Introduction

HISTAMINE
-imidazolyethylamine derivative
Medication of allergic and hypersensitivity reaction and the regulation
of gastric secretion.
Storage: Mast cells, Basophils, enterochromaffin-like cells, brain.

HISTAMINE RECEPTORS:
RECEPTOR
H1

LOCATION
Vascular SM
Extravascular SM
Endothelial cells
Sensory nerve endings
Brain
Gastric parietal cells
Cardiac muscles
Uterine SM
Mast cells

H2

H3

Brain

RESPONSE
Vasodilation
Contraction
Contraction
Itch and Pain
Wakefulness
HCl secretion
Atrial contraction
Uterine contraction
Release of inflammation
mediators
Alertness, wakefulness

Antihistamine
-

Drugs that block the action of H1, H2 and H3 receptors.

Classification:
o
o

Physiologic Antagonist
Epinephrine
Pharmacologic Antagonist
H1 Antagonist
H2 Antagonist

H1 Antagonist
-

Mechanism of Action
o Competitively inhibit the action of H1 receptors
Uses:

o
o
o

Allergic reactions
Motion sickness, vestibular disturbances
Nausea and Vomiting

H1 Antagonist: Classification
1st Generation
- Ethanolamine (Diphenhydramine)
- Ethylenediamine (Pyrilamine)
- Piperazine (Hydroxyzine)
- Alkylamine (Chlorpheniramine)
- Phenothiazine (Promethazine)

2nd Generation
- Loratadine
- Cetirizine
- Acrivastine
- Fexofenadine
- Terfanidine
- Astemizole

H1 Antagonist: SAR
Ar: Aryl Phenyl, substituted phenyl, heteroaryl group
Ar: 2nd aryl, aryl methyl group
H1 receptor affinity
Lipophilicity
Para substitution of Ome, Me, Br, Cl
Activity
o Replacement of phenyl ring with 2-pyridly: Activity
X: connecting atom of O, C, N
(CH2)n: carbon chain
NRR: Basic, terminal
o
o
o

H1 Antagonist: 1st Generation

o Ethanolamine
X: CHO
2 or 3 carbon atom chain
Diaryl 3 Amino Alkyl ether
Penetrate BBB- Sedation
M receptor affinity
GI side effects
Long Duration
o Ethylenediamine
X: N
2 carbon atom chain

Diarylethylenediamine (except antazoline)

CNS depressant, GI side effects
Anticholinergic actions

Piperazine
X: CHN
Piperazine moiety
Sedation
Peripheral and central antimuscarinic activity
Slow onset, long duration

Tricyclic Antihistamine

Dibenzocycloheptenes/ heptanes
- Y: Vinyl or ethyl
- X: sp2 carbon
- Anthistamine, anti-5TH, appetite-stmulating
- Sedation

H1 Antagonist: 2nd Generation

o
o

o
o

Selective H1 receptor affinity

Diaryl substituted piperazines or piperidines
Large aralkyl groups or polar groups linked to the piperidine/ piperazine
rings
Side effects: Affinity for M, adrenergic, 5TH receptor
DOA: Long
Non-sedating: Poor CNS penetration
Polar nature (cetirizine)

Piperidine
Terfenadine

Diphenylmethylpiperidine
o Receptor affinity
N-phenylbutanol substituted

o Affinity for M, adrenergic 5TH receptor

o CNS affinity
Fexofenadine

Oxidative metabolite of terfenadine

Less cardiotoxic