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Histamines and Antihistamines
- 1. AUTACOIDS HISTAMINE AND ANTIHISTAMINES A.VENKATRAMAN M.PHARM 1STYEAR 1ST SEM DEPARTMENT OF PHARMACOLOGY
- 2. HISTAMINES • Introduction- Autacoids •Histamine sites • Synthesis storage and destruction • Release of Histamine • Histamine Receptors and types • Pharmacological action with sites • Pathophysiological roles of Histamines • Uses of Histamine
- 3. ANTIHISTAMINES • Histamine Antagonists •Classification H1 Antagonists • Second generation Antihistamines • Pharmacological effects • Mechanism of action • Pharmacokinetics • Therapeutic uses and Side effects • Drug interactions • H2 Antagonist & Pharmacological effects • Drugs , Mechanism of action, Uses
- 4. INTRODUCTION- AUTACOIDS • AUTACOIDS auto=selfakos=healing/remedy • First autacoid to be discovered • Histamine was synthesized in 1907 and characterized in 1910 • Demonstrated to be a natural constituent of mammalian tissues(1927) • These are diverse substances produced by a wide variety of cells in the body, having intense biological activity, but generally act locally (e.g. within inflammatory pockets) at the site of synthesis and release. • Thus they have also been called ‘local hormones’
- 5. AUTACOIDS • Autacoids areinvolved in a number of physiological and pathological processes (especially reaction to injury and immunological insult) • And even serve as transmitters or modulators in the nervous system, but their role at many sites is not precisely known. • A number of useful drugs act by modifying their action or metabolism.
- 6. CLASSIFICATION Amine derived: Histamine(amino acid: Histidine), Serotonin (5 hydroxy tryptamine) Peptide derived: Plasmakinins (Bradykinin, Kallidin), Angiotensin Lipid derived: Prostaglandins, Leukotrienes, Platelet Activating Factor (PAF), etc. Others : Cytokines (interleukins, TNFα, GM- CSF, etc.) and several peptides like gastrin, somatostatin, vasoactive intestinal peptide (VIP) and many others may be considered as autacoids.
- 7. HISTAMINES • Histamine, meaning‘tissue amine’ (histos—tissue) • Imidazole ethylamine -formed from the amino acid Histidine • Important inflammatory mediator • Plays an important role in inflammation, anaphylaxis, allergies, gastric acid secretion, neurotransmission in parts of the brain and drug reaction • As part of an immune response to foreign pathogens, its produced by Basophils and Mast cells found in nearby connective tissues.
- 8. SITES OF HISTAMINE Mast cellsite: • Pulmonary tissue (mucosa of bronchial tree) • Skin • GIT(intestinal mucosa), lung, liver and placenta Concentration of histamine is particularly high in these tissues Non-mast cell sites: • CNS (neurons) • Epidermis of skin. • GIT(gastric cells) • Cells in regenerating or rapidly growing tissues • Basophils (in the blood)
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- 10. STORAGE AND DEGRADATION Storedin complex with: • Heparin • Chondroitin sulphate • Eosinophilic Chemotactic Factor • Neutrophilic Chemotactic Factor Proteases Degradation: • Degraded rapidly by oxidation to imidazole acetic acid • Degraded rapidly by methylation to N-methyl histamine • Very little histamine is excreted unchanged
- 12. RELEASE OF HISTAMINES: 1. Tissueinjury: Any physical or chemical agent that injures tissue, skin or mucosa are particularly sensitive to injury and will cause the immediate release of histamine from mast cells. • Chemical and mechanical mast cell injury causes degranulation and histamine release • Surface acting agents like Tween 80, compound 48/ 80 etc. The primary action of these substances is release of histamine from mast cells, therefore they are called histamine liberators. • They produce an ‘anaphylactoid’ reaction—itching and burning sensation, flushing, urticaria, fall in BP, tachycardia, headache, colic and asthma.
- 13. 2. Allergic reactions: •Exposure of an antigen to a previously sensitized (exposed) subject can immediately trigger allergic reactions. • If sensitized by IgE antibodies attached to their surface membranes will degranulate when exposed to the appropriate antigen and release histamine, ATP and other mediators
- 14. 3. Drugs andother foreign compounds: Morphine, dextran, antimalarial drugs, dyes, antibiotic bases, alkaloids, amides, quaternary ammonium compounds, enzymes (phospholipase C). Penicillins, Tetracyclines, Basic drugs- amides, amidines, diamidines, Toxins, venoms, Proteolytic enzymes, Bradykinin, Kallidin, and Substance P
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- 16. HISTAMINE RECEPTORS- Subtypes Histaminergicreceptors were classified by Asch and Schild (1966) into H1 & H2 H1 receptors: Mediate effects on smooth muscle leading to vasodilation (relaxation of vascular smooth muscle), increased permeability and contraction of non-vascular smooth muscle Sir James Black (1972) developed the first H2 blocker burimamide H2 receptors: Mediate histamine stimulation of gastric acid secretion and may be involved in cardiac stimulation H3 receptor, which serves primarily as an autoreceptor controlling histamine release from neurons in brain was identified in 1983. H3 receptor : Feedback inhibition in CNS, GIT, Lungs and Heart Molecular cloning has revealed yet another (H4 ) receptor in 2001 H4 receptors: Eosinophils, Neutrophils and CD4 T-cells All these four receptors are members of the 7-transmembrane (heptahelical) spanning family of receptors, are G protein-coupled (GPCR)
- 19. PHARMACOLOGICAL ACTIONS-H1 BLOOD VESSELS: •C5a andC3a stimulate mast cells to release Histamine, that causes marked dilatation of smaller blood vessels, including arterioles, capillaries and venules. • Like ACh and many other autacoids, vasodilatation caused by histamine is partly (H1 component) indirect, mediated through ‘endothelium dependent relaxing factor’ (EDRF) • If Injected intradermally, it elicits the triple response consisting of: Red spot: due to intense capillary dilatation. Wheal: due to exudation of fluid from capillaries and venules. Flare: redness in the surrounding area due to arteriolar dilatation mediated by axon reflex.
- 20. Exocrine Excretion(H1): •Increased productionof nasal and bronchial mucus Bronchial Smooth Muscle(H1) •Bronchiolar constriction •Asthmatic symptoms •Decreased Lung capacity Intestinal Smooth Muscle(H1) • Contraction - Intestinal cramps and diarrhea Sensory Nerve Endings(H1) • Itching and pain Central Nervous System • Histamine does not penetrate blood brain barrier—no central effects are seen on I V injection. However, intra cerebro ventricular administration produces rise in BP, cardiac stimulation, behavioral arousal, hypothermia, vomiting and ADH release. These effects are mediated through both H1 and H2 receptors
- 21. Pharmacological Actions (H1&H2): Cardiovascular System(H1&H2) • Decreased Peripheral resistance ----- decreased systemic BP • Positive chronotropism(H2) • Positive inotropism Skin (H1&H2) • Dilatation and increased permeability of the venules • Leakage of fluid + proteins into the tissues • Classic “triple-response”
- 22. Histamine- Pathophysiological roles: GASTRICSECRETION: • Histamine has dominant physiological role in mediating secretion of Hcl in stomach. • It is released locally under the influence of all stimuli that evoke gastric secretion (feeding, vagal stimulation, cholinergic drugs and gastrin) and activates the proton pump (H+K+ ATPase) through H2 receptors. • H2 blockers not only suppress acid secretion induced by histamine but also markedly diminish that in response to ACh and gastrin.
- 23. Allergic Phenomena: Released frommast cells following AG : AB reaction on their surface (involving IgE type of reaginic antibodies;) in immediate type of hypersensitivity reactions, histamine is causative in urticaria, angioedema, bronchoconstriction and anaphylactic shock. As Transmitter: Histamine is believed to be the afferent transmitter which initiates the sensation of itch and pain at sensory nerve endings. • In the brain H1 agonist suppresses appetite; certain H1 antagonists stimulate appetite. • Histamine also appears to act as a transmitter regulating body temperature, cardiovascular function, thirst, hormone release from anterior pituitary and possibly other functions
- 24. Inflammation: • Histamine hasbeen implicated as a mediator of vasodilatation and other changes that occur during inflammation. • It promotes adhesion of leukocytes to vascular endothelium by expressing adhesion molecule P-selectin on endothelial cell surface, sequestrating leukocytes at the inflammatory site. Tissue Growth and Repair: Because growing and regenerating tissues contain high concentrations of histamine, it has been suggested to play an essential role in the process of growth and repair. Headache: Histamine has been implicated in certain vascular headaches, but there is no conclusive evidence.
- 25. USES- HISTAMINE • No therapeuticvalue • Occasionally used in some diagnostic tests: • Testing gastric acid secretion. • Diagnosis of Phechromocytoma. • Pulmonary function: to test for bronchial hyperreactivity. Betahistine - H1 agonist • Used to control vertigo in patients of meniere’s disease. • Acts by causing Vasodilatation in internal ear. • It is contraindicated in asthmatics and ulcer patients. Betazole - H2 agonist • Used in gastric function tests
- 26. HISTAMINE EFFECTS ACCORDING TO PLASMA HISTAMINE CONCENTRATION Histamine Clinicaleffect concentration in ng/ml: • 0–1 Reference • 1–2 ↑ Gastric acid secretion ↑ Heart rate • 3–5 Tachycardia, headache, flush, urticaria • 6–8 ↓ Arterial pressure • 7–12 Bronchospasm ≈100 Cardiac arrest
- 28. H1 ANTIHISTAMINES The termantihistamine, refers to the classic H1- receptor blockers These compounds do not influence the formation or release of histamine; rather, they block the receptor mediated response of a target tissue These drugs competitively antagonize actions of histamine at the H1 receptors
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- 30. H1 ANTIHISTAMINES -GENERATIONS • The H1-receptor blockers can be divided into : First and Second generation drugs. • The first generation drugs penetrate the CNS and cause sedation • The second generation agents are specific for H1 receptors • Because they do not penetrate the blood-brain barrier, they show less CNS toxicity than the first-generation drugs • Among these agents loratadine/ desloratadine/ fexofenadine produce the least sedation
- 32. H1 Antihistamines- Secondgeneration drugs Fexofenadine: • It is the active metabolite of terfenadine • Fexofenadine does not cross blood-brain barrier—does not produce sedation or impair psychomotor performance • It is rapidly absorbed, excreted unchanged in urine and bile, has plasma t½ 11– 16 hours and duration of action 24 hours • Dose: For allergic rhinitis 120 mg OD; for urticaria and other skin allergies 180 mg OD.
- 33. Loratadine • Selective peripheralH1 antagonist which lacks CNS depressant effects and is fast acting. • No interaction with macrolides or antifungals has been noted. Good efficacy has been reported in urticaria and atopic dermatitis. Desloratadine • It is the major active metabolite of loratadine effective at half the dose • Noninterference with psychomotor performance and cardiac safety are documented.
- 34. PHARMACOLOGICAL EFFECTS OF ANTIHISTAMINES Sedation •A common effect of first-generation H1 antagonists is sedation, but the intensity of this effect varies among chemical subgroups. • Second-generation H1 antagonists have little or no sedative or stimulant actions COUGH • Antihistaminics like chlorpheniramine, diphenhydramine and promethazine are constituents of many popular cough remedies
- 35. PHARMACOLOGICAL EFFECTS OF ANTIHISTAMINES Acutemuscle dystonia Caused by antidopaminergic-antipsychotic drugs is promptly relieved by parenteral promethazine, diphenhydramine or hydroxyzine. Antihistaminics block symptoms produced by histamine liberators; afford symptomatic relief in insect bite and ivy poisoning Antinausea and Antiemetic Actions • Several first- generation H1 antagonists have significant activity in preventing motion sickness. • They are less effective against an episode of motion sickness already present ALSO HAS ANTIPARKINSON EFFECTS
- 36. PHARMACOKINECTICS Absorption These agents arerapidly absorbed after oral administration • Peak blood concentrations occur in 1–2 hours • Widely distributed throughout the body • First-generation drugs enter CNS readily Biotransformation(Metabolism) Some of them are extensively metabolized, primarily by microsomal systems in the liver • Several of the second-generation agents are metabolized by the CYP3A4 system
- 37. Antihistamines- Therapeutic Uses and • Usedin the treatment of allergy and inflammatory conditions MOTION SICKNESS Diphenhydramine, dimenhydrinate, cyclizine, meclizine, and hydroxyzine, are the most effective agents for prevention of the symptoms of motion sickness • USED IN THE TREATMENT OF VERTIGO
- 38. Adverse Effects ANDToxicity • Tremors • Hallucinations • muscular incordination, • convulsions, • flushing, • hypotension, • Fever • drowsiness
- 39. DRUG INTERACTIONS Antihistamines thatproduce sedation can potentiate CNS depressants (e.g., barbiturates, opiates, general anesthetics, and alcohol) Antihistamines that possess anticholinergic actions can produce manifestations of excessive blockade if given with anticholinergic drugs (e.g., dry mouth, constipation, or blurred vision)
- 40. H2 ANTAGONIST The first H2blocker Burimamide was developed by Black in 1972. Metiamide was the next. Cimetidine was introduced in 1977 and gained wide usage. Ranitidine, famotidine, roxatidine, and many others have been added subsequently. They are primarily used in peptic ulcer and other gastric hypersecretory states
- 41. Regulation of Gastricacid secreation H2 antagonists suppress not only histamine, but also ACh, gastrin and in fact any gastric acid secretory stimulus.
- 42. H2 Antagonist PharmacologicalEffects Cimetidine and all other H2 antagonists block histamine-induced gastric secretion, cardiac stimulation • They attenuate fall in BP due to histamine, especially the late phase response seen with high doses. • They are highly selective: have no effect on H1 mediated responses or on the action of other transmitters/autacoids. • The H2 blockers have antiulcerogenic effect. Gastric ulceration due to stress and drugs (NSAIDs, cholinergic, histaminergic) is prevented. • Reduces gastric acid volume and concentration of pepsin
- 43. Ranitidine • A nonimidazole(has a furan ring) H2 blocker, it has several desirable features compared to cimetidine: • About 5 times more potent than cimetidine. H2 Antagonist- Therapeutic Uses • Duodenal ulcer • Gastric ulcer • Zollinger-Ellison syndrome (a pathological hypersecretory state resulting in excessive gastric pepsin & HCl) • Gastroesophageal reflux disease (GERD)