Antihistamines systemic

Miscellaneous Pharmaceutical Processes. Solvent extraction is used for the preparation of many products that ate either isolated from naturally occurring materials or purified during synthesis. Among these are sulfa dmgs, methaqualone [72-44-6] phenobarbital [50-06-6] antihistamines, cortisone [53-06-5] estrogens and other hormones (qv), and reserpine [50-55-5] and alkaloids (qv). Common solvents for these appHcations are chloroform, isoamyl alcohol, diethyl ether, and methylene chloride. Distribution coefficient data for dmg species are important for the design of solvent extraction procedures. These can be determined with a laboratory continuous extraction system (AKUEVE) (244). 

In connection with their medicinal applications and activities to the respiratory system they showed antiallergic (83EUP80176 85USP4528288), antihistaminic [73BBA(304)693 85GEP(0)3427823 86EUP181282 ... 

Of the several syntheses available for the phenothiazine ring system, perhaps the simplest is the sulfuration reaction. This consists of treating the corresponding diphenylamine with a mixture of sulfur and iodine to afford directly the desired heterocycle. Since the proton on the nitrogen of the resultant molecule is but weakly acidic, strong bases are required to form the corresponding anion in order to carry out subsequent alkylation reactions. In practice such diverse bases as ethylmagnesium bromide, sodium amide, and sodium hydride have all been used. Alkylation with (chloroethyl)diethylamine affords diethazine (1), a compound that exhibits both antihista-minic and antiParkinsonian activity. Substitution of w-(2-chloroethyl)pyrrolidine in this sequence leads to pyrathiazine (2), an antihistamine of moderate potency. 

Since many of the uses of antihistamines involve conditions such as rashes, which should be treatable by local application, there is some rationale for developing drugs for topical use. The known side effects of antihistamines could in principle be avoided if the drug were functionalized so as to avoid systemic absorption. The known poor absorption of quaternary salts make such derivatives attractive for nonabsorbable antihistamines for topical use. Thus, reaction of the well-known anti his-taminic drug promethazine (104) with methyl chloride leads... 

The discovery of the antiulcer activity of H2 antihistamine antagonists has revolutionized the treatment of that disease. A benzimidazole. Omeprazole (55), inhibits gastric secretion and subsequent ulcer formation by a quite different mechanism. Studies at the molecular level suggest that this compound inhibits K /H dependent ATPase and consequently shuts down the proton pumping action of this enzyme system. 

There is an increased central nervous system (CNS) depressant effect when the skeletal muscle relaxants are administered with other CNS depressants, such as alcohol, antihistamines, opiates, and sedatives. There is an additive anticholinergic effect when cyclobenzaprine is administered with other drugs with anticholinergic effects (eg, antihistamines, antidepressants, atropine, haloperidol). See Chapter 30 for information on diazepam. 

There is an increase in anticholinergic effects when antihistamines are administered with the monamine oxidase inhibitors (MAOIs) and additive sedative effects if administered with central nervous system depressants (eg, narcotic analgesics or alcohol). When cimetidine and loratadine are administered together there is a risk for increased loratadine levels. 

There is an increased risk for bone marrow suppression when levamisole or hydroxyurea are administered witii other antineoplastic dni. Use of levamisole witii phenytoin increases die risk of phenytoin toxicity. Pegaspargase may alter drug response of the anticoagulants. When procarbazine is administered with other central nervous system (CNS) depressants, such as alcohol, antidepressants, antihistamines, opiates, or the sedatives, an additive CNS effect may be seen. Procarbazine may potentiate hypoglycemia when administered witii insulin or oral antidiabetic dru . ... 

Unit V has three chapters concerning drugs that affect the respiratory system. The first chapter in this unit discusses antihistamines and decongestants, the second chapter in the unit covers bronchodilators and antiasthma drugs, and the last chapter of the unit deals with antitussives, mucolytics, and expectorants. 

Tharion, WJ, McMenemy, DJ and Rauch, TM (1994) Antihistamine effects on the central nervous system, cognitive performance and subjective states. Neurophsychobiol. 29 97-104. 

Johnson, H.G., McNec, M.L. and Nugent, R,A. (1992). Canine in vivo tracheal chemotaxis of eosinophils to antigen in sensitized dogs inhibition by a steroid, a systemic lazaroid U-78517F, and several topical HI antihistamines. Am. Rev. Respir. Dis. 146, 621-625. 

Because the vestibular system is replete with muscarinic-type cholinergic and histaminic (Hx) receptors, anticholinergics and antihistamines are the most commonly used pharmacologic agents to prevent and treat motion sickness. 

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... 

Antihistamines are commonly used to prevent and treat nausea and vomiting due to motion sickness, vertigo, or migraine headache.1,17 Their efficacy is presumably due to the high concentration of histamine (Hx) and muscarinic cholinergic receptors within the vestibular system. Similarly to scopolamine, antihistamines such as diphenhydramine and... 

Antihistamines and intranasal corticosteroids are considered first-line therapy for allergic rhinitis, whereas decongestants, mast cell stabilizers, leukotriene modifiers, and systemic corticosteroids are secondary treatment options. 

Pharmacotherapy has an important role in managing AR symptoms (Table 59-2). Intranasal corticosteroids, systemic and topical antihistamines and decongestants, mast cell stabilizers, and immunotherapy all are beneficial in treating symptoms of AR.9 Antihistamines and intranasal corticosteroids are considered first-line therapy for AR, whereas decongestants, mast cell stabilizers, leukotriene modifiers, and systemic corticosteroids are secondary treatment options10-12 (Fig. 59-2). Whenever exposure to allergens can be predicted (e.g., SAR or visiting homes with a pet), medications should be used pro-phylactically to maximize effectiveness.11... 

Locally acting antihistamines act more quickly than oral agents but need to be administered intranasally at least twice daily due to the potential for removal by nasal secretions.13 Azelastine, an intranasal antihistamine, is as effective as systemic antihistamines in the treatment of perennial and seasonal AR. 

Oral (Systemic) Antihistamines V V V First-line therapy... 

Azelastine acts locally to reduce the same symptoms treated by oral antihistamines it also may reduce nasal congestion to a greater extent. Azelastine is administered twice daily and has a rapid onset of action. Many patients managed with azelastine complain of bitter taste. Drowsiness also has been reported, likely due to systemic absorption.11-13... 

Intranasal anticholinergic agents (e.g., ipratropium) reduce the severity and duration of rhinorrhea but have no effect on other nasal symptoms.11,12,21 Ipratropium reduces cholinergic hyperreactivity and cholinergically mediated histamine- and antigen-induced secretion. Intranasal ipratropium acts locally, with only minimal systemic absorption. Clinical trials demonstrated that ipratropium bromide 0.3% reduced rhinorrhea in adults and children with PAR.11,12 Intranasal ipratropium is an option for patients in whom rhinorrhea is refractory to topical intranasal corticosteroids and/or antihistamines.8,12 Intranasal ipratropium is available only by prescription, and the dose is two sprays nasally two to three times daily.15 Adverse effects are minimal, but dry nasal membranes have been reported.11,12... 

There is still debate whether oral antihistamines control ocular allergy as well as topical antihistamines. Topical antihistamines are recommended before oral agent in step therapy because of the increased risk of systemic side effects with oral drugs. Additionally, topical antihistamines provide faster relief of ocular symptoms. Consider oral antihistamines... 

Of ultimate importance are the full reports of the clinical studies in humans and their results. These data will be treated statistically for their validity. The number of studies for a specific compound or combination of compounds will vary with the type of drug being tested, as will the number of tests needed to appraise relative or absolute safety and to clearly demonstrate efficacy. The basic requirement is the proof of safety and efficacy of the product being submitted under the NDA system. A drug that does not contribute to therapy, such as a new antihistamine that does not demonstrate greater safety or efficacy, or both, compared with drugs already on the market, will have a difficult or impossible time achieving approval. 

Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class. The earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class. Instead, the ring system is used as the aromatic nucleus for a nonsteroidal antiinflammatory agent. Preparation of 130 starts with formylation of the rather complex aniline 123. Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement. The sequence begins with formation of the anion on the amide nitrogen addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126. Rearomatization... 

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