Flashcards in UNIT 5 Pharmacology II Deck (144):
Describe the components of the neuron & their functions.
dendrite: receives & processes signal
soma: integrates signal, cellular machinery
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
CV is increased by:
- myelination: the AP skips along the nodes of Ranvier (saltatory conduction)
- large fiber diameter
List the 3 different fiber types. Compare & contrast them in terms of myelination, function, diameter, conduction velocity, & block onset.
- heavy myelination
- skeletal muscle (motor) & proprioception
- fastest velocity
- 4th in block onset
- heavy myelination
- touch & pressure
- second fastest velocity
- 4th in block onset
- medium myelination
- skeletal muscle (tone)
- middle velocity (3rd)
- 3rd in block onset
- medium myelination
- fast pain, temp, touch
- middle velocity (3rd)
- 3rd in block onset
- light myelination
- preganglionic ANS
- 2nd slowest velocity
- 1st in block onset
- no myelination
- postganglionic ANS
- slowest velocity
- 2nd in block onset
- no myelination
- slow pain, temp, touch
- 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)
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 the neuron, then repolarization is the removal of positive charges from inside the cell. This is accomplished by 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?
1. benzene ring
- permits diffusion through lipid bilayers
2. intermediate chain
- class: ester or amide
- allergic potential
3. tertiary amine
- 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
amide: has "i" before suffix - caine
contrast the metabolism of ester & amide LA. Which LA participates in both metabolic pathways?
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
- however, 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?
- 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
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?
- 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
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
Rank the ester LA according to pKa
list 5 factors that govern the uptake & plasma concentrations of LA
- site of injection
- tissue blood flow
- physiochemical properties of LA
- addition of a vasoconstrictor
rank injection sites to the corresponding plasma concentrations of LA.
What is the maximum dose for each amide LA (weight based & max total dose)?
levobupivicaine 2mg/kg (150mg)
bupivicaine 2.5mg/kg (175mg)
bupivicaine w/ epi 3mg/kg (200mg)
lidocaine 4.5mg/kg (300mg)
ropivicaine 3mg/kg (200mg)
mepivacaine 7mg/kg (400mg)
lido w/ epi 7mg/kg (500mg)
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?
except in bupivicaine (cardiac arrest can occur before seizure)
List effects of lidocaine toxicity according to plasma concentration.
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
1. hypercarbia (increases CBF & increases drug delivery to the brain. Also decreases PB --> increased free fraction)
2. hyperkalemia (raises resting membrane potential)
3. 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.
1. affinity for the v-gated Na+ channel in the active & inactive state
2. 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
amio is the agent of choice for ventricular arrythmias
avoid vasopressin, lidocaine, & procainamide.
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)?
max dose of lidocaine for tumescent anesthesia = 55mg/kg.
90x55 = 4950mg
0.1% lido sln = 1mg/mL --> pt can receive 4950mL of the solution
In addition to LA toxicity, what are other potential complications of a large volume of tumescent anesthesia?
pulmonary edema d/t 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 sln is injected.
Name the two LA that are most likely to produce a L shift of the oxyhemoglobin dissociation curve. Why does this happen?
prilocaine & benzocaine; they can cause methemoglobinemia.
O2 binding site on the heme portion of Hgb contains an ion molecule in Fe++ form.
- oxidation of Fe++ to Fe+++ creates metHgb
- metHgb impairs O2 binding & unbinding from the Hgb molecule, shifting the curve to the L --> physiologic anemia.
What drugs are capable of causing metHgb?
- cetacaine (contains benzocaine)
- EMLA (prilocaine + lidocaine)
What are the s/s of metHgb?
chocolate colored blood
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++)
- those w/ G6PD don't have methemoglobin reductase, so an exchange transfusion may be required.
- fHgb 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 over 10cm2
5-10kg: 2g over 20cm2
10-20kg: 10g over 100cm2
>20kg: 20g over 200cm2
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
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
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
- skeletal m trauma
- prolonged chemical denervation (Mg++, NMB gtt, etc.)
- severe sepsis
- muscular dystrophy
What is the risk of using succinylcholine in the patient w/ upregulation of extrajunctional receptors?
w/out 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.
How do extrajunctional receptors affect the clinical use of NDMR?
those w/ upregulation of extrajunctional receptors are resistant to NDMR (potency is reduced) --> dose may need to be increased
Discuss fade in the context of succ & NDMR.
There are two supplies of ACh vesicles:
1. ACh that is available for immediate release
2. 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 stim #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
phase 2 = fade
2 situations that favor phase 2 development:
- 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 w/ the facial nerve
recovery: adductor pollicis w/ 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.
- 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
- & 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?
contraction of the abdominal muscles increases intragastric pressure. At the same time, sux increases LES tone --> these pressures cancel each other out, so the risk of aspiration is not increased.
List name 5 names for the enzyme that metabolizes ACh. List 5 names for the enyzme that metabolizes succinylcholine .
- type 1 cholinesterase
- true cholinesterase
- specific cholinesterase
- genuine cholinesterase
- type 2 cholinesterase
- false cholinesterase
- plasma cholinesterase
List all of the drugs and conditions that reduce pseudocholinesterase activity.
- neostigmine (not edrophonium)
- oral contraceptives/estrogen
- nitrogen mustard
- atypical PChE
- severe liver disease
- organophosphate poisoning
- advanced age
- 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 doesn't inhibit atypical plasma cholinesterase. If the patient has a dibucaine # of 20 = atypical variant.
What are the 3 variants of pseudocholinesterase, and what is the DOA of succinylcholine for each one?
1. typical homozygous (dibucaine 70-80); DOA sux = 5-10mins
2. heterozygous (dibucaine 50-60); DOA sux = 20-30mins
- 1/480 incidence
3. atypical homozygous (dibucaine 20-30); DOA 4-8hrs
- 1/3200 incidence
Why does succinylcholine have a black box warning?
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
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?
1. stabilize the myocardium:
- CaCl 20mg/kg
- Ca gluconate 60mg/kg
2. shift K+ into cells
- 10% glucose 0.3-0.5g/kg
- 1U insulin/4-5g of glucose
- 1-2mmol/kg NaHCO3
- albuterol nebulizer
3. enhance K+ elimination
- furosemide 1mg/kg
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 adults undergoing ambulatory surgery (women > men) & those that do not routinely engage in strenuous activity.
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
- lidocaine 1.5mg/kg
- higher sux dose
opiods don't reduce the incidence
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 developing hyperkalemia after succinylcholine?
- amyotrophic lateral sclerosis (ALS)
- Duchenne's muscular dystrophy
- Hyperkalemic periodic paralysis
- upregulation of extrajunctional receptors
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:
- miva = panc
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?
Discuss the metabolism of benzylisoquinolinium NMB.
undergo spontenous degradation in the plasma. They are not dependent on hepatic or renal function for metabolism & elimination.
atra = 33% hoffman elimination & 66% nonspecific plasma esterases (same as those that degrade esmolol & remi **not the same as psuedocholinesterase)
cis = Hoffman only
Miva = pseudocholinesterase (same as succinylcholine)
What factors impact Hoffman elimination?
- increased elimination w/ alkalosis, decreased elimination w/ acidosis
- increased elimination w/ hyperthermia, decreased elimination w/ hypothermia
What is the active metabolite of atra & cisatra? What is the clinical significance?
laudanosine (atra produces more)
- CNS stimulant, capable of producing 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.
- no metabolism
- >70% liver elimination, <30% renal elimination
- no metabolites
- 30-40% liver metabolism
- 40-50% liver elimination, 50-60% renal elimination
- 3-OH vecuronium
- 10-20% liver metablism
- 15% liver elimination, 85% renal elimination
- 3-OH pancuronium
What drugs can potentiate the effects of NMB?
abx: aminoglycosides, clindamycin, tetracycline
antidysrhythmics: verapamil, amlodipine, quinidine
LA: probably most
others: dantrolene, tamoxifen, cyclosporine.
What electrolyte disturbances can potentiate the effects of NMB?
high [lithium], [Mg++]
low [Ca++], [K+]
Compare and contrast the CV effects of NMB.
histamine release: succinylcholine, atra, miva
succ: autonomic ganglia stim (tachycardia) & cardiac M2 receptor stim (bradycardia)
panc: moderate cardiac M2 receptor blockade --> SNS unopposed --> tachycardia (roc does this maybe a little)
Which NMB has a vagolytic effect?
inhibits M2 at the SA node, stimulates the release of catechols, 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?
pancuronium (vagolytic effect) or atra/miva (histamine release)
- don't want the ventricle to contract too forcefully or too quickly --> decreased LVOT --> decreased CO & BP.
rank the NMB according to likelihood of causing anaphylaxis.
succ > atra > cis > roc > vec
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.
1. electrostatic attachment (competitive inhibition - edrophonium)
2. formation of carbamyl esters (competitive inhibition - neostigmine, pyridostigmine, physostigmine)
3. phosphorylation (noncompetitive inhibition - organophosphates & echothiopate)
regarding edrophonium, what is the dose, onset, duration, metabolism, and best antimuscarinic pairing?
metabolism 75% renal, 25% hepatic
best pairing atropine
regarding neostigmine, what is the dose, onset, duration, metabolism, and best antimuscarinc pairing?
metabolism 50/50 renal/hepatic
best pairing glycopyrrolate
regarding pyridostigmine, what is the dose, onset, duration, metabolism, and best antimuscarinic pairing?
metablism 75% renal, 25% hepatic
best pairing glycopyrrolate
How does renal failure affect the dosing of acetylcholinesterase inhibitors after an aminosteroid NMB is administered?
renal failure prolonges the DOA for both AChE inhibitors & aminosteroid NMB
since both drugs will remain in the body for a longer period of time there is no need to adjust dosing or re-dose it.
contrast neostigmine reversal in adults and children.
when compared to adults, antagonism w/ neostigmine is faster in infants and children.
Which acetylcholinesterase inhibitors pass through the BBB? Which do not? Why?
physostigmine is a tertiary amine - thus it passes through the BBB
edrophonium, neostigmine, and pyridostigmine are quaternary amines - they carry a positive charge w/ them that prevents them from passing through the BBB
List the side effects of acetylcholinesterase inhibitors
Compare and contrast the side effects of atropine, scopolamine, and glycopyrrolate.
tachycardia: atr > glyco > scop
smooth m relaxation: atr/glyco > scop
sedation: scop > atr > glyco
antisialagogue: scop > glyco > atr
mydriasis: scop > atr > glyco
antinausea: scop > atr > glyco
decreased gastric H+ section: all same
affect fetal HR: scop might
Which antimuscarinics pass through the BBB? Which do not? Why?
atropine & scopolamine are naturally occurring tertiary amines (lipophilic) --> cross BBB (as well as GI tract & placenta)
glyco is a quaternary ammonium derivative, thus is ionized & doesn't pass though lipid membranes.
In what situations can atropine cause a paradoxical bradycardia?
small doses <0.5mg IV in an adult
this is probably d/t inhibition of the presynaptic M1 receptor on vagal nerve endings (this receptor reduces ACh via negative feedback loop)
--> increased ACh release & bradycardia.
Do patients with a history of heart transplantation require an antimuscarinic for reversal of a nondepolarizaing block?
ANS influence has been removed from the heart - the HR is solely determined by intrinsic SA node firing.
For this reason, muscarinic antagonists do not affect the HR, but these pts will experience the other cholinergic effects from AChE inhibitors, so they should receive a muscarina antagonist w/ an AChE inhibitor
What is the mechanism of action 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.
What NMB can be reversed by sugammadex?
aminosteroid NMB: roc > vec > pan
no effect on the others.
How does sugammadex improve safety?
1. roc can be used for difficult intubation w/out the drawbacks of sux
2. can reverse a dense NMB quickly, reducing the risk of residual paralysis
3. allows for a dense block until the very end of the surgical procedure w/out the concern of delayed extubation.
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
How is sugammadex metabolized?
complexes & the drug alone are excreted unchanged by the kidneys.
What are the two most significant risks associated w/ sugammadex?
2. in the event that additional surgery is required shortly after sugammadex administration, there is a concern about hte ability to reparalyze the patient w/ an aminosteroid NMB
- larger dose of NMB will be required
- roc will have a longer onset & shorter DOA
- may want to select a benzylisoquinolinium instead.
Discuss the process of pain transduction.
experience of pain can be divided into 4 steps: transduction, transmission, modulation, and perception.
- injured tissues release a variety of chemicals that activate peripheral nerves &/or cause immune cells to release proinflammatory compounds
- peripheral nerves transduce this chemical soup into an AP
What type of nerve fibers transmit pain?
A-delta: fast pain (sharp & well localized)
C: slow pain (dull & poorly localized)
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.
pain signal is modified (inhibited or augmented) as it advances toward the cerebral cortex).
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.
pain is inhibited when:
- spinal neurons release GABA & glycine (inhibitory neurotransmitters)
- descending pain pathways release NE, 5-HT, and endorphins
pain is augmented by:
- central sensitization
- wind up phenomenon.
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 --> decreased cAMP --> alteration of ionic currents & reduction of neuronal function
- closes Ca++ channels (reducing neurotransmitter release from presynaptic neuron)
- opens K+ channel (inward rectifier) (hyperpolarizes postsynaptic neuron, making it more resistant to stimulation)
What are the precursors of the endogenous opioids?
pre-proopiomelanocortin --> endorphins (mu receptor)
pre-enkephalin --> enkephalins (delta receptor)
pre-dynorphin --> 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.
- analgesia (supraspinal & spinal)
- low abuse potential
- urinary retention
- analgesia (spinal only)
- respiratory depresison
- physical dependence
- immune suppression
what are the unique effects of kappa stimulation?
- antishivering effect
how do opioids affect HR, BP, and myocardial function?
- 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
- minimal effect in healthy patients
- hypotension w/ morphine/meperidine d/t histamine release
- contractility isn't affects
- myocardial depression can occur if combined w/ N2O
How do opioids affect ventilation?
stimulate the mu & delta receptors (& possibly kapp) 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 III) --> 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:
- 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
How do opioids contribute to urinary retention?
produce their GU effects through mu & delta receptor stimulation
- detrusor relaxation
- urinary sphincter contraction
What are the immunologic effects of opioids?
histamine release (morphine, meperidine, codeine)
inhibition of cellular & humoral immune function
suppression of NK cell function
How do opioids affect thermoregulation?
opioids reset the hypothalamic temperature set point --> decrease in core body temperature.
Rank the IV opioids in terms of potency.
fentanyl = remi
compare the equianalgesic opioid doses relative to 10mg of morphine
1000mcg alfentanil (1mg)
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?
impaired renal function --> MP6 excretion --> increased accumulation --> respiratory depression.
What is the active metabolite of meperidine & why is it a problem?
normeperidine is 1/2 as potent as its parent compound
- it reduces the seizure threshold & increases CNS excitability
- impaired renal function --> decreased normeperidine release --> increased accumulation --> seizures
Discuss the coadministartion of meperidine & MAOIs
can cause serotonin syndrome
meperidine is a weak serotonin reuptake inhibitor
- since MAO deaminates serotonin in the synaptic cleft, coadministration of meperidine & MAOI can cause serotonin syndrome
s/s: hyperthermia, MS changes, hyperreflexia, seizures, death
MAOI: phenelzine, isocarboxazid, tranylcypromine
How does the ionization characteristics of alfentanil influence it's onset of action?
of all the opioids, alfentanil has the fastest onset of action
pKa 6.5, less than physiologic
- 90% unionized & 10% ionized
- low Vd & high degree of PB (alpha-1 acid glycoprotein)
the high % unionized + the low Vd = more drug available to enter the brain.
Which opioid has the largest Vd? Which has the smallest?
largest = fentanyl 4L/kg
smallest = remi 0.39L/kg
discuss the PK/PD profile of remi
rapid on/rapid off mu agonist
- CS1/2t = 4mins
- contains an ester linkage = hydrolysis by erythrocyte & tissue esterases
- highly lipophilic, but behaves as tho small Vd d/t this fast rate of plasma clearance
- potency is similar to fentanyl
- obese: gtt rate is calculated w/ LBW since it doesn't distribute throughout the body
Discuss the relationship b/n remi & opioid induced hyperalgesia. What drugs can prevent this phenomenon?
remi causes acute opioid induced hyperalgesia following d/c
- post-op opioid reqs are particularly high in these patients
- OIH can be prevented w/ ketamine or mag sulfate
Can remi be used for neuroaxial anesthesia? Why or why not?
remi powder is mixed w/ a free base & glycine to provide a buffered solution following reconstitution
glycine is an inhibitory neurotransmitter --> skeletal m weakness, so shouldn't be administered in the epidural or intrathecal space.
How does methadone reduce pain?
by 3 mechanisms:
- Mu receptor agonist
- NMDA receptor antagonist (the only opioid that has this effect)
- inhibits reuptake of monoamines in the synaptic cleft
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 this d/t mu receptor stimulation in the CNS.
used to be described as chest wall rigidity, but cufrent evidence suggests that the greatest resistance to ventilation occurs at the larynx
What is the treatment of opioid induced skeletal m rigidity?
paralysis & intubation
naloxone can 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?
can never achieve the same intensity of effect at a specific receptor as a full agonist.
- 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.
- partial mu agonist
- >analgesia than morphine
- difficult narcan reversal (d/t high affinity for mu receptor)
- long DOA (8hrs), available transdermal
- kappa agonist, mu antagonist
- similar analgesia to morphine
- reversed by narcan
- no CV changes, useful w/ hx heart disease
- kappa agonist, weak mu antagonist
- >analgesia c/w morphine
- reversed by narcan
- 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