Drugs without prescription available to consumers - OTC drugs play a key role in the health care system and modern pharmaceutical practices. Currently, there are over 300.000 different OTC drugs available in the United States (1).
The US Food and Drug Administration (FDA) determines whether OTC drugs are safe and effective for use, and decides on the safety of drug sales directly, without a prescription. This regulatory process allows American population to take an active role in their health care, which requires the maturity of population that is able to make right decisions in the process of self-medication (2). Self-medication is a process that requires a high level of awareness, knowledge and general education of people, as well as satisfactory socio-economic status. Access to information, the quality of information, and the skills in interpreting and applying information to OTC drugs are important to support the process of self-medication (3). In order to safely and efficiently use an OTC drug, the consumer must accurately identify the symptoms, set the therapeutic goal, choose the product to use, determine the appropriate dose and method of dosing, taking into account contraindications, associated illnesses and medications that are taken regularly because of chronic problems, as well as tracking response to treatment with the identification of possible adverse effects (4).
The general rule for OTC drugs is to be used primarily for the treatment of conditions that do not require direct medical attention with the recognition and proper interpretation of the symptoms and the accompanying instructions on the medicine.
Research suggests that self-medication improves health care and reduces the economic costs of the health care system (5). Although there is an opinion that OTC drugs are safe and effective, it must be emphasized that they are not completely harmless. Acting on symptoms, they often mask the underlying disease and can cause unwanted side effects (6). Self-medication carries a serious risk of drug interactions, polypharmacy, wrong diagnosis, overuse of drug dosing, prolonged drug use, inappropriate drug selection, rare but serious adverse events, addiction, abuse and increased antimicrobial resistance (7). Doctors and pharmacists play a very important role in creating awareness about self-medication in patient education (8). When making a decision to purchase as well as when purchasing OTC drugs, patients are directly referred to pharmacists. Therefore, before proposing any OTC drugs, a pharmacist should thoroughly assess the nature and degree of patient’s condition and recommend them to seek professional care when necessary.
Motivating factors for self-medication could be: easy availability of many drugs, lack of strict control over medical advertising, low medical literacy of the population, prices of medical examinations, long wait in public health institutions, etc.
Therefore, very important step for this type of medication is the public education of the population about recognition of the symptoms of illness in the process of self-medication, as well as education on the use of OTC drugs and precautionary measures and information about the possible consequences and possibilities of their abuse (9).
The most commonly used OTC drugs are nasal decongestants that are used systemically or locally in the form of drops or nasal sprays. These preparations are most commonly used in viral infections to alleviate the symptoms (nasal obstruction, vomiting, increased nasal secretion, difficulty breathing, etc.), but it is necessary to inform the users about the type of preparation, the active substance it contains and the correct dosage regimen. Given their availability and the prevalence of safety precautions, these preparations can lead to numerous prolonged conditions and complications (medicaments rhinitis). Also, an increasing number of allergens, in many parts of the world, and climate change, cause allergic manifestations, so the users decide on the solubility and purchase of drops or sprays without consultation with a physician or pharmacist. Due to the long-lasting symptoms with short periods of improvement, nasal drops/nasal sprays are increasing used for months, even for years. However, it is necessary to inform that many products have restrictions in use, which depend on age, and some are contraindicated in children younger than two years of age, pregnant women, persons with thyroid gland diseases, cardiovascular diseases, prostate problems.
Decongestants are a group of drugs that can provide short-term relief of nasal congestion.
The mechanism of action is based on the reduction of blood vessels’ swelling in the nose, which helps in the opening of the airway. Decongestants are used to reduce nasal obstruction and relieve pain in common colds, flu, sinusitis, acute or chronic rhinitis, upper respiratory tract allergy, pollen cough, septum deviation, nasal mucosa hypotrophy, nasal polyps, etc (10).
Allergic rhinitis is one of the clinical conditions when nasal decongestants are most commonly used. This condition is present in about 10% to 20% of the world population and in 15% to 25% of children and adolescents (11). Among sympathomimetic vasoconstrictors for topical use in the nose, imidazole (naphazoline, oxymetazoline and xylomethazoline) and catecholamine derivatives (epinephrine, ephedrine and phenylephrine) produce vasoconstriction of the nasal blood vessels by stimulation through the endogenous release of noradrenaline, which acts on alpha receptors (12, 13).
However, prolonged use of nasal decongestants leads to side effects, e.g. medicamentous rhinitis. Because of this, local application of vasoconstrictor can be carried out only for a short period of time and for no longer than four or five days, due to the risk of damage to the mucociliary epithelium and reverse vasodilatation. Prolonged use of a decongestant leads to a decrease in the sensitivity of the alpha receptor, which leads to the need to increase the dose at shorter intervals to achieve the same effect. As a consequence, patients use excessive, uncontrolled doses of nasal decongestants (14), which are a public problem and warn of the necessity of identification and the taking of measures to prevent uncontrolled procurement and the use of nasal decongestants (15, 16).
Decongestants may comprise pseudoephedrine, phenylephrine, oxymetazolin or ksilometosolin. Nasal decongestants are available in the form of tablets, drops or nasal sprays. They are generally available as OTC drugs, and are often used without restriction, for a long period of time (17). It is recommended that they should not be given to children under the age of six (18) due to the risk of increased mucous membrane edema after cessation of decongestant use. It is advised that the use of a decongestant should not be longer than five days. Nasal decongestants generally act locally, but may have systemic effects, such as hypertension, headache, nausea, insomnia and dizziness (19). Using decongestant, individuals may develop tachyflilax (a rapid reduction in drug response after repeated doses over a short period of time). Therefore, long-term use of decongestants is not recommended because they lose their effectiveness after a few days.
Ephedrine and pseudoephedrine are the earliest molecules known in the treatment of nasal congestion. Their vasoconstrictive actions on the nasal mucosa make them highly effective amines in the treatment of nasal congestion. However, over the past few years, the French National Drugs Safety Agency (NSA), in its action plan of July 2013 (20), has reported against their use in rhinology, saying that vasoconstrictors “include the risk of stroke and severe neurological effects” and that they are “often too risky to use in a simple cold” (21).
Thanking to their molecular structure, these two sympathomimetic amines (ephedrine and pseudoephedrine) stimulate the adrenergic receptor system at the interface between the sympathetic nerve and the smooth muscles of the blood vessels, thus simulating the vasoconstrictive effect of norepinephrine, which is physiologically produced by the sympathetic nerve fiber. In the nose, the regulation of the vascular network of mucous membranes and, in particular, the filling and discharge of cavernous venous plexus, is essential for regulation of airflow, and hence for the feeling of obstruction (22). Venous plexus, as well as arterioles that accompany them, are surrounded by adrenergic nerve fibers that are associated with α and β adrenergic receptors: β receptors are vasodilators, and α receptors are vasoconstrictor and prevail. Efedrine and pseudoephedrine, therefore, perform a vasoconstriction effect on the blood vessels, which is the basis of the mechanism for reducing obstruction of the nose.
Studies have shown that repeated stimulation of α-2 receptors induces intense vasoconstriction with mucosal ischemia and interstitial edema, while in long-term use, the effect of regulating α-2 receptors is the opposite, i.e. there is a relative dilatation and a tachyphilactic effect leading to an increased need for decongestant (23).
Efedrine applied to the nasal mucosa reduces nasal resistance faster and stronger than oral pseudoephedrine over a short time interval (24).
However, at the end of therapy, a rebound effect may occur with increased nasal resistance and repeated obstruction of the nose. Several research studies have shown the efficacy of oral pseudoephedrine against nasal obstruction during an ordinary cold (25, 26).
Eccles et al., in a prospective randomized double blind study compared to placebo, which included 238 patients with a common cold, reported anti-obstruction without side effects: a dose of 60 mg of oral pseudoephedrine for 3 days (27).
Ephedrine and pseudoephedrine belong to the amphetamine family. In France, in 2008 and again in 2012, the National Pharmacovigilance Commission (28) emphasized their psychotropic effect and cardiovascular side effects. The vasoconstriction effect in oral use or directly by application to the nasal mucosa significantly increases blood pressure and leads to vasospasm (29). This effect, which lasts 5 to 6 times longer than adrenaline, can cause episodes of hypertension, myocardial infarction, stroke and various neurological symptoms (30, 31). Different cardiovascular adverse effects may occur after individual or long-term therapy (for more than 5 days) regardless of vascular status and age (31). The same dangers led to the fact that the French National Agency for the Protection of Health (Agence nationale de sécurité du médicament) in 2013 reassigned preparations containing only pseudoephedrine as medicinal products which are issued on a medical prescription (20, 32). The current literature review shows that their vasoconstrictive effects on the nasal mucosa make ephedrine and pseudoephedrine highly effective against nasal congestion. Given the serious, harmful cardiovascular and neurological effects that can occur even at low doses, it is necessary for doctors to conduct a rigorous assessment of the benefits in prescribing these drugs in allergic rhinitis (33).
Oral phenylephrine is generally used to alleviate symptoms associated with colds and flu, and no change in blood pressure is observed in the short duration of the use of phenylephrine. Several studies on the oral examination of phenylephrine in the recommended dosage of 10 mg have shown that phenylephrine was well tolerated in patients with obstruction of the nose. However, these studies focused on phenylephrine as a single agent, not in combination with paracetamol where its bioavailability is increased, while maximum plasma concentrations are two to four times higher (34).
Given these risks, it is recommended that distribution should be regulated by translating these products from the list of OTC drugs to the list of medicines that are issued on a prescription.
Oxymetazoline is a sympathomimetic amine that has vasoconstrictor effects and reduces the mucous membrane.
After application in the nose, the inflamed nasal mucous membrane is reduced, eliminating increased secretion and allowing breathing through the nose. Oxymetazoline is characterized by the dominant α-2 adrenergic activity. Its effect occurs within a few minutes of application and lasts for an average of 6 to 8 hours. Studies with oxymetazoline, a marked isotope, have shown that intranasally administered oxymetazoline had no systemic effect. In double blind studies in healthy volunteers, a dose of 1.8 mg of oxymetazoline (3.6 ml of 0.05% solution) was followed by non-specific ECG (electrocardiography) changes, but without a change in blood pressure or heart rate frequency.
Oxymetazoline, an imidazoline derivative, causes a reduced blood flow to the nose. Vaidyanathan with the coauthors conducted the research which aim was to evaluate the duration of action of oxymetazoline on nasal respiratory resistance and blood flow of nasal mucosa. During eight hours of measurement, blood flow was reduced by 30–40% over a period of six hours. A similar decongestant effect of about 30% was observed in the following period. The pharmacological profile of oxymetazoline is controversial, since the reduced blood flow to the nose may not be significant in the treatment of upper respiratory tract infections. Oxymetazoline-induced tachyphylaxis is contrary to the intranasal fluticasone effect. Further studies require an assessment of the combination of decongestant nasal sprays and corticosteroids in an effective strategy for the elimination of tachyphylaxis and the treatment of rhinitis (35).
After intranasal administration of multiple doses of the recommended amount, the absorbed amount cannot result in systemic cardiovascular effects. There are no data on the distribution of oxymetazoline in the human body. However, the following instruction indicates the precautionary measure: “The combination of two decongestants is contraindicated, regardless of the mode of administration (oral and/or nasal): such an application is useless and dangerous and corresponds to abuse” (36) Also, the drug is not recommended for use, due to the risk of vasoconstriction and/or hypertensive crises associated with its sympathomimetic alpha activity, with the following drugs: non-selective MAO inhibitors - monoamine oxidase inhibitors (iproniazid), vasoconstrictors (dihydroergotamine, ergotamine, methylergometrine) and drugs that reduce the epileptogenic threshold (37). However, in the literature, undesirable effects of oxymetazoline have been observed: increased nasal secretion, blurred vision, rapid, irregular heartbeats, headache, dizziness, drowsiness, appetite increased, high blood pressure, syncope, nervousness, trembling, sleep problems and weakness (38).
Intranasal corticosteroids are recommended as first-line therapy for patients with moderate to severe allergic rhinitis, especially when nasal congestion is the main symptom (39). Intranasal corticosteroids perform their antiinflammatory effect by inhibiting the production of many different cytokines, chemokines, enzymes and cell adhesion molecules, after their interactions with intracellular glucocorticoid receptors. The main advantage of intranasal corticosteroids is that high drug concentrations, with rapid onset of action, can be delivered directly to the target organ, so that systemic effects are minimal if they occur.
Fluticasone furoate is a topical corticosteroid with a high local potential and low potential for systemic effects, and is a good choice for the treatment of rhinitis (40). After intranasal application of one or more doses, the plasma fluticasone furoate concentration is below the lower limit of quantification for most (41). One study reported that only 2% of patients receiving 110 μg of fluticasone furoate had plasma quantitative concentrations (42).
It is known that many patients use intranasal corticosteroids independently, based on subjective symptoms, and stop using them when the symptoms are significantly reduced. In support of this approach, studies have shown that intermittent use of intranasal corticosteroids is moderately effective in many patients (43).
Also, additives and preservatives included in intranasal corticosteroids to prevent bacterial growth, add flavor and aroma, absorb additional water and maintain adequate levels of moisture, can irritate or dehydrate the nasal tissue and lead to hypersensitivity. Benzalkonium chloride, polysorbate, and carboxymethylcellulose are present in the fluticasone furoate formulation.
Benzalkonium chloride is a cationic surfactant used as a preservative in nasal solutions. Studies have shown that it can cause nasal mucous dysfunction, nasal irritation and hyper secretion, degenerative changes in stimulating and olfactory cells, and squamous cell metaplasia (44). However, clinical trials’ results of these effects on the nasal mucosa are often different (45, 46).
A parallel, randomized, double-blind study was performed in 30 healthy subjects to investigate the effects on the nasal mucosa of a one-month treatment with nasal sprays. Ten subjects received oxymetazoline nasal spray; 10 subjects used a nasal spray containing the preservative benzalkonium chloride, and the rest were treated with a placebo nasal spray. The three variables that were studied - nasal mucosal swelling, symptom scores, and nasal reactivity - were estimated by histamine challenge before and after 28 days of treatment. Rhinostereometry was used to measure nasal mucosal swelling and nasal reactivity. After 28 days of use, benzalkonium chloride spray alone induced an increase in nasal mucosal swelling, which explains why the presence of this preservative in a decongestant spray aggravates rhinitis medicamentosa (47).
Polysorbates are non-ionic surfactants and emulsifiers used as additives in drugs, shampoos and lotions. Polysorbate 80, depending on the concentration, reversibly inhibits the frequency of the ciliary epithelium in cultured human epithelial cells in the nose and is associated with allergy or sensitivity (48).
Carboxymethylcellulose is a thixotropic agent that increases the concentration of nasal drugs, but it also provides viscosity to the solution of intranasal corticosteroids, which is one of the reasons why the suspension must be shaken prior to use (49). It has been observed that it leads to drying of the nasal mucosa, which can contribute to the incidence of epistaxis, and in rare cases, to allergic anaphylactic reactions (50).
Oral antihistamines are often used concomitantly with intranasal corticosteroids in clinical practice, but serious adverse effects of chronic therapy with systemic corticosteroids have been demonstrated in many studies (51, 52). A literature review of the negative effects of local nasal steroids is confusing, but it is indisputable that each of these drugs causes unwanted events. The clinically significant fact is the suppression of the hypothalamic pituitary-adrenal axis and, most importantly, that these drugs have a negative effect on growth in children and osteoporosis in postmenopausal women (53).
Nasal decongestants, as OTC drugs, are available to a large number of users in the process of self-medication. Due to altered climate change, the occurrence of a large number of allergens, their use is increased, as well as uncontrolled. Opinion on their safety suggests users to take them for an extended period of time, which leads to the absence of the expected effect and damage to the function of the mucociliary epithelium (atrophic rhinitis and anosmia).
Decongestants can be absorbed from the nose and give systemic effects, mainly stimulation of the central nervous system and the increase in the blood pressure, so that the ignorance about contraindications of their use can lead to deterioration of the general health condition.
Medical and pharmaceutical practices have a new task, involving primarily user education and monitoring the issuance of nasal decongestants.