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25 Cards in this Set
- Front
- Back
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autocoid
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"self remedies" released locally at sites of injury and or allergic rxns
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5-Hydroxytyptamine (5-HT) "serotonin"
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Long history, got sexy when research on LSD became popular, has many effects
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5HT localization and physiological roles
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--1. enterocromafin celss in the GI, about 90% of 5HT resides here (intestinal motility emesis?)
--2. Platelets: 8%, local vasoconstriction after injury, hemostatitc effect --3. CNS: about 2% important NT, many behaviors ionfluenced |
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5HT synthesis, degradation, reuptake, storage
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--tryptophan hydroxylase is unique, but other enzymes are the same as in CA pathway
--5HIAA is the measured metabolite --precursor to melatonin in the pineal gland --reserpine will block vesicular uptake, will deplete 5HT at nerve terminals |
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Serotonin Receptors
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-most are G protein coupled (except 5HT3 which is a ligand gated ion channel much like the ACh R, will depolarize the membrane
-some decrease |
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5HT1 receptors
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-linked negatively to cAMP, tend to be negatively linked to AC, found presynaptically, produce inhibition of NT release
--selective agonists called the triptans, used for migraine headaches |
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5HT2 receptors
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THINK HEMOSTATIC EFFECTS
-linked to PLC, will increase calcium levels -evokes NO and prostaglandin release leading to vasodilation -also causes vasoconstriction in most beds due to increased Ca in vascular smooth m. -platelet aggreagation |
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5HT3 receptors
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-important in the stomach, ligand gated ion channels, stimulation on nerve endings mediate emesis
--5HT3 antaganosits, ondansetron, granisetron, inhibit vomiting (but not from motion sickeness, only chemotherapy) |
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Fluoxetine (and other SSRIs)
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inhibit 5HT transporter, increases 5HT at synapse, used to treat depression
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LSD
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ergot alkaloid, agonsit and antagonist effects on 5HT receptors
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Sumitiptan
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5HT1 agonist, used for migraine headaches
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Histamine
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-1. mast cells: predominant storage site (skin, bronchial mucosa, intestinal mucosa), major role in immediate allergic rxs, produces bronchoconstriciton, vasodilation at injury site and capilary permeabilty and edema
-2. gastric enterochromaffin-like cells, increases gastric acid secretion -3. CNS: plays role in drinking behavior, regulating body T and blood pressure and pain perception |
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History of histamine
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-First isolated from extracts of ergot, poisonous fungus, grows on rye
-St. anothony's fire |
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Synthesis of histamine
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-derived from histidine, synthesized in mast cells, and gastric ECL cells and neurons, stored in granules similar to synaptic vesicles and released by Ca dependent exocytosis, it is degraded by N-methyltransferease followed by MAO-B
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Histamine receptors
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-H1 thru H4, all G protein coupled receptors
(H1 inflammation, H2 stomach) |
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H1 receptor
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-linked to PLC and Ca generation,
-blood vessel vasodilation via action on endothelial cell action, via NO/cGMP pathway -increased capilary permiabiltiy, endotheila cells contract and separate boundaries, -bronchoconstriciton -sensory nerve afferents, pain perception |
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H2 receptor
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-linked positively to AC and increases cAMP
-parietal cells of stomach, leads to gastric acid secretion -blood vessels, smooth muscle cell stimulation leads to vasodilation, slower onset but longer acting |
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H3 and H4
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-H3
-H4 |
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Histamine in mast cells
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-histamine is stored in granules in mast cells, IgE binding leads to release of histamine, epinephrine and cromolyn sodium will prevent this release
--histamine release will result in bronchoconstriction, local vasodilation, and increased capillary permeability and edema |
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Triple response of Lewis
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1. localized red spot 1mm wide due to H1 and H2 receptors
2. Flare 1 cm wide, bright red flush due to vasodilatation mediated by axon refelexes (via H1) 3. Wheal 1 mm wide white spot due to enhanced capillary permeability and edema formation (via H1) |
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Gastric acid secretion
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-histamine is released by ECL cells, acts on H2 receptors and increases cAMP which activates ATP dependant proton pump
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Antihistamines: H1 receptor blockers
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1. first generation: chlorpheniramine (alka seltzer), diphenhydramine (benadryl), side effect of CNS drowsiness, dry mouth, difficulty urinating, due to anti muscarinic effects
2. second generation: do not cross BBB to avoid CNS effects, but had cardiac arrhythmia side effects ---but more recent second generation drugs don't have the cardiac problems, Loratadine (claritin) |
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Antihistamines: H1 receptor blockers (cont'd)
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others
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Antihistamines: H2 receptor blockers
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-H2 receptor antagonistsm major use is to treat stomach ulcers, and GERD
-***Ranitidine (Zantac) -Cimetidine (Tagamet) terrible CYP DDI -Famotidine (Pepcid) |
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Side effects of antihistamines
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-not too many, fairly safe drugs
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