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Adrenaline Pharmacology

Pharmacology

Clinical Particulars

Pharmacodynamics

Pharmacokinetics

Adrenaline (Epinephrine) is a sympathomimetic drug that antagonises the effects of histamine increases glycogenolysis and raises blood sugar. 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. (Booth, 2011; DeWitt et al., 2016; Maddison, 2008; Plumb, 2024; Farzam et al., 2024).


Adrenaline relaxes smooth muscles in the bronchi and iris and alleviates pruritus, urticaria, and angioedema. Because of its relaxing effects on the smooth muscles of the stomach, intestine, uterus, and urinary bladder, adrenaline may help relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis (Farzam et al., 2024; Oyebola, 2011). During reperfusion, adrenaline may counteract cerebral vasoconstriction (Kondo et al., 2022). 

Mechanism of Action

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).  Specific receptor effects include:


  1. ⍺-1 Sympathomimetic Activity: Smooth muscle contraction, mydriasis

  2. ⍺-2  Sympathomimetic Activity: Mixed smooth muscle effects

  3. β-1 Sympathomimetic Activity: Increased cardiac chronotropic and inotropic effects (increased heart rate, myocardial contractility, and renin release)

  4. β-2 Sympathomimetic Activity:  Bronchodilation

Clinical Applications

Adrenaline (Epinephrine) demonstrates a broad spectrum of pharmacologic activity. 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). 

Primary Systemic Applications

  1. Resuscitation associated with anaesthesia-induced cardiac arrest: ⍺-1 and β-1 activity is beneficial during CPR.

  2. Resuscitation outside general anaesthesia:  ⍺-1 and β-1 activity is beneficial during CPR.

  3. Anaphylaxis:  ⍺-adrenergic activity reduces vasodilation and increases vascular permeability during anaphylaxis.

  4. Bronchospasm: β-2 activity results in bronchodilator.

Pharmacodynamics

Biotransformation

  • Mixed sites:  Epinephrine is rapidly inactivated in the body mainly by the enzymes COMT (catechol-O-methyltransferase) and MAO (monoamine oxidase). The liver is a significant 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.

Pharmacokinetics

Precautions

Adverse Effects

  • Injection Site Necrosis: Repeated injections and use in extremities may result in tissue necrosis and sloughing at any injection site (Aljahany et al., 2020; Nayaz et al., 2023; Simons and Simons, 2010; SPC Data).

  • Systemic Effects: Arrhythmias, dysphoric behaviour  (e.g., anxiety, excitability), hyperglycemia, hypertension, lactic acidosis, pulmonary oedema, tachycardia, tremors, and vomiting, there is some evidence that inappropriate dosing reduces long term survival rates in CPCR (Cervellin et al., 2016; Reingardiene, 2006; Rosenberg et al., 2013; Rozanski et al., 2012; Towell et al., 1981; Zhong et al., 2023).

Contraindications

  • CPCR 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).

Potentially Significant 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).

  • Phentolamine: Used locally for the treatment of extravasation (Aljahany et al., 2020).

Precautions

Availability

Formulations

  • Commercial Availability: In the UK we are reliant upon the medical sector as there is limited veterinary availability; 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).(EMC, 2024a, 2024b, 2024c, 2024d, 2024e).

  • Smaller Patients: Some authors advocate diluting human adrenaline solutions 1:10 with saline or crystalloids to limit the possibility of excessive dosing in patient <1kg. 

Availability

Identifiers

  • Systematic Name:  IUPAC Name - 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol (PubChem, 2024).

  • Formula: C9H13NO3 (PubChem, 2024).

  • Pharmacotherapeutic Group(s): Cardiovascular; Adrenergic and dopaminergic agents; Respiratory System  (WHO, 2024).

  • ATC Code(s):  A01AD01; B02BC09; C01CA24; R01AA14; R03AA01; R03AA01; S01EA01; R03AK01; S01EA51 (WHO, 2024)

  • ATC Vet Code: -QC01CA (WHO, 2024)

Identifiers

Evidence Base

  1. Aljahany, M., Dk, A., Am, A.I., 2020. Reversal of Digital Ischemia with Phentolamine After Accidental Epinephrine Injection. The American journal of case reports 21. https://doi.org/10.12659/AJCR.923877

  2. Booth, D., 2011. Small Animal Clinical Pharmacology and Therapeutics - 2nd Edition [WWW Document]. URL https://shop.elsevier.com/books/small-animal-clinical-pharmacology-and-therapeutics/boothe/978-0-7216-0555-5 (accessed 1.24.24).

  3. Cervellin, G., Sanchis-Gomar, F., Lippi, G., 2016. Adrenaline in anaphylaxis treatment. Balancing benefits and harms. Expert Opin Drug Saf 15, 741–746. https://doi.org/10.1517/14740338.2016.1167870

  4. DeWitt, E.S., Black, K.J., Thiagarajan, R.R., DiNardo, J.A., Colan, S.D., McGowan, F.X., Kheir, J.N., 2016. Effects of commonly used inotropes on myocardial function and oxygen consumption under constant ventricular loading conditions. J Appl Physiol (1985) 121, 7–14. https://doi.org/10.1152/japplphysiol.00058.2016

  5. Farzam, K., Kidron, A., Lakhkar, A.D., 2024. Adrenergic Drugs, in: StatPearls. StatPearls Publishing, Treasure Island (FL).

  6. Maddison, G., 2008. Small Animal Clinical Pharmacology E-Book: 2nd edition | Edited by Jill E. Maddison | ISBN: 9780702037252 [WWW Document]. Elsevier Asia Bookstore. URL https://www.asia.elsevierhealth.com/small-animal-clinical-pharmacology-e-book-9780702037252.html (accessed 1.23.24).

  7. Nayaz, M., A, M., A, N., 2023. Accidental Digital Ischemia by an Epinephrine Autoinjector. Cureus 15. https://doi.org/10.7759/cureus.36429

  8. Plumb, 2024. Epinephrine [WWW Document]. URL https://app.plumbs.com/drug/yTTIqZPq6HPROD?source=search&searchQuery=epineph&section=doses (accessed 1.23.24).

  9. PubChem, 2024. Adrenaline (Epinephrine) [WWW Document]. URL https://pubchem.ncbi.nlm.nih.gov/compound/5816 (accessed 2.24.24).

  10. Reingardiene, D., 2006. [The consequence of epinephrine (adrenaline) overdose]. Medicina (Kaunas) 42, 606–609.

  11. Rosenberg, M.B., Phero, J.C., Giovannitti, J.A., 2013. Management of allergy and anaphylaxis during oral surgery. Oral Maxillofac Surg Clin North Am 25, 401–406, vi. https://doi.org/10.1016/j.coms.2013.04.001

  12. Rozanski, E.A., Rush, J.E., Buckley, G.J., Fletcher, D.J., Boller, M., RECOVER Advanced Life Support Domain Worksheet Authors, 2012. RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 4: Advanced life support. J Vet Emerg Crit Care (San Antonio) 22 Suppl 1, S44-64. https://doi.org/10.1111/j.1476-4431.2012.00755.x

  13. Simons, K., Simons, F., 2010. Epinephrine and its use in anaphylaxis: current issues. Current opinion in allergy and clinical immunology 10. https://doi.org/10.1097/ACI.0b013e32833bc670

  14. Towell, M.E., Lysak, I., Layne, E.C., Sayler, D., Bessman, S.P., 1981. The effect of epinephrine on blood and tissue PO2 in the rabbit. Circ Shock 8, 123–130.

  15. WHO, 2024. Adrenaline (Epinephrine) [WWW Document]. URL https://www.whocc.no/atc_ddd_index/ (accessed 2.24.24).

  16. Zhong, H., Yin, Z., Kou, B., Shen, P., He, G., Huang, T., Liang, J., Huang, S., Huang, J., Zhou, M., Deng, R., 2023. Therapeutic and adverse effects of adrenaline on patients who suffer out-of-hospital cardiac arrest: a systematic review and meta-analysis. Eur J Med Res 28, 24. https://doi.org/10.1186/s40001-022-00974-8

UK SPCs

  1. EMC, 2024a. Adrenaline (Epinephrine) 1mg/ml (1:1000) solution for injection (ampoule) - Summary of Product Characteristics (SmPC) - (emc) [WWW Document]. URL https://www.medicines.org.uk/emc/product/3673/smpc (accessed 1.23.24).

  2. EMC, 2024b. Adrenaline (Epinephrine) Injection BP 1 in 1000 - Summary of Product Characteristics (SmPC) - (emc) [WWW Document]. URL https://www.medicines.org.uk/emc/product/6284/smpc (accessed 1.23.24).

  3. EMC, 2024c. Adrenaline 1 mg/10 ml (1:10,000), solution for injection in pre-filled syringe - Summary of Product Characteristics (SmPC) - (emc) [WWW Document]. URL https://www.medicines.org.uk/emc/product/2024/smpc (accessed 1.23.24).

  4. EMC, 2024d. Adrenaline Injection BP 1/1000 (1mg/1ml) - Summary of Product Characteristics (SmPC) - (emc) [WWW Document]. URL https://www.medicines.org.uk/emc/product/6595/smpc (accessed 1.23.24).

  5. EMC, 2024e. Dilute Adrenaline (Epinephrine) Injection 1:10,000 (ampoules) - Summary of Product Characteristics (SmPC) - (emc) [WWW Document]. URL https://www.medicines.org.uk/emc/product/3675/smpc (accessed 1.23.24).

Evidence
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