Calcium channel blockers (CCBs)

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Calcium channel blockers (CCBs) use was associated with a 70% lower risk for frailty (95%CI = 0.09 to 0.77).[1] The use of CCBs in 75+ y.o. patients with renovascular disease. was associated with a significant reduction in overall mortality and cardiovascular death.[2]

The point estimates for calcium channel blockers (CCBs) indicated a decrease in seven DNAmAges (a decrease of 0.57 to 1.74 years in five PCDNAmAges, a 0.03-year decrease of aging rate in DunedinPACE, and an elongation of 0.01 in PCDNAmTL), among which the estimates for PCHorvathAge (beta = − 1.28, 95%CI = − 2.34 to − 0.21), PCSkin&bloodAge (beta = − 1.34, 95%CI = − 2.61 to − 0.07), PCPhenoAge (beta = − 1.74, 95%CI = − 2.58 to − 0.89), and PCGrimAge (beta = − 0.57, 95%CI = − 0.96 to − 0.17) excluded the null. In addition to DNAmAges, CCBs was also associated with decreased functional biological ages, shown in FAI (beta = − 2.18, 95%CI = − 3.65 to − 0.71) and FI (beta = − 1.31, 95%CI = − 2.43 to − 0.18).[3]

Patients with hypertension who were treated with calcium channel blocker (CCB), but not in diuretics demonstrated an association between telomere attrition rate and the differences in antihypertensive treatment response - their analyzes showed that the increase of leukocyte telomere length is associated with the decrease of systolic blood pressure and pulse pressure.[4]

CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients.

Classes

Dihydropyridine calcium channel blockers (dipines)

Dihydropyridine (DHP) calcium channel blockers are derived from the molecule dihydropyridine and often used to reduce systemic vascular resistance and arterial pressure.

  • Amlodipine (Norvasc)
  • Aranidipine (Sapresta)
  • Azelnidipine (Calblock)
  • Barnidipine (HypoCa)
  • Benidipine (Coniel)
  • Cilnidipine (Atelec, Cinalong, Siscard) Not available in US
  • Clevidipine (Cleviprex)
  • Efonidipine (Landel)
  • Felodipine (Plendil)
  • Isradipine (DynaCirc, Prescal)
  • Lacidipine (Motens, Lacipil)
  • Lercanidipine (Zanidip)
  • Manidipine (Calslot, Madipine)
  • Nicardipine (Cardene, Carden SR)
  • Nifedipine (Procardia, Adalat)
  • Nilvadipine (Nivadil)
  • Nimodipine (Nimotop) This substance can pass the blood-brain barrier and is used to prevent cerebral vasospasm.
  • Nisoldipine (Baymycard, Sular, Syscor)
  • Nitrendipine (Cardif, Nitrepin, Baylotensin)
  • Pranidipine (Acalas)

Non-dihydropyridine

Fendiline Gallopamil Verapamil (Calan, Isoptin) Diltiazem (Cardizem) Gabapentin Pregabalin Ziconotide

Magnesium have also been shown to act as calcium channel blocker when administered orally.

Ethanol also inhibits L-type calcium channel.[5]

Verapamil

(also: nifedipine, amlodipine, lacidipine, nicardipine) Verapamil, an L-type calcium channel blocker, extended the Caenorhabditis elegans (C. elegans) lifespan and delayed senescence in human lung fibroblasts. Verapamil treatment also improved healthspan in C. elegans as reflected by several age-related physiological parameters, including locomotion, thrashing, age-associated vulval integrity, and osmotic stress resistance. Moreover, verapamil extended worm lifespan by inhibiting calcineurin activity.[6]

Cinnarizine

Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. Cinnarizine is predominantly used to treat nausea and vomiting associated with motion sickness, vertigo, Ménière's disease, or Cogan's syndrome, also as a nootropic drug (memory and cognitive function enhancer) and as adjunct therapy for peripheral arterial disease.[7] As a selective calcium channel blocker (SCCB), it reduces the entry of Ca2+ ions into cells and decreases their concentration in the plasma membrane depot, reduces the tone of the smooth muscles of arterioles, and enhances the vasodilating effect of carbon dioxide. Сinnarizine dose-dependently inhibits the mammalian target of rapamycin (mTOR), and selectively mTOR complex 1 (mTORC1), but not mTOR complex 2 (mTORC2), which allows cinnarizine to be classified as an mTOR inhibitor (rapalog) that is a geroprotector.[8]

Chronic administration of the calcium channel blocker cinnarizine to senescent animals with significant aging-induced decreased density of dopamine D2 and especially D1 receptors, regain these pathological disorders.[9]

Fasudil

The small molecule fasudil, formerly known as HA1077 or AT‐877, is the ROCK inhibitor that has been used in Japan and China since 1995 for the treatment of vasospasms following subarachnoid haemorrhage, as well as to prevent the loss of intelligence and memory observed in stroke patients and the elderly.[10] Fasudil also could ameliorate impairments in skeletal muscle blood flow observed in older adults[11] It is marketed under the name ERIL®. It was initially characterized as a calcium antagonist, different from previously known calcium channel blockers such as verapamil, diltiazem and nicardipine in that it could prevent arterial contraction in conditions where other calcium channel blockers had failed.[12]

Despite its successful introduction into clinical practice in Japan and China for almost 30 years, the use of fasudil in other countries faces certain limitations. Although fasudil inhibits both ROCK isoforms (ROCK1 and ROCK2) more potently than other kinases, some of its side effects, including hypotension, skin reactions and reversible renal dysfunction, are major barriers to its widespread use.[13]

References

  1. ↑ Chuang, S. Y., Pan, W. H., Chang, H. Y., Wu, C. I., Chen, C. Y., & Hsu, C. C. (2016). Protective effect of calcium channel blockers against frailty in older adults with hypertension. Journal of the American Geriatrics Society, 64(6), 1356-1358.
  2. ↑ Deshmukh, H., Barker, E., Anbarasan, T., Levin, D., Bell, S., Witham, M. D., & George, J. (2018). Calcium channel blockers are associated with improved survival and lower cardiovascular mortality in patients with renovascular disease. Cardiovascular Therapeutics, 36(6), e12474. PMID: 30372589 DOI: 10.1111/1755-5922.12474
  3. ↑ Tang, B., Li, X., Wang, Y., Sjölander, A., Johnell, K., Thambisetty, M., ... & Hägg, S. (2023). Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging. GeroScience, 45(3), 2065-2078. PMID: 37032369 PMC10400489 DOI: 10.1007/s11357-023-00784-8
  4. ↑ Zhang, S. Y., Li, R. X., Yang, Y. Y., Chen, Y., Yang, S. J., Li, J., ... & Zhang, W. L. (2019). P1693 The longitudinal associations between telomere attrition and the effects of blood pressure lowering and antihypertensive treatment. European Heart Journal, 40(Supplement_1), ehz748-0448. https://doi.org/10.1093/eurheartj/ehz748.0448
  5. ↑ Uhrig, S., Vandael, D., Marcantoni, A., Dedic, N., Bilbao, A., Vogt, M. A., ... & Hansson, A. C. (2017). Differential roles for L-type calcium channel subtypes in alcohol dependence. Neuropsychopharmacology, 42(5), 1058-1069. PMC5506795 DOI: 10.1038/npp.2016.266
  6. ↑ Liu, W., Lin, H., Mao, Z., Zhang, L., Bao, K., Jiang, B., ... & Li, J. (2020). Verapamil extends lifespan in Caenorhabditis elegans by inhibiting calcineurin activity and promoting autophagy. Aging (Albany NY), 12(6), 5300. PMID: 32208362 PMC7138547 DOI: 10.18632/aging.102951
  7. ↑ Kirtane, M. V., Bhandari, A., Narang, P., & Santani, R. (2019). Cinnarizine: a contemporary review. Indian Journal of Otolaryngology and Head & Neck Surgery, 71, 1060-1068. PMID: 31750127 PMC6841794 DOI: 10.1007/s12070-017-1120-7
  8. ↑ Allen, S. A., Tomilov, A., & Cortopassi, G. A. (2018). Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochemical pharmacology, 155, 298-304. PMID 30028993 doi:10.1016/j.bcp.2018.07.013
  9. ↑ Camps, M., Ambrosio, S., Reiriz, J., Ballarin, M., Cutillas, B., & Mahy, N. (1993). Effect of age and cinnarizine treatment on brain dopamine receptors. Pharmacology, 46(1), 9-12. PMID: 8434032 DOI: 10.1159/000139023
  10. ↑ Suzuki, Y., Shibuya, M., Satoh, S. I., Sugimoto, Y., & Takakura, K. (2007). A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surgical neurology, 68(2), 126-131. PMID: 17586012 DOI: 10.1016/j.surneu.2006.10.037
  11. ↑ Darvish, S., Coppock, M. E., & Murray, K. O. (2022). Age-related impairments in ATP release by red blood cells as an important contributor to declines in skeletal muscle blood flow in older adults. The Journal of physiology, 600(16), 3643. PMC9378623
  12. ↑ Asano, T. O., Ikegaki, I. C., Satoh, S.,et al., & Hidaka, H. (1987). Mechanism of action of a novel antivasospasm drug, HA1077. Journal of Pharmacology and Experimental Therapeutics, 241(3), 1033-1040. PMID 3598899
  13. ↑ Wolff, A. W., Peine, J., Höfler, J., Zurek, G., Hemker, C., & Lingor, P. (2024). SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants. CNS drugs, 38(4), 291-302. PMC10980656
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