Description

Adrenaline (Epinephrine) is an endogenous adrenergic hormonal agent and medication that regulates visceral functions with mixed nonspecific α- and β-receptor activity (PubChem, 2024).

Action

Adrenaline relaxes smooth muscles in the bronchi and iris. Adrenaline antagonises the effects of histamine, increases glycogenolysis, and raises blood sugar (Booth, 2011; DeWitt et al., 2016; Maddison, 2008; Plumb, 2024; Farzam et al., 2024).

Mechanism of Action

Adrenaline (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. Epinephrine also alleviates pruritus, urticaria, and angioedema. Adrenaline may help relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxing effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder (Farzam et al., 2024; Oyebola, 2011). During reperfusion, adrenaline may counteract cerebral vasoconstriction (Kondo et al., 2022). Specific receptor effects include:

⍺-1 Sympathomimetic Activity: Smooth muscle contraction, mydriasis
⍺-2 Sympathomimetic Activity: Mixed smooth muscle effects
β-1 Sympathomimetic Activity: Increased cardiac chronotropic and inotropic effects (increased heart rate, myocardial contractility, and renin release)
β-2 Sympathomimetic Activity: Bronchodilation

Adrenaline may demonstrate valuable short-term benefits during CPCR, but it is also arrhythmogenic and increases the heart's workload. High doses in many species are considered harmful during CPCR (Rozanski et al., 2012) and have been shown to reduce body tissue oxygen levels in rabbits (Towell et al., 1981). Other catecholamines, such as dopamine and dobutamine, are generally preferred in major pet species if sustained Adrenaline use is anticipated (DeWitt et al., 2016).

Veterinary Applications

Resuscitation associated with anaesthesia-induced PEA/CPA: ⍺-1 and β-1 activity is beneficial during CPR.
Resuscitation associated with spontaneous cardiac arrest PEA /CPA: ⍺-1 and β-1 activity is beneficial during CPR.
Anaphylaxis: ⍺-adrenergic activity reduces vasodilation and increases vascular permeability during anaphylaxis.
Bronchospasm: β-2 activity results in bronchodilator.

Human Applications

In human medicine, adrenaline is used for emergency treatment of type I allergic reactions, including anaphylaxis; hypotension associated with septic shock, resuscitation; hemostasis, rhinitis, acute sinusitis; bronchial asthmatic paroxysms; syncope; urticaria, angioneurotic oedema; simple (open-angle) glaucoma; relaxation of uterine musculature and to inhibit uterine contractions; prolongation of action of local anaesthetics, and the maintenance of mydriasis during intraocular surgery (PubChem, 2024; Farzam et al., 2024).

Metabolism

Mixed sites: Epinephrine is rapidly inactivated in the body mostly by the enzymes COMT (catechol-O-methyltransferase) and MAO (monoamine oxidase). The liver is a major site, although the process also occurs in many other tissues.

Elimination

Urine: Epinephrine is rapidly inactivated mainly by enzymic transformation to metanephrine or normetanephrine, either of which is then conjugated and excreted in the urine in the form of both sulfates and glucuronides.

Adverse Effects

Various adverse effects are possible during CPCR, but their significance is limited as they depend on achieving ROSC and are of no consequence if the patient dies.

CPCR systemic adverse effects: Tremors, excitability, vomiting, hypertension, tachycardia, arrhythmias, pulmonary oedema, hyperglycemia, dysphoric behaviour changes (e.g., anxiety, excitability), and lactic acidosis have been described in humans.
Adverse effects at the injection site: Repeated injections may result in tissue necrosis and sloughing at any injection site (SPC Data).

Contraindications

DNR agreements: No absolute contraindications to epinephrine use in life-threatening situations are identified unless there is a preexisting legal request or agreement not to resuscitate.

Reproductive Safety

Pregnancy: Adverse effects upon pregnancy are of limited significance during life-threatening situations. A teratogenic effect has been demonstrated in animal experiments (SPC Data).
Lactation: Adverse effects upon suckling offspring are of limited significance during life-threatening situations. Adrenaline is distributed into breast milk.
Male Fertility: No data on subsequent post-CPCR fertility (SPC Data).
Female Fertility: No data on subsequent post-CPCR fertility (SPC Data).

Interactions

Sympathomimetic Agents: Physiological results are unpredictable, and additive effects may occur (SPC Data).
Adrenergic Agents: Diphenhydramine, chlorpheniramine, and levothyroxine may potentiate the effects of adrenaline (epinephrine) (SPC Data).
Antagonist Agents: Nitrates, α-blocking agents and diuretics may abolish or reduce the pressure effects of adrenaline (epinephrine) (SPC Data).
β-blockers: Concomitant use may potentiate hypertension and antagonise the bronchodilatory and cardiostimulatory benefits (SPC Data).
Oxytocin: Concurrent use may result in postpartum hypertension (SPC Data).
Proarrhythmic Agents: Concurrent use of proarrhythmic agents (e.g., halothane, digoxin) may sensitise the myocardium to arrhythmias (SPC Data).

Identifiers

Systematic Name: IUPAC Name - 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol (PubChem, 2024).
Formula: C9H13NO3 (PubChem, 2024).
Pharmacotherapeutic group:
ATC Code(s): A01AD01; B02BC09; C01CA24; R01AA14; R03AA01; R03AA01; S01EA01; R03AK01; S01EA51 (“Adrenaline (Epinephrine) WHOCC - ATC/DDD Index,” 2024)
ATC Vet Code: -QC01CA

Formulations

Adrenaline (epinephrine) is available in injectable formulations as 0.1 mg/mL (1:10,000) and 1 mg/mL (1:1000) solutions. 1: 10,000 is the most often used IV, and the 1: 1000 solution is used IM or SQ. Ampules for people are designed to deliver 1 mg/person (approximately 14 mcg/kg).
Our evidence review includes a range of UK SPCs (EMC, 2024a, 2024b, 2024c, 2024d, 2024e).
Some authors advocate diluting human ER adrenaline solutions 1:10 with saline or crystalloids to limit the possibility of excessive dosing in minor pet species.

Grapiprant