CiLNIDIPINE forth generation CCB it's mechanism

This sides takes us through a brief understanding other the 2025 CCB and its impact and role on reduction of hypertension we discuss a detailed MOA and drug strength and comparative with Amlodipine .

1. CILNIDIPINE

2. Draw backs of Amlodipine The major drawback of amlodipine is its adverse effect of peripheral edema. Incidence of peripheral edema with amlodipine has been found to be between 1.7% and 32% in different clinical studies. Almost 9.3% of patients discontinue amlodipine therapy due to the adverse effects most commonly pedal edema The most serious consequence of amlodipine induced edema is discontinuation of the effective antihypertensive therapy.

3. CONVENTIONAL CCB’S FAILS HERE Reflex tachycardia More incidences of Pedal Edema Elevated Proteinuria level

4. INTRODUCTION:CILNIDIPINE

5. INTRODUCTION:CILNIDIPINE

6. INTRODUCTION:CILNIDIPINE

7. CILNIDIPINE A new generation of CCB, cilnidipine is an N-type and L-type CCB that also inhibits sympathomimetic activity in contrast to other DHP. Cilnidipine is a dihydropyridine (DHP) type of calcium channel antagonistoriginally developed in Japan. Cilnidipine is a promising 4th generation Ca 2+ channel blocker with a rational pharmacological profile; i.e. dual L/N-type Ca 2+ channel-blocking action. The blockade of N-type Ca 2+ channels effectively suppresses neurohumoral regulation in the cardiovascular system, including sympathetic nervous system and renin–angiotensin–aldosterone system.

8. CILNIDIPINE Cilnidipine is a newer dihydropyridine calcium antagonist shown to have a prolonged antihypertensive property . Cilnidipine was first approved in Japan in 1995 and was subsequently approved by other countries to become one of the primary anti-hypertensive drugs used today.

9. CILNIDIPINE Unlike other calcium channel antagonists, cilnidipine blocks the influx of Ca2+ions into both vascular smooth muscle at the level of L-type Ca2+channels and neuronal cells at the level of N-type Ca2+channels. The L-type Ca2+channelblockade by cilnidipine affects predominantly vascular smooth muscle, thereby producing vasodilation of peripheral resistance vessels and coronary arteries. The blockade of N-typeCa2+channels affects predominantly peripheral nerve endings of sympathetic neurons,thereby dilating blood vessels by lowering plasma catecholamine levels. Indian Heart J v.65(6); 2013 Dec

10. CILNIDIPINE Cilnidipine has shown significant reduction in the incidence of pedal edema when compared to amlodipine ( P < 0.05). There were no other significant adverse reactions observed in either amlodipine or cilnidipine group (other than pedal edema). Old CCB like Amlodipine and a newer CCB like Cilnidipine have shown equal efficacy in reducing blood pressure in hypertensive individuals. But Cilnidipine being an N‑type and L‑type calcium channel blocker is associated with a lower incidence of pedal edema compared to only the L‑type channel blocked by Amlodipine.   Cureus · November 2021

11. CILNIDIPINE Cilnidipine pro- duced greater reductions in blood pressure in patients with hypertension than in healthyvolunteers . Although increases in heart rate were noted in studies with conventionalL -type selective DHPs, the changes in heart rate with cilnidipine were negligible, even inpatients with rapid blood pressure reduction. Thus, it appears that the hypotension- inducedbaroreflex sympathetic stimulation is attenuated by this inhibitory action on N-type Ca2+channels and that even greater blood pressure-lowering effects are achieved with cilni-dipine . Indian Heart J v.65(6); 2013 Dec

12. CILNIDIPINE   Cureus · November 2021

13. CILNIDIPINE Cilnidipine is an L/N-type calcium channel blocker, which lowers the BP in part by sympathetic nerve inhibition at the peripheral sympathetic nerve endings in vivo . It has been shown to reduce both systolic blood pressure (SBP) and diastolic blood pressure (DBP) but does not increase pulse rates (PR) or plasma catecholamines .   Cureus · November 2021

14. CILNIDIPINE Cilnidipine was reported to be effective in hypertensive patients with morning HTN in which sympathetic nerve overactivity was potentially involved. In hypertensive patients with abnormal nocturnal BP, Cilnidipine was also shown to significantly lower the BP, especially during sleep when exaggerated activation of the sympathetic nerve occurs . Cilnidipine also attenuates vascular endothelial dysfunction and thus is useful in the long-term management of cardiovascular disorders   Cureus · November 2021

15. CILNIDIPINE Cilnidipine has been reported to have more beneficial effects on proteinuria progression in hypertensive patients than Amlodipine, an L-type CCB . The N-type calcium channel blockade that inhibits renal sympathetic nerve activity might reduce glomerular hypertension by facilitating vasodilation of the efferent arterioles. However, the precise mechanism of the renoprotective effect of Cilnidipine remains unknown.   Cureus · November 2021

16. CILNIDIPINE Cilnidipine exerted significantly higher antioxidant activity than Amlodipine in cultured human mesangial cells, it can be hypothesized that Cilnidipine might exert a renoprotective effect by suppressing oxidative stress. oxidative stress. The urinary albumin, 8-hydroxy-2'-deoxyguanosine ( OHdG ), and liver-type fatty- acidbinding protein (L-FABP) to creatinine ratios significantly decreased with Cilnidipine (P with those with Amlodipine . Thus, Cilnidipine probably exerts a greater renoprotective effect through its antioxidative properties.   Cureus · November 2021

17. CILNIDIPINE In a study conducted by Ramya et al., Cilnidipine was found to be safe and effective in reducing microalbuminuria and blood pressure in Indian mild-to-moderate hypertensive patients with type 2 diabetes mellitus. In this study, Cilnidipine caused a significant reduction in the mean (SD) SBP from 150.07 (5.44) mm Hg at baseline to 123.03 (5.23) mm Hg after six months. Cilnidipine also produced a significant reduction in the microalbuminuria from 66.62 (8.39) mg/L to 38.8 (6.45) mg/L after six months .   Cureus · November 2021

18. CILNIDIPINE The anti-hypertensive effects of Cilnidipine are significant, with good oral absorption and long duration of action. After oral administration, drug concentrations peak at 1.8 to 2.2 hours and show a half-life of 7.5 hours. However, despite a shorter half-life, Cilnidipine exhibits a prolonged duration of antihypertensive action. It is postulated that Cilnidipine exhibits a high protein binding of 98%, which prolongs the duration of action.   Cureus · November 2021

19. CILNIDIPINE The multicenter, open labeled and randomized trial of Cilnidipine versus Amlodipine Randomized Trial for Evaluation in Renal disease (CARTER) has shown that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in patients with hypertension and chronic renal disease when coupled with a renin–angiotensin system inhibitor. Prevalence of cardiovascular disease and cardiovascular mortality have been suggested to be closely associated with renal function; namely, cardio–renal connection. Thus, the renal protective effects of cilnidipine may secondarily contribute to cardioprotection . Indian Heart J v.65(6); 2013 Dec

20. CILNIDIPINE Takashi Masuda, Misao N. Ogura, Tatsumi Moriya, et al (2011) have demonstrated the beneficial effects of L- and N-type calcium channel blocker on glucose and lipid metabolism and renal function in patients with hypertension and type II diabetes mellitus. A recent study by Fan et al (2011) indicates that cilnidipine relaxes human arteries through Ca 2+ channel antagonism and increases production of nitric oxide by enhancement of endothelial nitric oxide synthase in the human internal thoracic artery. Indian Heart J v.65(6); 2013 Dec

21. CILNIDIPINE Ranjan Shetty, G Vivek et al (2013) have conducted a study in 27 patients of essential hypertension with amlodipine-induced ankle edema and concluded that therapy with cilnidipine resulted in complete resolution of amlodipine-induced edema in all the cases without significant worsening of hypertension or tachycardia. Cilnidipine is an acceptable alternative antihypertensive for patients with amlodipine-induced edema. Indian Heart J v.65(6); 2013 Dec

22. CILNIDIPINE Cilnidipine antagonized the increase in blood pressure in response toacute cold stress, which is not usually depressed by L-type Ca2+channel antagonists. Direct negative inotropic effects were not, however, detected in hypertensive patients whoreceived cilnidipine. Recent developments of antihypertensive Ca2+channel antagonists have focused onachieving two desirable goals: 1) tissue selectivity among L-type Ca2+channels to reducethe likelihood of undesirable side effects, and 2) a gradual onset and long duration ofaction to improve compliance and also to reduce sympathetic stimulation due to hypo-tensive baroreflexes. Indian Heart J v.65(6); 2013 Dec

23. CILNIDIPINE J Adv Pharm Technol Res. 2015 Apr-Jun; 6(2): 81–85.

24. CILNIDIPINE Indian Heart J. 2013 Dec; 65(6): 691–695.

25. CILNIDIPINE Indian Heart J. 2013 Dec; 65(6): 691–695. Cilnidipine is a recently developed CCB, and possesses both L- and N-type calcium channels blocking activity. Since N-type calcium is distributed along the nerve and in the brain, cilnidipine is anticipated to exert specific action on nerve activity, such as inhibition of the sympathetic nervous system. Uneyama et al demonstrated that submicro molecular concentrations of cilnidipine effectively suppressed N-type Ca 2+ channel currents in isolated sympathetic neurons.

26. CILNIDIPINE Indian Heart J. 2013 Dec; 65(6): 691–695. Have demonstrated the beneficial effects of L- and N-type calcium channel blocker on glucose and lipid metabolism and renal function in patients with hypertension and type II diabetes mellitus.

27. CILNIDIPINE Indian Heart J. 2013 Dec; 65(6): 691–695. Cilnidipine is a new drug of Calcium Channel blocker group and blocks both L-type and N-type voltage-dependent calcium channels. The N-type voltage-dependent calcium channel regulates the release of norepinephrine from sympathetic nerve endings . Once-daily administration of cilnidipine results in BP decrease without reflex tachycardia than similar administration than once-daily administration of nifedipine . The morning rise in BP increases the risk of stroke independent of age and 24-h BP level in hypertensive patients significantly . Amlodipine due to its long duration of action, controls 24-BP and it is associated with morning rise which is useful for the prevention of cardiovascular events in hypertensive patients. Sympathetic nervous activity is high in the morning, and may contribute to morning BP surge , and cilnidipine, due to N-type calcium channel blockade, causes morning rise BP. Cilnidipine and Amlodipine have clinical benefits resulting from the unique characteristics of each agent. We compared the effects of cilnidipine and amlodipine on ambulatory BP and pulse rate (PR) monitoring in patients (n=100) with essential hypertension.

28. CILNIDIPINE Indian Heart J. 2013 Dec; 65(6): 691–695. Cilnidipine or amlodipine are used in treatment of hypertension and reduce the ambulatory BP and morning BP. Cilnidipine, does not increase in pulse rate . Cilnidipine causes significantly decrease in Pulse Rate than amlodipine treatment in hypertensive patients. It is well documented that a higher heart rate is associated with a long-term risk of cardiovascular mortality, independent of other cardiac risk factors . Cilnidipine is also a long-acting dihydropyridine calcium antagonist and it is associated with reduction of pulse rate along with significant reduction of BP.

29. CILNIDIPINE Indian Heart J. 2013 Dec; 65(6): 691–695. Both amlodipine and cilnidipine have been applied clinically based on their ability to blockade both the L-type and N-type calcium channels . Cilnidipine is significantly more selective in blocking the N-type calcium channel than other calcium antagonists. Blockade of the neural N-type calcium channel inhibits the secretion of norepinephrine from peripheral neural terminals . As sympathetic activity is not increased by blocking the N-type calcium channels with cilnidipine, it may be the cause a decrease in PR. Clinically, Sakata et al. demonstrated by using 123I-metaiodobenzylguanidine cardiac imaging that cilnidipine suppressed cardiac sympathetic overactivity while amlodipine had little suppressive effect .

30. CILNDIPINE :advantage Edema may result in the need for dose reduction or drug withdrawal, either of which can adversely affect the efficacy. A new generation of CCB, cilnidipine is an N-type and L-type CCB that also inhibits sympathomimetic activity in contrast to other DHP. Although L-type and N-type DHP CCBs are being used clinically, their specific effects on the pedal edema have not yet been elucidated.

31. CILNDIPINE :advantage Indian Heart J. 2013 Dec; 65(6): 691–695. Cilnidipine is also associated with less incidences of pedal edema which is main complaint of patient. It controls BP better with less reflex tachycardia and decrease in morning surge. Thus, Cilnidipine is better antihypertensive drug than amlodipine.

32. CILNDIPINE :advantage It has been shown that cilnidipine does not cause coronary sympathetic hypertonia in response to blood pressure reduction, unlike L-type channel blockers. When administered to the patients with essential hypertension, cilnidipine suppressed cardiac sympathetic over activity and an increase of heart rate with blood pressure reduction. Previous study has also shown that cilnidipine is well-tolerated by the hypertensive patients and associated with minor adverse effects such as headache, dizziness, cough, and gastrointestinal symptoms which are comparable to amlodipine. Indian Heart J. 2013 Dec; 65(6): 691–695.

33. CILNDIPINE : advantage Cilnidipine is a 1,4- DHP CCB that suppresses the influx of calcium ions via L-type and N-type calcium channels, thus reducing the blood pressure through vascular smooth muscle relaxation and arterial dilatation. It is used as an antihypertensive agent with a long duration of action that allows once-daily dosing. Cilnidipine is known to suppress catecholamine release from peripheral sympathetic nerves as it blocks N-type channels in sympathetic nerve terminals as well as having a common L-type calcium channel-blocking effect. Indian Heart J. 2013 Dec; 65(6): 691–695.

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53. CILNIDIPINE :SUPERIORITY

54. CILNIDIPINE: SUPERIORITY

55. Cilnidipine- RENO PROTECTION Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

56. CILNIDIPINE DOSAGE Cilnidipine (5 or 10 mg once daily). not change the average daytime, night-time, or 24-h heart rate Indian Heart J v.65(6); 2013 Dec

57. Efficacy of Cilnidipine (L/N-type Calcium Channel Blocker) in Treatment of Hypertension: A Meta-Analysis of Randomized and Non-randomized Controlled Trials November 2021. Cureus 13(11)

58. Efficacy of Cilnidipine (L/N-type Calcium Channel Blocker) in Treatment of Hypertension: A Meta-Analysis of Randomized and Non-randomized Controlled Trials November 2021. Cureus 13(11)

59. Cilnidipine- Role of Cilnidipine in Management of Hypertension and Co-morbid Conditions Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016 Cilnidipine a unique Ca2+ channel blocker because of its inhibitory action on the sympathetic N-type Ca2+ channels along with L-type Ca2+ channels. Cilnidipine has been classified as a fourth-generation CCB based on its actions on sympathetic neurotransmitter release Cardioprotective, renoprotective and neuroprotective effects of cilnidipine have been reported in clinical studies.

60. Cilnidipine- Cardio-protective Action Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016 N - t y p e c a l c i u m c h a n n e l s regulate sympathetic nerve activity, and aberrant sympathetic nerve stimulation is a major cause of hypertension. Antihypertensive Effects:The antihypertensive effect of cilnidipine has been demonstrated in various studies conducted in hypertensive patients and also in patients with severe hypertension. Once-daily administration of cilnidipine (5-20 mg) for 1-3 weeks decreased the 24-hour average BP significantly from 149±4/88±2 mmHg t o 141±3/82±2 mmHg without any change in the pulse rate. Cilnidipine is thus a useful antihypertensive drug that may not cause an excessive decrease in BP or a reflex tachycardia.

61. Cilnidipine- Cardio-protective Action Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016 In another study conducted by Minami J et al in patients with mild to moderate essential hypertension, Cilnidipine significantly decreased the 24 h blood pressure by 6.5 ± 1.7 mm Hg systolic (P 5.0±1.1 mmHg diastolic (P < 0.01), also cilnidipine did not change heart rate. It was concluded that Cilnidipine is effective as a oncedaily antihypertensive agent and causes little influence on heart rate.

62. Cilnidipine- Cardio-protective Action Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016 Kai T et al conducted a study to examine the effects of cilnidipine, on blood pressure, pulse rate, a n d a u t o n o m i c f u n c t i o n s i n patients with mild-to-moderate hypertension. The systolic or diastolic blood pressure decreased significantly from 151±15 mmHg to 129±14 mmHg or 84±11 mmHg to 71±9 mmHg, respectively. No significant changes in pulse rate reported.

63. Cilnidipine- Effect on Morning Hypertension Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016 An elevated morning BP has been associated with target organ damage. Treatment with cilnidipine significantly decreased morning hypertension. In ACHIEVE-ONE trial, the effects of cilnidipine on morning hypertension were examined in 2319 patients treated with cilnidipine for 12 weeks. Cilnidipine reduced both morning SBP and PR more markedly in patients with higher baseline morning SBP and PR Also a 12-week treatment with cilnidipine significantly, restored abnormal nocturnal dipping in hypertensive patients. Continued……..

64. Cilnidipine- Effect on Morning Hypertension Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016 Also clinical trials comparing the effect of Cilnidipine with Amlodipine reported significant reduction in BP, whereas reductions in pulse rate were significantly greater in the cilnidipine than with amlodipine. Cilnidipine has also emerged as a good candidate for combination therapy. Treatment with cilnidipine and ARB showed a significant reduction in SBP ( pDBP Cilnidipine has also emerged as a good candidate for combination therapy. Treatment with cilnidipine and ARB showed a significant reduction in SBP (p <0.0001 and DBP (p<0.0001) .

65. Cilnidipine- Effect on Left Ventricular (LV) Diastolic Dysfunction/Left Ventricular Hypertrophy (LVH) Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016 Six months treatment with cilnidipine improved LV diastolic function in patients with hypertensive heart disease by suppressing cardiac sympathetic over activity. Also, 8 weeks treatment with cilnidipine 5-10 mg/ day can improve left-ventricular systolic function independently of blood pressure changes. Cilnidipine produced a greater decrease in Left Ventricular Mass.

66. Cilnidipine- RENO PROTECTIVE/ANTIALBUMINURIC EFFECTS Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

67. Cilnidipine- RENO PROTECTIVE/ANTIALBUMINURIC EFFECTS Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

68. Cilnidipine- RENO PROTECTIVE/ANTIALBUMINURIC EFFECTS Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

69. Cilnidipine- RENO PROTECTIVE/ANTIALBUMINURIC EFFECTS Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

70. Cilnidipine- RENO PROTECTIVE/ANTIALBUMINURIC EFFECTS Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

71. Cilnidipine- EFFECT ON INSULIN SENSITIVITY Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

72. Cilnidipine-NEUROPROTECTION Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

73. Cilnidipine- NEURO-PROTECTIVE EFFECTS Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

74. Cilnidipine- clinical evidences

75. Comparison of amlodipine with cilnidipine on antihypertensive efficacy and incidence of pedal edema in mild to moderate hypertensive individuals: A prospective study J Adv Pharm Technol Res. 2015 Apr-Jun; 6(2): 81–85.

76. Abstract Cilnidipine, an L/N-type calcium channel blocker (CCB), has been reported to have more beneficial effects on proteinuria progression in hypertensive patients than amlodipine, an L-type CCB. The N-type calcium channel blockade that inhibits renal sympathetic nerve activity might reduce glomerular hypertension by facilitating vasodilation of the efferent arterioles. However, the precise mechanism of the renoprotective effect of cilnidipine remains unknown. Because cilnidipine exerted significantly higher antioxidant activity than amlodipine in cultured human mesangial cells, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing oxidative stress. A total of 35 hypertensive patients receiving a renin–angiotensin system inhibitor were randomly assigned to a cilnidipine ( n =18; 10 mg per day cilnidipine titrated to 20 mg per day) or amlodipine ( n =17; 5 mg per day amlodipine titrated to 10 mg per day) group; the target blood pressure (BP) was set at 130/85 mmHg. After 6 months of treatment, systolic and diastolic BPs were significantly reduced in both of the groups, without any significant difference between the groups. The urinary albumin, 8-hydroxy-2′-deoxyguanosine ( OHdG ) and liver-type fatty-acid-binding protein (L-FABP) to creatinine ratios significantly decreased in the cilnidipine group ( P <0.05) compared with those in the amlodipine group. The reductions in urinary albumin, 8-OHdG and L-FABP were not correlated with the change in systolic BP. In conclusion, cilnidipine, but not amlodipine, ameliorated urinary albumin excretion and decreased urinary 8-OHdG and L-FABP in the hypertensive patients. Cilnidipine probably exerts a greater renoprotective effect through its antioxidative properties. Hypertension Research volume 35 , pages 1058–1062 (2012)

77. Abstract Hypertension Research volume 35 , pages 1058–1062 (2012) Introduction : Many Calcium channel blocker drugs for control of hypertension are available. New drug Cilinidipine is available and approved for treatment of hypertension. It acts by blocking both L-type and N-type voltage-dependent calcium channels. The neural N-type blockade leads to stoppage of the secretion of norepinephrine and it also depresses sympathetic nervous system activity. The aim of the study is to assess the effect of cilnidipine and amlodipine on hypertensive patient. Method : Clinidipine (n=50) and Amolodipine (n=50) were given once daily and BP was measured daily before and after the medicine in 100 hypertensive patients on OPD basis in GDMC, Dehradun. Result : Only 4 patients (n=50; 8%) in cilnidipine group developed edema within 10 days of therapy, while 32 patients (n=50, 64%) developed with edema within 10 days of treatment in amlodipine group. Conclusion : Cilnidipine is also associated with less incidences of pedal edema which is main complaint of patient. It controls BP better with less reflex tachycardia and decrease in morning surge.

78. Abstract Hypertension Research volume 35 , pages 1058–1062 (2012) Cilnidipine is a new drug of Calcium Channel blocker group and blocks both L- typeand N-type voltage-dependent calcium channels . The N-type voltage-dependent calcium channel regulates the release of norepinephrine from sympathetic nerve endings . Once-daily administration of cilnidipine results in BP decrease without reflex tachycardia than similar administration than once-daily administration of nifedipine. The morning rise in BP increases the risk of stroke independent of age and 24-h BP level in hypertensive patients significantly . Amlodipine due to its long duration of action, controls 24-BP and it is associated with morning rise which is useful for the prevention of cardiovascular events in hypertensive patients. Sympathetic nervous activity is high in the morning, and may contribute to morning BP surge , and cilnidipine, due to N-type calcium channel blockade, causes morning rise BP. Cilnidipine and Amlodipine have clinical benefits resulting from the unique characteristics of each agent. We compared the effects of cilnidipine and amlodipine on ambulatory BP and pulse rate (PR) monitoring in patients (n=100) with essential hypertension.

79. Abstract Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

80. Abstract Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

81. Abstract Journal of The Association of Physicians of India ■ Vol. 64 ■ April 2016

82. Abstract Cureus, 22 Nov 2021, 13(11):e19822

83. Abstract Zaman ZA et al. Int J Basic Clin Pharmacol. 2013 Apr;2(2):160-164

84. Abstract Cureus, 22 Nov 2021, 13(11):e19822