HISTAMINES AND ANTIHISTAMINES

Group 7 Lim, Irene B. Lim, Philip Anthony G. Malilay, Darwin Ryan M. 3D Pharmacy

HISTAMINES
synthesized in Golgi apparatus stored in mast cells and basophilic granulocytes released by exocytosis in response to immune (antigen and antibody) and non-immune (bacterial products, xenobiotics, physical effects, and cholinergic effects) stimuli

HISTAMINES
Important proteins involved in many allergic reactions Contributes to inflammatory response Causes constriction of smooth muscle

In response to an allergen, histamine causes the contraction of smooth muscle.

RELEASE OF HISTAMINE

interaction of an antigen-IgE complex with the membrane of a histamine storage cell

Histamine receptor subtypes H1 H2 H3 H4

H1-RECEPTORS
expressed in CNS neurons, smooth muscle of respiratory, GI, uterine tissues, epithelial and endothelial cells, neutrophils, eosinophils, monocytes, dendritic cells, T cells, B cells, hepatocytes, and chondrocytes

H2 RECEPTORS

gastric acid secretion, vascular permeability, hypotension, flushing, headache, tachycardia, chronotropic and inotropic activity, bronchodilatation and respiratory mucus production

ANTIHISTAMINES
Inhibition of the histamine-mediated release of inflammatory mediators Neutralization of histamine

STRUCTURE-ACTIVITY RELATIONSHIPS AT H1RECEPTORS General Antihistamine structure

Ar = aryl (phenyl, substituted phenyl, heteroaryl group) Ar = second aryl or arylmethyl group X = connecting atom of O, C or N (CH2)n = carbon chain NRR = basic, terminal amine

STRUCTURE-ACTIVITY RELATIONSHIPS
Amine moiety = development of stable, solid dosage forms through salt-formation Branching of carbon = reduced antihistaminic activity (Exception: Promethazine) Lipophilicity = presence of two aryl rings and the substituted amino moieties

H1- RECEPTOR ANTAGONISTS

I. Alkylamines (Propylamines) - Chlorpheniramine, Brompheniramine II. Piperazines - Cyclizine, Meclizine III. Phenothiazines - Promethazine, Methdilazine

I. PROPYLAMINES
Monoaminopropyl or Alkylamine Derivatives composed of carbon-connecting atom with a carbon chain of two additional carbons linking tertiary amino and diaryl moieties

I. PROPYLAMINES
greater receptor selectivity fewer anticholinergic and CNS side effects than other antihistamines relatively long half-lives less sedation Chlorpheniramine Brompheniramine

PHENIRAMINES
propylamines with a saturated carbonconnecting moiety consist of a phenyl, 2-pyridyl aryl group and a terminal dimethylamino moiety differ in the phenyl substituent at para position Cl (Chlorpheniramine) Br (Brompheniramine)

PHENIRAMINES
if halogenated, significantly more potent (2050 times); and longer duration of action than pheniramine widely used in OTC products for seasonal allergies

CHLORPHENIRAMINE
IUPAC name: [3-(4-chlorophenyl)-3-(pyridin2-yl)propyl]dimethylamine Formula: C16H19ClN2

CHLORPHENIRAMINE
helps to relieve symptoms of cold and allergy, such as runny nose, itch, watery eyes and sneezing. helps relieve allergic skin conditions such as hives, itchy rash due to insect bites or chicken pox.

BRAND NAMES & MANUFACTURERS

Antamin Pascual/ADP Pharma Tai Yu Chlormin Atlantic Lab Phil Pharmawealth/Atlantic Chlorphenamine Valemine Betneton Histacort Celestamine Vamsler GlaxoSmithKline BioFemme Essex

I. PROPYLAMINES
Brompheniramine

IUPAC name: [3-(4-bromophenyl)-3-(pyridin-2yl)propyl]dimethylamine Formula: C16H19BrN2

BROMPHENIRAMINE

helps to relieve symptoms of cold and allergy, such as runny nose, itch, redness and swelling, watery eyes, sneezing and throat discomfort, rashes and hives

BRAND NAMES & MANUFACTURERS

Nasatapp Pediatapp Dimetapp Rhinotapp Snizee Zeditapp Prohealth PediaCare Wyeth Pharma Dynamin Metz Pharma MedHaus

CHLORPHENIRAMINE MALEATE
Chlorination increases potency 10-fold with no appreciable change in toxicity Half-life: 12 to 15 hours

BROMPHENIRAMINE MALEATE
differs from chlorpheniramine: Br instead of Cl actions and uses same with chlorpheniramine Half-life: 25 hours (twice that of chlorpheniramine)

II. PIPERAZINES
Ethylenediamine derivative Connecting moiety (X) = CHN group Primary structural differences: nature of para aromatic ring substituent (H or Cl) nature of terminal piperazine nitrogen substituent

II. PIPERAZINES
Activity: slow onset, but long duration of action Exhibit peripheral and central antimuscarinic activity = diminish vestibular stimulation and act on the medullary chemoreceptor trigger zone Therefore, significant use as antiemetics and antivertigo agents and in treatment of motion sickness.

II. PIPERAZINES
some exhibited a strong teratogenic potential (malformations in animal models) use during pregnancy is discouraged

 For prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness, and vertigo

BRAND NAME & MANUFACTURER

Marezine (Himmel Pharmaceuticals Inc.)

MECLIZINE

used to treat or prevent nausea, vomiting, and dizziness caused by motion sickness. It is also used for vertigo (or dizziness) caused by certain inner ear problems.

BRAND NAMES & MANUFACTURERS

Bonamine
Dizitab Postadoxine

Johnson & Johnson

Amherst Lab GlaxoSmithKline

III. PHENOTHIAZINES
antihistaminic activity useful psychotherapeutic agents derivatives with antihistaminic actions: with two- or three-carbon, branched alkyl chain between the ring system and terminal nitrogen atom unsubstituted heterocyclic ring

III. PHENOTHIAZINES

derivatives with antipsychotic actions: unbranched propyl chain is required substituted heterocyclic ring

III. PHENOTHIAZINES

Decreased antihistaminic activity and increased psychotherapeutic properties if there is:

lengthening

of side chain substitution of lipophilic groups in the 2-position of aromatic ring

III. PHENOTHIAZINES
Promethazine Methdilazine

PROMETHAZINE
relatively long-acting antihistamine sedative effects potent antiemetic and anticholinergic

***Concurrent administration of alcoholic beverages and other CNS depressants with phenothiazines should be AVOIDED.

PROMETHAZINE
used to relieve allergic conditions, such as runny nose, sneezing, watery and itchy eyes, rashes and hives helps to relieve nausea and vomiting helps prevent travel sickness may also be used as a sleep aid for a short period of time.

METHDILAZINE

Used for the symptomatic relief of hypersensitivity reactions and particularly for the control of pruritic skin disorders