An Overview of Efficacy of Cilnidipine over Amlodipine in Reno-Protective and Blood Pressure Lowering in the Hypertension with Chronic Disease Patients

Abstract

Hypertension is a medical condition it is characterized by elevated blood pressure in arteries due to high pressure it becomes harder for heart to pump this can ultimately leads to stoke, myocardial infraction, chronic kidney disease, and heart failure. Hypertension is a major risk factor for progression of kidney function, resulting in end-stage renal disease (ESRD). CKD in return, has an adverse effect on blood pressure and may leads to refractory hypertension and along with increased in proteinuria. The blood pressure can reduce the progression of the CKD and also cardiovascular risk. Calcium-channel blockers (CCBs) were considered first-line medication for both hypertension and CKD patients as they being potent vasodilators, are particularly effective in reducing peripheral resistance. Among the CCB’s comparison between the cilnidipine and amlodipine, cilnidipine shows the more additional therapeutical effect in decreasing of blood pressure along with proteinuria when compared with amlodipine which is mandatory in hypertension with CKD patients. Amlodipine acts on L-type calcium channel to reduce the blood pressure but it also increases the intraglomerular pressure causing the peripheral oedema where cilnidipine acts on both L-type and N-type calcium channel it helps to reduces the blood pressure by decrease the peripheral resistance and also reduces the intraglomerular pressure that helps to in reduction of peripheral oedema respectively by resisting sympathetic activity which leads inhibition of release of nor-epinephrine .These article explains the effective drug of choice in CCB’s. Among amlodipine and cilnidipine, cilnidipine has more incidence in reducing proteinuria than amlodipine.

Keywords

Introduction

Types of Calcium Channels and Calcium Channel Blockers Acting on them

MECHANISM OF ACTION:

Amlodipine:

1. Usually acts on L-type calcium channel blocker (CCB)
2. Vasodilates mainly peripheral and renal afferent arterioles
3.  It leads to increase in the intraglomerular pressure, potentially imbalance between oncotic and hydrostatic pressure it Worsen the proteinuria (protein loss) over the time.

Cilnidipine:

1. It’s a dual L- and N-type calcium channel blocker
2. N-type blockade reduces sympathetic nerve activity (release of Nor-epinephrine)
3. Dilates both efferent and afferent arterioles by lowering the hydrostatic pressure within the glomerular capillary that lowers intraglomerular pressure.
4. Leads to better proteinuria reduction and potential renal protection.

Pharmacokinetics: 

Cilnidipine is lipophilic drug where it’s been administered orally. As it’s a first-pass metabolism its bioavailability found to be approximately 13–24%. It reaches the maximum plasma concentration within 1-3 hours. It extensively metabolised in the liver mainly by the CYP3A4 enzyme and forms inactive metabolites. Elimination half-life about 7-8 hours but it maintains the anti-hypertensive effect about 24 hours. It excretes mainly via faeces and small amount is excreted via urine.

COMPARATIVE ANALYSIS:

Efficacy:

1. 1. 1. Hypertension associated with CKD worsens renal outcomes and increases cardiac risk. CCB are frequently used when RAAS inhibitors alone are inadequate. 
      2. Amlodipine [L-Type CCB] significantly reduces systemic BP and enhances cardiac outcomes. Mainly, it dilates afferent arteries, which could worsen pressure within the glomerulus and has little impact on proteinuria.
      3. Cilnidipine [L and N-Type CCB] shows comparable reduction in BP and loss of protein while reducing sympathetic activation via N-Type CCB suppression. This triggers to decreased intraglomerular pressure between afferent arterioles and efferent venules that result in significantly lowering in proteinuria, a crucial outcome measure in CKD.

Clinical studies suggest that cilnidipine is not worse than amlodipine in BP regulation and more effective in renoprotection

Safety profile and ADRs:

1. Peripheral oedema, a common ADR with amlodipine, is especially difficult in CKD patients.
2. Cilnidipine’s dual mechanism decreases venous resistance, reducing oedema prevalence and improving safety.

Drug Interactions:

1. These drugs are metabolised via cytochrome P450 3A4
2. Combined use with effective CYP3A4 inhibitors, can enhance plasma levels.
3. Both are well tolerated when used with ARBs or ACE inhibitors, a standard treatment in CKD.
4. Cilnidipine demonstrates fewer significant drug interaction -related adverse reactions in CKD patients.

Cost Effectiveness:

1. Amlodipine is cost-effective and globally available, reducing costs for chronic BP regulation.

2. Cilnidipine, although more expensive, could be cost-effective in CKD due to:  

• Lesser proteinuria
• Lower oedema
• Improved patient adherence

Patient Adherence:

1. These two agents allow for daily dosing, enhancing adherence.
2. Amlodipine stoppage is prevalent due to swelling
3. Patients with CKD show higher compliance with cilnidipine due to

• Reduced swelling discomfort
• Better heart rate regulation

 Special populations:

CKD Elderly patients:

1. Effective in both.
2.  Cilnidipine indicated when swelling or orthostatic effects appear.

Renal Impairment:

1. No dose modification needed for early stage of CKD.
2. Cilnidipine delivers added renal protection action.
3. Dose carefully indicated for both, due to liver breakdown.

Comparison of Guideline Recommendations

DISCUSSION:

Hypertension with chronic kidney disease (CKD) significantly induces the renal and cardiac  complications. To optimize it, drug of choice must be more efficient in comparing within CCBs. In comparison between amlodipine and cilnidipine both the drugs efficiently reduces blood pressure and regulating the heart rate efficiently by regulating blocking of L- type channel. However cilnidipine has a dual action by regulating blocking L- type and N- type calcium channel that results by inhibiting the sympathetic nerve action leading to potentially reduction of intraglomerular pressure and proteinuria.

Amlodipine majorly shows the therapeutic effect to reduce the blood pressure and sustained bp but more frequently associated with increasing in intraglomerular pressure leading to cause of pedal oedema.

Overall, both amlodipine and cilnidipine has an efficient to lower the blood pressure and regulating the heart rate, but cilnidipine has an additional therapeutic effect i.e renoprotection which is mandatory for the patients who are suffering from hypertension with chronic kidney disease.

CONCLUSION:

Both amlodipine and cilnidipine are effective antihypertensive agents, capable of decreasing the blood pressure and heart rate. Amlodipine is widely used because of its proven efficacy in reducing hypertension but some patients respond better to it than to cilnidipine. Cilnidipine, however offers additional benefits as it’s a dual action N- and L-type calcium channel blocking mechanism particularly in reducing proteinuria, enhances renal protection. Consequently, cilnidipine is often preferred for hypertensive patients with renal impairment, providing comprehensive management of the heart rate, blood pressure, and kidney health, potentially leading to better long-term clinical outcomes.

Future Perspectives

Despite the extensive use of amlodipine and cilnidipine in managing high blood pressure, various aspects are yet to be investigated to more clearly establish their long-term therapeutic uses. Current research shows similar reducing blood pressure effects, however new data indicates possibilities additional benefits with cilnidipine because of its L and N-Type calcium channel inhibition.

Potential New Indications:

Cilnidipine is being extensively explored to:

• Hypertension with CKD patients because of its proteinuria-reducing effects.
• Hypertension-related diabetes, where sympathetic suppression may afford metabolic benefits.
• Patients with elevated SNS activity or tachycardia, where reflex tachycardia is undesirable effect.

Amlodipine, simultaneously persists at high levels in combination therapies for uncontrolled hypertension and cardiovascular risk lowering.

Precision Medicine and Genomics:

Advances in genetic based therapy can assist in identifying patients who may benefit more from N-Type calcium channel inhibition, facilitating the path for patient-specific hypertension therapy. Ongoing research is needed to link genetic markers with therapeutic response and adverse effect profiles.

REFERENCES

1. Blood Pressure Reducing Potential and Renoprotective Action of Cilnidipine Among Hypertensive Patients Suffering From Chronic Kidney Disease: A Meta-Analysis 1 2 1 3 1 1 Kusum Kumari , Ritesh Sinha , Mary S. Toppo , Priyanki Mishra , Shadab Alam , DOI: 10.7759/cureus.37774
2. COMPARISON OF HEMODYNAMIC AND VASCULAR PARAMETERS BETWEEN PATIENTS WITH CKD AND ASSOCIATED HYPERTENSION TREATED WITH AMLODIPINE AND CILNIDIPINE  • DOI : 10.36106/gjra
3.  Y. Nisha Maheswari Department of Pharmacology, Government Tirunelveli Medical College, Tirunelveli, Tamilnadu, India B. Meenakshi Department of Pharmacology, Government Tirunelveli Medical College, Tirunelveli, Tamilnadu, India V. Ramasubramanian Department of Nephrology, Government Tirunelveli Medical College, Tirunelveli, Tamilnadu, India J. Ezhil Ramya Department of Pharmacology, Government Tirunelveli Medical College, Tirunelveli, Tamilnadu, India DOI: https://doi.org/10.18203/2319-2003.ijbcp20174380
4. https://pmc.ncbi.nlm.nih.gov
5. https://pubmed.ncbi.nlm.nih.gov
6. Biochemistry, Calcium Channels Cooper D, Dimri M.
7. Management of Hypertension in Chronic Kidney Disease Dan Pugh 1,2, Peter J Gallacher 1, Neeraj Dhaun 1,2, PMCID: PMC6422950 PMID: 30758803
8. Renal Function in Hypertensive Patients Receiving Cilnidipine and L-Type Calcium Channel Blockers: A Meta-Analysis of Randomized Controlled and Retrospective Studies Mayakalyani Srivathsan 1, Vikram Vardhan 2, Azra Naseem 1,??, Sayali Patil 1, Vivek Rai 1, Deepakkumar G Langade 1
9. Hoshide, S., Kario, K., Ishikawa, J. et al. Comparison of the Effects of Cilnidipine and Amlodipine on Ambulatory Blood Pressure. Hypertens Res 28, 1003–1008 (2005). https://doi.org/10.1291/hypres.28.1003
10. Pugh D, Gallacher PJ, Dhaun N: Management of hypertension in chronic kidney disease. Drugs. 2019, 79:365-79. 10.1007/s40265-019-1064-12. Wakar SS, Bonventre JV: Acute Kidney Injury. Harrison's Principle of Internal Medicine. Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J (ed): McGraw-Hill, 2022.
11. Hasibul Hasan. Comparison Between the Efficacies of Amlodipine and Cilnidipine in Treating Hypertensive Patients. Cardiology and Cardiovascular Medicine. 8 (2024): 1-6. Hasan H., Cardiol Cardiovasc Med 2024 DOI:10.26502/fccm.92920351
12. World J Nephrol. 2022 May 25;11(3):86–95. Doi: 10.5527/wjn.v11.i3.86 Georgi Abraham 1, A Almeida 2, Kumar Gaurav 3, Mohammed Yunus Khan 4, Usha Rani Patted 5, Maithrayie Kumaresan 6 PMCID: PMC9160710 PMID: 35733653
13. Asian J Pharm Clin Res, Vol 14, Issue 1, 2021, 144-146 © 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ajpcr.2021v14i1.39962. Journal homepage: https://innovareacademics.in/journals/index.php/ajpcr
14. Mehta KK, Tiwaskar M, Kasture P. Cilnidipine, a Dual L/N-type Ca 2+ Channel Blocker in Hypertension Management: A Review. J Assoc Physicians India 2024;72(4):54-58. Volume 72, Issue 4, P54-58, April – 2024
15. Doi: 10.5455/2319-2003.ijbcp20130308 Zaman ZA et al. Int J Basic Clin Pharmacol. 2013 Apr;2(2):160-164Department of Pharmacology, Shri Krishna Medical College, Muzaffarpur, India.
16. Cureus. 2023 Apr 18:25(4)37774. doi:10.1759/cureus 17774 Kusum Kumari,Ritesh Sinha, Mary's Toppe, Priyanki Mishra, Shadoly Atam, Lakhan Maihee PMCID: PMC10194430 PMID 172133
17. Cureus 2021 Nov 22,13(11) e19822. dok 10.7759/cureus. 19822 Rabindra Nath Chakraborty, Deepak Langade, Shyam More, Vaibhav Revondkar, Ashish Birla PMID: 34963839 PMCID: PMC8695827
18. Akram Al Makki, Donald DiPette, Paul K Whelton,M Hassan Murad, Reem A Mustafa,Shrish Acharya,Hind Mamoun Beheiry, Beatriz Champagne,Kenneth Connell, Marie Therese Cooney, Nnenna Ezeigwe,Thomas Andrew Gaziano, Agaba Gidio, Patricio Lopez Jaramillo, Unab 1 Khan 1,Vindya Kumarapell, Andrew E Moran, Margaret Mawema Silwimba, K Srinath Reddy, Taskeen Khan Brian Rayner, Apichard Sukanthasan Jing Yu, Nizal Saraffzadegan PMID: 34775787 PMCID: PMC8654104 DOI: 10.1161/HYPERTENSIONAHA, 121.18192
19. une 2004 Hypertension Research 27(6):379-85 DOI:10.1291/hyores 27.379 Shunichi Kojima, Mikio Shida, Hiroyuki Yokoyama
20. Umemura, S,Arima, H. Arima, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019) Hypertens Res 42, 1235-1481 (2019) https://doi.org/10.1038/941440-019-0284-9 DOI https://doi.org/10.1038/41440-019-0084-9
21. https://pmc.ncbi.nlm.nih.gov/articles
22. https://www.sciencedirect.com/topics/neuroscience/calcium-channel