Physiological Pharmaceutics

214 Physiological Pharmaceuticsvivo 66 . The benzalkonium chloride story is further confused by in vitro studies whichcompared its ciliotoxicity to that of chlorobutol using concentrations of 0.005% for bothcompounds 67 . In commercial formulations, different concentrations of both are used i.e.0.01% benzalkonium chloride and 0.5% chlorobutol. Hence, not surprisingly, the datagenerated using 0.005% chlorobutol demonstrated it to be less ciliotoxic thanbenzalkonium chloride, whereas studies using representative concentrations of both showthat the reverse is true 68 69 .Many drugs administered in nasal preparations can also influence ciliary motility. Thelist of materials which are cilioinhibitory includes anaesthetics 70 antihistamines,propranolol 71 and bile salts 72 . However, ß-adrenergic and cholinergic drugs stimulate ciliarymotility. Early in vitro studies indicated that penicillin had an inhibitory effect on ciliaryfunction, however this was not found in subsequent studies using orally administeredpenicillin 73 .Dexamethasone nasal drops (used in the treatment of allergic rhinitis) may causepathological changes leading to Cushing’s syndrome 74 . Cushing’s syndrome results fromhypersecretion of the adrenal cortex leading to symptoms such as protein loss, fatigue,osteoporosis, amenorrhoea, impotence and oedema. The drug acts by absorption throughthe nasal mucosa and partly through the intestinal mucosa after a portion of the dose isswallowed. This problem does not occur with the newer intranasal steroids (e.g.beclomethasone and flunisolide) which are less readily absorbed through the nasal mucosa,and are inactivated in the liver after gastrointestinal absorption.Care must be taken when extrapolating cilioinhibitory or toxicity data from in vitroto in vivo situations. For example, azelastine was claimed to be ciliotoxic, since it reducedin vitro ciliary beat frequency 75 , however, this effect was not observed in animals and in longterm use in allergic rhinitis patients it actually improved the nasal clearance rate 76 .Effect of formulation pHThe average baseline nasal pH is 6.4 in the anterior of the nose and 6.27 in the posteriorof the nose (Figure 9.7) 77 . The ranges were 5.5–6.5 and 5.0–6.7 in adults and childrenrespectively. Nasal pH varies with air temperature, sleep, emotions and food ingestion 37 . Inacute rhinitis and sinusitis the nasal secretion is alkaline.Figure 9.7. Diurnal variation of nasal pH.