Transcript Document

Antihistamines
Histamine receptors –
H1-
Allergic responses. Watery eyes, congestion, etc. from allergies.
Anaphylaxis – bronchial larynx constriction.
Skin allergic response – reddening, rashes, welts.
Edema from injury.
H2 –
Gastric secretion. Important for ulcer treatment and acid reflux
H3 –
? CNS receptors. There are also H1 receptors in the CNS.
Antihistamines are also used for motion sickness. In general their antimuscarinic
effects are similar to that of scopolamine, although weaker.
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H
HN
NH 2
HN
Histamine
N
H
Histamine Agonists
NH2
N
2-methyl histamine
H1 Agonist
CH3
H3 C
HN
NH2
N
H
HN
NH 2
N H3C
H
4-methylhistamine
H2 Agonist
(R)-methyl histamine
H3 Agonist
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Antihistamines – H1 Blockers
Ethylenediamines
Ar1
X
(CH2 )n
N
Ar2
CH 3
CH 3
SAR Prototype
CH 3
Phenbenzamine
N
CH 3
N
HN
Antazoline
N
N
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R1
CH 3
H
N
O
O
CH 3
Antihistamine SAR
CH 3
N
CH 3
SAR Prototype
R1 is a small group like H, CH 3,OCH 3
Aminoalkylethers
Diphenhydramine
(Benadryl)
Cl
O
NCH3
Cl
Diphenylpyraline
N
Meclizine
Good H 1 antagonist, but also
good antimuscarinic
N
Piperazine/N-heterocycle Series
CH3
Cl
CH3
O
Clemastine
(T avist)
N CH3
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Stereo- and regioisomers
Antihistamines are stereospecific. A
number of new, single isomer drugs are
being developed.
Antihistamines are structurally similar
To SSRIs and to antipsychotics. Notice
The subtle difference between fluoxetine
And several antihistamines.
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Alkyl Amines
N
CH3
N
CH3
N
R
Cl
R = H Pheniramine
R = Cl Chlorpheniramine (Chlortrimeton)
R = Br Brompheniramine (Dimetane)
Pyrrobutamine (Pyronil)
N
N
H3 C
N
CH3
N
CH3
N CH 3
CH3
Triprolidine (Actidil)
Dimethindene (Forhistal)
Phenindamine (Nolahist)
Long Duration, less sedation than ethylenediamines, ethanolamines. The
“next best thing” until the “2nd generation” were developed.
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Rigid Analogs (I)
A Cl at the 2-position weakens H1 activity relative to antimuscarinic activity and D2
antagonist activity
S
N
N
Mebhydrolin
Cl
CH2 CH2 CH2 N(CH 3 )2
NCH 3
Chlorpromazine
S
N
Fenthazine
N
CH 2 CH 2 N(CH 3 )2
N
N
N
S
OCH 3
H
Promethazine
(Pheregan)
N
CH 2 CHN(CH 3 )2
CH 3
F
Astemizole
(Hismanal)
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Rigid Analogs (II)
S
Cl
Cl
N
N
N
N
CH3
Primethixene
N
O
OCH2CH 3
Loratadine (Claritin)
H
Desloratadine (Clarinex)
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Astemizole
N
N
N
N
F
OCH 3
H
Astemizole
(Hismanal)
Hismanal was FDA approved in 1988 as an antihistamine for allergy and hay fever
symptom relief. The FDA first warned consumers and healthcare providers of new
safety information regarding Hismanal February 9, 1998 due to the risk of death,
cardiovascular adverse events, anaphylaxis, and serious drug interactions.
In addition, Hismanal labeling was changed to stress avoiding the use of Hismanal in
combination with certain other medications and for liver disorder patients to
completely avoid its' use.
After a series of labeling changes and warnings Hismanal was recalled on June 21,
1999.
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Antihistamines “related” to butyrophenones
Terfenadine was discontinued when it became apparent that there was a high frequency
of heart arrythmia associated with the drug. Fexofenadine is a metabolite and is the
activated form responsible for antihistamine activity. In patients with compromised liver
metabolism, or when the presence of other drugs limited the metabolism of terfenadine,
persistent levels resulted in the observed arrythmias. Therefore, the fexofenadine
replaced terfenadine (1997).
Ventricular Arrythmias are not good!
F
OH
N
Haloperidol (Haldol)
Prototype butyrophenone antipsychotic
10x Chlorpromazine
O
Cl
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Butyrophenone-like structures
OH
Terfenadine
(Seldane)
N
OH
[OX]
COOH
OH
Fexofenadine
(Allegra)
N
OH
H
Cl
N
N
OH
O
Cetirizine
(Zyrtec)
O
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Allegra Propaganda - www.allegra.com
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www.zyrtec.com
If you haven't gotten the relief you want from Claritinｨ (loratadine), Clarinexｨ
(desloratadine), or Allegraｨ (fexofenadine HCl), ask your doctor if ZYRTEC is right
for you.
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Structural Summary
Linking the first generation with Non-sedative
Antihistamines.
Big Picture - Bottom Line
Cl
O
N
N
CH3
N
CH3
CH3
Diphenhydramine
Meclizine
Cl
O
NH
Cl
N
O
OH
N
N
Desloratadine
Cetirizine
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Anti-emetics
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Anti-emetic Table
Synthetic
Tropane Alkaloids
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2005 Nobel Prize
Press Release: The 2005 Nobel Prize in Physiology or Medicine
3 October 2005
The Nobel Assembly at Karolinska Institutet has today decided to award
The Nobel Prize in Physiology or Medicine for 2005
jointly to
Barry J. Marshall and J. Robin Warren
for their discovery of
"the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease”
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Gastric
Secretions
Cell Biology
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H2 Histamine antagonists.
Gastric receptors are pharmacologically distinct. The classic H1 antagonists don’t
interact with H2 receptors. Antihistamines are an important treatment for gastric
disorders; antacids, ulcer treatment, acid-reflux disease.
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H2 Histamine antagonists. - Structures
H
H
H
N
N
H3 C
N
H
N
N
H
N
N
O
CH3
CHNO2
N
CN
CH2 N(CH3) 2
Cimetidine
(Tagamet)
S
N
N
H
S
CH3
N
S
S
H
S
HN
N
Metiamide
(H2 Selective)
Burimamide
(Non-selective)
H3 C
N
CH3
N
HN
S
H
S
CH3
HN
H
Ranitidine
(Xantac)
NH2
NSO2 NH2
Famotidine
(Pepcid)
C(NH2)2
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