?*These effects are also observed after the ingestion of spoiled fish (scombroid fish poisoning), and histamine produced by bacterial action in the flesh of the fish is the major causative agent. ?Contraindications: ?Patients with: ?asthma (except as part of a carefully monitored test of pulmonary function) ?active ulcer disease ?Gastrointestinal bleeding ? ?HISTAMINE ANTAGONIST ?Physiologic antagonist – have smooth muscle actions opposite to those of histamine, but they act at different receptor.
?Epinephrine (injection) – can be lifesaving in systemic anaphylaxis and in other conditions in which massive release of histamine and other more important mediators occurs. ?Release inhibitors – reduce the degranulation of mast cells that results from immunologic triggering by antigen-IgE interaction. ?Cromolyn ?Nedocromil ??? -adrenoceptor agonists – capable of reducing histamine release. ? ?HISTAMINE RECEPTOR ANTAGONISTS – third approach to the reduction of histamine-mediated responses. ?
H? -Receptor Antagonists – compounds that competitively block histamine – used in the treatment of allergic conditions. ?First-Generation Agents – block autonomic receptors. -Enter the central nervous system readily. -Metabolized by microsomal system in the liver. -Most extensively promoted and used over-the-counter drugs. ?Actions: 1. Sedation – common effect ?Effect: oSufficiently prominent with some agents to make them useful as “sleep aids” and unsuitable for daytime use oResembles that of some antimuscarinic drugs and is considered very different from the disinhibited sedation produced by sedative-hypnotic drugs.
?Ordinary dosages: children occasionally (adults rarely) manifest excitation rather than sedation ?High toxic dose level: stimulation, agitation, convulsion ??? coma ?*2nd-generation – have little or no sedative or stimulant actions. ?HAVE FAR FEWER AUTONOMIC EFFECTS THAN THE 1ST-GENERATION ANTIHISTAMINES 2. ANTINUSEA AND ANTIEMETIC ACTIONS – BECAUSE SEVERAL 1ST-GENERATION H? ANTAGONISTS HAVE SIGNIFICANT ACTIVITY IN preventing motion sickness. ?Doxylamine – widely used in the past in treatment of nausea and vomiting of pregnancy.
3. Antiparkinsonism effects ?Diphenhydramine – significant acute suppressant effecrs on the extrapyramidal symptoms associated with certain antipsychotic drugs. -Given parenterally for acute dystonic reactions to antipsychotics. 4. Anticholinoceptor actions ?Ethanolamine ?Ethylenediamine ?*This action may be responsible for some of the (uncertain) benefits reported for nonallergic rhinorrhea but may also cause urinary retention and blurred vision. 5. Adrenoreceptor-blocking actions ?Phenothiazine subgroup: Promethazine ?*This action may cause orthostatic hypotension in susceptible individuals.
6. Serotonin-blocking action ?Cyprohetadine – antiserotonin agent -Its structure resembles that of the phenothiazine antihistamines, and it is potent H? – blocking agent 7. Local anesthesia – block sodium channels in excitable membranes in the same fashion as procaine and lidocaine. used to treat asthma Subgroups that have significant atropine-like effects on peripheral muscarinic receptors ?More potent than procaine as local anesthetics; ?occasionally used to produce local anesthesia in patients allergic to conventional local anesthetic drugs;
?small # of these agents also blocks K channels ?Diphenhydramine ?Promethazine ? ? 8. Other actions ? Cetirizine – inhibit mast cell release of histamine and some other mediators of inflammation. ? Terfenadine ?Acrivastine ?Uses: 1. Allergic reactions – first drugs used to prevent or treat the symptoms of allergic reactions ?* ALLERGIC RHINITIS (HAY FEVER) – 2ND LINE DRUGS AFTER GLUCOCORTICOIDS ADMINISTERED BY NASAL SPRAY. ?* Urticarial – drug of choice ?* Bronchial asthma – ineffective ?* Atopic dermatitis – diphenhydramine are used mostly for their sedative side effect, w/c reduces awareness of itching. ?
Alkylamines – widely use drugs in the USA and the second-generation nonsedating agents. 2. Motion sickness and Vestibular Disturbances ?Diphenhydramine ?Promethazine ?Dimenhydrinate – salt of diphenhydramine and has similar efficacy. ?Piperazines: Cyclizines and Meclizines – less sedating than diphenhydramine in most patients. ?*Most effective when combined with ephedrine or amphetamine 3. Nausea and Vomiting of Pregnancy ?Piperazine derivatives – withdrawn because of its tetratogenic effects in rodents ?
Doxylamine – ethanolamine H?antagonist; withdrawn because of its continuing controversy about its possible effects. ?Toxicity: ?Systemic: excitation and convulsion in children, postural hypotension, and allergic responses. ?Topical: Drug allergy ?Drug Interactions ? ?Second-Generation Agents – less sedating, owing in part to their less complete distribution into the central nervous system. ?*rapidly absorbed after oral administration, with peak blood concentrations occurring in 1-2hrs. They are widely distributed throughout the body. -Metabolized by CYP3A4 system and thus are subject to important interactions when other drugs.
(such as ketonazole) inhibit this subtype of P450 enzymes. ?DOA of most drugs: 24-6hrs ?Meclizine – DOA: 12-24hrs ?Neutral H? antagonists & Inverse H? agonists – reduce or block the actions of histamine by reversible competitive binding to the H? receptor. ?Use: Treatment of allergic rhinitis and chronic urticarial ?H? -Receptor Antagonists – displays constitutive activity -Therapy for peptic disease -Has the ability to reduce gastric acid secretion with very low toxicity. ?Burimamide – antagonize the gastric acid-stimulating activity of histamine. ?Hз- & H?
– Receptor Antagonists ?Hз-selective ligands – of value in sleep disorders, narcolepsy, obesity, and cognitive, psychiatric disorders. ?Tiprolisant – inverse Hз-receptor agonist, has been shown to reduce sleep cycles in mutant mice and in humans with narcolepsy. ?H? – blockers – have potential in chronic inflammatory conditions such as asthma. ?H? -Receptor Antagonist – useful in pruritus, asthma, allergic rhinitis, and pain conditions. ? Inhibit P-glycoprotein transporter found in cancer cells, the epithelium of the gout, and the capillaries of the brain.