Chapter 12: Pharmacology of Adrenaline (Epinephrine)

1. Introduction/Overview

Adrenaline, also known internationally as epinephrine, is a prototypical catecholamine that functions as both a crucial endogenous hormone and a vital therapeutic agent. As a neurotransmitter of the sympathetic nervous system and a hormone secreted by the adrenal medulla, it orchestrates the physiological “fight-or-flight” response. Its pharmacological significance stems from its potent, rapid, and multifaceted actions on the cardiovascular, respiratory, and metabolic systems. The therapeutic utility of exogenous adrenaline is primarily rooted in its ability to reverse life-threatening conditions characterized by profound hypotension, bronchoconstriction, or systemic allergic reactions. Mastery of its pharmacology is essential for clinicians across emergency medicine, anesthesiology, cardiology, and allergy specialties.

Learning Objectives

• Describe the chemical nature of adrenaline and its classification within the autonomic nervous system pharmacopeia.
• Explain the detailed mechanism of action of adrenaline, including its affinity and intrinsic activity at various adrenergic receptor subtypes.
• Outline the pharmacokinetic profile of adrenaline, highlighting routes of administration, metabolism, and elimination.
• List the primary therapeutic indications for adrenaline, with emphasis on evidence-based applications in anaphylaxis, cardiac arrest, and severe hypotension.
• Identify the major adverse effects, contraindications, and significant drug interactions associated with adrenaline therapy.

2. Classification

Adrenaline can be classified according to several pharmacological and chemical schemas, reflecting its diverse characteristics.

Chemical and Biochemical Classification

Adrenaline is a catecholamine. Chemically, it is designated as (R)-4-(1-hydroxy-2-(methylamino)ethyl)benzene-1,2-diol. Its structure consists of a catechol nucleus (a benzene ring with two adjacent hydroxyl groups) and an ethylamine side chain with a methyl substitution on the amino group. This structure is essential for its affinity for adrenergic receptors and its susceptibility to enzymatic degradation by catechol-O-methyltransferase (COMT).

Pharmacotherapeutic Classification

• Sympathomimetic Amine: A direct-acting agonist that mimics the effects of sympathetic nervous system stimulation.
• Vasopressor: An agent used to increase blood pressure by inducing vasoconstriction.
• Inotrope and Chronotrope: A drug that increases the force (inotropy) and rate (chronotropy) of cardiac contraction.
• Bronchodilator: An agent that relaxes bronchial smooth muscle.
• Anaphylaxis Treatment: The first-line medication for the management of anaphylactic shock.
• Cardiac Resuscitation Agent: A key drug used in advanced cardiac life support (ACLS) protocols.

Receptor Specificity Classification

Adrenaline is a non-selective, direct-acting agonist at adrenergic receptors. It possesses high potency at α₁, α₂, β₁, β₂, and β₃ adrenergic receptors. Its effects are a composite of stimulation across all these receptor subtypes, with the net clinical outcome being highly dependent on the dose and route of administration.

3. Mechanism of Action

The pharmacodynamic effects of adrenaline are mediated through its direct agonist activity at G protein-coupled adrenergic receptors. The specific cellular response is determined by the receptor subtype activated and the associated intracellular signaling cascade.

Receptor Interactions and Signal Transduction

α₁-Adrenergic Receptors: Adrenaline binding to α₁-receptors (G_q-coupled) activates phospholipase C, leading to the generation of inositol trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ triggers the release of intracellular calcium from the sarcoplasmic reticulum, while DAG activates protein kinase C. The rise in intracellular calcium is the primary mediator of smooth muscle contraction in vascular beds (especially cutaneous, mucosal, and renal), resulting in potent vasoconstriction. This action also affects the radial muscle of the iris (mydriasis) and the smooth muscle of the bladder neck and prostate.

α₂-Adrenergic Receptors: Stimulation of presynaptic α₂-receptors (G_i-coupled) inhibits adenylyl cyclase, decreasing intracellular cyclic adenosine monophosphate (cAMP) levels. This leads to a reduction in neurotransmitter release (negative feedback), causing central sympatholytic effects which may contribute to a transient decrease in blood pressure at very low doses. Post-synaptic α₂-receptors in vascular smooth muscle can also mediate vasoconstriction.

β₁-Adrenergic Receptors: Activation of cardiac β₁-receptors (G_s-coupled) stimulates adenylyl cyclase, increasing intracellular cAMP. This activates protein kinase A, which phosphorylates key proteins involved in cardiac excitation-contraction coupling. The consequences include:

• Positive Chronotropy: Increased heart rate via acceleration of sinoatrial node depolarization.
• Positive Inotropy: Increased force of myocardial contraction.
• Positive Dromotropy: Increased conduction velocity, particularly through the atrioventricular node.
• Increased automaticity of latent pacemakers.

β₂-Adrenergic Receptors: Stimulation of β₂-receptors (G_s-coupled) also increases cAMP, but in different tissues this leads to smooth muscle relaxation. Key effects include:

• Bronchodilation in the respiratory tract.
• Vasodilation in skeletal muscle and hepatic arterioles.
• Relaxation of uterine smooth muscle.
• Increased glycogenolysis in the liver and skeletal muscle.
• Enhanced release of glucagon.
• Stimulation of the sodium-potassium ATPase, leading to a shift of potassium into cells (hypokalemia).

β₃-Adrenergic Receptors: Activation primarily stimulates lipolysis in adipose tissue.

Integrated Systemic Effects

The net physiological effect of adrenaline is a complex integration of these receptor-mediated actions, which is dose-dependent. At low infusion rates (0.01-0.05 µg/kg^-1/min^-1), β-adrenergic effects (vasodilation in muscle, increased cardiac output) may predominate, potentially leading to a slight decrease in mean arterial pressure and a marked rise in pulse pressure. At higher therapeutic doses, the powerful α₁-mediated vasoconstriction overcomes β₂-mediated vasodilation, resulting in a significant increase in systolic, diastolic, and mean arterial pressure. Coronary blood flow increases due to elevated perfusion pressure and possibly β₂-mediated coronary vasodilation. The metabolic effects include hyperglycemia (from hepatic glycogenolysis and gluconeogenesis) and increased free fatty acid levels (from lipolysis).

4. Pharmacokinetics

The pharmacokinetic profile of adrenaline is characterized by rapid onset but very brief duration of action, necessitating specific routes and modes of administration for clinical use.

Absorption

Adrenaline is poorly absorbed after oral administration due to extensive first-pass metabolism in the gut wall and liver. Therefore, parenteral routes are employed.

• Intravenous (IV): Provides immediate and complete bioavailability, used in critical care settings like cardiac arrest or septic shock. The effect is instantaneous but very short-lived.
• Intramuscular (IM): The preferred route for anaphylaxis, typically administered in the mid-anterolateral thigh. Absorption from IM sites is more rapid and reliable than from subcutaneous tissue, especially in states of shock. Onset of action is typically within 3-10 minutes.
• Subcutaneous (SC): Absorption is slower and less predictable than IM due to vasoconstrictive effects at the injection site, which can delay systemic delivery. Its use is generally discouraged in anaphylaxis.
• Inhalation: Used as a racemic mixture for its local effects in croup and sometimes in bronchospasm. Systemic absorption from the respiratory tract is minimal.
• Intracardiac: Reserved for extreme circumstances during open cardiac massage; carries significant risk of coronary artery laceration or intramyocardial injection.
• Topical: Used in conjunction with local anesthetics to prolong their effect via vasoconstriction, and for hemostasis in minor procedures.

Distribution

Adrenaline distributes widely throughout the body but does not cross the blood-brain barrier effectively due to its polar nature. The apparent volume of distribution is approximately 0.2 to 0.3 L/kg. It is actively taken up into adrenergic nerve terminals by the uptake-1 mechanism (norepinephrine transporter), which can terminate its action. Circulating adrenaline is loosely bound to plasma proteins.

Metabolism

Adrenaline undergoes extremely rapid and efficient metabolism by two principal enzymes:

1. Catechol-O-Methyltransferase (COMT): Located widely, including in the liver and kidneys, COMT methylates the meta-hydroxyl group of the catechol ring to form metanephrine.
2. Monoamine Oxidase (MAO): Located intracellularly, particularly in neuronal mitochondria and the liver, MAO deaminates adrenaline to 3,4-dihydroxymandelic acid.

These pathways often act sequentially. The primary end product is vanillylmandelic acid (VMA), which is excreted in the urine. The metabolism is so swift that the elimination half-life of exogenously administered adrenaline when given IV is only 1 to 3 minutes.

Excretion

Less than 5% of an administered dose is excreted unchanged in the urine. The majority is eliminated as inactive sulfate and glucuronide conjugates of metanephrine and VMA. Renal clearance of the metabolites is efficient.

Half-life and Dosing Considerations

The extremely short plasma half-life (t_1/2 ≈ 2 min) dictates its clinical use. For continuous effects, a continuous IV infusion is required, with titration against hemodynamic parameters. For discrete events like anaphylaxis, single IM injections are standard, with repeat doses possible every 5-15 minutes if needed. Dosing is weight-based in critical care (e.g., µg/kg/min for infusions, mg/kg for pediatric anaphylaxis) but often standardized in emergency situations (e.g., 1 mg for adult cardiac arrest, 0.3-0.5 mg IM for adult anaphylaxis).

5. Therapeutic Uses/Clinical Applications

The clinical applications of adrenaline leverage its potent α- and β-adrenergic effects in acute, life-threatening scenarios.

Approved and First-Line Indications

Anaphylaxis: Adrenaline is the undisputed first-line treatment. Its benefits are multifactorial: α₁-mediated vasoconstriction reverses peripheral vasodilation and edema (including laryngeal edema), β₁-mediated inotropy supports cardiac output, and β₂-mediated bronchodilation relieves bronchospasm. It also inhibits further mast cell and basophil degranulation. Intramuscular administration into the anterolateral thigh is the standard route.

Cardiac Arrest: In protocols for pulseless ventricular fibrillation, pulseless ventricular tachycardia, asystole, and pulseless electrical activity. The primary goal is to augment coronary and cerebral perfusion pressure during cardiopulmonary resuscitation (CPR) via its potent vasoconstrictive effects. The standard adult dose is 1 mg (10 mL of 1:10,000 solution) IV/IO every 3-5 minutes during resuscitation.

Severe Hypotension/Shock: Used as a vasopressor infusion in distributive shock states (e.g., septic shock, neurogenic shock) and cardiogenic shock when other agents are insufficient. It increases mean arterial pressure through vasoconstriction and provides inotropic support. It is typically titrated to a target mean arterial pressure (e.g., ≥ 65 mmHg).

Local Anesthesia Adjuvant: Added to local anesthetics (e.g., lidocaine) in concentrations of 1:200,000 or 1:100,000. The vasoconstrictive effect slows systemic absorption of the anesthetic, prolonging its duration of action, reducing systemic toxicity, and providing a drier surgical field.

Upper Airway Obstruction: Racemic epinephrine (a 1:1 mixture of D- and L-isomers) administered via nebulization is used in the management of croup (laryngotracheobronchitis). The L-isomer provides α-adrenergic-mediated mucosal vasoconstriction, reducing subglottic edema.

Topical Hemostasis: Applied topically on gauze or as a soak to control capillary bleeding during minor surgical procedures (e.g., dermatological surgeries, epistaxis control).

Bronchospasm: While selective β₂-agonists are preferred for asthma, adrenaline may be used in acute, severe exacerbations unresponsive to first-line therapy, particularly in a pre-hospital or emergency setting, due to its combined β₂ (bronchodilation) and α₁ (reduction of mucosal edema) effects.

Other Clinical Uses

Bradycardia: Can be used as an infusion in symptomatic bradycardia unresponsive to atropine or pacing, leveraging its positive chronotropic effects.

Hypersensitivity Reactions to Radiocontrast Media: Used similarly to anaphylaxis for severe reactions.

Prolongation of Spinal Anesthesia: Sometimes added to intrathecal local anesthetics to prolong sensory and motor blockade.

6. Adverse Effects

Adrenaline’s adverse effects are direct extensions of its pharmacological actions and are often dose-related. They are more pronounced with systemic administration, especially IV use.

Common Side Effects

• Cardiovascular: Tachycardia, palpitations, arrhythmias (including premature ventricular contractions), hypertension, angina pectoris in susceptible individuals. A reflex bradycardia may occur following a sharp rise in blood pressure.
• CNS: Anxiety, restlessness, tremor, headache, dizziness, and a sense of impending doom. These are primarily due to peripheral effects and possibly some central stimulation.
• Metabolic: Hyperglycemia, hyperlactatemia, hypokalemia (due to intracellular shift mediated by β₂-receptor stimulation).
• Local: Pain, pallor, and coldness at injection site due to local vasoconstriction. Necrosis can occur with accidental extravasation of an IV infusion.

Serious and Rare Adverse Reactions

• Severe Hypertension: May precipitate hypertensive crisis, leading to intracranial hemorrhage, aortic dissection, or pulmonary edema.
• Life-Threatening Arrhythmias: Ventricular fibrillation or tachycardia, particularly in patients with underlying heart disease, hypoxia, or hypercapnia.
• Myocardial Ischemia/Infarction: Increased myocardial oxygen demand due to positive inotropy and chronotropy, coupled with potential coronary vasoconstriction, can induce ischemia in patients with coronary artery disease.
• Cerebral Hemorrhage: A consequence of severe, acute hypertension.
• Pulmonary Edema: May result from increased pulmonary capillary pressure secondary to peripheral vasoconstriction and/or cardiac dysfunction.
• Tissue Necrosis: Severe vasoconstriction from extravasation or high-dose infusions can compromise blood flow, leading to tissue ischemia and necrosis, particularly in digits or limbs.
• Renal Failure: Prolonged renal vasoconstriction can reduce renal blood flow and glomerular filtration rate.

Black Box Warnings and Special Alerts

Official labeling for adrenaline auto-injectors contains strong warnings regarding the necessity of immediate medical supervision following use for anaphylaxis due to the risk of severe, potentially fatal reactions. While not a classic “black box,” these warnings emphasize that adrenaline is a temporary treatment and that repeat doses or additional therapies may be required. The solution intended for injection must be checked for discoloration (pinkish or brown) or precipitate, which indicates oxidation and degradation of the catecholamine.

7. Drug Interactions

Concomitant use of adrenaline with other drugs can lead to pharmacodynamic interactions that potentiate toxicity or antagonize therapeutic effects.

Major Drug-Drug Interactions

• Other Sympathomimetic Agents (e.g., dopamine, norepinephrine, phenylephrine, albuterol): Additive or synergistic adrenergic effects, significantly increasing the risk of severe hypertension, cardiac arrhythmias, and ischemia.
• Non-Selective Beta-Blockers (e.g., propranolol, nadolol): A critical interaction. Beta-blockade leaves the α-adrenergic vasoconstrictive effects of adrenaline unopposed, potentially leading to severe hypertension and reflex bradycardia. Furthermore, β₂-mediated vasodilation in skeletal muscle is blocked, enhancing the pressor response. This combination may also precipitate severe bronchospasm in asthmatic patients.
• Tricyclic Antidepressants (TCAs) and Monoamine Oxidase Inhibitors (MAOIs): These drugs inhibit neuronal reuptake of catecholamines (TCAs) or their metabolic degradation (MAOIs), respectively. Concomitant use can potentiate the hypertensive and cardiac effects of adrenaline, potentially leading to a hypertensive crisis. A significant period (at least 2 weeks for MAOIs) should elapse before administering adrenaline.
• General Anesthetics (especially halogenated hydrocarbons like halothane, isoflurane, sevoflurane): These agents sensitize the myocardium to the arrhythmogenic effects of catecholamines. The risk is historically highest with halothane but remains a consideration with others.
• Antihypertensive Agents (e.g., diuretics, ACE inhibitors, calcium channel blockers): The pressor effect of adrenaline may be diminished. Conversely, in patients on these medications, adrenaline may cause an exaggerated hypertensive response if the underlying condition is not well-controlled.
• Thyroid Hormones: Hyperthyroidism may increase sensitivity to catecholamines; co-administration could enhance adrenergic effects.
• Ergot Alkaloids (e.g., ergotamine): Potentiate vasoconstrictive effects, increasing the risk of peripheral ischemia and gangrene.

Contraindications

Absolute contraindications to the use of adrenaline are few in true life-threatening situations but must be carefully weighed.

• Hypersensitivity: To adrenaline or any component of the formulation (e.g., sulfites in some preparations).
• Narrow-Angle Glaucoma: Adrenaline can induce mydriasis, potentially precipitating an acute attack.
• Use in Fingers, Toes, Ears, Nose, or Genitalia with Local Anesthetics: Vasoconstriction may compromise blood flow and lead to tissue necrosis. Exceptions may be made for digital blocks with very low concentrations and specific techniques.

Relative contraindications require extreme caution and often dose adjustment:

• Underlying cardiovascular disease (hypertension, coronary artery disease, arrhythmias, cardiomyopathy).
• Hyperthyroidism or pheochromocytoma.
• Diabetes mellitus.
• Prostatic hyperplasia or bladder outlet obstruction (α₁ effects may increase urinary retention).
• Parkinson’s disease (theoretically may be exacerbated).

In contexts like anaphylaxis or cardiac arrest, the benefit of treatment almost always outweighs these relative risks.

8. Special Considerations

Pregnancy and Lactation

Pregnancy (FDA Category C): Adrenaline may pose a risk based on animal studies showing teratogenic effects at high doses. However, no adequate, well-controlled studies exist in pregnant women. It should be used only if the potential benefit justifies the potential risk to the fetus. In maternal anaphylaxis or cardiac arrest, it is unequivocally indicated. Uterine vasoconstriction may reduce blood flow, and β₂-mediated relaxation may inhibit labor, though these effects are dose-dependent. Fetal tachycardia and acidosis may occur secondary to maternal physiological changes.

Lactation: It is not known whether adrenaline is excreted in human milk in significant amounts. Given its poor oral bioavailability and rapid metabolism, it is considered unlikely that a breastfed infant would absorb a clinically relevant amount. However, caution is advised.

Pediatric Considerations

Dosing for pediatric anaphylaxis is weight-based: 0.01 mg/kg (maximum 0.3 mg) of the 1:1000 concentration IM. Auto-injectors are available in 0.15 mg and 0.3 mg doses. For cardiac arrest, the IV/IO dose is 0.01 mg/kg (0.1 mL/kg of 1:10,000 solution), repeated every 3-5 minutes. High doses (0.1-0.2 mg/kg) were previously used in resuscitation but are no longer recommended due to lack of proven benefit and potential harm. Children may be more susceptible to agitation and pallor.

Geriatric Considerations

Older patients frequently have concomitant cardiovascular disease (hypertension, coronary artery disease, arrhythmias). They are at significantly increased risk for adrenaline-induced adverse cardiac events, including myocardial infarction, severe hypertension, and arrhythmias. The lowest effective dose should be used, and hemodynamic monitoring is essential. Age-related decline in renal or hepatic function does not significantly alter adrenaline kinetics due to its rapid extra-hepatic/extra-renal metabolism.

Renal and Hepatic Impairment

Renal Impairment: Dose adjustment is not typically required. The metabolites are renally cleared, but accumulation is not associated with toxicity. However, the drug’s vasoconstrictive effects may further compromise renal perfusion in patients with pre-existing renal insufficiency.

Hepatic Impairment: Dose adjustment is not routinely necessary. While COMT is present in the liver, widespread extra-hepatic metabolism ensures rapid inactivation even in severe liver disease. However, patients with severe cirrhosis and hyperdynamic circulation may have an altered hemodynamic response.

9. Summary/Key Points

• Adrenaline is a direct-acting, non-selective agonist at α- and β-adrenergic receptors, producing a complex array of dose-dependent cardiovascular, respiratory, and metabolic effects.
• Its pharmacokinetics are defined by rapid onset, brief duration of action (t_1/2 ≈ 2 min), and extensive metabolism by COMT and MAO, precluding oral administration.
• The primary, life-saving indications are anaphylaxis (first-line, IM route), cardiac arrest (IV/IO), and vasopressor support in shock (IV infusion).
• Adverse effects, including tachycardia, hypertension, arrhythmias, anxiety, and tissue ischemia, are extensions of its pharmacologic actions and are more common with high doses or IV administration.
• Critical drug interactions exist with non-selective beta-blockers (risk of severe hypertension), TCAs/MAOIs (potentiation), and halogenated anesthetics (arrhythmogenesis).
• Use requires extreme caution in patients with underlying cardiovascular disease. In pregnancy and pediatrics, it is used when clinically indicated with appropriate dose adjustments.

Clinical Pearls

• For anaphylaxis, the IM route in the mid-anterolateral thigh is superior to SC for speed and reliability of absorption.
• In cardiac arrest, high-dose adrenaline does not improve survival or neurological outcomes compared to standard dosing and may be harmful.
• The “double-check” rule: Always confirm the concentration before drawing up adrenaline (1:1,000 for IM, 1:10,000 for IV). A ten-fold dosing error is potentially fatal.
• Adrenaline is an adjunct, not a substitute, for definitive airway management, fluid resuscitation in anaphylaxis, or high-quality CPR in cardiac arrest.
• Patients receiving adrenaline, especially for anaphylaxis, must be observed for a minimum of 4-6 hours due to the risk of biphasic reactions and delayed sequelae.

References

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