Download Histamine and Antihistaminic Agents

PHYSIOLOGICAL EFFECTS OF ENDOGENOUS HISTAMINE
• Mediator of hypersensitivity
• Regulation of gastric acid secretion
• Neurotransmitter in the CNS
• HISTAMINE H1-ANTAGONISTS
• Antihistamines historically refer to antagonists at H1 receptors.
• First generation or Classical H1-antagonists include:
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Aminoalkyl ethers
Piperazines
Propylamines
Phenothiazines
Dibenzocycloheptenes/heptanes
Second or Non-sedating generation
Some structural similarities to first generation.
More specific in action –lesser side effects.
Limited in distribution profiles
STRUCTURE ACTIVITY RELATIONSHIPS
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General Antihistamine Structure
Ar = Aryl (phenyl, substituted phenyl, heteroaryl)
Ar’ = Second aryl or arylmethyl; X = O, C or N; (CH2)n = carbon chain; NRR’ = Terminal
amine group
Subclassification of 1st generation antihistamines is based on nature of the connecting
atom; diaryl substitution pattern; and the terminal amine function
Diaryl substitution: is essential for significant H1 binding; present in 1st and 2nd
generation antihistamines; must not be co-planar; may be tricyclic e.g. Phenothiazines,
Dibenzocycloheptanes
Amine Moiety: may be: simple dimethyl amino or part of heterocycle e.g. some
Phenothiazines, Dibenzocycloheptenes, 2nd generation antihistamines, etc.
(CH2)n , n = 2 or 3
Diaryl causes 1st and 2nd generation antihistamines to be more hydrophobic than
histamine.
Atihistamine Metabolism
Oral administration results in 1st pass metabolism
N-dealkylation; deamination
Amino acid/glucuronide conjugation; aromatic hydroxylation to form phenols which can
then be conjugated.
Ar'
R
X
Ar
(CH2)n
N
R'
AMINOALKYL ETHERS (ETHANOLAMINES)
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General structure:
Diaryl tertiary aminoalkyl ether moiety is a shared pharmacophore for
muscarinic receptors. Aminoalkyl ethers display anticholinergic activity.
R''
Ar'
O
Ar
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R
CH2 CH2 N
R'
Diphenhydramine Hydrochloride (Benadryl):
Displays anticholinergic and sedative properties
Oral, IM and IV administration.
CHOCH2CH2N(CH3)2 HCl
Diphenhydramine
Hydrochloride
…AMINOALKYL ETHERS (ETHANOLAMINES)
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Dimenhydrinate (Dramamine)
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Used against motion sickness (30 min before trip) and
Hyperemesis gravidarum (nausea of pregnancy).
Oral, IM and IV administration.
H
CHOCH2CH2N(CH3)2
O
Cl
Dimenhydrinate
N
N
N
N
CH3
CH3
O
…AMINOALKYL ETHERS (ETHANOLAMINES)
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Doxylamine Succinate (Decapryn Succinate)
Potent like diphendydramine
Has sedating action
Carbinoxamine Maleate (Clistin)
Potent antihistamine
Is a racemic mixture
Cl
CH3
CHCOOH
CH2COOH
CHCOOH
CH2COOH
OCH2CH2N(CH3)2
OCH2CH2N(CH3)2
N
Doxylamine Succinate
Carbinoxamine Maleate
N
…AMINOALKYL ETHERS (ETHANOLAMINES)
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Clemastine Fumarate (Tavist)
Dextro clemastine has 2 chiral centers.
Long duration of action
Also has antimuscarinic activity
…AMINOALKYL ETHERS (ETHANOLAMINES)
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Phenyltoloxamine
Aromatic rings located differently
from diphenhydramine yet
produces potent antihistamine
activity
CHOCH2CH2N(CH3)2 HCl
Diphenhydramine
Hydrochloride
PROPYLAMINES (MONOAMINOPROPYL DERIVATIVES)
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General Structure:
Ar'
R
CH
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C
H2
C
H2
N
Pheniramines
Ar
R'
Propylamines with saturated connecting carbon; consist of phenyl and 2pyridyl aryl group and terminal dimethylamino. All pheniramines are chiral.
Antihistaminic activity almost exclusively on S-stereomers.
Pheniramines differ in phenyl substitution at para position: H, Cl and Br.
Halogenation yields 20-50-fold more potency. Poor oral availability – Firstpass metabolism. Metabolism by mono- & di-N-dealkylation and NOxidation & amino acid conjugation.
…PROPYLAMINES (MONOAMINOPROPYL DERIVATIVES)
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Chlorpheniramine Maleate (ChlorTrimeton).
Dextro enantromorph is most active.
Half-life of 12-15 hrs.
Chlorpheniramine
or
Dexchlorpheniramine maleate
HC
CH2CH2N(CH3)2
N
CHCOOH
CHCOOH
Cl
…PROPYLAMINES (MONOAMINOPROPYL DERIVATIVES)
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Triprolidine Hydrochloride
Geometric isomerism important for activity.
Trans isomers (pyrrolidinomethyl group is trans to the 2-pyridyl group)
possess activity. (E)- isomers are superior to (Z)- isomers as H1 antagonists.
Triprolidine HCl
N
C
C
H
C N
H2
HCl
CH3
PIPERAZINES (CYCLIZINES)
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General Structure:
CH
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N
N
R
Considered cyclic ethylenediamines
X
Connecting moiety is CHN
Terminal amine and connecting N are part of piperazine ring.
The 2 N are aliphatic with comparable pKas.
Piperazines are characterized by slow onset and long duration of action.
Peripheral and central antimuscarinic activity.
Cyclizine Hydrochloride (Marezine)
Light-sensitive crystalline powder with bitter taste.
Cyclizine HCl or
Treatment and prophylaxis of motion sickness.
Lactate
HC
N
N CH3
HCl or Lactate
…PIPERAZINES (CYCLIZINES)
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Meclizine HCl (Bonine, Antivert).
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Used mainly against nausea and vomiting associated with vertigo and motion sickness.
Meclizine HCl
CH3
HC
N
N
HCl
Cl
CH2
PHENOTHIAZINES
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General Structure:
R
S
N
CH2CH(CH2)N
R''
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R'
Ethylenediamines with bridged aryl units
2 or 3 carbons between ring system and terminal N.
Branched alkyl chain is required for the antihistaminic phenothiazines but
not the antipsychotic phenothiazines.
Chirality close to alkyl N has less effect on antihistaminic activity.
Metabolism by mono- & di-N-dealkylation, aromatic oxidation and Noxidation.
Promethazine Hydrochloride (Phenergan)
Promethazine HCl
S
N
CH2CHN(CH3)2
CH3
HCl
DIBENZOCYCLOHEPTENES/HEPTANES
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General Structure:
X
N
CH3
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Related to the phenothiazines except that the S and N atoms are replaced by 2
and 1 carbons, respectively.
Cyproheptadine Hydrochloride (Periactin)
Possesses both antihistamine and antiserotonin. Antipruritic agent.
Sedation as principal side effect.
SECOND GENERATION H1-ANTAGONISTS
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Structurally dissimilar; similar physiological profiles; high potency H1-antagonists
Prolonged antihistaminic effects due to slow receptor dissociation and active
antihistaminic metabolites.
Less affinity for muscarinic, adrenergic and serotonergic receptors.
Therefore less sedating side effects.
Serious arrhythmias when co-administered with drugs that inhibit their metabolism such
as imidazole antifungals.
…SECOND GENERATION H1-ANTAGONISTS
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Fexofenadine (Allegra)
Oxidized metabolite of Terfenadine
Less cardiotoxic than Terfenadine.
Marketed as a racemate.
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Selective for H1 with no sedative other CNS effects.
Experimental evidence shows it does not cross the BBB.
60-70% protein-bound, 5% is metabolized.
Remainder is eliminated in bile and urine.
OH
C
CH3
HO
N
COOH
CH3
HCl
Fexofenadine
Terfenadine
…SECOND GENERATION H1-ANTAGONISTS
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Loratadine
Structurally related to dibenzocycloheptenes/heptanes.
Selective peripheral H1-antagonist.
No CNS or autonomic side-effects.
Half-life of 8-15 hr.
Desloratadine (Clarinex)
Metabolite of Loratadine
More potent inhibitor of histamine release
Cl
N
Loratadine
N
COOCH2CH3
Desloratadine (Clarinex)
…SECOND GENERATION H1-ANTAGONISTS
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Cetirizine (Zyrtec)
Does not readily penetrate BBB.
Minimal CNS side effects and cardiac rhythm.
Levocetirizine (Xyzal)
Developed from Cetirizine
Active enantiomer
Higher affinity than S enantiomer
Cl
Cetirizine
HC
N
N
CH2CH2OCH2COOH
Levocetirizine (Xyzal)
TOPICAL HISTAMINE H1-RECEPTOR ANTAGONISTS
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Azelastine (Astelin)
Nasal spray for allergic rhinitis
N-dealkylated metabolite is active
Eyedrops for allergic conjunctivitis
Emedastine (Emadine)
Topically for conjunctivitis
Azelastine
Emedastine
TOPICAL HISTAMINE H1-RECEPTOR ANTAGONISTS
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Levocabastine (Livostin)
Conjunctivitis
Olopatadine (Patanol)
Structurally related to tricyclic antihistamines
Long duration of action
Rapid onset
Nasal and eyedrops
Levocabastine
Olopatadine
…HISTAMINE H2-RECEPTOR ANTAGONISTS
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Histamine
H2 antagonist are structurally related to histamine
General Structure of H2 Receptor Antihistamines
H
N
R
NHCH 3
X
HN
N
Y
…HISTAMINE H2-RECEPTOR ANTAGONISTS
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Cimetidine (Tagamet)
Relatively hydrophilic.
Affects Cytochrome P-450 metabolism of drugs.
60-70% oral bioavailability.
Plasma half-life of ~2 hrs.
Famotidine (Pepcid)
Treatment of duodenal and benign gastric ulcers, gastroesophageal reflux disease,
pathologic hypersecretory conditions and heartburn.
H3C
CH2SCH2CH2CNH2
CH2SHCH2CH2NHCNH2CH3
N
NSO2NH2
NCN
HN
N
Cimetidine
(H2N)2C
N
S
Famotidine
…HISTAMINE H2-RECEPTOR ANTAGONISTS
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Ranitidine (Zantac)
HCl salt is highly water-soluble.
Plasma half-life of 2-3 hr.
Used to treat active duodenal ulcers associated with H. pylori infections.
Nizatidine (Axid)
Soluble in water, chloroform and alcohol.
Half-life of 1-2 hr.
CH2SCH2CH2NHCNHCH3
CHNO2
(H3C)2N
Ranitidine
O
CH2SCH2CH2NHCNHCH3
CHNO2
S
N
Nizatidine
(H3C)2N