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
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.
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 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?
- 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
- 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?
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
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?
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
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
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.
interpleural intercostal caudal epidural brachial plexus femoral sciatic subcutaneous
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?
seizure
except in bupivicaine (cardiac arrest can occur before seizure)
List effects of lidocaine toxicity according to plasma concentration.
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
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?
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/ 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
- 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?
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:
- 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 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
