Beginning in the mid-l940s, several antihistaminic drugs were been discovered as a result of bridging the aryl units of agents related to the ethylenediamines. The search for effective antimalarials led to the investigation of phenothiazine derivatives in which the bridging entity is sulfur. Subsequent testing found that the phenothiazine class of drugs had not only anti-histaminic activity but also a pharmacological profile of its own, considerably different from that of the ethylenediamines (Fig. 23.11). Thus began the era of development of useful psychotherapeutic agents, the phenothiazine antipsychotics.
The phenothiazine derivatives that display therapeutically useful antihistaminic actions contain a two- or three-carbon, branched alkyl chain between the ring system and terminal nitrogen atom. This differs significantly from the phenothiazine antipsychotic series in which an unbranched propyl chain is required. The branched alkyl chain contains a chiral carbon, giving rise to optical isomerism. The enantiomers of the pro
Figure 23.11 • General structure of the phenothiazines.
totype of this class, promethazine, have been resolved and found to possess similar antihistaminic and other pharmacological properties as described later.40,41 This is in contrast with results of studies of the pheniramines and carbinoxamine compounds in which the chiral center is closer to the aromatic moieties of the molecule. Thus, asymmetry appears to have less influence on antihistaminic activity when the chiral center lies near the positively charged side-chain nitrogen. In general, the combination of lengthening of the side chain and substitution of lipophilic groups in the 2-position of the aromatic ring results in compounds with decreased antihista-minic activity and increased psychotherapeutic properties. Also, unlike the phenothiazine antipsychotics, the heterocyclic ring of the antihistamines is unsubstituted.
Promethazine, the parent member of this series, is a moderately potent antihistamine based on pA2 values and doses with pronounced sedative effects (Table 23.2). It is a relatively long-acting antihistamine as a result of slow metabolic inacti-vation, perhaps because of sterically hindered cytochrome n-dealkylation. In addition to its antihistaminic and sedating action, it is a potent antiemetic, anticholinergic, and significantly potentiates the action of analgesic and other sedative drugs.30 The other members of this series display a similar pharmacological profile and thus may cause drowsiness and impair the ability to perform tasks requiring alertness. Also, concurrent administration of alcoholic beverages and other CNS depressants with the phenothiazines should be avoided.10
Although few pharmacokinetic data are available for the phenothiazine antihistamines, the metabolism of a close structural analog promethazine has been studied in detail.31 This compound undergoes mono- and di-n-dealkylation, sulfur oxidation, aromatic oxidation at the 3-position to yield the phenol, and n-oxidation. Several of these metabolites, particularly the phenol, may yield glucuronide conjugates. It is expected that the phenothiazine antihistamines would display similar metabolic profiles.
Promethazine Hydrochloride. Promethazine hydrochloride, (± )10-[2-(dimethylamino)-propyl]phenothi-azine monohydrochloride (Phenergan), occurs as a white to faint yellow crystalline powder that is very soluble in water, in hot absolute alcohol, and in chloroform. Its aqueous solutions are slightly acid to litmus.
Figure 23.11 • General structure of the phenothiazines.
Dosage forms: Tablets (12.5, 25, and 50 mg), oral syrup (6.25 mg/5 mL), rectal suppositories (12.5, 25, and 50 mg), injection (25 and 50 mg/mL) Usual adult dose:
• Allergy: 25 mg taken before retiring; however, 12.5 mg may be taken before meals or on retiring, if necessary
• Transfusion reactions: 25-mg doses to control minor transfusion reactions
• Motion sickness: 25 mg taken 30 to 60 minutes before travel and repeated 8 to 12 hours later, if necessary
• Nausea and vomiting: 12.5 to 25 mg every 4 to 6 hours as necessary
• Prophylactic dosage: 25 mg every 4 to 6 hours as necessary for prophylactic dosing (given during surgery and the postoperative period) and 25 to 50 mg with analgesics postoperatively or preoperatively
• Sedation: 25 to 50 mg for nighttime, presurgical, or obstetrical sedation
Trimeprazine Tartrate. Trimeprazine tartrate, (±)10-[3-(dimethylamino)-2-methylpropyl] phenothiazine tartrate (Temaril), occurs as a white to off-white crystalline powder that is freely soluble in water and soluble in alcohol. Its an-tihistaminic action is reported to be from 1.5 to 5 times that of promethazine. Clinical studies have shown it has a pronounced antipruritic action that may be unrelated to its histamine-antagonizing properties.
Dosage forms: Syrup and tablets
Usual adult dose: Oral, 2.5 mg 4 times a day
Methdilazine. Methdilazine, 10- [(1 -methyl-3-pyrrol-idinyl)methyl]phenothiazine (Tacaryl), is a light-tan crystalline powder that has a characteristic odor and is practically insoluble in water. Methdilazine, as the free base, is used in chewable tablets because its low solubility in water contributes to its tastelessness. Some local anesthesia of the buccal mucosa may be experienced if the tablet is chewed and not swallowed promptly.
Methdilazine Hydrochloride. Methdilazine hydrochloride (Tacaryl Hydrochloride), also occurs as a light-tan crystalline powder with a slight characteristic odor. The salt is freely soluble in water and in alcohol, however. The activity is like that of methdilazine, and it is administered orally for its antipruritic effect.
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