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57 Cards in this Set
- Front
- Back
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histamine synthesis
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-from essential AA L-histidine
-via a specific histidine decarboxylase (inducible) using pyridoxal 5-phosphate as cofactor (inhibited by methyl-histidine) |
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histamine localization
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-ubiquitous with highest amounts in lung, skin, and stomach
-pools of histamine in tissues (mast cells) and blood (basophils) and in non-mast cell stores |
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Mast cell and basophil store of histamine
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-synthesized and stored in secretory granules
-complexed with heparin sulfate and ATP in mast cells -complexed with chondroitin in basophils -turnover is slow in mast cells |
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non-mast cell stores of histamine
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-epidermal cells, gastric mucosa, brain neurons, regenerative and tumor cells
-rapid turnover, no granules, continuously released -levels correlate with the activity of histidine decarboxylase (inducible) |
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release of histamine-- within seconds
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-burning/itching most marked in palms, face, scalp, ears
-intense warmth -skin redness -bp falls, HR increases -headache common |
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release of histamine--within minutes
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-bp recovers
-hives (urticaria) appear on skin |
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drugs/peptide/venom releasing histamine
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-stim direct release without prior exposure (can cause unexpected anaphylaxis)
-vancomycin-induced red man syndrome -substance P; complement-induced -venoms from wasps -all increase intracellular Ca2+ |
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other stimuli that release histamine
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-cold utricaria
-cholinergic (stress) utricaria -solar utricaria -nonspecific cell damage |
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what drug is for preventive management of asthma, allergic rhinitis, conjunctivitis
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-cromolyn sodium
-stabilizes most mast cell membranes and prevents histamine release |
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what drug is used for allergic asthma (last choice)
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-omalizumab
-monoclonal ab to dec amount of antigen specific IgE that normally binds to and sensitizes mast cells |
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b-adrenoceptor agonists
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-stim adenylyl cyclase which inc cAMP
-epi (a and b agonist), ephedrine (a and b agonist), albuterol (b2 agonist) |
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methylxanthines
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-phosphodiesterase inhibitors, block metabolism of cAMP
-can be used for migraines |
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corticosteroids and asthma
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-reduce histamine release but only at high concentrations which are not reached under normal therapeutic conditions
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histamine inhibiting its own release
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-autoreceptors (H3) on neurons
-H2 receptors on mast cells, mediated by inc in cAMP |
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histamine receptors
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-all located on cell membrane
-all are GPCRs -h1 and 2 are most important for pharmacology |
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H1 receptor
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-Gq: inc Ca2+, inc NO, inc cGMP
-found on smooth muscle, endothelial cells, and CNS |
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H2 receptor
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-Gs: inc cAMP
-found on gastric parietal cells, cardiac muscle, mast cells, CNS |
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H3 receptor
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-Gi: dec cAMP, inc MAP kinase
-found in CNS: presynaptic |
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H4 receptor
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-Gi: dec cAMP, inc Ca2+
-found on cells of hematopoietic origin |
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histamine's general effects on CV
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-dilates resistance vessels
-inc capillary permeability -causes overall dec in bp -can constrict veins --> edema |
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histamine and vasodilation
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-endothelial cells: H1 activation --> inc intracell Ca2+--> inc NO
-vasc smooth m: H2 activation --> inc cAMP |
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vasoconstriction of larger vessels from histamine
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-H1 receptors, if located on vascular smooth m, cause inc in intracell Ca2+ --> contraction
(versus on endothelial cells where H1 causes inc Ca which activates NO and causes vasodilation) |
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histamine and bp
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-acts on both H1 and H2
-overall decrease |
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histamine and increased vascular permeability
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-H1 receptors on endothelial postcapillary venules --> contract --> edema
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histamine and heart
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-mostly H2
-increased cardiac contractility and electrical events |
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histamine and bronchioles
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-H1: contraction (minor H2 relaxation)
-effect is more pronounced in asthma/pulm disease |
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histamine and intestinal smooth muscle
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-H1: contraction
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histamine and exocrine glands (GI secretory tissue)
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-H2 mediated gastric secretion
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histamine and peripheral nerve endings
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-H1: pain and itching
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Triple response of Lewis
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-Red line/Flush: H1 dilation
-Red Flare: axonal reflex by H1 receptors: dilation -Wheal: H1 mediated inc in vascular permeability--> edema |
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histamine neuroendocrine effects
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-H1: arousal
-H1: dec appetite |
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pharmacology of H1 blockers
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-specific reversible competitive antagonism of H1 receptors located in periphery and CNS
-an inverse agonist (constitutive activity is decreased) -capill permeability is inhibited -edema/itch suppressed -NO effect on hypotension or bronchoconstriction |
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are H1 blockers useful in treating anaphylaxis alone?
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-NO
-don't help with bronchoconstriction |
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1st gen vs 2nd gen H1 blockers
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-1st gen have more sedative and anticholinergic effects
-2nd gen are generally nonsedating (cetirizine is most sedating) |
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H1 blocker effects on CNS
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-1st gen depress CNS (sedation, slowed rxns, dec alertness) most often but can cause stimulation in overdose in children
-2nd gen do not cross BBB -1st gen prevent motion sickness via anti-cholinergic effect |
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anticholinergic effects of 1st gen H1 blockers
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-atropine-like effects (inhibit responses to ACh via blocking muscarinic receptors)
-dry mucous membranes, urinary retention |
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H1 blockers and anesthetic effects
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-local effect
-becase of nonspecific effect unrelated to H1 blocking |
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2nd gen H1 blocker metabolism
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-via CYP3A4 and 2D6
-some have active metabolites |
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Terfenadine is metabolized to...
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fexofenadine
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loratadine is metabolized to...
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desloratadine
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hydroxyzine is metabolized to...
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cetirizine
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1st gen H1 blocker sedation mechanism
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-inhibition of both cholinergic and histaminergic pathways in CNS
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GI side effects with H1 blockers
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-loss of appetite, nausea, vomiting
-rare cases with inc appetite and weight gain |
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loratadine and toxicity
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-although other drugs were pulled because of CV toxicity, none associated with this drug
-metabolized by CYP3A4 and 2D6 -even though certain drugs inhibit these enzymes, no CV toxicity |
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less effective use of H1 blockers for allergies
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-when allergens are most abundant
-when exposure to allergens is prolonged -when nasal congestion is prominent |
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what H1 blockers can be used to treat motion sickness
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-bc of anticholinergic effects
-promethazine -dimenhydrinate -diphenhydramine (scopolamine-- muscarinic antag) |
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what H1 blocker is used for vestibular disturbances
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dimenhydrinate
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what H1 blocker is used for chemo-induced nausea/vomiting
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promethazine
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what H1 blocker is used in early-stage Parkinson's
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diphenhydramine
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physiology of histamine in GI
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-vagus n and gastrin --> histamine released from mast cells and ECLs
-once relased, acts on H2 rec in parietal cells --> inc adenylyl cylclase --> inc cAMP --> inc protein kinases --> inc H+ (gastric acid) |
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H2 blocker pharmacology
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-competitive inhibitors of histamine at H2 rec on basolateral membrane of parietal cells
-inhibit gastric acid secretion from parietal cells -reduce vol of gastric acid and its H+ conc |
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side effects of H2 blockers
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-usually minor
-diarrhea, headache, drowsiness -less common CNS: confusion, delirium, slurred speech (usually from IV or in elderly) -may alter rate of absorption and bioavailability of certain drugs because of change in pH |
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what are the main H2 blockers in order of potency
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famotidine> ranitidine> cimetidine
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H2 blockers and CYP
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-cimetidine inhibits CYP
-ranitidine does also, but only has 10% of the affinity that cimetidine has -decreased metab and inc half-life of other drugs metabolized by these CYPs (phenytoin, cyclosporine, propanolol, warfarin, etc) |
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long term use of cimetidine at high doses
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-decreases testosterone binding and inhibits a CYP that hydroxylates estradiol
-in men, gynecomastia, reduced sperm count, impotence |
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Zollinger-Ellison syndrome
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-non beta cell tumor of pancreas with an overproduction of gastrin
-was treated with H2 blockers -now, use proton pump inhibitors |
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which H2 blocker has the most side effects
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cimetidine
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