Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIY57RISP)
Drug Name			Eplerenone		Drug Info		Trifluoperazine		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antihypertensive Agents				Antipsychotic Agents
Structure

Mechanism of Eplerenone-Trifluoperazine Interaction (Severity Level: Moderate)
Additive hypotensive effects Click to Show/Hide Mechanism Graph

Drug Name		Eplerenone				Trifluoperazine
Mechanism		Hypotensive effects Mineralocorticoid receptor Antagonist				Hypotensive effects Calmodulin Inhibitor
Key Mechanism Factor 1
		Factor Name		Mineralocorticoid receptor				× Structure Sequence METKGYHSLPEGLDMERRWGQVSQAVERSSLGPTERTDENNYMEIVNVSCVSGAIPNNSTQGSSKEKQELLPCLQQDNNRPGILTSDIKTELESKELSATVAESMGLYMDSVRDADYSYEQQNQQGSMSPAKIYQNVEQLVKFYKGNGHRPSTLSCVNTPLRSFMSDSGSSVNGGVMRAVVKSPIMCHEKSPSVCSPLNMTSSVCSPAGINSVSSTTASFGSFPVHSPITQGTPLTCSPNVENRGSRSHSPAHASNVGSPLSSPLSSMKSSISSPPSHCSVKSPVSSPNNVTLRSSVSSPANINNSRCSVSSPSNTNNRSTLSSPAASTVGSICSPVNNAFSYTASGTSAGSSTLRDVVPSPDTQEKGAQEVPFPKTEEVESAISNGVTGQLNIVQYIKPEPDGAFSSSCLGGNSKINSDSSFSVPIKQESTKHSCSGTSFKGNPTVNPFPFMDGSYFSFMDDKDYYSLSGILGPPVPGFDGNCEGSGFPVGIKQEPDDGSYYPEASIPSSAIVGVNSGGQSFHYRIGAQGTISLSRSARDQSFQHLSSFPPVNTLVESWKSHGDLSSRRSDGYPVLEYIPENVSSSTLRSVSTGSSRPSKICLVCGDEASGCHYGVVTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRLQKCLQAGMNLGARKSKKLGKLKGIHEEQPQQQQPPPPPPPPQSPEEGTTYIAPAKEPSVNTALVPQLSTISRALTPSPVMVLENIEPEIVYAGYDSSKPDTAENLLSTLNRLAGKQMIQVVKWAKVLPGFKNLPLEDQITLIQYSWMCLSSFALSWRSYKHTNSQFLYFAPDLVFNEEKMHQSAMYELCQGMHQISLQFVRLQLTFEEYTIMKVLLLLSTIPKDGLKSQAAFEEMRTNYIKELRKMVTKCPNNSGQSWQRFYQLTKLLDSMHDLVSDLLEFCFYTFRESHALKVEFPAMLVEIISDQLPKVESGNAKPLYFHRK
		Gene Name		NR3C2
		Uniprot ID		MCR_HUMAN
		KEGG Pathway		hsa:4306
		Protein Family		Nuclear hormone receptor family
		Protein Function		Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels. Click to Show/Hide
Key Mechanism Factor 2
		Factor Name		Calmodulin-1				× Structure Sequence MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMARKMKDTDSEEEIREAFRVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMTAK
		Gene Name		CALM1
		Uniprot ID		CALM1_HUMAN
		KEGG Pathway		hsa:801
		Protein Family		Calmodulin family
		Protein Function		Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Is a regulator of voltage-dependent L-type calcium channels (PubMed:31454269). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696). Forms a potassium channel complex with KCNQ1 and regulates electrophysiological activity of the channel via calcium-binding (PubMed:25441029). Acts as a sensor to modulate the endoplasmic reticulum contacts with other organelles mediated by VMP1:ATP2A2 (PubMed:28890335). Click to Show/Hide
Mechanism Description		Additive hypotensive effects by the combination of Eplerenone and Trifluoperazine

Recommended Action
Management		Close clinical monitoring for development of hypotension is recommended if phenothiazines or neuroleptic agents are used in patients receiving antihypertensive medications or vasodilators. A lower starting dosage and slower titration of the phenothiazine or neuroleptic may be appropriate, especially in the elderly. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery.

References
1	Aronowitz JS, Chakos MH, Safferman AZ, Lieberman JA "Syncope associated with the combination of clozapine and enalapril." J Clin Psychopharmacol 14 (1994): 429-30. [PMID: 7884028]
2	Fruncillo R, Gibbons W, Vlasses P, Ferguson R "Severe hypotension associated with concurrent clonidine and antipsychotic medication." Am J Psychiatry 142 (1985): 274. [PMID: 2857531]
3	Markowitz JS, Wells BG, Carson WH "Interactions between antipsychotic and antihypertensive drugs." Ann Pharmacother 29 (1995): 603-9. [PMID: 7663034]
4	Product Information. Abilify (aripiprazole). Bristol-Myers Squibb, Princeton, NJ.
5	Product Information. Clozaril (clozapine). Novartis Pharmaceuticals, East Hanover, NJ.
6	Product Information. Geodon (ziprasidone). Pfizer US Pharmaceuticals, New York, NY.
7	Product Information. Rexulti (brexpiprazole). Otsuka American Pharmaceuticals Inc, Rockville, MD.
8	Product Information. Risperdal (risperidone). Janssen Pharmaceutica, Titusville, NJ.
9	Product Information. Seroquel (quetiapine). Zeneca Pharmaceuticals, Wilmington, DE.
10	Product Information. Zyprexa (olanzapine). Lilly, Eli and Company, Indianapolis, IN.
11	White WB "Hypotension with postural syncope secondary to the combination of chlorpromazine and captopril." Arch Intern Med 146 (1986): 1833-4. [PMID: 3530167]