Λεξικό .. Second generation antihistmines
Second generation antihistmines, Î‘Î½Ï„Î¹Î¹ÏƒÏ„Î±Î¼Î¹Î½Î¹ÎºÎ¬ Î´ÎµÏÏ„ÎµÏÎ·Ï‚ Î³ÎµÎ½Î¹Î¬Ï‚. They are antihistamines with less sedating results than classical antihistamines (1st generation) and they exert a stabilizing effect on mast cells. They are included: Mequitazine, Dimethindene maleate, Ketotifen, Oxatomide, Azelastine etc.
Most patients with allergic rhinitis treat their symptoms with first-generation antihistamines (FGAs), which are available over-the-counter (OTC). Yet FGAs are generally considered less safe than the newer drugs. FGAs cause central nervous system (CNS) adverse effects and may increase users' risk for work-related injuries and motor vehicle accidents and, in children, for learning impairment. SGAs cause fewer CNS effects, do not appear to affect learning in children, and do not have significant drug interactions. Several other countries have made SGAs available OTC. The safety and efficacy of SGAs have been adequately established. Consumers should have the option of self-treating mild allergic rhinitis symptoms with these products .
The sedating effect of first generation H(1)-antihistamines has been associated with their ability to penetrate the blood-brain barrier (BBB) and lack of efflux by P-glycoprotein (Pgp). Second generation H(1)-antihistamines are relatively free of sedation and their limited brain penetration has been suggested to arise from Pgp-mediated efflux.
Reports of serious cardiac arrhythmia associated with some second-generation antihistamines have prompted concern for their prescription. The blockade of potassium channels, particularly the subtype responsible for the rapid component of the delayed rectifier current (IKr), is largely responsible for such adverse cardiac events. Consequently, antihistamines with little or no interaction with these channels are expected to have the greatest safety margin. The main cardiac arrhythmia of concern is that of torsades de pointes, a potentially fatal phenomenon characterized by prolonged ventricular depolarization that manifests as a prolonged QT interval and polymorphic ventricular tachycardia, with twisting of the QRS complexes.
The human ether-a-go-go related gene (hERG) potassium channel is critical to the QT interval in the human heart measured by the electrocardiogram (ECG). QT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiac K(+) channel encoded by human ether-a-go-go-related gene (HERG). . Sakaguchi T et al (2008) repored a case of drug-induced long QT syndrome associated with an H(1)-receptor antagonist, hydroxyzine, in which a mutation was identified in the HERG gene. After taking 75 mg of hydroxyzine for several days, a 34-year-old female began to experience repetitive syncope. The deleterious effect of hydroxyzine was suspected because QTc interval shortened from 630 to 464 ms after cessation of the drug. Later on, the patient was found to harbor an A614V-HERG mutation. By using the patch-clamp technique in the heterologous expression system, we examined the functional outcome of the A614V mutation and confirmed a dominant-negative effect on HERG expression. Hydroxyzine concentration-dependently inhibited both wild-type (WT) and WT/A614V-HERG K(+) currents.
Half-maximum block concentrations of WT and WT/A614V-HERG K(+) currents were 0.62 and 0.52 microM, respectively. Thus, accidental combination of genetic mutation and intake of hydroxyzine appeared to have led to a severe phenotype, probably, syncope due to torsade de pointes. Based on pre-clinical and clinical evidence, it appears that loratadine, cetirizine, and fexofenadine are safe from cardiac arrhythmia via the IKr  have a propensity to cause ventricular tachyarrhythmias. Cetirizine, widely used in the treatment of allergic reactions, is a second generation H1 antihistamine with as yet no precautions of use regarding rhythm disturbances. No documented case of arrhythmia attributable to this drug has been reported. We report the case of a dialysed patient with chronic renal failure who had symptomatic episodes of torsades de pointes in the context of hypokalaemia and cetirizine overdose. In the light of this observation it would appear that the prescription of cetirizine is contra-indicated under such conditions.
Cetirizine, widely used in the treatment of allergic reactions, is a second generation H1 antihistamine with as yet no precautions of use regarding rhythm disturbances. No documented case of arrhythmia attributable to this drug has been reported. We report the case of a dialysed patient with chronic renal failure who had symptomatic episodes of torsades de pointes in the context of hypokalaemia and cetirizine overdose. In the light of this observation it would appear that the prescription of cetirizine is contra-indicated under such conditions.
1. Sampey CS, Follin SL. Second-generation antihistamines: the OTC debate. J Am Pharm Assoc (Wash). 2001 May-Jun;41(3):454-7.
2. Obradovic T, Dobson GG, Shingaki T, Kungu T, Hidalgo IJ. Assessment of the first and second generation antihistamines brain penetration and role of P-glycoprotein. Pharm Res. 2007 Feb;24(2):318-27. Epub 2006 Dec 19.
3. Du L, Li M, You Q. The interactions between HERG potassium channel and blockers. Curr Top Med Chem. 2009;9(4):330-8..
4. Sakaguchi T, Itoh H, Ding WG, Tsuji K, Nagaoka I, Oka Y, Ashihara T, Ito M, Yumoto Y, Zenda N, Higashi Y, Takeyama Y, Matsuura H, Horie M. Hydroxyzine, a first generation H(1)-receptor antagonist, inhibits human ether-a-go-go-related gene (HERG) current and causes syncope in a patient with the HERG mutation. J Pharmacol Sci. 2008 Dec;108(4):462-71. Epub 2008 Dec 5.
5. Renard S, Ostorero M, Yvorra S, Zerrouk Z, Bargas E, Bertocchio P, Pracchia S, Ebagosti A. Torsades de pointes caused by cetirizine overdose. Arch Mal Coeur Vaiss. 2005 Feb;98(2):157-61.
Γκέλης Ν.Δ. - Λεξικό Αλλεργίας - Εκδόσεις ΒΕΛΛΕΡOΦΟΝΤΗΣ - Κόρινθος 2013
Gelis Ν.D. - Dictionary of Allergies - VELLEROFONTIS Publications - Corinth 2013