Histamines and antihistamine pharmacology

Histamine is a biogenic amine present in many animal and plant tissues that function as neurotransmitters and are also found in non-neural tissues, have complex physiologic and pathologic effects through multiple receptor subtypes, and are often released locally.
It is also present in venoms and stinging secretions. It is synthesized by decarboxylation of the amino acid, histidine. Histamine is mainly present in storage granules of mast cells in tissues like skin, lungs, liver, gastric mucosa, placenta, etc. It is one of the mediators involved in inflammatory and hypersensitivity reactions.

1. Histamines and antihistamines pharmacology D r . S P Srinivas Nayak , PharmD , RPh , ( M sc ), (PGDND) Assistant Professor, Dept. of Pharmacy Practice, PU.

2. Histamines and antihistamines pharmacology Histamine is a biogenic amine present in many animal and plant tissues that function as neurotransmitters and are also found in non-neural tissues, have complex physiologic and pathologic effects through multiple receptor subtypes, and are often released locally. It is also present in venoms and stinging secretions . It is synthesized by decarboxylation of the amino acid, histidine . Histamine is mainly present in storage granules of mast cells in tissues like skin, lungs, liver, gastric mucosa, placenta, etc . It is one of the mediators involved in inflammatory and hypersensitivity reactions .

3. histamine Histamine occurs in plants as well as in animal tissues and is a component of some venoms and stinging secretions. Histamine is formed by decarboxylation of the amino acid l- histidine , a reaction catalyzed in mammalian tissues by the enzyme histidine decarboxylase. Once formed, histamine is either stored or rapidly inactivated. Very little histamine is excreted unchanged

4. Actions of histamines Nervous system : Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching the urticarial response and reactions to insect and nettle stings. Cardiovascular system : in humans, injection or infusion of histamine causes a decrease in BP and an increase in heart rate, vasodilation. Bronchiolar smooth muscle : Causes bronchoconstriction mediated by H1 receptors. patients with asthma are very sensitive to histamine. GIT: smooth muscle contraction, acid secretion, and diarrhoea . Pregnancy: pregnant women suffering anaphylactic reactions may abort as a result of histamine-induced contractions. Secretory tissue : a powerful stimulant of gastric acid secretion by activation of H2 receptors on gastric parietal cells. The “triple response” : Intradermal injection of histamine causes a characteristic red spot, edema, and flare response.

5. antihistamines H1-receptor antagonists (classical antihistamines) lessen histamine-mediated symptoms of allergic reaction. Mainly used for allergic reactions. H2-receptor antagonists reduce gastric acidity. Clinically has benefits in peptic ulcers and hyper acid secretion. H3 and H4-receptor antagonists have no therapeutic indication .

6. Classification Depending on sedation Highly sedating — diphenhydramine , dimenhydrinate,doxylamine , embramine , promethazine and hydroxyzine . Moderately sedating — pheniramine , antazoline , trimeprazine , meclizine and buclizine . Mildly sedating — chlorpheniramine , methdilazine , mepyramine , dimethindene , triprolidine , mebhydroline , cyclizine and clemastine . Non-sedating— terfenadine , astemizole , cetirizine and loratidine . Anti-vertiginous— cinnarizine .

7. First-gen. H1-blockers ( CNS) depression — sedation and drowsiness. some antihistamines have antiemetic and antiparkinsonian effects. They have antiallergic action , hence most of the manifestations of Type-I reactions are suppressed. They have anticholinergic actions — dryness of mouth, blurring of vision, constipation, urinary retention , etc. H1-antihistamines are well absorbed after oral and parenteral administration. They are distributed widely throughout the body, metabolized extensively in liver and excreted in urine. Adverse effects sedation , drowsiness, lack of concentration, headache, fatigue, weakness , lassitude, incoordination, etc. Anticholinergic side effects such as dryness of mouth, blurring of vision, constipation and urinary retention.. Allergic reactions may occur rarely with these agents, especially contact dermatitis on topical application .

8. Second-gen. H1-blockers Cetirizine, loratadine , azelastine and fexofenadine are highly selective for H1-receptors and have the following properties. They: Have no anticholinergic effects, Lack antiemetic effect. Do not cross blood–brain barrier (BBB), hence cause minimal/no drowsiness., Do not impair psychomotor performance. Are relatively expensive .

9. Drug interactions Lethal ventricular arrhythmias occurred with terfenadine or astemizole , in combination with ketoconazole, itraconazole , or macrolide antibiotics such as erythromycin . These antimicrobial drugs inhibit the metabolism of many drugs by CYP3A4 and cause significant increases in blood concentrations of the antihistamines. Grapefruit juice also inhibits CYP3A4 and has been shown to increase blood levels of terfenadine significantly. Both terfenadine and astemizole were withdrawn from the US market in recognition of these problems. Where still available, terfenadine and astemizole should be considered to be contraindicated in patients taking ketoconazole, itraconazole , or macrolides and in patients with liver disease.

10. Uses of antihistamines(h1) Uses: various allergic disorders—rhinitis, dermatitis, conjunctivitis, urticaria , eczema, drug and food allergies. Preanaesthetic medication: Promethazine is used for its sedative and anticholinergic effects. As antiemetic: Promethazine, diphenhydramine, dimenhydrinate , etc. are useful for prophylaxis of motion sickness, Parkinsonism, controlling vertigo in Meniere’s disease, blood transfusion and saline infusion reactions Sedative and hypnotic: H1-antihistamines (e.g. promethazine and diphenhydramine) are used to induce sleep, especially in children during minor surgical procedures.

11. H-2 Blockers Histamine-2 receptor antagonists competitively inhibit the interaction of histamine with H2 receptors. They are highly selective and have little or minimal effect on H1 or other receptors. H2 antagonists mainly interfere with gastric secretion. Important examples of this group of drugs used widely in the treatment of peptic and duodenal ulcer , include cimetidine, ranitidine , famotidine , nizatidine and roxatidine .

12. Imp. Points of h2 blockers Cimetidine is the enzyme inhbitor and increases amitryptiline , benzodiazepines, carbamazepine, imipramine , lignocaine, nifedipine , phenytoin, quinidine, terfenadine , theophylline, verapamil and warfarin levels, Gynaecomastia , Teratogenecity and increased prolactin levels may be seen following therapeutic doses of cimetidine. H2 blockers can produce bradycardia , hypotension, AV block and sinus arrest (especially with rapid IV administration) , haematologic ( agranulocytosis , pancytopenia, aplastic anaemia , and thrombocytopenia ) and dermatologic ( including Stevens-Johnson syndrome, toxic epidermal necrolysis ). Cimetidine, ranitidine, and famotidine have been associated with drug-induced fever , which typically resolves within 48 to 72 hours after discontinuation of the drug and The most consistent adverse reaction reported with famotidine is a severe, throbbing headache. H2 antagonists compete with creatinine and certain drugs ( eg , procainamide) for renal tubular secretion

13. Controversies of zantac The U.S. Food and Drug Administration announced it is requesting manufacturers withdraw all prescription and over-the-counter (OTC) ranitidine drugs from the market immediately. This is the latest step in an ongoing  investigation  of a contaminant known as N- Nitrosodimethylamine (NDMA) in ranitidine medications (commonly known by the brand name Zantac).

14. H3 and h4 blockers Although no selective H3 or H4 ligands are presently available for general clinical use, there is great interest in their therapeutic potential . H3-selective ligands may be of value in sleep disorders, narcolepsy, obesity, and cognitive and psychiatric disorders. Tiprolisant , H3-blocker, has been shown to reduce sleep cycles in mutant mice and in humans with narcolepsy. No selective H4 ligand is available for use in humans, Several studies have suggested that H4-receptor antagonists may be useful in pruritus, asthma, allergic rhinitis, and pain conditions.

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