Bupivacaine and epinephrine

Bupivacaine and epinephrine Uses, Dosage, Side Effects, Food Interaction and all others data.

Bupivacaine injectioin is a preparation of bupivacaine, a long acting local anaesthetic agent that belongs to amide group. It blocks the generation and the conduction of nerve impulses, by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential.

Bupivacaine binds to the intracellular portion of voltage-gated sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. Without depolarization, no initiation or conduction of a pain signal can occur.

The rate of systemic absorption of bupivacaine and other local anesthetics is dependent upon the dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the preparation.

Onset of action (route and dose-dependent): 1-17 minDuration of action (route and dose-dependent): 2-9 hrHalf life: neonates, 8.1 hr, adults: 2.7 hrTime to peak plasma concentration (for peripheral, epidural, or caudal block): 30-45 minProtein binding: about 95%Metabolism: hepaticExcretion: renal (6% unchanged)Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both.

Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both.

Adrenaline is a direct-acting sympathomimetic agent exerting its effect on alpha and beta-adrenoceptors. The overall effect of adrenaline depends on the dose, and may be complicated by the homeostatic reflex responses. In resuscitation procedures it is used to increase the efficacy of basic life support. It is a positive cardiac inotrope. Major effects are increased systolic blood pressure by arterioral and venous vasoconstriction (alpha1 effects), reduced diastolic pressure, tachycardia and hyperglycaemia. Adrenaline is rapid in onset and with short duration. After IV infusion the half-life is approximately 5-10 minutes. It is rapidly distributed to the heart, spleen, several glandular tissues and adrenergic nerves. Adrenaline is rapidly metabolised in the liver and tissues by oxidative de-amination and O-methylation followed by reduction or by conjugation with glucuronic acid or sulphate. Up to 90% of the IV dose is excreted in the urine as metabolites. It is approximately 50% bound to plasma proteins.

Epinephrine is a sympathomimetic drug. It causes an adrenergic receptive mechanism on effector cells and mimics all actions of the sympathetic nervous system except those on the facial arteries and sweat glands .

Important effects of epinephrine include increased heart rate, myocardial contractility, and renin release via beta-1 receptors. Beta-2 effects produce bronchodilation which may be useful as an adjunct treatment of asthma exacerbations as well as vasodilation, tocolysis, and increased aqueous humor production . In croup, nebulized epinephrine is associated with both clinically and statistically significant transient reduction of croup symptoms 30 minutes post-treatment . Epinephrine also alleviates pruritus, urticaria, and angioedema and may be helpful in relieving gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxing effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder .

Bupivacaine and epinephrine
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Bupivacaine and epinephrine
Generic	Bupivacaine + epinephrine
Type	Injection
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Bupivacaine is used for the production of local or regional anaesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures. The routes of administration and used Bupivacaine concentrations are:

Local infiltration: 0.25%
Peripheral nerve block: 0.25%, 0.5%
Sympathetic block: 0.25%
Lumbar epidural: 0.25%, 0.5% and 0.75% (non-obstetrical)
Caudal: 0.25%, 0.5%

Adjunctive use in the management of cardiac arrest. It is used in cardiopulmonary resuscitation. Intracardiac puncture and intramyocardial injection of adrenaline may be effective when external cardiac compression and attempts to restore the circulation by electrical defibrillation or use of a pacemaker fail. Adrenaline is a drug that leads to increased blood pressure, increased heart rate, increased air entry, increased blood glucose, stimulates cardiac activity and reduces allergic reactions by reducing inflammatory response caused by histamine. Due to these properties, it is used for the treatment of allergic and anaphylactic reactions. Adrenaline is the favored treatment for anaphylactic shock and should be administered immediately if a person begins exhibiting severe allergic reactions. Adrenaline is also used in life threatening asthma when failing ventilation and continued deterioration despite nebulizer therapy.

Bupivacaine and epinephrine is also used to associated treatment for these conditions: Acute Gouty Arthritis, Adrenal cortical hypofunctions, Alopecia Areata (AA), Ankylosing Spondylitis (AS), Berylliosis, Bullous dermatitis herpetiformis, Congenital Adrenal Hyperplasia (CAH), Congenital Hypoplastic Anemia, Dermatomyositis, Discoid Lupus Erythematosus (DLE), Edema of the cerebrum, Epicondylitis, Hemolytic Anemia, Keloid Scars, Leukemias, Mycosis Fungoides (MF), Necrobiosis lipoidica diabeticorum, Ocular Inflammation, Ophthalmia, Sympathetic, Osteoarthritis (OA), Pain, Labor, Polymyositis, Postoperative pain, Psoriatic Arthritis, Psoriatic plaque, Pure Red Cell Aplasia, Regional Enteritis, Rheumatoid Arthritis, Secondary thrombocytopenia, Stevens-Johnson Syndrome, Synovitis, Systemic Lupus Erythematosus (SLE), Temporal Arteritis, Trichinosis, Tuberculous Meningitis, Ulcerative Colitis, Uveitis, Acute Bursitis, Acute Idiopathic Nephrotic Syndrome, Acute Lupus Erythematosus, Acute Multiple sclerosis, Acute Rheumatic heart disease, unspecified, Acute nonspecific tenosynovitis, Cancer-associated hypercalcemia, Cystic tumors of aponeurosis, Cystic tumors of tendon, Disseminated Pulmonary Tuberculosis, Exfoliative erythroderma, Inflammatory lesions of granuloma annulare, Inflammatory lesions of lichen planus, Inflammatory lesions of lichen simplex, Non-suppurative Thyroiditis, Permphigus, Severe Allergic Reactions, General Anesthesia, Regional nerve block therapy, Local anesthesia therapyAnaphylaxis, Angioneurotic Edema, Bleeding, Bronchospasm, Complete Heart Block, Hypotension, Idiopathic Anaphylaxis, Laryngotracheobronchitis, Mild Intermittent Asthma, Nasal Congestion, Open Angle Glaucoma (OAG), Respiratory Distress, Severe Asthma, Syncope, Urticaria, Uterine Contractions, Ventricular Fibrillation, Resuscitation in cardiac arrest following anesthetic accidents, Serious allergic reactions, Severe hypersensitivity, Unresponsive Asystole, Unresponsive Bradycardia

How Bupivacaine and epinephrine works

Local anesthetics such as bupivacaine block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. Bupivacaine prevents depolarization by bindng to the intracellular portion of sodium channels and blocking sodium ion influx into neurons. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. The analgesic effects of Bupivicaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia.

Epinephrine acts on alpha and beta-adrenergic receptors. Epinephrine acts on alpha and beta receptors and is the strongest alpha receptor activator . Through its action on alpha-adrenergic receptors, epinephrine minimizes the vasodilation and increased the vascular permeability that occurs during anaphylaxis, which can cause the loss of intravascular fluid volume as well as hypotension. Epinephrine relaxes the smooth muscle of the bronchi and iris and is a histamine antagonist, rendering it useful in treating the manifestations of allergic reactions and associated conditions . This drug also produces an increase in blood sugar and increases glycogenolysis in the liver . Through its action on beta-adrenergic receptors, epinephrine leads to bronchial smooth muscle relaxation that helps to relieve bronchospasm, wheezing, and dyspnea that may occur during anaphylaxis .

Dosage

Bupivacaine and epinephrine dosage

Percutaneous infiltration anesthesia For prolonged action: 9 mg with adrenaline (1 in 200,000), may repeat 2-10 mins later if needed. Max: 90 mg per dental sitting.

Peripheral nerve block: 12.5 mg (as 0.25% solution) or 25 mg (as 0.5% solution). Max: 150 mg/dose.

Sympathetic nerve block: As 0.25% solution: 50-125 mg.

Retrobulbar block: As 0.75% solution: 15-30 mg.

Caudal block In surgery: 37.5-75 mg (as 0.25% solution) or 75-150 mg (as 0.5% solution). Lumbar epidural block In surgery: 25-50 mg (as 0.25% solution) and 50-100 mg (as 0.5% solution).

Cardiac arrest:

1. Intravenous injection: 1 mg injection repeated every 2-3 minutes as necessary.

2. Endotracheal: 2-3 mg via an endotracheal tube, repeated as necessary.

3. Intracardiac injection: 0.1 to 1 mg, direct into the atrium of the heart.

4. Intraspinal use: Usual dose is 0.2 to 0.4 mg added to anesthetic spinal fluid mixture (to prolong anesthetic action by limiting absorption).

Anaphylaxis, asthma or severe bronchospasm: Adult dose is 0.25 - 0.5 mg. It may be repeated at 5 minutes intervals until perfusion and respiratory status normalizes. In case of dose dilution: 1 mg of Adrenaline to be diluted in 9 ml Normal Saline.

Children: Intravenous injection: Initially 10 mcg/kg body weight, not to exceed 250 mcg. May be repeated every 3-5 minutes if necessary. Subsequent doses should be 100 mcg/kg.

Side Effects

Central Nervous System and Neurological: Restlessness, excitement, nervousness, dizziness, tinnitus, blurred vision, miosis, nausea, vomiting, numbness of the tongue and perioral region, chills, tremors, muscle twitching, convulsions.

Cardiovascular System Reactions: Myocardial depression and peripheral vasodilatation resulting hypotension and bradycardia, ventricular arrhythmia, cardiac arrest.

Hypersensitivity: urticaria, pruritus, erythema, angioneurotic edema ,tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid reactions.

Anxiety, restlessness, dizziness, headache, palpitations, rapid pulse, tremors, weakness and coldness of the extremities may be reported even with small doses and especially when given in conjunction with local anaesthetics.

Toxicity

The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest.

Skin, LD₅₀ = 62 mg/kg (rat)

Pregnancy

Epinephrine is teratogenic in rats when given in doses about 25 times the human doses. It is unknown whether epinephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Epinephrine should be given to a pregnant woman only if clearly required in critical situations/emergencies .

Labor and Delivery Parenteral administration of epinephrine, if used as support for blood pressure during low or other spinal anesthesia for delivery, can lead to the acceleration of fetal heart rate and should not be used in obstetrics when maternal blood pressure is higher than 130/80. Epinephrine may delay the second stage of labour.

Common and generalized adverse effects: Transient and minor side effects of anxiety, headache, fear, and palpitations may occur with therapeutic doses of epinephrine, especially in hyperthyroid individuals. Repeated local injections may result in necrosis at sites of injection due to vascular constriction. Cerebral hemorrhage; hemiplegia; subarachnoid hemorrhage; anginal pain in patients with angina pectoris; anxiety; restlessness; throbbing headache; tremor; weakness; dizziness; pallor; respiratory difficulty; palpitation; apprehensiveness; sweating; nausea; vomiting .

Cardiovascular effects: Inadvertently induced high arterial blood pressure may result in angina pectoris (especially when coronary insufficiency is present), cardiac ischemia, or aortic rupture , . Epinephrine may cause serious cardiac arrhythmias in patients not suffering from heart disease and patients with organic heart disease receiving drugs that sensitize the cardiac muscle. With the injection of epinephrine 1:1,000, a paradoxical but transient lowering of blood pressure, bradycardia and apnea may occur immediately post-injection .

Cerebrovascular hemorrhage: Overdosage or accidental I.V. injection of epinephrine may lead to cerebrovascular hemorrhage resulting from the sharp rise in blood pressure .

Renal vasoconstriction: Parenterally administered epinephrine initially may produce constriction of renal blood vessels and decrease urine formation. High doses may cause complete renal shutdown .

Pulmonary edema: Fatality may also result from pulmonary edema due to the peripheral constriction and cardiac stimulation produced by epinephrine injection .

Digital vasoconstriction: Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may lead to the loss of blood flow to the affected area. Treatment should be directed at vasodilation in addition to further treatment of anaphylaxis .

Precaution

Readiness for emergencies.The lowest dosage that gives effective anaesthesia should be used in order to avoid high plasma levels and serious systemic side effects. Injection of repeated doses of Bupivacaine Hydrocholoride may cause significant increase in blood levels with each additional dose, due to accumulation of the drug or its metabolites or due to slow metabolic degradation. Tolerance varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with age and physical condition. Caution is advised in administration of repeat doses of Bupivacaine Hydrocholoride to patients with severe liver disease.Local anaesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection.

The solution should not be used if it is pinkish or darker than slightly yellow or if it contains a precipitate. Adrenaline is readily destroyed by alkalies and oxidizing agents. In the latter category are Oxygen, Chlorine, Iodine, Permanganates, Chromates, Nitrites and salts of easily reducible metals, especially Iron. Adrenaline should not be mixed with Sodium bicarbonate; the solution is oxidised to adrenochrome and then forms polymers.

Special warnings and precautions for use

Administer slowly with caution to elderly patients and to patients with ischemic heart disease, hypertension, diabetes mellitus, hyperthyroidism or psychoneurosis. Use with extreme caution in patients with long-standing bronchial asthma and emphysema who have developed degenerative heart disease. Anginal pain may be induced when coronary insufficiency is present.

Interaction

Bupivacaine should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide‐type local anaesthetics, e.g. certain anti‐arrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive.Specific interaction studies with Bupivacaine and anti arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution should be advised.

Use of Adrenaline with excessive doses of digitalis, mercurial diuretics or other drugs that sensitize the heart to arrhythmias is not recommended. The adverse effects of Adrenaline may be potentiated by tricyclic antidepressants; certain antihistamines; e.g, Diphenhydramine, Tripelennamine, Chlorpheniramine and L-thyroxine Sodium.

Elimination Route

Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution.

Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a C_max of 54 ± 33 ng/mL, a median T_max of 3 h, and an AUC_∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 ng*h/mL.

Following I.V. (intravenous) injection, epinephrine disappears rapidly from the blood stream. Subcutaneously or I.M. (intramuscular) administered epinephrine has a rapid onset and short duration of action. Subcutaneous (SC) administration during asthmatic attacks may produce bronchodilation within 5 to 10 minutes, and maximal effects may occur within 20 minutes. The drug becomes fixed in the tissues rapidly , .

Half Life

2.7 hours in adults and 8.1 hours in neonates.

Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 hours, depending on dose and application site.

The plasma half-life is approximately 2-3 minutes. However, when administered by subcutaneous or intramuscular injection, local vasoconstriction may delay absorption so that epinephrine's effects may last longer than the half-life suggests .

Clearance

Intravenous injection produces an immediate and intensified response. Following intravenous injection, epinephrine disappears rapidly from the blood stream .

Elimination Route

Only 6% of bupivacaine is excreted unchanged in the urine.

The majority of the dose of epinephrine is seen excreted in the urine , . About 40% of a parenteral dose of epinephrine is excreted in urine as metanephrine, 40% as VMA, 7% as 3-methoxy-4-hydroxyphenoglycol, 2% as 3,4-dihydroxymandelic acid, and the rest as acetylated derivatives. These metabolites are excreted mainly as the sulfate conjugates and, to a lesser extent, the glucuronide conjugates. Only small amounts of the drug are excreted completely unchanged .

Pregnancy & Breastfeeding use

There are no adequate and well‐controlled studies in pregnant women of the effect of bupivacaine hydrochloride on the developing fetus. Bupivacaine should not therefore be given in early pregnancy only if the potential benefit justifies the potential risk to the fetus. Bupivacaine enters the mother's milk, but in such small quantities that there is no risk of affecting the child at therapeutic dose levels.

Pregnancy Category C. It crosses the placenta and is excreted in breast milk. Adrenaline should only be used in pregnancy if the potential benefits outweigh the risks to the fetus.

Lactating mothers: It is excreted in breast milk and therefore Adrenaline is not recommended for use during lactation because of the risk of adverse effects of infants.

Contraindication

Hypersensitivity to Bupivacaine, other amide type local anaesthetics or other components of these preparations; Intravenous regional anaesthesia; obstetrical paracervical block anaesthesia.

Hypertension, arteriosclerosis, coronary disease and hyperthyroidism. Not to be given to patients taking monoamine oxidase inhibitors.

Special Warning

Paediatrics: For children a reduced dose based on body weight and surface area should be used. The dosage should be calculated for each patient individually and modified in accordance with the physician's experience and knowledge of the patient.

Geriatrics: A reduction in dosage may be necessary for elderly patients especially those with compromised cardiovascular and/or hepatic function. Where epidural administration is to be used, a small dose may provide sufficient anaesthesia.

Impaired hepatic function: Although bupivacaine is metabolised by the liver, dosage reduction is probably not warranted. However, caution should be exercised with repeated doses.

Impaired renal function: Impairment of renal function is unlikely to affect bupivacaine clearance in the short term (up to 24 hours). However, toxicity due to accumulation may develop with prolonged or repeated administration.

Acute Overdose

Symptoms: Cardiac arrhythmia leading to ventricular fibrillation, severe hypertension leading to pulmonary edema and cerebral hemorrhage.

Treatment: Combined alpha and beta-adrenergic blocking agents such as Labetalol may counteract the effects of adrenaline, or a beta-blocking agent may be used to treat any supraventricular arrhythmias and Phentolamine to control the alpha-mediated effects on the peripheral circulation. Rapidly acting vasodilators such as nitrates and Sodium Nitroprusside may also be helpful. Immediate resuscitation support must be available.