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A Simple Question... Histamine

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A Simple Question... Histamine A simple question... How was histamine discovered ? • by chemical synthesis … • from the analysis of plant extracts (ergot fungus Claviceps purpurea) • from the analysis of animal tissues extracts • through none of these approaches Antihistamines 21/03/2010 1 Histamine ... obtained by synthetic chemist in 1907 …as a chemical curiosity … detection of an identical compound in an extract from ergot fungus … and shown to cause a marked vasodilatation a similar effect is seen with tissues extracts produces a similar picture as a very severe allergic reaction recognized as a "biological" molecule (and not a product from putrefaction in 1927 ... Antihistamines 21/03/2010 2 1 From histidine to histamine ... HN HN CH CH NH 2 2 CH2 CH2 NH2 N COOH N L-histidine decarboxylase First inhibitor tritoqualine of histmine action … commercialized in France (HYPOSTAMINE ) Antihistamines 21/03/2010 3 Localization of histamine total blood leucocytes mastocytes 1. blood plasma other leucocytes 2. tissues ... the word comes from ("histos" = tissue !!) • skin • lung • gastrointestinal tract • central nervous system Antihistamines 21/03/2010 4 2 Actions of histamine • of capillary permability and vasodilatation cutaneous rednesses signs inflammation • bronchoconstriction important with the guinea-pig but under H2 retrocontol in man • of HCl secretion (pariteal cells of the stomach) • neurotransmission awakening reactions, tachycardia, hypertension nauseas, vomitting migraines neurological and comportmental signs Antihistamines 21/03/2010 5 Rappel: les 4 types de réactions d'hypersensibilité Réaction de type I Réaction de type II: cytotoxique anaphylactique • médiée par les IgG et/ou les IgM • action directe sur une cellule cible allergène • implique le complément • lyse, phagoytose (anémie hémolytique, agranulocytose, thrombopénie) IgE • délai: 5-12h Réaction de type III: formation de complexes immuns mastocyte • dépôts dans les tissus avec réaction inflammatoire disséminée • activation du complément et libération de toxines des leucocytes libération d'amines • agrégation plaquettaire, microthrombonses… vasoactives dont • délai: 3-8h l'histamine Réaction de type IV : cellulaire • activation directe des cellules T • rhinite, conjonctivite, urticaire, • libération de cytokines et de TNFα asthme aigu, • induit typiquement des manifestations cutanées (bronchospasme), oedème (dermatite de contact, exanthèmes, eczema, …) • délai: endéans les 30 min • délai: 24 à 48h Antihistamines 21/03/2010 6 3 From histamine to anti-histamines ... ! r ea y N st la CCH H N H n 2 2 2 ee S N starting in the 40s ... CCN Building two aromatic rings CCN or get a rigidified structure with the same shape (tricyclic) ALL H1 antihistaminics Antihistamines 21/03/2010 7 Rationalization through a deep understanding of the receptor •H1 receptor – CNS action mediated by the phosphoinositides – périphery •H2 receptor – stomach action mediated by –lung cyclic AMP –CNS •H3 receptor –CNS Antihistamines 21/03/2010 8 4 Binding of histamine to H1 receptor TM IV TM III Asp 127 TM VI TM V O - O + NH3 Asn 198 NH 2 O Phe 199 NH N Antihistamines 21/03/2010 9 Binding of histamine to H1 receptor TM IV TM III Asn 198: site for imidazole ring binding Asp 127 TM VI TM V O - O + NH3 Asp 127: biding site for bioamines Asn 198 NH 2 O Phe 199 NH N Phe 199: hydrophobic interaction Signal transduction !! Antihistamines 21/03/2010 10 5 Binding of an antagonist ... TM IV TM III Asp 127 TM VI TM V O - O NH Asn 198 NH 3 2 O Phe 199 Antihistamines 21/03/2010 11 Binding of an antagonist ... TM IV TM III Block ! Asp 127 TM VI TM V O - O NH Asn 198 NH 3 2 O Phe 199 Binding to the bioamines site hydrophobic interaction Antihistamines 21/03/2010 12 6 Une famille d’antagonistes H1…. Nom DCI nom commercial en Belgique * • alimémazine THERALENE • prométhazine PHENERGAN • dimenhydrinate PARANAUSINE / VAGOMIN • diphenhydramine BENYLIN • dexchlrorphéniramine POLARAMINE • ciproheptadine PERIACTIN • dimétindène FENISTIL • méclozine AGYRAX / POSTAFENE • cetirizine ZYRTEC / REACTINE / …. • loratadine CLARITINE / SANELOR • fexofenadine TELFAST et plus récemment • lévocetirizine XYZAL • desloratadine AERIUS * liste non limitative… Antihistamines 21/03/2010 13 Binding of an antagonist: what can you modify ? TM IV TM III Asp 127 TM VI TM V O - O NH Asn 198 NH 3 2 O Phe 199 Antihistamines 21/03/2010 14 7 Binding of an antagonist: what can you modify ? TM IV TM III Asp 127 TM VI TM V O - O NH Asn 198 NH 3 2 O Phe 199 Not much, or very little here ... Antihistamines 21/03/2010 15 Binding of an antagonist: what can you modify ? TM IV TM III Asp 127 TM VI TM V O - O NH Asn 198 NH 3 2 O Phe 199 Possibilities… Antihistamines 21/03/2010 16 8 Variations among antihistamines.... N Modifications of Dimenhydrinate CCH2 H 2 N H 2 Diphenhydramine the amine pole Dexchlorphenyramine N CC NH + dialkyl + Buclizine C N NH Meclozine Cétirizine pipérazine + C C NH Loratadine Terfenadine pipéridine Ebastine Antihistamines 21/03/2010 17 The ideal antihistaminic drug for the treatment of allergy What is your "wish list" ? • Low sedation activity * • No or little anticholinergic effects ** • Getting a rapid and prolonged action *** * most "old" antihistamines make you to fall asleep… ** because their structure is reminiscent of atropine *** I want a fast relief, and not needing taking pills every hour… Antihistamines 21/03/2010 18 9 Low sedation activity ... Modulation of the hematoencephalic barrier passage... Fast and important passage + C C NH CH3 Cyproheptadine Cl Low or no passage + C C NH CO O CH2 CH3 Loratadine N role of the side-chain... Antihistamines 21/03/2010 19 Low sedation activity ... Another example… Important passage O CC NH + Diphenhydramine Low or no pasage + - CN CH CH OCH COO NH 2 2 2 Cl Cétirizine role of the length and of the polarity of the side-chain Antihistamines 21/03/2010 20 10 Molécules à passage hémato-méningé important et causant de la sédation ... Nom DCI sédation OTC alimémazine +++ oui (partiel.) prométhazine +++ oui dimenhydrinate +++ oui +++ oui diphenhydramine +++ oui oxomémazine ++ non dexchlorphéniramine ++ oui ciproheptadine ++ oui dimétindène + oui méclozine + oui + oui Antihistamines 21/03/2010 21 The antihistaminic and the sedative actions of the "old" antihistaminics go side by side Promethazine (PHENERGAN 30 mg) placebo Antihistaminic action Sedative action Hindmarch et al., Curr. Med. Res. Opin., 17:241-255, 2001 Antihistamines 21/03/2010 22 11 First molecules with low level of passage through the hemato-encephalic barrier • astémisole withdrawn because of cardiac toxicity Torsades de pointe !!! • terfénadine • fexofénadine Active metabolite of terfenadine Antihistamines 21/03/2010 23 What was terfenadine... • terfenadine was a pro-drug OH + OH CH3 C C NH CH2 CH2 CH2 CH CCH3 CH3 • which underwent a "first pass" liver metabolism that released fexofenadine, the active product OH + OH CH3 C C - NH CH2 CH2 CH2 CH C COO CH3 Antihistamines 21/03/2010 24 12 The main problem of terfenadine ... • if terfenadine reaches the heart, it will block the K+ canal, causing a delay in repolarization (that translate into a prolongation of Q-T interval [visible at the ECG] that may lead to life-threatening arythmia and "Torsades de pointes" ... R T P U QS Q-T interval Antihistamines 21/03/2010 25 What is "Torsades de pointe" ? R R R T T T P U P U P U QS QS QS Antihistamines 21/03/2010 26 13 Mechanism(s) of Torsade de Pointe 1. Role of ectopic beats Balardinelli et al. TIPS (2003) 24:619-625 Antihistamines 21/03/2010 27 Mechanism(s) of Torsade de Pointes 2. role of dispersion of ventricular repolarization Balardinelli et al. TIPS (2003) 24:619-625 Antihistamines 21/03/2010 28 14 Risk of Torsade de pointes and inhibitors of cyt P450 metabolism disponible sur i-campus Simkó et al., Infection 2008;36:194-206 Antihistamines 21/03/2010 29 Molecules withdrawn because of risk of QT prolongation and Torsades de pointe R T wave Sparfloxacin Terfenadine (13–15 ms) cisapride (44 ms) Grepafloxacin + clari: 25 (10 ms) Q S Erythromycin (8-15 ms) 050Change in QTc Prolongation (msec) Adapted from Oberg and Bauman,1995; Baker et al,1997; van Haarst et al, 1998. Antihistamines 21/03/2010 30 15 Molecules with a weak hemato-encephalic passage ... • loratadine must be metabolized into desloratadine Cl Cl + + C C NH CO O CH2 CH3 C C NH2 N loratadine N desloratadine • ebastin • cetirizine not very sedative and acting as such Antihistamines 21/03/2010 31 Dissociation of the antiallergic and sedative activities Cetirizine (10 mg) placebo antiallergic activity sedative activity Hindmarch et al., Curr. Med. Res. Opin., 17:241-255, 2001 Antihistamines 21/03/2010 32 16 Dissociation of anti-allergic and sédative activities... But, beware: This is all related to dose… Antihistamines 21/03/2010 33 Dissociation of anti-allergic and sedative activities ... Everything is related to dose… (4 h) antiallergic activity sedative activity placebo cetirizine (4 h) placebo cetirizine 20 10 0 -20 5 10 mg 20 mg -40 20 mg % from baseline 10 mg -60 % from baseline 0 Sannita et al., Eur. J. Pharmacol. 300: 33-42, 1996 Antihistamines 21/03/2010 34 17 The ideal anti-H1 drug for treating allergy… Specifications (Cahier de charges) • Low sedative potential • Avoiding anti-cholinergic effects… – important for old molecules sight troubles, urinary retention ... – much improved for new ones (loratadine,fexofénadine, cétirizine) • Getting a rapid and sustained action Antihistamines 21/03/2010 35 The ideal anti-H1 drug for treating allergy… Specifications (Cahier de charges) • Low sedative potential • Avoiding anticholinergic effects • Getting a fast and sustained action Antihistamines 21/03/2010 36 18 Moelcular properties of cetirizine + C N - NH CH2 CH2 OCH2 COO carboxylate • fast action because no necessity of metabolic activation ( >< terfénadine, loratadine…) • little of no penetration through the blood-brain barrier • long occupation of the receptor ...
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