Lidocaine Hcl-Epinephrine-Nacl (lidocaine HCl/epinephrine in sodium chloride, iso-osmotic)

Dosage of lidocaine hydrochloride varies with the anesthetic procedure, the degree of anesthesia required, and individual patient response. The usual dosages should generally be reduced in children, geriatric patients, debilitated or acutely ill patients, and patients with cardiac and/or hepatic disease. The smallest dose and lowest concentration required to produce the desired effect should be used. Use of dilute solutions (i.e., 0.25-0.5%) and total dosages not to exceed 3 mg/kg are recommended for induction of IV regional anesthesia in children.

Single doses of lidocaine hydrochloride (for anesthesia other than spinal) should not exceed 4.5 mg/kg (or 300 mg) in healthy adults or 4.5 mg/kg in children younger than 10 years of age. When administered with epinephrine, lidocaine hydrochloride doses should not exceed 7 mg/kg (or 500 mg) in healthy adults or 7 mg/kg in children younger than 10 years of age. For spinal anesthesia, up to 100 mg of the drug may be given. For continuous epidural or caudal anesthesia, the maximum dose should not be repeated at intervals of less than 1.5 hours. When continuous lumbar or caudal epidural anesthesia is used for nonobstetric procedures, additional drug may be administered if necessary to attain adequate anesthesia. For paracervical block for nonobstetric and obstetric analgesia (including abortion), the maximum recommended dosage (200 mg) should not be repeated at intervals of less than 1.5 hours. For IV regional anesthesia in adults using a 0.5% solution without epinephrine, the dose administered should not exceed 4 mg/kg.

Solutions of 1-2% lidocaine hydrochloride with or without epinephrine and containing no preservatives are used for epidural or caudal anesthesia. To prevent intravascular or subarachnoid injection of a large epidural dose of lidocaine, a test dose (e.g., 2-3 mL of a 1.5% solution) of anesthetic solution should be injected at least 5 minutes prior to administering the total dose. When clinical conditions permit, use of a test dose solution that contains epinephrine (e.g., 10-15 mcg) should be considered to detect inadvertent intravascular injection. The test dose should be repeated if the patient is moved such that the epidural catheter may have been displaced. Rapid injection of a large, single dose through a catheter should be avoided; instead, the drug should be administered, when feasible, in fractional doses. In epidural anesthesia, 2-3 mL of the indicated solution is usually required for each dermatome to be anesthetized. In caudal block for production of obstetric analgesia or in epidural thoracic block, 20-30 mL of a 1% solution (200-300 mg) of the drug may be used. For surgical anesthesia with caudal block, 15-20 mL of a 1.5% solution (225-300 mg) is given. For epidural lumbar analgesia, the dose is 25-30 mL (250-300 mg) of a 1% solution, and for epidural lumbar anesthesia, the recommended dose is 15-20 mL of a 1.5% solution (225-300 mg) or 10-15 mL of a 2% solution (200-300 mg).

A solution of 5% lidocaine hydrochloride with 7.5% dextrose is used for spinal anesthesia in adults and adolescents 16 years of age or older. For obstetric low spinal or saddle-block anesthesia in a normal vaginal delivery, the dose is approximately 1 mL (50 mg). For cesarean section or deliveries which require intrauterine manipulations, 1.5 mL of the 5% solution (75 mg) may be given. For surgical anesthesia, 1.5-2 mL of the 5% solution (75-100 mg) may be administered.

The following doses of lidocaine hydrochloride have been suggested for various nerve blocks: brachial nerve block, 15-20 mL of a 1.5% solution (225-300 mg); dental nerve block, 1-5 mL of a 2% solution (20-100 mg); intercostal nerve block, 3 mL of a 1% solution (30 mg); paravertebral nerve block, 3-5 mL of a 1% solution (30-50 mg); pudendal nerve block (each side), 10 mL of a 1% solution (100 mg); and paracervical nerve block (each side) for obstetric analgesia, 10 mL of a 1% solution (100 mg). For sympathetic nerve blocks, the following doses may be used: cervical (stellate ganglion) nerve block, 5 mL of a 1% solution (50 mg), and lumbar nerve block, 5-10 mL of a 1% solution (50-100 mg). For percutaneous infiltration anesthesia, the dose of lidocaine hydrochloride is 1-60 mL of a 0.5 or 1% solution (5-300 mg). For IV regional anesthesia, 10-60 mL of a 0.5% solution (50-300 mg) may be employed.

For retrobulbar injection, 3-5 mL of a 4% sterile solution (120-200 mg) or 1.7-3 mg/kg is suggested; a portion of the dose is injected retrobulbarly and the remainder may be used to block the facial nerve.

For transtracheal injection, 2-3 mL of a 4% solution (80-120 mg) is administered rapidly. When both transtracheal injection and topical application (oropharyngeal spray) of a 4% solution are needed to achieve complete analgesia, the combined total dose of lidocaine hydrochloride administered by injection and by oropharyngeal spray should not exceed 5 mL of a 4% solution (200 mg) or 3 mg/kg.

Lidocaine hydrochloride with or without epinephrine is used for various dental procedures by infiltration injection or nerve block. In oral infiltration and/or mandibular block, initial doses of 1-5 mL of 2% lidocaine hydrochloride (20-100 mg) with epinephrine 1:100,000 are usually effective. If greater hemostasis is required, epinephrine 1:50,000 may be used. In children younger than 10 years of age, 0.9-1 mL of 2% lidocaine hydrochloride (18-20 mg) is adequate for a procedure involving 1 tooth (local infiltration), 2-3 teeth (maxillary infiltration), or teeth in an entire quadrant (mandibular block).

Dosage of epinephrine salts is expressed in terms of epinephrine. Dosage of racepinephrine hydrochloride is expressed in terms of racepinephrine; racepinephrine is about one-half as active as epinephrine.

Lidocaine hydrochloride may be administered by infiltration or by epidural (including caudal) block, peripheral or sympathetic nerve block, and subarachnoid block. The manufacturers state that only the preservative-free, epinephrine-free 0.5% lidocaine injection should be used for IV regional anesthesia. Local anesthetics, including lidocaine hydrochloride, have been administered by continuous intra-articular infusion+ (e.g., for control of postoperative pain); however, such use has been associated with chondrolysis. Lidocaine hydrochloride solutions containing preservatives shouldnot be used for spinal or epidural (including caudal) block. Partially used bottles of solutions that do not contain preservatives should be discarded.

Aspiration for blood should be performed prior to injection of lidocaine hydrochloride to avoid inadvertent intravascular administration; however, a negative aspiration does not ensure protection against inadvertent intravascular injection.

Local anesthetics should only be administered by clinicians who are experienced in the diagnosis and management of dose-related toxicities and other acute emergencies associated with these agents. Resuscitative equipment, oxygen, drugs, and personnel required for treatment of adverse reactions should be immediately available when lidocaine is administered. Proper positioning of the patient is extremely important in spinal anesthesia. For specific procedures and techniques of administration, specialized references should be consulted.

USP has changed its labeling standard for single-entity drug products to no longer allow the use of ratios to express drug concentrations. This labeling change was prompted by numerous reports of serious medication errors caused by confusion with different ratio expressions. Effective May 1, 2016, all single-entity preparations of epinephrine injection, USP should be labeled only in terms of strength per mL (i.e., mg/mL). While concentrations of some epinephrine preparations were historically expressed in ratios (e.g., 1:1000 or 1:10,000), such designation is no longer acceptable because of the risk of dosing errors.

Epinephrine usually is administered by IM, subcutaneous, or IV injection, or by continuous IV infusion. Epinephrine also has been administered by intraosseous (IO) injection+ in the setting of advanced cardiovascular life support (ACLS), generally when IV access is not readily available; onset of action and systemic concentrations are comparable to those achieved with venous administration. If vascular access (IV or IO) cannot be established during cardiac arrest, epinephrine may be administered endotracheally; however, this method of administration results in lower plasma concentrations compared with the same dose given intravascularly. Epinephrine also has been administered by intracardiac injection (into the left ventricular chamber) during cardiac arrest; however, this route of administration is not recommended in current ACLS guidelines.

The appropriate concentration and route of administration of epinephrine should be selected carefully; serious adverse effects (e.g., cerebral hemorrhage) have occurred after concentrated solutions of epinephrine intended for IM administration were administered IV. Because of the risks associated with IV use, epinephrine generally should be administered by the IV route only in extreme situations (such as in the treatment of septic or anaphylactic shock, cardiac arrest, or when the patient is unresponsive to multiple IM injections). Dilute solutions of epinephrine (e.g., 0.1 mg/mL) should always be used when administering the drug IV. Commercially available epinephrine solutions for IM or subcutaneous injection are tenfold more concentrated (1 mg/mL) and should not be administered IV without dilution.

Solutions of epinephrine should be inspected visually for particulate matter and discoloration prior to administration. Epinephrine injection must not be used if it is discolored or cloudy or contains any particulate matter.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Sympathomimetics/Dihydroergotamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of dihydroergotamine and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.(1)

CLINICAL EFFECTS: Concurrent use of dihydroergotamine and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Dihydroergotamine is contraindicated with sympathomimetics because the combination may result in additive or synergistic elevation of blood pressure.(1)

DISCUSSION: Significant elevation in blood pressure has been reported in patients treated with dihydroergotamine.(1) Sympathomimetics can be expected to have additional effects on blood pressure.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Epinephrine/Non-Cardioselective Beta-Blockers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of beta-blockers also block the beta effects of epinephrine, which results in predomination of alpha effects. The plasma clearance of epinephrine is decreased.

CLINICAL EFFECTS: Concurrent use of epinephrine with beta-blockers may result in hypertension with reflex bradycardia. Epinephrine resistance in patients with anaphylaxis has been reported.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant administration of epinephrine and beta-blockers if possible. If both drugs are administered, monitor blood pressure carefully. Hypertension and bradycardia are less likely to occur with cardioselective beta-blockers. Use caution when treating anaphylaxis with epinephrine since response may be poor.

DISCUSSION: In a study of 6 subjects, an increase in mean arterial pressure (MAP) of 15.1% (p < 0.05) was observed after an infusion of epinephrine (10 ng/kg/min) followed by an intravenous injection of propranolol (40 mcg/kg). In addition, plasma clearance of epinephrine decreased to 54.7% of the control value after the dose of propranolol.(1) In another study of 6 subjects, patients were intravenously administered 15 mcg epinephrine, followed by propranolol 0.04 mg/kg, and then another dose of epinephrine. A mean decrease in heart rate of 37% (p < 0.001) was observed following the second dose of epinephrine.(2) In a study in 10 healthy subjects, an increase in MAP was observed after infusion of epinephrine (5 mcg/min) followed by infusion of propranolol (10 mg).(5) In a study in 1 healthy subject, marked bradycardia and atrioventricular block occurred after administration of propranolol (40 mg orally) with epinephrine (17 mcg/min intravenously).(6) In a study in 7 healthy subjects, and increase in MAP (8% increase in systolic blood pressure, 10% increase in diastolic blood pressure) was observed after injection of epinephrine (45 mcg in lidocaine) in to the maxilla after pretreatment with pindolol (5 mg).(7) A retrospective analysis of sinus surgery patients found that 9.1% had exaggerated intraoperative hypertensive events during the first surgical hour (defined as relative increase greater than 20% of systolic blood pressure or single systolic blood pressure value above 200 mmHg). Subjects with established beta blockade were found to be three times as likely to experience an exaggerated hypertensive event during the first intraoperative hour.(8) In a study, intraoral injection with 2% lidocaine containing epinephrine (45 mcg) after pretreatment with pindolol (5 mg) resulted reduced stroke volume, increase in afterload, decreased myocardial contractility, decreased heart rate, and an increase in blood pressure.(9) In a study in 8 subjects, a comparison of propranolol (80 mg three times daily) or metoprolol (100 mg three times daily) with epinephrine (8 mcg/min for 6 minutes) showed that propranolol significantly increases MAP while metoprolol, a beta1-selective beta-blocker, does not.(10) There are several case reports of significant hypertension with reflex bradycardia.(9-12) In some of these case reports patients had strokes.(12)

Local Anesthetics/Long-Acting Bupivacaine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of other local anesthetics or use of other local anesthetics within 96 hours following long-acting bupivacaine may result in additive neurologic and cardiovascular effects. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also increase the risk of methemoglobinemia.(1,2) Non-liposomal bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally.(1)

CLINICAL EFFECTS: Concurrent or use of local anesthetics with 96 hours of use of long-acting bupivacaine may result in neurologic and cardiovascular toxicity. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also result in methemoglobinemia.(1,2) Non-liposomal bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally.(1)

PREDISPOSING FACTORS: Use of additional agents that are associated with methemoglobinemia may further increase the risk of methemoglobinemia.(1) Patients who are at increased risk of developing methemoglobinemia include those with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.(1)

PATIENT MANAGEMENT: Avoid the use of other local anesthetics within 96 hours following the administration of long-acting bupivacaine. In patients for whom use is required, monitor for neurologic and cardiovascular effects. Also monitor for methemoglobinemia with use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine.(1,2) Non-liposomal bupivacaine may be administered in the same syringe as bupivacaine liposomal or injected immediately before bupivacaine liposomal as long as the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Lidocaine may be administered 20 minutes or more prior to bupivacaine. It is unknown if other local anesthetics may be used without compromising the release characteristic of bupivacaine liposomal.(1)

DISCUSSION: Concurrent use of other local anesthetics or use of other local anesthetics within 96 hours following long-acting bupivacaine may result in additive neurologic and cardiovascular effects. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also increase the risk of methemoglobinemia.(1,2) Non-liposome bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally. Lidocaine may be administered 20 minutes or more prior to bupivacaine. It is unknown if other local anesthetics may be used without compromising the release characteristic of bupivacaine liposomal.(1)

Selected Direct-Acting Sympathomimetics/Tricyclic Compounds

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, it is speculated that direct-acting sympathomimetic amines have an enhanced effect due to tricyclic blockage of norepinephrine reuptake.

CLINICAL EFFECTS: Increased effect of direct acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider avoiding the concurrent use of direct-acting sympathomimetics and tricyclic compounds. If concurrent use of direct-acting sympathomimetics and tricyclic compounds is warranted, the initial dose of the sympathomimetic should be lowered and the patient should be monitored for adverse cardiovascular effects. Use of tricyclic compounds and other sympathomimetics should be approached with caution.

DISCUSSION: Epinephrine and other direct-acting sympathomimetic amines exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and tachycardia) in individuals concurrently receiving or previously treated with tricyclic antidepressants. Other direct and mixed acting sympathomimetic amines have also been reported to interact with tricyclic antidepressants. These include norepinephrine, phenylephrine, dopamine, and methoxamine. Protriptyline, amitriptyline, and desipramine have also been reported to interact with direct-acting sympathomimetics.

Sympathomimetics/Ergot Alkaloids

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of ergot alkaloids and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.

CLINICAL EFFECTS: Concurrent use of ergot alkaloids and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid the concurrent use of ergot alkaloids and sympathomimetics. If concurrent use is warranted, monitor blood pressure and for signs of vasoconstriction. Decreasing the dose of one or both drugs may be necessary.

DISCUSSION: There have been reports of severe vasoconstriction resulting in gangrene in patients receiving intravenous ergonovine with dopamine or norepinephrine.

Sympathomimetics/Selected Inhalation Anesthetic Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. The anesthetics produce conduction changes that increase impulse re-entry into the myocardial tissue.(1) The anesthetics' ability to precipitate arrhythmias is enhanced by elevated arterial blood pressure, tachycardia, hypercapnia, and/or hypoxia, events that stimulate the release of endogenous catecholamines.(1)

CLINICAL EFFECTS: Concurrent use of inhalation anesthetic agents and sympathomimetics may result in ventricular arrhythmias or sudden blood pressure and heart rate increase during surgery.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood pressure and avoid use of sympathomimetics in patients being treated with anesthetics on the day of surgery.(2) Intravenous use of epinephrine during surgery with halothane and related halogenated general anesthetics should be strongly discouraged. When intravenous epinephrine is necessary, nitrous oxide anesthesia supplemented with ether, muscle relaxants, or opioids should be used instead of halothane.(3,4) Epinephrine may safely be used subcutaneously with the following precautions: the patient is adequately ventilated to prevent hypoxia or respiratory acidosis; the total dose of epinephrine is limited to 100 mcg/10 minute period or 300 mcg/hour in adults, 3.5 mcg/Kg in infants, 2.5 mcg/Kg in children up to two years of age, and 1.45 mcg/Kg in children over two years of age; a minimum effective concentration of anesthetic is maintained; the drugs are not co-administered in patients with hypertension or other cardiovascular disorders; and the cardiac rhythm is continuously monitored during and after injection.(3-10) If arrhythmias occur after the administration of the epinephrine, the drugs of choice are lidocaine or propranolol, depending on the type of arrhythmia.(1)

DISCUSSION: Administration of epinephrine during halothane anesthesia may may lead to serious ventricular arrhythmias.(3-6,11-18) This has occurred when epinephrine was administered intravenously,(6) when it was administered with lidocaine as a dental block,(11,14) or when it was administered supraperiosteally.(5) Norepinephrine has been shown to interact with halothane in a manner similar to epinephrine.(1) In two case reports, patients were given terbutaline (0.25 to 0.35 mg) for wheezing following induction of anesthesia with halothane. One patient's heart rate increased from 68 to 100 beats/minute, and the ECG showed premature ventricular contractions and bigeminy, while the other patient developed multiple unifocal premature ventricular contractions and bigeminy. The arrhythmias resolved in both patients following lidocaine administration.(19) Although not documented, isoproterenol causes effects on the heart similar to terbutaline(20) and would probably interact with halothane in a similar manner. Other inhalation anesthetics that increase the incidence of arrhythmias with epinephrine include chloroform,(20) methoxyflurane,(20) and enflurane.(12) A similar interaction may be expected between the other inhalation anesthetics and sympathomimetics.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Comt-Metabolized Agents/Entacapone; Opicapone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Entacapone and opicapone are selective and reversible inhibitors of catechol-O-methyltransferase (COMT) and drugs that are metabolized by COMT can not be fully metabolized when given with entacapone or opicapone.(1)

CLINICAL EFFECTS: COMT-metabolized agents can interact with entacapone or opicapone and may result in an increased heart rates, arrhythmias, or an excessive change in blood pressure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of entacapone and opicapone recommend using caution when administering entacapone or opicapone and a COMT-metabolized agent regardless of the route of administration (including inhalation).(1-3)

DISCUSSION: In an interaction study, ventricular tachycardia was observed after epinephrine and entacapone administration.(1) Another study on the effect of entacapone given with isoproterenol and epinephrine concluded that entacapone may potentiate the chronotropic and arrhythmogenic effects of isoproterenol and epinephrine.(4)

Epinephrine/Antidiabetics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gluconeogenesis, glycogenolysis, and lipolysis are increased by epinephrine. Also, insulin secretion and glucose uptake by peripheral tissues are decreased by epinephrine.

CLINICAL EFFECTS: Increased blood glucose resulting in decreased effectiveness of the antidiabetic agent.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Caution when starting or stopping epinephrine in diabetic patients. Adjust the antidiabetic dose as needed based on blood glucose levels.

DISCUSSION: This interaction is likely to occur based upon well documented properties of the interacting drugs. However, there is individual variability in its occurrence.

Epinephrine/Cardioselective Beta-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of beta-blockers also block the beta effects of epinephrine, which results in predomination of alpha effects. The plasma clearance of epinephrine is decreased.

CLINICAL EFFECTS: Concurrent use of epinephrine with beta-blockers may result in hypertension with reflex bradycardia. Epinephrine resistance in patients with anaphylaxis has been reported.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Hypertension and bradycardia are less likely to occur with cardioselective beta-blockers. If both drugs are administered, monitor blood pressure carefully. Use caution when treating anaphylaxis with epinephrine since response may be poor.

DISCUSSION: A 29-year-old male undergoing elective nasal septoplasty developed severe hypertension with a blood pressure of 207/123 mmHg after topical epinephrine (1:1000) was applied to the nasal mucosa. Intravenous metoprolol was administered but the patient went into cardiogenic shock thought to be a result of unopposed alpha stimulation by the combination of epinephrine and metoprolol.(1) A study observed the differences in cardiovascular responses to subcutaneous epinephrine (given to provide hemostasis during scalp incision for craniotomy) between patients who received propranolol vs. metoprolol vs. no pretreatment. While metoprolol prevented the cardiovascular effects of epinephrine infiltration, propranolol pretreatment was associated with a highly significant increase (P less than 0.01) in mean arterial pressure and a significant decrease (P less than 0.05) in heart rate.(2) A double-blind cross-over trial studied the effects of epinephrine infusion during treatment with propranolol vs. metoprolol in 8 hypertensive patients. Patients on propranolol experienced significant increases in blood pressure and systemic vascular resistance (SVR), whereas patients on metoprolol had less increase in systolic blood pressure while the diastolic pressure remained unchanged and SVR decreased.(3) In spontaneously hypertensive rats, epinephrine in combination with pindolol induced remarkable hemodynamic changes (in particular, increase in diastolic blood pressure), which were prevented by phentolamine pretreatment, whereas epinephrine with acebutolol pretreatment induced no significant hemodynamic changes.(4)

Sympathomimetics (DIRECT, MIXED-ACTING)/Guanethidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Direct or mixed-acting sympathomimetics may inhibit uptake of guanethidine at the adrenergic neuron.

CLINICAL EFFECTS: Decreased antihypertensive effectiveness. Effects may be seen for several days after discontinuation of the direct or mixed-acting sympathomimetic.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. If both drugs are administered, adjust the guanethidine dose as needed based on blood pressure.

DISCUSSION: Documentation supports routine monitoring of this interaction. It should be noted that this interaction can occur quickly.

Sympathomimetics (DIRECT, MIXED-ACTING)/Methyldopa

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: The pressor response to sympathomimetics may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Start with low doses of sympathomimetics and monitor blood pressure of patients during concurrent administration of sympathomimetics and methyldopa.

DISCUSSION: The pressor response to sympathomimetics has been reported to be increased during methyldopa administration. In addition to increased duration of pressor response, severe hypertension has been reported.

Sympathomimetics/Rauwolfia Alkaloids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Reserpine depletes catecholamine stores within the peripheral vascular adrenergic nerve endings, thus indirect acting sympathomimetics are unable to trigger the release of catecholamines. The reserpine-induced catecholamine release increases sensitivity to the effects of direct acting sympathomimetics.

CLINICAL EFFECTS: Increased effects of direct acting sympathomimetics. Decreased effects of indirect acting sympathomimetics. Mixed acting sympathomimetics will show effects based on the predominance of either direct or indirect activity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If these agents are administered concurrently, monitor blood pressure. The dose of the sympathomimetic may need to be adjusted.

DISCUSSION: This interaction has been well documented in animal studies and human case reports have confirmed the interaction. Reserpine has been shown to decrease the response to epinephrine administered for hypotension. Reserpine has also been shown to decrease the effectiveness of ophthalmic epinephrine, a direct acting sympathomimetic. Ophthalmic phenylephrine has been shown to decrease the hypotensive effects of reserpine.

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• Adams-stokes syndrome
• Methemoglobinemia
• Severe heart block
• Systemic lidocaine toxicity
• Wolff-parkinson-white pattern

• Angina
• Angle-closure glaucoma
• Cardiac arrhythmia
• Cardiogenic shock
• Cerebral arteriosclerosis
• Chronic heart failure
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Congenital long QT syndrome
• Coronary artery disease
• Dilated cardiomyopathy
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Hemolytic anemia from pyruvate kinase and g6PD deficiencies
• Hemorrhagic shock
• Hypertension
• Hyperthyroidism
• Hypokalemia
• Hypomagnesemia
• Hypovolemia
• Hypoxia
• Incomplete AV heart block
• Myasthenia gravis
• Respiratory depression
• Shock
• Sinus bradycardia
• Sinus tachycardia

• Atrial fibrillation
• Diabetes mellitus
• Disease of liver
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Parkinsonism
• Pheochromocytoma

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Less Frequent

• Hypertension
• Hypotension

Rare or Very Rare

• Acute myocardial infarction
• Anaphylaxis
• Angina
• Bradycardia
• Cardiac arrhythmia
• Cardiac arrhythmia
• Cardiomyopathy
• Cerebrovascular accident
• Chest pain
• Chondrolysis of articular cartilage
• CNS toxicity
• Extravasation injury
• Gangrene
• Hemiparesis
• Hyperglycemia
• Hypertension
• Hypokalemia
• Intracranial bleeding
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Lactic acidosis
• Methemoglobinemia
• Myocardial dysfunction
• Myocardial ischemia
• Necrotizing fasciitis
• Paradoxical bronchospasm
• Pulmonary edema
• Respiratory depression
• Seizure disorder
• Status asthmaticus
• Supraventricular tachycardia
• Tachycardia
• Unconsciousness
• Urticaria
• Vasodilation of blood vessels
• Ventricular arrhythmias
• Ventricular arrhythmias
• Ventricular fibrillation
• Ventricular premature beats

More Frequent

• Dizziness
• General weakness
• Headache disorder
• Nausea
• Nervousness
• Pallor
• Palpitations
• Symptoms of anxiety
• Tachycardia
• Tremor
• Vomiting

Less Frequent

• Chills
• Headache disorder

Rare or Very Rare

• Acute cognitive impairment
• Acute cognitive impairment
• Agitation
• Apprehension
• Apprehension
• Blanching of skin
• Blurred vision
• Diplopia
• Dizziness
• Drowsy
• Drowsy
• Dysgeusia
• Edema
• Euphoria
• Hyperhidrosis
• Hypoesthesia
• Hypoesthesia
• Injection site infection
• Injection site sequelae
• Injection site sequelae
• Memory impairment
• Miosis
• Muscle fasciculation
• Nausea
• Nervousness
• Oliguria
• Oral hypoesthesia
• Panic disorder
• Paresthesia
• Rales
• Sensation of cold
• Sensation of warmth
• Skin rash
• Symptoms of anxiety
• Tinnitus
• Tremor
• Visual changes
• Vomiting
• Xerostomia

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Epinephrine usually inhibits spontaneous or oxytocin-induced contractions of the pregnant human uterus and may delay the second stage of labor. In dosages sufficient to reduce uterine contractions, the drug may cause a prolonged period of uterine atony with hemorrhage. If used during pregnancy, epinephrine may cause anoxia to the fetus and/or spontaneous abortion. When administered in advanced cardiovascular life support (ACLS) during cardiac resuscitation, epinephrine may decrease blood flow to the uterus; however, the woman must be resuscitated for survival of the fetus. Some manufacturers state that epinephrine should be avoided during the second stage of labor; parenteral administration of the drug to maintain blood pressure during spinal anesthesia for delivery can cause acceleration of fetal heart rate and should not be used in obstetric patients when maternal systolic/diastolic blood pressure exceeds 130/80 mm Hg. Epinephrine should be administered cautiously by oral inhalation to pregnant patients. Epinephrine should be used during pregnancy only if the potential benefits justify the possible risks to the fetus. There is some evidence to support that epidural administration of some local anesthetics (e.g., lidocaine) with epinephrine during labor is safe.

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