Adrenaline/Epinephrine

Epinephrine is a sympathomimetic agent belonging to the Alpha and Beta Adrenergic Receptor Agonist class.

Epinephrine is approved for the treatment of anaphylaxis, angioedema, asthma exacerbation, bronchospasm, cardiac arrest, cardiopulmonary resuscitation, glaucoma, hypotension, laryngotracheobronchitis (croup), mydriasis induction, nasal congestion, pulseless electrical activity, septic shock, surgical bleeding, urticaria, ventricular asystole, ventricular fibrillation. It is also used to treat bradycardia, cardiogenic shock, chloroquine overdose, and epistaxis

When administered parenterally or intraocularly, epinephrine has a rapid onset and short duration of action. The Volume of Distribution of Epinephrine was found to be 1.6 L/kg. Epinephrine undergoes sulphation or glucuronidation prior to elimination. The subcutaneous dose elimination of Epinephrine is 40% after 72 hrs. While the IV dose eliminated is 90% in urine.

The common side effects associated with Epinephrine are tachycardia, hypertension, headache, anxiety, apprehension, palpitations, diaphoresis, nausea, vomiting, weakness, and tremors.

Epinephrine is available in the form of prefilled autoinjector or syringe, injectable solution, oral inhalation spray, and eye drops.

Epinephrine is available in India, the U.K, the U.S, China, Japan, and Australia.

• Epinephrine belonging to the Alpha and Beta Adrenergic Receptor Agonist acts as a Sympathomimetic therapeutic agent. Epinephrine acts via the series of pathways causing increasing cAMP, thereby deactivating the myosin light chain kinase and activating myosin light chain phosphate leading to smooth muscle relaxation in the bronchioles. Epinephrine hence leads to Bronchodilation of the smooth muscles and reverses bronchospasm.
• Epinephrine has an onset of action within 5 minutes.
• Epinephrine has a duration of action of 6 hours.
• Epinephrine Tmax was achieved within 0.5-1.5 hours and Cmax was found within 9.6 ± ng/mL

• Lay the person flat on the ground. If breathing is difficult, they can sit on the ground.
• Remove the autoinjector from the carry tube. Keep the fingers and thumb away from the orange tip. With the orange tip facing down, hold the epinephrine autoinjector firmly in the fist and pull off the blue safety release.
• Hold the leg still and place the orange end against the outer mid-thigh. Hold the autoinjector at a right angle to the outer part of the thigh.
• Give the injection through clothing but avoid pockets or seams. Push down firmly until one hears or feel a click. Hold for 3 seconds. Remove the Epinephrine autoinjector. Record the time the injection was given.

Epinephrine is approved for the treatment of anaphylaxis, angioedema, asthma exacerbation, bronchospasm, cardiac arrest, cardiopulmonary resuscitation, glaucoma, hypotension, laryngotracheobronchitis (croup), mydriasis induction, nasal congestion, pulseless electrical activity, septic shock, surgical bleeding, urticaria, ventricular asystole, ventricular fibrillation. It is also used to treat bradycardia, cardiogenic shock, chloroquine overdose, and epistaxis.

• Epinephrine can help to relax bronchial smooth muscle leading to Bronchodilation and improving the patient's respiration. . Epinephrine acts via a series of pathways causing increasing cAMP, thereby deactivating myosin light chain kinase and activating myosin light chain phosphate leading to the smooth muscle relaxation in the bronchioles.
• Epinephrine hence leads to Bronchodilation of the smooth muscles and reverses bronchospasm.

Epinephrine is approved for use in the following clinical indications:

• For the treatment of anaphylaxis

NOTE: Epinephrine absorption is rapid and complete if administered IM in the anterolateral aspect of the thigh. Subcutaneous epinephrine is not routinely recommended due to delayed absorption.

Intramuscular or Subcutaneous dosage

Adults

0.3 to 0.5 mg subcutaneously or IM; may be repeated if necessary every 5 to 10 minutes.

• For the temporary relief of mild symptoms of intermittent asthma (i.e., transient mild bronchospasm or episodic wheezing)

Oral Inhalation dosage (non-prescription oral inhaler; e.g., Primatene Mist)

Adults

1 oral inhalation (0.125 mg); may repeat once after 1 minute if needed. Wait at least 4 hours between doses. Max: 2 inhalations (0.25 mg)/dose and 8 inhalations (1 mg)/day. Guidelines for asthma treatment do not recommend use; prescribe a selective short-acting beta-agonist (SABA).

• For asthma exacerbation (e.g., acute care management)

Subcutaneous dosage

Adults

0.3 to 0.5 mg subcutaneously every 20 minutes for 3 doses. Guidelines state there is no proven advantage of systemic therapy over the use of inhaled short-acting beta-agonists.

Adolescents

0.3 to 0.5 mg subcutaneously every 20 minutes for 3 doses. Guidelines state there is no proven advantage of systemic therapy over the use of inhaled short-acting beta-agonists.

• For the treatment of laryngotracheobronchitis (croup)

Nebulized dosage

Infants and Children 6 months to 12 years

0.05 to 0.1 mL/kg/dose of 2.25% racemic epinephrine solution (Max: 0.5 mL/dose) diluted in 2 to 2.5 mL of normal saline and given via nebulizer; may repeat every 20 minutes as needed. Some experts use 0.5 mL/dose for all patients, regardless of size. Alternatively, if racemic epinephrine is not available, L-epinephrine 1 mg/mL can be substituted in a dosage of 0.5 mL/kg/dose (Max: 5 mL/dose) and given via nebulizer; 5 mL of L-epinephrine 1 mg/mL is equivalent to 0.5 mL of racemic epinephrine 2.25%. In general, improvement is seen within 10 to 30 minutes and lasts 2 hours after administration; closely observe patients for recurrence of symptoms for 2 to 3 hours after administration.

• For the treatment of open-angle glaucoma

Ophthalmic dosage (epinephrine ophthalmic solution 0.5%, 1% or 2%; e.g., Epifrin)

Adults

NOTE: These products are discontinued in the U.S. Instill 1 to 2 drops of 0.5%, 1%, or 2% ophthalmic solution into the affected eye(s) once or twice daily.

• For mydriasis induction and maintenance during intraocular surgery

Ophthalmic dosage

Adults

Must dilute prior to intraocular use. Dilute 1 mL of epinephrine 1 mg/mL in 100 to 1,000 mL of an ophthalmic irrigation fluid to create an epinephrine concentration of 10 mcg/mL to 1 mcg/mL. Use the irrigating solution as needed for the surgical procedure. After dilution in an ophthalmic irrigating fluid, the solution may also be injected intracamerally as a bolus dose of 0.1 mL at a dilution of 10 mcg/mL to 2.5 mcg/mL. Only use 1 mg/mL of single-use products intended for ophthalmic administration.

Although not indicated there have been several label indication documented for Epinephrine which includes:

• For the treatment of bradycardia

Intravenous or Intraosseous dosage

Infants, Children, and Adolescents

0.001 mg/kg/dose IV or IO (one-tenth the standard resuscitation dose); titrate to desired hemodynamic effect. A continuous infusion of 0.01 to 0.2 mcg/kg/minute IV or IO has also been recommended

• For the treatment of cardiogenic shock

Continuous Intravenous Infusion dosage

Adults

0.01 to 2 mcg/kg/minute continuous IV infusion. Titrate by 0.05 to 0.2 mcg/kg/minute every 10 to 15 minutes to clinical response. After hemodynamic stabilization, wean incrementally every 10 to 30 minutes over a 12- to 24-hour period. Guidelines consider epinephrine as an alternative to norepinephrine in settings where norepinephrine is not available and suggest adding epinephrine to norepinephrine and vasopressin if inadequate mean arterial pressure (MAP) for patients with septic shock. Epinephrine may be useful in refractory septic shock patients with myocardial dysfunction.

• For the treatment of chloroquine overdose.

Intravenous dosage

Adults

Initially, 0.25 mcg/kg/minute and increase by 0.25 mcg/kg/minute to maintain a systolic blood pressure of 100 mmHg or more in combination with IV diazepam, general anesthesia with thiopental, and FiO₂ 40%. Diazepam was continued for 2 to 4 additional days. Other vasopressors and/or inotropic agents were used as necessary. Eleven cases of acute chloroquine overdose (total ingested dose ranged from 5 to 12 g) were treated with epinephrine; 10 patients were discharged alive from the hospital. The 1 patient who died ingested the largest total dose (15 g) of chloroquine.

• For the treatment of epistaxis

Nasal dosage

Adults

Soak gauze or a cotton pledget in 0.1 to 1 mg/mL solution and place in the affected nostril(s) for 30 minutes.

1mg/ml, 0.5mg/0.3ml, 0.3mg/0.3ml, 0.1 mg/ml

Epinephrine is available in the form of prefilled autoinjector or syringe, injectable solution, oral inhalation spray, and eye drops.

Epinephrine should be used for the treatment of anaphylaxis, angioedema, asthma exacerbation, bronchospasm, cardiac arrest, cardiopulmonary resuscitation, glaucoma, hypotension, laryngotracheobronchitis (croup), mydriasis induction, nasal congestion, pulseless electrical activity, septic shock, surgical bleeding, urticaria, ventricular asystole, ventricular fibrillation.

• Anaphylaxis:

Start with a baseline diet made up of only those foods not implicated in food allergy, and eliminate cow’s milk, eggs, tree nuts, peanuts, fish, shellfish, and wheat. Well-tolerated foods include:

Grains: brown, white, and puffed rice, and gluten-free grains such as amaranth, millet, and buckwheat.

Cooked and dried fruits: cherries, cranberries, pears, prunes, peaches, apricots, papaya, and plums, unless there is a documented allergy to these or to birch pollen.

Cooked green, yellow, and orange vegetables: artichokes, asparagus, broccoli, chard, collards, lettuce, spinach, squash, string beans, sweet potatoes, tapioca, and taro.

Plain and carbonated water.

Condiments: modest amounts of salt, maple syrup, or vanilla extract.

• Angioedema

Common food allergy triggers, such as nuts, shellfish, and eggs, are always excluded. Processed or cured meats or meat products, black pepper, and sweets can also increase inflammation, and so are not permitted.

Because store-bought items may contain flavor enhancers, coloring, preservatives, and other additives, they are avoided.

Many fruits and vegetables contain substances that can cause inflammation, so they are usually avoided at first, with some exceptions.

· For Asthma exacerbation:

Eat plenty of fruits and vegetables. They're a good source of antioxidants such as beta carotene and vitamins C and E, which may help to decrease the lung swelling and irritation (inflammation) caused by cell-damaging chemicals known as free radicals.

Avoid allergy-triggering foods. Allergic food reactions can cause asthma symptoms. In some people, exercising after eating an allergy-causing food leads to asthma symptoms.

Take in vitamin D. People with more-severe asthma may have low vitamin D levels. Milk, eggs, and fish such as salmon all contain vitamin D. Even spending a few minutes outdoors in the sun can increase vitamin D levels.

Avoid sulfites. Sulfites can trigger asthma symptoms in some people. Used as a preservative, sulfites can be found in wine, dried fruits, pickles, fresh and frozen shrimp, and some other foods.

Epinephrine may be contraindicated in the following

• Preexisting hypertension;
• Occlusive vascular disease;
• Angle-closure glaucoma (eye drops);
• Hypersensitivity;
• Cardiac arrhythmias or tachycardia.
• When used in addition to local anesthetics: Procedures involving digits, ears, nose, penis, or scrotum.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

• Injury with Undiluted Intraocular Solution

This product must be diluted before intraocular use. Epinephrine containing sodium bisulfite has been associated with corneal endothelial damage when used in the eye at undiluted concentrations (1 mg/mL)

Incorrect Locations of Injection

Injection into the anterolateral aspect of the thigh (vastus lateralis muscle) is the most appropriate location for administration because of its location, size, and available blood flow. Injection into (or near) smaller muscles, such as in the deltoid, is not recommended due to possible differences in absorption associated with this use. Do not administer repeated injections of epinephrine at the same site, as the resulting vasoconstriction may cause tissue necrosis. Do not inject into the buttock. Injection into the buttock may not provide effective treatment of anaphylaxis and has been associated with the development of gas gangrene. Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower this risk. Do not inject into digits, hands, or feet. Epinephrine is a strong vasoconstrictor. Accidental injection into the digits, hands, or feet may result in loss of blood flow to the affected area and has been associated with tissue necrosis.

• Disease Interactions

Some patients may be at greater risk for developing adverse reactions after systemic epinephrine administration. Despite these concerns, the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation.

• Patients with Heart Disease

Epinephrine should be administered with caution in patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, cerebrovascular disease, or hypertension. In such patients, or in patients who are on drugs that may sensitize the heart to arrhythmias, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias.

• Other Patients and Diseases

Epinephrine should be administered with caution to patients with hyperthyroidism, Parkinson’s disease, diabetes mellitus, pheochromocytoma, elderly individuals, and pregnant women. Patients with Parkinson’s disease may experience psychomotor agitation or notice a temporary worsening of symptoms. Diabetic patients may experience transient increases in blood sugar.

• Allergic Reactions

Associated with Sulfite Epinephrine contains sodium bisulfite which may cause mild to severe allergic reactions including anaphylaxis or asthmatic episodes in susceptible individuals. However, the presence of bisulfite in this product should not preclude its use for the treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive, as the alternatives to using epinephrine in a life-threatening situation may not be satisfactory.

Consumption of alcohol is not recommended while receiving this medicine as it may increase the risk of adverse effects and lowers blood pressure.

Epinephrine or the components of the drug medication has not been known to be excreted in milk but a decision should be made by the treating physician whether to continue or discontinue this medication and should be only used if the benefits outweigh the risks.

Pregnancy Category C.

There is no well-established data on pregnant patients. Epinephrine should be administered used during pregnancy only if the potential benefit outweighs the risks. Epinephrine is found to be teratogenic in rabbits, mice, and hamsters when they were dosed during organogenesis. Epinephrine found to be shown to have teratogenic effects which include gastroschisis and embryonic lethality when they were administered with subcutaneous doses in rabbits at approximately 15 times the maximum recommended intramuscular or subcutaneous dose. In mice, teratogenic effects including embryonic lethality have been observed at approximately 3 times the maximum recommended intramuscular or subcutaneous dose. These effects have not been observed in mice at approximately 2 times the maximum recommended daily intramuscular or subcutaneous dose. In hamsters, teratogenic effects were observed at approximately two times the maximum recommended intramuscular or subcutaneous dose.

The adverse reactions related to Terbutaline can be categorized as:

Common Adverse Reaction

• Blurred vision
• Pounding in the ears
• Slow, fast, or irregular heartbeat
• Unusual tiredness or weakness
• Chest pain or discomfort
• Headache
• Lightheadedness, dizziness, or fainting
• Nervousness

Less common Adverse Reaction

• Vomiting
• Nervousness
• Generalized Weakness
• Anxious Feelings
• Fast Heartbeat
• Dizziness
• Muscle Tremors
• Loss Of Skin Color
• Headache
• Heart Throbbing Or Pounding
• Nausea

Rare Adverse Reaction

• Itching of the skin
• Numbness and tingling of the face, fingers, or toes
• Pain in the arms legs, or lower back, especially in the calves or heels upon exertion
• Pale, bluish-colored, cold hands or feet
• Pale skin
• Blue lips and fingernails
• Confusion
• Coughing that sometimes produces a pink frothy sputum
• Difficult, fast, noisy breathing
• Dizziness, fainting, or lightheadedness when getting up suddenly from a lying or sitting position
• Increased sweating
• Swelling in the legs and ankles
• Weak or absent pulses in the legs

Drugs antagonizing pressor effects of epinephrine:

• Antihypertensives
• Ergot alkaloids
• α-blockers, such as phentolamine
• Vasodilators, such as nitrates
• Diuretics

Drugs potentiating pressor effects of epinephrine:

• Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone
• Clonidine
• Doxapram
• Oxytocin
• Sympathomimetics
• β-blockers, such as propranolol
• Tricyclic anti-depressants
• Monoamine oxidase (MAO) inhibitors

Drugs potentiating arrhythmogenic effects of epinephrine.

Patients who are concomitantly receiving any of the following drugs should be observed carefully for the development of cardiac arrhythmias.

• Thyroid hormones
• Diuretics
• β-blockers, such as propranolol
• Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane
• Antihistamines
• Cardiac glycosides, such as digitalis glypoygdsxcosides
• Quinidine

Drugs potentiating hypokalemic effects of epinephrine

• Potassium depleting diuretics
• Corticosteroids
• Theophylline

The common side of Adrenaline/Epinephrine includes the following:

• Loss Of Skin Color
• Headache
• Heart Throbbing Or Pounding
• Dizziness
• Nervousness
• Generalized Weakness
• Anxious Feelings
• Fast Heartbeat
• Muscle Tremors
• Nausea
• Vomiting

Pregnancy

Pregnancy Category C.

There is no well-established data on pregnant patients. Epinephrine should be administered used during pregnancy only if the potential benefit outweighs the risks. Epinephrine is found to be teratogenic in rabbits, mice, and hamsters when they were dosed during organogenesis. Epinephrine found to be shown to have teratogenic effects which include gastroschisis and embryonic lethality when they were administered with a subcutaneous dose in rabbits at approximately 15 times the maximum recommended intramuscular or subcutaneous dose. In mice, teratogenic effects including embryonic lethality have been observed at approximately 3 times the maximum recommended intramuscular or subcutaneous dose. These effects have not been observed in mice at approximately 2 times the maximum recommended daily intramuscular or subcutaneous dose. In hamsters, teratogenic effects were observed at approximately two times the maximum recommended intramuscular or subcutaneous dose.

Labor and Delivery

Use Epinephrine/Adrenaline with caution during labor and delivery. Although epinephrine improves maternal hypotension associated with anaphylaxis, it may result in uterine vasoconstriction, decreased uterine blood flow, and fetal anoxia.

Nursing Mothers

Adrenaline/Epinephrine or the components of the drug medication has not been known to be excreted in milk but a decision should be made by the treating physician whether to continue or discontinue this medication and should be only used if the benefits outweigh the risks.

Pediatric Use

Clinical use data support weight-based dosing for treatment of anaphylaxis in pediatric patients, and other reported clinical experience with the use of epinephrine suggests that the adverse reactions seen in children are similar in nature and extent to those both expected and reported in adults. The safety and effectiveness of epinephrine (at a dilution of 1:100,000 to 1:400,000) for induction and maintenance of mydriasis during intraocular surgery have been established in pediatric patients. The use of Adrenalin for induction and maintenance of mydriasis during intraocular surgery in pediatric patients is supported by adequate and well-controlled studies in adults and uncontrolled studies in pediatric patients.

Geriatric Use

Clinical studies for the treatment of anaphylaxis have not been performed in subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical experience with the use of epinephrine for the treatment of anaphylaxis has identified that geriatric patients may be particularly sensitive to the effects of epinephrine. Therefore, for the treatment of anaphylaxis, consider starting with a lower dose to take into account potential concomitant disease or other drug therapy. For induction and maintenance of mydriasis during intraocular surgery, no overall differences have been observed between the elderly and other patients.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of molecule Adrenaline/Epinephrine.

Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients. Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Treatment consists of a rapidly acting α-adrenergic blocking drug and respiratory support. Epinephrine is rapidly inactivated in the body and treatment following overdose with epinephrine is primarily supportive. If necessary, pressor effects may be counteracted by rapidly acting vasodilators or α-adrenergic blocking drugs. If prolonged hypotension follows such measures, it may be necessary to administer another pressor drug. Epinephrine overdosage can also cause transient bradycardia followed by tachycardia and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (fibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists of the administration of a beta-adrenergic blocking drug such as propranolol. Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis due to elevated blood lactic acid levels, and kidney failure. Suitable corrective measures must be taken in such situations.

Pharmacodynamics

Intravenous use for hypotension associated with septic shock Following intravenous administration of epinephrine, increases in systolic blood pressure and heart rate are observed. Decreases in systemic vascular resistance and diastolic blood pressure are observed at low doses of epinephrine because of β2-mediated vasodilation but are overtaken by α1-mediated peripheral vasoconstriction at higher doses leading to an increase in diastolic blood pressure. The onset of blood pressure increase following an intravenous dose of epinephrine is < 5 minutes and the time to offset blood pressure response occurs within 20 min. Most vascular beds are constricted including renal, splanchnic, mucosal, and skin. Intramuscular and subcutaneous use for anaphylaxis Through its action on alpha-adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension. Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation and helps alleviate bronchospasm, wheezing, and dyspnea that may occur during anaphylaxis.

Epinephrine also alleviates pruritus, urticaria, and angioedema and may relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder.

Epinephrine increases glycogenolysis, reduces glucose uptake by tissues, and inhibits insulin release in the pancreas, resulting in hyperglycemia and increased blood lactic

Intraocular use for mydriasis Epinephrine causes mydriasis when administered intraocularly or parenterally.

Pharmacokinetics

• Absorption:

When administered parenterally or intraocularly, epinephrine has a rapid onset and short duration of action. Following intravenous injection, epinephrine is rapidly cleared from the plasma with an effective half-life of < 5 min.

• Distribution:

A pharmacokinetic steady state following continuous intravenous infusion is achieved within 10-15 min. In patients with septic shock, epinephrine displays dose-proportional pharmacokinetics in the infusion dose range of 0.03 to 1.7 mcg/kg/min. The extent of human systemic exposure at the labeled intraocular dose has not been evaluated, however, significant systemic concentrations or plasma exposure of epinephrine are not expected when administered intraocularly.

• Metabolism

Epinephrine is extensively metabolized with only a small amount excreted unchanged.

• Excretion:

Epinephrine is rapidly degraded to vanillylmandelic acid, an inactive metabolite, by monoamine oxidase and catechol-O-methyltransferase that are abundantly expressed in the liver, kidneys, and other extraneuronal tissues. The tissues with the highest contribution to the removal of circulating exogenous epinephrine are the liver (32%), kidneys (25%), skeletal muscle (20%), and mesenteric organs (12%)

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