MMCh 16 Flashcards
Na ions pass thru which subunit?
Alpha
Amide LA metabolism
(N- dealkylation and hydroxylation) microsomal P-450
liver
Areas where LA [ ] increases fastest
fastest → slowest:
intravenous (or intraarterial)
tracheal
intercostal
paracervical
epidural
brachial plexus
sciatic
subcutaneous
T/F
Rising local anesthetic concentrations in the CNS can consistently warn us of LA toxicity.
False
applies to awake patients
Major cardiovascular toxicity usually requires about ___ times the
LA [ ] required to produce seizures.
3
Accidental IV injxn of bupivicaine during regional
risk severe CV toxicity
left ventricular depression
AV block
arrhythmias: VT & VF
mediate hypersensitivity reactions
IgG or IgE
Why is ICF normally negative?
K+ is more “leaky” than Na+
relative excess of anions
accumulate intracellularly
Membrane-associated, voltage-gated Na channels in ____ can produce and transmit membrane depolarizations
peripheral nerve axons
Baseline concentration gradients are maintained by
the sodium–potassium pump
LA binds to alpha subunit
What happens next?
they prevent channel activation and Na influx
T/F
LAs elicit their actions by altering the membrane potential.
False
bind to channel
channel cant conduct Na+
as more LA binds,
threshold increases
How do LAs affect impulse transmission?
increases:
-threshold (excitation & conduction)
decreases:
- AP rate of rise & magnitude
-impulse conduction velocity
if levels high enough:
-cannot generate AP at all
-no impulse propagation
Local anesthetics have a greater affinity for the Na channel in which state(s)
open or inactivated
more than resting
Depolarizations lead to …. channels
open and inactivated
LA has higher affinity for these states
so
depolarization favors LA binding
local anesthetic inhibition of Na channels is dependent on (2)
voltage (membrane potential)
frequency
Other channels LAs can inhibit
Ca
K
transient receptor potential vanilloid-1 (TRPV1)
many others
Other drugs that also inhibit Na channels
-TCAs (amitriptyline)
-meperidine
-volatiles
-Ca Ch blockers
-α2-receptor agonists
-nerve toxins
Which are more susceptible?
Ad
Aa
Aα fibers: larger, faster-cndxn = less sensitive
Aδ fibers: smaller, slower-conducting = more sensitive
Which is more susceptible?
small unmyelinated C fibers
larger myelinated fibers
larger myelinated fibers
Myelinated = more sensitive
Large= less sensitive
inhibition generally follows what sequence?
first to last:
autonomic
sensory
motor
NOTE: at steady state, if sensory anesthesia is present, usually all modalities are inhibited
basis of the classification of local anesthetics as either esters or amides
intermediate chain
This LA is an amide, but it contains a thiophene ring rather than a benzene ring
Articaine
Local anesthetics are ___ that at physiological pH usually carry a positive charge at the ___
weak bases
tertiary amine group
Physicochemical properties of local anesthetics depend on (3)
substitutions in the aromatic ring
type of linkage in the intermediate chain,
alkyl groups attached to the amine nitrogen
Potency is increased by
adding large alkyl groups to a parent molecule
(acidic/basic) environment antagonizes clinical nerve block
acidic
Which electrolyte imbalances antagonize blockade?
↓K
↑Ca
agent of fastest onset
What is peculiar about this?
2-chloroprocaine
greatest pKa of all agents
(showing that pka is not the sole determinant of onset)
LA preparation
water-soluble HCl salts (pH 6–7)
w/ epi:
more acidic (pH 4–5)
(epi unstable in basic enviornment)
decreases pain during subcutaneous infiltration
alkalinization
Ie: addition of sodium bicarbonate to LA
T/F
Instead of commercially prepared LA w/ epi, the epinephrine can be added by the clinician immediately prior to use for faster onset.
True
commercially prepared = less free base & slower onset
↑ lipid solubility = __ doA
why?
longer
more slowly diffuse from a lipid-rich environment to the aqueous bloodstream
Sustained-release
systems using liposomes or microspheres can significantly prolong
Which proteins do LAs bind to?
mainly α1-acid glycoprotein
also albumin
Can we block sensory while keeping motor intact?
Somewhat
bupivacaine & ropivacaine
-somewhat selective
-Sx anesthesia [ ] = almost always some motor block
regional anesthesia
LA typically applied close to
their intended site of action
*pharmacokinetic profiles in blood
determine:
-elimination & toxicity
-not DoE
EMLA (Eutectic Mixture of Local Anesthetics)
formulated to overcome the obstacles presented by intact skin
mixture of lidocaine & prilocaine bases in an emulsion
Topical LA
depth
DoA
<0.5 cm
< 2H
EMLA (Eutectic Mixture of Local Anesthetics)
C/A
do not apply to:
mucous membranes
broken skin
<1 month old
C/A to lidocaine or prilocaine
Dermal analgesia for inserting an IV catheter requires…
1 h under an occlusive dressing
Systemic absorption of injected local anesthetics depends on ___, which is determined by…
blood flow
injxn site
additives
agent (↑L. sol, tissue bound = slower; unique vasodilator properties)
epinephrine causes site vasoconstriction leading to…
↓ peak blood [ ]
↓ toxic side effects
↑ quality of analgesia
↑duration
facilitated neuronal uptake
T/F
Vasoconstrictors have more pronounced effects on longer-acting agents
False
shorter
T/F
addition of epinephrine to bupivicaine usually extends the duration of anesthesia by at least 50%
False
lidocaine
adding vasopressors strongly affects short acting LAs
augment analgesia through the activation of α2-adrenergic receptors
Epinephrine and clonidine
T/F
steroids do not affect LA DoA
false
dexamethasone
or other steroids
can prolong blocks by up to 50%.
Mixtures of local anesthetics produce nerve blocks with…
onset & duration that are intermediate of the 2
The highly perfused organs
brain, lung, liver, kidney, and heart
patients with ___ are more susceptible to toxic side effects of lidocaine injected as an antiarrhythmic agent.
right-to-left cardiac shunts
(first pass metab of LAs = lots of lung)
T/F
↑ lipid solubility = ↑ plasma protein binding
True
greatest reservoir for the distribution of LA in the bloodstream because of its large mass
muscle
T/F
LAs are excreted renaly, with much of the metabolism already completed.
True
very little nonmetabolized renal excretion
Ester metab
mostly pseudoAChase
rapid Ester hydrolysis
Procaine & benzocaine:
p-aminobenzoic acid (PABA)
T/F
AChase deficiency pts should not receive ester LAs as they lack the enzymes necessary for ester hydrolysis.
False
alternative metabolic pathways via liver
Amide metab
liver
N-dealkylation & hydroxylation
P-450 enzymes
rate is agent-dependent
slower than ester metab
Fastest to slowest amide metab
prilocaine > lidocaine > mepivacaine > ropivacaine > bupivacaine
Decreases hepatic function or liver blood flow
fxn: cirrhosis
blood flow: CHF, β-blockers, H2-
receptor blockers
reduces rate of amide metab; risk toxic [ ]
o-toluidine
prilocaine metabolite
DD methemoglobinemia
>10 mg/kg (possibly lower)
LAs a/w methemoglobinemia
Prilocaine
Benzocaine (topical sprays)
note: only prilocaine has o-toluidine m’lite
methemoglobinemia Tx
IV methylene blue (1–2 mg/kg of a 1% solution over 5 min)
reduces methemoglobin (Fe3+) → Hgb (Fe2+)
“Maximum safe doses”
varies per: patient, specific nerve block, rate of injection, ETC
Mixtures of local anesthetics should be considered to have ___ toxic effects
additive
dont inject 50% of the toxic dose of LA A and 50% of LA B and expect not to have toxicity
Local anesthetic systemic
toxicity (LAST)
S/S
circumoral numbness
tongue paresthesia
dizziness
tinnitus
blurred vision
impending doom
restlessness
agitation
nervousness
garrulous
Muscle twitching → tonic–clonic seizures.
can progress to CNS depression:
coma & respiratory arrest
(PNS/CNS) is vulnerable to LAST
CNS
produce seizures at lower blood concentrations than less potent agents
Potent, highly lipid-soluble
LAST results in (inhibitory/excitatory) effects
excitatory
selective blockade of inhibitory pathways
LA-induced seizures threshold
what increases/decreases it?
increased threshold:
Benzodiazepines, propofol, and hyperventilation
decreased:
acidosis (resp & metab)
Quickly and reliably stops seizure activity
Propofol (0.5–2 mg/kg)
comparable doses of BZDs or BARBs
IV lipids
can reduce the MAC of volatile anesthetics by up to 40%
lidocaine & procaine
Lidocaine gtt & IVP benefits
inhibit ventricular arrhythmias
reduce MAC up to 40%
inhibit inflmtn
reduce pain & postop opioids
IVP:
(1.5 mg/kg)
↓ CBF & rise in ICP d/t ETT
Accidental spinal w/ large volumes of ___ produced total spinal anesthesia, marked hypotension, and prolonged neurological deficits
chloroprocaine
possibly d/t preservative (sodium bisulfite); new formulation w/o seems safe
Caution with Lidocaine in spinal anesthesia
5% lidocaine a/w neurotoxicity (cauda equina syndrome) after use in cont spinal anesthesia
Lidocaine resp fx
↓ response to low PaO2
risk of apnea:
-phrenic & intercostal nerve paralysis (“high” spinals)
-↓ medullary respiratory center
LA fx on bronchi
relax bronchial smooth muscle
IV lidocaine (1.5 mg/kg)
may block the possible reflex bronchoconstriction a/w ETT
All local anesthetics depress which cardiac fxn?
🩷 automaticity (spontaneous phase IV depolarization)
direct actions on 🩷 muscle membrane (ie, cardiac Na channel inhibition)
inhibit the ANS
At low concentrations, all local anesthetics ___ nitric oxide, causing ____.
inhibit
vasoconstriction
In GA, what warns us of LAST?
Cardiac arrhythmias or circulatory collapse
LAST risk factors
Pregnancy, hypoxemia, and respiratory acidosis
young children
bupivacaine is a/w (less/more) changes in conduction & greater risk of arrhythmias than comparable doses of lidocaine
more
have a chiral carbon & exist as one of two optical isomers (enantiomers)
Mepivacaine, ropivacaine, and bupivacaine
Resuscitation from ___-induced cardiac toxicity is often difficult and resistant to standard resuscitation drugs
bupivacaine
give lipid emulsions at 1.5 mL/kg
first-line treatment for cardiovascular LAST
nutritional lipid emulsions at 1.5 mL/kg
nearly risk free
Ropivacaine vs bupivacaine
similar onset & duration
ropivacaine = less motor block
(vs same volume & [ ] as bupivacaine)
Cocaine’s cardiovascular reactions
unlike any other LA
↓ norepi reuptake = potentiating adrenergic stimulation
hypertension & ventricular ectopy
Tx:
BZDs (↓ central stimulation)
arrhythmias: α-adrenergic antagonists & amiodarone
Esters more likely to cause allergy
procaine or benzocaine
PABA dreivatives!
Amide allergies
methylparaben
(commercial preparations)
structure vaguely similar to PABA
LA muscle fx
injxn into muscle = mild muscle toxicity
regenerate <4 weeks
steroids & epi will worsen
prolonged injxn = severe chondromalacia
LA hematologic fx
mildly reduced thrombosis and decreased platelet aggregation
