Nonsedating antihistamine drugs

The carboxylic acid fexofenadine (Allegra) is a top-selling nonsedating antihistamine drug for the treatment of allergy symptoms. It contains a stereocenter, but both enantiomers are equally effective, hence it is sold as a racemate. 

Yet another related approach to pharmacotherapy management is step protocols or step therapy. Step protocols limit access to certain drugs until less costly alternative drugs have been tried first. For example, a step protocol might require a patient to have tried a relatively low-cost antihistamine, such as chlorpheniramine, before being prescribed a more expensive nonsedating antihistamine. Step therapy procedures were in place at 68.5% of HMOs in 1998 [1]. 

Drugs that may be affected by SSRIs Drugs that may be affected by SSRIs include alcohol, benzodiazepines, beta blockers, buspirone, carbamazepine, cisapride, clozapine, cyclosporine, diltiazem, digoxin, haloperidol, hydantoins, lithium, methadone, mexiletine, nonsedating antihistamines, NSAIDs, olanzapine, phenothiazines, phenytoin, pimozide, procyclidine, ritonavir, ropivacaine, sumatriptan, sulfonylureas, sympathomimetics, tacrine, theophylline, tolbutamide, tricyclic antidepressants, and warfarin. 

Coadministration of ritonavir with certain nonsedating antihistamines, sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse reactions due to possible effects of ritonavir on the hepatic metabolism of certain drugs (see Contraindications). 

Drugs that may affect nelfinavir include anticonvulsants, azithromycin, azole antifungals, efavirenz, delavirdine, HMG-CoA reductase inhibitors, indinavir, interleukins, nevirapine, rifabutin, rifampin, ritonavir, saquinavir, St. John s wort. Drugs that may be affected by nelfinavir include amiodarone, antiarrhythmics (amiodarone, quinidine), azithromycin, benzodiazepines, efavirenz, ergot alkaloids, delavirdine, didanosine, fentanyl, indinavir, lamivudine methadone, nonsedating antihistamines, oral contraceptives, phenytoin, pimozide, quinidine, rifabutin, saquinavir, sildenafil, sirolimus, tacrolimus, zidovudine. 

Enantiomerically pure diarylmethylamines are important intermediates in the synthesis of biologically active compounds such as 28 or 29 (Fig. 2.1.3.8). Among several drug candidates, Cetirizine hydrochloride (28) stands out as a commercially important nonsedative antihistamine agent. Binding studies indicate that... 

One can find many more examples where a subtle modification in a side chain leads to a new drug that produces a drastically different therapeutic or toxicological outcome. This is clearly illustrated by the nonsedating antihistamine terfenadine (Seldane), which produces cardiotoxicity when given with certain drugs that inhibits its metabolism. This product is no longer marketed. It has been replaced by its safer but no less effective carboxylic oxidative metabolite fexofenadine (Allegra). 

Occasionally a metabolite may provide a safer or more effective pharmaceutical than the parent compound selected for development. For example, fexofenadine, a widely sold nonsedating antihistamine, is the active metabolite of terfenadine. Fexofenadine is a safer drug than terfenadine and has replaced it on the market. 

The newer drugs therefore represent a substantial improvement over original antihistamines. They are not, however, devoid of side effects. For example, certain nonsedating antihistamines such as astemizole and terfenadine may be cardiotoxic, and problems such as severe ventricular arrhythmias (torsades de pointes) have occurred when these drugs are taken in high doses or taken by individuals with preexisting cardiac and liver problems.70,71 These cardiac effects, however,... 

Potentially harmful drug interactions may not be identified during controlled clinical trials, due to the exclusion of patients taking concomitant medications, which are not allowed to be taken during a study. For example, terfenadine, a novel nonsedating antihistamine which was found to cause a serious and potentially fatal cardiac arrhythmia, torsades de pointes, when administered with keto-conazole or erythromycin, and this could not realistically have been expected to be identified in the clinical trial setting. The mechanism of this adverse drug interaction was found to be due to cumulation of unmetabolized terfenadine, due to inhibition of cytochrome P-450 (CYP) by ketoconazole or erythromycin the parent terfenadine molecule is usually cleared very rapidly when there is no concomitant CYP inhibitor. 

The second of the nonsedating antihistamine is the benzimidazole derivative astemizole (Table 13-2). This is an extremely long-acting drug (txn = 104 hs). The skin reaction to histamine, for example, is modified for several days following a single oral 10 mg dose. A single... 

Loratadine, where the lipophilic N-methyl group of azatidine (No. 20, Fig. 13-1) has been exchanged for the much more hydrophilic carbamate, is largely devoid of CNS activity and has been shown to be a nonsedating antihistamine. As azatidine, this drug is also isosterically related to cyproheptadine (Chapter 12), which is also a serotonin antagonist, in addition to being clinically useful as an antihistamine. 

Figure 19.19 Compounds related to the antihistamine arena. Compound 41, diphenhydramine (Benadryl ) is an older antihistamine that exhibits considerable sedating side-effects. Analogs 42 to 44 (fexofenadine (Allegra ), loratadine (Claritin ), cetirizine (Zyrtec ), respectively) are newer, nonsedating antihistamines. Many of the newer agents are now thought to be good substrates for P-glycoprotein (Pgp), which is situated within the BBB and serves to pump drugs out of the CNS and into the cerebral circulation (brain capillaries).

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