaine (cardiac arrest can occur before seizure)
List effects of lidocaine toxicity according to plasma concentration.
What range would you have seizures?
What ranges would you have resp. Distress and coma?
1-5: analgesia
5-10: tinnitus, circumoral numbness, skeletal m twitching, restlessness, vertigo, blurred vision, hypotension, myocardial depression
10-15: seizures, loss of consciousness
15-25: coma, respiratory distress
>25: CV collapse
What conditions increase the risk of CNS toxicity from LAST
- hypercarbia (increases CBF & increases drug delivery to the brain. Also decreases PB –> increased free fraction)
- hyperkalemia (raises resting membrane potential)
- metabolic acidosis (decreases the convulsion threshold & favors ion trapping inside of the brain).
Why is the risk of cardiac morbidity higher with bupivicaine than w/ lidocaine?
two features determine the extent of CV toxicity of any LA.
- affinity for the v-gated Na+ channel in the active & inactive state
- rate of dissociation from the receptor during diastole.
When c/w lido, bupi is greater in both of these features.
This also explains why resuscitation is so difficult.
Difficulty of CV resuscitation
bupi > levobupi > ropi > lido
Discuss the modifications to the ACLS treatment protocol when applied to LAST.
epi can hinder resus from LAST & also reduces the effectiveness of lipid emulsion therapy. If used, give in doses < 1mcg/kg
amiodarone is the agent of choice for ventricular arrythmias and give Benzos for the seizure!
avoid vasopressin, CCB, BB, lidocaine, & procainamide, epi, lidocaine
Factors that increase LAST risk:
- Hypercarbia
- Hyperkalemia
- metabolic acidosis
1) call for help
2) give benzos for the seizure
3) lipid emulsion if under 70kg give 1.5ml/kg. If over 70kg give 100ml bolus
Discuss the lipid emulsion for the treatment of LAST.
acts as a lipid sink: an IV reservoir that sequesters LA & reduces plasma concentration.
Treatment for LAST:
- bolus 20% 1.5mL/kg (LBW) over 1min
- infusion 0.25mL/kg/min
- if symptoms are slow to resolve, repeat bolus up to 2 more times & increase infusion to 0.5mL/kg/min
- continue gtt for 10min after achieving hemodynamic stability
- max recommended dose is 10mL/kg for first 30mins
You are providing anesthesia for a 90kg pt undergoing liposuction. The plastic surgeon wants to use tumescent lidocaine 0.1% & asks you to calculate the max dose. How much tumescent lidocaine can this patient receive (in mL)?
Tumescent lidocaine is usually for liposuction
max dose of lidocaine for tumescent anesthesia = 55mg/kg. common cause of death during liposuction is a P.E.
90x55 = 4950mg
0.1% lido sln = 1mg/mL –> pt can receive 4950mL of the solution
GA recommended if you use 2-3L of tumescent lidocaine
In addition to LA toxicity, what are other potential complications of a large volume of tumescent anesthesia?
pulmonary edema from volume overload
- if CV collapse, first calculate max dose of lido received - if acceptable range, then consider pulmonary edema or PE.
- GA is recommended if >2-3L of tumescent solution is injected
Name the three LA that are most likely to produce a L shift of the oxyhemoglobin dissociation curve. Why does this happen?
prilocaine & benzocaine, and ceticaine; they can cause methemoglobinemia
O2 binding site on the heme portion of Hgb contains an ion molecule in Ferric form it decreases O2 carrying capacity
- oxidation of Fe++ to Fe+++ (there’s an added +) = metHgb
- metHgb impairs O2 binding & unbinding from the Hgb molecule, shifting the curve to the L –> physiologic anemia.
Methehemoglobin absorbs 660 nm red light and 940 nm infrared light EQUALLY and SpO2 will read 85%
What drugs are capable of causing metHgb?
LA:
- benzocaine
- cetacaine (contains benzocaine)
- prilocaine
- EMLA (prilocaine + lidocaine)
others:
- SNP
- NTG
- sulfonamides
- phenytoin
What are the s/s of metHgb?
hypoxia cyanosis chocolate colored blood tachycardia tachypnea MS changes coma or death
**cyanosis in the presence of a normal PaO2 is highly suggestive of metHgb
What is the treatment for metHgb? How does it work?
methylene blue 1-2mg/kg over 5mins up to a max of 7-8mg/kg.
methylene blue is metabolized by methemoglobin reductase to form leucomethylene blue
This metabolite functions as an e- donor & reduces metHgb (Fe+++) back to Hgb (Fe++)
other considerations:
- those w/ G6P Deficiency don’t have methemoglobin reductase, so an exchange transfusion may be required
- Fetal Hgb is relatively deficient in methemoglobin reductase, making it susceptible to oxidation –> neonates are at a higher risk for toxicity.
Name two populations who are at an increased risk for developing metHgb.
G6PD (lack methemoglobin reductase)
neonates (relative deficient in methemoglobin reductase)
What are the constituents of EMLA cream?
5% EMLA = 50/50 of 2.5% lidocaine & 2.5% prilocaine
prilocaine is metabolized to o-toluidine, which oxidizes Hgb to metHgb. infants and small children are more likely to become toxic
What is the max dose for EMLA cream?
<5kg: 1g
5-10kg: 2g
10-20kg: 10g
> 20kg: 20g
You can add nitro hasten the onset
Put a dressing over it after
How does sodium bicarb affect LA onset of action. Are there any other benefits?
shortens LA onset time. Alkalization increases # of lipid soluble molecules, which speeds up onset.
- 1mL of 8.4% sodium bicarb w/ 10mL of LA
- it also reduces pain on injection
How does adding epi affect the DOA of LA
extends LA duration
vasoconstrictor effects decreases systemic uptake of LA –> prolonging block duration & enhancing block quality.
What drugs can be added to LA to provide supplemental analgesia? What is the mechanism of action for each one?
clonidine (a2 agonist)
epi (a2 agonist)
opioids (mu agonist)
What drug can be used to improve LA diffusion through tissue?
hyaluronidase can improve LA diffusion through tissue
hyaluronic acid is present in the interstitial matrix & basement membrane, hindering the spread of substances through tissue.
- hyaluronidase hydrolyzes hyaluronic acid, facilitating diffusion of substances through tissues.
- commonly used in opthalmic blocks to increase speed of onset, enhance block quality, & mitigate a rise in IOP
What are the 2 types of nicotinic receptors present at the NMJ? What is the function of each?
prejunctional nAChR (Nn)
- present on the presynaptic nerve
- regulates ACh release
postsynaptic nAChR (Nm)
- present at the motor end plate on the muscle cell
- responds to ACh (depolarizes muscle)
Describe the structure of the post-synaptic, nicotinic receptor at the NMJ.
pentameric ligand-gated ion channel located in the motor endplate at the NMJ
comprised of 5 subunits that align circumferentially around an ion conducting pore
normal receptor contains the following subunits:
- 2 alpha
- 1 beta
- 1 delta
- 1 epsilon
What happens when ACh activates the post-synaptic nicotinic receptor at the NMJ?
ACh binds the alpha subunits (1 at each)
- -> the channel opens, Na+, Ca++ enters, K+ exits.
- -> interior of the cell becomes more positive, opening the V-gated Na+ channels
- -> depolarization occurs & AP is initiated
- -> this results in Ca++ release from the ER into the cytoplasm, where it engages w/ the myofilaments & initiates muscle contraction
Alpha alpha subunits must be open on the nicotinic receptor on the motor endplate, both must be occupied by either Ach or Sux in order for the channel to open
How is the ACh signal “turned off” at the NMJ?
acetylcholinesterase is strategically positioned around the pre and postsynaptic nAChR; it hydrolyzes ACh almost immediately after it activates receptors
It metabolizes ach into choline and acetate
Why are extrajunctional receptors sometimes called fetal receptors?
2 pathologic variants of the nicotinic receptors:
- one w/ a gamma subunit in lieu of an epsilon subunit
- one w/ 5 alpha subunits
extrajunctional receptors resemble those that are present in early fetal development. Once innervation takes place, fetal receptors are replaced by the adult receptors.
Denervation later in life allows for the return of both types of extrajunctional receptors. They are distributed at the NMJ but also throughout the sarcolemma.
What conditions allow extrajunctional receptors to populate the myocyte?
- upper/lower motor neuron injury
- SC injury
- burns
- skeletal m trauma
- CVA
- prolonged chemical denervation (Mg++, NMB gtt, etc.)
- tetanus
- severe sepsis
- muscular dystrophy
What is the risk of using succinylcholine in the patient w/ upregulation of extrajunctional receptors?
sux increases K+ by 0.5-1mEq/L x10-15mins
extrajunctional receptors are more sensitive to sux; they remain open for a longer period of time putting the pt at risk for hyperkalemia that can be lifethreatening. But theyre also more resistant to nondepolarizers
How do extrajunctional receptors affect the clinical use of NDMR?
Give examples of unregulated extrajunctional receptors:
those w/ upregulation of extrajunctional receptors have increased risk of hyperkalemia but they are resistant to NDMR and will need higher dose
extrajunctional receptors- epsilon subunit replaces the gamma, it opens for a longer period of time, it’s opened by choline
Best to avoid 24-48 hours after injury up to a year
Discuss fade in the context of succ & NDMR.
There are two supplies of ACh vesicles:
- ACh that is available for immediate release
- ACh that must be mobilized before it can be released (req nAChR stim)
NDMR blocks #2, thus the only available ACh in the NMJ is #1, which runs out quickly w/ repeated stim (TOF) –> fade
sux stimulates #2, thus allowing for continued availability of ACh –> no fade
What is the difference b/n a phase 1 and phase 2 block? What risk factors increase the likelihood of a phase 2 block w/ sux?
phase 1 = no fade. Normal response to sux
phase 2 = fade. Occurs with excessive dose of sux, will have fade and prolonged duration (non depolarizers produce phase 2)
2 situations that favor phase 2 development with sux:
- dose >7-10mg/kg
- 30-60mins of continuous exposure (IV gtt)
if you get a phase 2 block, you have to just wait it out. Do not reverse
Compare and contrast phase 1 & 2 block in terms of TOF, tetany, DBS, and post tetanic potentiation.
TOF, tetany, DBS: phase 1 responses are diminished but equal (no fade); phase 2 responses have a fade.
PTP: absence w/ phase 1 block, present w/ phase 2 block
What TOF ratio correlates w/ full recovery from NMB?
normal upper airway and respiratory muscle function doesn’t return until a TOF ratio of >0.9 is achieved at the adductor pollicis
What is the best location to assess the onset of NMB? How about recovery?
onset: orbicularis oculi or corrugator supercilii muscle- the facial nerve
recovery: adductor pollicis muscle - the ulnar nerve
List all of the tests of recovery from NMB. What values suggest recovery and to what degree?
% = maximum % of receptors occupied
Tv >5mL/kg = 80%
strong single twitch = 75-80%
no fade on TOF = 70-75%
VC >20mL/kg = 70%
sustained tetanus x5sec = 60%
no fade on DBS = 60%
inspiratory force >40cmH2O = 50%
head lift >5 sec = 50%
strong handgrip = 50%
bite on tongue blade x5sec = 50%
How does succinylcholine affect HR? Why?
can cause bradycardia or tachycardia.
bradycardia:
- stimulates M2 receptor on the SA node
- a second dose increases the risk (esp <5yrs)
- succinylmonocholine (primary metabolite) is probably responsible for this effect
- antimuscarinics may prevent or reverse bradycardia
tachycardia:
- & HTN by mimicking ACh at the sympathetic ganglia
- in adults, tachycardia more common than bradycardia.
Is succinylcholine safe to give a patient w/ renal failure?
it can increase K+ 0.5-1mEq/L x10-15mins
thus, it is safe in CKD w/ normal K+ level
CKD pts do not have an increased release, but the normal response to sux may increase the K+ to a dangerous level.
How does sux affect IOP?
transiently increases it 5-15mmHg for up to 10mins. concern if the pt has an open globe injury
How does sux affect intragastric pressure?
- increased intragastric pressure
- sux increases LES tone (tightens) = these pressures cancel each other out, risk of aspiration is not increased
(Where as with glyco- it decreases LES tone and risk of aspiration is higher)
List name 5 names for the enzyme that metabolizes ACh.
List 5 names for the enyzme that metabolizes succinylcholine .
ACh:
- type 1 cholinesterase
- acetylcholinesterase
- true cholinesterase
- specific cholinesterase
- genuine cholinesterase
Succinylcholine:
- type 2 cholinesterase
- butrylcholinesterase
- false cholinesterase
- plasma cholinesterase
- pseudocholinesterase
List all of the drugs and conditions that reduce pseudocholinesterase activity.
drugs:
- reglan
- esmolol
- neostigmine (not edrophonium)
- echothiophate
- oral contraceptives/estrogen
- cyclophosphamide
- MAOI
- nitrogen mustard
conditions:
- atypical PChE
- severe liver disease
- CKD
- organophosphate poisoning
- burns
- neoplasm
- advanced age
- malnutrition
- late stage pregnancy
How do you interpret the test results of the dibucaine test?
normal dibucaine # = 80.
This means that dibucaine has inhibited 80% of the pseudocholinesterase in the sample and suggests that normal enzyme is present
dibucaine # of 20 = atypical homozygous variant it does not inhibit the abnormal atypical PchE
What are the 3 variants of pseudocholinesterase, and what is the DOA of succinylcholine for each one?
- typical homozygous (dibucaine 70-80); DOA sux = 5-10mins
- heterozygous (dibucaine 50-60); DOA sux = 20-30mins
- atypical homozygous (dibucaine 20-30); DOA 4-8hrs
Why does succinylcholine have a black box warning for children?
details the risk of cardiac arrest and sudden death d/t hyperkalemia in children w/ undiagnosed skeletal m myopathy
- caused by a MH like syndrome characterized by rhabdo
- not due to MH
- treatment: give 20mg/kg calcium chloride
Why is calcium used to treat hyperkalemic cardiac arrest caused by succinylcholine?
hyperkalemia raises resting membrane potential
IV Ca++ increases threshold potential, which helps re-establish the normal difference b/n transmembrane potentials
How do you treat a patient who’s become hyperkalemic in response to succinylcholine?
- stabilize the myocardium:
- CaCl 20mg/kg
- Ca gluconate 60mg/kg - shift K+ into cells
- 10% glucose 0.3-0.5g/kg
- 1U insulin/4-5g of glucose
- 1-2mmol/kg NaHCO3
- hyperventilation
- albuterol nebulizer - enhance K+ elimination
- furosemide 1mg/kg
- volume
- hemodialysis
- hemofiltration
What is the difference in elemental calcium b/n CaCl and calcium gluconate?
10% CaCl = 27.2mg/mL of elemental calcium
10% calcium gluconate = 9mg/mL of elemental calcium
Who is at the highest risk of myalgia following succinylcholine? Who is at the lowest risk?
highest risk = young females undergoing ambulatory surgery and those that do not routinely engage in strenuous activity. Pretreat with NSAIDS
Children, elderly, and pregnant patients have the lowest rate of occurrence
How can the risk of succinylcholine induced myalgia be reduced?
- pretreatment w/ a NDMR
- NSAIDs
- lidocaine 1.5mg/kg
- higher sux dose
opioids don’t reduce the incidence they don’t help!!!
Which patient populations shouldn’t receive a defasciculation dose of a NDMR?
pre-existing skeletal muscle weakness (i.e. myasthenia gravis)
What patient populations are at risk for hyperkalemia after Sux?
- amyotrophic lateral sclerosis (ALS)
- Charcot-Marie-Tooth- defects in formation and structure of myelin
- Duchenne’s muscular dystrophy
- Guillain-Barre
- Hyperkalemic periodic paralysis
- MS
- upregulation of extrajunctional receptors- will be more resistant to Nondepolarizers!!
Rank the NDMR in terms of ED95 (lowest to highest).
ED95 = dose at which there is a 95% decrease in twitch height.
smallest to largest:
- cisatracurium
- vecuronium
- miva = panc
- atracurium
- rocuronium
the dose required to provide optimal conditions for tracheal intubation = 2-3x ED95
What are the two classes of nondepolarizing NMB? Which drugs belong in each?
benzylisoquinolinium compounds:
- atra
- cis
- miva
aminosteroid compounds:
- roc
- vec
- panc
Discuss the metabolism of benzylisoquinolinium NMB.
They are not dependent on hepatic or renal function for metabolism & elimination.
- Atracurium = 33% hoffman elimination & 66% nonspecific plasma esterases (same as those that degrade esmolol & remi not the same as psuedocholinesterase
- Cisatracurium = Hoffman only
- Mivacurium = pseudocholinesterase (same as succinylcholine)
What factors impact Hoffman elimination?
Hoffman elimination is dependent on pH and temperature!
1) blood pH: decreased elimination w/ acidosis
2) temperature: decreased elimination w/ hypothermia
What is the active metabolite of atra & cisatra? What is the clinical significance?
-laudanosine (atra produces > Cisatracurium): CNS stimulant, capable of producing =seizures
-avoid in history of seizures
- not a problem during routine administration in the OR - but may be a problem w/ IV gtt in the ICU
- laudanosine has no muscle relaxant properties.
Discuss the metabolism, elimination, and active metabolites of the aminosteroid NMB.
roc:
- no metabolism
- >70% liver biliary elimination <30% renal elimination
vec
- 30-40% liver metabolism
- 40-50% liver elimination, 50-60% renal elimination
- 3-OH vecuronium metabolite
panc
- 10-20% liver metablism
- 15% liver elimination, 85% renal elimination
- 3-OH pancuronium metabolite
What drugs can potentiate NMB?
- Desflurane potentiates neuromuscular blockers the most. Nitrous is the least!
- aminoglycosides, clindamycin, tetracycline, gentamicin
- verapamil, amlodipine, quinidine
- LA: probably most
- lasix
- dantrolene, tamoxifen, cyclosporine
- low potassium low calcium
- increase magnesium and increase lithium
- hypothermia- reduces metabolism and clearance
What electrolyte disturbances can potentiate the effects of NMB?
high lithium and Mg
low Ca++ and K+
Compare and contrast the CV effects of NMB.
- histamine release: SAM: Sux, Atracurium, Mivacurium
- sux: autonomic ganglia stimulation that can cause tachycardia & cardiac M2 receptor stimulation that can cause bradycardia
- panc: moderate cardiac M2 receptor blockade = tachycardia (roc does this maybe a little)
Which NMB has a vagolytic effect?
pancuronium
inhibits M2 at the SA node, stimulates the release of catecholemines, and inhibits catechol reuptake.
–> increased HR & CO w/ no change in SVR.
can be used to mitigate opioid induced bradycardia in cardiac surgery.
Which NMB should be avoided in the patient w/ IHSS?
1) pancuronium- vagolytic effect, it increases HR
2) atracurium and Mivacurium- histamine release
Cisatracurium IS FINE!! NO HISTAMINE RELEASE unless in high doses
- don’t want the ventricle to contract too forcefully or too quickly –> decreased LVOT –> decreased CO & BP.
Which 2 NMB can cause an anaphylaxis?
What enzyme lab do you check to diagnose anaphylaxis?
Sux and roc
Tryptase- elevated level, it peaks 15 mins after exposure
How do cholinesterase inhibitors reverse paralysis caused by a NDMR?
acetylcholinesterase hydrolyzes ACh into choline & acetate.
drugs such as edrophonium, neostigmine, and pyridostigmine reversibly inhibit AChE –> increasing the [ACh] at the NMJ.
Increased [ACh] = more competive binding for the alpha subunits on the nAChR
List 3 ways to inhibit acetylcholinesterase. Give examples of each bond:
- electrostatic bond: competitive inhibition - edrophonium
- carbamyl ester bond: competitive inhibition - neostigmine, pyridostigmine, physostigmine
- phosphorylation bond: noncompetitive inhibition - organophosphates & echothiopate
regarding edrophonium, what is the dose, onset, duration, metabolism, and best antimuscarinic pairing?
dose 0.5-1mg/kg
onset 1-2mins it’s the fastest!
duration 30-60mins
metabolism 75% renal
best pairing atropine
regarding neostigmine, what is the dose, onset, duration, metabolism, and best antimuscarinc pairing?
dose 0.02-0.07mg/kg onset 5-15mins duration 45-90mins metabolism 50/50 renal/hepatic best pairing glycopyrrolate
pyridostigmine, what is the dose, onset, duration, metabolism, and best antimuscarinic pairing?
dose 0.1-0.3mg/kg
onset 10-20mins
duration 60-120min
metablism 75%
best pairing glycopyrrolate
Compare and contrast the side effects of atropine, scopolamine, and glycopyrrolate.
tachycardia: atr smooth muscle relaxation: atropine and glyco sedation: scop antisialagogue: scop mydriasis: scop antinausea: scop decreased gastric H+ section: all same affect fetal HR: scop might
In what situations can atropine cause a paradoxical bradycardia?
small doses <0.5mg IV in an adult
Due to inhibition of the presynaptic M1 receptor on vagal nerve endings (this receptor reduces ACh via negative feedback loop) = increased ACh release & bradycardia.
MOA of Sugammadex
gamma-cyclodextrin made up of 8 sugars assembled into a ring. The ring encapsulates the NMB, rendering it inactive & unable to engage w/ the nAChR.
It’s excreted unchanged by the kidneys
Roc is excreted biliary system
How do you dose sugammadex?
TOF >2/4 –> 2mg/kg
TOF >0/4 + 2PTC –> 4mg/kg
for roc only, if no twitches + >3mins post roc administration –> 16mg/kg
Discuss the process of pain transduction.
experience of pain can be divided into 4 steps: transduction, transmission, modulation, and perception.
transduction:
- injured tissues release chemicals that activate peripheral nerves & cause immune cells to release proinflammatory compounds
- peripheral nerves transduce this chemical soup into an = AP
What is the role of inflammation in pain transduction?
inflammation contributes to:
- reduced threshold to pain stimulus (allodynia)
- increased response to pain stimulus (hyperalgesia)
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 dorsal horn)
third order neuron: thalamus –> cerebral cortex (cell body in the thalamus).
Discuss the process of pain modulation.
Most important site of modulation = substantia gelatinosa in the dorsal horn (rexed lamina II & III)
- descending inhibitory pain pathway begins in the periaqueductal gray & rostoventral medulla, projecting to the substantia gelatinosa.
Discuss the process of pain perception.
perception describes the processing of afferent pain signals in the cerebral cortex & limbic system.
how we “feel” about pain.
What is the mechanism of action of opioids?
each opioid receptor is linked to a G protein.
GPCR agonism = decrease in adenylate cyclase and decreased cAMP
- closes Ca++ channels- reducing neurotransmitter release from presynaptic neuron
- opens K+ channel- hyperpolarizes postsynaptic neuron
What are the precursors of the endogenous opioids?
Opioid receptors:
endorphins (mu receptor)
enkephalins (delta receptor)
dynorpins (kappa receptor)
Pretend for a moment that mu receptor subtypes exist. What are the physiologic effects of mu-1, mu-2, and mu-3 receptor stimulation?
This has yet to be proven, and most newer texts don’t delineate b/n the effects of the different subtypes.
mu-1
- analgesia (supraspinal & spinal)
- bradycardia
- euphoria
- low abuse potential
- miosis
- hypothermia
- urinary retention
mu-2
- analgesia (spinal only)
- respiratory depresison
- constipation
- physical dependence
mu-3
- immune suppression
what are the unique effects of kappa stimulation?
- antishivering effect
- diuresis
- dysphoria
- delirium
- hallucinations
- miosis
how do opioids affect HR, BP, and myocardial function?
HR:
- bradycardia is the result of mu stimulation (mu-2)
- meperidine can increase HR d/t atropine-like ring in it’s chemical structure producing anticholinergic effects
BP
- minimal effect in healthy patients
- hypotension w/ morphine/meperidine d/t histamine release
myocardial function:
- myocardial depression can occur if combined w/ N2O
How do opioids affect ventilation?
stimulate the mu & delta receptors (& possibly kappa) to produce their ventilatory effects:
- decreased ventilatory response to CO2 R shift of CO2 response curve
- decreased RR & compensatory increased in Vt (partial compensation)
- increased PaCO2 –> increased ICP if ventilation isn’t maintained.
How do opioids affect the pupil?
Edinger Westphal nucleus stimulation –> increased PNS stimulation of ciliary ganglion & oculomotor nerve (CN 3) = pupil constriction
How do opioids produce nausea & vomiting?
via mu receptor stimulation:
- chemoreceptor trigger zone stimulation (area postrema of medulla) (this area isn’t protected by the BBB)
- possibly interaction w/ the vestibular apparatus.
How do opioids affect biliary pressure, gastric emptying, and peristalsis?
via mu receptor stimulation:
biliary pressure
- contraction of SOO –> increased biliary pressure
- reversed by naloxone or glucagon
- meperidine = lowest incidence of this effect
gastric emptying is prolonged
peristalsis is slowed –> constipation
Rank the IV opioids in terms of potency.
sufentanil fentanyl = remi alfentanil hydromorphone morphine= women experience more analgesia potency meperidine
compare the equianalgesic opioid doses relative to 10mg of morphine
100mg meperidine 10mg morphine 1.4mg hydromorphone 1000mcg alfentanil (1mg) 100mcg fentanyl 100mcg remi 10mcg sufenta
which opioids produce an active metabolite?
except for remi, all of the opioids undergo hepatic biotransformation
of these, only morphine & meperidine produce active metabolites.
What is the active metabolite of morphine & why is it a problem?
morphine-3-gluconoride (inactive)
morphine-6-gluconoride (active)
impaired renal function –> MP6 excretion –> increased accumulation –> respiratory depression.
Meperidine:
What is the active metabolite of meperidine & why is it a problem?
What receptors does it stimulate?
What structures is it similar to?
Avoid in?
- normeperidine is 1/2 as potent as its parent compound
- mu and kappa
- side effects similar to anticholinergic due to similar structure = mydriasis
- also has similar structure of local anesthetics and inhibit nerve conduction
- it reduces the seizure threshold & increases CNS excitability
- impaired renal function –> decreased normeperidine release = seizures
- Avoid in elderly and renal patients = risk for toxicity
How does the ionization characteristics of alfentanil influence it’s onset of action?
of all the opioids, alfentanil has the fastest onset of action due to low degree of ionization
pKa 6.5, less than physiologic it has the lowest pKa
- 90% unionized
- low Vd & high degree of PB (alpha-1 acid glycoprotein)
- high % unionized + the low Vd = faster to enter brain
Which opioid has the largest Vd? Which has the smallest?
largest = fentanyl 4L/kg smallest = remi 0.39L/kg
Opioid pka, protein binding, and Vd:
Remi receptor:
Potency is similar to?
rapid on/rapid off mu agonist
- CS1/2t = 4mins
-metabolized by hydrolysis by erythrocyte & tissue esterases NOT pseudocholinesterase - highly lipophilic, but behaves as tho small Vd d/t this fast rate of plasma clearance
- potency is similar to fentanyl
- 0.1-1mcg/kg/min
- obese: gtt rate is calculated w/ LBW since it doesn’t distribute throughout the body
REMI= LBW
Remi opioid induced hyperalgesia. What drugs can prevent this phenomenon?
remi causes acute opioid induced hyperalgesia following discontinuation
- Opioid induced hyperalgia can be prevented with ketamine or mag sulfate
Can remi be used for neuroaxial anesthesia? Why or why not?
no.
remi powder is mixed w/ a free base & glycine to provide a buffered solution following reconstitution
glycine is an inhibitory neurotransmitter –> skeletal muscle weakness, so shouldn’t be administered in the epidural or intrathecal space.
Remi is a mu agonist
Methadone reduces pain 3 ways:
by 3 mechanisms:
1) Mu receptor agonist
2) NMDA receptor antagonist (the only opioid that has this effect)
3) MAOI in synaptic cleft
It’s metabolized by the liver
Info about: Oliceridine is an IV opioid analgesic, can cause seizures, avoid in GI obstruction
Which opioid is most likely to cause QT prolongation?
methadone (but this is rare)
What is the etiology of opioid induced skeletal m rigidity?
rapid IV administration of the potent IV opioids can cause mu receptor stimulation in the CNS.
used to be described as chest wall rigidity, evidence suggests that the greatest resistance to ventilation occurs at the larynx
From sufentanil, fentanyl, remi, Alfentanil
What are the common characteristics of the opioid partial agonists?
can never achieve the same intensity of effect at a specific receptor as a full agonist.
Examples include buprenorphine, nalbuphine, and butorphanol.
common characteristics:
- anaglesia w/ decreased risk of resp depression
- ceiling effect present
- reduce efficacy of previously administered opioids
- can cause acute opioid withdrawal in those dependent
- can cause dysphoric rxns
- low risk of dependence
- used in those that can’t tolerate a full agonist.
compare and contrast buprenorphine, nalbuphine, and butorphanol.
buprenorphine
- only partial mu agonist
- greater analgesia than morphine
- difficult narcan reversal (d/t high affinity for mu receptor)
- long DOA (8hrs), available transdermal
nalbuphine
- kappa agonist, mu antagonist
- similar analgesia to morphine
- reversed by narcan
- no CV changes, useful w/ hx heart disease
butorphanol
- kappa agonist, weak mu antagonist
- greater analgesia than morphine
- useful for post-op shivering, available intranasally
discuss the potential complications of opioid reversal w/ naloxone
- short duration (30-45mins) - may be shorter than the opioid
- SNS stimulation –> tachycardia, dysrhythmias, pulmonary edema, sudden death (use slow titration)
- N/V: slower titration over 2-3mins decreases this
- fetal withdrawal (narcan crosses the placenta)
Which opioid antagonist is least likely to reverse respiratory depression? Why?
methylnaltrexone has a quaternary amino group that prohibits its passage across the BBB. –> doesn’t reverse respiratory depression
it is useful for mitigating the peripheral effects of opioids, such as opioid induced bowel dysfunction
Which opioid antagonist has the longest DOA?
naltrexone doesn’t undergo first pass metabolism (narcan does)
- can be given orally and has a DOA up to 24hrs
- ER formulation may be used for alcohol withdrawal treatmnet
- can be used alone to maintain recovering opioid abusers
Cocaine toxicity avoid BB but if given the choice to give one, which one would you choose?
Labetolol
Methehemoglobinemia
Which 2 patient populations are at risk?
• Patients with glucose-6-phosphate reductase deficiency do not possess methemoglobin reductase. An exchange transfusion may be required.
• Fetal hemoglobin is relatively deficient in methemoglobin reductase, making it susceptible to oxidation. Therefore, neonates are at higher risk for toxicity.
Things that can cause methemoglobinemia: benzocaine, prilocaine, ceticaine, phenytoin, Nitroprusside, sulfanomides, nitroglycerin
Treat with methylene blue 1-2mg/kg IV max dose 7-8mg/kg
Hyaluronidase- helps with diffusion, useful in eye blocks to help with speed of onset, and mitigate rise in intraocular pressure
Local anesthetic additives
Things that prolong: decadron, dextran, epi
Things that help with pain: clonidine, opioids, epi
Cocaine max dose
200mg
Choose an ester instead. Tetracaine
Rank protein binding
C fibers they’re unmyelinated
This image represents the MOA of local anesthetics
Local anesthetic degree of ionization
Label the nicotinic receptor
Adult- epsilon
Fetal- gamma
Fade:
Fade: antagonism of presynaptic Nn receptors
When an action potential arrives at the nerve terminal, voltage-gated calcium channels open and calcium enters the nerve terminal. Increased intracellular calcium destabilizes the proteins that hold the Ach vesicles in place. Next, the vesicles exit the nerve via exocytosis, and each vesicle releases 5,000 - 10,000 Ach molecules into the synaptic cleft.
Ach diffuses toward the postsynaptic Nm receptors on the motor endplate, where it depolarizes the motor endplate and initiates skeletal muscle contraction.
Nondepolarizing neuromuscular blockers competitively antagonize the presynaptic Nn receptors. This impairs the mobilization process, so now only the vesicles that are available for immediate release can be used. With each successive stimulation, less Ach is released. You can observe this as fade with train-of-four, double burst stimulation, and tetanus.
succinylcholine stimulates the prejunctional receptors - it has the same effect as Ach. When succinylcholine binds to the presynaptic Nn receptor, it facilitates the mobilization process, so there’s always Ach available for immediate release. This explains why fade is not observed with a depolarizing neuromuscular blocker.
Clinical assessment of neuromuscular blockade
Sux can you use it for ocular sx?
Yes you can
Reglan, late pregnancy, esmolol
Things that prolong sux aka reduce pseudocholinesterase activity
7 drugs that reduce pseudocholinesterase activity
Risk of hyperkalemia
Roc- biliary excretion
Pan- liver metabolism but renal excretion
Cis- Hoffman
Also roc and miva- don’t produce a metabolite
What muscles are the slowest to undergo spontaneous recovery after rocuronium administration? (Select 2.)
Flexor hallucis
Corrugator supercilii
Diaphragm
Adductor pollicis
Which neuromuscular blocker is capable of producing a phase 1 block?
Pancuronium
Vecuronium
Succinylcholine
Cisatracurium
Sux!
presynaptic nicotinic receptor is an integral component of the fade mechanism.
As an agonist of the presynaptic nicotinic receptor, succinylcholine produces a phase 1 block. In this situation, the mobilization of Ach functions as it normally does - there’s an ample supply of Ach.
Which enzymes are present in the synaptic cleft? (Select 2.)
Type 1 cholinesterase
False cholinesterase
Butyrylcholinesterase
Specific cholinesterase
Type 1 cholinesterase
Specific cholinesterase
Specific cholinesterase and type 1 cholinesterase are synonyms for acetylcholinesterase. This enzyme metabolizes Ach in the neuromuscular junction.
Read over
AchEI dose
Physostigmine can also help reduce shivering!
Neostigmine can cause:
- bronchospasm (bronchoconstriction)
- bradycardia
- QT prolongation
- nausea
- miosis
Match the muscle
- orbicularis oculi closes the eyelid- CN 7
- corrugator supercilii moves the eyebrow- CN 7
- medial rectus adducts the eyeball- CN 3
Which finding is MOST consistent with recovery from neuromuscular blockade in a 70 kg patient?
Vital capacity = 1,400 mL
Tidal volume = 350 mL
Train-of-four monitor reveals 4 equal twitches
Patient holds tongue blade in mouth against force
Patient holds tongue blade in mouth against force
Select the BEST acetylcholinesterase inhibitor to antagonize a block with 90 percent twitch suppression.
Select the BEST statement regarding the use of an anticholinergic agent and edrophonium when used to antagonize neuromuscular blockade.
- Glycopyrrolate should be mixed in the same syringe as edrophonium.
- Atropine is given after edrophonium.
- Atropine pairs better than glycopyrrolate.
- Atropine should be avoided because of CNS side effects.
- Atropine and Edrophonium should be paired
Neostigmine antagonizes rocuronium by:
A. reversibly binding to butyrylcholinesterase.
B. potentiating acetylcholinesterase activity.
C. competing with rocuronium at the nicotinic receptor.
D. decreasing acetylcholine hydrolysis.
D. decreasing acetylcholine hydrolysis.
Which conditions may produce hyperkalemia with the administration of succinylcholine? (Select 3.)
Myasthenia gravis
Renal failure in a recently dialyzed patient
Hemiplegia
Immobilization
Eaton-Lambert syndrome
Sepsis
Hemiplegia
Immobilization
Sepsis
Identify the process by which a nociceptor converts a chemical stimulus into an action potential.
• Transmission
• Transduction
• Perception
• Modulation
• Transduction-
Potency to morphine
Alfentanil is 10
Meperidine is 0.1
Opioid pka, protein binding, nonionization
Meperidine has the lowest nonionization 7%, Alfentanil has the highest 89%
Increase PVR, ICP, consumption
Mixed VO2 is decreased
Hydromorphone 0.7 mg
Alfentanil 500 mcg
Hydromorphone 0.7 mg
Alfentanil 500 mcg
Know this well
BB characteristics
Atenolol:
Propanolol:
Carvedilol:
Metoprolol:
There’s some info about BB in ANS flashcard section
