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    Capítulo 37 - Antihistaminicos

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    37. Antihistamines and Related Antiallergic and Antiulcer Agents WENDEL L. NELSON DruGs COVERED IN THIS CHAPTER: ANTIHISTAMINES * Levocetitiine * Famotidine *# Activastine + Levocobastine + Lansoprazole + Avelasine * Lodoxamide © Metoclopromide © Carebastine * Loratadine + Misoprostol ° Cetirzine * Mizolastine * Nizatidine * Cromolyn * Nedocromil + Omeprazole + Desloratadine + Olopatadine Saeed * Bhastine * Pemirolast © Rabeprazole * Emedastine + Terfenadine . + Fpinastine ANTIOLEER AGENTS + Sucralfate * Fexofenaine «Cimetidine + Ketosifen + Esomeprazole INTRODUCTION novel H, receptor also been described where histamine , - . tates the synthesis and release of other proinflam- Histamine [2-(imidazol4-y))ethylamine] was synthesized matory mediators and modulates the chemotactic and its effects in model biological systems were studied before it was found physiologically. Its synthesis occurs in many tissues, including mast cells, parietal cells of the gastric mucosa, and neurons of the central nervous s}s- tem (CNS) and the periphery. Early hypotheses about its physiological function were based on the observed, dra- matic effects of histamine in guinea pigs. These effects include massive bronchial spasm and effects on smooth muscle and the vasculature that resemble anaphylactic shock. Marked species differences in the observed effects occur, however, and these dramatic effects are not observed Histamine is located in many tissues, and on release, its effects are principally local ones, because it functions as an autocoid or paracrine (1). Its physiological func- tion is complex and not completely understood. Hista- mine is one of the many mediators involved in allergic inflammatory responses, and it has an important role in regulating the secretion of gustric acid. These observa- tions have led to development of many important drugs that antagonize its effects and are useful in treatment of allergic inflammatory disorders (H, antihistamines) and in the treatment of gastric hypersecretory disorders (Hy antihistamines). Besides its role in allergic inflammatory processes and gastric acid secretion, a physiological role at axons in se eral regions of the CNS has established its role in the reg- ulation of sleeping and waking, in energy and endocrine homeostasis, and in cognition and memory. Histamine modulates the release of neurotransmitiers via Hy auto- and heteroreceptors located at histaminergie and non- histaminergic neurons both centrally and peripherally. A 1004 humans. responses, principally at mast cells and eosinophils. CHEMISTRY Histamine has pK, values of 5.80 (imidazole) and 9.40 (aliphatic primary amine) (2). At physiological pH, it exists as an equilibrium mixture of tautomeric cations, with the monocation making up more than 96% of the total and the dication approximately 3%, with only avery small amount of the nonprotonated species. At lower pH values (e.g. the pH of acidic lipids), a much larger pro- portion of the dication exists. The two protonated species (mono- and dication) often are considered to be the biologically active forms. Penetration of membranes by histamine would be expected to occur via the nonpro- tonated species, and the unprotonated imidazole grou ‘would be expected to participate readily in proton-trans- fer processes physiologically. Several aromatic ring con- geners of histamine with weakly and very weakly basic heteroaromatic rings (cg. 4chloroimidazole, 1,2, azole, thiazole, and pyridine) exhibit histamine agonist activity (Table 37.1) (3), although they are less potent than histamine. These data suggest that the monocation (protonated aliphatic amine) is sufficient for agonist activity and that protonation of the heterocyclic ring is not an absolute requirement. In aqueous solutions, the tautomeric equilibrium of the idazole ring apparently favors the N’-H tautomer by approximately 4:1. The free base also prefers the N-H tau: tomer. In the erystalline form of the monohydrochloride salt of histamine, however, where intermolecular crystal 1006 PARE / PHARMACODYNAMIC AGENTS Table 37.1. Histamine-Related Agonists* FelaiveHy Relive He Relative Hy activity vs. activity vs. activity vs. Netnieo __hicamioe__Nlanioe “oC 100 100 100 wh oo A "rk 17 @ No® we , woh mw 0.23 cd <0.008 ™ ato ar 197 No B we a6 -03 0.008 i 0.01 04 No 1 25 095 v Ne 88 Me CO tn te 0 "hehe epresedolatve ohistanine = 101, deemed iro on ona pig tam (PrLgutea par (Hard vt coretral cart) ‘This conversion is catalyzed by t-histidine decarboxylase, with pyridoxal phosphate serving as a cofactor for this process. The reaction mechanism for this decarboxyia tion probably involves the formation of an imine inter- mediate, followed by the loss of carbon dioxide, a mechanism demonstrated to occur for decarboxylation ‘of many e-amino acids (Fig. 37.2). Pyridoxal phosphate provides an important catalytic function, and in the final step, the product is released by hydrolysis of the enzyme- bound Schiff base of histamine. Mechanism-based inhibitors of this process, such as a-fluoromethylhistidine, decrease the rate of synthesis of histamine and, thus, deplete cells of histamine. As such, a-fluoromethylhis dine is an important pharmacological tool (4). This approach, however, has not been successfully developed into agents for the treatment allergic inflammatory dis- orders, peptic ulcer, or motion sickness. ‘Once released, histamine is rapidly metabolized vivo (based on products from radiolabeled histamine administered intradermally) to nearly inactive metabo- lites by two major pathways: N-methylation, and oxida- tion (Fig. 37.3). Methylation (S-adenosylmethionine), which is catalyzed by the intracellular enzyme N-methyl. transferase, yields an inactive metabolite, A portion of the Nmethyiated metabolite is oxidized sequentially via Fig. 37.2, Formation of histamine by decarboxylation of histidine monoamine oxidase and then via aldehyde oxidase to the corresponding N-methylimidazole acetic acid, Hista- mine also is oxidized to imidazole acetic acid by diamine oxidase (histaminase). A small amount of this acid inter. mediate is converted to the corresponding ribotide, an unusual metabolite (5) Storage and Release of Histamine In mast cells, histamine is stored in secretory granules as a complex with acidic residues of the proteoglycan heparin and in basophils in the blood as a complex with chondroitin sulfate (6,7). Mast cells are distributed in areas of skin and mucous membranes of the respiratory, gastrointestinal, and genitourinary tracts and. adjacent to blood and lymph vessels, Although histamine is secreted at low levels from these mast cells and basophils, the primary mechanism of release is associated tion by immunoglobulin (IgE)-mediated hypersensitivity processes (Fig. 37.4). Immediate hyper- sensitivity is initiated when allergen molecules crossdink to Fab components of adjacent IgE. antibody molecules bound to highaffinity FceRI receptors on the surface of these cells (FeeRI* cells). Dimerization of occupied IgE: Fe receptors results in several membrane and cytosolic events. These include release of preformed mediators yrighted material (CHAPTER 37 / ANTIHISTAMINES AND RELATED ANTIALLERGIC AND ANTIULCER AGENTS, 1011 an ether oxygen atom in the ethanolamine ether series, or only a carbon atom in the alkyl amines. The spacer usually is wo or three carbons in length, and it may be in arring, may be branched, and may be saturated or unsat- urated. The R groups attached to the aliphatic amine usually are simple alkyl groups, generally methyl or, occa~ sionally, aralkyl groups. One of the early thiophene-con- taining analogues was carcinogenic in rats. After thiophene versus benzene replacement in other series of ‘compounds demonstrated some toxic effects, thiophene ‘was relegated to one of the low-priority choices for isos. teric replacement of a phenyl group. Most H, antihistamines are inverse agonists rather than neutral antagonists. Like other histamine receptors, H, receptors have constitutive G protein-coupled activity in the absence of the agonist histamine that results in activation of second-messenger signaling pathways, such as phospholipase activity and NFkBmediated gene transcription (19). A model of active and inactive confor- mations of histamine receptors has been advanced to accommodate these biochemical findings. Inverse ago- nists bind to the inactive conformation of the receptor, shifting the equilibrium toward the inactive state. Neuw- tral antagonists interact with both conformations of the receptor. First-Generation H, Antihistamines Ethylenediamines ‘The earliest series of H, antihistamines is the ethylenedi- amines. Two 2-carbon spacers may appear between the two nitrogen atoms in the piperazine series (vide infra). Examples of agents in the ethylenediamine class. of which phenbenzamine was the first of these agents, appear in Table 37.2. Compounds with several different but closely related aromatic rings are useful, such as phenyl, 2pyridyl, halogen- and methoxy-substituted phenyl, or pyrimidyl. Thiazole-, furanyl, and thiophene- ring congeners also were available in the past. The small alkyl substituents on basic nitrogen usually are methyl ‘groups. A number of these agents are still used. With the ‘exception of antazoline, all have the ethylenediamine spacer. In antazoline, the alkyl tertiary amine in phen- benzamine is replaced with an imidazoline group. Cen- tral nervous system effects, usually sedation, are very ‘common among agents in this class. Information regarding pharmacokinetic and met bolic disposition is limited, because this early group of ‘compounds was notstudied in depth. Only later, with sec- ‘ond-generation H, antihistamines, and /or when issues of potential toxicity have arisen concerning some of the early compounds, has the metabolic disposition been ‘examined more completely. Thus, the available informa- tion concerning the metabolism on these early antihista- mines is sparse. From some of the ethylenediamines, expected products of N-demethylation and subsequent deamination have been reported. In addition, some produce quaternary Nglucuronides as urinary metabo- Table 37.2. Examples of Ethylenediamine Anthistamines ” Gee Xho . ws ongs xy ne Prenberzaring cH cH Tipelenramine Gowen 8 verapyiere wk Tromyening NN owoXT)= Related compound: lites, a process that occurs, to some extent, in many rela- tively unhindered tertiary aliphatic amines among the antihistamines.and also in other lipophilic aliphatic te ary amine drug classes. Ethanolamine Ethers STRUCTURE ACTIVITY RELATIONSHIPS. The prototype of the aminoalkyl ethers is diphenhydramine, a benzhydryl ether which more than a half-century after its introduc- tion remains still widely used for allergic conditions, Structural analogues with various ring substituents (Me, ‘OMe, Cl, and Br) in one of the aromatic rings also have heen developed. as have compounds with a 2-pyridyl group replacing one of the phenyl groups (Table 37.3). Significant anticholinergic side effects are observed among members of the group (€.g.. dry mouth, blurred sision, tachycardia, urinary retention, and constipation). It should be noted that diphenydramine is used in the treatment of parkinsonism because of its central anti cholinergic properties. Other anticholinergic agents that are structurally related to the benzydryl ether antihist mines also are used in the treaument of parkinson (see Chapter 25). Sedative properties are very common as well. Sedation, accompanied by a short halFlife and a wide margin of safety, allows some of these compounds to be used as OTC sleep aids. The &chlorotheophyllinate salt of diphenhydramine is marketed as dimenhydlrinate for use in the treatment of motion sickness. The com- pound with the aryl groups pCIPh and 2pyridyl is carbinoxamine, a potent antihistamine. Substitution of a methyl group at the carbon « to the ether function affords the related compound doxylamine, in which the aryl groups are phenyl and 2pytidyl. Clemastine, a yrighted material 1012 PART Ill / PHARMACODYNAMIC AGENTS Table 37.3. Ethanolamine Ether Antihistamines Cs oS ons G Drugs Trade Name Ry Re X Dipherhydiamine Benadryl «=H HGH Dmenhycrinaio Dramamine ‘Bromodiphenhydramine 8 oH oH Chiorodiphenhydramine aH oH Carbinoxamine Costin a ow oN Dowylamine Decapyn HH N Unisom’ Related compounds: GH arene pomfn0 Setastine (Loderix) homologue with an additional carbon atom between the ‘oxygen and the basic nitrogen, which is incorporated into a ring, is a recent addition to the group, with less sedative properties. Other analogues are used elsewhere. For example, setastine,a compound with the alkyl amine substituent being incorporated into a 7-membered hexa- hydroazepine ring, is available in Europe. ANTIHISTAMINIC VERSUS ANTICHOUNERGIC ACTIVITY. Besides the structural analogues in Table 37.3 that possess increased selectivity for histamine H, receptors over mus- carinic receptors, introduction of alkyt substituents at G2" or’ of one aromatic ring results in significant changes in selectivity in tissue-based assays for antihistaminic ver- sus anticholinergic activity. With increasing alkyl group size (Me, Et, iPr, and tBu) at C2’, large decreases in anti- histaminic activity and inereases in anticholinergic activity are observed (20). With larger alkyl groups, the possible spatial orientations of the two aromatic rings with regard to each other are limited because of increasing rotameric restrictions. Introduction of these alkyl substituents at C4" decreases anticholinergic activity and yields small increases in antihistaminic activity. A chiral center duced with these changes, and differences in pharmaco- logical properties of the enantiomers of each compound are observed. Two examples are shown in Table 37.4. ‘STEREOCHEMICAL AND STRUCTURAL EFFECTS. The observed differences in potency of enantiomers in tissue-based assays suggest significant stereoselective interactions of antagonists at the receptor level. Differences in affinity of 60- to 200-fold are noted between enantiomers in several Table 37.4. Antihistamine and Anticholinergic Activity of Enantiomers of Ring Substituted Ethanolamine Ethers (20) (iy a R om chy Anthistaminic Acivity Antichotivergic Actviy Ratio of Ratio of Potency of Pasoney of (10 oC) pe Llnee” poe Sor” were 78 eu 18 Geer Ose 4 CH (4/636 2.3 (46.03 0.008 (ers ‘Most potent enantoner in each assy ‘(-}Esantameris ~125 mes as pont asthe (+}-erantomer analogues where the chiral center results because of dif. ferences in the two aromatic rings, such as Ph and 2- pyridyl, or Ph and pBrPh (21). Enantiomers with the Sabsolute configuration usually are more potent Clemastine, a more complex homologue, the R.Renantiomer, which is the more potent of the RR and S,Senantiomeric pair and more potent than either the RS and SRenantiomers of the other diastereomer (22). Consistent with results from related compounds, the chiral center at the benzhydryl carbon has a signifi- cant influence on potency, whereas the one in the pyrro- lidine ring is of lesser importance (Table 37.5). Very small changes in the arrangement of aromatic groups in the members of the ethanolamine ether series significantly alter the scope of their pharmacological properties. Previous work has shown that the two aro- matic rings in diphenhydramine can be located slightly differently with respect to each other, as in phenyltolox: amine, a potent antihistamine. A retro arrangement of carbon and oxygen atoms, however, prepared in an narketed as Table $7.5. Antihisiamine Activity of Stereoisomers of _____Glemastine (22) Be Drug Disstereorners EDset Clemastine (R.R) 945 0.04mgkg ss) 793 50 RS) 940 0.28 sR) 857110 "Edin vi. fetal done of hstanine n gunea os (2) yrighted material (CHAPTER 37 / ANTIHISTAMINES AND RELATED ANTIALLERGIC AND ANTIULCER AGENTS. X=C, CH,N, etc. Y = CH, S,0, NH, CH.O, a CH,CH,, CH=CH, etc. Cae Saver = two orthree carbons A, Re = Me, or five membered ring Fig. 37.11. General structure of tricyclic antihistamines. carbons long, unbranched, and usually, without sub- stituents in the aromatic ring. Besides useful antihista- minic effects, most have pronounced sedative effects and long durations of action. Other uses include the treat- ment of nausea and vomiting associated with anesthesia and for the treatment of motion sickness. CONFORMATIONAL AND STEREOCHEMICAL EFFECTS. In the active agents, the steric restrictions and decreased degrees of conformational freedom resulting from the connection of the two aromatic rings together suggests that certain spatial relationships between these two rings are acceptable in the drug-receptor interaction of H, antihistamines. These ring systems are not flat but, rather, are somewhat puckered, with the two aromati rings not in the same plane. Usually, however, the con- formations undergo rapid intraconversion. In some closely related systems, in which this intraconversion is very slow, conformational enantiomers (atropisomers) have been obtained and studied, including cyproheptadine, doxepine, and hydroxylated metabolites of loratadine (27,28). The enantiomers of $-methoxycyproheptadine have significantly different pharmacological potency as ‘Table 37.7. Examples of Tricyclic Antihistamines. ODD Droge Tadenare Y 2 a Promethazine Phenergan S — NYPHoy, be Pyrathiazine s yA ‘Trimeprazine Temas sy bon Notriacne Team 8 SQ “ot W or ba Cyprchepiadine (Periactin) _Azatatine (Optimine) 1015 antihistamines, antiserotonin, and anticholinergic agents (Fig. 37.12) (29). The (—)isomer retained antihistaminic antixerotonin, and appetite-stimulating effects similar to yproheptadine, whereas the (+)-enantiomer had greater anticholinerigic potency. Differences of ¥- to 60-fold have been observed in the reported assays. Promethazine, an early agent in the series, has many usefull pharmacological affects other than being an anti amine. It has significant antiemetic and anticholi gic properties. It also has sedative-hypnotic properties and has been used to potentiate the effects of analgesic rugs. Subsequent analogues, such as trimeprazine and methdilazine, are used as antipruritie agents in the treat- ‘ment of urticaria. Compounds in which the sulfur atom is replaced with another bridge (e.g., two methylene groups) also are avail- able. Some have a pyridine ring replacing one of the ber zenoid systems. Cyproheptadine, with a 2carbon spacer between the aromatic rings, also has anticholinergic, anti serotonergic, and appetite-stimulating properties, which are useful in treatment of anorexic nervosa and in cachexia. The pyridine analogue apparently lacks most of these qualities. Doxepine, an oxygen-containing congener of cyproheptadine, also has significant affinity for other receptors, and it has CNSlepressant qualities. Itexistsas a mixture of Z- and isomers (15:85) in its olefinic, non- piperidine side chain, In tissuebased assays, the is more potent than the Eisomer by more than threefold (27). The most widely used among the group is loratadine, which is considered to be in the category of nonsedating, second-generation antihistamines (vide infra). Metasousm. Information regarding the metabolic dis position and pharmacokinetic properties of agents in this group is limited, including incomplete identification of primary metabolic pathways, results of liver microso- mal metabolic experiments, and only occasionally, phar- macokinetic information. In humans, products from the ‘OCH, . 4 HN Nenplarar dbenzieyconeptene N74 7 N Nonpanaribenyleroheptare Fig. 37.12. heptadine Enantiomers (antropisomers) of 3-methoxycypro. yrighted material 1016 PART lll / PHARMACODYNAMIC AGENTS phenothiazines include products of Nelemethylation, aromatic hydroxylation, and occasionally, sulfoxidation. From tricyclic analogues, metabolites resulting from N- demethylation, aromatic hydroxylation, and formation ‘of N-quaternary glucuronides have been reported (30). ‘Second-Generation Nonsedating H, Antihistamines Background The secondgeneration antihistamines marketed over the last 20 to 25 years have improved Hj selectivity, have little or no sedative qualities, and they may have antial- lergic effects apart from antihistaminic activity (31). They vary widely in structure (Table 37.8) but less so in pharmacological properties, having effects principally in the periphery. Structural resemblance to the firstgenera- tion H, antagonists is not always obvious. because some of these agents were discovered while investigating new molecular structures for other pharmacological targets. ‘These agents possess selective peripheral Hy antihista- minic effects, and they usually have less anticholinergic Furthermore, they also have decreased affinity for adrenergic and/or serotonergic receptors and lim- ited CNS effects. The active agents apparently do not penetate the blood-brain barrier significantly, perhaps because of their amphoterie nature (most are zwitteri- onic at physiological pH) and partitioning characteristics and/or because they are substrates for the drug efflux P-glycoprotein transporter or organic anion transporter proteins. A slow rate of dissociation from Hy receptors also is reported for some of the agents. Several have antiallergic properties that are separate from their anti- histaminic properties, which are not thoroughly under- ‘Table 37.8. Second Generation Non-sedating Anti stood. In most cases, the parent drug or its important metabolites have haltives that are sufficiently long to account for the extended duration of action (32). Most are administered once daily. Specific Drugs FEXOFENADINE (ALLEGRA) AND TERFENADINE Pharmacological Effects. This group of nonsedating an histamines usually is thought to include fexofenadin and its parent terfenadine, astemizole, cetirizine, and loratadine and its metabolite desloratadine. Terfena- ine was synthesized as an analogue of azacyclanol in a search for antipsychotic agents. The initial reports of its antihistaminic properties included the observation of similar effects of it acid metabolite fexofenadine (88). ‘Whereas terfenadine is no longer available, itwas once a very widely used nonsedating antihistamine, Extensive clinical experience resulted in the reports of dangerous cardiac arrhythmias occurring occasionally when ceria other drugs were taken concomitantly. These cardiac arrhythmias included prolongation of the QT interval and torsades de pointes, a life-threatening ventricular arrhythmia. These cardiac effects are now known to be h blockade of the HERG (h go-go) gene product, the e-subunit of an ing cardiac K* channel (84,35). These effects are associated only with the parent molecule. The side effects occur primarily at high concentrations of this lipophilic amine and, usually, in the presence of other CYPSA4 substrates, such as ketoconazole or macrolide antibiotics (e.g., triacetyloleandomycin). In the pres- ence of competing CYP3A4 substrates and inhibitor associated ihistamines Tertenadine (R = cH) Fexofenadine (R = COOH) ‘Muzolasune Nor Desloratadine (F = H) Loratadine (R = COOCHECH: ) Qo oF oO gro , SC pcrivastine Ebastine (A =CH,) Carebastine (A = C0oH) yrighted material (CHAPTER 37 / ANTIHISTAMINES AND RELATED ANTIALLERGIC AND ANTIULCER AGENTS. Emadasine Assasine ‘ i : oy Ketotifen Epinastine histamine receptor affinity and a slow rate of receptor dissociation. The presence of the carboxylic acid side chain apparently is responsible for the observed lack of muscarinic receptor affinity. This feature also may be responsible for limited penetration. Olapatadine also a mast cell stabilizer as well. The mechanism for this activ- ty has not been delineated, but ithas been shown to sta- bilize model cell_ membranes by interaction with phospholipid monolayers. Levocosasnine (Livosmn). Levocobastine is a potent, selective Hy receptor antagonist used topically in eye drops for seasonal allergic conjunctivitis. A small amount of systemic absorption of the compound is reported. The agent also prevents release of transmitters from mast cells. A nasal spray used for allergic rhinitis is available outside the United States. EmeDASTINE (EMADINE). _Emeciastine also is a newer anti- histamine used topically in the eye for conjunc! has very high H, receptor selectivity characteristics, and it is structurally related to the benzimidazoles, such as astemizole, Inhibition of mast cell release of inflamma- tory mediators has been noted. Azeiasmine (ASTEUN). Azelastine, although not a close structural analogue to the benzimidazoles, has some structural similarities to them, It is used as a nasal spray for allergic rhinitis and as eye drops for allergic con} tivitis. Like olopatadine, azelastine also stabilizes mast 1019 cells, preventing degranulation and subsequent release of histamine, leukotrienes, and PGD,. It is available in Europe for systemic use in the treatment of asthma and seasonal allergies. Besides antihistaminic effects, it also may block release of histamine and other inflammatory mediators from mast cells. When administered orally, the Nedealkylated metabolite appears to contribute signifi cantly to its pharmacological effects. KeromiFen (ZaorToR). Ketotifen is a potent, selective Hy antihistamine that also prevents release of transmitters from mast cell. It is approved in the United States for topical use to prevent itching of the eye because of aller gic conjunctivitis, It is used as a systemic antiallergy agent in several countries outside the United States for the treatment of seasonal allergic rhinitis, hay fever, and asthma. Being structurally analogous to the cyprohepta- dinedike antihistamines, differences in activity of the two enantiomers (atropisomers) has been noted, being approximately six- to seven-fold in ligand displacement and rodenthased assays (44). Ketotifen has been shown to stabilize mast cells and to inhibit degranulation of cosinophils. Like olopatadine, it has been shown to inter- act with model membranes, stabilizing them by interac tion with phospholipids monolayers Epiastive (Etestat). Epinastine isa potent, long-acting 1, antihistamine and an inhibitor of the release of hista- mine and other transmitters from mast cells. It has some affinity for Hy receptors as well. It is used as an eye drop for allergic conjunctivitis. It does not penetrate into the CNS and is classified as a nonsedating antihistamine. Antiulcer Agents Background The secretion of gastric acid occurs at the level of parietal cellsof the oxyntic gland in the gastric mucosa (Fig. 37.17), producing 2 t0 3 L of gastric juice per day, pH 1 in hydrochloric acid. Ultimately, this secretory process occurs via an H*K*-ATPase that exchanges hydronium ion (H,O*) with uptake of a potassium ion. Several mediators regulate this secretion by way of receptor systems on the basolateral membrane. The Hy histaminergic pathway is cAMP dependent. Gastrin and muscarinic receptors also regulate the secretion of gastric acid through calcium ion dependent pathways. In parietal cells, E-series prostaglandins work in opposition to the histaminergic pathway, inhibiting histamine-stimulated adenylyl cyclase activity. Otherepithe- lial cells in the mucosal lining under the influence of prostaglandin-mediated pathways secrete bicarbonate and mucus, both of which are important in protecting the gas trie lining from the effects of acid secretion, In many cases, hypersecretion of gastric Helicobacter pyloniinfection, " in mucosal protective defenses. Evidence suggests that some Hy antihistamines, particularly cimetidine and ranit ine, have regulatory effects on Teell lymphocyte prolifer: ation by augmenting cytokine production and Ig yrighted material CHAPTER 37 / ANTIHISTAMINES AND RELATED ANTIALLERGIC AND ANTIULCER AGENTS, Table 37.10. H, Receptor Antihistamines R Rac wey Drug Tradename x Y Burimamide | 4 ow Ss Gimeiidine Tagamet CH s Metiamide os s 8 Drug Ranitdine Nzatdine Aid a ee Famotidine (Peocid) ‘Merasousm. ine, and famotidine are subject to first-pass metabolism, and each has oral bioavailability of approximately 50%. The oral bioavail- ability of nizatidine is approximately 90%. All have half lives of 1.5 to 4.0 hours, with that of ne being the shortest. Significant amounts of each of these Hy antihis- tamines are excreted unchanged, with small amounts of urinary products of sulfoxidation being a common meta- bolic feature. As expected, hydroxylation of the imida- zole C-4 methyl group of cimetidine occurs. Ranitidine is excreted largely unchanged, but minor metabolic pathways include Nelemethylation aswell as N-and Soxidation. The metabolites are not thought to contibute 1 the thera- peutic properties of the parent drugs, with the exception of nizatidine, from which the Nelesmethy! metabolite retains Hi antihistamine activity (47) SIDE EFFECTS AND DRUG INTERACTIONS. earliest of these agents, shows the greatest number of drug interactions (48). Among them are somnolence and confusion in elderly patients with decreased renal function. Gynecomastia, presumably related to increased prolactin secretion, has been reported. Cimetidine inhibits CYP450-dependent metabolic processes, afford- ing increased concentration of several agents, the most ‘important being those having narrow therapeutic con- centration windows (e.g., phenytoin, theophylline, some benzodiazepines, warfarin, and quinidine). Inhibition of 1021 several CYP450 oxidative processes is associated with the presence of imidazole ring of cimetidine, which appar- ently replaces the histidine that serves as a ligand to the porphyrin iron in CYP450 enzymes. Other agents in this group contain heterocyclic rings other than imidazole and do not show this effect. Cimetidine is an inhibitor of renal tubular secretion of some drugs (e.g, pro- cainamide), These tubular secretion effecis also are less prevalent or even absent with other agents in this class, The other agents in the group are more potent than metidine, and significant differences are noted among them. Of these, ranitidine is the most widely used. The agents have OTC status and are widely available for gas- tric hyperacidity. Proton Pump Inhi Proton pump inhibitors are widely used in the treatment ‘of duodenal and gastric ulcer, erosive esophagitis, GERD, GERD-related laryngitis, and hypersecretory conditions (c.g. ZollingerEllison syndrome) (49,50). The final step in acid secretion in parietal cells of the gastric mucosa is a process mediated by H”,K”-ATPase, the gastric proton pump, an enzyme with significant homology to Na* K"- ATPase. This H*,K*-ATPase has some similarities to the H*K"ATPase in osteoclasts, which is involved in bone resorption. Gastric acid secretion can be inhibited i many ways. These include by antagonists at muscarinic, gastrin, or histamine Hy receptors; by agonists at inhibitory receptors for prostaglandins and somatostatin; by proton pump inhibitors: or by carbonic anhydrase inhibitors. itors MECHANISM OF ACTON, Omeprazole, lansoprazole, and related analogues (Table 37.11), produce inhibition of stimulated gastric acid secretion irrespective of the recep- tor stimulation process. Nearly all the compounds are close structural relatives, being weakly basic 2-pyridyl methylsulfinylbencimidazoles. An analogue, tenatopr zole, which is an imidazopyridine isostere, is currently linical trials. Table 97.11 “ATPase Proton Pump Inhibitors OF f ong sN chiral corter Drugs name XP; Pe Re Omeprazole Prilosec CH-OCH, CH CH oH Esomeprazole Nexum C4 OCH, CH CHy Hy G-onantiomer) Tenaioprazole N 00H, cH, oH, Hy Lansoprazole Prevacid CH H Cy CHC, oH Rabeprazole Acighex CH H CH, (CH)LOCH, 4 Pantoprazole Protonix CH OCH, OCH, Gly 4 yrighted material (CHAPTER 37 / ANTIHISTAMINES AND RELATED ANTIALLERGIC AND ANTIULCER AGENTS. COMBINATION THERAPY IN HIELICOBACTER PYLORI INFECTIONS. ‘The majority of peptic ulcers are related to H. pylon infec- tions and nonsteroidal antiinflammatory drug (NSAID) therapy. Helicobacer pylor apparently penetrates the layer of gastric mucus by producing ammonia and carbon dioxide (urease-catalyzed hydrolysis of urea) to withstand the acidic environment of the stomach. More than 90% of patients with duodenal ulcer, excluding those with gastrinoma or taking NSAIDs, show the presence of H. pylori Determina- tion of H. pylor infection is routinely performed by meas- uring production of carbon dioxide (breath) or bicarbonate (blood) after oral administration of "'C-or “C- labeled urea. Endoscopic examination and antigen-based serological tests may be used as confirmation (58). Eradica- tion of 1. pylori markedly decreases the incidence of ulcer recurrence. Several regimens of antibiotic therapy, widely used with proton pump inhibitors or less commonly with Heantagonists, are effective. Double- and triple1004old) for Hy receptors than other histamine receptor subtypes (66). ‘A selective H, antihistamine has recently been reported, JNJ 7777120 (Fig. 37.22). It blocks many mediated functions, including histamine-induced chemotaxis in mast cells and eosinophils (67). Con ions in which Hy antagonists might be useful include autoimmune inflammatory and allergic disorders, including rheumatoid arthritis, asthma, and allergic rhinitis, Nasal stuffiness and blockage in allergic rhinitis, conditions that are poorly treated with Hy and Hy anti- histamines, suggest the possible use of Hyantihista in these conditions as well. 1026 PART Ill / PHARMACODYNAMIC AGENTS See Victoria F. Roche and S. Willam Zito BLis a71-yearcold financial advisor onvacation atthe Gulf Coast with his wife 0747 years. has been a therapeutic getaway, espe- cially for Mrs. BL, who lost her central vision to exudative macular degeneration 18 months ago. While they hate to see their week of surf sun, and relaxation come to an end, they are really looking forward to the drive to Albuquerque they will begin tomorrow for the wedding of their only granddaughter. On ther last Gulf Shore night, they made reservations for a gala evening aboard the cruise ship Chichibabin, complete with dancing to the area's best Dix: ieland jazz band and a sumptuous buffet of Cajun foods. They had a ball, but unfortunately, BL experienced a severe allergic reaction to the crayfish he consumed (he ae two dozen) and had tobe taken off the ship co the emergency room, where he received an injection of hydrocortisone. Although he can now breathe eas- ier, he sil has a re, itchy, and unsightly rash on the upper half of hisbogy, including his arms, hands, and fac. n addition to being uncomfortable, heit worried about how heillook forhiegrand- daughter's big day. Before heading out on their drive to Albuquerque, BL and his wife stop at a local pharmacy for some calamine lotion and an antihistamine to keep BL comfortable on the trip. He will be behind the wheel the whole way, because his wife can no longer see well enough to drive. As the pharmacist on duty that day, co the antihistaminic structures below, and provide this couple with some much-needed pharmaceutical care 1. densify the therapeutic problems) in which the pharma- ‘sts intervention may benefit the patient, 2. Identity and prioritise the patient-specific Factore that must be consdered to achieve che desired therapeutic out- 3. Conduct a thorough and mechanistically oriented struc: ture-actsity nalyisofalltherapeutic altematves provided in the case. 4. valuate the structure-activty relationship findings against the patient-specific factors and desired therapeutic out ‘comes, and make a therapeutic decision. 5. Counsel your patient N te mm, Cron 7 foot O ro 2 : a Wo Ge g. c wt yn fren ocr-onon ‘ 5 1. Babe KS), Serafin WE. Histamine, brad Haréman JG, Limbird LE, Molino PB, etal editor. Geodman and 2, Gooper DG, Young RC, Durant J, ta Himamin receptors In Ene JC fd. Comprehensive Medicina Chemisuy. The Rauonal dgn, Mech Stay and Thera of Chemie compounds, ol Mee sane Re pn Press: 1990343421 Mistamine Hyecepor ragoniss ts ‘Wolf ME ed, Barge’ Medicinal Chemty and Deng Dincovery. 5th A New ork John Wily & Sons, 197495559, 4. Watanabe T. Yamatodani A. Maevama K, ct al. Pharmacology of «= uoromenyfhstdine, aspect inhibiorofhistcine decarbowlase Trends Pharmacol Sct 199011: 958-857 5. Schaer RC, Coope JAD. Membotam cf “Chisamine in man, J Appl Phyl 1oseo-a8\—a8, Genovese A, Grinaa F, etal Pharmacdlogial modultion of ‘Clin Exp Aen 20028-18168, ‘immunologically meatd signaling in ascot Terapeute eget for alerge dseases it the human Fed] signaling pathway. nmunopharmacolegy 200; 200 2 8. Ghuseh MK, SnuteJR, Jensen HM Mas: cellderited meiaors In: Adkinon NE Tangaer JW. Busse WW, et al, ed. Middleton's Mery: Pancpls and Pracce 6h EA. PHladlphi: Mosby: 2008189-212. 8. GoctaF. Lipid mediators of hypersensitty and inflammation In: Adlnson [NF unginer JW: Buse WW, etal, ed Middleton’ Allergy: Principle and Petice th Pl Pilaelphia: Moy, 2008:213-280, 10, Holgate ST, Robinson C, Church MKC Medatorof immediate hypesensivin fs Alergy: Prinilesand Practice ih Ea St Louis Moy, 198:257 92 11, Daher RA, Timmerman H, Leas R. Hisamine recepeor: specie Hinds 12 Laur R Smet Mj. Tinmerman H. Molec pharmacological aspects hie ‘amine receptors Pharmacol Ther 1995:5:415-463. 18, Leary, Balker RA Timmerman H, de Esch IP. The hisamine Hy receptor from gene caning to My receptor drags. Nature Rey Drag Dicovery 205: aii. ‘Adkinson NF, Yunginer JW, Base WW, etl, et Midleton’ Allergy rin ples and Practice 6th Ed Philadephia: Mosby, 2008015027 ‘Gook HB, Sah! JL, Barney NP, Graziano FM. Mechanisas of antistanines ‘Online 20081.888-847 Fomeaa E, BovetD, RecherchessurTacion sypmathicoheique d'un now

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