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Oral versus Nasal Topical Therapy, and Pharmakokinetics

Niels Mygind
Department of Respiratory Diseases
Aarhus University Hospital
Aarhus, Denmark


Introduction

Rhinitis is a disease characterized by inflammation of the nasal mucous membrane. As inflammation cannot be identified by ordinary diagnostic procedures, a clinical diagnosis of rhinitis is based on the symptoms of sneezing, rhinorrhea and nasal blockage.

Patients with these symptoms may belong to three different groups of diseases with different response to therapy. 1) A disease associated with eosinophil-dominated inflammation, e.g. allergic rhinitis and nasal polyposis. 2) A disease associated with neutrophil-dominated inflammation, e.g. common cold. 3) A disease not associated with inflammation, e.g. a subgroups of perennial non-allergic rhinitis ("vasomotor rhinitis"), as seen in cold-air induced rhinorrhea ("skier's nose", "old man's nose drip").

Types of drugs

There are 6 types of drugs used for the therapy of rhinitis.
1) Corticosteroids, which are effective on all symptoms in eosinophil-dominated inflammation, but not in neutrophil-dominated inflammation.
2) Antihistamines, which are effective on sneezing and rhinorrhea but not on blockage in eosinophil-dominated inflammation.
3) Vasoconstrictors, which are effective on all types on nasal blockage.
4) Ipratropium bromide, which is effective on all types of watery rhinorrhea.
5) Leukotrienes, which have a marginal effect on rhinorrhea and nasal blockage in allergic rhinitis and nasal polyposis.
6) Cromoglycate and similar drugs, which are only marginally effective in allergic rhinitis. These drugs will not be mentioned further, as they can be replaced by more effective drugs.

Advantages of topical treatment

Rhinitis is confined to the nose, which is a small organ. The surface area of the nasal mucosa is only 200 cm2. With an average thickness of the nasal mucosa of 3 mm, the volume of the diseased tissue in rhinitis is about 60 cm3 and the weight 60 gr. This is about 0.1% of the total body mass. When this small amount of diseased tissue can be reached by topical treatment this is, in principle, preferable to systemic treatment, reaching about 60 kg of completely normal tissue. The correctness of this principle was illustrated some years ago when it was realized that the oral antihistamines, terfenadine and astemizole can induce serious cardiac adverse events and death, when they are used together with e.g. ketokonazole. This disclosure was made after terfenadine had been for years the best-selling antihistamine worldwide and considered to be very safe.

Corticosteroids

The side effects from systemic corticosteroids are well known. There is overwhelming evidence (more than 100 placebo-controlled studies) that topical treatment is highly effective and very safe (not a single death reported) in the treatment of allergic rhinitis. Although controlled drug-comparative studies are very few, they have indicated that topical treatment is at least as effective as systemic low-dose treatment with 7.5 mg prednisolone. The advantage of using topical instead of systemic drug administration is obvious for corticosteroids.

Antihistamines

A number of drug-comparative studies have indicated that topical treatment with an antihistamine is as effective as oral treatment. A quicker onset-of-action is an advantage of topical treatment and systemic side effects have not been described.

For associated eye itching, topical antihistamine usage has a definite advantage antihistamine as the effect starts within minutes. It takes one hour to onset-of-action an oral preparation, and within that period of time a patient with itchy eyes cannot avoid rubbing the eye, causing further irritation.

Vasoconstrictors

The effect of a topical vasoconstrictor starts within minutes while it takes one hour before an oral compound is effective, and the decongestant effect is more pronounced with a nasal vasoconstrictor than with a tablet. In addition, an oral vasoconstrictor, acting on all blood vessels in the body, has a low therapeutic index with regard to systemic side effects and there are a number of contraindications for oral treatment.

Ipratropium bromide

When watery rhinorrhea is a problem, nasal use of the anti-cholinergic drug ipratropium bromide can significantly reduce this symptom within 30 minutes. On the other hand, systemic use of this type of medication will cause intolerable side effects such as mouth dryness. For this reason, systemic use of anti-cholinergic drugs cannot be used for the treatment of rhinorrhea. A running nose is preferable to a dry mouth.

Disadvantages of topical treatment

Thereare a number of problems associated with topical treatment.

Intranasal drug distribution

Studies have shown that the intranasal drug distribution of nasal medication is not optimal. Only 20% of a pressurized aerosol and 50% of an aqueous spray/powder inhaler will reach the target, i.e. the ciliated mucous membrane. In addition, there is no reason to believe that intranasal medication will reach the ostiometal complex, which is the origin of nasal polyps and of decisive importance for the development of pathology in the paranasal sinuses. In addition, intranasal medication will not reach the paranasal sinuses.

Irritancy of added preservatives

It is necessary to add a preservative to an aqueous spray, which may cause immediate nasal irritation. This symptoms is, in part, a sign of rhinitis-induced hyperresponsiveness, and it will diminish with time when a nasal corticosteroid is used. However, the commonly used anti-microbial preservative, benzalkonium chloride is cytotoxic, and in vitro studies have shown that it damages ciliary motility. The clinical significance of this adverse effect, however, has not been documented in some in vivo studies.

Local side effects

Nasal corticosteroids frequently cause nose bleeding and in the rare case, the development of a septal perforation. Prolonged use of a nasal vasoconstrictor involves a risk of the development of rhinitis medicamentosa, not seen with oral treatment. The use of nasal ipratropium bromide can cause an unpleasant feeling of nasal dryness.

Nasal pathology, rhinitis symptoms and drug efficacy

When nasal medication is used in a sneezing nose with associated rhinorrhea and blockage it is resonable to assume that the drug may not reach the relevant receptors and that the treatment may have a reduced efficacy. This important question has been insufficiently studied in controlled trials. Studies of the effect of sneezing are not available, while a single study has shown that rhinorrhea does not reduce the efficacy of a nasally administered antihistamine.

Obviously, nasal medication cannot be given in a completely blocked nose or nostril. The effect of a partially blocked nose has not been studied. However, one study has shown that pretreatment with systemic corticosteroid, which will open a blocked nose, can significantly increase the subsequent responsiveness to a nasal corticosteroid in perennial rhinitis.

Patient compliance

When a patient has symptoms from the eyes, the nose, and perhaps the lower airways, it is easier to treat all symptoms with one therapy, i.e. a single tablet, used once daily. Therefore, oral treatment may have a better patient compliance than nasal treatment in such patients. The high sales figures for oral antihistamines support this statement. However, the marked difference in the use of oral and nasal treatment between countries indicates that the doctor's information and recommendation is important for the patient's choice of therapy. Probably, information on the advantages of topical treatment, which offers quick relief with no or little risk of systemic side effects, will increase the usage of this type of therapy.

Advantages of systemic treatment

Corticosteroids

Clinical experience indicates that when the nose is severely blocked a short course of systemic corticosteroid treatment is indicated. This treatment is also considerably more effective than topical treatment with regard to the sense of smell in nasal polyposis.

Antihistamines

Many patients prefer to use the 2nd generation oral antihistamines, not only because they almost lack sedative adverse effects, but also because they are long-acting. It is easy to treat both nose and eye symptoms by a single tablet, taken in the morning.

Vasoconstrictors

In principle, it is an advantage that an oral preparation can reach all parts of the nasal mucosa and the paranasal sinuses and middle ears as well. However, reports on the treatment of sinusitis and otitis media do not indicate a significant effect in these conditions.

Disadvantages of systemic treatment

Corticosteroids

While continuous treatment for rhinitis is not justified due to the well known side effects, a short 2-3 week course has very few side effects.

Antihistamines

As mentioned above, it is in principle, most correct to limit the effect and side effects of drug treatment to the diseased tissue, although practical experience and a long series of controlled studies have shown the 2nd generation antihistamines to be very safe and well tolerated.

A relatively slow onset-of-action is a drawback of oral as compared with topical treatment, when the treatment is used on an as-needed basis.

Leukotriene antagonists

These oral preparations have a marginal effect in allergic rhinitis. Their place in therapy is not yet well defined and probably is very limited. It is doubtful whether they can offer added effect to treatment with antihistamine or corticosteroid.

Vasoconstrictors

While these preparations are often used together with an oral antihistamine in the USA, they are rarely used in Europe due to their poor therapeutic index and risk of side effects.

Pharmacokinetics

While the pharmacokinetics of systemic drug treatment are studied in great detail and are well described in textbooks, this is not the case with topical treatment. There are few studies on the intranasal drug distribution and on the fate fn the drugs due to mucociliary clearance and to absorption from the nose and from the gut.

It is proven that modern corticosteroids, antihistamines, vasoconstrictors, and ipratropium bromide are effective by a local mode of action. In therapeutic doses, these drugs show no signs of systemic side effects although a minor part may be absorbed.

It is claimed that some modern corticosteroids have a very low bioavailability, but it is difficult to explain how a compound can reach intracellular glucocorticoid receptors without being absorbed. There is no evidence of a local metabolism and deactivation of any of the compounds.

Pharmacodynamics

Corticosteroids

It is generally believed that we know the mode of action of the anti-inflammatory corticosteroids. However, the precise type and location of target cells is poorly defined. Is it antigen-presenting Langerhans cells, T-lymphocytes, or both? Are other cell types also responsive? Apparently, corticosteroids have no effect on mast cell degranulation. In addition, anti-inflammatory corticosteroids are not effective e.g. in the common cold, which is characterized by a neutrophil-dominated inflammation.

It is also an open question whether the main target for treatment is the surface epithelium of the submucosa which is reached by very different drug concentrations during topical and oral treatment.

Antihistamines

H1 histamine receptors are found on nasal blood vessels, but antihistamines have a poor effect on nasal blockage. Apparently, H1 histamine receptors on epithelial nerve endings are responsible for the marked effect on itching, sneezing and reflex-induced rhinorrhea. Submucosal glands and goblet cells do not have H1 histamine receptors.

Leukotriene antagonists

A nasal leukotriene provocation does not induce itching and sneezing, indicating that there are no neural leukotriene receptors. On the other hand, a leukotriene provocation has a slight effect on nasal blood vessels, and it is known that leukotrienes are secretagogues, having an effect on submucosal glands in the airways.

Vasoconstrictors

The decongestant effect is due to stimulation of a-adrenergic receptors on the capacitance vessels. Probably, a similar effect on arteries and arterioles is the cause of rhinitis medicamentosa.

Ipratropium bromide

This drug has an effect on watery rhinorrhea but not on viscous mucus secretion. This may in part be due to the lack of cholinergic receptors on goblet cells and their presence on submucosal glands. It is not known whether the most important effect is on the few anterior serous glands or on the many seromucous glands in the nose. It is in favour of the importance of the anterior serous glands that watery secretions are mainly produced in the anterior part of the nose and that ipratropium bromide has no effect on mucus secretion in the lower airways.

Conclusion

In rhinitis, the diseased mucous membrane has a small size and it is easily accessible for topical treatment. This is, in principle, preferable to systemic treatment because drug effect and risk of side effects can be confined to the diseased tissue. However, there are some disadvantages of topical treatment, which requires good information and instruction from the physician. Sales figures indicate that many patients prefer oral treatment. Pharmacokinetics is well studied for oral compounds but less so for topical preparations. Also our knowledge about pharmacodynamics is poorly understood.

References

  1. Borum S, Nielsen K, Bisgaard H, Mygind N. Experimentally induced nasal secretion does not reduce the efficacy of intranasal levocabastine. Rhinology 1999;36:153-6.
  2. Bousquet J, Gaudano EM, Palma Carlos AG, Staudinger H. A 12-week, placebo-controlled study of the efficacy and safety of ebastine, 10 and 20 mg once daily, in the treatment of perennial allergic rhinitis. Allergy 1999;54:562-8.
  3. Nielsen LP, Mygind N, Dahl R. Intranasal corticosteroids for allergic rhinitis. Drugs (in press).
  4. Naclerio RM, Durham SR, Mygind N, eds. Rhinitis. Mechanisms and management. New York: Marcel Dekker, 1999:1-539.
  5. Szefler SJ. Pharmacokinetics of intranasal corticosteroids. J Allergy Clin Immunol 2001;108:S26-31.

 

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