Local Anesthetics Flashcards
Local anesthetics produce ___ (reversible/irreversible) conduction blockade of impulses along the ___ and ___ nerve pathways
Local anesthetics produce reversible conduction blockade of impulses along the central and peripheral nerve pathways
What was the first local anesthetic?
Cocaine–1884
What was the first synthetic ester local?
Procaine–1905
What was the first amide local?
Lidocaine–1943
Chemical structure of local anesthetics–___philic and ___philic portion separated by ___
Chemical structure of local anesthetics–lipophilic and hydrophilic portion separated by hydrocarbon
Lipophilic portion of LA is the ___ ring
Lipophilic portion of LA is the benzene ring–necessary for activity!
What part of LA structure is necessary for its activity?
Lipophilic benzene ring
___ (ester/amide) intermediate chain = -CO
Ester local intermediate chain = -CO
___ (ester/amide) intermediate chain = -NHC-
Amide local intermediate chain = -NHC-
Core structure for local anesthetics = a ___ ring and a ___ amine separated by an intermediate ___ group
Core structure for local anesthetics = a benzene ring and a quaternary amine separated by an intermediate carbon group
The bond between the benzene ring and the carbon group determines whether the drug is an amide or an ester–T/F?
True
There are ___ (few/many) lipid layers for local anesthetics to cross
There are many lipid layers for local anesthetics to cross
What are (2) types of enantiomers?
S and R enantiomers
Racemic mixtures contain ___ (one/both) type(s) of enantiomers
Racemic mixtures contain BOTH (S and R) types of enantiomers
Pure isomers contain ___ (one/both) type(s) of enantiomers
Pure isomers contain ONE type of enantiomer
What are the only (2) pure isomer local anesthetics? What enantiomer type are they?
-Ropivacaine
-Levobupivicaine
Both are pure isomers, S enantiomers
Each enantiomer binds to different receptors or enzymes, which changes pharmacokinetics, pharmacodynamics, and toxicity–T/F?
True
Which enantiomer is more beneficial? (R or S?) Why?
S enantiomers are more beneficial because they are less neuro- and cardiotoxic
How do local anesthetics work?–inhibit ___ ions passage through ion-selective ___ channels; this ___ (slows/speeds up) the rate of depolarization; threshold potential ___ (is/is not) reached; action potential ___ (is/is not) propagated
LAs inhibit sodium ions passage through ion-selective sodium channels; this slows the rate of depolarization; threshold potential is NOT reached; action potential is NOT propagated
LAs alter resting membrane potential and threshold potential–T/F?
FALSE–LAs do NOT alter resting membrane potential or threshold potential
What are (2) sodium channel subunits? Which subunit allows ion conduction and binds local?
- Alpha
- Beta
Alpha subunit allows ion conduction and binds local
Local anesthetic binds to receptors in ___ (activated/inactivated/both) state(s)
Local anesthetic binds to receptors in BOTH activated/inactivated states
When local anesthetics bind to receptors, the cells become ___ (permeable/impermeable) to sodium
When local anesthetics bind to receptors, the cells become IMPERMEABLE to sodium
Threshold potential not reached, action potential not propagated as a result
LA binding on ___ (internal/external) part of channel is thought to be most important
LA binding on INTERNAL part of channel is thought to be most important
LA binding to receptors is ___ (strong/weak)
LA binding to receptors is WEAK
LAs have access to receptors only when in ___ (activated/inactivated) state
LAs have access to receptors only when in activated-open state
More frequent firing = ___ (more/less) opportunity for access
More frequent firing = more opportunity for access
Nerves with more activity = ___ (slower/faster) blockade
Nerves with more activity = faster blockade
Other sites of LA action–voltage-dependent ___ ion channels (much ___ [lower/higher] affinity); ___ ion currents (L-type); ___ protein-coupled receptors
Other sites of LA action–voltage-dependent potassium ion channels (much LOWER affinity); calcium ion currents (L-type); G protein-coupled receptors
Cm = minimum concentration required to produce ___ blockade; analogous to ___
Cm = minimum concentration required to produce conduction blockade; analogous to MAC
Larger nerve diameter ___ (increases/decreases) Cm
Larger nerve diameter INCREASES Cm
Higher frequency and higher pH ___ (increase/decrease) Cm
Higher frequency and higher pH DECREASE Cm
Cm for motor blockade is about ___ Cm for sensory blockade
Cm for motor blockade is about twice Cm for sensory blockade
Possible explanation for sensory block without motor block
Epidural vs. spinal–Cm is ___ (increased/decreased/unchanged); allows for direct access to nerves, so ___ (more/less) is needed
Epidural vs. spinal–Cm is unchanged; allows for direct access to nerves, so LESS is needed
Nodes of Ranvier–must block at least ___, preferably ___
Nodes of Ranvier–must block at least 2, preferably 3
Order of blockade/differential blockade (ATP-TP-MVP)
- Autonomic
- Temperature
- Pain
- Touch
- Pressure
- Motor
- Vibration
- Proprioception
Order of blockade/differential blockade (according to Nagelhout)
- Autonomic
- Superficial pain, touch, temperature
- Motor function
- Proprioception
___ blockade is blockade of some fibers but not others
Differential blockade is blockade of some fibers but not others
i.e.: may block B fibers, C fibers, and small/medium A fibers but may NOT block large A fibers
Differential blockade results in ___thectomy; loss of sensation for ___ and ___; may still have ___ and ___ function
Differential blockade results in sympathectomy; loss of sensation for pain and temperature; may still have proprioception and motor function
Pharmacokinetics of LAs–___ (strong/weak) ___ (acids/bases); pK values ___-___; just above physiologic pH, thus get >50% ___ (ionized/unionized)
Pharmacokinetics of LAs–weak bases; pK values 7.6-8.9; just above physiologic pH, thus get >50% ionized
What form crosses the lipid bilayer–ionized or unionized?
UNIONIZED
Locals with pKs nearest physiologic pH have a ___ (slower/faster) onset
Locals with pKs nearest physiologic pH have a FASTER onset
What is one local anesthetic that is a weak acid?
Benzocaine
pKa of benzocaine = ___
pKa of benzocaine = 3.5
Benzocaine ___ (does/does not) ionize based on pH
Benzocaine does NOT ionize based on pH
Mechanism of blockade with benzocaine is unknown–T/F?
True
pKa of lidocaine = ___
pKa of lidocaine = 7.9
pKa = ___% ionized, ___% unionized
pKa = 50% ionized, 50% unionized
If pH of environment is 7.9 and pKa of lidocaine is 7.9, what % is ionized, what % is unionized?
If pH of environment is 7.9 and pKa of lidocaine is 7.9, 50% is ionized, 50% is unionized
If pH of environment is 7.2 and pKa of lidocaine is 7.9, ___ (more/less) will be ionized, ___ (more/less) will be unionized
If pH of environment is 7.2 and pKa of lidocaine is 7.9, MORE will be ionized and LESS will be unionized
Point is that if you inject a weak base into a more acidic pH, you will have more ionized (non-working) and less unionized (working)
Adding bicarb [alkalization] to LA allows for ___ (faster/slower) onset by 3-5 minutes; higher pH thought to ___ (increase/decrease) sting of local infiltration
Adding bicarb [alkalization] to LA allows for faster onset by 3-5 minutes; higher pH thought to decrease sting of local infiltration
Adding bicarb to LA allows for more ___ (ionized/unionized) to cross
Adding bicarb to LA allows for more unionized to cross
So you have more working local
Absorption of LA into systemic circulation is influenced by ___ of injection, ___age, use of ___, and characteristics of the drug
Absorption of LA into systemic circulation is influenced by site of injection, dosage, use of epi, and characteristics of the drug
Distribution of LA–1st = large uptake to ___; 2nd = distribution to highly perfused tissue–i.e.: ___, ___, ___; 3rd = distribution to low perfused tissue–i.e.: ___ and ___
Distribution of LA–1st = large uptake to lungs; 2nd = distribution to highly perfused tissue–i.e.: heart, brain, kidneys; 3rd = distribution to low perfused tissue–i.e.: muscle and fat
___ (amides/esters) are more widely distributed
Amides are more widely distributed
Placental transfer is influenced by ___ binding
Placental transfer is influenced by protein binding
What (2) local anesthetics are highly protein bound?
- Bupivacaine
- Ropivacaine
Proteins are too large to cross placenta, so low risk of fetal transfer with bupi/ropi
Which local anesthetic is not as protein bound?
-Lidocaine
Higher risk of placental transfer with lido
What can occur in the fetus once local anesthetic crosses the placenta?
Ion trapping
Why do we worry about which vasopressor can cause fetal acidosis?–once unionized local crosses placenta and hits low fetal pH, more drug becomes ___ (ionized/unionized) and ___ (can/cannot) cross back; build up of trapped local in fetal circulation leads to ___ in fetus
Once ionized local crosses placenta and hits low fetal pH, more drug becomes ionized and cannot cross back; build up of trapped local in fetal circulation leads to toxicity in fetus
Potency is related to ___ solubility
Potency is related to lipid solubility
More lipid soluble = ___ (easier/harder) to cross lipid bilayer
More lipid soluble = easier to cross lipid bilayer
What is most important factor for determining onset of LA?
Most important for onset of LA = state of ionization
Lipid solubility also relates to onset of LA
Duration of action for LA is related to ___ binding and ___ solubility
Duration of action for LA is related to protein binding and lipid solubility
Higher affinity to proteins and lipids = ___ (stronger/weaker) attachment
Higher affinity to proteins and lipids = stronger attachment…drug remains close to the Na+ channels to act longer
Metabolism/clearance of LAs–amides = mainly ___ metabolism; minimal ___ excretion of unchanged drug
Amides = mainly hepatic metabolism; minimal renal excretion of unchanged drug
Amide with fastest metabolism = ___
Fastest = prilocaine
Amides with intermediate metabolism = ___ and ___
Intermediate = lidocaine and mepivacaine
Amides with slow metabolism = ___, ___, and ___
Slow = etidocaine, bupivacaine, and ropivacaine
Ester anesthetics undergo rapid ___ by ___
Ester anesthetics undergo rapid hydrolysis by plasma cholinesterases
Ester with rapid metabolism/clearance = ___
Ester with rapid metabolism/clearance = chloroprocaine
Ester with intermediate metabolism/clearance = ___
Ester with intermediate metabolism/clearance = procaine
Ester with slow metabolism/clearance = ___
Ester with slow metabolism/clearance = tetracaine
Which ester anesthetic is an exception to rapid hydrolysis and instead undergoes significant metabolism in the liver?
Cocaine
Metabolites of ester anesthetics are mostly ___ (active/inactive)
Metabolites of ester anesthetics are mostly inactive
What metabolite of ester anesthetics has been linked to allergic reactions?
Paraaminobenzoic acid (PABA) has been linked to allergic reactions
What common local injection site contains little to no cholinesterase enzyme? How does this effect ester anesthetics?
CSF
Must wait until the drug goes into systemic circulation for hydrolysis
Plasma cholinesterase is inhibited in what (5) conditions?–___, ___ disease, increased ___, ___, ___ patients
- Deficiency
- Liver disease
- Increased BUN
- Parturients
- Chemotherapy patients
What are (3) vasoconstrictors that can be added to LAs? Which is superior?
- Epi–superior
- Phenylephrine
- Norepi
Which vasoconstrictor, when added to LA, can be used as a marker for intravascular injection?
Epi
Adding epi to LA ___ (increases/decreases) systemic absorption; maintains drug concentration around ___; can prolong lidocaine by ___; no effect to ___; helps to decrease risk of ___
Adding epi to LA decreases systemic absorption; maintains drug concentration around nerves; can prolong lidocaine by 1/3; no effect to onset; helps to decrease risk of toxicity
Which 2 local anesthetics have no vasodilator activity?
- Cocaine
- Ropivacaine
What happens when ropivacaine is given parenterally?–vaso___ activity
Vasoconstrictive activity
When adding opioids to spinal or epidural, there is a risk for respiratory ___ and oxygen ___
When adding opioids to spinal or epidural, there is a risk for respiratory depression and oxygen desaturation
What is a preservative free alpha-2 agonist that can be added to enhance neuraxial anesthesia and can be used in combo with opioids?
Clonidine
Clonidine epidural dose–___ mcg or ___ mcg/kg
Clonidine epidural dose–150 mcg or 2 mcg/kg
Clonidine added to epidural increases duration of action from ___ to ___ hours
Clonidine added to epidural increases duration of action from 1.8 to 5.3 hours
Clonidine spinal dose–___-___ mcg
Clonidine spinal dose–15-45 mcg
Clonidine 45 mcg increases spinal duration from ___ to ___ minutes
Clonidine 45 mcg increases spinal duration from 170 to 215 minutes
Mixing locals allows for ___ (slower/faster) onset and ___ (shorter/longer) duration
Mixing locals allows for faster onset and longer duration
Examples:
- Lido/bupi
- Chloroprocaine/bupi
Effects of mixing locals are ___, not ___
Effects of mixing locals are additive, NOT synergistic
Allergic reactions from LAs are rare–T/F?
True–<1% allergic reaction
Which are more likely to case allergic reaction–amides or esters?
Esters d/t PABA metabolite
What preservative in some LAs may cause allergic reactions?
Methylparaben
Is cross sensitivity likely?
No
i.e.: if someone had an allergic reaction to an ester LA, it is safe to use an amide LA instead
Systemic toxicity is most common from ___ injection, less common from ___
Systemic toxicity is most common from IV injection, less common from absorption
Magnitude of systemic toxicity is dependent on ___, ___ of site, presence of ___, properties of the drug
Magnitude of systemic toxicity is dependent on dose, vascularity of site, presence of epi, properties of the drug
Systemic toxicity depends on volume or concentration used–T/F?
FALSE–depends on total amount of drug, NOT volume or concentration used
i.e.: 40 ml of 1% or 80 ml of 0.5% – both = 400 mg, so extent of systemic toxicity is equivalent
___ progression describes the dose-dependent CNS effects from systemic lidocaine absorption
Hadzic’s progression describes the dose-dependent CNS effects from systemic lidocaine absorption
Plasma lido concentration 1-5 mcg/ml = ___
1-5 mcg/ml = analgesia
Plasma lido concentration 5-10 mcg/ml = circumoral ___; ___itus; skeletal muscle ___; systemic ___tension; myocardial ___
5-10 mcg/ml = circumoral numbness; tinnitus; skeletal muscle twitching; systemic hypotension; myocardial depression
Plasma lido concentration 10-15 mcg/ml = ___ures, un___
10-15 mcg/ml = seizures, unconsciousness
Plasma lido concentration 15-25 mcg/ml = __nea, ___
15-25 mcg/ml = apnea, coma
Plasma lido concentration > 25 mcg/ml = CV ___
> 25 mcg/ml = CV depression
Treatment of seizures from lidocaine toxicity = ___ with oxygen, administration of ___
Treatment of seizures from lidocaine toxicity = ventilation with oxygen, administration of benzos
Systemic levels of LA are related to blood flow to tissue–T/F?
True
Fastest to slowest absorption of LA–In Time I Can Please Everyone But Suzi and Sally
- IV
- Tracheal
- Intercostal
- Caudal
- Paracervical
- Epidural
- Brachial plexus
- Subarachnoid
- Subcutaneous
Transient Neurologic Symptoms (TNS) = moderate to severe pain in lower __, ___, posterior ___; unknown etiology; highest risk after intrathecal ___
TNS = moderate to severe pain in lower back, buttocks, posterior thigh; unknown etiology; highest risk after intrathecal lidocaine
Cauda Equina Syndrome = diffuse injury across ___ plexus; various degrees of ___ anesthesia; ___ and ___ sphincter dysfunction; ___plegia; related to ___
Cauda Equina Syndrome = diffuse injury across lumbosacral plexus; various degrees of sensory anesthesia; bowel and bladder sphincter dysfunction; paraplegia; related to lidocaine
Anterior Spinal Artery Syndrome = lower extremity ___ and variable ___ deficit
Anterior Spinal Artery Syndrome = lower extremity paresis and variable sensory deficit
Cardiotoxicity is ___ (more/less) common than CNS toxicity from LAs
Cardiotoxicity is LESS common than CNS toxicity from LAs
Need ~3 times concentration for cardio toxicity to occur
Cardiotoxicity = profound ___tension d/t ___ (contraction/relaxation) of arteriolar vascular smooth muscle; direct myocardial ___
Cardioxicity = profound hypotension d/t relaxation of arteriolar vascular smooth muscle; direct myocardial depression
With what LA might you see cardiac symptoms before CNS?
Bupivacaine
Treatment of LA toxicity–initial focus = ___ management, 100% ___; ___ suppression–give ___, AVOID ___ if CV instability
Treatment of LA toxicity–initial focus = airway management, 100% O2; seizure suppression–give benzos, avoid prop if CV instability
Treatment of LA toxicity–management of arrhythmias–avoid ___, ___ blockers, ___ blockers, and ___ anesthetic; reduce epi to < ___ mcg/kg
Treatment of cardiotoxicity–management of arrhythmias–avoid vasopressin, calcium channel blockers, beta blockers, and local anesthetic; reduce epi to < 1 mcg/kg
Treatment of LA toxicity–lipid emulsion (20%) therapy–___ ml/kg (lean body weight) IV over ___ minute; maintenance dose ___ ml/kg/min; repeat bolus ___ or ___ for persistent CV collapse; double infusion rate to ___ ml/kg/min if BP remains low; continue infusion for at least ___ mins after circulatory stability; upper limit approx ___ ml/kg lipid emulsion over first 30 minutes
Treatment of LA toxicity–lipid emulsion (20%) therapy–1.5 ml/kg (LBW) IV over 1 minute; maintenance dose 0.25 ml/kg/min; repeat bolus once or twice for persistent CV collapse; double infusion rate to 0.5 ml/kg/min if BP remains low; continue infusion for at least 10 mins after circulatory stability; upper limit approx 10 ml/kg lipid emulsion over first 30 minutes
What locals can cause methemoglobinemia?–___ > 8mg/kg, ___, ___, ___
Prilocaine > 8mg/kg, benzocaine, cetacaine, lidocaine
What other drugs (aside from local anesthetics) can cause methemoglobinemia?–___, ___, and ___
NTG, phenytoin, sulfonamides
What happens in methemoglobinemia?–hemoglobin is ___ (oxidized/reduced) to methemoglobin and cannot carry ___
Hemoglobin is oxidized to methemoglobin and cannot carry oxygen
Treatment of methemoglobinemia = ___
Methylene blue
Dose of methylene blue to treat methemoglobinemia ___-___ mg/kg IV over ___ minutes
1-2 mg/kg IV over 5 minutes
Methylene blue–do not exceed ___ mg/kg
Do not exceed 7.8 mg/kg
