Antihistamines
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Terms | Definitions |
|---|---|
 Histamine synthesis | from histadine - decarboxylated by histadine decarboxylase leaving histamine |
| Histamine distribution | majority in mast cells (tissues) and basophils (blood) ECL cells in gastric fundus and body (secrete acid in stomach) neurons in CNS (release as NT) |
| Histamine storage | polar molecule, sequestered in vesicles (called granules) released upon stimulation; degranulation = release of histamine from mast cells or basophils |
| Histamine release | two mech: antigen mediated (MOST COMMON) non-antigen mediated (drug/drug interactions that cause problems to release histamine) |
| Antigen mediated release | You're exposed to an antigen; first time you increase immune system to release IgE - goes into blood stream; then second time you're exposed immune system is primed - FC receptors on mast cells can bind immunoglobulin (IgE) then if exposed to antigen again it induces the pathway to release histamine |
| Antigen mediated release - requrements | requires Ca2+ and ATP via the IP3/DAG pathway; released histamine is a mediator of immediate (type 1) allergic rxn; degranulation blocked by cromolyn sodium; modulated by feedback inhibition via H2 receptors |
| Non-antigen mediated release | mediated by drugs, peptides, venoms, sunburn can damage or disrupt mast cells membranes resulting in release; some drugs displace histamine from granules (morphine, codeine); some toxins that cause release of histamine by activating the IP3/DAG signal pathway |
| H1 receptors location | smooth muscle*, endothelium*, brain and heart |
| H2 location | gastric mucosa (parietal cells)**, mast cells, brain (neg feedback) and heart |
| H3 location | presynaptic: brain or myenteric plexus neurons |
| H4 location | eosinophils, neutrophils and T-cells (CD4+) |
| H1, H2, H3, H4 - mech | ALL are G-protein coupled receptors; outside the cell = outer domain to bind histamine; 7 transmembrane domain; associated with G-proteins: alpha, beta, gamma subunits; bind it and get dissociation of gamma, beta from alpha |
| H1 mediates | allergic rxns |
| H2 mediates | gastric secretion; antagonists used to inhibit gastric secretions |
| H3 mediates | cognition, sleep-wake cycle, obesity and epilepsy; antagonists used to improve memory and attention; stimulate arousal or antiepileptic |
| H4 mediates | chemotaxis of eosinophils, neutrophils and CD4+ T cells; antagonists used to improve inflammatory conditions like allergic rhinitis, asthma, rheumatoid arthritis |
| Responses to H1 activation | vasodilation; increased capillary permeability (produces edema); smooth muscle contraction (bronchoconstriction) - uterus too; pain or itching |
| Lewis Triple Response | dilation of capillaries = flush; dilation of arterioles = flare; swelling = wheal; pain or itching; this is a POSITIVE control for skin testing |
| anaphylaxis | exposure to specific antigens; via food, insect bites or from drugs; can lead to a massive release of mast cell contents; OVER produce IgE = too dramatic release of histamine; decreased BP, impaired resp fxn, abdominal cramps, urticaria (leads to welts) |
| Clinical uses of Histamine | broad and largely undesirable effects; NO clinical indications except for positive skin tests; most BLOCK effects of histamine |
| histamine antagonists - physiological | Epi has actions on smooth muscle that are oppostie of histamine, working through adrenergic receptors; cause bronchoconstriction and vasoconstriction |
| histamine antagonists - release inhibitors | block or reduce the degranulation of mast cells (ex: cromolyn sodium); give prophylactically |
| histamine antagonists - receptor antagonists | compete for binding to specific histamine receptors and block the activation of that receptor; BLOCK histamine from binding to H1 |
| antihistamines - good news | they ALL work by the SAME mech; they are reversible, competitive inhibitors of histamine at the histamine H1 receptor; they are all just as effective! |
| antihistamines structure | have 4 places to modify |
| antihistamines MOA | all competitive and reversible blockers of histamine at the H1 |
| antihistamines absorption | oral, parenteral, topical distribution = variable |
| antihistamines duration, tolerance and elimination | duration 3-24 hrs; tolerance = with prolonged use; elimination = hepatic metabolism; excreted as inactive metabolites |
| main reason to CHOOSE a specific H1 antagonist | to avoid certain side effects or take advantage of certain side effects (non-H1 receptor properties) or duration of action |
| antihistamines side effects - CNS | sedation - varies; antinausea/antiemetic - treat motion sickness |
| antihistamines side effects - anticholinergic | anticholinergic effects = dry response |
| antihistamines side effects - antiparkinson | antiparkinsonism effects = from anticholinergic effect in CNS, used to combat parkinsonism like sympmtoms of some antipsychotic drugs |
| antihistmaine side effects - local anesthesia | block sodium channels in excitable membranes (similar to procaine and lidocaine) |
| antihistamine side effects - adrenoceptor blocking | primarily alpha may cause ortho hypotension |
| antihistamine side effects - cocaine-like | block reuptake of NE (diphenhydramine) - produce a sympathomimetic effect |
| antihistamine drug interactions | alcohol, barbiturates, other depressants, tranquilizers, MAO inhibitors |
| Dibenzoxepin tricyclics - Doxepin | TCA and also an antihistamine; in depressed pts they tolerate this well; in non-depressed they don't like the side effects |
| Ethanolamines - Diphenhydramine | used in sleep preparations and for motion sickness; **side effects = marked sedation and anticholinergic |
| Ethylenediamines - Pyrilamine | side effects = **lack anticholinergic activity |
| Alkylamines - Chlorpheniramine | may have SSRI activity; side effects = **CNS stimulation and sutible for daytime! |
| Piperazines - Meclizine | often used as antinausea; side effects = **moderate sedation, teratogenic? |
| Phenothiazines - Promethazine | side effects = **anticholinergic, prominent sedation |
| Piperidines - Phenindamine | no longer available; side effects = **moderate sedation, teratogenic? |
| 2nd generation H1 blockers | DO NOT penetrate CNS??; bind preferentially to peripheral H1 receptors; FREE of anticholinergic and adrenergic blocking activities; doesn't potentiate CNS effects of alcohol, diazepam and other CNS active drugs |
| 2nd generation piperazines - Cetirizine | lower incidence of side effects |
| 2nd generation piperidines - Loratadine | unclear if it manifests arrhythmias? others in its class do |
| 2nd generation Phthalazinones - Azelastine | low incidence of side effects |
| Why prescribe? | Symptomatic relief of allergic symptoms; adjunct to Epi in anaphylactic rxns; antipruritic agents; sedative (diphenhydramine, promethazine, hydroxyzine) in OTC sleep aid |
| H1 antagonist | most effective for seasonal rhinitis and conjunctivitis; not for COLDS!; useful adjunct with Epi in anaphylaxis; useful for allergic dermatoses |
| AVOID antihistamines | acute glaucoma (anticholinergic); herat disease (esp 2nd generation); preg/lact (avoid 1st tri esp; Chlorphenamine in 2nd or 3rd; NONE for lact) |
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