The ethylenediamine antihistamines are characterized by the presence of a nitrogen-connecting atom (X) and a two-carbon atom chain as the linking moiety between the key diaryl and tertiary amino moieties (Fig. 23.8). All compounds in this series are simple diarylethylenediamines except antazoline, in which the terminal amine and a portion of the carbon chain are included as part of an imidazoline ring system. Because it differs significantly in its pharmacological profile, antazoline is not always classified as an ethylenediamine derivative.

Phenbenzamine was the first clinically useful member of this class and served as the prototype for the development of more effective derivatives. Replacement of the phenyl moiety of phenbenzamine with a 2-pyridyl system yielded

Figure 23.8 • General structure of the ethylenediamines.

tripelennamine, a significantly more effective histamine receptor blocker as was also observed in the aminoalkyl ether series described previously.31 Substitution of a para methoxy (pyrilamine or mepyramine), chloro (chloropyra-mine), or bromo (bromtripelennamine) further enhances activity, as observed earlier. Replacement of the benzyl group of tripelennamine with a 2-thienylmethyl group provided methapyrilene, and replacement of tripelennamine's 2-pyridyl group with a pyrimidinyl moiety (along with p-methoxy substitution) yielded thonzylamine, both of which function as potent H1-receptor antagonists.31

In all of these compounds, the aliphatic or terminal amino group is required for H1-blocking activity and is significantly more basic than the nitrogen atom bonded to the diaryl moiety; the nonbonded electrons on the diaryl nitrogen are delo-calized by the aromatic ring, and the resultant reduction in electron density on nitrogen decreases basicity. Thus, the aliphatic amino group in the ethylenediamines is sufficiently basic for the formation of pharmaceutically useful salts.

Historically, the ethylenediamines were among the first useful antihistamines. They are moderately effective ^-antihistamines based on pA2 values and doses, but they also display a relatively high frequency of CNS depressant and GI side effects.27,31 The anticholinergic and antiemetic actions of these compounds are relatively low compared with those of most other classical, first-generation antihistamines (Table 23.2). The piperazine- and phenothiazine-type anti-histamines also contain the ethylenediamine moiety, but these agents are discussed separately because they exhibit significantly different pharmacological properties.

Relatively little information is available concerning the pharmacokinetics of this series of compounds. Tripelenna-mine is metabolized in humans by N-glucuronidation, N-oxidation, and pyridyl oxidation followed by phenol glu-curonidation. It is anticipated that other members of this series are similarly metabolized.31 The known pharmacoki-netic properties of representative members of this class of antihistamines are summarized in Table 23.3.

The structures of the salt forms of the marketed ethyl-enediamine antihistamines, along with physicochemical properties, therapeutic activity profiles, and dosage form information, are provided in the monographs that follow.

Tripelennamine Citrate. Tripelennamine citrate, 2-[ben-zyl[2-dimethylamino)-ethyl]amino]pyridine citrate (1:1), PBZ (Pyribenzamine Citrate), is available as a monocitrate salt, which is a white crystalline powder freely soluble in water and in alcohol. A 1% solution has a pH of 4.25. For oral administration in liquid dose forms, the citrate salt is less bitter and thus more palatable than the hydrochloride. Because of the difference in molecular weights, the doses of the two salts must be equated —30 mg of the citrate salt is equivalent to 20 mg of the hydrochloride salt.

Tripelennamine Citrate

Dosage forms: Elixir

Usual adult dose: Oral, 25 to 50 mg/4 to 6 hours

Tripelennamine Hydrochloride. Tripelennamine hy-drochloride is a white crystalline powder that darkens slowly on exposure to light. The salt is soluble in water (1:0.77) and in alcohol (1:6). It has a pKa of about 9, and a 0.1% solution has a pH of about 5.5.

Tripelennamine, the first ethylenediamine developed in the United States and is well absorbed when given orally. It appears to be as effective as diphenhydramine and may have the advantage of fewer and less severe side reactions. Drowsiness may occur, however, and may impair the ability to perform tasks requiring alertness. The concurrent use of alcoholic beverages should be avoided.

Dosage forms: Tablets, extended-release tablets Usual adult dose: Oral tablets, 25 to 50 mg/4 to 6 hours; extended-release tablets, 100 mg/8 to l2 hours

Pyrilamine Maleate. Pyrilamine, 2-[4-methoxybenzyl [2-dimethylamino)ethyl]-amino]pyridine, is available as the acid maleate salt (1:1), which is a white crystalline powder with a faint odor and a bitter, saline taste. The salt is soluble in water (1:0.4) and freely soluble in alcohol. A 10% solution has a pH of approximately 5. At a pH of 7.5 or above, the free base begins to precipitate.

Pyrilamine differs structurally from tripelennamine by having a methoxy group in the para position of the benzyl radical. It differs from its more toxic and less potent precursor phenbenzamine (Antergan) by having a 2-pyridyl group on the nitrogen atom in place of a phenyl group.

Clinically, pyrilamine and tripelennamine are considered among the less potent antihistaminics. They are highly potent, however, in antagonizing histamine-induced contractions of guinea pig ileum.22 Because of the pronounced local anesthetic action, the drug should not be chewed, but taken with food.

Dosage forms: Tablets

Usual adult dose: Oral, 25 to 50 mg/6 to 8 hours

Methapyrilene Hydrochloride. Methapyrilene hydrochloride, 2-[[2-(dimethylamino)-ethyl]-2-thienylarnino] pyridine monohydrochloride (Histadyl) is available as the bitter-tasting, white crystalline powder that is soluble in water (1:0.5), in alcohol (1:5), and in chloroform (1:3). Its solutions have a pH of about 5.5. It differs structurally from tripelennamine in having a 2-thiophene—methylene group in place of the benzyl group. The thiophene ring is considered isos-teric with the benzene ring, and the isosteres exhibit similar activity. A study of the solid-state conformation of methapyrilene hydrochloride showed that the trans--conformation is preferred for the two ethylenediamine nitrogen atoms. The Food and Drug Administration declared methapyrilene a potential carcinogen in 1979, and all products containing it have been recalled.

Thonzylamine Hydrochloride. Thonzylamine hydrochloride, 2-[[2-(dimethylamino)-ethyl](p-methoxyben-zyl)amino]pyrimidine hydrochloride, is a white crystalline powder soluble in water (1:1), in alcohol (1:6), and in chloroform (1:4). A 2% aqueous solution has a pH of 5.5. It is similar in activity to tripelennamine but is claimed to be less toxic. The usual dose is 50 mg taken up to 4 times daily. It is available in certain combination products.

Antazoline Phosphate. Antazoline phosphate, 2-[(N-benzylanilino)methyl]-2-imidazoline dihydrogen phosphate, is a bitter, white to off-white crystalline powder that is soluble in water. It has a pKa of 10.0, and a 2% solution has a pH of about 4.5. Antazoline, like the ethylenedi-amines, contains an N-benzylanilino group linked to a basic nitrogen through a two-carbon chain.

Antazoline is less active than most of the other antihistamine drugs, but it is characterized by the lack of local irritation. The more soluble phosphate salt is applied topically to the eye in a 0.5% solution. The less soluble hydrochloride is given orally. In addition to its use as an antihistamine, an-tazoline has more than twice the local anesthetic potency of procaine and also exhibits anticholinergic actions.


The piperazines or cyclizines can also be considered ethylenediamine derivatives or cyclic ethylenediamines (cy-clizines); in this series, however, the connecting moiety (X) is a CHN group, and the carbon chain, terminal amine functionality, and the nitrogen atom of the connecting group are all part of a piperazine moiety (Fig. 23.9). Both nitrogen atoms in these compounds are aliphatic and thus display comparable basicities. The primary structural differences within this series involve the nature of the para aromatic ring substituent (H or Cl) and, more importantly, the nature of the terminal piperazine nitrogen substituent.

The piperazines are moderately potent antihistaminics with a relatively high potential to cause drowsiness and psy-chomotor and cognitive dysfunction (Table 23.2).26,27,31 The activity of the piperazine-type antihistaminics is characterized by a slow onset, but a long duration of action. These

Figure 23.9 • General structure of the piperazines.

agents exhibit peripheral and central antimuscarinic activity, and thereby diminish vestibular stimulation and act on the medullary chemoreceptor trigger zone.10,26,27 Thus, as a group, these agents have found significant use as antiemetics and antivertigo agents and in the treatment of motion sickness (Table 23.2).

Some members of this series have exhibited a strong teratogenic potential, inducing several malformations in animal models. The n-dealkylayed metabolites, the norchlor-cyclizines, have been proposed as responsible for the teratogenic effects of the parent drugs.37 Although terato-genicity has not been observed in humans, its use during pregnancy is discouraged. Metabolic studies in this series of compounds have focused primarily on cyclizine and chlorcyclizine, and these compounds undergo similar biotransformation. The primary pathways involve n-oxidation and n-demethylation, and both of these metabolites are devoid of antihistaminic activity.

The structures of the marketed salt forms of the piper-azine antihistamines, along with physicochemical properties, basic therapeutic activity profiles, and dosage form information, are provided in the monographs that follow. The known kinetic properties of representative members of this class of antihistamines are summarized in Table 23.3.

Cyclizine Hydrochloride. Cyclizine hydrochloride, 1-(diphenylmethyl)-4-methylpiperazine monohydrochloride

(Marezine), occurs as a light-sensitive, white crystalline powder with a bitter taste. It is slightly soluble in water (1:115), in alcohol (1:115), and in chloroform (1:75). It is used primarily in the prophylaxis and treatment of motion sickness. The lactate salt (Cyclizine Lactate Injection, United States Pharmacopoeia [usp]) is used for intramuscular (IM) injection because of the limited water solubility of the hydrochloride. The injection should be stored in a cold place, because if it is stored at room temperature for several months, a slight yellow tint may develop. This does not indicate a loss in biologic potency.

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