Antihistamines distribution

Miscellaneous Pharmaceutical Processes. Solvent extraction is used for the preparation of many products that ate either isolated from naturally occurring materials or purified during synthesis. Among these are sulfa dmgs, methaqualone [72-44-6] phenobarbital [50-06-6] antihistamines, cortisone [53-06-5] estrogens and other hormones (qv), and reserpine [50-55-5] and alkaloids (qv). Common solvents for these appHcations are chloroform, isoamyl alcohol, diethyl ether, and methylene chloride. Distribution coefficient data for dmg species are important for the design of solvent extraction procedures. These can be determined with a laboratory continuous extraction system (AKUEVE) (244). 

Mechanism of Action A propylamine derivative antihistamine that competes with histamine for histamine receptor sites on cells in the blood vessels, gastrointestinal (GI) tract, and respiratory tract. TAerapfiMtic Effect Inhibits symptoms associated with seasonal allergic rhinitis such as increased mucus production and sneezing. Pharmacokinetics Well absorbed after PO and parenteral administration. Food delays absorption. Widely distributed. Metabolized in liver. Primarily excreted in urine. Not removed by dialysis. Half-life 20 hr. 

In case of an obstruction of the nasal airways, the swelling should first be reduced and then the patient should apply the anti-inflammatory medication to ensure its necessary distribution over the complete mucosa. Antihistamines in addition to oral therapy may also be applied locally, intranasally or conjunctivally. The combination of all three substance groups (H, antihistamines, topic glucocorticoids and antileukotrienes) as a pretreatment as well as a symptomatic treatment during immunotherapy increases the chances of success of hyposensitization in our experience [unpubl. data]. 

Chou, K.J., and M.D. Donovan. 1997. Distribution of antihistamines into the CSF following intranasal delivery. Biopharm Drug Disp 18 335. 

In the case of a structurally inhomogeneous series of antihistamines, the sedative side-effects were found to be much better described by their octanol-water distribution coefficient at pH 7.4, log D, than by Alog P0ct.-aik. or their hydration capacity, Aalkane [b7[. 

Quinones-Torrelo et al. (1999 2001) have demonstrated a correlation of pharmacokinetic properties with results from micellar liquid chromatography. In this method micellar solutions of nonionic surfactants are used as the mobile phase in reverse-phase liquid chromatography. Interactions between the mobile and stationary phases are purported to correspond to the membrane/water interface of biological barriers as hydrophobic, steric, and electronic interactions are important for both. For a series of 18 antihistamines Quinones-Torrelo et al. (2001) showed that both volume of distribution and half-life values were better correlated with retention on these columns than with the classical log K, w descriptor. 

The mean uses per compound in Table V is 1.7. The mean uses per compound can be counted tor each ot the uses, it was shown (9) that mean uses per compound is distributed statistically and the outliers on each side could be identified. The ones with low mean uses per compound were highly specific uses such as antimicrobial, antineoplastics, antihistaminics, estrogenics, etc. The ones with high mean uses were the ones which were present in dominant use pairs or clusters such as diuretics, vasodilator, CNS depressant, etc., or which had old imprecise use descriptors such as sudorific, diaphoretic, dermatoses, etc. 

Muscarinic effects, mediated by acetylcholine, the primary transmitter of the autonomic nervous system ganglia, are inhibited by the anticholinergic effects exerted by antihistamines. Anticholinergic side effects include dry mouth, urinary retention, blurred vision, and constipation. Because first-generation antihistamines also distribute into the CNS, sedation is a prominent side effect. The development of second-generation antihistamines, such as loratadine and fexofenadine, lack anticholinergic activity and do not distribute into the CNS (Table 31-1). Hence, they are not typically associated with sedation and do not possess antiemetic properties. 

Fig. 25. A comparison of the distribution and excretion of two antihistamines, the tertiary promethazine (a) and the quaternary (Aprobit) phenothiazine compound (6) labeled with3sS. Note the high concentrations of the tertiary amine in brain tissue and the restriction in the distribution of the quaternary compound mainly to the liver and the intestines. After Hansson and Schmiterlow145 ...

Phosphodiesterase Inhibitors — LM 209 (19) has been shown to be a noncompetitive inhibitor of lung phosphodiesterase (PDE) (2.5 x 10 4M) in contrast to theophylline, which is a competitive inhibitor. 19 is antihistaminic, orally effective and inhibits bronchospasm provoked by histamine, serotonin or citric acid. It is distinguished from other antihistamines by its lack of sedation and long duration of action. Absorption, distribution and elimination studies in rat and dog after i.v. or oral administration have been reported. ... 

In general, the antihistamines are well absorbed, have large vol-nmes of distribution, and are metabolized by the liver. Serum half-hves vary considerably between patients. Also, the therapeutic effects of these agents are more prolonged than might be predicted by their half-hves. 

Histamine receptors have been classified into two major subtypes, H, and H2, on the basis of quantitative studies on isolated peripheral tissues. Histamine H,-receptors mediate the contractile actions of histamine on numerous visceral smooth muscles, most notably from the trachea, ileum and uterus of the guinea-pig [36-39]. These responses are antagonized by the classical -antihistamines [36-39] such as mepyramine (1) [36] and diphenhydramine (3) [40] (see Figure 2.1). Histamine also stimulates the secretion of acid by stomach, increases the rate of contraction of guinea-pig isolated atria and inhibits electrically evoked contractions of rat isolated uterine horn [41 ]. However, these responses are not affected by H, -receptor antagonists and have been defined as histamine H2-receptor responses following the development of specific antagonists to these responses such as burimamide [41], cimetidine [42] and ranitidine [43]. The distribution and classification of histamine H,-and H2-receptors in various mammalian peripheral tissues have been reviewed elsewhere [44-46a]. 

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