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 ...
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1 From histidine to histamine ...
HN HN CH CH NH 2 2 CH2 CH2 NH2
N COOH N
First inhibitor tritoqualine of histmine action … commercialized in France (HYPOSTAMINE )
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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
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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
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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
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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
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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
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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
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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 !!
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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
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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
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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…
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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
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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 ...
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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…
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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
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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…
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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...
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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
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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
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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
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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
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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
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What is "Torsades de pointe" ?
R R R T T T P U P U P U QS QS QS
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13 Mechanism(s) of Torsade de Pointe
1. Role of ectopic beats
Balardinelli et al. TIPS (2003) 24:619-625
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Mechanism(s) of Torsade de Pointes
2. role of dispersion of ventricular repolarization
Balardinelli et al. TIPS (2003) 24:619-625
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14 Risk of Torsade de pointes and inhibitors of cyt P450 metabolism
disponible sur i-campus Simkó et al., Infection 2008;36:194-206
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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.
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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
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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…
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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
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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
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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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Binding of an H1 antagonist to the receptor...
TM IV TM III
Asp 127 TM VI Presence TM V O of a lysine - O Lys191 NH3 Asn 198 NH in position 191 2 O
Phe 199
Gillard et al., Mol. Pharmacol. 61:391-399, 2002
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19 Slow release of an antagonist ...
TM IV TM III
- -OOC O Asp 127 TM VI TM V O - O Lys191 NH3 N Asn 198 NH 2 + O N Phe 199 additional electrostatic bound
Slow dissociation Cl and long- cetirizine lasting Gillard et al., Mol. Pharmacol. 61:391-399, 2002 action
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Prolonged action ...
Cetirizine (10 mg)
placebo
anti-allergic action
Hindmarch et al., Curr. Med. Res. Opin., 17:241-255, 2001 Antihistamines 21/03/2010 40
20 Cetirizine and levocetirizine....
cetirizine
OH N O
N O Cl
levocetirizine
OH N O
N O Cl
Acetic acid, 2-[2-[4-[(R)-(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-
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Optic isomers and binding to the receptor …
TM IV TM III
- -OOC O Asp 127 TM VI TM V O - O Lys191 NH3 The correct N Asn 198 NH 2 O configuration of + this C (linking the N Phe 199 two hydrophobic groups and the piperazine) is critical for a correct positioning, and, thereby, for Cl activity cetirizine
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21 Do you speak English in Braine l'Alleud or Gosselies ?
disponible sur i-campus
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Une longue histoire, mais ...
Sur base de ce que vous avez appris jusqu'ici, quel est, à votre avis, le conseil le plus essentiel à donner au patient lors de la délivrance d'un antihistaminique de type cétérizine, loratadine …
• faire attention aux autres médicaments • ne pas abuser du produit (ne pas reprendre trop rapidement) • attention à l'alcool ! • respecter la posologie • attention à la somnolence
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22 Et pour la suite ...
Sur quel point, selon vous, le pharmacien doit-il être particulièrement bien informé par la firme XXX à propos de YYY qui est en vente sans prescription ?
• les propriétés de base du produit •les indications •la posologie • les effets indésirables • les interactions médicamenteuses
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Et pour la vraie suite ...
Quelle est la différence entre A et B … ?
A
B
C
Et pourquoi C est-il sous prescription ?
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23 Et voyons les applications ...
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24