Concentration–Response Relationship of Hearing Impairment Caused by Quinine and Salicylate: Pharmacological Similarities but Different Molecular Mechanisms

Abstract

This review has the purpose to summarize concentration-effect studies made with quinine and to compare the effects on hearing between quinine and salicylate. Quinine and salicylate have roles in experimental hearing research and may induce pronounced and reversible hearing impairment when administered in sizeable doses. The quinine-induced increase in hearing threshold and its recovery can be analysed according to 'the psychophysical power function'. The power function is a special case of the Hill equation when the stimulus (e.g. a drug concentration) is exceedingly small compared with the concentration that would elicit a half-maximum response. Quinine and salicylate induce sensorineural hearing impairment and tinnitus when given in higher dose ranges in man. The drugs influence the presence, magnitude, and quality of audiological responses, such as spontaneous and evoked otoacoustic emissions. Quinine reversibly reduces frequency selectivity and hearing sensitivity, whereas the self-attained most comfortable speech level and the acoustic stapedius reflex are not affected, that is the dynamic range of hearing is reversibly reduced. This observation supports the view that quinine acts on the outer hair cell of the cochlea. Both drugs share a protective effect against the permanent hearing damages caused by gentamicin. This action is interpreted as a request for functioning mechanoelectric transducer (MET) channels to elicit the ill effect of aminoglycosides. Both drugs may interfere with the cochlear amplifier through blocking MET channels and the motor protein prestin. This review finds considerable overlap between type and extent of pharmacological actions of quinine and salicylate, supposedly caused by partly shared mechanisms of action but performed with different molecular mechanisms.The aim of this MiniReview was to explore key findings from the few concentration-effect (pharmacokinetic-pharmacodynamic, PK-PD) studies that have been performed with quinine, to understand the extent and mechanisms of reversibly impaired hearing. With respect to salicylate, concentration-effect studies are scarce. Considering the overlap of sensorineural effects of quinine and aspirin, we have compared studies on their respective mechanisms to interfere with hearing. Quinine has been used as a drug since the 17th century, in the beginning as bark from the cinchona tree. The most significant medical indication is severe malaria where it still has a role. It has been argued that the availability of quinine was a key factor in making Africa safe for non-immune Europeans as malaria was a deadly threat [1]. Quinine has been used to induce abortion and has killed many women because of its general toxicity. Both quinine and its isomer quinidine affect ion channels and cause life-threatening arrhythmia taken in overdose. Salicylate was known to the ancients and manufactured synthetically in the 19th century. Its neuropharmacological effects on hearing both peripherally and centrally have recently been updated [2].The heari...

Drug‐induced ototoxicity: Mechanisms, Pharmacogenetics, and protective strategies

“…Salicylates rapidly enter the cochlea and diffuse all parts of the cochlear duct. In animals, serum salicylate levels correlated with perilymph salicylate concentrations and hearing loss . In addition, they suppressed cochlear function preferentially at high and low frequencies and enhanced the neural activity in the auditory thalamus, cortex, and amygdala .…”

“…This increase is dose dependent and already occurs at therapeutic doses in the high frequency range. Thus, to avoid an increase in ototoxicity, co‐administration of quinine with other ototoxic drugs should be avoided …”

The Ototoxicity of Antimalarial Drugs—A State of the Art Review

“…QN also induced tinnitus in the behavioral model of tinnitus in rats (41); however, in another study animals treated with 200 mg/kg/d QN did not exhibit tinnitus-like behavior when assessed using the gap prepulse inhibition of acoustic startle (42). Interestingly, quinoline drugs have been found to prevent ototoxicity by loop diuretics (furosemide/ethacrynic acid), aminoglycosides, and cisplatin in animal models based on chinchilla and zebrafish (20,(43)(44)(45). QN derivatives reduce uptake of gentamicin, neomycin, and cisplatin into hair cells (44,45).…”

“…Quinine can negatively affect the auditory system at the level of the central auditory pathway and the auditory periphery. Several hypotheses about changes in cochlea have also been proposed, such as impairment of outer hair cells (OHCs), reduction in the blood flow, and microangiopathy due to quinine-induced thrombocytopenia and disseminated intravascular coagulation (19)(20)(21).…”

DNA methylation of the prestin gene and outer hair cell electromotileresponse of the cochlea in salicylate administration*

“…In addition to its blocking effect on prestin, salicylate may affect the mechanical properties of the stereocilia bundle by decreasing its bending stiffness (8). Accordingly, several studies have demonstrated decreased OHC motility with high-dose aspirin intake, which may result in hearing loss (9,10). Salicylate administration may cause tinnitus in real life and some studies suggest that tinnitus may be considered an auditory nerve dysfunction (11).…”