Epinephrine: Drug Whys

A comprehensive examination of epinephrine and its prehospital uses, administration routes, doses and pharmacology


Updated August 31, 2016

Generic Name: Epinephrine auto-injector (several brands available, most widespread in U.S. is EpiPen, patent expires September 11, 2025)
Common U.S. Brand Names: EpiPen and EpiPen Jr. (Dey Pharma, USA)
Popularity: 1.5 million prescriptions dispensed 2010 (U.S.)
Class: Alpha/beta agonist, vasopressor

Treatment Uses
For emergency treatment of Type I (anaphylactic) allergic reactions. Also approved for emergency treatment of asthma, blood coagulation disorder, cardiac arrest, mucosal congestion (when applied in topical spray form), excessive uterine contractions, glaucoma (in eye drop form), hypersensitivity reactions, syncope (fainting) due to complete heart block or carotid sinus hypersensitivity, hyperkalemia (high serum potassium levels), and an adjunct to decrease bleeding and increase duration of action when mixed with local anesthetic agents.

Mohawk Ambulance uses a syringe-based epinephrine injection to treat anaphylaxis. (Photo/Mohawk Ambulance Service)
Mohawk Ambulance uses a syringe-based epinephrine injection to treat anaphylaxis. (Photo/Mohawk Ambulance Service)

Epinephrine is also directly injected during endoscopy to treat actively bleeding upper gastrointestinal ulcers. Topical (applied to the skin) epinephrine solutions have been used to treat herpes simplex lesions.

Very dilute solutions have been injected into the penis to treat prolonged priapism (erection). Inhaled mixtures of epinephrine are used to treat asthma, croup, stridorous (reactive) upper airway conditions, acute wheezing and, with mixed results, cluster headaches. In cases of severe asthma, subcutaneous administration is superior to inhaled epinephrine.

Epinephrine has a wide variety of uses and can be administered by multiple routes. For the purposes of this column, discussion will be limited to uses of epinephrine auto-injectors, most often used for treatment of allergic reactions and severe asthma.

Of particular note, delays in epinephrine administration are an important contributor to adverse outcomes in allergic reactions and severe asthma. Epinephrine administration should be considered even when allergic symptoms involve only one body system (i.e., the skin).

Anaphylaxis is a life-threatening condition. Millions of severe allergic reactions occur annually; several hundred people die from food, insect sting and drug induced anaphylaxis.

A significant risk factor for death from anaphylaxis is delay administering epinephrine after onset of symptoms. Most allergic reactions are immune mediated, meaning that an individual is exposed to an allergen, develops antibodies to the allergen, and experiences an allergic response the next time they are exposed to the allergen. Hence, an individual may be very allergic to a food, insect, or drug but totally unaware of the allergy until they are exposed a second or third time.

Signs and symptoms are varied and may involve the skin (itching, swelling, rash, redness, hives), respiratory tract (runny nose, wheezing, congestion, cough, difficulty breathing), gastrointestinal tract (cramps, nausea, vomiting, diarrhea), and/or cardiovascular system (increased heart rate, low blood pressure, fainting, chest pain).

While cutaneous (skin) symptoms and wheezing are very common in anaphylaxis, cutaneous signs are absent in 20 percent of severe allergic reactions and respiratory symptoms occur in only 50 percent of cases. Treatment should not be delayed to observe for worsening symptoms.

Asthma, like anaphylaxis, can also be a life threatening problem. EMS providers who respond to an asthmatic patient in severe distress may find the patient unable to inhale metered dose or nebulized bronchodilators.

An EpiPen is an ideal (and often life saving) emergency treatment for these patients, allowed under many EMS protocols. In severe asthma, epinephrine is the agent of choice for emergency treatment.

Dosing and Administration
The United States Joint Task Force on Practice Parameters for Allergy and Immunology guidelines for management of anaphylaxis in adults call for epinephrine 0.2 to 0.5 milligrams (0.2 to 0.5 mL of a 1:1000 solution) injected intramuscularly in the lateral thigh muscle every 5 to 10 minutes as needed. If clinically appropriate, injections can be given more frequently than every 5 minutes.

Auto-injectors contain fixed doses of epinephrine. Hence, for adults and children 30 kilograms (66 pounds) and heavier with anaphylaxis, give 0.3 milligrams of epinephrine intramuscular which equals 0.3 milliliters of a 1:1000 solution as contained in an auto-injector.

If severe anaphylaxis persists, the same dose may be repeated after 5 to 10 minutes or sooner if needed. The same dose is used for adults with intractable asthma, blood coagulation disorder, excessive uterine contractions and syncope due to complete heart block or carotid sinus hypersensivity.

For pediatric patients weighing between 15 and 30 kilograms (33 to 66 pounds), give 0.15 milligrams epinephrine intramuscular which equals 0.3 milliliters of a 1:2000 solution contained in the pediatric auto-injector. 

Administer an epinephrine auto-injector into the anterolateral aspect (side) of the thigh. If the patient is wearing clothing, administer through the clothing. It is important to hold the auto-injector in place on the thigh once the audible activation click is heard to assure delivery of the drug into the leg.

Auto-injector epinephrine should not be given intravenously (IV) or into the buttock. Do not use epinephrine that is pinkish colored, has precipitate present or is otherwise discolored.

The EpiPen manufacturer operates an excellent website with videos and instructional materials on proper use of the auto-injector (www.epipen.com).

Earlier preloaded epinephrine emergency kits were designed for subcutaneous administration; patients were often taught to administer the drug in the upper arm (deltoid muscle). However, studies have demonstrated that intramuscular injection achieves significantly faster maximum plasma epinephrine levels compared to subcutaneous administration.

Additionally, intramuscular injection into the vastus lateralis (anterolateral thigh) muscle are more effective than intramuscular or subcutaneous injection into the upper arm, produce faster effects and greater peak plasma epinephrine levels.

Many drugs intended for injection work equally well orally (taken by mouth). Not so with epinephrine. Given orally, epinephrine will rapidly degrade in the GI tract and is not absorbed at all.

Epinephrine contained in auto-injectors contains sodium metabisulfite as a preservative. This should not deter administration of the medication to patients with sulfa allergies who have a legitimate allergic reaction or emergency condition. In fact, there are NO absolute contraindications for administration of epinephrine in a life-threatening emergency.

Earlier recommendations suggested that the risk of cardiac side effects in elderly patients outweighed use of epinephrine. A study of three sequential doses of auto-injector epinephrine in asthmatics aged 40 to 96 years old spaced 20 minutes apart demonstrated that epinephrine appears safe for asthmatic patients of any age.

Multiple other studies have confirmed the safety of epinephrine for treatment of severe asthma in patients of all ages. While epinephrine is a powerful medication with potential for significant cardiovascular effects, this should not preclude its use in any life-threatening emergency.

Overdoses of epinephrine can markedly elevate blood pressure and cause a multitude of tachy- and brady-arrhythmias. Pulmonary edema may result from simultaneous bronchodilation, peripheral vasoconstriction and excessive cardiac stimulation.

Treatment should be supportive and may require administration of beta blockers. Be mindful that epinephrine is rapidly inactivated in the body – symptoms are unlikely to be prolonged.

Pharmacology/Pharmacokinetics/Stability
Following subcutaneous or intramuscular administration for anaphylaxis or asthma, initial response to epinephrine is rapid. Duration is short. Injected epinephrine is rapidly inactivated and degraded by liver enzymes. Most of the degraded epinephrine is excreted by the kidneys.

Repeated injections of epinephrine, spaced at approximately 20 minute intervals, have been shown to sustain initial improvements without cumulative effects.

There are no studies on effects of epinephrine during pregnancy. It should be used if the potential benefits to the mother outweigh risks to the developing fetus. No studies have been conducted on breast milk of nursing mothers given epinephrine for anaphylaxis.

The mechanism of action of epinephrine is as a sympathomimetic catecholamine acting on both alpha- and beta-andrenergic receptors. Of catecholamines, it is the most potent activator of alpha receptors resulting in intense vasoconstriction. Its beta receptor action promotes bronchial smooth muscle relaxation, resulting in significant bronchodilation.

EpiPen and EpiPen Jr. are supplied in a 2-Pak carton containing two EpiPen Auto-Injectors (clipped together with an S-clip) and one EpiPen Auto-Injector training device. Single EpiPen and EpiPen Jr. units are no longer sold in the U.S.

EpiPen auto-injectors should be stored at controlled room temperature (77 F) with excursions between 59 and 86 F allowed. Epinephrine is theoretically light sensitive; keeping it in the carrier tube provided protects it from light. EpiPens should not be refrigerated.

Stability studies have shown degradation to less than 90 percent of labeled dose when stored for more than 3 months in low humidity (15 percent) and 4 months storage at high humidity (95 percent). 

Interestingly, light had no effect on stability. There was no degradation when stored at 5 C (41 F) or at 70 C (158 F) for 8 hours a day over 12 weeks. Interestingly, 1:10,000 concentration epi completely degraded at the high temperature when stored for similar periods (of note for ALS drug boxes).

From a chemical standpoint, higher pH (above 5.5) promotes oxidation of epinephrine (causing it to become very unstable). This is a slow process, and is not likely to be clinically significant over short time periods (less than 2 hours). Hence, for ALS providers, it is not necessary to separate epinephrine from bicarbonate when administered through the same line.

Cautions and Warnings
Epinephrine auto-injectors are designed for self-administration in emergency situations. Their safety profile and ease of use has led to widespread use by EMS personnel, school officials, camp counselors and medical personnel.

An auto-injector should not substitute for immediate medical care; patients should be advised to seek medical treatment following any use of an auto-injector.

Inadvertent injection of epinephrine into hands, feet, fingers or toes may result in loss of blood flow and severe tissue damage. A recent redesign of the EpiPen and EpiPen Jr. highlighted the needle with a brightly colored orange self retracting cap and warning label.

Unfortunately, a popular insulin auto-injector pen already on the market is operated by pressing on a brightly orange colored activator button. This has caused health care providers and patients with diabetes to inadvertently stab their fingers attempting to use EpiPens.

Every EpiPen package includes a training auto-injector; EMS personnel should practice frequently with the trainer to prevent misuse of the actual EpiPen in an emergency. In the event of injection into fingers or toes, seek immediate medical attention.

Important Side Effects and Interactions
Pulse rate and blood pressure are increased due to the alpha stimulating effects of epinephrine. Metabolic effects of epinephrine include elevated blood glucose resulting from inhibition of insulin secretion and increased lactate and free fatty acid concentrations in the blood due to receptor activation and a 20 to 30 percent increase in oxygen consumption with usual doses.

Side effects of epinephrine include increased heart rate, palpitations, sweating, nausea, vomiting, nervousness, tremors, dizziness, headache, and difficulty breathing.

There are 54 drugs and drug classes specifically reported to interact with epinephrine. Some are worth noting. Patients taking tricyclic antidepressants (TCAs), monomine oxidase inhibitors (MAOIs), or levothyroxine may experience greater and longer lasting effects of epinephrine.

Beta blockers may lessen or interfere with the therapeutic effects of epinephrine. Patients with hyperthyroidism, cardiovascular disease, diabetes, hypertension, pregnancy, or those weighing less than the recommended weights (30 kilograms for EpiPen and 15 kilograms for EpiPen Jr.) are at greater risk of developing side effects or adverse reactions. Angina may occur in patients with significant coronary artery disease.

Rapid rises in blood pressure leading to stroke have been reported following epinephrine administration, particularly in elderly patients with cardiovascular disease. As mentioned previously, none of these potential side effects should inhibit use of epinephrine in life-threatening emergencies.

Average Costs – U.S. in 2012

EpiPen 2-Pak and EpiPen Jr. 2-Pak (brand name)

Patient cost: $187.89 and 203.29 each*
Large Hospital cost: $176.00 each (both adult and Jr.)
*(Wal Mart and Target don’t include this med in their $4/month programs)

Editor's note: The significant price increase of the EpiPen became a top concern for EMS leaders, parents and health care advocates in August 2016. Read our continuing coverage in our epinepherine topic section.

References:
1. MICROMEDEX Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed January, 2012).
2. Albany Medical Center Pharmacy, Albany, New York.

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