Mechanism of action
The action of ephedrine is mixed, but the indirect component dominates, which is why it is classified as an indirect-acting adrenomemic (sympathomimetic).
- Primary (indirect) mechanism: Ephedrine penetrates presynaptic terminals (varicosities of sympathetic nerve fibers) and promotes the massive release of the neurotransmitter norepinephrine into the synaptic cleft.
- Secondary (direct) mechanism: Direct, but mild stimulation of adrenoceptors.
Unlike plant-derived ephedrine (levorotatory isomer), the synthetic drug is a racemic mixture. In medicine, it is used as a salt — Ephedrini hydrochloridum.
Pharmacokinetics and metabolism
The drug is rapidly and completely absorbed from the gastrointestinal tract when taken orally (prescribed before meals).
The main difference between ephedrine and catecholamines (e.g., adrenaline) is the absence of hydroxyl groups in the aromatic ring. Because of this, it is practically unaffected by the enzyme monoamine oxidase (MAO). It is metabolized in the liver via microsomal oxidation (deamination mediated by cytochrome P-450). The half-life ($t_{1/2}$) is 3–6 hours, and elimination occurs through the kidneys.
Comparison with Adrenaline and Tachyphylaxis
In terms of its pressor effect (ability to raise blood pressure), ephedrine is significantly inferior to adrenaline — a 50 times higher dose is required to achieve a comparable effect. However, the action of ephedrine lasts considerably longer (1–1.5 hours).
A crucial pharmacological feature of the drug is tachyphylaxis. This is the rapid development of tolerance upon repeated administration at short intervals (10–30 minutes). Mechanism of tachyphylaxis: frequent administration leads to the depletion of norepinephrine stores in sympathetic nerve terminals. Neurotransmitter release decreases, and the pressor effect of the drug rapidly weakens.
Indications for use
The use of ephedrine is due to its stimulating effect on the central nervous system and its peripheral effects:
- Antidote therapy: in poisonings with central nervous system depressants (hypnotics, narcotic analgesics).
- Neurology: treatment of narcolepsy (pathological sleepiness).
- Urology: nocturnal enuresis. The effect is achieved through a dual action: reducing the depth of sleep (central nervous system effect) and increasing the tone of the urinary bladder sphincter (peripheral effect).
Side effects and contraindications
Adverse reactions are associated with excessive sympathetic stimulation:
- Cardiovascular system: tachycardia, elevated blood pressure, circulatory disturbances, risk of ventricular fibrillation.
- CNS: agitation, insomnia, limb tremor.
- Autonomic manifestations: loss of appetite, vomiting, hyperhidrosis (sweating), urinary retention.
Contraindications: insomnia, uncompensated hypertension, atherosclerosis, ventricular fibrillation, pheochromocytoma, and hyperthyroidism.
Drug interactions
Ephedrine requires strict monitoring during combination therapy:
- MAO inhibitors (e.g., nialamide): enhance the pressor effect of ephedrine. When MAO is blocked, norepinephrine accumulates in nerve endings, and ephedrine triggers its massive release, which can lead to a hypertensive crisis.
- Tricyclic antidepressants: co-administration is strictly prohibited. A "washout period" of 2–3 weeks is required between courses.
- Functional antagonism: drugs that prevent the release of norepinephrine diminish the effect of ephedrine.
Briefly: answers to topical questions
Which specific types of adrenoceptors are directly stimulated by ephedrine?
Ephedrine is a non-selective drug that affects $\alpha$- and $\beta$-adrenoceptors. Its action is of a mixed nature with a predominance of the indirect component. An additional mechanism is that the drug causes a direct stimulating effect on adrenoceptors, although it is less pronounced. The primary effect is due to the indirect action — the release of the neurotransmitter norepinephrine from presynaptic terminals.
How does ephedrine affect the smooth muscles of the bronchi?
Ephedrine possesses bronchodilator activity and causes bronchodilation. Due to this property, the drug is used for relieving bronchial asthma attacks. Currently, ephedrine is not used on its own, but only as part of combination drugs, which is associated with its potential to cause drug dependence.
Ephedrine is like a strict boss: it does little work itself (weak direct action on receptors), but makes its subordinates (norepinephrine) work to the fullest until they run out of steam (depletion of stores and tachyphylaxis).
Class and exam questions
Why does ephedrine last longer than adrenaline?
Unlike catecholamines, ephedrine lacks hydroxyl groups in the aromatic ring. Consequently, it is virtually unaffected by the enzyme monoamine oxidase (MAO), which significantly prolongs its effect.
What is tachyphylaxis in the context of ephedrine?
This is the rapid decrease in the pressor effect upon frequent drug administrations (every 10–30 minutes). It is associated with the depletion of norepinephrine reserves in presynaptic terminals.
How does ephedrine help with nocturnal enuresis?
The drug works on two levels: it stimulates the central nervous system, reducing the depth of sleep, and simultaneously exerts a peripheral effect, increasing the tone of the urinary bladder sphincter.
Why must ephedrine not be combined with MAO inhibitors?
MAO inhibitors promote the accumulation of norepinephrine in nerve endings. Ephedrine causes a sharp release of this massive store of neurotransmitter, leading to a dangerous rise in blood pressure.
What else to study on this topic
- Differences between sympathomimetics and direct-acting adrenomimetics
- Mechanisms of microsomal oxidation and the role of cytochrome P-450
- Synaptic transmission: synthesis, storage, and release of norepinephrine
- Rules for prescribing medications subject to subject-quantitative accounting
- Functional antagonism and synergism in pharmacodynamics
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