Antihistamines in driving and piloting ORIGINAL Antihistamines in Drivers, Aircrew and Occupations of Risk I Jáuregui1, M Ferrer2, J Montoro3, I Dávila4, J Bartra5, A del Cuvillo6, J Mullol7, J Sastre8, A Valero5 1 Allergy Department, Basurto University Hospital, Bilbao, Spain 2 Allergology Department, University Clinic of Navarra, Pamplona, Spain 3 Allergy Unit, Arnau de Vilanova University Hospital, Faculty of Medicine, Catholic University of Valencia "San Vicente Mártir", Valencia, Spain 4 Immunoallergy Department, Salamanca University Welfare Complex, IBSAL, Salamanca, Spain 5 Allergy Unit, Pneumology and Respiratory Allergy Department, Hospital Clínic (ICT), Barcelona, Spain 6 Dr. Lobatón Clinic, Cadiz, Spain 7 Rhinology and Olfactory Clinical Unit, Otorhinolaryngology Department, Hospital Clínic (ICT), Barcelona, Spain 8 Allergy Department, Jiménez Díaz Foundation, Madrid, Spain QResumen Las enfermedades alérgicas más prevalentes pueden cursar con somnolencia diurna asociada a la propia condición. Los antihistamínicos empleados en su tratamiento pueden tener además efectos centrales y afectar a determinadas ocupaciones de riesgo, la seguridad vial o la navegación marítima y aérea. Las pruebas cognitivas, los estudios experimentales y los datos epidemiológicos aconsejan evitar los antihistamínicos de 1ª generación en conductores habituales y/o profesiones críticas de seguridad. Aunque no hay estudios comparativos en conducción real entre antihistamínicos de 2ª generación, en este tipo de pacientes debería tenderse a prescribir los de menor efecto central posible, especialmente aquellos que sean un buen sustrato de bombas de transporte transmembrana como la glicoproteína P y tengan por tanto baja capacidad de cruzar la barrera hemato-encefálica, permitiendo una ventana terapéutica más amplia. En este sentido, la bilastina es un buen sustrato de glicoproteína P y muestra buena tolerancia a nivel del SNC, tanto a nivel de pruebas psicométricas como en las pruebas protocolizadas de conducción real, aún a dosis dobles de las recomendadas en fi cha técnica. Palabras clave: Antihistamínico. Bilastina. Estudios de conducción real. Glicoproteína P. Pruebas cognitivas. Seguridad vial. Sistema nervioso central. QAbstract The most commonly occurring allergic diseases can involve a daytime drowsiness associated with the condition itself. The antihistamines used in their treatment can also have central effects and affect certain occupations concerned with risk, road safety and maritime and air navigation. Cognitive tests, experimental studies and epidemiological data recommend avoiding 1st generation antihistamines for people who must drive regularly and/or professions concerned with safety. Although there are no comparative studies on real driving between 1st and 2nd generation antihistamines, in this type of patients there should be a preference for prescribing those with least possible central effect, especially those which are a good substrate for transmembrane transporter pumps such as P-glycoprotein and therefore have a low capacity for crossing the hematoencephalic barrier, thus allowing a broader window for therapy. In this sense, bilastine is a good P-glycoprotein substrate and shows good tolerance at CNS level, in both psychometric trials and real driving test protocols, even at double the dose recommended in the technical fi le. Key words: Antihistamine. Bilastine. Real driving studies. P-glycoprotein. Cognitive tests. Road safety. Central nervous system. © 2013 Esmon Publicidad J Investig Allergol Clin Immunol 2013; Vol. 23, Suppl. 1: 27-34 28 I Jáuregui, et al Introduction Table 1. Psychotropic medicines which can affect the driving of vehicles [7] 1.1. Allergy, sleep and antihistamines Opiates (the whole group) Allergy can be a factor of risk in handling vehicles. Antipsychotics On the one hand, some very common allergic pathologies can involve daytime somnolence associated with these Anxiolytics conditions: allergic rhinitis itself can cause alterations in the Hypnotics and tranquillisers quantity and quality of sleep [1-2], and chronic urticaria can Antidepressants (the whole group) produce deleterious effects on all the areas of health-related • Non-selective monoamine reuptake inhibitors quality of life, including sleep [3]. That is to say, daytime • Selective serotonin reuptake inhibitors somnolence can be considered as a problem associated, at Drug substitutes in addiction disorders (the whole group) least partly, with the allergic pathology itself. On the other • Bupropion hand, the symptoms of allergic rhinitis (bursts of sneezing, • Methadone difÀ culties in vision, irritability) can affect the driving of • Levacetylmethadol vehicles and, in the case of aviation pilots, can also cause Antihistamines for systemic use (the whole group) otalgia due to barotrauma, changes in vision and cabin • 1st generation antihistamines distractions [4]. • Piperazine derivatives On the other hand, all the classic antihistamines (AH) • Other antihistamines for systemic use and many of the more recent ones can have more or less depressant effects on the CNS (somnolence, lassitude, giddiness, lack of coordination, slowed reaction time), as well as peripheral anticholinergic effects (pupil dilatation, blurred vision or dry mouth), which could affect the control of vehicles and aircraft. Around 15% of the Spanish between 1990 and 2005; the use of AH, with/without other population receives AH at some point every year, with or drugs and/or alcohol, was considered as the principal cause without medical prescription, since they are the most frequent in 13 cases and as a concurrent factor in another 50 out of form of self-medication in allergic illnesses, the common 338 aviation accidents [10]. cold, insomnia and other conditions. The people treated Many specialists agree in limiting the free sale of 1st with AH are mostly outpatients and are generally regular generation AH, alone or included in multiple anti-catarrhal drivers. For all these reasons, the use of AH by drivers, preparations, especially for their involvement in trafÀ c and especially professionals, aircrew and all those people whose air or maritime navigation accidents [11]. It is evident that occupations involve critical safety has been a motive for non-sedative AH as a whole are safer from this viewpoint concern and debate for some years [5]. than the classical AH; nevertheless in the study of new AH it has been made essential to assess their effects on psycho- 1.2. Antihistamines and road and air accidents motor performance and on driving and piloting, simulated or real. The most recent data on road accidents from the General Directorate of TrafÀ c allows a certain optimism in the balance for the decade: in relation with 2001, the data for the years 2010-2011 show a reduction of more than 55% in deaths and 2. Psychomotor performance and 2nd serious injuries from trafÀ c accidents [6]. Many variables may generation antihistamines have had an inÁ uence in this reduction in morbimortality: safer roads and vehicles, continuous checks on speed and alcohol In studies on the effect of antihistamines and other drugs intake, or a more responsible attitude among drivers. Even so, on psychomotor performance a series of examinations or in Spain there are still around 2,000 deaths and 120,000 peo- subjective and objective tests have been used, which are ple injured on the roads every year, mostly those aged under summarised in another article in this supplement. 40. Among the recurrent factors in accidents with victims, in Apart from their direct action on the CNS and the addition to carelessness, alcohol stands out, together with a peripheral anticholinergic effects which can limit the capacity series of medicines which are psychotropic or with collateral to drive vehicles, AH can present interactions with alcohol, effects on the CNS (Table 1) [7], present in Spain in up to 6% with the mutual enhancement of sedative effects; as well of drivers killed in trafÀ c accidents [8]. In 1998 the presence as multiple medicament interactions, most problematical of AH was found in 2% of drivers involved in accidents, and in AH metabolized in the liver through cytochrome p-450 in 5% of drivers examined by breathalyser when driving under isoenzymes (CYP3A4, CYP2D6). suspicion of having consumed drugs and alcohol [9]. The sedative effects of AH are associated with their Again, 1st generation AH were found in samples from capacity to penetrate the blood-brain barrier (BBB), pilots in 4-11% of aircraft accidents with victims in the USA which depends above all on the lipophilia of the molecule J Investig Allergol Clin Immunol 2013; Vol. 23, Suppl. 1: 27-34 © 2013 Esmon Publicidad Antihistamines in driving and piloting 29 and its interaction with active transport pumps such as Table 2. Classifi cation of medicines according to their capacity to alter glycoprotein-P (P-gp) or organic anion transporter proteins the driving of vehicles [18] (OATP), responsible for the outflow or expulsion of Blood alcohol xenobiotics from the CNS [12]. Various 2nd generation Category Characteristics of contents AH are substrata of P-gp, which has been related with their the medicine considered low penetration in the brain [13-14]; however, other studies equivalent suggest large differences between the various molecules in their capacity of crossing the BBB and in the role of P-gp I Presumably safe <0,2 g/L in limiting their transport to the CNS [15]. II Produces light or moderate 0,2-0,5 g/L More than 80 comparative