COCAINE: Max Dose
*4% Topical: 3 mg/kg (200mg total)
COCAINE: VD/PB%
VD: 2 L/kg
PB: >95%
COCAINE: pKa/ % ionized at pH 7.4
*pKa: 8.5
*% Ionized: 95
COCAINE: Class
*Local Anesthetic
*Aminoester
-ester of benzoic acid,
COCAINE: MOA
*Norepinephrine Reuptake Inhibitor
*Dopamine Reuptake Inhibitor
*Serotonin Reuptake Inhibitor
COCAINE: Metabolism
*Only LA that metabolized by both liver and pseudocholinesterase
*Hepatic P450, CYP3A4
*Plasma pseudocholinesterase
*1% excreted unchanged in the urine
*Renal metabolites are benzoylecgonine and ecgonine methyl ester
COCAINE: Considerations
*Only vasoconstrictor,
*High PB
*SE: HTN, Tachy, coronary vasospasm, V-fib, MI,
*Caution with TCAs, EPI, ketamine& Pancuronuim
COCAINE: Onset/Peak/DOA
*Onset: IV-Immediate Intranasal-
*Peak: IV- 5 mins Intranasal- 15 mins
*DOA: IV-30 min after peak Intranasal- 60 mins after peak
COCAINE: EHL
*30-90 mins
PROCAINE (Novocaine): Class
*Local Anesthetic
*Aminoester
PROCAINE (Novocaine): Max Dose
*14 mg/kg
PROCAINE (Novocaine): VD/PB%
VD: 0.95 L/kg
PB: 6%
PROCAINE (Novocaine): pKa/ % ionized at pH 7.4
*pKa: 8.9
*Ionized: 95%
PROCAINE (Novocaine): Onset/DOA
*SAB: 2-5 min/30-60 min
PROCAINE (Novocaine): EHL
*9 min
PROCAINE (Novocaine): Metabolism
*Plasma cholinesterases
*Metabolite is PABA
PROCAINE (Novocaine): Considerations
...
CHLOROPROCAINE (Nesacaine): Class
*Local Anesthetic
*Aminoester
CHLOROPROCAINE (Nesacaine): Max Dose
*MAX DOSE: 14mg/kg
*PNB: 10 mg/kg
*EPI: 10 mg/kg
CHLOROPROCAINE (Nesacaine): VD/PB%
VD: 0.5L/kg
PB%:
CHLOROPROCAINE (Nesacaine): pKa/ % ionized at pH 7.4
pKa: 9.1
Ionized: 95%
CHLOROPROCAINE (Nesacaine): Onset
*PNB: 5 min/30-60 min
*Epi: 5 min/30-60 min
CHLOROPROCAINE (Nesacaine): EHL
*7 min
CHLOROPROCAINE (Nesacaine): Metabolism
*Plasma cholinesterases
*Resulting pharmacologically inactive metabolites of chloroprocaine are 2-chloro-aminobenzoic acid and 2-diethylaminoethanol.
*Metabolite is PABA
CHLOROPROCAINE (Nesacaine): Considerations
*Fast onset
*Fast offset
*Lowest PB
*Neurotoxic with SAB
TETRACAINE (Pontocaine): Class
*Local Anesthetic
*Aminoester
TETRACAINE (Pontocaine): Dose
*MAX DOSE: 1mg/kg
*
TETRACAINE (Pontocaine): VD/PB%
VD: n/a
PB%: 94
TETRACAINE (Pontocaine): pKa/ % ionized at pH 7.4
*pKa: 8.5
*% Ionized: 95
TETRACAINE (Pontocaine): Spinal Dose
*C-Section: 8mg
*Abdominal Surgery:
<5'6": 12mg
5'6"-6': 15mg
>6": 18mg
TETRACAINE (Pontocaine): Onset/DOA
*PNB: 7-10 min/1-3 hrs
*Spinal: 7-10 min
TETRACAINE (Pontocaine): EHL
...
TETRACAINE (Pontocaine): Metabolism
*Plasma cholinesterases
*Metabolite is PABA
TETRACAINE (Pontocaine): Considerations
*Most potent
*Most Toxic ester LA
*No IV injection
*Max topical 100 mg
*Avoided for PNB
BENZOCAINE (Anbesol, Cepacol, Lanacane): Class
*Local Anesthetic
*Aminoester
LIDOCAINE (Xylocaine): Class
*Local Anesthetic
*Aminoamide
LIDOCAINE (Xylocaine): Dose
*Cardiac: 1-1.5mg/kg
*Infusion: 1-4mg/min
*PNB: 4mg/kg, 7mg/kg w/epi
*Epi: 4mg/kg
*SAB: 1.5mg/kg
*Bier Block: 200mg in 10-40ml (0.5%, 1% or 2%)
LIDOCAINE (Xylocaine): VD/PB%
VD: 1.3L/kg
PB: 65%
LIDOCAINE (Xylocaine): pKa/ % ionized at pH 7.4
*pKa: 7.9
*% Ionized: 75
LIDOCAINE (Xylocaine): Onset
*IV: 1 min
*PNB: 5 min/1-3 hrs
*Epi: 5 min/1-2 hrs
*SAB: <5 min/ 30-60 mins
LIDOCAINE (Xylocaine): EHL
*100 min
LIDOCAINE (Xylocaine): Metabolism
*1st pass lung (lipophilic drugs taken quickly into lungs which are the 1st vascular bed after heart)
*Hepatic P450, CYP3A4/5
Dealkylated to monoethylglycine xylidide and glycine xylidide, which can be metabolized further to monoethylglycine and xylidide.
LIDOCAINE (Xylocaine): Considerations
*CES
*TNS
*Most potent vasodilator
*Metabolites can accumulate in liver disease causing toxicity
PRILOCAINE (Citanest): Class
*Local Anesthetic
*Aminoamide
PRILOCAINE (Citanest): Dose
*MAX DOSE: 8.5mg/kg
*PNB:
PRILOCAINE (Citanest): VD/PB%
VD: 2.7L/kg
PB: 55%
PRILOCAINE (Citanest): pKa/ % ionized at pH 7.4
*pKa: 7.9
*% Ionized: 75
PRILOCAINE (Citanest): Onset/DOA
*PNB: 10 min/1-2 hrs
*Spinal: 5 min
*Epidural: 5-15 min
PRILOCAINE (Citanest): EHL
*100 min
PRILOCAINE (Citanest): Metabolism
...
PRILOCAINE (Citanest): Considerations
...
ROPIVICAINE (Naropin): Class
*Local Anesthetic
*Aminoamide
-pipecoloxylidide
ROPIVICAINE (Naropin): Dose
*PNB: 3.5 mg/kg
*Epi: 3 mg/kg
ROPIVICAINE (Naropin): VD/PB%
VD: 0.85L/kg
PB%: 95
ROPIVICAINE (Naropin): pKa/ % ionized at pH 7.4
*pKa: 8.1
*% Ionized: 85%
ROPIVICAINE (Naropin): Onset/DOA
*PNB: 15 min/5-8 hrs
*Epi: 10 min/2-6 hrs
*SAB: 5 min
ROPIVICAINE (Naropin): EHL
*110 min
ROPIVICAINE (Naropin): Metabolism
*1st pass lung (lipophilic drugs taken quickly into lungs which are the 1st vascular bed after heart)
*Hepatic P450, CYP3A4/5
*Metabolized to 2,6-pipecoloxylidide and 3-hydroxyropivacaine
*Renal excretion
ROPIVICAINE (Naropin): Considerations
*More motor sparing than Bupivacaine
*Less cardiotoxic than Bupivicaine
*S Enantiomer
*Favored in OB as "walking" epidurals
BUPIVICAINE (Marcaine, Sensorcaine): Class
*Local Anesthetic
*Aminoamide
-pipecoloxylidide
BUPIVICAINE (Marcaine, Sensorcaine): Dose
*PNB: 2.5 mg/kg
*Epi: 2 mg/kg
*SAB: 0.3 mg/kg
BUPIVICAINE (Marcaine, Sensorcaine): VD/PB%
VD: 1 L/kg
PB: 95%
BUPIVICAINE (Marcaine, Sensorcaine): pKa/ % ionized at pH 7.4
*pKa: 8.1
*% Ionized: 85
BUPIVICAINE (Marcaine, Sensorcaine): Onset/DOA
*PNB: 15 min/4-14 hrs
*Epi: 10 min/2-5 hrs
*SAB: 5 min/1-6 hrs
BUPIVICAINE (Marcaine, Sensorcaine): EHL
*210 min
BUPIVICAINE (Marcaine, Sensorcaine): Metabolism
*1st pass lung (lipophilic drugs taken quickly into lungs which are the 1st vascular bed after heart)
*Hepatic Metabolism
*Renal excretion
BUPIVICAINE (Marcaine, Sensorcaine): Considerations
*Highest risk for cardiotoxicity
*Concentrations >0.5% contraindicated in OB
*Not for Bier Blocks or trans-art Axillary blocks
ARTICAINE (Septocaine): Class
*Local Anesthetic
*Aminoamide
MEPIVICAINE (Carbocaine, Polocaine): Class
*Local Anesthetic
*Aminoamide
-pipecoloxylidide
MEPIVICAINE (Carbocaine, Polocaine): Dose
*MAX DOSE: 7mg/kg
*PNB: 5 mg/kg
*Epi: 5 mg/kg
*SAB: 1.5 mg/kg
MEPIVICAINE (Carbocaine, Polocaine): VD/PB%
VD: 1.2L/kg
PB: 75%
MEPIVICAINE (Carbocaine, Polocaine): pKa/ % ionized at pH 7.4
*pKa: 7.6
*% Ionized: 60
MEPIVICAINE (Carbocaine, Polocaine): Onset/DOA
*PNB: 5 min/2-4 hrs
*Epidural: 15 min/1-3 hrs
*SAB: 10 min/1-2 hrs
MEPIVICAINE (Carbocaine, Polocaine): EHL
*115 min
MEPIVICAINE (Carbocaine, Polocaine): Metabolism
*Hepatic Metabolism
*Renal excretion
MEPIVICAINE (Carbocaine, Polocaine): Considerations
*May induce ALA synthetase activity resulting in acute porphyria attack
*Not used in OB
*Lacks vasodilator properties
EMLA Cream: Class
*Local Anesthetic
EMLA Cream: Dose
*Roughly 2.5 g of the cream applied over a 25 cm2 area of skin.
*Lidocaine 2.5%/Prilocaine 2.5%
*Apply 1 hr prior and no longer than 4 hrs
EMLA Cream: Indications
*Topically prior to IV starts or blood draws
EMLA Cream: Onset/Peak
*Onset: 5 min
*Peak: 30-45 mins
EMLA Cream: Considerations
*Methemoglobinemia
BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): Class
*Local Anesthetic
*Aminoester
-the ethyl ester of p-aminobenzoic acid (PABA)
BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): Dose
*A brief spray of 20% benzocaine delivers the recommended dose of 200 to 300 mg.
BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): Onset/Peak/DOA/HL
*Onset: Rapid
*DOA: 30-60 mins
BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): pKa
*pKa: 3.5
BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): Considerations
*Methemoglobinemia
BENZOCAINE (Anbesol, Cepacol, Lanacane, Hurricaine): Indications
*Topical anesthetic
*Procedural Airway anesthesia
*Pruritus
Clinically used local anesthetics are often classified as amino-amides or amino-esters. This classification is based on the type of chemical bond, amide or ester, linking the...
lipophilic phenyl ring with the hydrophobic tertiary amine.
Amide compounds undergo enzymatic degradation in the liver, whereas ester compounds are...
hydrolyzed in plasma by esterase enzymes. Cocaine, an ester, is an exception, as it is metabolized predominantly by the liver.
The metabolites of esters include...
p-aminobenzoic acid (PABA), which can occasionally induce allergic reactions.
Local anesthetics are available either as single enantiomers or racemic mixtures. Enantiomers consist of two stereoisomers (left/sinister or right/dexter) that are...
mirror images of each other with respect to a specific chiral center. A racemic mixture contains equal amounts of the two enantiomers.
With increasing length of the carbon backbone, local anesthetics exhibit greater...
lipid solubility, protein binding, potency, and duration of action. However, these relationships are not linear and are often influenced by multiple other factors.
Local anesthetics must penetrate through the lipid-rich nerve sheaths and cell membrane in order to reach their targets, voltage-gated...
Na+ channels (Nav). The binding site of local anesthetics is located inside the channel pore and is not readily reachable from the extracellular side as inferred from pharmacologic studies.
Local anesthetics must cross the nerve membrane into the cell interior by diffusing through the lipid bilayer in order to reach their binding site. Consequently, the potency of each local anesthetic is closely related to...
its lipid solubility and its dependence on pH.
Most local anesthetics have pKa values relatively close to but higher than...
physiologic pH (with some exceptions such as prilocaine that has a secondary amine and benzocaine that has a primary amine).
Around physiologic pH (7.4), local anesthetics exist in these two forms:
*The positively charged conjugated acid
*The unprotonated neutral form
...the ratio described by the Henderson-Hasselbach equation.
Henderson-Hasselbach equation:
pH = pKa + log ([A-]/[HA])
Local anesthetics cross the lipid membrane much faster in their...
neutral lipophilic form than their cationic form.
Alkalinization by sodium bicarbonate addition to local anesthetic solutions increases the pH and shifts the equilibrium in favor of the...
neutral base forms, which facilitates translocation of the local anesthetic into the cellular interior. Once inside the cell, the lower pH shifts the equilibrium toward the positively charged protonated form. The charged form antagonizes Na + channels mor
The onset of action of local anesthetic action depends on the...
route of administration and the dose or concentration of drug.
For a given route of administration, increasing the concentration can...
accelerate onset. For instance, chloroprocaine is much slower in onset than lidocaine at equal concentrations because its pKa of 9.1 favors the positively charged form at physiologic pH. However, a 3% solution is the typical concentration of chloroprocain
In the subarachnoid space where the nerves lack a sheath, local anesthetics are able to reach their targets more readily, leading to a more rapid onset of nerve block with a much smaller dose compared to...
peripheral nerves. In peripheral nerve blocks, deposition of local anesthetic is in the vicinity of the nerves and the amount of drug that reaches the nerve depends on the diffusion of the drug and the proximity of the injection to the nerve.
The duration of action of local anesthetics is determined primarily by their...
protein binding. Local anesthetics with a high affinity for protein remain bound to the nerve membrane longer. In other words, binding to Na + channels with higher affinity results in a channel blocking effect of longer duration.
Duration of action is also influenced by the rate of...
vascular uptake of local anesthetic from the injection site.
The rate of vascular uptake significantly affects local anesthetic...
duration of action as local anesthetics provide their effect as long as they remain at the site of deposition. Therefore deposition of local anesthetics at a highly vascular site such as the intercostal space has a higher rate of vascular uptake. Vasocons
The surface of the nerve axon is formed by the...
lipid bilayer membrane that is embedded with various proteins including ion channels.
Myelinated nerve axons are surrounded by...
Schwann cells.
Schwann cells produce...
myelin that wraps around the axons to form the myelin sheath.
When seen lengthwise, the myelin sheath is punctuated by gaps called...
nodes of Ranvier.
Axons such as postganglionic autonomic efferent and some of the nociceptive afferent fibers lack...
a myelin sheath.
Nerve axons are further organized within three layers of connective tissue:
*Endoneurium
*Perineurium
*Epineurium
Nerve fibers are encased in...
endoneurium, loose connective tissue that consists of glial cells and fibroblasts along with blood capillaries. These fibers are grouped together by dense collagenous perineurium to form a unit called a fascicle. The fascicles are surrounded by a thicker
Nerves are typically characterized by their degree of myelination, axonal diameter, and speed of impulse conduction. They are classified as...
A, B, and C fibers, which roughly corresponds to their decreasing cross-sectional diameters.
A and B fibers are...
myelinated
C fibers are...
unmyelinated.
A and C fibers are further divided into...
subclasses by their anatomic location and physiologic functions.
The lipid bilayer of the axonal membrane is relatively impermeable to...
sodium ions but selectively permeable to potassium ions.
Ion channels are multi-subunit transmembrane proteins that fold in a complex manner to form...
ion selective pores gated by voltage or ligands.
Voltage-gated Na+ channels consist of...
a single ?-subunit and varying auxiliary ?-subunits. The ? subunit forms the ion-conducting pore of the channel and consists of four homologous domains, each with six ?-helical transmembrane segments.
Local anesthetics dose-dependently decrease...
peak Na+ current through voltage-gated Na+ channels.
The binding site for local anesthetics is located interior of the ion-selective pore and can be approached via two different pathways:
*Through the pore interior, or hydrophilic pathway
*Laterally through the lipid membrane, or hydrophobic pathway When bound, local anesthetics stabilize the inactivated state and prevent further activation. They can also bind in the ion channel pore to pr
Local anesthetics have a higher affinity for Na+ channels in the...
activated (open) and inactivated (channel pore in open conformation but intracellularly closed by inactivation gate) state than those in the resting closed state.
In the presence of local anesthetics, repeated depolarization results in an incremental decrease in Na + current until it reaches a newer steady level of inhibition, which is termed...
use-dependent or phasic inhibition. With repeated depolarization, a greater number of Na+ channels are in the active or inactivated state and are bound to local anesthetics.
Only a very small fraction (1%-2%) of local anesthetic reaches the...
nerve membrane even when placed in close proximity to the nerve.
The quality of nerve blockade is determined not only by the potency of the individual local anesthetic, but also by the...
concentration and volume of the local anesthetic.
The potency of a local anesthetic can be expressed as the...
minimum effective concentration (MEC) at which complete nerve block is established.
The volume of local anesthetic is also important as a sufficient length of axon must be blocked in order to prevent...
regeneration of the impulse in the adjacent node of Ranvier.
If less than the critical length of the axon is blocked, the action potential can be...
regenerated in the proximal membrane segment or node when the decaying depolarization is still above threshold for Na+ channel activation.
Local anesthetics block other ion channels besides Na+ channels including...
voltage-gated K+ channels and Ca2+ channels, but with lower potency compared to Na+ channels. Local anesthetics also bind intracellular G protein-coupled receptors and possibly influence the regulation of intracellular Ca2+.
Peripheral nerves are covered by a nerve sheath while axial nerves are encased in three layers of meninges:
*Pia matter
*Arachnoid
*Dura matter
Different nerve types show varying susceptibility to nerve block. Clinically, sensory functions are blocked before...
motor function.
The rate and extent of systemic absorption of local anesthetic depend on multiple factors:
*site of injection
*dose
*physiochemical properties of the drugs
*presence of vasoconstrictive or other adjuvants
Local anesthetics affect the cardiovascular system both directly by affecting...
cardiac myocytes and peripheral vascular smooth muscle cells, and indirectly by actions on the autonomic nervous system.
The more potent, lipophilic local anesthetics such as bupivacaine, tetracaine, and etidocaine are more cardiotoxic than...
the less lipophilic agents such as procaine, prilocaine, and lidocaine.
Local anesthetics act directly on the cardiovascular system by...
decreasing the conduction in Purkinje fibers and cardiomyocytes by prolonging the recovery time. Local anesthetics are also direct myocardial depressants via a mechanism related to reduced Ca2+ influx and release from the sarcoplasmic reticulum.
The action of local anesthetics on peripheral vascular smooth muscle is biphasic with...
vasoconstriction at low concentrations and vasodilation at higher concentrations. The exception is cocaine, which produces vasoconstriction at any dose.
Indirect cardiovascular effects of local anesthetics are related to the use of neuraxial techniques and include...
hypotension, bradycardia, and cardiopulmonary collapse if not treated promptly. Mild to moderate symptoms are usually responsive to intravenous fluids and indirect or direct acting adrenergic agents such as ephedrine and phenylephrine.
Central nervous system toxicity manifests initially as...
anxiety, dizziness, circumoral numbness, lightheadedness, and tinnitus. Objective symptoms include shivering, muscle twitching, tremors, and eventually generalized tonic-clonic seizure.
Factors that increase susceptibility to CNS toxicity include...
the use of more potent local anesthetics and the concomitant presence of respiratory or metabolic acidosis (by decreasing the convulsive threshold).
Respiratory acidosis also reduces protein binding of local anesthetics, increasing...
local anesthetic availability for further toxic effects.
Elevated PaCO2 leads to cerebral vasodilation and increased...
delivery of drug to the CNS. However, acidosis promotes amine protonation leading to less diffusion into nerve cells.
When unintentional intravenous injection of local anesthetic is suspected or systemic toxicity is detected, benzodiazepine should be given...
prophylactically as an anticonvulsant. The patient should be monitored closely for any early neurologic signs and symptoms. If the patient seizes, the airway must be protected to prevent aspiration and hypoventilation, and the seizure should be treated pr
Appropriate monitoring should be applied to assess cardiovascular and pulmonary function. Hypoventilation and respiratory acidosis should be supported with supplemental oxygen or artificial airway and mechanical ventilation. Hypotension and bradycardia sh
mainstay of immediate treatment and the use of vasopressin has also been suggested.
Intravenous administration of lipid emulsion has been used with immediate and successful resuscitation of patients with...
refractory local anesthetic induced cardiac toxicity, and is now a part of standardized treatment algorithms.
True allergy to local anesthetics is rare but occurs more commonly with...
ester local anesthetics than with amide local anesthetics. The accepted explanation is that amino-esters are metabolized to PABA, which is immunogenic. Some preparations of amino-amides contain methylparaben, which has a similar chemical structure as PABA
Direct neuronal tissue toxicity (e.g., transient neurologic symptoms [TNS] and cauda equina syndrome) has been described with multiple local anesthetics, but the incidence appears to be significantly higher with...
lidocaine and mepivacaine than bupivacaine, prilocaine, and procaine.
TNS is characterized by...
transient hyperalgesia or dysesthesia in the low back, buttocks, and lower extremities following seemingly uneventful spinal anesthesia but without permanent neurologic damage.
Risk of TNS is associated with...
the use of lidocaine, lithotomy position, and ambulatory procedures. The risk increases with dose, but does not appear to correlate with the concentration of local anesthetic because there is no difference in the incidence of TNS with 0.5% and 5% lidocain
The typical local anesthetics contain hydrophilic and hydrophobic moieties that are separated by...
an intermediate ester or amide linkage.
The hydrophilic group usually is a...
tertiary amine but also may be a secondary amine; the hydrophobic moiety must be aromatic.
Local anesthetics block conduction by decreasing or preventing the large transient increase in the...
permeability of excitable membranes to Na+ that normally is produced by a slight depolarization of the membrane.
Hydrophobicity increases both the...
potency and the duration of action of the local anesthetics; association of the drug at hydrophobic sites enhances the partitioning of the drug to its sites of action and decreases the rate of metabolism by plasma esterases and hepatic enzymes.
The receptor site for these drugs on Na+ channels is thought to be...
hydrophobic, so that receptor affinity for anesthetic agents is greater for more hydrophobic drugs.
Hydrophobicity also increases...
toxicity, so that the therapeutic index is decreased for more hydrophobic drugs.
As the anesthetic action progressively develops in a nerve, the threshold for electrical excitability gradually...
increases, the rate of rise of the action potential declines, impulse conduction slows, and the safety factor for conduction decreases. These factors decrease the probability of propagation of the action potential, and nerve conduction eventually fails.
In general, autonomic fibers, small unmyelinated C fibers (mediating pain sensations), and small myelinated A? fibers (mediating pain and temperature sensations) are blocked...
before the larger myelinated A?, A?, and A? fibers (mediating postural, touch, pressure, and motor information).
Therefore, it is unlikely that the fiber size per se determines the...
sensitivity to local anesthetic block under steady-state conditions.
Esters are hydrolyzed and inactivated primarily by a plasma esterase, probably...
plasma cholinesterase. The liver also participates in hydrolysis of local anesthetics.
Since spinal fluid contains little or no esterase, anesthesia produced by the intrathecal injection of an anesthetic agent will persist until...
the local anesthetic agent has been absorbed into the circulation.
The amide-linked local anesthetics are, in general, degraded by...
the hepatic CYPs the initial reactions involving N-dealkylation and subsequent hydrolysis.
With prilocaine, the initial of metabolism step is hydrolytic, forming o-toluidine metabolites that can cause...
methemoglobinemia.
The extensive use of amide-linked local anesthetics in patients with severe...
hepatic disease requires caution.
The amide-linked local anesthetics are extensively (55-95%) bound to...
plasma proteins, particularly ?1-acid glycoprotein.
Age-related changes in protein binding of local anesthetics also occur. The neonate is relatively deficient in...
plasma proteins that bind local anesthetics and thereby is more susceptible to toxicity.
Uptake by the lung also may play an important role in the distribution of...
amide-linked local anesthetics in the body.
Reduced cardiac output slows delivery of the amide compounds to the....
liver, reducing their metabolism and prolonging their plasma half-lives.
Order of Nerve fiber blockade by LA from first to last:
1. B
2. C
3. A?
4. A?
5. A?
6. A?
A? Fiber: Location
*Efferent to muscles
A? Fiber: Location
*Afferent from skin and joints
A? Fiber: Location
*Sensory roots and Afferent peripheral nerves
A? Fiber: Location
*Efferent to muscle spindles
B Fiber: Location
*Preganglionic sympathetic
C Sympathetic Fiber: Location
*Postganglionic sympathetic
C Dorsal Root Fiber: Location
*Sensory roots and Afferent peripheral nerves
A? Fiber: Diameter
*6-22 ?m
A? Fiber: Diameter
*6-22 ?m
A? Fiber: Diameter
*1-4 ?m
A? Fiber: Diameter
*3-6 ?m
B Fiber: Diameter
*<3 ?m
C Sympathetic Fiber: Diameter
*0.3-1.3 ?m
C Dorsal Root Fiber: Diameter
*0.4-1.2 ?m
A? Fiber: Function
*Motor
A? Fiber: Function
*Tactile & Proprioception
A? Fiber: Function
*Pain
*Temperature
*Touch
A? Fiber: Function
*Muscle tone
B Fiber: Function
*Autonomic Function
*Vasomotor
*Visceromotor
*Sudomotor
*Pilomotor
C Sympathetic Fiber: Function
*Vasomotor
*Visceromotor
*Sudomotor
*Pilomotor
C Dorsal Root Fiber: Function
*Pain
*Temperature
*Touch
A? Fibers: General
*Fast/Sharp Pain
*Synapse at Rexed lamina 1 & 5
*First order neurons form A-delta fibers communicate with second order neuron in Rexed lamina 1 & 5.
*The major neurotransmitter released from A-delta fibers is Glutamate which binds to AMPA receptors on the
C Fibers: General
*Slow/Chronic Pain
*Synapse at Rexed lamina 2 & 3 (Substantia gelatinosa)
*First order neurons from C-fibers release the excitatory neurotransmitter substance P (SP) which binds to NK-1 receptors on the postsynaptic membranes of second order neurons in th
Local anesthetics are poorly soluble in water and therefore are marketed most often as...
water-soluble hydrochloride salts. These hydrochloride salt solutions are acidic (pH 6), contributing to the stability of the local anesthetic.
Alkalinization of local anesthetic solutions shortens the...
onset of neural blockade, enhances the depth of sensory and motor blockade, and increases the spread of epidural blockade.
The pKa of local anesthetics used clinically is near 8, so that only a small fraction (about 3%) of the local anesthetic exists in the...
lipid-soluble form.
Alkalinization increases the percentage of local anesthetic existing in the...
lipid-soluble form that is available to diffuse across lipid cellular barriers.
Adding sodium bicarbonate will speed the onset of peripheral nerve block and epidural block by...
3 to 5 minutes.
Local anesthetics consist of a lipophilic and a hydrophilic portion separated by a connecting...
hydrocarbon chain. The hydrophilic group is usually a tertiary amine, such as diethylamine, whereas the lipophilic portion is usually an unsaturated aromatic ring, such as paraaminobenzoic acid.
The lipophilic portion is essential for...
anesthetic activity, and therapeutically useful local anesthetics require a delicate balance between lipid solubility and water solubility.
In almost all instances, an ester (-CO-) or an amide (-NHC-) bond links the...
hydrocarbon chain to the lipophilic aromatic ring. The nature of this bond is the basis for classifying drugs that produce conduction blockade of nerve impulses as ester local anesthetics or amide local anesthetics
Substituting a butyl group for the amine group on the benzene ring of procaine results in...
tetracaine.
Compared with procaine, tetracaine is more...
lipid soluble, is ten times more potent, and has a longer duration of action corresponding to a four- to fivefold decrease in the rate of metabolism.
Halogenation of procaine to chloroprocaine results in a three- to fourfold increase in the hydrolysis rate of chloroprocaine by...
plasma cholinesterase. This rapid hydrolysis rate of chloroprocaine limits the duration of action and systemic toxicity of this local anesthetic.
The pipecoloxylidide local anesthetics (mepivacaine, bupivacaine, ropivacaine, levobupivacaine) are chiral drugs because their molecules possess an asymmetric carbon atom. As such, these drugs may have a...
left- (S) or right- (R) handed configuration. Mepivacaine and bupivacaine are available for clinical use as racemic mixtures (50: 50 mixture) of the enantiomers.
Local anesthetics prevent transmission of nerve impulses (conduction blockade) by inhibiting passage of...
sodium ions through ion-selective sodium channels in nerve membranes.
Failure of sodium ion channel permeability to increase slows the rate of depolarization such that...
threshold potential is not reached and thus an action potential is not propagated.
Local Anesthetic MOA:
*LA blocks voltage gated NA+ channels. The unionized form of the LA diffuses through the nerve axon into the axolemma. A lower pH inside the neuron/axolemma causes nonionized portion to split into ionized/unionized portions; the ionized portion binds to a
LA blocks voltage gated NA+ channels. The unionized form of the LA diffuses through the nerve axon into the axolemma. A lower pH inside the neuron/axolemma causes nonionized portion to split into ionized/unionized portions; the ionized portion binds to a
sodium channel when the channel is in the inactivated state. When the sodium channel is inactivated, action potentials cannot be generated.
2-3 nodes of Ranvier must be blocked to...
stop nerve conduction
Conduction block is frequency dependent=>the greater the frequency of action potentials, the faster the nerve is blocked by LA and LA must attach to sodium channel when it is in the...
inactivated/closed (yet open)/absolute refractory state, thus the faster the nerve fires, the more opportunities for LA to catch the sodium channel in inactivated state and sensory fibers fire at greater frequency than motor fibers thus more likely to be
Local anesthetics, once bound to the inside of the voltage-gated sodium channel, stabilize and prolong the duration of the...
inactivated state, thus inhibiting VGSC opening during further depolarization. This inhibits neuronal conduction.
LA Neuroaxial MOA:
*Diffuses through the axolemma, across the dura in an uncharged form to act on nerve roots and the spinal cord. Once inside the neuron, where the pH is lower, the drug becomes protonated and binds to the Na+ channel on the cytoplasm side. It blocks initia
Sodium ion channels tend to recover from local anesthetic-induced conduction blockade between...
action potentials and to develop additional conduction blockade each time sodium channels open during an action potential (frequency-dependent blockade). Therefore, local anesthetic molecules can gain access to receptors only when sodium channels are in a
Local anesthetic molecules can gain access to receptors only when sodium channels are in...
activated-open states. For this reason, selective conduction blockade of nerve fibers by local anesthetics may be related to the nerve's characteristic frequencies of activity as well as to its anatomic properties, such as diameter. Indeed, a resting nerv
A resting nerve is less sensitive to local anesthetic-induced conduction blockade than...
is a nerve that has been repetitively stimulated.
A minimal length of myelinated nerve fiber must be exposed to...
an adequate concentration of local anesthetic for conduction blockade of nerve impulses to occur. For example, if only one node of Ranvier is blocked (site of change in sodium permeability), the nerve impulse can jump (skip) across this node and conductio
For conduction blockade to occur in an A fiber, it is necessary to expose at least...
two and preferably three successive nodes of Ranvier (approximately 1 cm) to an adequate concentration of local anesthetic.
Both types of pain-conducting fibers (myelinated A-delta and nonmyelinated C fibers) are blocked by...
similar concentrations of local anesthetics, despite the differences in the diameters of these fibers.
Preganglionic B fibers are more readily blocked by local anesthetics than...
any fiber, even though these fibers are myelinated.
Differential conduction blockade is illustrated by selective blockade of preganglionic sympathetic nervous system B fibers using low concentrations of local anesthetics. Slightly higher concentrations of local anesthetics interrupt conduction in...
small C fibers and small- and medium-sized A fibers, with loss of sensation for pain and temperature. Nevertheless, touch, proprioception, and motor function are still present such that the patient will sense pressure but not pain with surgical stimulatio
Local anesthetics are weak bases that have pK values somewhat above physiologic pH. As a result, < 50% of the local anesthetic exists in a...
lipid-soluble nonionized form at physiologic pH. For example, at pH 7.4, only 5% of tetracaine exists in a nonionized form. Acidosis in the environment into which the local anesthetic is injected (as is present with tissue infection) further increases the
Local anesthetics with pKs nearest to physiologic pH have the most...
rapid onset of action, reflecting the presence of an optimal ratio of ionized to nonionized drug fraction.
Lipid solubility of the local anesthetic is important in this redistribution, as well as being a primary determinant of...
intrinsic local anesthetic potency. After distribution to highly perfused tissues, the local anesthetic is redistributed to less well perfused tissues, including skeletal muscles and fat. Consideration of cardiac output is important for describing the ove
Protein binding of local anesthetics will influence their...
distribution and excretion. In this regard, protein binding parallels lipid solubility of the local anesthetic and is inversely related to the plasma concentration of drug.
The lungs are capable of extracting local anesthetics such as...
lidocaine, bupivacaine, and prilocaine from the circulation. After rapid entry of local anesthetics into the venous circulation, this pulmonary extraction will limit the concentration of drug that reaches the systemic circulation for distribution to the c
For bupivacaine, first-pass pulmonary extraction is...
dose dependent, suggesting that the uptake process becomes saturated rapidly.
Propranolol impairs...
bupivacaine extraction by the lungs, perhaps reflecting a common receptor site for the two drugs).
Propranolol decreases plasma clearance of...
lidocaine and bupivacaine, presumably reflecting propranolol-induced decreases in hepatic blood flow or inhibition of hepatic metabolism
Clearance values and elimination half-times for amide local anesthetics probably represent mainly...
hepatic metabolism, because renal excretion of unchanged drug is minimal.
Amide local anesthetics undergo varying rates of metabolism by...
microsomal enzymes located primarily in the liver. Prilocaine undergoes the most rapid metabolism; lidocaine and mepivacaine are intermediate; and etidocaine, bupivacaine, and ropivacaine undergo the slowest metabolism among the amide local anesthetics.
The initial step of amide metabolism is conversion of the amide base to...
aminocarboxylic acid and a cyclic aniline derivative. Complete metabolism usually involves additional steps, such as hydroxylation of the aniline moiety and N-dealkylation of the aminocarboxylic acid.
The traditional mechanism of action of local anesthetics
is via blockade of axonal action potential generation or
propagation by prevention of...
voltage-gated sodium (Na+) channel (VGSC) conductance that mediates these action potentials. Additionally, local anesthetics also interact with calcium (Ca2+) signaling G protein-coupled receptors (GPCRs), and may mediate their anti-inflammatory actions.
The potency of local anesthetics correlates with increasing
molecular weight, which confers increased...
lipid solubility and protein binding, both of which increase the duration of action, but slow the onset of conduction block.
The potential systemic toxic effects of local anesthetics include...
methemoglobinemia (primarily due to benzocaine and the metabolite of prilocaine, o-toluidine), seizures, and malignant ventricular dysrhythmias with cardiovascular collapse.
True allergic reactions to local anesthetics are rare, but may be associated with the metabolites of the...
aminoester local anesthetics or preservatives in the local anesthetic solutions
The presence of myelin increases conduction velocity via...
saltatory conduction, and the increased nerve diameter increases conduction velocity via improved cable conduction properties.
Local anesthetics inhibit neuronal conduction by directly
binding to and inhibiting the ability of...
VGSCs to conduct the inward Na+ current that mediates the rapid depolarizing phase of the action potential. The inhibition results from local anesthetic binding at a receptor site in the channel's
inner pore, accessible from the axoplasmic opening.
Binding of the local anesthetic is a dynamic process characterized by differing affinities for the receptor site based on...
conformational changes of the VGSC, induced by temporal changes in the membrane potential.
Lipid solubility is the primary determinant of local anesthetic...
potency and duration of action. The more lipophilic local anesthetics are able to permeate the axonal membranes more readily, and thus are able to bind to the VGSCs with greater affinity.
It is likely that highly protein-bound local anesthetics
are removed from the nerve at a decreased rate, resulting in slower uptake and absorption, which accounts for the
increased...
duration of action. Thus, increased protein binding correlates with increased lipid solubility, which leads to increased potency and duration of action of the local anesthetic as a result of increased local anesthetic content within nerves.
pKa generally correlates with...
speed of onset, because penetration by the neutral lipid-soluble form across the lipid bilayer of the axonal membrane is the primary mechanism by which local anesthetics gain access to the local anesthetic binding site.
The receptor site for opioids administered in the intrathecal or epidural space is within the...
gray matter of substantia gelatinosa located in the dorsal horn of the spinal cord. Opioids bind to presynaptic and postsynaptic receptor sites, which selectively blocks transmission of afferent nociceptive stimuli from A? and C fibers.
Opioids bind to presynaptic and postsynaptic receptor sites, which selectively blocks transmission of afferent nociceptive stimuli from A? and C fibers:
*Presynaptic effects include release of spinal adenosine, which seems to be an important mediator specific for spinally mediated analgesia, as well as inhibition of Ca2+ influx and the subsequent release of glutamate and neuropeptides (such as substance P
In general, areas with greater tissue perfusion will have more rapid and complete uptake than those with more fat, regardless of type of local anesthetic. Thus, rates of absorption generally decrease in the following order:
interpleural > intercostal > caudal > epidural > brachial
plexus > sciatic/femoral > subcutaneous tissue
Clearance of aminoesters is primarily dependent on hydrolysis of the ester bond by plasma cholinesterases. The rate of enzymatic degradation varies, with chloroprocaine being the most...
rapid, tetracaine being the slowest, and procaine being intermediate.
Aminoamides are metabolized in the liver by the...
cytochrome P450 enzymes CYP1A2 and CYP3A4 via N-dealkylation,
amide bond hydrolysis, and hydroxylation.
The elimination of amide local anesthetics is highly dependent on...
hepatic function. Thus hepatic perfusion, extraction, enzyme function, as well as protein binding determine the rate of clearance of aminoamides.
Impairment of hepatic function and decreases in hepatic perfusion (congestive heart failure) prolong..
the elimination of aminoamide local anesthetics.
Benzocaine and a metabolite of prilocaine (o-toluidine) may cause clinically significant...
methemoglobinemia, a condition in which the ferrous form (Fe2+) of hemoglobin is oxidized to the ferric form (Fe3+). While in this oxidized state, hemoglobin cannot bind or transport oxygen.
Serious cases of methemoglobinemia present with...
central cyanosis that is refractory to oxygen therapy, which may be fatal if unrecognized. Diagnosis requires a high index of suspicion, which is confirmed by qualitative measurements of methemoglobinemia by co-oximetry. Treatment consists of intravenous
Dose-dependent systemic effects of lidocaine: Plasma
concentration (?g/mL)
1-5:Analgesia
5-10: Lightheadedness, Numbness of tongue, Tinnitus, Muscular twitching
10-15: Seizures, Unconsciousness
15-25: Coma, Respiratory arrest
> 25: Cardiovascular depression
The more potent, more lipid-soluble drugs (bupivacaine, etidocaine, and ropivacaine) appear to have an inherently greater...
cardiotoxicity than the less potent drugs.
Although all local anesthetics block the cardiac conduction system through a dose-dependent block of Na+ channels, two features of bupivacaine's Na+-channel blocking abilities may enhance its cardiotoxicity:
*Bupivacaine exhibits a much stronger binding affinity to resting
and inactivated Na+ channels than lidocaine.
*Local anesthetics bind to Na+ channels during systole and dissociate during diastole. Bupivacaine dissociates from Na+ channels during cardiac
Determinants of LA speed of onset:
*pKa
*The amount of LA in unionized form is that determines speed of onset since it is this form that penetrates the axon to gain access to the axolemma.
*The closer the drugs pKa is to physiologic pH, the quicker the onset. (except chloroprocaine with a
Determinants of LA potency:
*The more lipid soluble the LA, the greater the potency.
Determinant of LA DOA:
*The greater the protein binding the longer the DOA
*Protein bound LA at the site provides a reservoir of LA. As the portion of LA that is not protein bound diffuses away, the protein bound reservoir releases LA to diffuse into the nerve axons.
*Lipid sol
Lidocaine, one of the most studied local anesthetics, has been shown to possess an...
antiinflammatory effect. Lidocaine appears to inhibit the release of proinflammatory cytokines and prevent leukocyte adhesion.
Lidocaine appears to inhibit the release of...
proinflammatory cytokines and prevent leukocyte adhesion.
Risk of TNS is associated with the use of...
lidocaine, lithotomy position, and ambulatory procedures.
Lidocaine was the first widely used local anesthetic, and is available for infiltration as well as...
peripheral (including Bier's block), spinal, and epidural blocks. Its use for spinal anesthesia has declined due to concerns about neurotoxicity and transient neurologic symptoms.
Lidocaine causes vasodilation at most concentrations; the addition of epinephrine can significantly reduce...
absorption of lidocaine by nearby vessels, allowing more of the initially administered dose to enter the neural compartment, thereby prolonging the duration of action by as much as 50%.
Experimentally, intravenous lidocaine profoundly suppresses both...
increased peripheral neuronal "firing" induced by injury and inflammation as well as central sensitization of wide dynamic range neurons in the spinal cord dorsal horn.
Lidocaine is the archetypal class Ib antiarrhythmic. Like all class Ib drugs, its rapid binding and unbinding rates (endowing it with use-dependency or frequency-dependency) greatly diminish its effects at...
low heart rates, and exaggerate its effects at high heart rates.
Lidocaine selectively targets the open and inactivated states of...
Nav1.5, with low affinity for the deactivated (closed or resting) state.
Lidocaine and other class Ib drugs can be efficacious in the therapy of rapid heart rate conditions including...
ventricular tachycardia and ventricular fibrillation prevention, and also in cases of symptomatic premature ventricular beats.
Lidocaine is dealkylated in the liver by CYPs to...
monoethylglycine xylidide and glycine xylidide, which can be metabolized further to monoethylglycine and xylidide. Both monoethylglycine xylidide and glycine xylidide retain local anesthetic activity. In humans, ?75% of the xylidide is excreted in the uri
The side effects of lidocaine seen with increasing dose include...
drowsiness, tinnitus, dysgeusia, dizziness, and twitching. As the dose increases, seizures, coma, and respiratory depression and arrest will occur.
Clinically significant cardiovascular depression usually occurs at serum lidocaine levels that produce marked...
CNS effects. The metabolites monoethylglycine xylidide and glycine xylidide may contribute to some of these side effects.
Ester local anesthetics undergo hydrolysis by cholinesterase enzyme, principally in the plasma and to a lesser extent in the liver. The rate of hydrolysis varies, with chloroprocaine being most...
rapid, procaine being intermediate, and tetracaine being the slowest. The resulting metabolites are pharmacologically inactive, although paraaminobenzoic acid may be an antigen responsible for subsequent allergic reactions.
The exception to hydrolysis of ester local anesthetics in the plasma is...
cocaine, which undergoes significant metabolism in the liver.
Lidocaine at clinically useful plasma concentrations depresses the ventilatory responses to...
arterial hypoxemia). In this regard, patients with carbon dioxide retention whose resting ventilation depends on hypoxic drive may be at risk of ventilatory failure when lidocaine is administered for treatment of cardiac dysrhythmias.
Systemic absorption of bupivacaine, such as follows a brachial plexus block, stimulates the ventilatory...
response to carbon dioxide.
Plasma lidocaine concentrations of 5 to 10 ?g/ mL, and equivalent plasma concentrations of other local anesthetics, may produce profound...
hypotension due to relaxation of arteriolar vascular smooth muscle and direct myocardial depression.
Excessive plasma concentrations of lidocaine may slow conduction of cardiac impulses through the heart, manifesting as...
prolongation of the P-R interval and QRS complex on the electrocardiogram.
Both bupivacaine and lidocaine block cardiac sodium ion channels during systole, whereas during diastole, highly lipid soluble bupivacaine dissociates off these channels at a...
slow rate compared with lidocaine, thus accounting for the drug's persistent depressant effect on Vmax and subsequent cardiac toxicity.
At normal heart rates, diastolic time is sufficiently long for lidocaine dissociation but bupivacaine block intensifies and depresses electrical conduction, causing...
reentrant-type ventricular dysrhythmias, Less lipid-soluble lidocaine dissociates rapidly from cardiac sodium channels and cardiac toxicity is low.
Nebulized lidocaine is used to produce surface anesthesia of the upper and lower respiratory tract before...
fiberoptic laryngoscopy and/ or bronchoscopy and as a treatment for patients experiencing intractable coughing.
Inhalation of nebulized lidocaine can cause bronchoconstriction in some patients with...
asthma, which may become an important consideration when bronchoscopy is planned in these patients.
Systemic absorption of tetracaine, and to a lesser extent lidocaine, after placement on the tracheobronchial mucosa produces plasma concentrations similar to those present after...
IV injection of the local anesthetic. For example, plasma lidocaine concentrations 15 minutes after laryngotracheal spray of the local anesthetic are similar to those concentrations present at the same time after an IV injection of lidocaine.
Lidocaine is commonly used for epidural anesthesia because of its...
good diffusion capabilities through tissues.
Vasoconstrictors appear to be most effective in prolonging tetracaine-induced spinal anesthesia (up to 100%) and less effective at prolonging...
lidocaine spinal anesthesia, whereas the effect on bupivacaine spinal anesthesia remains controversial and is, at best, minimal.
Grand mal seizures have been suppressed by IV administration of low doses of...
lidocaine or mepivacaine. Presumably, these and perhaps other local anesthetics, when present at low plasma concentrations, are effective in suppressing seizures through initial depression of hyperexcitable cortical neurons.
sought. Bupivacaine is a racemic mixture of the (+) and (?) enantiomers, with lesser toxicity associated with the...
S-( ?) form compared to the R-( +) form.
Levobupivacaine demonstrates comparable potency and efficacy as bupivacaine but has significantly less...
cardiac and central nervous system toxicity likely related to reduced affinity for subtypes of Na+ channels expressed in brain and cardiac tissues.
Bupivacaine (a racemic mixture of both the R and S enantiomers) provides prolonged and intense...
sensory analgesia, often outlasting the motor block.
For epidural analgesia and anesthesia, bupivacaine is usually used at concentrations from...
0.25% to 0.5%, with a 2- to 5-hour duration of action.
Ventricular tachycardia and fibrillation are relatively uncommon consequences of local anesthetics other than...
bupivacaine.
Bupivacaine is a potent agent capable of producing prolonged anesthesia. Its long duration of action plus its tendency to provide more...
sensory than motor block has made it a popular drug for providing prolonged analgesia during labor or the postoperative period.
Bupivacaine is more cardiotoxic than equi-effective doses of lidocaine. Clinically, this is manifested by severe...
ventricular arrhythmias and myocardial depression after inadvertent intravascular administration.
Although lidocaine and bupivacaine both rapidly block cardiac Na + channels during systole, bupivacaine dissociates much more slowly than does lidocaine during...
diastole, so a significant fraction of Na+ channels at physiological heart rates remains blocked with bupivacaine at the end of diastole. Thus, the block by bupivacaine is cumulative and substantially more than would be predicted by its local anesthetic p
At least a portion of the cardiac toxicity of bupivacaine may be mediated centrally, as direct injection of small quantities of bupivacaine into the...
medulla can produce malignant ventricular arrhythmias.
Bupivacaine-induced cardiac toxicity can be very difficult to treat, and its severity is enhanced by...
coexisting acidosis, hypercarbia, and hypoxemia.
Lidocaine and bupivacaine are marketed in both...
isobaric and hyperbaric preparations, and if desired, can be diluted with sterile, preservative-free water to make them hypobaric.
Local anesthetics such as bupivacaine, which are highly lipid soluble, are distributed less into the...
circulation than are less lipid-soluble agents such as lidocaine.
Bupivacaine is not recommended for IV regional anesthesia considering its greater likelihood than other local anesthetics for producing...
cardiotoxicity when the tourniquet is deflated at the conclusion of the anesthetic.
Bupivacaine and ropivacaine at similar concentrations (0.5% to 0.75%) produce similar prolonged sensory anesthesia (ropivacaine has a greater tendency to block A-delta and C fibers) when used for epidural anesthesia, but the motor anesthesia produced by r
less intense and of shorter duration.
Bupivacaine used for spinal anesthesia is more effective than tetracaine in preventing...
lower-extremity tourniquet pain during orthopedic surgery. This effectiveness may reflect the ability of bupivacaine to produce greater frequency-dependent conduction blockade of fibers than does tetracaine.
Ropivacaine is structurally similar to bupivacaine but was developed as a...
single, less toxic enantiomer (as with levo-bupivacaine); it can be administered in larger doses than racemic bupivacaine before early signs of toxicity develop. However, if equipotent concentrations/ dosages are compared, the difference between bupivacai
Overall the clinical profile of ropivacaine is similar to...
racemic bupivacaine, taking into account that it is less lipid soluble and less potent than bupivacaine.
Ropivacaine appears to be suitable for both epidural and regional anesthesia, with a duration of action similar to that of bupivacaine. Interestingly, it seems to be even more motor-sparing than...
bupivacaine.
Mepivacaine, bupivacaine, and ropivacaine are chiral drugs because the molecules possess an...
asymmetric carbon atom.
Becuse only a very small fraction of ropivacaine is excreted unchanged in the urine (about 1%) when the liver is functioning normally, dosage adjustments based on renal function...
do not seem necessary. However, in uremic patients, 2,6-pipecoloxylidide may accumulate and produce toxic effects.
Ropivacaine is highly bound to...
alpha1-acid glycoprotein.
Most local anesthetics, with the exception of ropivacaine, possess...
intrinsic vasodilator properties.
Although, ropivacaine-induced cardiac arrest has been described following peripheral nerve block anesthesia, in contrast to bupivacaine, cardiac resuscitation is more...
likely to be successful.
Ropivacaine, although less likely to produce cardiotoxicity than bupivacaine, is not recommended for...
IV regional anesthesia.
Due to its relatively low potency and extremely low toxicity, relatively high concentrations of chloroprocaine can be used. It also has an extremely short...
plasma half-life because it is metabolized rapidly by plasma cholinesterase.
Chloroprocaine is thought to have the lowest...
CNS and cardiovascular toxicity of all agents in current use.
Chloroprocaine is used commonly for epidural anesthesia. It is also used for peripheral blocks in combination with other...
long-acting, slow-onset local anesthetics for the combined effect of rapid onset and prolonged duration.
In obstetrics, epidural chloroprocaine, with or without bicarbonate, is used to attain rapidly surgical levels of anesthesia in preparation for...
cesarean section. Another theoretical advantage in obstetrics is that there is virtually no transmission of chloroprocaine to the fetus.
Controversy exists regarding the use of chloroprocaine related to reports of persistent, serious neurologic deficits associated with...
accidental massive subarachnoid injection (i.e., adhesive arachnoiditis). Initially, the agent itself was implicated, but subsequent evaluation suggested that the preservative antioxidant bisulfite is responsible. However, after elimination of bisulfite a
Chloroprocaine. Chloroprocaine (NESACAINE, others) is a chlorinated derivative of procaine. Its major assets are its...
rapid onset and short duration of action and its reduced acute toxicity due to its rapid metabolism (plasma t1/ 2 ? 25 seconds).
A higher than expected incidence of muscular back pain following epidural anesthesia with 2-chloroprocaine has also been reported. This back pain is thought to be due to tetany in the paraspinus muscles, which may be a consequence of...
Ca2+ binding by the EDTA included as a preservative; the incidence of back pain appears to be related to the volume of drug injected and its use for skin infiltration.
Placement of chloroprocaine in the epidural space may decrease the efficacy of subsequent epidural...
bupivacaine-induced analgesia during labor. It is speculated that the low pH of the chloroprocaine solution could decrease the nonionized pharmacologically active fraction of bupivacaine. Tachyphylaxis to the local anesthetic mixture could also reflect lo
Adjustment of the pH of the chloroprocaine solution with the addition of 1 mL of 8.4% sodium bicarbonate added to 30 mL of chloroprocaine solution just before placement into the epidural space may improve the efficacy of...
a chloroprocaine-bupivacaine combination.
Procaine and chloroprocaine penetrate mucous membranes...
poorly and are ineffective for topical anesthesia.
Chloroprocaine is not selected for IV regional anesthesia because of a high incidence of...
thrombophlebitis.
Cocaine is usually consumed orally or by snorting. The alkalinized form ("crack cocaine") can be injected, smoked, or snorted and has even greater addictive potential due to...
very rapid absorption with high peak plasma levels. The elimination half-life is 0.5 to 1.5 hours and metabolism is by liver and plasma cholinesterases.
Cocaine produces intense euphoria and feelings of increased energy. The drug acts by blocking the reuptake of...
the neurotransmitters dopamine, serotonin, and norepinephrine into nerve terminals, thereby increasing the synaptic concentrations of these neurotransmitters. Effects on dopaminergic neurons are thought to be responsible for the high addictive potential o
The sympathetic effects of cocaine can precipitate...
vasoconstriction or vasospasm in arteries supplying the brain and heart, leading to strokes and myocardial infarction or ischemia. Higher doses lead to ventricular arrhythmias and death.
Users who smoke crack cocaine can induce...
asthma or develop pulmonary hemorrhages.
Patients can become severely hypertensive, particularly during laryngoscopy. Direct acting vasodilators including nitroglycerin and hydralazine or calcium channel blockers are appropriate for treatment and prophylaxis although they worsen...
preexisting tachycardia. Caution should be exercised in the use of beta blockers, in that unopposed ?-receptor action can worsen hypertension and lead to myocardial ischemia. The induction agents, ketamine and etomidate, can exacerbate the underlying hemo
Chronic cocaine users can develop intraoperative hypotension that is unresponsive to...
ephedrine that will usually respond to direct acting vasoconstrictors such as phenylephrine.
The development of modern organic chemistry enabled the synthesis of the first analogue of cocaine...
procaine (known today by its trade name Novocaine) in 1905.
Cocaine and procaine are both...
ester local anesthetics.
Biologically, cocaine acts as a serotonin-norepinephrine-dopamine reuptake inhibitor, also known as a...
triple reuptake inhibitor (TRI)
Cocaine inhibits the neuronal reuptake of catecholamines and can therefore cause...
hypertension, tachycardia, dysrhythmias, and other serious cardiac effects.
Epinephrine should not be used in patients with acute cocaine intoxication due to...
the potential for exacerbation of myocardial ischemia and stroke.
The reinforcing effects of cocaine and cocaine analogs correlate best with their effectiveness in blocking the transporter that recovers DA from the synapse. This leads to increased...
DA concentrations at critical brain sites. However, cocaine also blocks both NE and 5-HT reuptake, and chronic use of cocaine leads to reductions in the neurotransmitter metabolites 3-methoxy-4 hydroxyphenethyleneglycol (MOPEG or MHPG) and 5-hydroxyindole
Cocaine produces a dose-dependent increase in heart rate and blood pressure accompanied by increased...
arousal, improved performance on tasks of vigilance and alertness, and a sense of self-confidence and well-being. Higher doses produce euphoria, which has a brief duration and often is followed by a desire for more drug. Repeated doses may lead to involun
The t1/2 of cocaine in plasma is ? 50 minutes, but inhalant (crack) users typically desire more cocaine after...
10-30 minutes. Intranasal and intravenous uses also result in a high of shorter duration than would be predicted by plasma cocaine levels, suggesting that a declining plasma concentration is associated with termination of the high and resumption of cocain
The major route for cocaine metabolism involves hydrolysis of each of its two...
ester groups. Benzoylecgonine, produced on loss of the methyl group, represents the major urinary metabolite and can be found in the urine for 2-5 days after a binge.
Risks of cocaine, beyond the potential for addiction, include...
cardiac arrhythmias, myocardial ischemia, myocarditis, aortic dissection, cerebral vasoconstriction, and seizures. Death from trauma also is associated with cocaine use.
Cocaine may induce premature...
labor and abruptio placentae.
Cocaine hydrochloride is provided as a...
1%, 4%, or 10% solution for topical application. For most applications, the 1% or 4% preparation is preferred to reduce toxicity.
A unique feature of cocaine is its ability to produce localized...
vasoconstriction, making it useful to shrink the nasal mucosa in rhinolaryngologic procedures and nasotracheal intubation.
There is no difference between the intranasal anesthetic or vasoconstrictive effects of cocaine and those of a...
lidocaine-oxymetazoline or tetracaine-oxymetazoline mixture, emphasizing the usefulness of these combinations as substitutes for cocaine.
Urinary excretion of unchanged cocaine (< 1% of the total dose) and metabolites (benzoylecgonine and ecgonine methyl ester representing about 65% of the dose) is similar regardless...
of the route of administration.
Acute cocaine administration is known to cause...
coronary vasospasm, myocardial ischemia, myocardial infarction, and ventricular cardiac dysrhythmias, including ventricular fibrillation. Associated hypertension and tachycardia further increase myocardial oxygen requirements at a time when coronary oxyge
Even remote cocaine use can result in myocardial ischemia and hypotension for as long as...
6 weeks after discontinuing cocaine use. Presumably, delayed episodes of myocardial ischemia are due to cocaine-induced coronary artery vasospasm.
Cocaine-abusing parturients are at higher risk for...
interim peripartum events such as hypertension, hypotension, and wheezing episodes.
Cocaine produces dose-dependent decreases in uterine blood flow that result in...
fetal hypoxemia . Cocaine may produce hyperpyrexia, which could contribute to seizures.
Cocaine should be used with caution, if at all, in patients with...
hypertension or coronary artery disease and in patients receiving drugs that potentiate the effects of catecholamines, such as monoamine oxidase inhibitors.
Nitroglycerin has been used to treat cocaine-induced...
myocardial ischemia.
Although esmolol has been recommended to treat tachycardia due to cocaine overdose, there is also evidence that...
beta-adrenergic blockade accentuates coronary artery vasospasm in the setting of acute cocaine overdose.
Whether beta-adrenergic blockade is harmful for coronary vasospasm in the setting of chronic cocaine use is...
not known. Furthermore, administration of beta-blocking drugs in the presence of catecholamine-induced hypertension and tachycardia has been associated with profound cardiovascular collapse and cardiac arrest that is unresponsive to aggressive cardiopulmo
Alpha-adrenergic blockade may be effective in treatment of coronary vasoconstriction due to cocaine, but in the presence of hypotension this intervention...
questionable. IV administration of a benzodiazepine such as diazepam is effective for control of seizures associated with cocaine toxicity.
Tetracaine is a slow onset, potent and intermediate to long acting...
ester-type local anesthetic. Even longer duration of action can be achieved when administered along with a vasoconstrictor such as epinephrine. However it is quite toxic, and has been suggested to cause neurotoxicity at high doses in animal studies result
Tetracaine is highly lipid soluble and a significant amount can be absorbed when used in the...
mucous membrane or wounded skin.
Lidocaine in combination with tetracaine (PLIAGLIS) in a formulation that generates a "peel" is approved for topical local analgesia prior to...
superficial dermatological procedures such as filler injections and laser-based treatments.
Lidocaine in combination with tetracaine is marketed in a formulation that generates heat upon exposure to air (SYNERA), which is used prior to...
venous access and superficial dermatological procedures such as excision, electrodessication, and shave biopsy of skin lesions. The mild warming is intended to increase skin temperature by up to 5 � C for the purpose of enhancing delivery of local anesthe
Tetracaine (PONTOCAINE), is a long-acting amino ester. It is significantly more potent and has a longer duration of action than...
procaine.
Tetracaine may exhibit increased systemic toxicity because it is more...
slowly metabolized than the other commonly used ester local anesthetics. Currently, it is widely used in spinal anesthesia when a drug of long duration is needed.
Tetracaine also is incorporated into several...
topical anesthetic preparations.
With the introduction of bupivacaine, tetracaine is rarely used in...
peripheral nerve blocks because of the large doses often necessary, its slow onset, and its potential for toxicity.
The first local anesthetic used in ophthalmology, cocaine, has the severe disadvantages of producing mydriasis and corneal sloughing and has fallen out of favor. The two compounds used most frequently today are...
proparacaine (ALCAINE, OPHTHAINE, others) and tetracaine
cocaine. Proparacaine and tetracaine are used topically to perform...
tonometry, to remove foreign bodies on the conjunctiva and cornea, to perform superficial corneal surgery, and to manipulate the nasolacrimal canalicular system. They also are used topically to anesthetize the ocular surface for refractive surgery using e
Because cerebrospinal fluid contains little to no cholinesterase enzyme, anesthesia produced by subarachnoid placement of tetracaine will persist until...
the drug has been absorbed into the systemic circulation.
Vasoconstrictors prolong the effect of tetracaine for...
spinal anesthesia. Epinephrine added to a low dose of tetracaine (6 mg) increases the success rate of spinal anesthesia, whereas the success rate is not altered by epinephrine when the subarachnoid dose of tetracaine is 10 mg
Tetracaine, with a slow onset of anesthesia and a high potential to cause systemic toxicity, is not recommended for...
local infiltration or peripheral nerve block anesthesia.
Injected intrathecally, tetracaine produces a significant increase in...
spinal cord blood flow, an effect that can be prevented or reversed by epinephrine.
Addition of clonidine, 75 to 150 �g, to a solution containing tetracaine or bupivacaine and placed in the subarachnoid space...
prolongs the duration of sensory and motor blockade produced by the local anesthetic.
Oral clonidine, 150 to 200 �g, administered 1.0 to 1.5 hours before institution of spinal anesthesia with tetracaine or lidocaine results in...
a significant prolongation of sensory anesthesia. In another report, oral clonidine, 200 �g, shortened the onset time of tetracaine's sensory block and prolonged the duration of sensory and motor block.
Absorption of local anesthetics from the mucous membrane is significant and therefore can result in systemic toxicity. Tetracaine has the most rapid rate of absorption, followed by...
cocaine and lidocaine, respectively. Peak plasma levels occur 5 minutes after the application of tetracaine or cocaine to the pyriform fossae of the laryngopharynx.
There are no plasma cholinesterases in either the...
epidural space or the CSF.
Direct neuronal tissue toxicity (e.g., transient neurologic symptoms [TNS] and cauda equina syndrome) has been described with multiple local anesthetics, but the incidence appears to be significantly higher with...
lidocaine and mepivacaine than bupivacaine, prilocaine, and procaine.
The anesthetic profile of mepivacaine is also similar to lidocaine but with a slightly...
longer duration of action. However, it is not as effective when applied topically.
Although toxicity appears to be less than with lidocaine, metabolism of mepivacaine is prolonged in the fetus and newborn and is, therefore...
not used for obstetric anesthesia.
Mepivacaine, however, is more toxic to the neonate and thus is not used in obstetrical anesthesia. The increased toxicity of mepivacaine in the neonate is related to...
ion trapping of this agent because of the lower pH of neonatal blood and the pKa of mepivacaine rather than to its slower metabolism in the neonate.
Addition of a butyl group to the piperidine nitrogen of mepivacaine results in...
bupivacaine, which is 35 times more lipid soluble and has a potency and duration of action three to four times that of mepivacaine.
The S enantiomers of bupivacaine and mepivacaine appear to be less toxic than...
the commercially available racemic mixtures of these local anesthetics.
Amide local anesthetics undergo varying rates of metabolism by microsomal enzymes located primarily in the liver. Prilocaine undergoes the most rapid metabolism; lidocaine and mepivacaine are...
intermediate; and etidocaine, bupivacaine, and ropivacaine undergo the slowest metabolism among the amide local anesthetics.
Mepivacaine has pharmacologic properties similar to those of...
lidocaine, although the duration of action of mepivacaine is somewhat longer.
In contrast to lidocaine, mepivacaine lacks...
vasodilator activity.
Lidocaine, mepivacaine, and prilocaine demonstrate effects on the CNS at plasma concentrations of...
5 to 10 ?g/mL.
Mepivacaine 4%, placed in the subarachnoid space, has also been associated with...
transient neurologic symptoms.
Amide metabolism: fastest=>slowest
prilocaine (fastest) > lidocaine > mepivacaine > ropivacaine ? bupivacaine and levobupivacaine (slowest).
Mepivacaine is slowly metabolized by the fetus, making it a...
poor choice for epidural anesthesia in the parturient.
When used for spinal anesthesia, mepivacaine has a slightly lower incidence of TNS than..
lidocaine.
Benzocaine has a slow onset, short duration of action and is both minimally potent and minimally toxic. Its clinical use is limited to...
topical anesthesia to anesthetize mucous membranes; for example to anesthetize the oral and pharyngeal mucosa before fiberoptic endotracheal intubation.
Excessive use of benzocaine is associated with...
methemoglobinemia.
Benzocaine (ethyl aminobenzoate) is unique among clinically useful local anesthetics because it is a...
weak acid (pKa 3.5), so that it exists only in the nonionized form at physiologic pH. As such, benzocaine is ideally suited for topical anesthesia of mucous membranes prior to tracheal intubation, endoscopy, transesophageal echocardiography, and bronchosc
A brief spray of 20% benzocaine delivers the recommended dose of...
200 to 300 mg.
Systemic absorption of topical benzocaine is enhanced by defects in the...
skin and mucosa as well as from the gastrointestinal tract should any of the local anesthetic be swallowed.
Cetacaine is a combination of...
14% benzocaine, 2% tetracaine, and 2% butamben.
Methemoglobinemia is a rare but potentially life-threatening complication following topical application of...
benzocaine, especially when the dose exceeds 200 to 300 mg.
Benzocaine's pronounced lipophilicity has relegated its application to...
topical anesthesia.
Order of loss of Blockade: First>>>Last
1.Autonomic regulation
2. Temperature (esp. cold)
3. Dull pain
4. Sharp pain
5. Deep pressure
6. Proprioception
7. Somatic muscle function
In neuraxial anesthesia, the first indication a block is working is usually a...
drop in blood pressure.
All the local anesthetics EXCEPT Cocaine and Ropivacaine, possess the ability to cause...
vasodilation in the area injected.
Protein Binding best indicates...
*Duration of Action
pKa best indicates...
*Speed of Onset
Lipid Solubility best indicates...
*Potency
EMLA cream is a eutectic mixture of the local anesthetics...
lidocaine and prilocaine, each at a concentration of 2.5%.
EMLA should be applied to intact skin surfaces because application to breached skin surfaces can lead to...
unpredictably rapid absorption.
Although there is considerable interpatient variation, EMLA cream should be applied under an occlusive dressing for about...
1 hour to provide adequate analgesia for insertion of an intravenous catheter or the drawing of blood at roughly 2.5 g of the cream applied over a 25 cm2 area of skin.
The maximum recommended duration of exposure for EMLA is...
4 hours, although exposures of up to 24 hours have not led to toxic plasma levels of local anesthetics.
The enzyme capacity for red blood cell methemoglobin reductase in children <3 months of age can be overloaded when EMLA cream is administered concurrently with...
other methemoglobin-inducing drugs (sulfonamides, acetaminophen, phenytoin, nitroglycerin, nitroprusside). Likewise, EMLA cream should not be used in those rare patients with congenital or idiopathic methemoglobinemia.
Local skin reactions, such as pallor, erythema, and alterations in temperature sensation, edema, pruritus, and rash are common after...
EMLA cream application.
EMLA cream is not recommended for use on mucous membranes because of the...
faster absorption of lidocaine and prilocaine than through intact skin. Similarly, EMLA cream is not recommended for skin wounds, and the risk of wound infection may be increased .
Patients being treated with certain antidysrhythmic drugs (mexiletine) may experience...
additive and potentially synergistic effects when exposed to EMLA cream.
How do you identify Amide and Ester local anesthetics by their names?
*Amides contain 2 of the letter "I" in their name
*Esters have only 1
What are the chemical structural requirements for a drug to be a local anesthetic?
*A lipophilic end
*A hydrophilic end
*An intermediate chain which is either an "Este" or an "Amide
Esters: Metabolism
*Catalyzed by plasma and tissue cholinesterase via hydrolysis - it occurs throughout the body and is rapid
Amides: Metabolism
*Metabolized in the liver by enzymes. A significant blood level may develop.
Esters: Allergies
LA allergy is uncommon, esters have a higher allergy potential - if there is a reaction to one, all other esters should be avoided
Amides: Allergies
Allergy to amides is extremely rare, there is no cross allergy among amide class or between the ester and amide agents
Esters: Duration of action
Ester drugs tend to be shorter acting due to ready metabolism - tetracaine is the longest acting ester
Amides: Duration of action
Amides are longer acting because they are more lipophilic and protein bound and require transport to the liver for metabolism
What is the mechanism of action of local anesthetics?
*Short answer: Blocks sodium channels
*Longer answer: The non-ionized portion which is lipid soluble enters the nerve, reequilibrates and the remaining ionized fraction attaches to the local anesthetic receptor on the inside of the sodium channel.
What does the pKa of a local anesthetic affect?
*The lower the pKa is the faster the onset
*The closer the pKa is to 7.4 the closer it is to being 50% ionized
What does the level of protein binding affect?
*The more protein bound a local anesthetic is, the longer the duration of action
How does the addition of epinephrine affect local anesthetics?
*Provides a marker for inadvertent intravascular injection
*Decreases the rate of vascular absorption
*Decreases onset time
*Decreases peak concentration
*Increases blockade
*Increases duration of action
*Increases area of blockade
The respiratory depression associated with local anesthetic overdose results in hypoxia and acidosis - what are the CNS implications?
*Local anesthetic accumulation in the fetal circulation is enhanced by the fact that fetal pH is lower than maternal pH. This may result in high fetal levels of local anesthetics
What happens if you inject local anesthetic into acidotic or infected tissues?
*They are rendered ineffective due to the loss of lipid solubility - that is, they become more ionized and lose their ability to cross nerve membranes
What does carbonation do to local anesthetics?
*Speeds the onset and intensity of action of neural blockade - CO2 readily diffuses into the nerve lowering its pH - the lipid form of anesthetic enters the nerve and becomes more ionized, increasing the concentration affecting sodium channels
What are the signs of local anesthetic toxicity - in order of appearance?
1. Lightheadedness, tinnitus, circumoral and tongue numbness
2. Visual disturbances
3. Muscular twitching
4. Convulsions
5. Unconsciousness
6. Coma
7. Respiratory arrest
8. CVS depression occurs at plasma concentrations of around 25 ng/mL
Some quick tips on avoiding local anesthetic systemic toxicity
*Use the lowest effective dose
*Use incremental injections
*Aspirate before injection
*Use an intravascular marker such as epinephrine which increases heart rate by about 10 and SBP by about 15
*Ultrasound is recommended but not proven to reduce incidence
What is the onset for local anesthetic toxicity?
*It varies
*If under 60 seconds, it implies intravascular injection
*If 60-300 seconds, it implies partial intravascular - but can occur up to 30 minutes after injection
What is the one sign that a practitioner should look for when assessing for local anesthetic toxicity?
*There isn't one, the initial signs vary considerably and may be CNS or cardiovascular
How do you treat local anesthetic systemic toxicity
*Airway first
*Halt seizures - avoiding large doses of propofol for its cardiac effects, benzodiazepines are primary
*Use succinylcholine if there is nothing else
*Start ACLS with lower doses of epi
*No vasopressin, no calcium channel or beta blockers
*Li
Dosing for lipid emulsion therapy?
*1.5mL/kg 20% bolus followed by 0.25ml/kg/min for at least 10 minutes after circulatory stability. If circulatory stability is not attained consider another bolus and increasing infusion to 0.5ml/kg/min.
What factors increase the likelihood of local anesthetic systemic toxicity?
*Advanced age
*Heart failure
*Ischemic heart disease
*Conduction abnormalities
*Metabolic disease
*Liver disease
*Low plasma protein concentration
*Acidosis
*Medications that inhibit sodium channels
*Severe cardiac dysfunction with low ejection fraction
How does pregnancy affect the effects of local anesthetics?
*Pregnancy enhances their effect
*Due to progesterone's effects on the susceptibility of nerves to conduction blockade and probably partly due to venous dilation
How does local anesthetics affect uterine tone and blood flow?
*Uterine tone, uterine and umbilical blood flow are unaffected
How does preeclampsia change the accumulation of local anesthetics?
*May result in a greater accumulation of the drug
Is the elimination half-life of amide local anesthetics shorter or longer in a newborn than an adult? Why?
*The elimination half life is longer in the newborn because of a greater volume of distribution
What is the downside to adding bicarbonate sodium to local anesthetics?
*It reduces the onset but can induce hypotension during the administration of epidural anesthesia
Using opioids in administration of neuraxial anesthesia does what exactly?
*Produces analgesia without loss of sensation or proprioception
*When combined with a local anesthetic it increases block density and allows for lower doses of local anesthetic
How is spinal bioavailability of the opioids affected by their ionization?
*Hydrophilic drugs like morphine or dilaudid are less available than lipophilic opioids such as fentanyl or sufentanil
What are the most common side effects of neuraxial opioid administration in obstetrics?
*Pruritus & N/V
*Fetal bradycardia and maternal respiratory depression are the most serious complications
What is "Tumescent Anesthesia"?
*Subcutaneous injection of dilute local anesthetic with epinephrine with doses of lidocaine from 35 to 55mg/kg which peak in 8 to 12 hours after infusion - used most commonly by plastic surgeons during liposuction. Mostly good outcomes.
Prilocaine can be metabolized in the...
kidney.
Prilocaine shows the least systemic toxicity of all amide local anesthetics and is therefore useful for intravenous regional anesthesia. However, it causes...
methemoglobinemia (>500 mg dose) due to its metabolite o-toluidine, which has significantly limited its use.
The amide-linked local anesthetics are, in general, degraded by the hepatic CYPs the initial reactions involving N-dealkylation and subsequent hydrolysis. However, with prilocaine, the initial step is...
hydrolytic, forming o-toluidine metabolites that can cause methemoglobinemia.
The lungs are capable of extracting local anesthetics such as lidocaine, bupivacaine, and prilocaine from the circulation. After rapid entry of local anesthetics into the venous circulation, this pulmonary extraction will...
limit the concentration of drug that reaches the systemic circulation for distribution to the coronary and cerebral circulations.
Prilocaine is an amide local anesthetic that is metabolized to orthotoluidine. Orthotoluidine is an oxidizing compound capable of converting hemoglobin to...
its oxidized form, methemoglobin, resulting in a potentially life-threatening complication, methemoglobinemia (see the section, Methemoglobinemia).
When the dose of prilocaine is >600 mg, there may be sufficient...
methemoglobin present (3 to 5 g/dL) to cause the patient to appear cyanotic, and oxygen-carrying capacity is decreased.
Methemoglobinemia is readily reversed by the administration of...
methylene blue, 1 to 2 mg/ kg intravenously (IV), over 5 minutes (total dose should not exceed 7 to 8 mg/kg).