Cardiac toxic effects induced by Hi-antihistamines occur rarely and are independent of H1-receptor occupation.10'33'34 As mentioned previously, first-generation ^-antihistamines have antimuscarinic and ^-adrenergic blockade activity and thus may cause dose-related prolongation of the QT interval. The first two second-generation ^-antihistamines, astemi-zole and terfenadine, were found to be even more cardiotoxic than the first-generation agents, especially when used in combination with other drugs. This led to their withdrawal from the market. The cardiac effects of the second-generation anti-histamines are discussed in more detail in the next section of this chapter.
The primary objective of antihistamine drug development over the past several decades has centered on developing new drugs with higher selectivity for H1-receptors and lacking undesirable CNS and cardiovascular actions.103334 These efforts led to the introduction of the second-generation antihistamines, which are classified as "nonsedating" and have little antagonist activity at other neurotransmitter receptors, including muscarinic receptors, and cardiac ion channels at therapeutic concentrations. The pharmacological properties of these agents will be discussed in more detail.
There are relatively few published studies concerning the pharmacokinetic and biodisposition profiles of the firstgeneration antihistamines.1031 Generally, the compounds are orally active and well absorbed, but oral bioavailability may be limited by first-pass metabolism. The metabolites formed depend on drug structure to a large extent but commonly involve the tertiary amino moiety. This functionality may be subject to successive oxidative n-dealkylation, deamination, and amino acid conjugation of the resultant acid. The amine group may also undergo n-oxidation (which may be reversible) or direct glucuronide conjugation. First-generation agents with unsubstituted and activated aromatic rings (phe-nothiazines) may undergo aromatic hydroxylation to yield phenols, which may be eliminated as conjugates. More detailed pharmacokinetic data are available for the second-generation agents and are included in the monographs that follow and Table 23.3.
The ^-antihistamines display various significant drug interactions when coadministered with other therapeutic agents. For example, MAO inhibitors prolong and intensify the anticholinergic actions of the antihistamines. Also, the sedative effects of these agents may potentiate the depressant activity of barbiturates, alcohol, narcotic analgesics, and other depressants.102331
First-Generation Antihistamine Classes
AMINOALKYL ETHERS (ETHANOLAMINES)
The aminoalkyl ether antihistamines are characterized by the presence of a CHO connecting moiety (X) and a two- or three-carbon atom chain as the linking moiety between the key diaryl and tertiary amino groups (Fig. 23.7). Most compounds in this series are simple n, n-dimethylethanolamine derivatives and are so classified in several texts. Clemastine and diphenylpyraline differ from this basic structural pattern, in that the basic nitrogen moiety and at least part of the carbon chain are part of a heterocyclic ring system and
Figure 23.7 • General structure of the aminoalkyl ethers.
there are three carbon atoms between the oxygen and nitrogen atoms. The basic nitrogen in all of these compounds is not only essential for binding affinity, but also serves as a moiety for the formation of stable, solid salts.
The simple diphenyl derivative diphenhydramine was the first clinically useful member of the ethanolamine series and serves as the prototype. Other therapeutically useful derivatives of dipherthydraniine have been obtained by para substitution of methyl (methyldiphenhydramine), methoxy (me-drylamine), chloro (chlorodiphenhydramine), or bromo (bromodiphenhydramine) on one of the phenyl rings. These derivatives reportedly have better therapeutic profiles than diphenhydramine because of reduced adverse effects.10,31 Replacement of one of the phenyl rings of the diphenhydramine with a 2-pyridyl group, as in doxylamine and carbinoxamine, enhances antihistaminic activity as demonstrated by pA2 values in vitro and therapeutic dosing data (Table 23.2). These compounds display oral antihistaminic activities 40 and 2 greater, respectively, than diphenhy-dramine in animal test models.31
As a result of an asymmetrically substituted benzylic carbon, most of the aminoalkyl ethers are optically active. Most studies indicate indicate that the individual enantiomers differ significantly in antihistaminic activity, with activity residing predominantly in the S-enantiomers.30,35
The diaryl tertiary aminoalkyl ether structure that characterizes these compounds also serves as a pharmacophore for muscarinic receptors (Table 23.2). As a result, the drugs in this group possess significant anticholinergic activity, which contributes not only to their therapeutic use as antiemetic, motion sickness, and anti-Parkinson drugs but also to their adverse effect profile (dry mouth, blurred vision, urinary retention, constipation, tachycardia). Drowsiness, as well as other CNS effects, is a common side effect to the tertiary aminoalkyl ethers, presumably as a result of the ability of these compounds to penetrate the BBB and occupy central Hi-receptors. Although this central action is exploited in over-the-counter (OTC) sleeping aids, it may interfere with the performance of tasks requiring mental alertness.10,26,27 The frequency of GI side effects in this series of antihistamines is relatively low, compared with the ethylenediamine antihistamines.10,26,27
In spite of their long and extensive use, pharmacokinetic data on this series of compounds are relatively limited. Most members of this series appear to be extensively metabolized by pathways including n-oxidation and successive oxidative n-dealkylation followed by aldehyde oxidation and amino acid conjugation.31 The known kinetic properties of representative members of this class of antihistamines are summarized in Table 23.3.10
The structures of the aminoalkyl ether derivatives with physicochemical properties, basic therapeutic activty data, and dosage form information are provided in the monographs that follow.
Diphenhydramine Hydrochloride, Tannate, and Citrate. Diphenhydramine hydrochloride, 2-(diphenylme-thoxy)-n,n-dimethylethanamine hydrochloride (Benadryl), is an oily, lipid-soluble free base available as the bitter-tasting hydrochloride salt, which is a stable, white crystalline powder soluble in water (1:1), alcohol (1:2) and chloroform (1:2). The salt has a pKa value of 9, and a 1% aqueous solution has a pH of about 5. The other salts display comparable properties.
In addition to antihistaminic action, diphenhydramine exhibits antidyskinetic, antiemetic, antitussive and antimus-carinic, and sedative properties. In the usual dose range of 25 to 400 mg, diphenhydramine is not a highly active H1-antihistamine. Conversion to a quaternary ammonium salt does not alter the antihistaminic action greatly but does increase the anticholinergic action.
As an antihistaminic agent, diphenhydramine is recommended in various allergic conditions and, to a lesser as an antitussive and Parkinsonism drug. It is also used in OTC sleep-aid products. It is administered either orally or par-enterally in the treatment of urticaria, seasonal rhinitis (hay fever), and some dermatoses. The most common side effect is drowsiness, and the concurrent use of alcohol and other CNS depressants should be avoided.
Dosage forms: Tablets (12.5, 25, and 50 mg); capsules (25 and 50 mg); oral disintegrating strips (12.5 and 25 mg); solutions, elixirs, and syrups (12.5 mg/5 mL); suspension (25 mg/5 mL); and injection (50 mg/mL). Usual adult doses:
• Antihistamine: 25 to 50 mg every 4 to 6 hours (maximum of 300 mg/day)
• Antitussive liquid: 25 to 50 mg every 4 hours (liquid) or 25 mg every 4 hours (syrup); do not exceed 300 mg/day
• Motion sickness: 25 to 50 mg every 4 to 6 hours (maximum of 300 mg/day)
Dimenhydrinate. The 8-chlorotheophyllinate (theo-clate) salt of diphenhydramine, 8-chlorotheophylline 2-(diphenylmethoxy)-n,n-dimethylethylamine (Dramamine), is a white crystalline, odorless powder that is highly soluble in water and freely soluble in alcohol and chloroform.
Dimenhydrinate is recommended for nausea of motion sickness and for hyperemesis gravidarum (nausea of pregnancy). For the prevention of motion sickness, the dose should be taken at least 0.5 hour before beginning a trip. The cautions listed for diphenhydramine should be observed.
Dosage forms: Tablets (50 mg), liquid (12.5 mg/5 mL,
15.62 mg/5 mL), injection (50 mg/mL) Usual dosage (motion sickness):
• Adult/children >12 years of age: 1 to 2 chewable tablets or tablets (50-100 mg) every 4 to 6 hours, not to exceed 8 chewable tablets or tablets (400 mg) in 24 hours
• Children 6 to younger than 12 years of age: /2 to 1 chew-able tablet or tablet (25-50 mg) every 6 to 8 hours, not to exceed 3 tablets in 24 hours
• Children 2 to younger than 6 years of age: M to M chew-able tablet or tablet (12.5-25 mg) every 6 to 8 hours, not to exceed 1 M tablets in 24 hours
Bromodiphenhydramine Hydrochloride. Bromo-diphenhydramine hydrochloride, 2-[(4-bromophenyl)-phenylmethoxy]-N, N-dimethylethanamine hydrochloride (Ambodryl Hydrochloride), is a white to pale buff crystalline powder that is freely soluble in water and in alcohol. Relative to diphenhydramine, bromodiphenhydramine is more lipid soluble and was twice as effective in protecting against the lethal effects of histamine aerosols.
Dosage forms: Capsules and elixir Usual adult dose: Oral, 25 mg/4 to 6 hours
Doxylamine Succinate. The acid succinate salt (bisuc-cinate) of doxylamine, 2-[a-[2-(dimethylamino)ethoxy]-a-methylbenzyl]pyridine bisuccinate (Decapryn Succinate), is a white to creamy-white powder with a characteristic odor. It is soluble in water (1:1), alcohol (1:2), and chloroform (1:2). A 1% solution has a pH of about 5.
Doxylamine succinate is comparable in potency to diphenhydramine. It is indicated for the relief of seasonal
rhinitis symptoms, but is also used as a nighttime sedative. Concurrent use of alcohol and other CNS depressants should be avoided.
Dosage forms: Tablets (5 mg), oral suspension (1 mg/mL), and oral liquid (2.5 mg/2.5 mL) Usual adult dose: Oral, 12.5 to 25 mg/4 to 6 hours
Carbinoxamine Maleate. Carbinoxamine is available as a bitter bimaleate salt, (d, l)-2-[^-chloro-a-[2-(dimethyl-amino)ethoxy]benzyl]pyridine bimaleate (Clistin), which is a white crystalline powder that is very soluble in water and freely soluble in alcohol and in chloroform. The pH of a 1% solution is between 4.6 and 5.1.
Carbinoxamine is a potent antihistaminic and is available as the racemic mixture. It differs structurally from chlorpheniramine only in having an oxygen atom separate the asymmetric carbon atom from the aminoethyl side chain. The more active levo isomer of carbinoxamine has the (S) absolute configuration30 and can be superimposed on the more active dextro isomer (s configuration) of chlorpheniramine.
Dosage forms: Tablets (4 and 8 mg), capsules (10 mg), liquid (1.67 mg/5 mL), solution (4 mg/5 mL), and suspension (3.2 mg/5 mL) Usual dose (tablets):
• Adults and children 12 years of age and older: 1 tablet (8 mg) twice daily
• Children 6 to 12 years of age: M tablet twice daily (every 12 hours). The tablets are not recommended for children younger than 6 years of age.
Clemastine Fumarate. Dextrorotatory clemastine, R,R-2[2[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine hydrogen furnarate (1:1) (Tavist), has two chiral centers, each of which has the (R) absolute configuration. A comparison of the activities of the enantiomers indicates that the asymmetric center close to the terminal side chain nitrogen is of lesser importance to antihistaminic activity.36
This member of the ethanolamine series is characterized by a long duration of action, with an activity that reaches a maximum in 5 to 7 hours and persists for 10 to 12 hours. It is well absorbed when administered orally, and it is excreted primarily in the urine. The side effects are those usually encountered with this series of antihistamines. Clemastine is closely related to chlorphenoxamine, which is used for its central cholinergic-blocking activity. Therefore, it is not surprising that clemastine has significant antimuscarinic activity.
Dosage forms: Tablets (1.34 and 2.68 mg) and syrup
• Allergic rhinitis: 1.34 mg every 12 hours or twice daily (maximum 8.04 mg/day for the syrup or 2.68 mg in 24 hours for the tablets) for adults; 0.67 mg twice daily (maximum 4.02 mg) for children 6 to 12 years of age (syrup only)
• Urticaria/angioedema: 2.68 mg twice daily, not to exceed 8.04 mg/day for adults; 1.34 mg twice daily, not to exceed 4.02 mg/day for children 6 to 12 years of age (syrup only)
Diphenylpyraline Hydrochloride. Diphenylpyr aline hydrochloride, 4-(diphenylmethoxy)-1-methylpiperidine hydrochloride (Hispril, Diafen) is a white or slightly off-white crystalline powder that is soluble in water or alcohol. Diphenylpyraline is structurally related to diphenhydramine with the aminoalkyl side chain incorporated in a piperidine ring. It is a potent antihistaminic, and the usual dose is 2 mg 3 or 4 times daily.
Dosage forms: Extended-release capsules (5 mg) Usual adult dose: Oral, 5 mg/l2 hours
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