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Iatrogenic hypertension: a bioinformatic analysis

The Pharmacogenomics Journal volume 19, pages 337–346 (2019)Cite this article

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Abstract

It is well known that a myriad of medications and substances can induce side effects that are related to blood pressure (BP) regulation. This study aims to investigate why certain drugs tend to cause iatrogenic hypertension (HTN) and focus on drug targets that are implicated in these conditions.

Databases and resources such as SIDER, DrugBank, and Genomatix were utilized in order to bioinformatically investigate HTN-associated drug target-genes for which HTN is a side effect. A tree-like map was created, representing interactions between 198 human genes that relate to the blood pressure system. 72 HTN indicated drugs and 160 HTN-inducing drugs were investigated. HTN-associated genes affected by these drugs were identified. HTN indicated drugs, which target nearly all branches of the interaction tree, were shown to exert an effect on most functional sub-systems of the BP regulatory system; and specifically, for the adrenergic and dopaminergic receptor pathways. High prevalence (25 genes) of shared targets between the HTN indicated and HTN-inducing drug categories was demonstrated. We focus on six drug families which are not indicated for HTN treatment, yet are reported as a major cause for blood pressure side effects. We show the molecular mechanisms that may lead to this iatrogenic effect. Such an analysis may have clinical implications that could allow for the development of tailored medicine with fewer side effects.

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References

  1. Kunes J, Zicha J. The interaction of genetic and environmental factors in the etiology of hypertension. Physiol Res. 2009;58(Suppl 2):S33–41.

    PubMed  Google Scholar 

  2. Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann Intern Med. 2003;139:761–76.

    Article  CAS  PubMed  Google Scholar 

  3. Handler J. Drug-induced hypertension. J Clin Hypertens. 2003;5:83–5.

    Article  Google Scholar 

  4. de Leeuw PW. Drug-induced hypertension. Recognition and management in older patients. Drugs Aging. 1997;11:178–85.

    Article  PubMed  Google Scholar 

  5. Fournier JP, Sommet A, Durrieu G, Poutrain JC, Lapeyre-Mestre M, Montastruc JL, et al. Drug interactions between antihypertensive drugs and non-steroidal anti-inflammatory agents: a descriptive study using the French Pharmacovigilance database. Fundam Clin Pharmacol. 2014;28:230–5.

    Article  CAS  PubMed  Google Scholar 

  6. Wood AJ. Drug interactions in hypertension. Hypertension. 1988;11:II1–3.

    Article  CAS  PubMed  Google Scholar 

  7. Bitner A, Zalewski P, Klawe JJ, Newton JL. Drug interactions in Parkinson’s disease: safety of pharmacotherapy for arterial hypertension. Drugs - Real World Outcomes. 2015;2:1–12.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation. 2013;127:e6–245.

    PubMed  Google Scholar 

  9. Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet. 2004;363:1783–93.

    Article  CAS  PubMed  Google Scholar 

  10. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525–35.

    Article  PubMed  Google Scholar 

  11. Hajjar ER, Cafiero AC, Hanlon JT. Polypharmacy in elderly patients. Am J Geriatr Pharmacother. 2007;5:345–51.

    Article  PubMed  Google Scholar 

  12. Elliott WJ. Improving outcomes in hypertensive patients: focus on adherence and persistence with antihypertensive therapy. J Clin Hypertens. 2009;11:376–82.

    Article  CAS  Google Scholar 

  13. Grossman A, Messerli FH, Grossman E. Drug induced hypertension - An unappreciated cause of secondary hypertension. Eur J Pharmacol. 2015;763:15–22.

    Article  CAS  PubMed  Google Scholar 

  14. Botzer A, Grossman E, Moult J, Unger R. A system view and analysis of essential hypertension. J Hypertens. 2018;36:1094–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Genomatix Software GmbH. Genomatix Pathway System. http://www.genomatix.de (Accessed 14 Mar 2018).

  16. Kuhn M, Campillos M, Letunic I, Jensen LJ, Bork P. A side effect resource to capture phenotypic effects of drugs. Mol Syst Biol. 2010;6:343.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Law V, Knox C, Djoumbou Y, Jewison T, Guo AC, Liu Y, et al. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res. 2014;42:D1091–7.

    Article  CAS  PubMed  Google Scholar 

  18. Padmanabhan S, Newton-Cheh C, Dominiczak AF. Genetic basis of blood pressure and hypertension. Trends Genet. 2012;28:397–408.

    Article  CAS  PubMed  Google Scholar 

  19. Chopra S, Baby C, Jacob JJ. Neuro-endocrine regulation of blood pressure. Indian J Endocrinol Metab. 2011;15(Suppl 4):S281–8.

    PubMed  PubMed Central  Google Scholar 

  20. Danzi S, Klein I. Thyroid hormone and blood pressure regulation. Curr Hypertens Rep. 2003;5:513–20.

    Article  PubMed  Google Scholar 

  21. Tisdale JE, Miller DA. American Society of Health-System Pharmacists. Drug-induced diseases: Prevention, detection, and management. 2nd edn. American Society of Health System Pharmacists: Bethesda, 2010.

  22. Craig CR, Stitzel RE. Modern pharmacology with clinical applications. Lippincott Williams & Wilkins: Philadelphia, 2004.

  23. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse. 2001;39:32–41.

    Article  CAS  PubMed  Google Scholar 

  24. Weinshenker D, Schroeder JP. There and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacology. 2007;32:1433–51.

    Article  CAS  PubMed  Google Scholar 

  25. Elsworth JD, Morrow BA, Nguyen VT, Mitra J, Picciotto MR, Roth RH. Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: role of autoreceptors. Neuroscience. 2007;147:419–27.

    Article  CAS  PubMed  Google Scholar 

  26. Mateo Y, Pineda J, Meana JJ. Somatodendritic alpha2-adrenoceptors in the locus coeruleus are involved in the in vivo modulation of cortical noradrenaline release by the antidepressant desipramine. J Neurochem. 1998;71:790–8.

    Article  CAS  PubMed  Google Scholar 

  27. Guimarães S, Moura D. Vascular adrenoceptors: an update. Pharmacol Rev. 2001;53:319–56.

    PubMed  Google Scholar 

  28. Michel MC, Brodde OE, Insel PA. Peripheral adrenergic receptors in hypertension. Hypertension. 1990;16:107–20.

    Article  CAS  PubMed  Google Scholar 

  29. Green T, Gonzalez AA, Mitchell KD, Navar LG. The complex interplay between cyclooxygenase-2 and angiotensin II in regulating kidney function. Curr Opin Nephrol Hypertens. 2012;21:7–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Harris RC. Interactions between COX-2 and the renin-angiotensin system in the kidney. Acta Physiol Scand. 2003;177:423–7.

    Article  CAS  PubMed  Google Scholar 

  31. Crofford LJ, Lipsky PE, Brooks P, Abramson SB, Simon LS, van de Putte LB. Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum. 2000;43:4–13.

    Article  CAS  PubMed  Google Scholar 

  32. Stichtenoth DO, Marhauer V, Tsikas D, Gutzki FM, Frölich JC. Effects of specific COX-2-inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers. Kidney Int. 2005;68:2197–207.

    Article  CAS  PubMed  Google Scholar 

  33. Taler SJ, Textor SC, Canzanello VJ, Schwartz L. Cyclosporin-induced hypertension: incidence, pathogenesis and management. Drug Saf. 1999;20:437–49.

    Article  CAS  PubMed  Google Scholar 

  34. Cífková R, Hallen H. Cyclosporin-induced hypertension. J Hypertens. 2001;19:2283–5.

    Article  PubMed  Google Scholar 

  35. Koch CA. Endocrine hypertension: what is new? Rev Port Endocrinol Diabetes e Metab. 2012;7:52–61.

    Google Scholar 

  36. Hjemdahl P, Olsson G. Rebound phenomena following withdrawal of long-term beta-adrenoceptor blockade. Acta Med Scand Suppl. 1982;665:43–7.

    CAS  PubMed  Google Scholar 

  37. Reid JL, Campbell BC, Hamilton CA. Withdrawal reactions following cessation of central alpha-adrenergic receptor agonists. Hypertension. 1984;6:II71–5.

    Article  CAS  PubMed  Google Scholar 

  38. Lewis MJ, Ross PJ, Henderson AH. Rebound effect after stopping beta-blockers. Br Med J. 1979;2:606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Krukemyer JJ, Boudoulas H, Binkley PF, Lima JJ. Comparison of hypersensitivity to adrenergic stimulation after abrupt withdrawal of propranolol and nadolol: influence of half-life differences. Am Hear J. 1990;120:572–9.

    Article  CAS  Google Scholar 

  40. Reid JL. Central alpha 2 receptors and the regulation of blood pressure in humans. J Cardiovasc Pharmacol. 1985;7(Suppl 8):S45–50.

    CAS  PubMed  Google Scholar 

  41. Reid JL. Alpha-adrenergic receptors and blood pressure control. Am J Cardiol. 1986;57:6E–12E.

    Article  CAS  PubMed  Google Scholar 

  42. Lönnqvist PA. Alpha-2 adrenoceptor agonists as adjuncts to Peripheral Nerve Blocks in Children–is there a mechanism of action and should we use them? Paediatr Anaesth. 2012;22:421–4.

    Article  PubMed  Google Scholar 

  43. Goodman LS, Brunton LL, Chabner B, Knollmann BC. Gilman’s pharmacological basis of therapeutics. McGraw-Hill: New York, 2011.

  44. Milazzo V, Di Stefano C. Drugs and orthostatic hypotension: evidence from literature. J Hypertens Open Access. 2012;1:1–8.

    Article  Google Scholar 

  45. Tran TP, Panacek EA, Rhee KJ, Foulke GE. Response to dopamine vs norepinephrine in tricyclic antidepressant-induced hypotension. Acad Emerg Med. 1997;4:864–8.

    Article  CAS  PubMed  Google Scholar 

  46. Shannon M, Merola J, Lovejoy FH. Hypotension in severe tricyclic antidepressant overdose. Am J Emerg Med. 1988;6:439–42.

    Article  CAS  PubMed  Google Scholar 

  47. Iversen LL. Introduction to neuropsychopharmacology. Oxford University Press: Oxford, 2009.

  48. Samson SL, Garber AJ. Metabolic Syndrome. Endocrinol Metab Clin North Am. 2014;43:1–23.

    Article  PubMed  Google Scholar 

  49. Warner TD, Mitchell JA. COX-2 selectivity alone does not define the cardiovascular risks associated with non-steroidal anti-inflammatory drugs. Lancet. 2008;371:270–3.

    Article  CAS  PubMed  Google Scholar 

  50. White WB. Cardiovascular effects of the cyclooxygenase inhibitors. Hypertension. 2007;49:408–18.

    Article  CAS  PubMed  Google Scholar 

  51. Messerli FH, Sichrovsky T. Does the pro-hypertensive effect of cyclooxygenase-2 inhibitors account for the increased risk in cardiovascular disease? Am J Cardiol. 2005;96:872–3.

    Article  CAS  PubMed  Google Scholar 

  52. Schnitzer TJ. Cyclooxygenase-2–specific inhibitors: are they safe? Am J Med. 2001;110:46S–49S.

    Article  CAS  PubMed  Google Scholar 

  53. DeMaria AN, Weir MR. Coxibs–beyond the GI tract: renal and cardiovascular issues. J Pain Symptom Manag. 2003;25:S41–9.

    Article  CAS  Google Scholar 

  54. Stöllberger C, Finsterer J. Side effects of conventional nonsteroidal anti-inflammatory drugs and celecoxib: more similarities than differences. South Med J. 2004;97:209.

    Article  PubMed  Google Scholar 

  55. CKSKS Ong, Lirk P, Tan CHH, Seymour RAA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. 2007;5:19–34.

    Article  Google Scholar 

  56. US Food and Drug Administration. Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs). https://www.fda.gov/downloads/Drugs/DrugSafety/ucm088646.pdf (Accessed 14 Mar 2018).

  57. Sostres C, Gargallo CJ, Lanas A. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Res Ther. 2013;15:S3.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Aljadhey H, Tu W, Hansen RA, Blalock SJ, Brater DC, Murray MD. Comparative effects of non-steroidal anti-inflammatory drugs (NSAIDs) on blood pressure in patients with hypertension. BMC Cardiovasc Disord. 2012;12:93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pringsheim T, Jette N, Frolkis A, Steeves TD. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord. 2014;29:1583–90.

    Article  PubMed  Google Scholar 

  60. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311:1670–83.

    Article  PubMed  Google Scholar 

  61. Pavy-Le Traon A, Piedvache A, Perez-Lloret S, Calandra-Buonaura G, Cochen-De Cock V, Colosimo C, et al. New insights into orthostatic hypotension in multiple system atrophy: a European multicentre cohort study. J Neurol Neurosurg Psychiatry. 2016;87:554–61.

    Article  CAS  PubMed  Google Scholar 

  62. Palma JA, Gomez-Esteban JC, Norcliffe-Kaufmann L, Martinez J, Tijero B, Berganzo K, et al. Orthostatic hypotension in Parkinson disease: how much you fall or how low you go? Mov Disord. 2015;30:639–45.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Koller WC, Rueda MG. Mechanism of action of dopaminergic agents in Parkinson’s disease. Neurology. 1998;50:S11–4. discussion S44–8.

    Article  CAS  PubMed  Google Scholar 

  64. Fox SH. Non-dopaminergic treatments for motor control in Parkinson’s disease. Drugs. 2013;73:1405–15.

    Article  CAS  PubMed  Google Scholar 

  65. Crosby NJ, Deane K, Clarke CE. Amantadine in Parkinson’s disease. Cochrane Database Syst Rev. 2003;1:CD003468.

    Google Scholar 

  66. Heinonen EH, Myllylä V. Safety of selegiline (deprenyl) in the treatment of Parkinson’s disease. Drug Saf. 1998;19:11–22.

    Article  CAS  PubMed  Google Scholar 

  67. Douvier JJ, Vergeret J, Taytard A, Brottier E, Domblides P, Dubos F, et al. Bromocriptine in Parkinson’s disease: pleuropulmonary toxicity. Ann Med Interne. 1985;136:416–8.

    CAS  Google Scholar 

  68. Jost WH, Angersbach D. Ropinirole, a Non-Ergoline Dopamine Agonist. CNS Drug Rev. 2006;11:253–72.

    Article  PubMed Central  Google Scholar 

  69. Kvernmo T, Houben J, Sylte I. Receptor-binding and pharmacokinetic properties of dopaminergic agonists. Curr Top Med Chem. 2008;8:1049–67.

    Article  CAS  PubMed  Google Scholar 

  70. Eden RJ, Costall B, Domeney AM, Gerrard PA, Harvey CA, Kelly ME, et al. Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist. Pharmacol Biochem Behav. 1991;38:147–54.

    Article  CAS  PubMed  Google Scholar 

  71. Presthus J, Hajba A. Deprenyl (selegiline) combined with levodopa and a decarboxylase inhibitor in the treatment of Parkinson’s disease. Acta Neurol Scand Suppl. 1983;95:127–33.

    Article  CAS  PubMed  Google Scholar 

  72. Lew MF, Pahwa R, Leehey M, Bertoni J, Kricorian G, Group ZSS. Safety and efficacy of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa in the management of ‘off’ episodes in patients with Parkinson’s disease. Curr Med Res Opin. 2007;23:741–50.

    Article  CAS  PubMed  Google Scholar 

  73. Dopamine Injection - FDA prescribing information, side effects and uses. https://www.drugs.com/pro/dopamine-injection.html (Accessed 14 Mar 2018).

  74. Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. Cambridge University Press: New York, 2008.

  75. Schumacher-Schuh AF, Rieder CR, Hutz MH. Parkinson’s disease pharmacogenomics: new findings and perspectives. Pharmacogenomics. 2014;15:1253–71.

    Article  CAS  PubMed  Google Scholar 

  76. Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov. 2004;3:353–9.

    Article  CAS  PubMed  Google Scholar 

  77. Westerink BH. Can antipsychotic drugs be classified by their effects on a particular group of dopamine neurons in the brain? Eur J Pharmacol. 2002;455:1–18.

    Article  CAS  PubMed  Google Scholar 

  78. Becker DE. Basic and clinical pharmacology of autonomic drugs. Anesth Prog. 2012;59:159–68. quiz 169.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Sankary RM, Jones CA, Madison JM, Brown JK. Muscarinic cholinergic inhibition of cyclic AMP accumulation in airway smooth muscle. Role of a pertussis toxin-sensitive protein. Am Rev Respir Dis. 1988;138:145–50.

    Article  CAS  PubMed  Google Scholar 

  80. Yang CM, Chou SP, Sung TC. Muscarinic receptor subtypes coupled to generation of different second messengers in isolated tracheal smooth muscle cells. Br J Pharmacol. 1991;104:613–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Campbell TJ, Williams KM. Therapeutic drug monitoring: antiarrhythmic drugs. Br J Clin Pharmacol. 1998;46:307–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Beckers J, Kulbertus HE. Class IIIdrugs: amiodarone. Eur Hear J. 1987;8(Suppl A):53–9.

    Article  Google Scholar 

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Acknowledgements

We want to thank Matanya Tirosh for helpful discussion and critical reading of the manuscript. JM’s contribution was partly supported by NIH R01 GM104436.

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Authors and Affiliations

  1. The Mina & Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel

    Alon Botzer & Ron Unger

  2. Neurology and Toxicology Service and Unit, Shaare Zedek Medical Center, Jerusalem, Israel

    Yoram Finkelstein

  3. Department of Internal Medicine D and Hypertension Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel

    Ehud Grossman

  4. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Ehud Grossman

  5. Institute for Bioscience and Biotechnology Research and Department of Cell Biology and Molecular Genetics, University of Maryland, Rockville, MD, USA

    John Moult

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Botzer, A., Finkelstein, Y., Grossman, E. et al. Iatrogenic hypertension: a bioinformatic analysis. Pharmacogenomics J 19, 337–346 (2019). https://doi.org/10.1038/s41397-018-0062-0

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