Pharmacology II Flashcards
A-alpha
Heavy myelination
Sk. muscle motor, proprioception
12 - 20 um
4th block
A-(beta)
Heavy myelination
Touch, pressure
5 - 12 um
4th block
A-Gamma
Medium myelination
Skeletal muscle, tone
3 - 6 um
3rd to block
Delta
Medium myelination
Fast pain, temperature, touch
2 - 5 um
3rd to block
B fibers
Light myelination
preganglionic ANS fibers
3 um
1st to block
C fibers - sympathetic
no myelination
post ganglionic ans fibers
0.3 - 1.3
2nd to block
C-fibers dorsal root
no myelination
slow pain, temperature, touch
0.4 - 1.2
2nd to block
ED50 for local anesthetics
Cm = minimum effective concentration is a unit of measure that quantifies the concentration of local anesthetic that is required to block conduction
Rank the nerve fibers according to their sensitivity to LA in vivo (most to least sensitive)
B-fibers –> C fibers –> Alpha-delta, gamma –> Alpha beta –> Alpha alpha
3 possible configurations of the VG sodium channel
resting = channel closed, but can depolarize
active = channel open, Na+ moving along concentration gradient into the neuron
inactive = channel closed, cannot be opened
How and when do LA bind to the VG sodium channel?
Active and Inactive states ONLY!
LA are more likely to bind to axons conducting APs and less likely to bind to those that are not conducting APs
More frequently nerve depolarized, more open, more time for LA to bind = use-dependent or phasic blockade
What is an AP? How does it depolarize a nerve?
Temporary change in a transmembrane potential followed by a return to transmembrane potential.
-Na or Ca must enter cell (makes inside more +)
-Threshold potential reached, cell depolarizes
What happens when a nerve repolarizes?
Removal of positive charges from inside the cell via removing potassium
How does LA affect neuronal depolarization?
Bind to the alpha subunit on the inside of the sodium channel
-critical # of sodium ch. blocked, there aren’t enough open channels for sodium to enter in sufficient quantity
-the cell can’t depolarize
THEY DO NOT AFFECT RMP OR THRESHOLD POTENTIAL
Role of ionization w/ respect to LA
-Weak baes w/pka values > 7.4
-We can predict > 50% of the LA will exist as the ionized, conjugate acid after injection
-Non-ionized passes through axolemma, but the ionized binds to alpha-subunit on the interior of VG Na channel
What are the 3 building blocks of LA?
Benzene ring = lipophilic
Intermediate chain = ester/amide, metabolism, allergy
Tertiary amine = hydrophilic, accepts proton, m makes a molecule a weak base
Incidence of allergies w/LA
Esters - d/t para-aminobenzoic acid which is an immunogenic molecule
Amides - rare, d/t methylparaben preservative
What determines LA onset? Which drug disobeys this rule
pKa (potency, dose)
Chlorprocaine b/c its 3% so lots of molecules
What determines local anesthetic potency?
Lipophilicity- think, more drug able to traverse the neuronal membrane
Intrinsic vasodilating effect
What factors determine LA DOA
Protein binding
The intrinsic vasodilating effect, lipid solubility (more lipophilic = long DOA)
Discuss the intrinsic vasodilating effects of LA. Which LA has the opposite effect?
At low doses, they all vasoconstrict. At high doses (clinical doses) they all vasodilate except cocaine.
Amide Local Anesthetic pKa
Bupivacaine 8.1 (96% protein)
Levobupivacaine 8.1
Ropivacaine 8.1 (94% protein)
Lidocaine 7.9 (65%)
Prilocaine 7.9 (55%)
Mepivacaine 7.6 (78%)
Ester LA pKa
Procaine 8.9 (6% protein)
Chloroprocaine 8.7 (0% protein)
Tetracaine 8.5 (76% protein)
List 5 factors that govern the uptake and plasma concentration of LA
- tissue blood flow
- properties of LA
- metabolism
- additives
- site of injection
Rank injection sites w/corresponding LA concentrations
IV
Tracheal
interpleural
intercostal
caudal
epidural
brachial plexus
femoral
sciatic
subcutaneous
Max dosing for amide LA
Levobupi (2/150 mg)
Bupi (2.5 vs 3/175 vs 200 mg)
Ropi (3/200 mg)
Lido (4.5 vs 7 / 300 vs 500 mg)
Mepivacaine (7/400 mg)
Prilocaine (8/ 500 - 600 mg)
Max dose for ester LA
Procaine (7 and 350 - 600)
Chloroprocaine (11 vs 14 mg/kg and 800 vs 1000 mg)
What is the most common sign of LA toxicity?
Seizure
Bupi - cardiac arrest
Lidocaine toxicity according to plasma concentration
1 - 5 = analgesia
5 - 10 = tinnitus, sk. muscle twitching, numb lips, restlessness, vertigo, blurry vision, hypotension, myocardial depression
10 - 15 = seizures, LOC
15 - 25 = coma, respiratory arrest
> 25 = CV collapse
What increases risk of CNS toxicity?
Hypercarbia/acidosis, Hyperkalemia
Why is the risk of cardiac morbidity higher with bupivacaine than with lidocaine
- affinity for VG sodium channels in the inactive and active states
- rate of dissociation from the receptor during diastole
bupi has a slower rate of dissociation from this receptor during diastole
rank the difficulty of cardiac resuscitation w/LA
bupi > levobupi > ropi > lidocaine
Discuss ACLS modifications w/LAST
- no epi (keep it less < 1 mcg/kg)
- no vaso, lido, procainamide
- use amio
Discuss LAST treatment
100 mL bolus over 2 - 3 minutes
< 70 kg - 1.5 mL/kg over 2 - 3 minutes
250 mL over 15 minutes
< 70 kg - 0.25 mL/kg/min
max dosing = 12 mg/kg
How much tumescent lidocaine can you use?
50 - 55 mg/kg
Potential complications of tumescent anesthesia?
pulmonary edema, pulmonary embolus
GA recommended if > 2 - 3 L of the tumescent solution is used
Name two LA that produce leftward shift of oxyhgb curve?
Prilocaine + benzocaine b/c they can cause methemoglobinemia
Oxygen binding site on the heme portion of the hemoglobin molecule contains ferrous iron
oxidation of iron –> ferric (fe 3+)
methgb impairs oxygen binding and unbinding from hgb molecule
What drugs are capable of causing methemoglobinemia
nitroglycerin
nitroprusside
sulfonamides
phenytoin
benzocaine
cetacine
prilocaine
emla
s/s methemoglobinemia
tachycardia
tachypnea
chocolate colored blood
cyanosis
oxygen @ 85%
LOC, coma, death
treatment for methemoglobinemia
methylene blue 1-2 mg/kg over 5 minutes
max = 7 - 8 mg/kg
MOA: methgb reductase metabolizes methylene blue to form leucomethylene blue which functions as an electron donor and reduces ferric back to ferrous
Two patient populations at risk for methgb
neonates (deficient in methgb reductase, thus sus to oxidation)
g6pd (no methgb reductase, exchange tx)
EMLA cream is made of
2.5% prilocaine
2.5% lidocaine
prilocaine metabolizes to o-toluidine, which oxidizes hgb to methgb
Max dosing EMLA cream
0 - 3 mo, 1 g or 10 cm2
3 - 12 mo, 2 g or 20 cm2
1 - 6 yrs, 10 g or 100 cm2
7 - 12 years, 20 g or 200 cm2
Sodium bicarb + LA
shortens LA onset
reduces pain during injection
1 mL of 8.4% sodium bicarb with 10 mL LA
Drugs added to LA for supplemental analgesia?
Opioids (Mu)
Clonidine (Alpha2)
Epi (alpha2)
hyaluronidase
hyaluronic acid is present in the interstitial matrix and basement membrane. it hinders the spread of substances through tissue
-hyaluronidase hydrolyzes hyaluronic acid - facilitating the diffusion of LA thru tissues
ophthalmic blocks = speeds onset enhances quality, mitigates the rise in IOP
Discuss pain transduction
injured tissues release various chemicals that activate peripheral nerves and/or cause immune cells to release proinflammatory compounds. the peripheral nerves transduce this chemical soup into an AP
inflammation’s role in pain transduction
-reduced threshold to pain stimulus (allodynia)
-increased response to pain stimulus (hyperalgesia)
Pain transmission
Three-neuron afferent pain pathway along the spinothalamic tract
-first-order neuron: periphery –> dorsal horn
-second order: dorsal horn –> thalamus
-third order: thalamus –> cerebral cortex
Pain modulation most important site
Most important site: substantia gelatinosa in dorsal horn (Rexed Lamina II + III)
Pain modulation descending inhibitory pathway
Periaqueductal gray and rostroventral medulla –> substantia gelatinosa
Inhibition of pain occurs via
spinal neurons release GABA + glycine
descending pathway release Ne, 5-Ht, endorphins
Pain is augmented by
central sensitization + wind-up
Discuss the process of pain perception
Limbic system and cerebral cortex process pain signals
What is the MOA of opioids?
Each opioid receptor links to a G-Protein, and agonism of the receptor instructs the G-Protein to turn off adenylyl cyclase
Reduction of cAMP –> alters ionic current
How does decreased cAMP alter ionic current
- VG Ca Ch inhibited –> decreased NT release
- Augment K+ Ch inward rectifier –> hyperpolarizes
What are the precursors of the endogenous opioids?
Pre-proopiomelanocortin –> Endorphins (MU)
Pre-enkephalin –> Enkephalin (DELTA)
Pre-dynorphin –> Dynorphins (KAPPA)
mu 1
analgesia (spinal + supraspinal)
bradycardia
euphoria, miosis, urinary retention, low abuse
mu 2
-analgesia (spinal only)
-bradycardia
-rr depression
-constipation
-dependence
mu 3
immune suppression
kappa stimulation
antishivering
diuresis
dysphoria
delirium
hallucinate
opioids affect on cv
bradycardia (Unless meperidine – tachycardia)
bp remain stable if patient is cv healthy
hypotension w/morphine + meperidine (histamine release)
opioids affect on ventilation
via mu + delta
CO2 response curve rightward
Drop in RR and increase in Vt
how do opioids affect the pupil?
edinger westphal nucleus stimulation –> PNS stim. ciliary ganglion and oculomotor nerve (CN 3) –> miosis
how do opioids produce n&v?
CTZ (area postrema of medulla)
vestibular apparatus
how do opioids contribute to urinary retention?
mu + delta
detrusor relaxation + urinary sphincter contraction
Immunologic effects of opioids
histamine (meperidine, morphine, codeine)
inhibits cellular + humoral immune function
suppress NK cell function
How do opioids affect thermoregulation?
Reset the hypothalamic temperature set point to decrease core body temperature
Rank IV opioids in terms of potency
-sufentanil > remifental = fentanyl > alfentanil > dilaudid > morphine > meperidine
compare the equianalgesic opioid dose r/t 10 mg of morphine
100 mg meperidine
1.4 mg dilaudid
1000 mcg alfentanil
100 mcg fentanyl/remifentanil
10 mcg sufentanil
Discuss the co-admin of meperidine and MAOI
can cause serotonin syndrome
meperidine is a weak SRI
MAO deaminates serotonin in the synaptic cleft, co-admin of these drugs can cause serotonin syndrome
s/s = hyperthermia, LOC, hyperreflexia, sz, death
MAOi’s = phenelzine, isocarboxazid, tranylcypromine
Alfentanil pka
6.5
90% unionized
Low vd, high degree of plasma protein binding (alpha - 1)
Largest VD of opioids vs smallest
Fentanyl = 4 L/kg
Remi = 0.39 L/kg
PK/PD Remi
Ester linkage hydrolysis by erythrocyte and tissue esterases
-highly lipophilic
- 0.1 - 1 mcg/kg/m
- obese pt use LBW
- avoid intrathecal b/c glycine causes sk. muscle weakness
How does methadone reduce pain?
-mu receptor agonist
-NMDA receptor antagonist
-inhibits monoamine reuptake
Etiology of opioid-induced sk. muscle rigidity?
mu stim in the CNS
greatest resistance at the larynx
Buprenorphine
mu agonist partial
greater than morphine analgesia
cannot be reversed by naloxone
DOA 8 hour
can give transdermal
Nalbuphine
Kappa agonist, mu antagonist
Similar to morphine
Reversed by naloxone
Useful for cardiac pt b/c no changes HD
Butorphanol
-Kappa agonist, mu antagonist (weak)
-greater than morphine analgesia
-reversed by naloxone
-postop shivering treatment
-intranasal route
Which opioid antagonist is least likely to reverse respiratory depression?
Methylnaltrexone b/c quaternary amine group
Good for opioid-induced constipation
Which opioid antagonist has the longest DOA?
Naltrexone (no 1st pass)
DOA = 24 hours
ER formula
