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10-26-09 Bioenic Amines 1. Diagram how histamine is made and released.

Biosynthesis: Precursor: histidine Enzyme: 1-histidine-decarboxylase Present in ever tissue Storage: mast cells in skin, mucosa of bronchial tree, an intestinal mucosa. Also in !aso"hils in !loo an #S$% &elease: IgE !in ing to $c rece"tors on mast cells an !aso"hils Tyrosine kinase auto"hos"horylation &elease o' intracellular calcium stores, increasing cytosolic calcium an activating calcium(calmo ulin- e"en ent "rotein )inases an "rotein )inase #% Promotion o' 'usion o' secretory granules *ith "lasma mem!rane +e,ocytosis-. /ote: in a ition to causing histamine release, 0gE also results in activation o' "hos"holi"ase A2, *hich lea s to "ro uction o' platelet-activating factor, prostaglandin D2, an leukotriene D4% #onse1uently, there2s lea s to the allergic res"onses o' !ronchoconstriction, hy"otension, increase ca"illary "ermea!ility, an e ema% 03 organic bases cause release o' histamine% Tubocurarine, succinylcholine, morphine an ra iocontrast me ia cause ra"i histamine release resulting in ana"hyla,is% Beta-adrenergic agonists inhi!it histamine release% Chromolyn sodium is s"eci'ically use 'or inhi!ition in the lung% 2. Chart histamine elimination. 1! 2! and " receptors and diagram histamine metabolism and

/ote that all three histamine rece"tor ty"es are 4-"rotein cou"le % 1: elicits phosphoinositol hydrolysis% 0t is the target o' !oth classic an secon -generation antihistamines% releases en othelium- erive rela,ing 'actor +E5&$.vaso ilation ro" in systolic( iastolic BP contraction o' en othelial cellse ema 'ormation intestinal smooth muscle contractionincrease 40 motility( iarrhea at high ose !ronchial smooth muscle contraction!ronchoconstriction uterine contractionsa!ortion in "regnant *omen un ergoing ana"hyla,is stimulation o' sensory nerve en ings"ain an itching has role in triple response +re 'lare, e ema, *heal. 2: increases in cyclic AMP% 0t is the target o' antagonists use to ecrease gastic aci secretion% Stimulation o' gastric "arietal cells +increase cA6P.increase gastric aci secretion 0ncrease heart rate 6inor role in vaso ilation !y me iating smooth muscle rela,ation

": "resyna"tic feedback inhibition o' histamine, nore"ine"hrine, serotonin, an Ach release% Thioperamide is an 78 antagonist that has yet to !e a""rove % 9thio three: 7istamine meta!olism 6ost histamine is meta!olize !y histamine-#-methyl trans$erase 'ollo*e !y %&'B% ;esser amounts o' histamine are meta!olize !y D&' via an o,i ative eamination mech% Elimination <he meta!olites 'rom the a!ove !rea) o*n mechs have little activity an are e,crete in the urine ". Describe and distinguish pharmacologic actions o$ histamine on airway smooth muscles! exocrine glands! the cardio(ascular system and sensory ner(e endings. Air*ay smooth muscles Bronchoconstriction via !in ing to 71 + ue to smooth muscle rela,ation. E,ocrine glan s 0ncrease gastric aci secretion via !in ing to 72 + ue to increase in cA6P an intracellular calcium. #ar iovascular system 5irect vaso ilation ue to 71 an +to a lesser e,tent. 72 !in ing + ue to E5&$ release an smooth muscle relat,ation. 0ncrease heart rate ue to 72 !in ing E ema ue to 71 !in ing +causing contraction o' en othelial cells. Sensory nerve en ings Pain an itching ue to 71 !in ing ). Delineate pharmacological properties! ad(erse e$$ects and therapeutic uses o$ antihistaminic drugs. 71 rece"tor antagonists: com"etitive antagonists *ith "oor a''inity 'or 72 = 78 /ames: i"henhy ramine, "yrilamine, chlor"heniramine, "romethazine, cetirizine, cyr"ohe"ta ine, lorati ine, 'e,o'ena ine Pharmaco)inetics o' <>? classes-- $irst generation 71 rece"tor antagonists ;i"i solu!le, so they ra"i ly "enetrate the #/S an have se ative e''ects 5uration o' action @-6 hrs Secon generation 71 rece"tor antagonists ;ess li"i solu!le, so they on2t "enetrate the #/S an have no se ative e''ects 5uration o' action 12-2@ hrs "harmaco ynamics

Se ation +'irst generation only. Anti-emetic Anti-"ar)insonism Peri"heral antimuscarinic e''ects: urinary retention, rhinorrhea, !lurre vision Al"ha-a renorece"tor !loc)ing actions: orthostatic hy"ertension Serotonin-!loc)ing action ;ocal anesthetic actions #linical uses Allergic reactions i%e% 'or allergic rhinitis an urticaria +hives.% /?< e''ective 'or !ronchial asthma +!ecause several me iators are involve . 4oal is to minimize se ation: 2n generation 71 antagonists li)e ceterizine, 'e,o'ena ine, an lorati ine are very e1ually e''ective Se ation Diphenhydramine Anti-"ar)insonism Diphenhydramine Anti-emetic >orries a!out teratoenic e''ects A verse e''ects <eratogenesis Se ation Antimuscarinic e''ects E,citation an convulsions in chil ren Postural hy"otension +thin) vaso ilation an BP ro". 5rug allergy

72 rece"tor antagonists: com"etitive antagonists /ames: cimeti ine, raniti ine, 'amoti ine, nizanti ine Pharmaco)inetics Su!Aect to first pass in liver ButBni*antidine has 90C !ioavaila!ility 6aAority o' cimetidine an ranitidine is secrete unchange !y the )i neys 7ave little access to #/S 0ssues *ith the el erly: #/S e''ects an ramatically increase hal' li'e *ith renal im"airment Pharmaco ynamics Bloc) aci secretion #i*antidine is an A#hesterase inhi!itor that not only re uces aci secretion, !ut increases 40 motility an re uces gastric em"tying time #linical uses 4astric ulcers Pe"tic uo enal ulcer 4E&5 Dollinger-Ellison Syn rome +gastrioma tumor that hy"ersecretes gastrin.

A verse e''ects +very rare E1-2C. 5iarrhea 5izziness &ash 7ea ache #/S e''ects on el erly, es"ecially *ith cimetidine Eon ocrine e''ects li)e gynecomastiaFother antian rogen e''ects in men an galactorrhea in *omen, es"ecially *ith cimetidine Bloo yscrasias +granulocyto"enia, throm!ocyto"enia, neutro"enia, a"lastic anemia. &eversi!le he"atitis F(- Aaun ice Cimetidine inhi!its P@G0 an re uces he"atic !loo 'lo* 0ncrease "otential to,icity *hen ta)en *ith !arfarin" beta-blockers" #achannel blockers" an antiarrhythmic agents li)e lidocaine an phenytoin

+. Diagram how serotonin ,+- T- is synthesi*ed and released. Synthesis: Su!strate: try"to"han Enzyme: tryptophan hydroxylase +*hich re1uires o,ygen an "teri ine as co'actors. 'ollo*e !y .-amino acid decarboxylase Enterochroma''in cells synthesize an store 9GC o' G-7< &elease: &elease 'rom enterochroma''in cells is ictate !y mechanical stretch an e''erent vagal stimulation Serotonin is se$uestered in platelets in ense granules !y a /a- e"en ent u"ta)e "rocessH activation o' "latelets causes serotonin release /. Explain the peripheral e$$ects o$ serotonin in smooth muscle! bronchi! gastrointestinal tract and cardio(ascular system. Smooth muscle 3ascular muscle rela,ation via +- T0 +can cause migraines. Smooth muscle contraction via +- T2&!C Bronchi

Bronchoconstriction ue to +- T2&!C !in ing

40 0ncrease 40 motility via si% different &-'T receptors Emesis ue to +- T" #ar iovascular irect vasoconstriction via +- T1B an +- T2& in irect vaso ilation via +- T2B +E5&$ release. an +- T0

subcardial $ibroplasias results 'rom chronic high serotonin levels + amage to valves an electrical con uction.

0. &ssociate the clinically important serotonin agonists and antagonists with their receptors. ;o* try"to"han ietoverall ecline in G-7< levels p-chloroamphetaminerelease o' G-7< 'orm "latelets an #/S 1en$luramineincreases G-7< release as an appetite suppressant *ith ra*n 'rom mar)et ue to car ioto,icity 656A similar mech 1luoxetineinhi!ition o' G-7< reu"ta)e to treat depression an (#D 2umatriptanG-7<1B, G-7<15, an G-7<1$ agonist to treat migraine !y causing vasoconstriction o' intracranial !loo vessels TegaserodG-7<@ "artial agonist to treat irritable bo!el syndrome !y stimulating "eristalsis >ith ra*n 'rom mar)et ue to incrase 60, angina, an stro)e ris) 'ndansetronG-7<8 antagonist to treat chemo-induced nausea and emesis %ethysergideG-7<2A(2B(2# antagonist 'or prophylactic treatment of migraine also com!ats iarrhea, mala!sor"tion, an "ostgastrectomy um"ing syn rome

not meant 'or chronic use +*hich *ill attenuate vasoconstrictive event an su!se1uent vaso ilation, thus causing migraine. *ith ra*n 'rom mar)et since chronic treatment *ill also result in inflammatory fibrosis CyproheptadineG-7<2A antagonist use 'or postgastrectomy dumping syndrome