PathWhiz

Pathway Description

Ziprasidone H1-Antihistamine Blood Vessel Constriction Action Pathway

Homo sapiens

Drug Action Pathway

Ziprasidone is a weak H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. Allergies causes blood vessel dilation which causes swelling (edema) and fluid leakage. Ziprasidone inhibits the H1 histamine receptor on blood vessel endothelial cells. This normally activates the Gq signalling cascade which activates phospholipase C which catalyzes the production of Inositol 1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG). Because of the inhibition, IP3 doesn't activate the release of calcium from the sarcoplasmic reticulum, and DAG doesn't activate the release of calcium into the cytosol of the endothelial cell. This causes a low concentration of calcium in the cytosol, and it, therefore, cannot bind to calmodulin. Calcium bound calmodulin is required for the activation of the calmodulin-binding domain of nitric oxide synthase. The inhibition of nitric oxide synthesis prevents the activation of myosin light chain phosphatase. This causes an accumulation of myosin light chain-phosphate which causes the muscle to contract and the blood vessel to constrict, decreasing the swelling and fluid leakage from the blood vessels caused by allergens.

References

Ziprasidone H1-Antihistamine Blood Vessel Constriction Pathway References

Simons FE, Simons KJ: Histamine and H1-antihistamines: celebrating a century of progress. J Allergy Clin Immunol. 2011 Dec;128(6):1139-1150.e4. doi: 10.1016/j.jaci.2011.09.005. Epub 2011 Oct 27.

Pubmed: 22035879

Simons FE: H1-receptor antagonists. Comparative tolerability and safety. Drug Saf. 1994 May;10(5):350-80. doi: 10.2165/00002018-199410050-00002.

Pubmed: 7913608

Mignery GA, Sudhof TC: The ligand binding site and transduction mechanism in the inositol-1,4,5-triphosphate receptor. EMBO J. 1990 Dec;9(12):3893-8. doi: 10.1002/j.1460-2075.1990.tb07609.x.

Pubmed: 2174351

Zhao Y, Vanhoutte PM, Leung SW: Vascular nitric oxide: Beyond eNOS. J Pharmacol Sci. 2015 Oct;129(2):83-94. doi: 10.1016/j.jphs.2015.09.002. Epub 2015 Sep 28.

Pubmed: 26499181

Pubmed: 11752352

Taniguchi K, Urakami M, Takanaka K: [Effects of antiallergic agents on polymorphonuclear leukocytes. The inhibition of arachidonic acid release and superoxide production]. Nihon Yakurigaku Zasshi. 1987 Aug;90(2):97-103. doi: 10.1254/fpj.90.97.

Pubmed: 2890562

Hallberg T, Dohlsten M, Baldetorp B: Demonstration of histamine receptors on human platelets by flow cytometry. Scand J Haematol. 1984 Feb;32(2):113-8. doi: 10.1111/j.1600-0609.1984.tb02165.x.

Pubmed: 6701456

Dorsch W, Hintschich C, Neuhauser J, Weber J: Sequential histamine inhalations cause increased bronchial histamine reactivity in guinea pigs: role of platelets, thromboxanes and prostacyclin. Naunyn Schmiedebergs Arch Pharmacol. 1984 Sep;327(2):148-55. doi: 10.1007/BF00500910.

Pubmed: 6387510

Taniguchi K, Masuda Y, Takanaka K: Inhibitory effects of histamine H1 receptor blocking drugs on metabolic activations of neutrophils. J Pharmacobiodyn. 1991 Feb;14(2):87-93. doi: 10.1248/bpb1978.14.87.

Pubmed: 1678430

Pubmed: 4074605

Thomson NC, Kerr JW: Effect of inhaled H1 and H2 receptor antagonist in normal and asthmatic subjects. Thorax. 1980 Jun;35(6):428-34. doi: 10.1136/thx.35.6.428.

Pubmed: 6449094

Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.

Pubmed: 29126136

Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.

Visualize Compound Data

		Calcium
		Citrulline
		FAD
		Flavin Mononucleotide
		Heme
		Histamine
		Hydrogen Ion
		Inositol 1,4,5-trisphosphate
		L-Arginine
		Magnesium
		Manganese
		NADP
		NADPH
		Nitric oxide
		Oxygen
		Phosphatidylinositol 4,5-bisphosphate
		Tetrahydrobiopterin
		Water
		Ziprasidone

Visualize Protein Data

		1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1
		Calmodulin-1
		Guanine nucleotide-binding protein G(q) subunit alpha
		Histamine H1 receptor
		Inositol 1,4,5-trisphosphate receptor type 1
		Myosin light chain 3
		Myosin light chain kinase, smooth muscle
		Nitric oxide synthase, endothelial
		Protein kinase C alpha type
		Serine/threonine-protein phosphatase PP1-beta catalytic subunit
		Voltage-dependent calcium channel subunit alpha-2/delta-2
		Voltage-dependent L-type calcium channel subunit beta-1
		Voltage-dependent P/Q-type calcium channel subunit alpha-1A

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