Antihistamines, metabolism

Yet another nonsedating zwitterionic H-1 antihistamine consists of the product from metabolism of the terminal hydroxyl of the potent antihistamine hydroxyzine terminating in hydroxymethyl instead of a carboxylic acid. This compound, cetirzine (123), can be obtained in straightforward fashion by alkylation of the monosubstituted piperazine 120 with halide 121, via the amide 122 [27]. 

The latter approach is used in the enantioselective determination of a Phase I metabolite of the antihistaminic drug, terfenadine. Terfenadine is metabolized to several Phase I compounds (Fig. 7-13), among which the carboxylic acid MDL 16.455 is an active metabolite for which plasma concentrations must often be determined. Although terfenadine can be separated directly on Chiralpak AD - an amy-lose-based CSP - the adsorption of the metabolite MDL 16.455 is too high to permit adequate resolution. By derivatizing the plasma sample with diazomethane, the carboxylic acid is converted selectively to the methyl ester, which can be separated in the presence of all other plasma compounds on the above-mentioned CSP Chiralpak AD [24] (Fig. 7-14). Recently, MDL 16.455 has been introduced as a new antihistaminic drug, fexofenadine. 

Profuse or prolonged vomiting can lead to complications of dehydration and metabolic abnormalities. Patients must have adequate hydration and electrolyte replacement orally (if tolerated) or intravenously to prevent and correct these problems. Some pharmacologic treatments work locally in the GI tract (e.g., antacids and prokinetic agents), whereas others work in the central nervous system (e.g., antihistamines and antiemetics).1... 

Clemastine, an antihistamine closely related to chlorphenoxamine in which the dimethylamino group is replaced by 1 -methylpyrrolidin-2-yl, appears to be comparable in stability to chlorphenoxamine. Indeed, cleavage of the ether was the dominant feature of metabolism in humans [51] [52], and, in fact, all metabolites recovered in humans were either the benzhydrol analogue or products of its further biotransformation. Here again, the ether cleavage pathway may be entirely or only partly nonenzymatic, although the extent of the reaction suggests an enzymatic contribution. 

Matsumoto S, Hirama T, Matsubara T, Nagata K, Yamazoe Y. 2002. Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, astemizole. Drug Metab... 

Histidine is characterized by a heterocyclic side chain known as imidazole. The imidazole group will bear a positive charge under physiological conditions. Histidine is the metabolic precursor to histamine, a potent inflammatory molecule. Antihistamines work by antagonizing the action of histamine. 

Antihistamines, nonsedating/Cisapride/Pimozide- Cisapride and pimozide are metabolized by the cytochrome P-450 3A4 isozyme inhibitors of 3A4 can block the metabolism of these drugs, resulting in increased plasma concentrations of parent drug, which is associated with QT prolongation and with rare cases of serious cardiovascular adverse events, including death, because of ventricular tachycardia of the torsades de pointes type. In vitro, nefazodone inhibits 3A4. It is recommended that nefazodone not be used in combination with cisapride or pimozide. 

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). 

Tricyclic antidepressants are notorious for their risk to be involved in drug-drug interactions. Additive anticholinergic effects can be expected in combination with antihistamines, antipsychotics and anticholinergic-type anti-Parkinson agents. Hepatic enzyme-inducing agents increase their hepatic metabolism while enzyme inhibitors may potentiate the effects of tricyclics. Concomitant use with monoamine oxidase inhibitors will produce hypertension, hyperpyrexia and convulsions. 

The reduction in therapeutic effectiveness that can occur when antihistamines are given for long periods is probably related to an induction of hepatic drug-metabolizing enzymes. Children tend to eliminate antihistamines more rapidly than adults, while individuals with hepatic impairment may eliminate them more slowly. 

C. Histamine stimulates gastric acid secretion through an effect on Hj-receptors of gastric parietal cells. Although certain antihistamines are metabolized by cytochrome P450 enzymes, histamine does not induce their production. Histamine helps to maintain a wakeful state through an effect on Hj-receptors. Histamine-mediated hronchoconstriction is mediated by Hj-receptors, while histamine-mediated vasodilation occurs as a result of stimulation of Hi- and Hj-receptors. 

Nicolas JM. The metabolic profile of second-generation antihistamines. Allergy 2000 55 46-52. 

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. 

Mechanism of Action An antihistamine and anticholinergicthat competes for H,-receptor sites on effector cells of the G1 tract, blood vessels, and respiratory tract. The anticholinergic action diminishesvestibular stimulation and depresses labyrinthine function. Therapeutic Effect Prevents symptoms of motion sickness. Pharmacokinetics Well absorbed following PO administration. Metabolized in liver. Excreted in urine. Half-life Unknown. 

Geriatric Considerations - Summary One of the least likely antihistamines to cause CNS effects. No dose adjustments required in older adults with decreased renal function. Slow metabolizers likely to experience increased side effects and anticholinergic effects. Increased risk of sedation at higher doses. 

Olanzapine is metabolized by several pathways and is therefore unlikely to be affected by concurrent administration of other medications. Because olanzapine does not appear to inhibit any cytochrome P450 enzymes, it should not increase the availability of other medications through inhibition of such enzymes. Additive pharmacodynamic effects are expected if olanzapine is combined with medications that also have anticholinergic, antihistaminic, or aj-adrenergic side effects. 

Quetiapine is metabolized by hepatic CYP 3A3/4. Concurrent administration of cytochrome P450-inducing drugs, such as carbamazepine, decreases blood levels of quetiapine. In such circumstances, increased doses of quetiapine are appropriate. Quetiapine does not appreciably affect the pharmacokinetics of other medications. Pharmacodynamic effects are expected if quetiapine is combined with medications that also have antihistaminic or a-adrenergic side effects. Because of its potential for inducing hypotension, quetiapine also may enhance the effects of certain antihypertensive agents. 

It is a cromolyn analogue. It is an antihistaminic (H antagonist) and probably inhibits airway inflammation induced by platelet activating factor (PAF) in primate. It is not a bronchodilator. It is used in asthma and symptomatic relief in atopic dermatitis, rhinitis, conjunctivitis and urticaria. It is absorbed orally and well tolerated. Bioavailability is 50% due to first pass metabolism and is primarily metabolized. The common side effects include dry mouth, sedation, dizziness and nausea. 

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). 

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