Adrenaline

Adrenaline (also known as epinephrine) is a critical hormone and neurotransmitter that orchestrates rapid, body-wide responses under stress. It plays a central role in the “fight-or-flight” reaction, coordinating cardiovascular, respiratory, metabolic, and nervous-system changes to prime the organism for sudden exertion or danger. This article provides a 360° exploration of adrenaline—its synthesis, physiology, mechanisms, effects, clinical uses, regulation, and pathological states.

Biosynthesis and Release

Adrenaline is produced primarily in the medulla of the adrenal glands—small triangular endocrine glands that sit atop the kidneys. Within the adrenal medulla, specialised chromaffin cells convert the precursor norepinephrine (noradrenaline) into adrenaline via the enzyme phenylethanolamine N-methyltransferase (PNMT), using a methyl group donor (S-adenosylmethionine). PNMT is regulated in part by cortisol levels from the adrenal cortex, so the adjacent cortex indirectly influences medullary synthesis.
The synthetic pathway broadly follows:Tyrosine → L-dopa → Dopamine → Norepinephrine → Adrenaline
Under conditions of stress or perceived threat (physical or psychological), the sympathetic nervous system activates preganglionic neurons that innervate the adrenal medulla, releasing acetylcholine. This stimulates chromaffin cells to exocytose adrenaline into the bloodstream, generally within seconds to minutes of the stimulus.
Some neurons in the central nervous system also produce and release adrenaline locally, but the systemic hormone effects are mostly attributed to adrenal release.

Mechanism of Action: Receptor Binding & Signalling

Once in circulation, adrenaline exerts its effects by binding to adrenergic receptors (a class of G-protein-coupled receptors) present on target cells. There are several relevant subtypes:

• α₁-adrenergic receptors: primarily mediate vasoconstriction in many vascular beds.
• α₂-adrenergic receptors: often function as presynaptic autoreceptors regulating neurotransmitter release.
• β₁-adrenergic receptors: found in the heart, mediate increased heart rate and contractility.
• β₂-adrenergic receptors: located in bronchial smooth muscle and skeletal muscle vessels; cause dilation (bronchodilation, vasodilation).
• β₃-adrenergic receptors: in adipose tissue, mediating lipolysis.

Through coupling to G proteins (Gs or Gi depending on subtype), these receptors alter intracellular second messengers (notably cAMP) and activate downstream kinases that bring about physiological responses.
Because adrenaline is a nonselective agonist, it can stimulate all these receptor classes to varying extents, with the net effect depending on receptor density and tissue context.

Physiological Effects of Adrenaline

Adrenaline’s actions are pervasive; the aim is to redistribute energy and resources for immediate survival. The main physiological changes include:

1. Cardiovascular Effects
   • Increases heart rate (chronotropy) and contractility (inotropy) via β₁ receptors.
   • Raises cardiac output.
   • Induces vasoconstriction in many peripheral vascular beds (skin, gut) via α₁ receptors, thereby redirecting blood toward skeletal muscles or vital organs.
   • In certain vascular beds (e.g. coronary, skeletal muscle), β₂-mediated vasodilation may also occur under some conditions.
2. Respiratory Effects
   • Bronchodilation through β₂ receptor activation.
   • Increased ventilation rate and improved airflow to support oxygen supply under stress.
3. Metabolic Effects
   • Stimulates glycogenolysis in liver and muscle, increasing blood glucose levels.
   • Promotes lipolysis in adipose tissue (via β₃) to free fatty acids for alternative fuel.
   • Inhibits insulin secretion (via α₂) and enhances glucagon release, further supporting glucose mobilization.
4. Sensory / Neural Effects
   • Pupil dilation (mydriasis) for clearer vision under threat.
   • Heightened alertness and arousal in the central nervous system.
   • Reduced pain sensitivity (analgesic effect) under acute stress.
5. Other Effects
   • Sweating increases (sympathetic cholinergic pathways) to assist cooling.
   • Redistribution of blood away from nonessential systems (digestion, renal perfusion decreases).
   • Fine hairs may rise (piloerection) under some stimuli.

These collective changes prepare the body to fight or flee—redirecting blood flow, growing energy supply, and enhancing physical and mental performance under duress.

Regulation & Feedback

Adrenaline release is tightly regulated via neural and hormonal pathways:

• Neural input: Sympathetic preganglionic neurons drive the adrenal medulla’s rapid secretion in response to stress.
• Hormonal interplay: Cortisol from the adrenal cortex upregulates PNMT, aiding adrenaline synthesis.
• Negative feedback: After the acute stressor subsides, neural signals diminish and adrenaline release falls. Adrenaline is rapidly metabolised by enzymes monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).
• Homeostatic balance: Persistent stimuli may lead to receptor desensitization or downregulation if adrenaline remains elevated chronically.

Clinical Uses & Therapeutics

Because of its powerful, wide-ranging effects, synthetic adrenaline (epinephrine) finds use in several medical emergencies and procedures:

• Anaphylaxis: Adrenaline is first-line therapy—reversing airway constriction (bronchodilation), raising blood pressure (vasoconstriction), and reducing swelling (anti-edema).
• Cardiac arrest / advanced cardiac life support (ACLS): Used in resuscitation protocols to increase coronary and cerebral perfusion.
• Asthma exacerbations or severe bronchospasm (less common now, given more selective alternatives): adrenaline may be used when other bronchodilators are insufficient.
• Local anaesthesia adjunct: Added to local anesthetics (e.g. lidocaine) to cause vasoconstriction, thereby prolonging anaesthetic action and reducing systemic absorption.
• Superficial bleeding / capillary oozing: Topical or local adrenaline can control bleeding by vasoconstriction.
• Airway obstruction / croup: Nebulised adrenaline helps reduce laryngeal edema.

However, therapeutic use must be carefully controlled because of risks: tachycardia, arrhythmias, hypertension, anxiety, tremor, and possible ischemia in vulnerable tissues.

Pathophysiological Conditions

When adrenaline signalling or release becomes dysregulated, several clinical states arise:

• Pheochromocytoma: A tumour of the adrenal medulla secretes excess adrenaline (and noradrenaline), leading to episodic or sustained hypertension, headaches, tachycardia, sweating, weight loss, and palpitations.
• Excess stress / chronic overproduction: High tonic adrenaline may contribute to hypertension, arrhythmias, metabolic disturbances (elevated glucose, insulin resistance), anxiety, tremors, and cardiac strain.
• Adrenergic storm (sympathomimetic toxicity): A massive surge of adrenaline and noradrenaline (e.g. from stimulants, hemorrhage, intracranial bleed) causes extreme hypertension, arrhythmias, hyperthermia, rhabdomyolysis, delirium, kidney injury.
• Deficient response: If adrenaline release is blunted (rarely isolated), the ability to mount an effective fight-or-flight reaction may be compromised, risking poor stress tolerance.

Comparative Roles: Adrenaline vs Noradrenaline

Although adrenaline often acts alongside noradrenaline (noradrenaline is the primary neurotransmitter of sympathetic nerves), there are distinctions:

• Noradrenaline is more selective, focusing on α₁/α₂ and β₁ receptors, with primary action on vasoconstriction (raising blood pressure) rather than bronchodilation or broad metabolic stimulation.
• Adrenaline has stronger β₂ effects, which mediate bronchodilation and vasodilation in specific beds, making it more versatile in acute systemic stress responses.

In the body’s stress cascade, the sympathetic nervous system triggers rapid noradrenaline release locally, while the adrenal medulla floods the circulation with adrenaline for more global systemic effects.

Integration in the Stress Response

Adrenaline does not act in isolation; it works in concert with hormones such as cortisol, glucagon, growth hormone, and vasopressin in a coordinated cascade known as the general adaptation syndrome. While adrenaline provides immediate response, cortisol manages sustained metabolic adjustment. Together they orchestrate vascular tone, energy mobilisation, immune modulation, and homeostasis under threat.