Professional Drug Information > Marcaine

Anesthetics (Parenteral-Local)

This monograph includes information on the following:

1) Articaine
2) Bupivacaine
3) Chloroprocaine
4) Etidocaine
5) Levobupivacaine
6) Lidocaine
7) Mepivacaine
8) Prilocaine
9) Procaine
10) Tetracaine


INN:
Lidocaine— Lignocaine

BAN:
Articaine—Carticaine

VA CLASSIFICATION
Primary: CN204

Commonly used brand name(s): Astracaine 4%¹; Astracaine 4% Forte¹; Carbocaine⁷; Carbocaine with Neo-Cobefrin⁷; Chirocaine⁵; Citanest Forte⁸; Citanest Plain⁸; Dalcaine⁶; Dilocaine⁶; Duranest⁴; Duranest-MPF⁴; Isocaine⁷; Isocaine 2%⁷; Isocaine 3%⁷; L-Caine⁶; Lidoject-1⁶; Lidoject-2⁶; Marcaine²; Marcaine Spinal²; Nesacaine³; Nesacaine-CE³; Nesacaine-MPF³; Novocain⁹; Octocaine⁶; Octocaine-100⁶; Octocaine-50⁶; Polocaine⁷; Polocaine-MPF⁷; Pontocaine¹⁰; Sensorcaine²; Sensorcaine Forte²; Sensorcaine-MPF²; Sensorcaine-MPF Spinal²; Septocaine™¹; Ultracaine D-S¹; Ultracaine D-S Forte¹; Xylocaine⁶; Xylocaine 5% Spinal⁶; Xylocaine Test Dose⁶; Xylocaine-MPF⁶; Xylocaine-MPF with Glucose⁶.

A commonly used name for lidocaine is
lignocaine .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anesthetic (local)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
Parenteral-local anesthetics are generally used to provide local or regional anesthesia, analgesia, and varying degrees of motor blockade prior to surgical procedures, dental procedures, and obstetric delivery. They also may be used for other diagnostic or therapeutic purposes via routes of administration that are stated in product labeling. ^{{01} {04} {07} {11} {20}{137}}

Mixtures or combinations of local anesthetics are sometimes used to provide a rapid onset of action and a prolonged duration of action. However, the possibility of additive toxicity must be considered when such combinations are used ^{94}.

Vasoconstrictors are added to local anesthetic injections to decrease the rate of local clearance of the local anesthetic ^{124}. Local anesthetic injections containing a vasoconstrictor generally have the same indications as the corresponding local anesthetic injection without a vasoconstrictor. However, additional precautions pertinent to the use of a vasoconstrictor must be considered. ^{21}{137}

Dextrose is added to anesthetic solutions for subarachnoid administration to render the solution hyperbaric (heavier than cerebrospinal fluid [CSF]); the local anesthetic will exert its effect above or below the site of injection, depending upon the position of the patient during and immediately following the injection. ^{37}

Local anesthetics may be combined with opioid analgesics for epidural administration for inducing postoperative analgesia. This combination may allow lower doses of both the local anesthetic and the opioid to be used as compared with either agent used alone, and may reduce the incidence of motor block, nausea, and urinary retention ^{90}.

Accepted

Central neural blocks—Caudal or lumbar epidural: Bupivacaine (with or without epinephrine) ^{{09} {35}}, chloroprocaine ^{04}, etidocaine (with or without epinephrine) ^{05}, lidocaine (with or without epinephrine) ^{{12} {16}}, levobupivacaine ^{135}, and mepivacaine ^{{20} {21}} are indicated. Only single-dose vials that do not contain an antimicrobial preservative should be used.
—Subarachnoid: Bupivacaine and dextrose ^{02}, lidocaine and dextrose ^{{06} {22}}, procaine¹ , and tetracaine (with or without dextrose) ^{98} are indicated. Commercially available products intended specifically for subarachnoid administration contain no antimicrobial preservatives ^{98}. Solutions and diluents containing antimicrobial preservatives are not to be injected into the subarachnoid space and should not be used when preparing injections for administration via this route ^{21}.

Dental infiltration or nerve block—Articaine with epinephrine^{{48} {137}}; bupivacaine and epinephrine ^{09}; chloroprocaine (with or without added epinephrine) ^{04}; etidocaine and epinephrine ^{05}; lidocaine (with or without epinephrine) ^{{12} {91} {103}}; mepivacaine (with or without levonordefrin) ^{{20} {21}}; prilocaine (with or without epinephrine) ^{{07} {38}} are indicated. Unless specifically contraindicated, a vasoconstrictor-containing solution is preferred.

Intravenous regional anesthesia (Bier block)¹—[Chloroprocaine], lidocaine ^{12}, and [mepivacaine] are indicated.

Local infiltration—Bupivacaine (with or without epinephrine) ^{09}, chloroprocaine ^{04}, etidocaine (with or without epinephrine ^{05}), levobupivacaine ^{135}, lidocaine (with or without epinephrine) ^{12}, mepivacaine ^{{20} {21}}, and procaine ^{11} are indicated.

Peripheral nerve block—Bupivacaine (with or without epinephrine) ^{09}, chloroprocaine ^{04}, etidocaine (with or without epinephrine) ^{05}, levobupivacaine ^{135}lidocaine (with or without epinephrine) ^{12}, mepivacaine ^{{20} {21}}, and procaine ^{11} are indicated.
—Retrobulbar block: Bupivacaine ^{09}, etidocaine ^{05}, lidocaine ^{23}, and [ procaine]¹ are indicated.

Sympathetic block—Bupivacaine (with or without epinephrine) ^{09} and lidocaine (with or without epinephrine) ^{12} are indicated.

Transtracheal—Lidocaine ^{23}, [mepivacaine]¹ , and [tetracaine]¹ are indicated.

Unaccepted
For paracervical administration—Use of bupivacaine is not recommended for nonobstetrical procedures because of insufficient data concerning safety and dosage. Use of bupivacaine is not recommended in obstetrical procedures because such use has resulted in fetal bradycardia and death ^{35}.

Solutions containing a vasoconstrictor should not be used for intravenous regional anesthesia (Bier block). Also, bupivacaine and levobupivacaine are not recommended for intravenous regional anesthesia ^{35}{135}.

For central neural block (peridural [lumbar or caudal epidural] or subarachnoid [spinal] administration)—Do not use solutions containing an antimicrobial preservative such as chlorobutanol or methylparaben ^{16}.

Chloroprocaine and mepivacaine are not recommended for subarachnoid (spinal) administration ^{04}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics—Anesthetics (Parenteral-Local)

Drug	pKa	Lipid solubility (pH 7.4)	Protein binding	Half-life adult/neonate	Onset of action *	Duration of action †	Relative toxicity ‡
Articaine	7.8 {48}{137}	High {48}	Medium (60% to 80%) {137}{48} {134}	1.2 hr {48}{137}	Rapid (1 to 6 minutes) {137}{48}	Intermediate (1 hour) {137}{48}
Bupivacaine	8.1	High	Very high	3.5 hr/8.1–14 hr {96}	Intermediate to Slow	Long §
Chloroprocaine	9			19–26 sec/41–45 sec {04}	Rapid {04}	Short {04}
Etidocaine	7.74 {05}	High	Very high	2.5 {05} hr/4–8 hr	Rapid {05}	Long {05}
Levobupivacaine	8.1{135}	High{135}	Very high{135}	1.3 hours{135}	Immediate to slow{135}	Short to long{135}
Lidocaine	7.9	Medium	Moderate to high {06}	1.5–2 {06} {91} hr/3.2 {105} hr	Rapid {06} #	Intermediate {06}	2
Mepivacaine	7.6	Medium	High {101}	1.9–3.2 hr/9 hr {101}	Rapid to intermediate {101} #	Intermediate {101}	2
Prilocaine	7.9	Medium	Moderate	1.6 hr {07}	Rapid {07}	Intermediate	1.7
Procaine	8.9	Low	Very low	30–50 sec/54–114 sec {11}	Intermediate	Short {11}	1
Tetracaine	8.2	High	High		Rapid	Intermediate to long	10

^* Influenced by the site, route, and technique of administration; dosage (volume and concentration) administered; pH at injection site; physical characteristics, such as lipid solubility, molecular size, and pKa of the individual anesthetic; and individual patient.
^† Short = 30 to 60 minutes; Intermediate = 1 to 3 hours; Long = 3 to 10 hours. Influenced by factors affecting rate of clearance from the injection site and individual patient.
^‡ As compared with procaine (the least toxic of these agents).
^§ Via nerve block, may produce analgesia for considerably longer than 10 hours.
^# Adjustment of pH with 1 mEq (1 mmol) of sodium bicarbonate per 10 mL may increase the onset of conduction blocks (lidocaine hydrochloride injection, lidocaine and epinephrine injection, or mepivacaine hydrochloride injection).

Physicochemical characteristics:

Chemical group—
    Amides: Articaine ^{{48}{137} {95}}, bupivacaine ^{35}, etidocaine ^{05}, levobupivacine ^{135}, lidocaine ^{06}, mepivacaine ^{{20} {21}}, prilocaine ^{38}
    Esters, aminobenzoic acid (PABA)–derivative: Chloroprocaine ^{04}, procaine ^{11}, tetracaine
Molecular weight—
    Articaine: 284.38 ^{59}
    Bupivacaine hydrochloride: 342.91 ^{72}
    Chloroprocaine hydrochloride: 307.22 ^{73}
    Etidocaine: 276.42 ^{74}
     levobupivacine: 324.9^{135}
    Lidocaine hydrochloride: 288.82 ^{75}
    Mepivacaine hydrochloride: 282.81 ^{76}
    Prilocaine hydrochloride: 256.78 ^{77}
    Procaine hydrochloride: 272.78 ^{78}
    Tetracaine hydrochloride: 300.83 ^{80}

pKa—
    See Table 1


Lipid solubility
    See Table 1.

Mechanism of action/Effect:


Local anesthetics:

Local anesthetics block both the initiation and conduction of nerve impulses by decreasing the neuronal membrane's permeability to sodium ions, perhaps by attaching to a site on the sodium channel. This reversibly stabilizes the membrane and inhibits depolarization, resulting in the failure of a propagated action potential and subsequent conduction blockade ^{57}.

The concentration of drug needed to block large nerve trunks is greater than that needed for smaller peripheral nerves.



Vasoconstrictors:

Act on alpha-adrenergic receptors in the vasculature of the skin, mucous membranes, conjunctiva, and viscera to produce vasoconstriction, thereby decreasing blood flow in the area of injection. The resultant reduction in the rate of local clearance of the local anesthetic prolongs the duration of action, lowers the peak serum concentration, decreases the risk of systemic toxicity, and increases the frequency of complete conduction blocks with low concentrations of the local anesthetic. Vasoconstrictors may also reduce bleeding when injected at the site of surgery. ^{24}



Other actions/effects:

Local anesthetics—Actions on the central nervous system (CNS) may cause CNS stimulation and/or CNS depression ^{{05} {09} {35}}. Actions on the cardiovascular system may cause depression of cardiac conduction and excitability and, with most of these agents, peripheral vasodilation ^{09}.

Vasoconstrictors—Vasoconstrictors having beta-adrenergic activity (epinephrine, levonordefrin, and norepinephrine) may cause cardiac stimulation resulting in increased heart rate, contractility, conduction velocity, and irritability ^{35}. Also, when used for obstetrical anesthesia, vasoconstrictors having beta-adrenergic activity ^{10} may decrease the intensity of uterine contractions and prolong labor. Phenylephrine is also rarely used as a vasoconstrictor in conjunction with local anesthesia; it has only alpha-adrenergic activity and does not have these additional effects ^{42}.

Absorption:

Complete systemic absorption ^{05}. The rate of absorption is influenced by the site and route of administration (especially the vascularity or rate of blood flow at the injection site), total dosage (volume and concentration) administered, physical characteristics (such as degree of protein binding and lipid solubility) of the individual agent, and whether or not a vasoconstrictor is used concurrently ^{{05} {09}}.

Biotransformation:


Amides:

Hepatic ^{{05} {06} {09}}.

Articaine: Inactivated by ester hydrolysis via plasma carboxyesterase to articainic acid ^{137}{48}. Approximately 5% to 10% of articaine is metabolized by liver microsome P450 isoenzymes to articainic acid^{137}.

Levobupivacaine: Metabolized by cytochrome P450 (CYP) 3A4 and CYP1A2 isoforms to desbutyl levobupivacaine and 3–hydroxy levobupivacaine, respectively. ^{135}

Lidocaine: Xylidide metabolites are active and toxic, but less so than the parent compound ^{{06} {12} {23}}.

Prilocaine: May also be metabolized renally to some extent ^{38}.



Esters:

PABA derivatives: Hydrolyzed primarily in the plasma and, to a much lesser extent, in the liver, by cholinesterases ^{04}. Procaine is hydrolyzed to PABA ^{11}. Chloroprocaine and tetracaine are hydrolyzed to PABA-containing compounds ^{04}.


Time to peak concentration:

Usually 10 to 30 minutes. May occur 1 to 3 minutes after intravascular or transtracheal injection.

Elimination:
    Renal, primarily as metabolites ^{04}. For some of these agents, including lidocaine, mepivacaine, and tetracaine, renal excretion may follow biliary excretion into, and reabsorption from, the gastrointestinal tract.


Quantity of dose excreted unchanged—
        Articaine: 2% to 5% ^{48}{137}.
        Bupivacaine: 5% ^{35}.
        Etidocaine: Less than 10% ^{05}.
        Lidocaine: 10%.
        Levobupivacaine: 0% ^{135}
        Mepivacaine: 5 to 10% ^{21}.
        Procaine: Less than 2% ^{11}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to para-aminobenzoic acid (PABA) or parabens may be sensitive to procaine, chloroprocaine, or tetracaine also ^{04}. They may also be sensitive to other local anesthetic solutions containing parabens as preservatives ^{04}.

Patients sensitive to one ester-type local anesthetic may be sensitive to other ester-type local anesthetics also ^{04}.

Patients sensitive to one amide-type local anesthetic rarely may be sensitive to other amide-type local anesthetics also ^{{05} {20} {21} {35}}.

Cross-sensitivity between ester-type local anesthetics and amide-type local anesthetics has not been reported ^{23}.

Carcinogenicity

Articaine—Studies evaluating the carcinogenic potential of articaine in animals have not been conducted ^{137}.

Mutagenicity

Articaine— In vitro (nonmammalian Ames test, mammalian Chinese hamster ovary chromosomal aberration test, mammalian gene mutation test) and in vivo (mouse micronucleous tests) mutagenicity tests showed no mutagenic effects^{137}.

Pregnancy/Reproduction
Fertility—
Articaine—In rats, doses approximately 2 times the maximum recommended human dose (MRHD) had no effect on male or female fertility ^{137}.

Pregnancy—
Local anesthetics cross the placenta by diffusion ^{{05} {12} {35}}. The rate and degree of diffusion vary considerably among the various agents as determined by their rate of metabolism and physical characteristics such as plasma protein binding (reduced placental transfer with highly protein-bound agents), lipid solubility (greater placental transfer with highly lipid soluble agents), and degree of ionization (greater placental transfer with nonionized form of agent) ^{09}.

All parenteral-local anesthetics—Adequate and well-controlled prospective studies in humans have not been done. Retrospective studies of pregnant women receiving local anesthetics for emergency surgery early in pregnancy have not shown that local anesthetics cause birth defects.

Articaine—Adequate and well-controlled studies in humans have not been done ^{137}. Studies of articaine in rats and rabbits using doses of up to 2.9 times the maximum recommended human dose (MRHD) have not shown adverse effects on the fetus ^{48}{137}. In rabbits, doses approximately 4 times the MRHD did cause fetal death and increase fetal skeletal variations, but these effects may be attributable to severe maternal toxicity. In rats, doses approximately 2 times the MRHD increased the number of stillbirths and adversely affected passive avoidance (a measure of learning)^{137}.

FDA Pregnancy Category C ^{137}

Bupivacaine—Studies in rats and rabbits using doses 9 and 5 times the MRHD, respectively, have shown decreased survival in newborn rats and embryocidal effects in rabbits ^{35}.

FDA Pregnancy Category C ^{35}.

Chloroprocaine, mepivacaine, and tetracaine—Studies in animals have not been done.

FDA Pregnancy Category C ^{{04} {21}}.

Etidocaine, levobupivacaine, lidocaine, and prilocaine —Studies in rats or rabbits with etidocaine (using up to 1.7 times the MRHD) ^{05}, levobupivacaine (using 0.5 times the MRHD) ^{135}, lidocaine (using up to 6.6 times the MRHD) ^{{06} {12} {23}}, or prilocaine (using 30 times the MRHD) have not shown adverse effects on the fetus ^{38}.

FDA Pregnancy Category B ^{{05} {06} {12} {23}}.

Procaine—Studies in animals have not been done.

FDA Pregnancy Category C ^{11}.


Labor and delivery—

Epidural, subarachnoid, paracervical, or pudendal administration of a local anesthetic may produce changes in uterine contractility and/or maternal expulsive efforts ^{99}. Paracervical block may shorten the first stage of labor and facilitate cervical dilation ^{99}. However, epidural or subarachnoid administration of local anesthetics may prolong the second stage of labor by interfering with motor function or removing the patient's reflex urge to bear down ^{99}. Use of a local anesthetic during delivery may increase the need for forceps-assisted delivery ^{04}. Bupivacaine and etidocaine are not recommended for paracervical administration ^{{05} {35}}. Also, etidocaine may cause profound motor block; epidural administration of this agent is not recommended for normal vaginal delivery (although it may be used for cesarean section) ^{05}.

Maternal hypotension, caused by sympathetic nerve blockade resulting in vasodilation, may occur during regional anesthesia ^{16}.

Maternal convulsions and cardiovascular collapse have been reported following paracervical administration of local anesthetics early in pregnancy (for elective abortion), suggesting rapid systemic absorption under these circumstances ^{16}.

Maternal fatalities due to cardiac arrest have been reported following inadvertent intravascular injection of 0.75% bupivacaine during intended placement of an epidural block ^{35}. Although the 0.75% strength is not recommended for epidural administration in obstetrics, lower concentrations of bupivacaine may be used ^{35}.

Fetal bradycardia, possibly associated with fetal acidosis, has been reported in 20 to 30% of patients receiving amide-type local anesthetics via paracervical block ^{{20} {21}}. Fetal bradycardia without fetal acidosis also has been reported in 5 to 10% of patients receiving chloroprocaine via paracervical block ^{04}. The risk of this complication may be increased if prematurity, postmaturity, toxemia of pregnancy, pre-existing fetal distress, or uteroplacental insufficiency is present ^{04}. Risk-benefit must be considered when amide-type local anesthetics are considered for paracervical block in these conditions. Paracervical block with chloroprocaine is not recommended if prematurity, pre-existing fetal distress, or toxemia of pregnancy is present because its safety in these conditions has not been established ^{04}. Monitoring of fetal heart rate is recommended during paracervical block ^{{20} {21}}.

Postpartum —
Neonatal neurological disturbances such as diminished muscle strength and tone may occur for 1 to 2 days postpartum. Marked neonatal CNS depression has been reported following paracervical block. Also, inadvertent fetal intracranial injection during intended caudal, paracervical, or pudendal administration may cause neonatal depression and convulsions. ^{21}

Breast-feeding

It is not known whether most local anesthetics are distributed into breast milk. Bupivacaine is distributed into breast milk in small quantities ^{09}. Lidocaine is distributed into breast milk ^{30}. However, problems in humans have not been documented.

Pediatrics

Although there is some evidence that systemic toxicity may be more likely to occur in pediatric patients, appropriate studies performed to date with mepivacaine have not demonstrated pediatrics-specific problems that would limit the use of the medication in children ^{13}. Also, no information is available on the relationship of age to the effects of procaine ^{11}and levobupivacaine ^{135} in pediatric patients. Although articaine is not approved for use in children younger than 4 years of age ^{137}, a retrospective study of its use in patients younger than 4 years of age did not reveal any pediatrics-specific problems that would limit its use in children ^{53}.

Infants up to 9 months of age have low plasma concentrations of alpha ₁-acid glycoprotein (AAG) ^{{108} {109} {110}}. This results in an increased unbound fraction of bupivacaine and etidocaine, and may lead to systemic toxicity ^{{108} {109} {110}}.

Reduced clearance of bupivacaine in pediatric patients may be more important than AAG concentrations in causing toxicity. Neonates may have total body clearance of bupivacaine only one third to one half the clearance of adults ^{36}.

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of lidocaine in children.


Geriatrics


Systemic toxicity may be more likely to occur in geriatric patients ^{07}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.


For all local anesthetics
Anticoagulants, such as:
Ardeparin or
Dalteparin or
Danaparoid or
Enoxaparin or
Heparin or
Warfarin    (trauma to a blood vessel during peridural or subarachnoid administration of the local anesthetic may result in CNS or soft tissue hemorrhage in patients receiving anticoagulant therapy ^{{06} {32}})


Antimyasthenics    (inhibition of neuronal transmission by local anesthetics may antagonize the effects of antimyasthenics on skeletal muscle, especially if large quantities of the anesthetic are rapidly absorbed; temporary dosage adjustment of antimyasthenics may be necessary to control symptoms of myasthenia gravis ^{{128} {131}})


Beta-adrenergic blocking agents    (may slow metabolism of lidocaine by reducing hepatic blood flow, leading to increased risk of lidocaine toxicity ^{{31} {33} {34}})


Cimetidine    (cimetidine may inhibit hepatic metabolism of bupivacaine and lidocaine, leading to increased risk of toxicity ^{39})


» CNS depression–producing medications, including those commonly used as preanesthetic medication or for supplementation of local anesthesia (see Appendix II )    (concurrent use with a local anesthetic may result in additive depressant effects ^{16})


Disinfectant solutions containing heavy metals    (local anesthetics may cause release of heavy metal ions from these solutions, which, if injected along with the anesthetic, may cause severe local irritation, swelling, and edema; such solutions are not recommended for chemical disinfection of the container, and preventive measures are recommended if they are used for skin or mucous membrane disinfection prior to anesthetic administration ^{{21} {35}})


Guanadrel or
Guanethidine or
Mecamylamine or
Trimethaphan    (the risk of severe hypotension and/or bradycardia may be increased if high levels of spinal or epidural anesthesia [i.e., sufficient to produce sympathetic blockade] are induced in patients receiving these ganglionic-blocking antihypertensive agents ^{131})


Halothane    (may increase the cardiotoxicity of bupivacaine ^{40})


Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (concurrent use in patients receiving local anesthetics may increase the risk of hypotension ^{{05} {35}}; discontinuation of MAO inhibitors 10 days before elective surgery may be advisable if subarachnoid block anesthesia is planned)


Neuromuscular blocking agents    (inhibition of neuronal transmission by local anesthetics may enhance or prolong the action of neuromuscular blocking agents if large quantities of the anesthetic are rapidly absorbed ^{126})


Opioid (narcotic) analgesic anesthesia adjuncts    (alterations in respiration caused by high levels of spinal or peridural blockade may be additive to opioid analgesic–induced alterations in respiratory rate and alveolar ventilation)

    (the vagal effects of alfentanil, fentanyl, or sufentanil may also be more pronounced in patients with high levels of spinal or epidural anesthesia, and may lead to bradycardia and/or hypotension)


» Vasoconstrictors such as epinephrine, methoxamine, or phenylephrine    (use of methoxamine in combination with local anesthetics to prolong their action at local sites is not recommended, since methoxamine"s extended effect may cause excessive restriction of circulation and lead to sloughing of tissue )

    (other vasoconstrictors should be used cautiously and in carefully circumscribed quantities, if at all, with local anesthetics when anesthetizing areas with end arteries [such as the fingers, nose, toes, or penis] or with otherwise compromised blood supply; ischemia leading to gangrene may result ^{{35} {91}})


For ester-type local anesthetics (in addition to those interactions listed above as applying to all local anesthetics)
Cholinesterase inhibitors such as:
Antimyasthenics
Cyclophosphamide
Demecarium
Echothiophate
Insecticides, neurotoxic, possibly including large quantities of topical malathion
Isoflurophate
Thiotepa    (concurrent use with an ester-type local anesthetic may inhibit the metabolism of the anesthetic, leading to increased risk of toxicity ^{131})


Sulfonamides    (antibacterial activity may be antagonized by ester-type local anesthetics, which are metabolized to PABA or PABA derivatives ^{11})


For concurrent use of sympathomimetic vasoconstrictors such as epinephrine, levonordefrin, norepinephrine, or phenylephrine (in addition to those interactions listed above and applicable to the specific local anesthetic)

Note: The risk of a significant systemic effect resulting from an interaction between any of the following and a vasoconstrictor-containing local anesthetic solution depends on the total dose (volume and concentration) of vasoconstrictor administered and on factors affecting the rate of absorption of the vasoconstrictor (site and route of administration and potential for inadvertent intravascular administration) ^{17}.

Alpha-adrenergic blocking agents, such as
Labetalol
Phenoxybenzamine
Phentolamine
Prazosin
Tolazoline or
Other medications with alpha-adrenergic blocking action, such as
» Droperidol
» Haloperidol
Loxapine
» Phenothiazines
Thioxanthenes or
Vasodilators, rapidly acting, such as nitrates    (these medications may reduce the efficacy of the vasoconstrictor ^{{05} {09} {11}})

    (in patients receiving epinephrine alpha-adrenergic blockade may result in unopposed beta-adrenergic activity with a risk of severe hypotension and tachycardia ^{86})

    (vasoconstrictors may also decrease the therapeutic effects of vasodilators, including the antianginal effects of nitrates)


» Anesthetics, hydrocarbon inhalation    (halothane and, to a much lesser extent, enflurane, isoflurane, or methoxyflurane may sensitize the heart to the effects of a sympathomimetic vasoconstrictor; concurrent use with a vasoconstrictor may cause dose-related cardiac arrhythmias ^{35})


» Antidepressants, tricyclic or
» Maprotiline    (concurrent use may potentiate the cardiovascular effects of the vasoconstrictor, possibly resulting in arrhythmias, tachycardia, or severe hypertension or hyperpyrexia ^{{21} {35} {130}})


Antihypertensives    (antihypertensive effects may be decreased by vasoconstrictors; monitoring of blood pressure is recommended)


» Beta-adrenergic blocking agents, including ophthalmic agents    (concurrent use of nonselective beta-adrenergic blocking agents with a vasoconstrictor may result in unopposed alpha-adrenergic activity with a dose-dependent risk of hypertension and bradycardia with possible heart block ^{129})


CNS stimulation–producing medications, other, (see Appendix II ), especially
» Cocaine, mucosal-local    (concurrent use with a vasoconstrictor may result in excessive CNS stimulation, leading to nervousness, irritability, insomnia, and possibly convulsions or cardiac arrhythmias; close observation of the patient is recommended)

    (concurrent use of other sympathomimetics with vasoconstrictors also increases the risk of adverse cardiovascular effects; although vasoconstrictor-containing local anesthetic solutions are sometimes used in conjunction with low doses of cocaine for mucous membrane anesthesia, caution is recommended ^{83})

    (concurrent use of doxapram, mazindol, or methylphenidate with a vasoconstrictor may also increase the pressor effects of the vasoconstrictor; concurrent use may also increase the pressor effect of doxapram ^{{97} {127}})


» Digitalis glycosides or
Levodopa    (concurrent use with a vasoconstrictor may increase the risk of cardiac arrhythmias ^{119})


Ergot derivatives, including antimigraine agents and oxytocics     (the vasoconstrictive effects of ergot derivatives may be additive to those of sympathomimetic vasoconstrictors; concurrent or sequential administration may cause severe, persistent hypertension ^{{05} {11} {35}}; rarely, rupture of a cerebral blood vessel has occurred postpartum after an ergot-type oxytocic was administered within 3 to 4 hours following caudal block anesthesia with a vasoconstrictor)


Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (concurrent use may prolong and intensify cardiac stimulant and vasopressor effects of phenylephrine, possibly leading to headache, cardiac arrhythmias, and/or severe, sustained hypertension ^{{05} {12} {21} {35}})


Rauwolfia alkaloids    (in addition to possibly decreasing the antihypertensive effect of rauwolfia alkaloids, a “denervation supersensitivity” response is possible; although problems with systemic vasoconstrictors have not been reported, a significant increase in blood pressure has been documented with administration of phenylephrine ophthalmic drops to patients taking reserpine; caution and close observation are recommended ^{44})


Ritodrine    (concurrent use with epinephrine, levonordefrin, or norepinephrine may increase the effect of either medication and the risk of side effects ^{45})


Thyroid hormones    (concurrent use with a sympathomimetic agent may increase the risk of coronary insufficiency in patients with coronary artery disease; dosage adjustment of the sympathomimetic is recommended, although the risk is reduced in euthyroid patients)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Pancreatic function determinations using bentiromide    (administration of PABA-derivative local anesthetics or of lidocaine within 3 days before the bentiromide test may invalidate the test results because these anesthetics are metabolized to PABA or other arylamines and will therefore increase the true or apparent quantity of PABA recovered)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Note: A standard reference source should be consulted for more specific information concerning medical problems that may apply to specific local anesthetic procedures.


Except under special circumstances, this medication should not be used when the following medical problems exist:

For levobupivacaine and bupivacaine:
For paracervical administration in obstetrics    (increased risk of fetal bradycardia and death ^{35}{135})


For prilocaine only:
» Methemoglobinemia    (may be induced or exacerbated ^{07})


For subarachnoid block:
» Complete heart block or
» Hemorrhage, severe or
» Hypotension, severe or
» Shock    (may be exacerbated by cardiac depressant effects and vasodilation; also, metabolism of amides may be decreased because of reduced hepatic blood flow ^{05})


» Local infection at site of proposed lumbar puncture    (lumbar puncture may spread infection into the arachnoid space; also, infection may alter pH at site of injection, resulting in decrease or loss of local anesthetic effect ^{06})


» Septicemia    (decreased patient tolerance to CNS stimulant effects ^{05})


Risk-benefit should be considered when the following medical problems exist

For all local anesthetic usage:
Any condition in which hepatic blood flow may be decreased, such as:
Congestive heart failure or
Hepatic disease or impairment     (increased risk of toxicity because of reduced clearance, especially with amides ^{{12} {35}{135}}; a decrease in dosage and/or an increase in the interval between doses may be necessary, especially with lidocaine)


» Cardiovascular function impairment, especially heart block or shock or
Hypotension or
Hypovolemia    (cardiovascular function impairment may be exacerbated by cardiac depressant effects ^{{05} {35}})


» Drug sensitivity, history of, especially to the anesthetic being considered for use and chemically related anesthetics or other compounds     (increased risk of hypersensitivity reactions ^{11})


» Inflammation and/or infection in region of injection    (may alter pH at site of injection resulting in decrease or loss of anesthetic effect ^{11})


Plasma cholinesterase deficiency—for esters    (increased risk of toxicity because of decreased metabolism ^{{04} {11}})


Renal disease    (anesthetic or metabolites may accumulate)


Caution is also recommended in very young, elderly, acutely ill, or debilitated patients, who may be more susceptible to systemic toxicity induced by local anesthetics.
For paracervical administration in obstetrics:
Fetal distress, pre-existing or
Prematurity or
Postmaturity or
Toxemia of pregnancy or
Uteroplacental insufficiency, pre-existing    (increased risk of fetal bradycardia and acidosis ^{16})


Note: Use of chloroprocaine is not recommended if prematurity, pre-existing fetal distress, or toxemia of pregnancy is present because its safety in these conditions has not been established ^{04}.


For peridural (caudal or lumbar epidural) anesthesia:
Neurological disease, pre-existing ^{05}
Septicemia    (decreased patient tolerance to CNS stimulant effects ^{05})


Spinal deformity that may interfere with administration and/or effectiveness of local anesthetic ^{05}
For subarachnoid anesthesia:
Backache, chronic    (may be exacerbated ^{06})


» CNS disease, pre-existing, attributable to infection, tumor or other causes
» Coagulation defects induced by anticoagulant therapy or hematologic disorders    (trauma to a blood vessel during administration may result in uncontrollable CNS or soft tissue hemorrhage ^{06})


Headache, pre-existing, especially history of migraine    (may be induced or exacerbated ^{06})


Hemorrhagic spinal fluid    (risk of inadvertent intravascular administration ^{06})


Hypertension ^{05}
Hypotension    (may be exacerbated by cardiac depressant and vasodilating effects ^{06})


Paresthesias, persistent
Psychosis, hysteria or uncooperative patient ^{06}
Spinal conditions or deformities that may interfere with administration and/or effectiveness of anesthetic ^{05}
For vasoconstrictor-containing preparations:
Asthma    (increased risk of anaphylactic or bronchospastic allergic-like reactions induced by the sulfites in commercially available solutions ^{09})


» Cardiac disease or arrhythmias ^{35} or
Diabetes mellitus or ^{48}
» Hyperthyroidism    (cardiac stimulant effects may be detrimental to patients with these conditions ^{07})


» Hypertension or
» Vascular disease, peripheral    (exaggerated vasoconstrictor response may occur, leading to increased risk of severe hypertension or ischemic injury or necrosis ^{07})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Cardiovascular status and
Respiratory status and
State of consciousness    (should be monitored after each local anesthetic injection to detect impending CNS and/or cardiovascular toxicity. ^{{05} {91}}Early signs of CNS toxicity include restlessness, anxiety, incoherent speech, light-headedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness. ^{135})


Fetal heart rate    (should be monitored during paracervical administration in obstetrics to detect fetal bradycardia ^{16})




Side/Adverse Effects

Note: Adverse reactions are generally dose-related and may result from high plasma concentrations of anesthetic caused by inadvertent intravascular administration, excessive dosage, or rapid absorption from the injection site as well as reduced patient tolerance, idiosyncrasy, or hypersensitivity.
Adverse effects are also related to the specific local anesthetic used and the route and site of administration. Small doses of local anesthetics injected into the head and neck area (including retrobulbar, dental, and stellate ganglion blocks) or in the tracheobronchial area may produce adverse reactions similar to those caused by inadvertent intravascular injection of larger doses ^{{16} {91}}. Also, unintentional subarachnoid administration during intended performance of a peridural block or a nerve block near the vertebral column (especially in the head and neck area) may result in adverse effects that depend at least partially on the quantity of anesthetic administered subdurally.
Systemic reactions may occur rapidly or may be delayed for up to 30 minutes following administration.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Anemia^{135} (pale skin ; troubled breathing, exertional ; unusual bleeding or bruising ; unusual tiredness or weakness)
    
back pain ^{{05} {06} {35} {60} {102}}
    
bradycardia ^{{04} {05} {11} {35}} (dizziness)
    
cardiac arrhythmias ^{{107} {123} {125}} ( irregular heartbeat)
    
chest pain —may be sympathomimetic effect caused by vasoconstrictor added to local anesthetic, or may be caused by decreased perfusion resulting from hypotension
    
constipation
^{135}    
dizziness ^{12}
    
drowsiness ^{{04} {05} {11} {12} {35}}
    
headache ^{12}
    
hives ^{{04} {12}} ( raised red swellings on the skin, lips, tongue, or in the throat)
    
hypertension ^{12} —may be sympathomimetic effect caused by vasoconstrictor added to local anesthetic
    
hypotension ^{{04} {05} {11} {12} {35}} ( dizziness)
    
fever ^{135}
    
hypothermia ^{{89} {101}} (shivering)
    
impotence ^{{05} {35}} (loss of sexual function)
    
incontinence, fecal and/or urinary ^{{35} {64} {100}} ( inability to hold bowel movement and/or urine)—may indicate cauda equina syndrome
    
methemoglobinemia ^{07} ( bluish lips and fingernails; breathing problems; dizziness; fatigue; headache ; rapid heart rate; weakness)
    
nausea and/or vomiting
    
numbness or tingling of lips and mouth, prolonged ^{38} —may occur when an anesthetic is used for dental anesthesia
    
paralysis of legs ^{64} —may indicate cauda equina syndrome
    
paresthesias ^{64} (tingling or “pins and needles” sensation )—may indicate cauda equina syndrome
    
persistent anesthesia ^{38} (numbness)
    
pruritus ^{04} ( itching)
    
respiratory paralysis (inability to breath without assistance)
    
restlessness ^{12} —may be caused by vasoconstrictor added to local anesthetic
    
seizures ^{{04} {05} {11} {35} {94}} (convulsions)
    
skin rash ^{04}
    
tachycardia ^{12} (rapid heart rate)—may be caused by vasoconstrictor added to local anesthetic
    
trismus of facial muscles ^{05} (difficulty in opening the mouth)^{08}—may occur when an anesthetic is used for dental anesthesia
    
unconsciousness ^{12}
    
vasodilation, peripheral ^{05} (dizziness)

Note: Anaphylactoid reactions, including shock, have been reported rarely. The effectiveness of a small test dose in predicting the risk of allergic reactions has not been determined.
Motor and sensory block extending higher on the trunk of the body than intended may occur following subarachnoid administration of local anesthetics. This may also occur following inadvertent subarachnoid administration during intended performance of a peridural block. Occasionally paralysis of chest wall muscles may result in respiratory paralysis.
Some patients receiving lidocaine for spinal anesthesia have developed neurologic complications following anesthesia ^{{06} {60} {61} {62} {63} {64} {65} {66} {67} {68} {69} {70} {71} {85}}. The neurologic complications usually are temporary paresthesias and back pain (transient radicular irritation) . However, persistent paresthesia, paralysis of legs, or impairment of bodily functions (e.g., incontinence) may indicate a serious neurologic complication, cauda equina syndrome. Uneven distribution of hyperbaric lidocaine following spinal administration may contribute to cauda equina syndrome ^{{06} {63} {64} {65}}. In cases of transient radicular irritation, symptoms resolve within a few days to a few weeks ^{{60} {61} {62} {66} {67} {68} {69} {70} {71} {85}}. However, neurotoxic effects may not resolve in cases of cauda equina syndrome ^{64}. Other anesthetics may cause cauda equina syndrome also ^{{120} {121} {122}}.







Overdose
For specific information on the agents used in the management of a local anesthetic overdose, see:    • Benzodiazepines (Systemic) monograph;
   • Ephedrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) ;
   • Mephentermine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) ;
   • Metaraminol in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) ;
   • Methylene Blue (Systemic) monograph;
   • Neuromuscular Blocking Agents (Systemic) monograph; and/or
   • Thiopental in Anesthetics, Barbiturate (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Apnea
    
circulatory depression^{05}{09}
    
methemoglobinemia^{07}
    
seizures^{09}


Treatment of overdose


Specific treatment:
For circulatory depression: Administering a vasopressor and intravenous fluids is recommended. For maternal hypotension during obstetrical anesthesia, it is recommended that the patient be placed on her left side, if possible, to correct aortocaval compression by the gravid uterus. Delivery of the fetus may improve the response of the obstetric patient to cardiopulmonary resuscitation ^{47}.

For seizures: Protect the patient and administer oxygen immediately ^{84}. If seizures do not respond to respiratory support, administering a benzodiazepine such as diazepam or an ultrashort-acting barbiturate such as thiopental or thiamylal intravenously is recommended ^{04}. The fact that these agents, especially the barbiturates, may cause circulatory depression when administered intravenously must be kept in mind. A neuromuscular blocking agent may also be used to decrease the muscular manifestations of persistent seizures if positive-pressure ventilation can be immediately provided ^{84}. Hypoxia, hypercapnea, and acidosis can develop quickly following the onset of seizures.

For methemoglobinemia: If methemoglobinemia does not respond to administration of oxygen, administration of methylene blue is recommended ^{07}.

Monitoring—Blood pressure, heart rate, neurologic status, and respiratory status should be monitored continuously.

Supportive care—Securing and maintaining a patent airway ^{09}, administering oxygen, and instituting assisted or controlled respiration as required. In some patients, endotracheal intubation may be required.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Anesthetics (Parenteral-Local) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Allergies to the anesthetic considered for use, related anesthetics, other related compounds, and additives (methylparaben, sulfites)

Pregnancy—Potential rare unwanted effects with obstetrical use





Use in children—Increased risk of systemic toxicity






Use in the elderly—Increased risk of systemic toxicity
Other medications, especially nonselective beta-adrenergic blocking agents, CNS depression–producing medications, cocaine, digitalis glycosides, droperidol, haloperidol, hydrocarbon inhalation anesthetics, maprotiline, phenothiazines, tricyclic antidepressants, or vasoconstrictors such as epinephrine, methoxamine or phenylephrine
Other medical problems, especially cardiac disease or arrhythmias, cardiovascular function impairment, coagulation defects, hypertension, hyperthyroidism, local infection at the site of injection or proposed lumbar puncture, methemoglobinemia, peripheral vascular disease, pre-existing CNS disease

Proper use of this medication

Proper dosing

Precautions after receiving this medication
Caution that injury may occur undetected while numbness persists in the affected area; using care to prevent injury, including not eating or chewing gum following dental anesthesia (to prevent biting trauma) ^{{09} {91}}


Side/adverse effects
Signs and/or symptoms of potential side effects, especially anemia, back pain, bradycardia, constipation, cardiac arrhythmias, chest pain, dizziness, drowsiness, fever, headache, hives, hypertension, hypotension, hypothermia, impotence, incontinence (fecal and/or urinary), methemoglobinemia, nausea and/or vomiting, numbness or tingling of lips and mouth (prolonged), paralysis of legs, paresthesias, persistent anesthesia, pruritus, respiratory paralysis, restlessness, seizures, skin rash, tachycardia, trismus of facial muscles, vasodilation (peripheral)


General Dosing Information
The safety and effectiveness of local anesthetics depend upon proper dosage, correct technique, adequate precautions, and readiness for emergencies. Local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of drug-related toxicity and other acute emergencies which might arise from the block being administered. Resuscitative equipment, oxygen, and other resuscitative drugs should be immediately available when any local anesthetic is used ^{91}.

A standard text should be consulted for specific techniques and procedures for administering local anesthetics ^{{09} {11} {91}}.

The dosage of local anesthetics depends on the specific anesthetic procedure; vascularity of the tissues at or near the site of injection; specific nerve, plexus, or fiber to be blocked; type of surgery being performed (number of neuronal segments to be blocked, depth of anesthesia and degree of muscle relaxation required, and duration of anesthesia desired); and patient variables such as age and weight ^{04}.

The recommended adult doses are given as a guideline for use in the average adult. The actual dosage and maximum dosage must be individualized, based on the age, size, and physical status of the patient and the expected rate of systemic absorption from the injection site. The lowest dosage (volume and concentration) that produces the desired results should be used ^{09}.

Lower doses should be used for pediatric, geriatric, acutely ill, or debilitated patients and patients with cardiac or hepatic disease ^{{09} {91}}. Lower doses are also required for repeated injections (as for multiple nerve blocks or continuous catheter [intermittent] administration techniques), and for nerve blocks in highly vascular areas, in order to prevent excessively high plasma concentrations.

Dilutions of anesthetics for epidural injections should be made with preservative free 0.9% saline according to standard hospital procedures for sterility. ^{135}

Local anesthetics may be administered as single injections or continuously or intermittently through an indwelling catheter. Fractional doses are especially recommended for peridural blocks ^{04}.

Local anesthetics should be injected slowly, with frequent aspirations before and during the injection, to reduce the risk of inadvertent intravascular administration ^{09}. Additional aspirations should be performed before and during each supplemental injection via an indwelling catheter. However, intravascular administration is possible even when aspiration for blood is negative. Consider including epinephrine with a test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. ^{135} In one study, intravascular administration occurred despite negative results on aspiration in 20% of patients undergoing dental treatment ^{54}.

For epidural anesthesia it is recommended that a test dose of a local anesthetic with a fast onset be administered initially and that the patient be monitored for central nervous system and cardiovascular toxicity, as well as for signs of unintended intrathecal administration before proceeding. ^{135}

For central neural blocks in obstetrical anesthesia, the anesthetic should not be injected during a strong uterine contraction or while the patient is bearing down because excessively high levels of anesthesia may result.

For peridural blocks, injection of a small test dose (usually 2 to 5 mL of solution, consult manufacturers" product information for details) is recommended so that the patient can be monitored for signs of inadvertent subarachnoid or intravascular administration ^{{04} {05} {09}}. If clinical conditions permit, the use of a vasoconstrictor-containing solution is recommended because circulatory changes produced by a vasoconstrictor may indicate intravascular administration ^{{05} {09}}. The test dose should be repeated if a patient is moved in any manner that may cause displacement of the catheter.

For retrobulbar block, lack of corneal sensation should not be relied upon to determine readiness for surgery because lack of corneal sensation usually precedes clinically acceptable external ocular muscle akinesia ^{35}.

The extent and degree of subarachnoid block depend on the position of the patient during and immediately after injection, dosage, specific gravity of the solution, volume of solution used, force of injection, and the level of puncture. Hyperbaric solutions (with dextrose added to render the solution heavier than cerebrospinal fluid [CSF]) are usually used for low spinal anesthesia. Isobaric solutions (having the same specific gravity as CSF) produce anesthesia at the level of intrathecal injection. Hypobaric solutions (diluted to have a lower specific gravity than CSF) are used to produce anesthesia of thoracic structures and for low spinal anesthesia. A standard text and/or manufacturers" product information may be consulted for details concerning dilution and positioning of patient during and following administration. ^{{06} {37}}

Vasoconstrictors decrease the rate of local clearance of the local anesthetic, thereby reducing the risk of systemic toxic reactions, prolonging the anesthetic effect, increasing the frequency of complete conduction blocks at low anesthetic concentrations, and permitting larger maximum single doses of anesthetic to be administered. Epinephrine 1:200,000 is the most commonly used vasoconstrictor for most purposes; levonordefrin, norepinephrine, and phenylephrine may also be used. In dentistry, epinephrine 1:50,000 to 1:200,000 and levonordefrin 1:20,000 are the most commonly used vasoconstrictors. ^{{124} {133}}

Solutions containing a vasoconstrictor should be used cautiously and in carefully circumscribed quantities, if at all, in tissues supplied by end arteries (such as the fingers, nose, toes, or penis) or having otherwise compromised blood supply; ischemia leading to gangrene may result ^{35}. Also, a vasoconstrictor should not be injected repeatedly at the same site for dental procedures because reduced blood flow and increased oxygen consumption in the affected tissues may cause tissue anoxia, delayed healing, edema, or necrosis at the injection site.

Intravenous access should be obtained prior to the placement of major nerve blocks to permit the administration of emergency drugs during resuscitation if a serious adverse reaction occurs ^{28}.

For treatment of adverse effects
Recommended treatment consists of the following:

   • For seizures—If seizures do not respond to respiratory support, administering a benzodiazepine such as diazepam (in 2.5-mg increments) or an ultrashort-acting barbiturate such as thiopental or thiamylal (in 50- to 100-mg increments) intravenously every 2 to 3 minutes is recommended ^{04}. The fact that these agents, especially the barbiturates, may cause circulatory depression when administered intravenously must be kept in mind. A neuromuscular blocking agent may also be used to decrease the muscular manifestations of persistent seizures; artificial respiration is mandatory if such an agent is used.
   • For methemoglobinemia—If methemoglobinemia does not respond to administration of oxygen, administration of methylene blue (intravenous, 1 ^{07} to 2 mg per kg of body weight (mg/kg) as a 1% solution, over a 5-minute period) is recommended.

ARTICAINE
Summary of Differences


Indications:
Indicated for dental infiltration or nerve block^{58}{137}.
Note: Anesthesia of mandibular pulpal and lingual soft tissue and of maxillary palatal soft tissue with buccal infiltration of articaine is not effective in all patients who require the administration of articaine by nerve block technique. In a study in adults, there was no difference between prilocaine and articaine in providing successful anesthesia of mandibular pulpal and lingual soft tissue and of maxillary palatal soft tissue with buccal infiltration. After buccal infiltration of articaine, anesthesia was successful in 63% of cases for the mandibular pulp, 50% for mandibular lingual tissue, and 20% for palatal tissue^{50}. The use of mandibular infiltration in pediatric patients for procedures in primary mandibular teeth has had mixed success, with one study showing results similar to those seen in adults.





Pharmacology/pharmacokinetics:


Physicochemical characteristics—
Chemical group: Amide-type local anesthetic with an ester linkage and a thiophene ring ^{48}{137}

Molecular weight: 284.38 ^{{48} {59}}



Half-life—
1.2 hours ^{48}{137}



Onset of action—
Rapid (within 1 to 6 minutes) ^{{48} {49}{137}}



Duration of action—
Intermediate (1 to 3 hours) ^{137}




Precautions:


Cross-sensitivity and/or related problems—
May occur with other amide-type local anesthetics ^{48}and additives (sulfites) ^{137}.



Pediatrics—
Although articaine is not approved for use in children younger than 4 years of age^{137}, a retrospective study of its use in 211 pediatric patients younger than 4 years of age did not reveal any pediatrics-specific problems that would limit its use in children.




Additional Dosing Information
See General Dosing Information.


Parenteral Dosage Forms

ARTICAINE HYDROCHLORIDE WITH EPINEPHRINE INJECTION

Usual adult and adolescent dose
Dental infiltration anesthesia
20 to 100 mg (0.5 to 2.5 mL) as a 4% solution ^{48}{137}.

Dental nerve block anesthesia
20 to 136 mg (0.5 to 3.4 mL) as a 4% solution ^{48}{137}.

Oral surgery anesthesia
40 to 204 mg (1 to 5.1 mL) as a 4% solution ^{48}{137}.


Usual adult prescribing limits
7 mg per kg of body weight (0.175 mL/kg)^{48}{137}.

Usual pediatric dose
Children younger than 4 years of age—Safety and efficacy have not been established.
Children 4 to 12 years of age—Dosage must be individualized, based on the age and weight of the patient^{48}{137}.

Usual pediatric prescribing limits
Children 4 to 12 years of age—5 mg per kg of body weight.

Strength(s) usually available
U.S.—


4% (40 mg per mL), with epinephrine 1:100,000 (Rx) [Septocaine™ (sodium chloride 1.8 mg per mL) ( sodium metabisulfite 0.5 mg per mL)]^{137}

Canada—


4% (40 mg per mL), with epinephrine 1:100,000 (Rx) [Ultracaine D-S Forte (sodium metabisulfite 0.5 mg per mL) ( methylparaben 1 mg per mL)]^{48} [Astracaine 4% Forte^{95} (sodium metabisulfite)]


4% (40 mg per mL), with epinephrine 1:200,000 (Rx) [Ultracaine D-S ( sodium metabisulfite 0.5 mg per mL) (methylparaben 1 mg per mL)]^{48} [Astracaine 4%^{95} (sodium metabisulfite)]

Packaging and storage:
Store below 25 °C (77 °F), unless otherwise specified by manufacturer. Protect from freezing. Protect from light.


BUPIVACAINE
Summary of Differences


Indications:
Except as noted below, indicated (without epinephrine) for retrobulbar block; indicated (with or without epinephrine) for caudal or lumbar epidural block, local infiltration, peripheral nerve block, and sympathetic block; indicated (with epinephrine) for dental infiltration or nerve block; and indicated (with dextrose) for subarachnoid block.

Paracervical administration not recommended.

Not recommended for intravenous regional anesthesia (Bier block).



Pharmacology/pharmacokinetics:


Physicochemical characteristics—
Chemical group: Amide-type local anesthetic

Molecular weight: bupivacaine hydrochloride—342.91 ^{72}

pKa: 8.1

Lipid solubility: High ^{28}



Protein binding—
Very high ^{28}



Half-life—
3.5 hours (adults); 8.1 to 14 ^{09} hours (neonates)



Onset of action—
Intermediate



Duration of action—
Long (3 to 10 hours) ^{{09} {28}}



Elimination—
5% of a dose may be excreted unchanged ^{{09} {35}}




Precautions:


Cross-sensitivity and/or related problems—
May occur rarely with other amide-type local anesthetics ^{09}



Pregnancy—
Embryocidal effects have been demonstrated in rats and rabbits ^{{09} {35}}



Breast-feeding—
Distributed into breast milk



Pediatrics—
Infants up to 9 months of age may have low plasma concentrations of alpha ₁-acid glycoprotein (AAG)^{110}. This results in an increased unbound fraction of bupivacaine, and may lead to systemic toxicity.

Reduced clearance of bupivacaine in pediatric patients may be more important than AAG concentrations in causing toxicity. Neonates may have total body clearance of bupivacaine only one third to one half the clearance of adults^{36}.




Drug interactions and/or related problems:
Interaction with cimetidine.

Interaction with halothane.



Side/adverse effects:
Prolonged cardiovascular depression and arrhythmias have been reported. The cardiotoxicity of bupivacaine may be increased if the patient experiences hypothermia, hyponatremia, hyperkalemia or myocardial ischemia^{106}. Concomitant use of halothane may cause increased cardiotoxicity of bupivacaine.



Additional Dosing Information
See also General Dosing Information .

Bupivacaine 0.25% generally produces incomplete motor block and is used when muscle relaxation is not important^{35}. However, intercostal nerve block with this strength of bupivacaine may produce complete motor block for intra-abdominal surgery in some patients.

Bupivacaine 0.5% produces motor block and some muscle relaxation when used for caudal, epidural, or nerve block^{35}. With continuous catheter (intermittent) administration techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% bupivacaine may produce complete motor block.

Bupivacaine 0.75% produces complete motor block and complete muscle relaxation. When used for epidural block, the 0.75% solution is intended for single-dose administration only; it should not be used for intermittent administration techniques.

Bupivacaine 0.75% is not recommended for epidural block in obstetrics because inadvertent intravascular injection has caused maternal cardiac arrest^{35}. However, lower concentrations may be used. When bupivacaine is used for epidural block in obstetrics, the dose of bupivacaine should be chosen to provide safe and adequate relief of pain without causing toxicity, prolonged hypotension, or loss of motor strength^{41}. The majority of obstetric patients will achieve analgesia with continuous epidural infusions of 0.0625 to 0.125% bupivacaine at 10 to 15 mL per hour^{41}. The addition of subarachnoid narcotics or epidural fentanyl (1 to 2 mcg per mL) or sufentanil (0.1 to 0.2 mcg per mL) usually will allow the use of a lower concentration or a lower infusion rate of bupivacaine. The use of the lowest possible concentration usually will reduce the risk of fetal or maternal toxicity while providing appropriate analgesia. However, in some patients where the goals are different, e.g., blood pressure control or the obliteration of any contraction sensation, higher concentrations may be required.


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

BUPIVACAINE HYDROCHLORIDE INJECTION USP

Usual adult and adolescent dose
Caudal anesthesia
Moderate motor block: 37.5 to 75 mg (15 to 30 mL) as a 0.25% solution, repeated once every three hours as needed ^{{28} {35}}.

Moderate to complete motor block: 75 to 150 mg (15 to 30 mL) as a 0.5% solution, repeated once every three hours as needed^{35}.

Epidural anesthesia
Partial to moderate motor block: 25 to 50 mg (10 to 20 mL) as a 0.25% solution, repeated once every three hours as needed.

Moderate to complete motor block: 50 to 100 mg (10 to 20 mL) as a 0.5% solution, repeated once every three hours as needed.

Complete motor block: 75 to 150 mg (10 to 20 mL) as a 0.75% solution.

Epidural obstetric analgesia
Continuous infusion, 6.25 to 18.75 mg per hour as a 0.0625 to 0.125% solution.

Local infiltration
Single dose: 175 mg (70 mL) as a 0.25% solution.

Peripheral nerve block
Moderate to complete motor block: 12.5 to 175 mg (5 to 70 mL) as a 0.25% solution; or 25 to 175 mg (5 to 37.5 mL) as a 0.5% solution^{35}. Dosage may be repeated every three hours if necessary.

Retrobulbar block
15 to 30 mg (2 to 4 mL) as a 0.75% solution.

Sympathetic block
50 to 125 mg (20 to 50 mL) as a 0.25% solution, repeated once every three hours as needed.


Usual adult prescribing limits
175 mg as a single dose or 400 mg per day.

Usual pediatric dose
Children weighing over 10 kg


[Caudal analgesia, single dose]:
1 to 2.5 mg per kg of body weight as a 0.125 or 0.25% solution.



[Caudal analgesia, continuous infusion]:
0.2 to 0.4 mg per kg of body weight per hour as a 0.1, 0.125, or 0.25% solution, not to exceed 0.4 mg per kg of body weight per hour.



[Caudal or epidural anesthesia, single dose]:
1 to 2.5 mg per kg of body weight as a 0.125 or 0.25% solution^{112}.



[Caudal or epidural anesthesia, continuous infusion]:
0.2 to 0.4 mg per kg of body weight per hour as a 0.1, 0.125, or 0.25% solution, not to exceed 0.4 mg per kg of body weight per hour.



[Local infiltration]:
0.5 to 2.5 mg per kg of body weight as a 0.25 or 0.5% solution^{114}.



[Peripheral nerve block]:
0.3 to 2.5 mg per kg of body weight as a 0.25 or 0.5% solution^{114}.


Infants and children weighing up to 10 kg


[Caudal analgesia, single dose]:
1 to 1.25 mg per kg of body weight as a 0.125 or 0.25% solution^{111}.



[Caudal analgesia, continuous infusion]:
0.1 to 0.2 mg per kg of body weight per hour as a 0.1, 0.125, or 0.25% solution, not to exceed 0.2 mg per kg of body weight per hour.



[Caudal or epidural anesthesia, single dose]:
1 to 1.25 mg per kg of body weight as a 0.125 or 0.25% solution^{19}.



[Caudal or epidural anesthesia, continuous infusion]:
0.1 to 0.2 mg per kg of body weight per hour as a 0.1, 0.125, or 0.25% solution, not to exceed 0.2 mg per kg of body weight per hour.



[Local infiltration]:
0.5 to 2.5 mg per kg of body weight as a 0.25 or 0.5% solution^{114}.



[Peripheral nerve block]:
0.3 to 2.5 mg per kg of body weight as a 0.25 or 0.5% solution.



Note: Bupivacaine is approved in the U.S. for use in patients older than 12 years of age. Bupivacaine is approved in Canada for use in patients older than 2 years of age^{09}.


Usual pediatric prescribing limits
[Local infiltration or]
[Peripheral nerve block]
The usual maximum dose is 1 mL per kg of body weight of 0.25% bupivacaine. If bupivacaine 0.5% is used, the usual maximum is 0.5 mL per kg of body weight. The maximum dose to be used depends on the site of administration.


Strength(s) usually available
U.S.—



With preservative (methylparaben 1 mg per mL)


0.25% (2.5 mg per mL) (Rx) [Marcaine^{01}] [Sensorcaine^{35}][Generic]


0.5% (5 mg per mL) (Rx) [Marcaine^{01}] [Sensorcaine^{35}][Generic]



Without preservative


0.25% (2.5 mg per mL) (Rx) [Marcaine^{01}] [Sensorcaine-MPF^{35}][Generic]


0.5% (5 mg per mL) (Rx) [Marcaine^{01}] [Sensorcaine-MPF^{35}][Generic]


0.75% (7.5 mg per mL) (Rx) [Marcaine^{01}] [Sensorcaine-MPF^{35}][Generic]

Canada—



With preservative (methylparaben 1 mg per mL)


0.25% (2.5 mg per mL) (Rx) [Marcaine^{28}]


0.5% (5 mg per mL) (Rx) [Marcaine^{28}]



Without preservative


0.25% (2.5 mg per mL) (Rx) [Marcaine^{28}] [Sensorcaine^{09}]


0.5% (5 mg per mL) (Rx) [Marcaine^{28}] [Sensorcaine^{09}]


0.75% (7.5 mg per mL) (Rx) [Marcaine^{28}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
May be autoclaved.

For chemical disinfection of container surface, 91% isopropyl alcohol or 70% ethyl alcohol without denaturants is recommended; solutions containing heavy metals should not be used^{28}.

Unused portions of solutions without a preservative must be discarded^{28}.


BUPIVACAINE HYDROCHLORIDE AND EPINEPHRINE INJECTION USP

Usual adult and adolescent dose
Dental
For infiltration and nerve block in maxillary and mandibular area: 9 mg (1.8 mL) of bupivacaine hydrochloride as a 0.5% solution with epinephrine 1:200,000 per injection site. A second dose may be administered if necessary to produce adequate anesthesia after allowing up to 10 minutes for onset .

Other indications
See Bupivacaine Hydrochloride Injection USP . Administration of epinephrine concurrently with the local anesthetic may permit use of doses somewhat larger than those listed.


Usual adult prescribing limits
In dentistry
90 mg of bupivacaine hydrochloride per dental visit ^{09}.

Other indications
225 mg as a single dose or 400 mg per day of bupivacaine hydrochloride^{09}.


Usual pediatric dose
See Bupivacaine Hydrochloride Injection USP.

Strength(s) usually available
U.S.—



With preservative (methylparaben 1 mg per mL)


0.25% (2.5 mg per mL), with epinephrine 1:200,000 (Rx) [Marcaine^{01} (sodium metabisulfite 0.5 mg per mL) (edetate calcium disodium)] [Sensorcaine^{35} (sodium metabisulfite 0.5 mg per mL)^{35}][Generic]


0.5% (5 mg per mL), with epinephrine 1:200,000 (Rx) [Marcaine^{01} (sodium metabisulfite 0.5 mg per mL) (edetate calcium disodium)] [Sensorcaine^{35} (sodium metabisulfite 0.5 mg per mL)][Generic]



Without preservative


0.25% (2.5 mg per mL), with epinephrine 1:200,000 (Rx) [Marcaine^{01} (sodium metabisulfite 0.5 mg per mL) (edetate calcium disodium)] [Sensorcaine-MPF^{35} (sodium metabisulfite 0.5 mg per mL) (citric acid, anhydrous 0.2 mg per mL )][Generic]


0.5% (5 mg per mL), with epinephrine 1:200,000 (Rx) [Marcaine^{01} (sodium metabisulfite 0.5 mg per mL) (edetate calcium disodium)] [Sensorcaine-MPF^{35} (sodium metabisulfite 0.5 mg per mL ) (citric acid, anhydrous 0.2 mg per mL)][Generic]


0.75% (7.5 mg per mL), with epinephrine 1:200,000 (Rx) [Marcaine^{01} (sodium metabisulfite 0.5 mg per mL) (edetate calcium disodium)] [Sensorcaine-MPF^{35} (sodium metabisulfite 0.5 mg per mL ) (citric acid, anhydrous 0.2 mg per mL)][Generic]



For dental use


0.5% (5 mg per mL; 9 mg per 1.8-mL dental cartridge), with epinephrine 1:200,000 (Rx) [Marcaine^{03} (sodium metabisulfite 0.5 mg per mL) (edetate calcium disodium)]

Canada—



Without preservative


0.25% (2.5 mg per mL), with epinephrine 1:200,000 (Rx) [Marcaine^{28} (sodium bisulfite 0.5 mg per mL) (edetate calcium disodium)] [Sensorcaine^{09} (sodium bisulfite 0.55 mg per mL) (citric acid 0.2 mg per mL)]


0.5% (5 mg per mL), with epinephrine 1:200,000 (Rx) [Marcaine^{28} (sodium bisulfite 0.5 mg per mL) (edetate calcium disodium)] [Sensorcaine^{09} (sodium bisulfite 0.55 mg per mL) (citric acid 0.2 mg per mL)]



For dental use


0.5% (5 mg per mL; 9 mg per 1.8-mL dental cartridge), with epinephrine 1:200,000 (Rx) [Sensorcaine Forte^{09} ( sodium metabisulfite 0.55 mg per mL) ( citric acid 0.2 mg per mL)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Stability:
On removal of doses from the vial, air is introduced, which slowly oxidizes the epinephrine causing discoloration of the solution and possible loss of potency. Do not use if solution is discolored or contains a precipitate^{28}.

Should not be autoclaved. For chemical disinfection of the container surface, 91% isopropyl alcohol or 70% ethyl alcohol without denaturants is recommended; solutions containing heavy metals are not recommended^{28}.

Unused portions of solutions without a preservative must be discarded.


BUPIVACAINE HYDROCHLORIDE IN DEXTROSE INJECTION USP

Usual adult dose
Hyperbaric spinal anesthesia


Obstetrical anesthesia:
Normal vaginal delivery—6 mg (0.8 mL) of bupivacaine hydrochloride as a 0.75% solution^{02}.

Cesarean section—7.5 to 10.5 mg (1 to 1.4 mL) of bupivacaine hydrochloride as a 0.75% solution.



Surgical anesthesia:
Lower extremity and perineal procedures—7.5 mg (1 mL) of bupivacaine hydrochloride as a 0.75% solution.

Lower abdominal procedures—12 mg (1.6 mL) of bupivacaine hydrochloride as a 0.75% solution^{28}.

Upper abdominal surgery—15 mg (2 mL) in the horizontal position.



Usual pediatric dose
[Hyperbaric spinal anesthesia ]
0.3 to 0.6 mg per kg of body weight as a 0.75% solution^{115}.


Strength(s) usually available
U.S.—



Without preservative


0.75% (7.5 mg per mL), with dextrose 8.25% (82.5 mg per mL) (Rx) [Marcaine Spinal^{02}] [Sensorcaine-MPF Spinal^{35}][Generic]

Canada—



Without preservative


0.75% (7.5 mg per mL), with dextrose 8.25% (82.5 mg per mL) (Rx) [Marcaine]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
May be autoclaved once; with repeated autoclaving or prolonged storage, caramelization of the dextrose may occur, leading to discoloration. Discolored solutions should not be used.

Do not use if solution contains a precipitate.


CHLOROPROCAINE
Summary of Differences


Indications:
Indicated for caudal or lumbar epidural block, dental infiltration or nerve block, local infiltration, peripheral nerve block, and intravenous regional anesthesia (Bier block).

Not recommended for subarachnoid administration.



Pharmacology/pharmacokinetics:


Physicochemical characteristics—
Chemical group: Ester-type local anesthetic ^{{04} {29}}

Molecular weight: chloroprocaine hydrochloride—307.22 ^{73}

pKa: 9



Biotransformation—
Metabolized to a PABA derivative ^{04}



Half-life—
19 to 26 seconds (adults); 41 to 45 seconds (neonates) ^{04}



Onset of action—
Rapid ^{04}



Duration of action—
Short (30 to 60 minutes) ^{04}




Precautions:


Cross-sensitivity and/or related problems—
May occur with PABA, parabens, or other ester-type local anesthetics^{04}.



Pregnancy—
Paracervical administration not recommended if prematurity, pre-existing fetal distress, or toxemia of pregnancy present, because safety in these conditions has not been established ^{04}.

May cause uterine artery constriction.



Drug interactions and/or related problems—
Interaction with cholinesterase inhibitors

Interaction with sulfonamides