j. fac. pharm. ankara Journal of Faculty of Pharmacy of Ankara University 1015-3918 2564-6524 Ankara University 10.33483/jfpau.1597966 Pharmaceutical Chemistry Farmasotik Kimya KARDİYOVASKÜLER SİSTEM HASTALIKLARINDA KALSİYUM KANAL BLOKÖRLERİ CALCIUM CHANNEL BLOCKERS IN CARDIOVASCULAR SYSTEM DISEASES https://orcid.org/0009-0001-4508-1268 Harmanşah İrem ANKARA ÜNİVERSİTESİ, ECZACILIK FAKÜLTESİ https://orcid.org/0009-0007-1180-1611 Güney Kalkan Sümeyye ANKARA ÜNİVERSİTESİ, ECZACILIK FAKÜLTESİ https://orcid.org/0000-0002-7070-8181 Ünlüsoy Meltem Ankara University Faculty of Pharmacy 05 19 2025 49 2 539 561 12 07 2024 12 23 2024 Copyright © 1971, Journal of Faculty of Pharmacy of Ankara University 1971 Journal of Faculty of Pharmacy of Ankara University

Amaç: Kalsiyum kanal blokörü bileşiklerin (KKB'ler) kalsiyum girişini engelleyerek ve voltaja bağlı kalsiyum kanallarında tanımlanan bağlanma bölgeleriyle etkileşime girerek arterlerin kasılmasını azalttıkları gösterilmiştir. Bu bileşikler toplam periferik direnci azaltarak arteriyel basıncı düşürür. Kalbin yükünü boşaltarak ve koroner kan akışını artırarak miyokard oksijenlenmesini iyileştirir. Bu çalışmada kalsiyum kanal yapısı, alt tipleri ve özellikleri; KKB'lerin sınıflandırılması, yapı-aktivite ilişkileri, kimyasal yapısı, metabolizması, farmakolojik özellikleri, bunların kardiyovasküler bozukluklar için yerleşik terapötik kullanımları ve genel terapötik endikasyonları hakkında bilgi verilmesi amaçlanmıştır.Sonuç ve Tartışma: Hipertansiyonun etkili tedavisi, hipertansiyona bağlı kardiyovasküler ve böbrek hastalıklarının yükünü azaltmak için önemli bir stratejiyi temsil eder. Rasyonel, entegre ve sinerjik kombinasyon tedavileri, birinci basamak strateji olarak önerilen kan basıncı hedeflerine ulaşmayı amaçlamıştır. Hipertansiyonun klinik tedavisi için halihazırda mevcut olan olası antihipertansif ilaç sınıfları içinde, hem monoterapi hem de kombinasyon terapisinde, renin-anjiyotensin sistemini inhibe eden ilaçların ve kalsiyum kanal blokörlerinin (KKB'ler), kan basıncı seviyelerini düşürmede ve hedefe ulaşmada etkili aynı zamanda güvenli olduğu gösterilmiştir. İyi bir tolere edilebilirlik profiline sahip olan KKB'ler kan basıncını düşürmedeki etkinlikleri, hipertansiyonun kardiyovasküler ve renal sonuçlarını azaltmaya yönelik çok sayıda bilimsel kanıt nedeniyle son 20 yılda en yaygın kullanılan antihipertansif sınıflarından biri olmuştur.

Objective: Calcium calcium channel blockers (CCBs) have been shown to reduce arterial constriction by blocking calcium entry and interacting with binding sites identified on voltage-gated calcium channels. These compounds reduce arterial pressure by reducing total peripheral resistance. They improve myocardial oxygenation by disloading the heart and increasing coronary blood flow. In this study, an exploration has been undertaken concerning the makeup, variations, and attributes of calcium channels. Furthermore, an examination has been conducted regarding the categorization of compounds that block calcium channels, encompassing their molecular structure, mechanism of aciton, structure-activity relationships, metabolic pathways, recognized therapeutic applications in cardiovascular conditions, and broader therapeutic implications.Result and Discussion: Hypertension represents a substantial strategy to reduce the burden of cardiovascular and renal diseases associated with hypertension. Rational, integrated, and synergistic combination therapies which are recommended as a first-line strategy aimed at achieving the blood pressure targets. Among the currently available classes of antihypertensive drugs for the clinical treatment of hypertension, both in monotherapy and combination therapy, it has been shown that drugs inhibiting the renin-angiotensin system and calcium channel blockers (CCBs) are effective and safe in lowering and reaching the target blood pressure levels. Due to extensive scientific evidence demonstrating their efficacy in mitigating cardiovascular and renal complications linked to hypertension, calcium channel blockers have gained widespread use as a preferred class of antihypertensive medications over the last two decades, primarily attributed to their favorable tolerability profile.

 Hipertansiyon kalsiyum kanalları kalsiyum kanal blokörleri kalsiyum kanal tipleri Calcium channels calcium channel blockers hypertension types of calcium channels 1. World Health Organization. (2020). Cardiovascular diseases. From https://www.who.int/. Accessed date: 01.10.2024. 2. Al-Makki, A., DiPette, D., Whelton, P.K., Murad, M.H., Mustafa, R.A., Acharya, S., Beheiry, H.M., Champagne, B., Connell, K., Cooney, M.T., Ezeigwe, N., Gaziano, T.A., Gidio, A., Lopez-Jaramillo, P., Khan, U.I., Kumarapeli, V., Moran, A.E., Silwimba, M.M., Rayner, B., Khan, T. (2022). Hypertension pharmacological treatment in adults: A World Health Organization Guideline Executive Summary. Hypertension, 79(1), 293-301. [CrossRef] 3. Sipahi, I., Tuzcu, E.M., Schoenhagen, P., Wolski, K.E., Nicholls, S.J., Balog, C., Crowe, T.D., Nissen, S.E. (2006). Effects of normal, pre-hypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis. Journal of the American College of Cardiology, 48(4), 833-838. [CrossRef] 4. Wahl, L., Tubbs, R.S. (2019). A review of the clinical anatomy of hypertension. Clinical Anatomy, 32(5), 678-681. [CrossRef] 5. Wang, J.G., Palmer, B.F., Vogel Anderson, K., Sever, P. (2023). Amlodipine in the current management of hypertension [Review]. Journal of Clinical Hypertension, 25(9), 801-807. [CrossRef] 6. World Health, Organization. (2023). Retrived April 8, 2025, from https://iris.who.int/handle/. Accessed date: 01.10.2024. 7. Aydoğdu, S., Güler, K., Bayram, F., Altun, B., Derici, Ü., Abacı, A., Tükek, T., Sabuncu, T., Arıcı, M., Erdem, Y., Özin, B., Sahin, İ., Ertürk, Ş., Bitigen, A., Tokgözoğlu, L. (2019). 2019 Turkish hypertension consensus report. Türk Kardiyoloji Dernegi arsiv, 47(6), 535-546. [CrossRef] 8. Navadiya, K., Tiwari, S. (2015). Pharmacology, efficacy and safety of felodipine with a focus on hypertension and angina pectoris. Current Drug Safety, 10(3), 194-201. [CrossRef] 9. Whelton, P.K., Carey, R.M., Mancia, G., Kreutz, R., Bundy, J.D., Williams, B. (2022). Harmonization of the american college of cardiology/american heart association and european society of cardiology/european society of hypertension blood pressure/hypertension guidelines: Comparisons, reflections, and recommendations. European Heart Journal, 80(12), 1192-1201. [CrossRef] 10. Tocci, G., Battistoni, A., Passerini, J., Musumeci, M.B., Francia, P., Ferrucci, A., Volpe, M. (2015). Calcium channel blockers and hypertension. Journal of Cardiovascular Pharmacology and Therapeutics, 20(2), 121-130. [CrossRef] 11. Drapak, I., Perekhoda, L., Tsapko, T., Berezniakova, N., Tsapko, Y. (2017). Cardiovascular calcium channel blockers: Historical overview, development and new approaches in design. Journal of Heterocyclic Chemistry, 54(4), 2117-2128. [CrossRef] 12. Catterall, W.A. (2023). Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology. Channels, 17(1), 2281714. [CrossRef] 13. Shah, K., Seeley, S., Schulz, C., Fisher, J., Gururaja Rao, S. (2022). Calcium Channels in the Heart: Disease States and Drugs. Cells, 11(6). [CrossRef] 14. Bean, B.P. (1989). Classes of calcium channels in vertebrate cells. Annual Review of Physiology, 51, 367-384. [CrossRef] 15. Yan, N., Gao, S. (2020). Structural basis of Cav1.1 modulation by dihydropyridine compounds. Angewandte Chemie International Edition, 60(6), 3131-3137. [CrossRef] 16. Simms, B.A., Zamponi, G.W. (2014). Neuronal voltage-gated calcium channels: Structure, function, and dysfunction. Neuron, 82(1), 24-45. [CrossRef] 17. Ishibashi, H., Rhee, J.S., Akaike, N. (1995). Regional difference of high voltage-activated Ca2+ channels in rat CNS neurones. Neuroreport, 6(12), 1621-1624. [CrossRef] 18. Dolphin, A.C. (2016). Voltage-gated calcium channels and their auxiliary subunits: Physiology and pathophysiology and pharmacology. The Journal of Physiology, 594(19), 5369-5390. [CrossRef] 19. Harraz, O., Visser, F., Brett, S., Goldman, D., Zechariah, A., Hashad, A., Menon, B., Watson, T., Starreveld, Y., Welsh, D. (2015). CaV1.2/CaV3.x channels mediate divergent vasomotor responses in human cerebral arteries. The Journal of General Physiology, 145, 405-418. [CrossRef] 20. Uebele, V.N., Gotter, A.L., Nuss, C.E., Kraus, R.L., Doran, S.M., Garson, S.L., Reiss, D.R., Li, Y., Barrow, J.C., Reger, T.S., Yang, Z.Q., Ballard, J.E., Tang, C., Metzger, J.M., Wang, S.P., Koblan, K.S., Renger, J.J. (2009). Antagonism of T-type calcium channels inhibits high-fat diet-induced weight gain in mice. The Journal of Clinical Investigation, 119(6), 1659-1667. [CrossRef] 21. Weiss, N., Zamponi, G. (2019). T-Type channel druggability at a crossroads. ACS Chemical Neuroscience, 10(3), 1124-1126. [CrossRef] 22. Melgari, D., Frosio, A., Calamaio, S., Marzi, G.A., Pappone, C., Rivolta, I. (2022). T-Type calcium channels: a mixed blessing. International Journal of Molecular Sciences, 23(17), 9894. [CrossRef] 23. Striessnig, J., Pinggera, A., Kaur, G., Bock, G., Tuluc, P. (2014). L-type Ca(2+) channels in heart and brain. Wiley interdisciplinary reviews: Membrane Transport and Signaling, 3(2), 15-38. [CrossRef] 24. Tianhua, F., Subha, K., Khaled, B. (2018). L-Type calcium channels: structure and functions. Ion Channels in Health and Sickness, 77305 [CrossRef] 25. Jurkovicova-Tarabova, B., Lacinova, L. (2019). Structure, function and regulation of Ca(V) 2.2 N-type calcium channels. Gen Physiol Biophys, 38(2), 101-110. [CrossRef] 26. Emre, M. (2018). Voltaj kapılı kalsiyum kanalları ve moleküller özellikleri. Arşiv Kaynak Tarama Dergisi, 27, 1-17. [CrossRef] 27. Schneider, T., Neumaier, F., Hescheler, J., Alpdogan, S. (2020). Cav2.3 R-type calcium channels: From its discovery to pathogenic de novo CACNA1E variants: a historical perspective. Pflügers Archiv - European Journal of Physiology, 472(7), 811-816. [CrossRef] 28. Reuter, H. (2013). Voltage-Gated Ca2+ Channels. In Encyclopedia of Biological Chemistry: Second Edition, Elsevier, Amsterdam, p. 560. [CrossRef] 29. Snutch, T.P., Peloquin, J., Mathews, E., McRory, J.E. (2005). Molecular Properties of Voltage-Gated Calcium Channels. In G.W. Zamponi (Ed.), Voltage-Gated Calcium Channels (pp. 61-94). Springer US. [CrossRef] 30. Ferron, L., Zamponi, G.W. (2024). A tale of two calcium channels: Structural pharmacology of Cav2.1 and Cav3.2. Cell Research, 34(6), 401-402. [CrossRef] 31. Elliott, W.J., Ram, C.V. (2011). Calcium channel blockers. The Journal of Clinical Hypertension, 13(9), 687-689. [CrossRef] 32. Catterall, W.A. (2023). Voltage gated sodium and calcium channels: Discovery, structure, function and Pharmacology. Channels, 17(1), 2281714. [CrossRef] 33. Sueta, D., Tabata, N., Hokimoto, S. (2017). Clinical roles of calcium channel blockers in ischemic heart diseases. Hypertension Research, 40(5), 423-428. [CrossRef] 34. Catterall, W.A. (1991). Structure and function of voltage-gated sodium and calcium channels. Current Opinion in Neurobiology, 1(1), 5-13. [CrossRef] 35. Kuthan, J., Kurfürst, A. (1982). Development in dihydropyridine chemistry. Industrial & Engineering Chemistry Product Research and Development, 21, 191-261. [CrossRef] 36. Ozer, E.K., Gunduz, M.G., El-Khouly, A., Sara, Y., Simsek, R., Iskit, A.B., Safak, C. (2018). Synthesis of fused 1,4-dihydropyridines as potential calcium channel blockers. Turkish Journal of Biochemistry, 43(6), 578-586. [CrossRef] 37. Ioan, P., Carosati, E., Micucci, M., Cruciani, G., Broccatelli, F., Zhorov, B.S., Chiarini, A., Budriesi, R. (2011). 1,4-Dihydropyridine scaffold in medicinal chemistry, the story so far and perspectives (part 1): Action in ion channels and GPCRs. Current Medicinal Chemistry, 18(32), 4901-4922. [CrossRef] 38. Pal, D., Maji, S., Maiti, R. (2023). Efficacy and safety of azelnidipine as an antihypertensive compared to amlodipine: A systematic review and meta-analysis. High Blood Pressure & Cardiovascular Prevention, 30(5), 401-410. [CrossRef] 39. Bulsara, K.G., Patel, P., Cassagnol, M. (2024). Amlodipine. In StatPearls [Internet]. StatPearls Publishing. Retrieved April, 8, 2025, from https://www.ncbi.nlm.nih.gov/books/. 40. He, Y., Si, D., Yang, C., Ni, L., Li, B., Ding, M., Yang, P. (2013). The effects of amlodipine and s(-)-amlodipine on vascular endothelial function in patients with hypertension. American Journal of Hypertension, 27(1), 27-31. [CrossRef] 41. Fares, H., DiNicolantonio, J.J., O'Keefe, J.H., Lavie, C.J. (2016). Amlodipine in hypertension: A first-line agent with efficacy for improving blood pressure and patient outcomes. Open Heart, 3(2), e000473. [CrossRef] 42. Ferrari, R., Pavasini, R., Camici, P.G., Crea, F., Danchin, N., Pinto, F., Manolis, A., Marzilli, M., Rosano, G.M.C., Lopez-Sendon, J., Fox, K. (2019). Anti-anginal drugs-beliefs and evidence: Systematic review covering 50 years of medical treatment. Eur Heart J, 40(2), 190-194. [CrossRef] 43. Khan, M.Y., Pandit, S., Ray, S., Mohan, J.C., Srinivas, B.C., Ramakrishnan, S., Mane, A., Mehta, S., Shah, S. (2020). Effectiveness of amlodipine on blood pressure control in hypertensive patients in India: A real-world, retrospective study from electronic medical records. Drugs - Real World Outcomes, 7(4), 281-293. [CrossRef] 44. Gandhi, S., Fleet, J.L., Bailey, D.G., McArthur, E., Wald, R., Rehman, F., Garg, A.X. (2013). Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury. Jama, 310(23), 2544-2553. [CrossRef] 45. Siriangkhawut, M., Tansakul, P., Uchaipichat, V. (2017). Prevalence of potential drug interactions in Thai patients receiving simvastatin: The causality assessment of musculoskeletal adverse events induced by statin interaction. Saudi Pharm J, 25(6), 823-829. [CrossRef] 46. IUPAC, Fischer, J., Ganellin, C.R. (2006). Analogue-based Drug Discovery, Wiley, p.181-192 [CrossRef] 47. Navadiya, K., Tiwari, S. (2015). Pharmacology, efficacy and safety of felodipine with a focus on hypertension and angina pectoris. Current Drug Safety, 10(3), 194-201. [CrossRef] 48. Khzam, N., Bailey, D., Yie, H.S., Bakr, M.M. (2016). Gingival enlargement ınduced by felodipine resolves with a conventional periodontal treatment and drug modification. Case Reports in Dentistry, 2016, 1095927. [CrossRef] 49. Savage, R.D., Visentin, J.D., Bronskill, S.E., Wang, X., Gruneir, A., Giannakeas, V., Guan, J., Lam, K., Luke, M.J., Read, S.H., Stall, N.M., Wu, W., Zhu, L., Rochon, P.A., McCarthy, L.M. (2020). Evaluation of a common prescribing cascade of calcium channel blockers and diuretics in older adults with hypertension. JAMA Internal Medicine, 180(5), 643-651. [CrossRef] 50. Umemoto, S., Ogihara, T., Matsuzaki, M., Rakugi, H., Shimada, K., Kawana, M., Kario, K., Ohashi, Y., Saruta, T. (2018). Effects of calcium-channel blocker benidipine-based combination therapy on cardiac events -subanalysis of the COPE trial-. Circulation Journal, 82(2), 457-463. [CrossRef] 51. Koçak, M.N., Arslan, R., Albayrak, A., Tekin, E., Bayraktar, M., Çelik, M., Kaya, Z., Bekmez, H., Tavaci, T. (2021). An antihypertensive agent benidipine is an effective neuroprotective and antiepileptic agent: an experimental rat study. Neurological Research, 43(12), 1069-1080. [CrossRef] 52. Yao, K., Nagashima, K., Miki, H. (2006). Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker. Journal of Pharmacological Sciences, 100(4), 243-261. [CrossRef] 53. Sadoon, N., Ghareeb, M. (2020). Formulation and characterization of ısradipine as oral nanoemulsion. Iraqi Journal of Pharmaceutical Sciences, 29(1), 143-153. [CrossRef] 54. Morikawa, H., Young, C.C., Smits, J.A. (2022). Usage of L-type calcium channel blockers to suppress drug reward and memory driving addiction: Past, present, and future. Neuropharmacology, 221, 109290. [CrossRef] 55. Dalal, J., Mohan, J.C., Iyengar, S.S., Hiremath, J., Sathyamurthy, I., Bansal, S., Kahali, D., Dasbiswas, A. (2018). S-Amlodipine: an ısomer with difference-time to shift from racemic amlodipine. International Journal of Hypertension, 2018(1), 8681792. [CrossRef] 56. Mishra, A.P., Bajpai, A., Rai, A.K. (2019). 1,4-dihydropyridine: A dependable heterocyclic ring with the promising and the most anticipable therapeutic effects. Mini-Reviews in Medicinal Chemistry, 19(15), 1219-1254. [CrossRef] 57. van Geijn, H.P., Lenglet, J.E., Bolte, A.C. (2005). Nifedipine trials: Effectiveness and safety aspects. BJOG: An International Journal of Obstetrics & Gynaecology, 112(s1), 79-83. [CrossRef] 58. Arman, B.M., Binder, N.K., de Alwis, N., Beard, S., Debruin, D.A., Hayes, A., Tong, S., Kaitu’u-Lino, T.J., Hannan, N.J. (2023). Assessment of the tocolytic nifedipine in preclinical primary models of preterm birth. Scientific Reports, 13(1), 5646. [CrossRef] 59. Pratt, M., Mahmood, F., Kirchhof, M.G. (2021). Pharmacologic treatment of idiopathic chilblains (pernio): A systematic review. Journal Of Cutaneous Medicine And Surgery, 25(5), 530-542. [CrossRef] 60. Medhi, B., Rao, R.S., Prakash, A., Prakash, O., Kaman, L., Pandhi, P. (2008). Recent advances in the pharmacotherapy of chronic anal fissure: An update. Asian Journal Of Surgery, 31(3), 154-163. [CrossRef] 61. Miyoshi, K., Miyake, H., Ichihara, K., Kamei, H., Nagasaka, M. (1996). Contribution of aranidipine metabolites with slow binding kinetics to the vasodilating activity of aranidipine. Naunyn-Schmiedeberg's Archives of Pharmacology, 355(1), 119-125. [CrossRef] 62. Jiang, J., Tian, L., Huang, Y., Li, Y., Xu, L. (2008). Pharmacokinetic and pharmacodynamic characteristics of aranidipine sustained-release, enteric-coated tablets in healthy chinese men: A phase I, randomized, open-label, single- and multiple-dose study. Clinical Therapeutics, 30(7), 1290-1299. [CrossRef] 63. Araie, M., Mayama, C. (2011). Use of calcium channel blockers for glaucoma. Progress in Retinal and Eye Research, 30(1), 54-71. [CrossRef] 64. Tsuruga, H., Murata, H., Araie, M., Aihara, M. (2023). Neuroprotective effect of the calcium channel blocker nilvadipine on retinal ganglion cell death in a mouse ocular hypertension model. Heliyon, 9(3), e13812. [CrossRef] 65. Chen, B.L., Zhang, Y.Z., Luo, J.Q., Zhang, W. (2015). Clinical use of azelnidipine in the treatment of hypertension in Chinese patients. Ther Clin Risk Manag, 11, 309-318. [CrossRef] 66. Sada, T., Saito, H. (2003). Pharmacological profiles and clinical effects of azelnidipine, a long-acting calcium channel blocker. Nihon Yakurigaku Zasshi, 122(6), 539-547. [CrossRef] 67. Pal, D., Maji, S., Maiti, R. (2023). Efficacy and safety of azelnidipine as an antihypertensive compared to amlodipine: A systematic review and meta-analysis. High Blood Pressure & Cardiovascular Prevention, 30(5), 401-410. [CrossRef] 68. Ram, C.V.S. (2022). Therapeutic usefulness of a novel calcium channel blocker azelnidipine in the treatment of hypertension: A narrative review. Cardiology and Therapy, 11(4), 473-489. [CrossRef] 69. Godfraind, T. (2017). Discovery and development of calcium channel blockers. Front Pharmacol, 8, 286. [CrossRef] 70. Nakano, N., Ishimitsu, T., Takahashi, T., Inada, H., Okamura, A., Ohba, S., Matsuoka, H. (2010). Effects of efonidipine, an L- and T-type calcium channel blocker, on the renin-angiotensin-aldosterone system in chronic hemodialysis patients. International Heart Journal, 51(3), 188-192. [CrossRef] 71. Godfraind, T. (2014). Calcium channel blockers in cardiovascular pharmacotherapy. Journal Of Cardiovascular Pharmacology And Therapeutics, 19(6), 501-515. [CrossRef] 72. Carlson, A.P., Hänggi, D., Macdonald, R.L., Shuttleworth, C.W. (2020). Nimodipine reappraised: An old drug with a future. Curr Neuropharmacol, 18(1), 65-82. [CrossRef] 73. Nimmrich, V., Eckert, A. (2013). Calcium channel blockers and dementia. British Journal Of Pharmacology, 169(6), 1203-1210. [CrossRef] 74. Tomassoni, D., Lanari, A., Silvestrelli, G., Traini, E., Amenta, F. (2008). Nimodipine and its use in cerebrovascular disease: Evidence from recent preclinical and controlled clinical studies. Clinical and Experimental Hypertension, 30(8), 744-766. [CrossRef] 75. Chen, Y.H., Liu, R.C., Wang, S.P. (1996). Antianginal and anti-ischemic efficacy of nisoldipine in stable angina pectoris: A randomized, double-blind, placebo-controlled trial. Zhonghua Yi Xue Za Zhi (Taipei), 58(5), 323-328. 76. Hu, H., Marban, E. (1998). Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. Molecular pharmacology, 53(5), 902-907. 77. White W.B., Saunders E., Noveck R.J., Ferdinand K. (2003). Comparative efficacy and safety of nisoldipine extended-release (ER) and amlodipine (CESNA-III study) in African American patients with hypertension. American Journal Of Hypertension. 16(9), 739-45. [CrossRef] 78. Basile, J. (2004). The role of existing and newer calcium channel blockers in the treatment of hypertension. The Journal of Clinical Hypertension, 6(11), 621-629. [CrossRef] 79. Bialy, L.P., Wojcik, C., Mlynarczuk-Bialy, I. (2018). Mucosal delivery systems of antihypertensive drugs: A practical approach in general practice. Biomedical Papers, 162(2), 71-78. [CrossRef] 80. Iimura, O., Shimamoto, K. (1993). Efficacy and mode of action of manidipine: A new calcium antagonist. American Heart Journal, 125(2), 635-641. [CrossRef] 81. SaizSatjes, M., Martinez-Martin, F.J. (2018). Manidipine: an antihypertensive drug with positive effects on metabolic parameters and adrenergic tone in patients with diabetes. Drugs Context, 7, 212509. [CrossRef] 82. Martínez Martín, F.J. (2009). Manidipine in hypertensive patients with metabolic syndrome: The MARIMBA study. Expert Review of Cardiovascular Therapy, 7(7), 863-869. [CrossRef] 83. Barrios, V., Escobar, C., Echarri, R. (2009). Importance of medication adherence from the ONTARGET and TRANSCEND points of view. Fundamental & Clinical Pharmacology, 23(2), 259-260. [CrossRef] 84. Cheer, S.M., McClellan, K. (2001). Manidipine: A review of its use in hypertension. Drugs, 61, 1777-1799. [CrossRef] 85. Narotam, P.K., Puri, V., Roberts, J.M., Taylon, C., Vora, Y., Nathoo, N. (2008). Management of hypertensive emergencies in acute brain disease: Evaluation of the treatment effects of intravenous nicardipine on cerebral oxygenation. Journal of Neurosurgery, 109(6), 1065-1074. [CrossRef] 86. Peacock, W.F., Hilleman, D.E., Levy, P.D., Rhoney, D.H., Varon, J. (2012). A systematic review of nicardipine vs labetalol for the management of hypertensive crises. The American Journal Of Emergency Medicine, 30(6), 981-993. [CrossRef] 87. Chandra, K.S., Ramesh, G. (2013). The fourth-generation Calcium channel blocker: Cilnidipine. Indian Heart Journal, 65(6), 691-695. [CrossRef] 88. Chakraborty, R., Langade, D., More, S., Revandlkar, V., Birla, A. (2021). Efficacy of cilnidipine (L/N-type Calcium Channel Blocker) in treatment of hypertension: A meta-analysis of randomized and non-randomized controlled trials. Cureus, 13. [CrossRef] 89. Khatun Kali, M.S., Islam Khan, M.R., Barman, R.K., Hossain, M.F., Ibne Wahed, M.I. (2022). Cilnidipine and magnesium sulfate supplement ameliorates hyperglycemia, dyslipidemia and inhibits oxidative-stress in fructose-induced diabetic rats. Heliyon, 8(1), e08671. [CrossRef] 90. Buchiya, F.V., Jain, V., Raj, H. (2014). A review: Analytical methods for determination of cilnidipine in biological fluid and pharmaceutical dosage forms. Pharma, 2(11), 22-29. 91. Minami, J., Ishimitsu, T., Kawano, Y., Numabe, A., Matsuoka, H. (1998). Comparison of 24-hour blood pressure, heart rate, and autonomic nerve activity in hypertensive patients treated with cilnidipine or nifedipine retard. Journal of Cardiovascular Pharmacology, 32(2), 331-336. [CrossRef] 92. Gordon, E.H., Wong, S.C., Klaustermeyer, W.B. (1987). Comparison of nifedipine with a new calcium channel blocker, flordipine, in exercise-induced asthma. Journal of Asthma, 24(5), 261-265. [CrossRef] 93. Sprague, P., Powell, J.R. (1984). Antihypertensive agents. In Annual Reports in Medicinal Chemistry, 19, 61-70. [CrossRef] 94. Deeks, E.D., Keating, G.M., Keam, S.J. (2009). Clevidipine. American Journal of Cardiovascular Drugs, 9(2), 117-134. [CrossRef] 95. Widiastuti, M., Bisri, D.Y., Rachman, I.A. (2024). The safety and efficacy of clevidipine for blood pressure management in neurocritical patients: a systematic review and meta-analysis. Scientific Reports, 14(1), 6355. [CrossRef] 96. Adlesic, E.C. (2013). Cardiovascular anesthetic complications and treatment in oral surgery. Oral and Maxillofacial Surgery Clinics, 25(3), 487-506. [CrossRef] 97. Wang, X., Guo, X.Y., Xu, L., Liu, B., Zhou, L.L., Wang, X.F., Wang, D., Sun, T. (2017). Studies on the competitive binding of cleviprex and flavonoids to plasma protein by multi-spectroscopic methods: A prediction of food-drug interaction. Journal of Photochemistry and Photobiology B: Biology, 175, 192-199. [CrossRef] 98. McCormack, P.L., Wagstaff, A.J. (2003). Lacidipine. Drugs, 63(21), 2327-2356. [CrossRef] 99. Palit, P., Ali, N. (2008). Oral therapy with amlodipine and lacidipine, 1,4-dihydropyridine derivatives showing activity against experimental visceral leishmaniasis. Antimicrob Agents Chemother, 52(1), 374-377. [CrossRef] 100. Malhotra, H.S., Plosker, G.L. (2001). Barnidipine. Drugs, 61(7), 989-996. [CrossRef] 101. Grassi, G., Robles, N.R., Seravalle, G., Fici, F. (2017). Lercanidipine in the management of hypertension: An update. Journal of Pharmacology and Pharmacotherapeutics, 8(4), 155-165. [CrossRef] 102. Ferri, N., Corsini, A., Pontremoli, R. (2022). Antihypertensive treatment with calcium channel blockers and renal protection: Focus on lercanidipine and lercanidipine/enalapril. European Review for Medical & Pharmacological Sciences, 26(20), 7482-7492. 103. Budriesi, R., Cosimelli, B., Ioan, P., Carosati, E., Ugenti, P.M., Spisani, R. (2007). Diltiazem analogues: The last ten years on structure activity relationships. Current Medicinal Chemistry, 14(3), 279-287. [CrossRef] 104. Ganekal, S., Dorairaj, S., Jhanji, V., Kudlu, K. (2014). Effect of topical calcium channel blockers on ıntraocular pressure in steroid-induced glaucoma. Journal of Current Glaucoma Practice, 8(1), 15-19. [CrossRef] 105. Davogustto, G., Taegtmeyer, H. (2015). Perhexiline, cardiac energetics, and heart failure. JACC: Heart Failure, 3(8), 659-660. [CrossRef] 106. Brogden, R.N., Benfield, P. (1994). Gallopamil. Drugs, 47(1), 93-115. [CrossRef] 107. Xu, G., Grimes, T.D., Grayson, T.B., Chen, J., Thielen, L.A., Tse, H.M., Li, P., Kanke, M., Lin, T.T., Schepmoes, A.A., Swensen, A.C., Petyuk, V.A., Ovalle, F., Sethupathy, P., Qian, W.J., Shalev, A. (2022). Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes. Nature Communications, 13(1), 1159. [CrossRef] 108. Steuber, T.D., Lee, J., Holloway, A., Andrus, M.R. (2019). Nondihydropyridine calcium channel blockers for the treatment of proteinuria: A review of the literature. Annals of Pharmacotherapy, 53(10), 1050-1059. [CrossRef] 109. Sokolov, S., Timin, E.N., Hering, S. (2001). On the role of Ca2+- and voltage-dependent iInactivation in Cav1.2 sensitivity for the phenylalkylamine (-)gallopamil. Circulation Research: Journal of the American Heart Association, 89, 700-708. [CrossRef] 110. Zhou, P.Z., Babcock, J., Liu, L.Q., Li, M., Gao, Z.B. (2011). Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules. Acta Pharmacologica Sinica, 32(6), 781-788. [CrossRef] 111. Tripathi, O., Schreibmayer, W., Tritthart, H.A. (1993). Fendiline inhibits L-type calcium channels in guinea-pig ventricular myocytes: a whole-cell patch-clamp study. British Journal of Pharmacology, 108(4), 865-869. [CrossRef] 112. Brizzolara, A., Garbati, P., Vella, S., Calderoni, M., Quattrone, A., Tonini, G.P., Capasso, M., Longo, L., Barbieri, R., Florio, T., Pagano, A. (2020). Co-Administration of fendiline hydrochloride enhances chemotherapeutic efficacy of cisplatin in neuroblastoma treatment. Molecules, 25(22), 5234. [CrossRef] 113. Abozguia, K., Elliott, P., McKenna, W., Phan, T.T., Nallur-Shivu, G., Ahmed, I., Maher, A.R., Kaur, K., Taylor, J., Henning, A., Ashrafian, H., Watkins, H., Frenneaux, M. (2010). Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation, 122(16), 1562-1569. [CrossRef] 114. Cole, P.L., Beamer, A.D., McGowan, N., Cantillon, C.O., Benfell, K., Kelly, R.A., Hartley, L.H., Smith, T.W., Antman, E.M. (1990). Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation, 81(4), 1260-1270. [CrossRef] 115. Ren, Z., Chen, S., Seo, J.E., Guo, X., Li, D., Ning, B., Guo, L. (2020). Mitochondrial dysfunction and apoptosis underlie the hepatotoxicity of perhexiline. Toxicol In Vitro, 69, 104987. [CrossRef] 116. Kazatani, T., Higaki, A., Tanaka, Y., Kawada, Y., Hiasa, G., Yamada, T., Okayama, H. (2022). Bepridil monotherapy failed to prevent coronary vasospasm in a Brugada syndrome patient. Oxford Medical Case Reports, 2022(8). [CrossRef] 117. Asai, Y., Arihara, H., Omote, S., Tanio, E., Yamashita, S., Higuchi, T., Hashimoto, E., Yamada, M., Tsuji, H., Kondo, Y., Hayashi, M., Yamamoto, Y. (2023). Effect of polypharmacy on plasma bepridil concentration in patients with heart failure: A multicenter retrospective study. Journal of Pharmaceutical Health Care and Sciences, 9(1), 10. [CrossRef] 118. Awni, W.M., Halstenson, C.E., Nayak, R.K., Opsahl, J.A., Desiraju, R.K., Minn, F.L., Matzke, G.R. (1995). Pharmacokinetics of bepridil and two of its metabolites in patients with end-stage renal disease. The Journal of Clinical Pharmacology, 35(4), 379-383. [CrossRef] 119. Vatansever, E.C., Yang, K.S., Drelich, A.K., Kratch, K.C., Cho, C.C., Kempaiah, K.R., Hsu, J.C., Mellott, D.M., Xu, S., Tseng, C.K., Liu, W.R. (2021). Bepridil is potent against SARS-CoV-2 in vitro. Proceedings of the National Academy of Sciences of the United States of America, 118(10). [CrossRef] 120. Johansen, L.M., DeWald, L.E., Shoemaker, C.J., Hoffstrom, B.G., Lear-Rooney, C.M., Stossel, A., Nelson, E., Delos, S.E., Simmons, J.A., Grenier, J.M., Pierce, L.T., Pajouhesh, H., Lehár, J., Hensley, L.E., Glass, P.J., White, J.M., Olinger, G.G. (2015). A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity. Science Translational Medicine, 7(290), 290ra289-290ra289. [CrossRef] 121. Renneberg, D., Hubler, F., Rey, M., Hess, P., Delahaye, S., Gatfield, J., Iglarz, M., Hilpert, K. (2015). Discovery of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers. Bioorganic & Medicinal Chemistry Letters, 25(18), 3941-3946. [CrossRef] 122. Souza Bomfim, G.H., Mitaishvili, E., Aguiar, T.F., Lacruz, R.S. (2021). Mibefradil alters intracellular calcium concentration by activation of phospholipase C and IP(3) receptor function. Molecular Biomedicine, 2(1), 12. [CrossRef] 123. Mullins, M.E., Horowitz, B.Z., Linden, D.H., Smith, G.W., Norton, R.L., Stump, J. (1998). Life-threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers. Jama, 280(2), 157-158. [CrossRef]