Entries Tagged 'Histamine' ↓

Antihistamine agents:The term antihistamine historically has referred to drugs that antagonize the actions of histamine at H1  receptors rather than H2 receptors.

H1 –antagonist : block and opposite effect. H1 antagonists may be defined as drugs that competitively inhibit the action of histamine on  tissues containing H1 receptors.

Classification of H1 – receptors antagonist: the H1 antagonist are now commonly subdivided into two broad groups-

• First generation or classical antihistamines
• Tricyclie dibenzoxipins.
• Ethanolamines : E.G, carbinoxamine maleate, clemastine fumerate, diphenhydramine HCl, dimenhydranate.
• Ethylenediamines :  E.g; pyrilamine maleate, tripepennamine HCL/ citrate.
• Alkylamines : E.g; chlorophenaramine maleate, bromophencramine maleate.
• Piperazines : E.g; hydroxyzine hcl, hydroxyzine pamoate, cyclizine hcl, cyclizine lactate, meclizine hcl.
• Phenothiazines : Eg ; promithazine hcl.
• Piperidines : E.g; cyproheptadine hcl, phenindamine tartrate.

Second generation agents (non-sedating) .

• Alkylamines : E.g; acrivastine.
• Piperazines : E.g cetirizine hcl
• Pthalazinones : E.g, azelastine hcl.
• Piperidines : E.g levocabastine hcl, loratidine, desloralidine, ebastine, mizolastine, fexotenadine.

Pharmacological consideration of H1 antagonist:

• Sneezing
• Rhinorrtea
• Itching of eye , nose throat
• Hay fener
• Pollinosis
• Chronic, idiopathic, urticaria.

H2- receptors blockers : Are those druges which inhibit effect are not acceptable.

E.g,  Ranitidine , cimetidine , famotidine, nizatidine.

The action of  histamine by blocking H2 receptors.

In many of the first generation or classical antihistamines the terminal nitrogen atom is a simple dim ethyl amino moiety. In all classes the amino moiety is basic with PKa ranging from 8.5 to 10 and thus is presumed to be prorogated when bound on the receptors. The moiety is also important in the development of stable solid dosage forms through salt formation.

In some series branching of the carbon chain results in reduced  antihistamine activity. There are exceptions however as evidenced by promethazine, which has greater activity than its non branched counter part.

Termination of histamine action:Three principal ways exit to terminate the physiological effects of histamine.

• Cellular uptake : animal studies have documented the uptake of histamine by many cells. The histamine is metabolized once in the cell.
• Desensitization of cells: Some H1 receptors containing tissues exhibit a homogeneous loss of sensitivity to the  actions of histamine , perhaps as a result of receptors modification.
• Metabolism : the most common pathway for terminating histamine action involves enzymatic inactivation.

The enzyme histamine N- methyltransferase (HMT) is widely distributed among mammalian tissues and catalyzes the transfer of a methyl group from S- adenosyl L-Methionine (SAM) to the ring tele nitrogen of histamine producing N1- methyl histamine and  S- adenosyl- L- homocysteine. Histamine is also subject to oxidative deaminalion by diamine ozidase, yielding imidazole acetic acid, a physiologically inactive product excreted in the urine.  Similarly , NT – methyl  histamine is centered by both DAO and monoamine oxidase (MAO) to N-Methylimidazole acetic acid.

Receptors :Once released , the physiological effects of histamine are mediated by specific cell surface receptors. There are three different subtypes of histamine receptors , H₁, h₂, h₃

H₁ – Receptors: histamine h₁ receptors have been detected in wide variety of tissues including mammalian brain smooth muscle from airways, gastro intislinal GI tract, genitourinary system and the cardiovascular system, adrenal medulla and endothelial cells and lymphocytes.

H₂- receptors: H₂ –receptors have been detected in a wide variety of tissues(myocardial cells and cell membranes of acid secreting cells of the gastric mucosa) and mediate the gastric acid secretor actions of histamine. The H₂ receptors has the general characteristics of a G- protein coupled receptors.

H₃ – Receptors: the H₃ receptors is proposed to function as a neural auto receptors (presynaptic) serving to modulate histamine synthesis and release in the CNS.

Storage and release :Most histamine is synthesized and stored in mast cells and basophilic granulocytes. Protein complexes  histamine in then stored in secretory granules and released by exocylosis in response to a wide variety of immune cantigen and antibody and non immune ( bacterial products, xenobioties, physical effects and cholinergic effect) stimuli. The release of histamine as one of the mediators of hypersensitivity reactions in initiated by the interaction of an antigen- I_GE  complex with the membrane of histamine storage cells. This interaction triggers activation of intracellular phosphokinase (PKC) leading to accumulation of inositol phosphates diacylglycerols and CA²⁺ . exocytotie release of histamine follows the degranulation of histamine storage cells. Histamine is released from mast cells in the gastric mucosa by gastric and acetylcholine.

Biosynthesis and distribution:Histamine is synthesized in cytoplasmic granules of its principal storage cells, mast cells and basophils. Histamine is formed from the naturally occurring amino acid, S- histamine , via the catalysis of either the pyridozal phosphate-dependent enzyme histidine decarboxy lase or aromatic amino acid decarboxy lase.