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Physiology of the upper respiratory tract:
Main defence mechanisms

GEDEVANISHVILI M.
Deputy Director of Research and Development,
Institute of Pharmacochemistry, Tbilisi (Georgia)

New Treatment Approaches to Rhinosinusitis: Less is more.
Crete. Greece. 15-19 June 2008
Keywords New Treatment approaches to Rhinosinusitis - PDF

ABSTRACT

Control of the airway defence mechanisms is primarily cholinergic, which produces an increase in blood flow, gland secretion and ciliary function. Consequently, a reflex response could induce curative effects. When adsorbed locally, the saponins contained in the cyclamen extract reduce cell surface tension, ultimately giving rise to a positive cholinergic response through its action on the distal afferent branch of the reflex arc in the nasal mucosa. The ensuing osmotic and antioedematous action has a cholinergic, decongestant, curative action, soothing, relieving and reversing the swelling.

With the goal of reviewing the physiology of the upper respiratory tract and studying its defence mechanisms, one of the speakers at this symposium was Professor Michael Gedevanishvili who, among other contributions, showed the advantages provided by cholinergic stimulation versus adrenergic decongestant stimulation as the main physiological mechanism for the treatment of rhinosinusitis.

The upper airway has a series of physiological defence mechanisms that are able to counter certain aggressions. These defence mechanisms (which are primarily physical) usually manifest in three typical forms: 1) increased drainage from the nasal and paranasal cavities induced by a secretory response; 2) increase in ciliary cleansing activity; and 3) increased arterial blood flow to ensure adequate microcirculation. The increased blood flow around the glands is fundamental for assuring increased gland secretion. The secretions in themselves possess certain defensive properties, which are well-known and described. However, in addition, they also contain gel-forming mucins, antimicrobial elements, anti-inflammatory molecules and inflammatory process mediators.

These events are the outcome of a natural reflex response and are controlled positively by cholinergic mechanisms. The airways’ physiological defence mechanism, in particular the acute defence reflex (which is mediated by specific nerve pathways), is primarily cholinergic and stimulates the formation of large quantities of secretions in response to a severe challenge of the airway.

As part of the emergency defence response against aggression, the blood flow, gland secretion and ciliary function are increased.

Therefore, on the basis of this evidence, it has been suggested that the induction of an intense reflex response could not only promote the airways’ defence mechanisms but also induce curative effects. Similar effects can be caused by pharmacological cholinomimetic stimulation.

RATIONALE FOR THE USE OF CYCLAMEN EXTRACT

The saponins contained in the cyclamen europaeum extract trigger the main defence mechanisms that are elicited in the upper airways in response to an acute aggression. Nasodren®/Sinuforte®/Fluirespira Forte® are the trade names for the lyophilised cyclamen extract, which has curative properties known for many centuries and which has recently started to be marketed in Europe.

The first written information on the medical use of cyclamen extract for the treatment of certain nasal disorders dates back more than 25 centuries and is attributed to the Greek philosopher Theophrastes, a disciple of Aristotle and considered to be the father of Botany. This renowned author recommended the intranasal use of cyclamen sap to “clear the head”, as a treatment for migraine and blocked nose.

As regards the saponins and their mechanism of action, it is known that they are adsorbed onto the surface of the nerve endings in the nasal mucosa, leading to an increased permeability of the ion exchange cell membrane. This activity is due basically to the reduction in the interfacial tension between the saponin-detergent phase and the cell membrane.

Saponins properties and action

The adsorption of saponins onto the cell membrane is a physical process and reversible. The saponins reduce cell surface tension and act on the distal afferent branch of the reflex arc in the nasal mucosa (this is a property shared by all surfactants). This gives rise to increased ion permeability. Thus, the saponins contained in cyclamen extract are capable of changing the ion concentrations (Na/K) and, consequently, of stimulating the sensory free endings of the trigeminal nerve. In addition, the saponins’ physical impact on the cell surface causes a change in the electrical potential, possibly by stretching the terminal axon membrane. These events are very similar to the physiological response elicited in tactile or stretching receptors in any part of the body.

Saponins properties and action - physiologic responses

Although Nasodren®/Sinuforte®/Fluirespira Forte® is not a direct cholinomimetic, it is a detergent-surfactant because of the saponins it contains. When it is instilled in the nasal passages, it is not dispersed over the entire surface of the nasal mucosa and does not enter the paranasal cavities; its initial activity is confined to a specific part of the anterior inferior nasal meatus and inferior turbinate, where it stimulates the afferent nociceptive endings, causing a reflex cholinergic response.

Afferent terminals of trigeminal nerve in nasal cavities


PHARMACOLOGICAL EVIDENCE

The cholinergic nature of the response to Nasodren® has been confirmed by atropine antagonism and also by pharmacological inhibition of acetylcholinesterase. The fact that it is a reflex response has been shown by inhibition with the administration of a local anaesthetic aerosol prior to instillation of Nasodren®. This anaesthetic inhibits conduction of nerve impulses and reduces cell membrane permeability to ions, anaesthetising the local nerve endings.

Cholinergic nature of response to Nasodren® was confirmed by means of atropine antagonism

At the same time, the concurrent administration of neostigmine, a cholinesterase inhibitor, has been shown to intensify the cholinergic effect.

This effect demonstrates that glandular cells are stimulated

The action of Nasodren® has been assessed in non-anaesthetised rabbits. First of all, it is seen that the response to neostigmine is dose-dependent. It is also shown that the mean neostigmine dose that strongly intensifies the response is within the dose range used clinically in humans (10 μg/kg). It is also shown that it is possible to use Nasodren® and acetylcholinesterase inhibitors to enhance the clearing effect produced by the increased secretion. Threshold concentrations of Nasodren® and neostigmine are mutually enhanced, showing a typical action synergism and/or an action potentiation phenomenon.

In another study, atropine was administered before instillation of Nasodren®, with total inhibition of the reflex secretion. In Dr. Gedevanishvili’s opinion, this “shows that the gland cells were stimulated through their muscarinic cholinergic receptors.”

The sensory endings of the trigeminal nerve are responsible for the sneezing, eye-watering and reflex responses associated with the nociceptive stimulus, irrespective of its origin. When compared by histological examination with systemic cholinergics (such as acetylcholine, neostigmine or pilocarpine), it is seen that the signs of secretory activity are much stronger in the case of reflex secretion.

As the speaker suggested, “the clinically proven cure of rhinosinusitis achieved in humans with the instillation of Nasodren® could presumably be explained by its ability to promote active reflex secretion (hyperosmolar mucus) from the hyperplastic/hypertrophic glands around the ostium, acting by means of an osmotic and antioedematous effect. This promotes expulsion of the exudate from the nasal and paranasal cavities.” In other words, this drug induces an anti-inflammatory effect, causing a reflex secretion and clearance of the hyperplastic and hypertrophic glands in the proximity of the ostium, consequently facilitating discharge of exudate from the nasal and paranasal cavities thanks to the increased ciliary movement.

The hyperplasia and hypertrophy of the nasal glands, particularly around the ostium, are common signs of both experimentally-induced and clinical rhinosinusitis. As Professor Gedevanishvili suggested, “taking into account the consequences of nociceptive nasal stimulation (which manifests as rhinorrhea, watering eyes and salivation), it can be assumed that stimulation of the parasympathetic efferent nerves may have diffuse effects.”

Upon studying in greater depth the autonomic innervation of the nasal reflexogenic area, it is deduced that the reflex secretion is confined to the specific area of the lacrimal, nasal and submandibular / sublingual glands, due to the nature of the autonomic innervation in this region. For this reason, the Georgian expert explained, “this reflex response may be considered a fairly specific step in physiological defence mechanisms.”

Accepting this hypothesis, it is postulated that the cholinergic response targeting specifically local stimulation of the nerve endings in limited areas of the nasal mucosa not only causes abundant secretion but also clears obstruction of the ostium (due to a detumes cent effect) and facilitates clearance of the paranasal cavities.

In the case of treatment with Nasodren®, it has been suggested that the reduction in oedema is achieved by the release of secretions from the seromucous glands and goblet (mucin-secreting) cells, which presumably favours an osmotic effect that leads to dehydration of the swollen mucosa. Therefore, Professor Gedevanishvili deduced, “it is possible to talk of a detumescent effect for Nasodren® and, more specifically, of a detumescent cholinergic action; in this sense, to achieve treatment goals, this is a more appropriate action than adrenergic vasoconstriction.” A decongestant is defined as an agent that relieves excessive accumulation of blood in the blood vessels, while a detumescent is an agent that calms and relieves swelling.

In the light of these findings, as the speaker concluded, “Nasodren® should not be considered as just a symptomatic treatment which relieves the symptoms of rhinosinusitis, but also as a curative treatment.”


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