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Histamine
- an amine chemical messenger
- autocoid
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Histamine mediates a wide range of cellular responses including
- allergic reactions
- inflammatory reactions
- gastric acid secretion
- neurotransmissions in the brain
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Physiologic antagonist of histamine
- epinephrine
- does not act on the same receptor
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Histamine is synthesized in these cells
- enterochromaffin-like cells
- mucosal mast cells
- neurons
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Histamine is synthesized from _____ by _____.
- L-histadine
- L-Histadine Decarboxylase
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Histamine is stored in ____ in _____
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Storage granules in mast cells consist of
inactive complex composed of histamine and polysulfated anion heparin with anionic proteins
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histamine is rapidly inactivated by_____ to _____.
- monoamine oxidase type B
- methylimidazole acetic acid
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Slowly turning over pool of histamine is found in ____ and ____.
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Rapidly turning over pool of histamine is found in ____ and ____.
- gastric ECL cells
- histaminergic CNS neurons
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Extcretion of histamine
- very little excreted unchanged
- mostly metabolized by MAO B
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Neoplasms associaded with increased # of mast cells or basophils or with increased excretion of histamine and its metabolites
- systemic mastycytosis
- urticaria pigmentosa
- gastric carcinoid
- myelogenous leukemia
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Much lower concentrations of histamine are found in
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Location of histamine
- practically all tissues
- high amounts in lung, skin, GI tract
- Brain
- high concentrations in mast cells and basophils
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Ros of histamine in the CNS
- pain transmission
- arousal
- hormone release
- energy metabolism
- sexual behavior
- analgesia
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Histamine is a component of
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Drugs that stimulate histamine release
- reserpine
- codeine
- meperidine
- morphine
- D-tubocurarine
- papaverine
- Hydralazine
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Histamine release in the brain and other sites involves ______ . It is induced by ___ and dependent upon _____.
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Histamine release from mast cells
not released by K+ induced depolarization or by reserpine
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Other stimuli that release histamine from tissues
- destruction of cells
- cold
- bacterial toxins
- bee sting venoms
- trauma
- Allergies/anaphylaxis
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Diagnostic uses of histamine
- pheochromocytoma (increases release of catecholamines)
- bronchial hyper-reactivity
- pernicious anemia (lack of acid release indicates achlorydia)
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Histamine exerts is effects bin binding these receptors
- H1, H2, H3 and H4
- all G-protein coupled receptors
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In the brain H1 and H2 are located
post-synaptic
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In the brain H3 are located
presynaptic
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H3 and H4 have ____% homology
40%
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H1 receptors are present in these tissues
- smooth muslce
- endothelium
- brain
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H1 Post receptor mechanism
increase IP3 and DAG
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Partial H1 Agonist
2-m-fluophenyl-histamine
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Partial H1 antagonist
mepyramine
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H2 receptor tissue distribution
- Gastric mucosa
- cardiac mucle
- mast cells
- brain
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H2 Post receptor mechanism
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Partial H2 agonist
Impromidine
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H3 tissue distribution
- Presynaptic
- brain
- myenteric plexus
- other neurons
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H3 Post receptor mechanism
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H3 partial agonist
alpha-Methylhistamine
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H4 post receptor mechanism
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H4 Partial antagonist
thioperamide
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Gastric secretagogues
- acetylcholine
- histamine
- gastrin
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Action of acetylcholine blocked by
atropine
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Action of histamine blocked by
- cimetidine
- burimamide
- metiamide
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Antagonist for gastrin
no specific antagonist
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Histmaine action in the peripheral nervous system
- capilary dialation and increased permeability
- bronchoconstriction and GI contraction
- stimulation of chromaffin cells
- stimulation of sensory nerve endings causing pain
- vasodilation, tachycardia, headache
- stimulation of lung and gastric secretions
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H1 & H2 receptors in the cardiovascular system
- lower peripheral resistance
- positive chronotropism
- positive inotropism
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Antihistamine mechanism of action
- competitively block histamine receptors
- do not affect formation or release of histamine
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Chromolyn Sodium
degranulation of mast cells where histamine is stored
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1st generation H1 receptor blockers
- effective
- inexpensive
- high lipid solubility
- significant anti-cholinergic effects
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2nd generation H1 blockers
- do not penetrate BBB
- less CNS toxicity
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Ethanolamines
- 1st generation
- strong anti-cholinergic
- available as injection
- diphenhydramine
- doxylamine
- carbinoxamine
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Ethylamine diamines
- 1st gen
- mild anti-cholinergic
- pyrilamine
- tripelennamine
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Piperazines
- 1st generation
- no anti-cholinergic, injectable
- cyclizine
- meclizine
- hydroxyzine
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Alkalamines
- chlorpromazine
- bromphenirmaine
- mild-anticholinergic
- injectable
- 1st generation
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Phenothiazines
- promethazine - strong anticholinergic
- cyproheptadine - mild anticholinergic
- injectable
- 1st generation
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Piperidines
- fexofenadine
- loratadine
- 2nd generation (non-sedating)
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Piperazines (2nd generation)
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Alkylamines
- 2nd generation
- acrivastine
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Phthalazinones
- azelastine
- 2nd generation
- nasal spray
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H1 blockers are useful in treating acute allergies cause by antigens actin on
IgE antibody sensitized mast cells
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antihistamines are drug of choice in controlling symptoms of
- allergic rhinitis
- urticaria
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H1 receptor blockers are ineffective as monotherapy for
- bronchial asthma
- histamine is not the only cause
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H1 blockers used for motion sickness
- diphenhydramine
- meclizine
- cyclizine
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Antihistamines diminish nausea and vomiting mediated by
chemoreceptor and vestibular pathways
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Antiemetic action of antihistamines
independant of antihistamine and other actions
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antihistamines used as somnifacients
- diphenhydramine
- doxylamine
- may cause grogginess
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Pharmacokinetics of antihistamines
- max serum levels w/in 1-2 hours
- average t1/2 = 4-6 hours
- majority of metabolism in the liver
- metabolites excreted in the urine
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meclizine t1/2
12-24 hours
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H1 receptor blockers (esp. 1st gen) may interact with
- histamine receptors
- muscarinic cholinergic receptors
- alpha adrenergic receptors
- serotonin receptors
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Adverse effects of antihistamines
- sedation
- dry mouth and nasal passages
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Drug interactions with antihistamines
- potentiate effects of CNS depressants (alcohol)
- MAOI can exacerbate anti-cholinergic effects
- Erythromycin and clarithromycin interfere with metabolism of terfenadine and astemizole and may cause sever arrhythmias
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H1 recepor blockers do not interact with
- dopamine receptors
- beta adrenergic receptors
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Effective antidote for antihistamine poisoning that can reverse CNS excitement and convulsion
diazepam
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Untreated antihistamine overdosage may result in
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Major clinical use of H2 inhibitors
inhibit gastric acid secretion for the treatment of ulcers
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4 H2 blockers used in the US
- cimetidine
- ranitidine
- famotidine
- nizatidine
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H3 receptors are located
- outside of the parietal cells
- presyntaptically on cholinergic and noradrenergic noncholinergic neurons of the myenteric plexus where they inhibit release of neurotransmitters
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Potential applications of H3 agents have potential applications for
- obesity
- sleep disorders
- psychiatric disorders
- attention deficit disorders
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Tiprolisant
- inverse H3 receptor agonist
- decreases sleep cycles in narcolepsy
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H4 receptor blockers have potential use in
- chronic inflammatory asthma
- none avaiable for human use
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H1 selective blockers that show affinity for H4
diphenhydramine
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