Ionization antihistamines

The Hi-antagonists are classified as either first- or second-generation compounds. Second-generation antihistamines have lipophilicity and ionization profiles that make them less able to cross the blood-brain barrier thus they produce dramatically less sedation than do the first-generation drugs. 

C per minute injection port temperature, 270°C carrier gas, helium flow rate, 1 ml/min and MS conditions-scan mode, ionization energy, 70 eV ion source temperature 220°C capillary direct interface heated at 260°C. After acid hydrolysis of the conjugates, extraction, and acetylation, the urine samples were analyzed by computerized gas chromatography-mass spectrometry. The presence of aUcylamine antihistamines and their metabolites were indicated with the selected ions m/z 58, 169, 203, 205, 230, 233, 262, and 337. 

Based on correlations of pKa values and lipophilicity data, it appears that compounds with a log D (the sum of the partition coefficients of both the ionized and unionized species) near 1.0 60.5 at pFI 7.4 are most efficacious, and their water-soluble salts also show a low incidence of ocular irritation. Relationships between partitioning characteristics of these and other antihistamines indicate (at least moderate) receptor affinity and that a particular range of optimal lipophilicity for topical ocular antihistamines with minimal ocular irritation (43). Some of these compounds are currently available (Table 37.9) or are being evaluated as nasal sprays, and some also are occasionally used as systemic antihistamines. 

Andrews determined die ionization constant of diphenhydramine at 0°, pK a = 9.67, and 25°, pJ a = 9.12 in water. These values compare well with those obtained by Lordi (NB Lordi NG and Christian JE, Physical properties and pharmacological activity antihistaminics, /. Am. Pharm. Assn., Sci. Edn., 45, 300-305 (1956)) of pK a = 9.00 in water. DeRoos (NB deRoos AM, Rekker RF and Nauta WT, Arzneim.-Forsch., 20,1763-65 (1970)) has determined die pK a at 20° to be 9.06 in water. The pKa of diphenhydramine USP has been determined in a watenmethanol (1 1) system to be 8.4 (Spurlock CH and Parke Davis Co., personal communication). Since the pK a varies slightly with the alcohol content, the value obtained is acceptable."... 

Matrix-assisted laser desorption/ionization-tandem mass spectrometric method (MALDI-MS/MS) has proven to be a reliable tool for direct measurement of the disposition of small molecules in animal tissue sections. As example, MALDI-MS/MS imaging system was employed for visualizing the spatial distribution of astemizole and its primary metabolite in rat brain tissues. Astemizole is a second-generation antihistamine, a block peripheral HI receptor, which was introduced to provide comparable therapeutic benefit but was withdrawn in most countries due to toxicity risks. Astemizole was observed to be heterogeneously distributed to most parts of brain tissue slices including cortex, hippocampus, hypothalamic, thalamus, and ventricle regions while its major metabolite, desmethylastemizole, was only found around ventricle sites. We have shown that astemizole alone is likely to be responsible for the central nervous system (CNS) side effects when its exposures became elevated. 

Acids and bases. Unlike salts, acids and bases need not be completely ionized in solution. Strong acids (e.g. hydrochloric acid) and strong bases (e.g. sodium hydroxide) are completely ionized in the pH range of 0-14, but weak acids or bases show variable ionization within this pH range. Even small variations in pH on either side of the neutral point (pH 7) make considerable changes in the proportions of drug ionized in such cases as barbiturates, alkaloids, local anaesthetics, and antihistaminics. Several examples will be given later. 

Very many alkaloids, local anaesthetics, and antihistaminics have values about 8, so that they are about 16 per cent non-ionized at pH 7.3. It is almost certain that these penetrate as molecules and act biologically as cations. The H -type histamine antagonists, like cimetidine 9-43) need to be largely ionized at pH 7, to exert their action, but if totally ionized at this pH, they cannot penetrate to their receptor (Black et aL 1974). 

---