Discovering Epinephrine: The Adrenaline Rush That Changed Medicine
Beyond its role in anaphylaxis treatment, epinephrine has shaped modern drug development and medicine.
Throughout every hour of every day, our immune system patrols our external and internal environment looking for harmful substances.
An allergic reaction occurs when the body mistakenly perceives something harmless as a threat and triggers a disproportionate immune response.
Specialized immune cells start this chain reaction by releasing inflammatory molecules into the blood, which increase vascular permeability and cause smooth muscles in the airways to contract. This results in symptoms ranging from mild swelling to breathlessness, which can progress to anaphylactic shock as significant fluid is lost to surrounding tissues, blood pressure drops, and the airways close.
In cases of anaphylaxis, intramuscular epinephrine is considered the most effective first-line treatment, supported by international groups such as the World Allergy Organization. Despite being among the oldest and most common treatments in emergency medicine, not all clinicians reach for it when needed. While logistical barriers and apprehension delay its use for some, for others, it is simply not available.
This article will explore how epinephrine works, its journey into clinical practice, barriers to access, and novel approaches aiming to address treatment gaps.
Understanding anaphylaxis, to understand epinephrine
There are numerous triggers for anaphylaxis: food, medication, insect stings, and even exercise.
Regardless of the trigger, common to every anaphylactic reaction is the inappropriate activation of mast cells. These are the aforementioned specialized immune cells that release histamines and other inflammatory mediators.
Through binding to receptors on the smooth muscle and endothelial cells lining the blood vessels, these molecules lead to an array of symptoms across the respiratory, cardiovascular, dermatological, and gastrointestinal systems:
- Respiratory: Smooth muscle contraction in the airways results in wheezing, shortness of breath, and a reduction in circulating oxygen.
- Circulatory: As the smooth muscles surrounding blood vessels relax, they dilate, resulting in reduced resistance and low blood pressure. At the same time, endothelial cells surrounding the dilated vessels contract, creating gaps that allow fluid to leak into surrounding tissues. As pressure and perfusion fall, patients may experience confusion, altered consciousness, and circulatory collapse as the brain and heart are deprived of adequate blood and oxygen supply.
- Gastrointestinal: Smooth muscle surrounding the gastrointestinal tract is also affected, with spasms leading to abdominal cramping, vomiting, and diarrhea.
- Dermatological: Blood vessel leakage also allows fluid to seep into the skin, causing swelling and hives.
Appreciating the systemic, rapid-onset pathophysiology of anaphylaxis allows us to understand the role of epinephrine.
From fight-or-flight to life-saving treatment
Epinephrine, also known as adrenaline, is a naturally occurring hormone responsible for our autonomous “fight-or-flight” response.
Thousands of years ago, when our ancestors recognized danger, the body released large amounts of epinephrine and cortisol to trigger a physical response that increased their chances of survival.
This response holds true today. Epinephrine is released during periods of stress, increasing heart rate and blood pressure to facilitate greater blood flow to muscles for action, dilating the airways to maximize oxygen intake, and suppressing non-essential functions, such as digestion, to conserve energy. Although we are no longer running from predators, the body has maintained the same physiological stress response.
Considering the consequences of epinephrine release, it makes sense that it was a fitting candidate for reversing or managing many of the changes observed in anaphylaxis.
A rush for conclusions: The history of epinephrine
The systemic response resulting from an increase in epinephrine was observed as early as the 1800s. Physician Henry Hyde Slater noted that the symptoms of asthma, which most often occur due to an allergic response, were relieved by “violent emotion” and mental excitement.”
In 1894, physician George Oliver and physiologist Edward Albert Sharpey-Shafer demonstrated these effects in the laboratory using an extract from the adrenal medulla, part of the adrenal gland situated on top of the kidneys. Unbeknownst to them, the adrenal medulla produces epinephrine. After administering the extract to animals, they observed increases in heart rate and blood pressure.
In the following years, researchers studied the extract’s properties, endeavoring to isolate the active ingredient and determine its formula. By the early 1900s, they had achieved just this.
Soon after, the purified product was patented and manufacturers began developing synthetic forms. Despite a lack of understanding surrounding epinephrine’s mechanism of action, its therapeutic effects in asthma were becoming increasingly evident.
Adrenaline or epinephrine?
Today, epinephrine and adrenaline are commonly used interchangeably, which continues to cause confusion. The two names stem from challenges encountered during isolation of the active compound. To isolate a compound means to obtain it in a pure form, separate from all else.
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In 1897, John Jacob Abel, a physiological chemist at Johns Hopkins University, described an adrenal gland product that appeared to reproduce the effects Oliver and Schafer had observed. By 1899, he had seemingly isolated the active compound and named it epinephrine.
However, chemist Jokichi Takamine later disputed this work and determined that neither Abel nor other scientists had successfully isolated a pure form of the compound. In 1901, he achieved this himself and thereafter patented both the isolation process and the extract, which was marketed under the trade name “Adrenalin” by the pharmaceutical company Parke-Davis.
Different names, similar meanings
The word adrenaline comes from the Latin prefix ad- (meaning “on” or “toward”) and rēnālis (meaning “of the kidneys”).
The word epinephrine comes from the Greek prefix epi- (meaning “above”) and nephros (meaning “kidney”).
Both terms refer to the adrenal glands, which produce the hormone and are located above the kidneys.
While Europe adopted “adrenaline,” later approving it as the official name, “epinephrine” was already in use throughout the United States and was adopted in scientific literature. The confusion that ensued prompted the World Health Organization to introduce a naming system, in which each pharmaceutical substance should be identified by a single, globally recognized, generic name.
Defining delivery: Right route, right dose, right patient
In the case of anaphylaxis, intramuscular injection of epinephrine is standard across many guidelines after emerging as superior. The journey to reach this conclusion looked very different from the drug development pipelines we are now familiar with.
In the early 1900s, scientists didn’t understand how epinephrine worked and, without the privilege of in silico testing and high-throughput screening, they resorted to testing the extract on as many tissue types as possible to observe its effects. At the same time, clinicians were not beholden to clinical trials or modern drug regulations. Prior to the Food, Drug, and Cosmetic Act in the late 1930s, if a drug existed, a doctor could give it.
So, as researchers endeavored to figure out the “how”, doctors aimed to identify the “who.”
Clinicians administered epinephrine to patients, recorded observations, and shared their findings via case reports. Its dramatic effects led many to believe it was a “cure-all.” It was tested across numerous conditions, from anesthesia to gonorrhea, and via various routes: ocular, nasal, topical, and injectable.
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It was physician George Crile who demonstrated that epinephrine administration, alongside cardiopulmonary resuscitation, could revive patients following a cardiac arrest. This laid the groundwork for its use in emergency medicine in the management of cardiac arrest and shock.
Shock
Shock is a life-threatening condition characterized by inadequate blood flow to the body’s tissues. There are four different types of shock: hypovolemic, cardiogenic, obstructive, and distributive. Anaphylaxis is a type of distributive shock.
By the 1980s, epinephrine was embedded in clinical management protocols and was classified as an essential medicine by the World Health Organization, meaning it should always be available within functioning health systems.
Benefits limited by boundaries
As much as epinephrine is now a staple in emergency medicine, not everyone receives this life-saving treatment when it is needed most. Hesitations among both patients and clinicians, along with logistical barriers and cost concerns, can delay or prevent timely access and administration.
At a minimum, it would be reasonable to expect that a medication indicated for two life-threatening conditions is readily available in emergency departments (EDs). Though this is the case in most established healthcare systems, it has been historically underused; for example, Banergi et al., found that as few as 8% of individuals presenting with drug-induced anaphylaxis received epinephrine on presentation.
Physician barriers to administering epinephrine generally fall into three categories: diagnostic uncertainty, fear of adverse effects, and logistical roadblocks, including dose calculation, medication preparation, and site identification. While autoinjectors—pre-filled syringes predominantly designed for use by patients and carers—could help overcome logistical barriers, only one-third of countries provide access to these devices, with global disparities in availability, affordability, and regulatory approval.
If individuals ring the emergency services rather than attend an ED, they may encounter the same difficulties. In the United States, emergency medical services (EMS) are regulated by state law, which determines whether ambulances must stock epinephrine. While all ambulances are allowed to stock it, only 17 states are bound by law to do so.
Given barriers in epinephrine administration in emergency care settings, individuals living with severe allergies may find comfort in carrying their own autoinjectors. When dealing with severe allergies, every minute matters; it makes sense that those affected can self-administer medication upon recognizing the signs and symptoms.
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However, studies have also found that use of autoinjectors is low, with only a third of patients or carers administering the treatment prior to seeking medical attention. Patients face multiple barriers: high out-of-pocket costs may mean they do not have an injector available; if they do, it may be outdated; and, even if it is within date and suitable for use, they may be hesitant to use it due to misconceptions and fear. Global inequality persists, with only 60% of countries—predominantly high-income—providing devices to patients.
As fatalities following anaphylaxis are often linked to late administration of epinephrine, findings from emergency care settings and patient-reported experiences remain concerning.
A surge in innovation to improve epinephrine uptake
Manufacturers, pharmaceutical companies, and charities are working to overcome barriers in epinephrine access and use. Many companies now offer training devices, which are pens without needles or medication, for patients to build muscle memory and reduce apprehension about self-injecting. Charities also have expiry alert systems in place to encourage patients to renew their prescriptions.
At the same time, revisions to consensus criteria for anaphylaxis provide up-to-date management guidelines, aiming to reduce clinician delays in recognizing symptoms and administering medication.
Given that using a syringe and vial for dose calculation is more cost-effective and provides an opportunity for weight-based dosing, it seemed logistical barriers in clinical settings were unlikely to change. However, in recent years, this view has started to shift.
Following a 2024 trial, the FDA granted neffy™, the first needle-free epinephrine nasal spray for anaphylaxis, fast-track approval. In 175 healthy adults, the spray increased blood epinephrine concentrations to levels similar to those achieved with autoinjectors. While designed for use by patients and carers, the device is increasingly being adopted in medical settings as an additional tool. Real-world data collection is now underway, facilitated by rapid uptake of the device, with over one million prescriptions issued annually in the United States alone.
Ultimately, neffy’s fast-track approval, the subsequent surge in prescriptions, and growing clinician interest all demonstrate the significant unmet medical need in anaphylaxis care that is starting to be addressed. As global access is often considered following development rather than as part of drug design, novel approaches may encounter the same barriers as existing interventions, potentially widening access gaps.
Quite the shock: What epinephrine taught us
Few discoveries have had as profound an impact as epinephrine. From its influence on patent law and drug nomenclature to its role in advancing our understanding of fundamental physiological principles.
The offerings of epinephrine surprised us a century ago, and its potential continues to unfold today.
- Hormones: Before the 1900s, scientists understood that the body communicated through nerves, but the idea that organs could also communicate via the bloodstream had not yet been established. While epinephrine was not the first substance to be officially classified as a hormone, its study helped introduce the concept of a chemical messaging system.
- Receptors: Epinephrine forced researchers to ask: How can one molecule cause multiple responses across different organs? From this, physiologist John Newport Langley proposed that chemical messengers must act selectively on specific sites, introducing the idea of specific receptors for the first time.
- The nervous system: Physiologists understood that stimulation of the vagus nerve slowed the heart, and that stimulation of other nerves could increase heart rate and blood pressure, but they did not yet understand how these effects were coordinated. The physiological changes observed following epinephrine injection were the opposite of those produced by vagus nerve stimulation, which introduced the concept of opposing, chemically mediated divisions within the nervous system.
- Patents: Patenting the epinephrine isolate presented two key challenges: firstly, determining whether Takamine was truly the first to isolate epinephrine; and secondly, whether it was appropriate to patent a natural product. Today, natural products can be patented only if significant intervention—from isolation to modification and transformation—is required to obtain the active compound, with specific rules applying in different regions.
- Access: The efficacy of a medicine depends on both pharmacology and availability. Unless both are optimized, the potential to improve patient outcomes may not be met.
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