Calcium Channel Blockers in Hypertension

Calcium channel blockers are useful treatments in the management of hypertension. In this presentation by Dr Vivek Baliga, we look at the added benefits of newer types of CCBs in treating high blood pressure. Read more from Dr Baliga here - http://drvivekbaliga.net

1. CCBs in Hypertension: it is time to look beyond BP reduction

2. Preamble Amlodipine is a very safe and effective drug for management of Hypertension There are some minor shortcomings with amlodipine, like pedal edema seen in some patients So, newer CCBs which can overcome this shortcomings are always a good option for management of Hypertension

3. Generations of CCBs and Cilnidipine Generation Drugs Plasma NE level Heart rate Charact - eristics Ca 2+ channel blocked 1 st generation Nifedipine Increased Increased Rapid sympathetic activation L-type 2 nd generation Nicardipine Benitidine Increased Increased Slow acting on L-type Ca 2+ channels 3 rd generation Amlodipine Azelnidipine Increased Increased Slow acting on L-type of Ca 2+ channels 4 th generation Cilnidipine No change or decreased No change or Decreased L- type and N-type Ca 2+ channel L-type and N-type

4. Conventional CCB ’ s fails here… Reflex tachycardia More incidence of Pedal Edema Elevated Proteinuria level

5. Looking beyond the conventional CCB Lets care for Heart & Kidney together

6. Cilnidipine Cilnidipine is a fourth Gen. dihydropyridine (DHP) type of CCB originally developed in Japan. Unlike other calcium channel antagonists, cilnidipine blocks the influx of Ca 2+ ions into both vascular smooth muscle at the level of L-type Ca channels and neuronal cells at the level of N-type Ca channels. The blockade of N-type Ca 2+ channels affects predominantly peripheral nerve endings of sympathetic neurons So cilnidipine reduces sympathetic over activity in addition to reducing vascular resistance (though L type Ca2+ Channel blockage)

7. Tachycardia ↑ Oxidative stress ↑ Cardiac O 2 consumption Platelet activation Activation of RAS Constriction of post- glomerular vessels Effort angina perctoris Chronic heart failure Myocardial infarction Cerebral infarction Chronic renal failure Glomerular HT Sympathetic Overactivity Activation of N-type Ca++ Channels Arterial thrombosis Xs glutamate release Effort angina perctoris Chronic heart failure Myocardial infarction Cerebral infarction

8. Ca 2+ NE Pure L-type Ca 2+ channel blockers like nifedipine , amlodipine Ca 2+ Vessels Vessels Heart Kidney α 1 adrenoceptors β 1 adrenoceptors α 1 & β 1 adrenoceptors Vasoconstriction Vasoconstriction ↑ Cardiac contraction ↑ Heart rate ↓ Renal blood flow Renin secretion L-type Ca 2+ channels N-type Ca 2+ channels Cilnidipine Norepinephrine Cilnidipine : Pharmacology

9. Superior N-Type blockade by CCBs Uneyama H 1999 ; Kitahara 2004 Cilnidipine had the highest selectivity for N-type channels Ratio of IC50 ( L-type & N-type Ca ++ channels) With Cilnidipine the IC50 ratio is 21 This is about 50 times more than that of Amlodipine (ratio : 0.43) 21 0.43 0.082 0.34 AMLODIPINE CILNIDIPINE NIMODIPINE NISOLDIPINE NICARDIPINE IC50 (L/N) ratio 5 10 15 20 25 0.01

10. In clinical trials, BP lowering efficacy of cilnidipine is equivalent to Amlodipine Cilnidipine has shown following benefits beyond BP reductions over amlodipine and other CCBs Reduction in proteinuria Less pedal edema

11. Shifting from other CCBs to Cilnidipine : Blood and urine catecholamines 33 DM + HT patients who were on other CCBs (26 on Amlodipine) were shifted to cilnidipine for 3 months Cilnidipine reduced blood and urine levels of catecholamines , suggesting suppression of sympathetic activity Diabetes Res Clin Pract . 2014 Dec;106(3):504-10

12. Shifting from other CCBs to Cilnidipine : Renal markers Cilnidipine reduced urinary FABP and ACR, suggesting nephroprotective effects Diabetes Res Clin Pract . 2014 Dec;106(3):504-10

13. Cilnidipine in BP Reduction 339 subjects were randomly allocated to the cilnidipine group or amlodipine group The final dose was 11.57±5.6 mg /day in cilnidipine group 5.37±2.4 mg /day in amlodipine group Fujita T et al. Kidney International. 2007; 72: 1543–1549 Cilnidipine , administered once daily effectively Reduces BP and provides 24 hour BP control At once daily dosing, the BP lowering effect is same as that of amlodipine Changes in systolic and diastolic BP during 12 month treatment period

14. Effect on Pulse Rate Cilnidipine Vs Amlodipine) Hoshide S, et al. Hypertens Res 2005;28: 1003–1008 In 110 hypertensive patients, Patients on cilnidipine have lower pulse rate Vs amlodipine

15. Cilnidipine in the Control of Early Morning BP surge Kitahara Y, et al. J Cardiovasc Pharmacol . 2004;43(1):68-73 Cilnidipine administered once daily is an efficient antihypertensive drug regardless of the time of dosing, without reflex tachycardia and increase in sympathetic nervous activity, and with partial inhibition of the morning activation of the sympathetic nervous system

16. Effect of Cilnidipine on BP and Heart Rate: ACHIEVE ONE trial An open label post-marketing study Total 2319 patients treated with cilnidipine for 12 weeks. The effects of cilnidipine on morning hypertension were examined. Patients were divided in groups as per their morning systolic BP (MSBP) and morning pulse rate (MPR) MSBP : analysed in 4 quartiles MPR : analysed in 3 quartiles

17. Changes in mean systolic blood pressure (MSBP) and mean pulse rate (MPR) in relation to baseline a) MSBP quartiles (b) Changes in MSBP from baseline to after 12 weeks of treatment (c) Changes in MPR from baseline to after 12 weeks of treatment

18. (d) Comparison of MPR between baseline and after 12 weeks of treatment (e) MPR: <70 beats per minute (bpm) Changes in MPR from baseline to after 12 weeks of treatment (f) Changes in MSBP from baseline to after 12 weeks of treatment Conclusion : Cilnidipine significantly reduced BP and PR in hypertensive patients at the clinic and at home, especially with higher sympathetic hyperactive morning BP and PR .

19. Cilnidipine Vs Amlodipine : An I ndian study ESC 2014 A prospective randomized study in Amritsar, Punjab 120 HT patients were divided in 2 groups of 60 each Treated with – 10 mg C ilnidipine or 5 mg A mlodipine Change in SBP were compared in both the groups Follow up: 3 months European Heart Journal ( 2014 ) 35 ( Abstract Supplement ), 66 Conclusion :   Cilnidipine offers greater reduction of BP and preventing of ankle edema in HT patients A nkle edema with amlodipine (6) Vs cilnidipine (0 )

20. PODOCYTE INJURY

21. Destruction of the podocytes can lead to massive proteinuria where large amounts of protein are lost from the blood. GLOMERULOSCLEROSIS ESRD Podocyte Damage

22. Cilnidipine & Podocyte

23. Cilnidipine & Podocyte

24. Renoprotection by Cilnidipine : A hypothesis L-type calcium channels are present primarily on afferent arterioles the inhibition of these channels causes dilation of only afferent arterioles resulting in an elevation of glomerular pressure. Efferent arterioles Afferent arterioles On the other hand, N-type calcium channels, which are located in sympathetic nerve endings, control both afferent and efferent arterioles, resulting in well-balanced dilation of both arterioles . Furthermore, secretion of renin from periglomerular cells can be reduced as a result of sympathetic suppression

25. Afferent arteriole Efferent arteriole Glomerulus Afferent arteriole dilated Efferent arteriole constricted Glomerulus Afferent arteriole dilated Efferent arteriole dilated Glomerulus Conventional L-type CCBs on afferent and efferent arterioles Cilnidipine on afferent and efferent arterioles Increased Glomerular pressure Balanced Vasodilation No increase in glomerular pressure Cilnidipine : In Reno-protection: A hypothesis

26. CLEARED– Cilnidipine Reno protective benefits in DM Multicenter, Cross over open label trial T2DM Patients treated continuously with a CCB for > 6 months; P atients with normo to micro albuminuria with a urinary albumin excretion (urinary albumin/Cr ratio, UAE) of less than 300 mg/ gCr

27. CLEARED– Cilnidipine Reno protective benefits in DM P value : 0.0002 P value : 0.0027 Cilnidipine therapy may lower proteinuria in DM patients compared to amlodipine

28. Cilnidipine Vs other CCBs in Hypertension and proteinuria 28 proteinuric hypertensive patients (13 men and 15 women, aged 62) who had been maintained on CCBs > 3 months were randomly assigned to a group receiving amlodipine besilate (14 patients) or a group receiving cilnidipine (14 patients ). C oncentrations of urine protein, urine albumin, serum and urine creatinine (Cr), and serum alpha 2-microglobulin were determined at 6 and 12 months Hypertens Res 2004; 27: 379–385

29. Cilnidipine Vs other CCBs in Hypertension and proteinuria Hypertens Res 2004; 27: 379–385 Cilnidipine group has lower proteinuria than amlodipine group

30. CARTER TRIAL : RAS-I + Cilnidipine in HT + CKD In an open label study, 339 HT + CKD patients , (on RAAS blockers), were randomly assigned to cilnidipine or amlodipine. P rimary endpoint: decrease in urinary protein to creatinine ratio. Follow up: 1-year Kidney International (2007) 72, 1543–1549

31. CARTER TRIAL Kidney International (2007) 72, 1543–1549 Both Amlodipine and Cilnidipine were equally effective for BP reduction

32. CARTER TRIAL Cilnidipine (added to ARB), can reduce proteinuria in HT + CKD patients Kidney International (2007) 72, 1543–1549

33. Cilnidipine Vs Amlodipine (with RAS – I) in DM + HT A multicenter, randomized, active-controlled study in Korea Total of 74 DM + HT patients Randomized to Cilnidipine 10mg + RAS Blocker (n = 37) or Amlodipine 5mg + RAS Blocker (n = 37). Patients were assessed at baseline, 12 weeks and 24 weeks after treatment UACR (Urinary Albumin to Creatinine Ratio) was measured at baseline and at 12 and 24 weeks 34 EASD Conference Sept 2014

34. Cilnidipine Vs Amlodipine (with RAS – I) in DM + HT In cilnidipine group, UACR was significantly reduced after 12 weeks (-53.0 mg/g, p<0.01) and 24 weeks (-57.3 mg/g, p<0.01). However, amlodipine did not show any decrease in UACR at 12 weeks or 24 weeks treatment. 35 EASD Conference Sept 2014

35. CCB induced pedal edema : Mechanism Dilates Arterioles Does not dilate venules

36. Cilnidipine in pedal edema “ Cilnidipine effectively controls BP without causing significant Leg edema ” The JASH and NAJMs states….

37. Indian Study on Safety and Tolerability to Cilnidipine A prospective open label study on 27 HT patients with amlodipine-induced edema Amlodipine was substituted with cilnidipine . A nkle edema, bilateral ankle circumference, body weight, BP, and pulse rate measured at onset of study and after 4 weeks of cilnidipine therapy. N Am J Med Sci. 2013 January; 5(1): 47–50.

38. Indian Study on Safety and Tolerability to Cilnidipine At completion of the study, edema had resolved in all the patients. There was a significant decrease in bilateral ankle circumference and body weight (P < 0.001). There was no significant change in mean arterial blood pressure and pulse rate. N Am J Med Sci. 2013 January; 5(1): 47–50.

39. An open label study on 56 HT patients with Amlodipine-induced oedema in BHU. Amlodipine substituted with Cilnidipine Ankle oedema and bilateral ankle circumference, body weight, BP were taken at baseline & 4 weeks. Mean duration of Amlodipine therapy : 12 months Cilnidipine For Amlodipine-induced Oedema : APICON Feb 2015 DP Singh, Kundan Sinha , AK Srivastava , SS Singh Sir Sunderlal Hospital, Institute of Medical Sciences, BHU, Varanasi http://www.japi.org/february_2015/015_hypertension_oral.html

40. Results At study completion, oedema had resolved in ALL patients . There was a significant decreases in bilateral ankle circumference and body weight (P<0.001). N o significant change in mean arterial BP and pulse rate . Conclusion Cilnidipine caused complete resolution of Amlodipine induced oedema in all cases without worsening of HT or tachycardia. It is an acceptable alternative for Amlodipine induced oedema . Cilnidipine For Amlodipine-induced Oedema : APICON Feb 2015 DP Singh, Kundan Sinha , AK Srivastava , SS Singh Sir Sunderlal Hospital, Institute of Medical Sciences, BHU, Varanasi http://www.japi.org/february_2015/015_hypertension_oral.html

41. Effect of Cilnidipine Vs Amlodipine on cardiac function and uric acid: 2016 study HEART AND VESSELS · JANUARY 2016 DOI : 10.1007/s00380-016-0796-z LAVI: left atrial volume index 62 HT patients randomised to cilnidipine or amlodipine for 48 weeks Cilnidipine reduced serum uric acid and improved LV diastolic function better than amlodipine

42. Cilnidipine vs Other CCBs ^ With RAS-I: Effect on LVMI in HT+ CKD patients LVMI: left ventricular mass index * p < 0.05 versus baseline; † p < 0.05 versus control group. Values are means ± SD . ^: Other CCBs: amlodipine ( n = 17), nifedipine ( n = 3), azelnidipine ( n = 2), benidipine ( n = 1) and Manidipine (n=1) 45 CKD patients were treated with cilnidipine (n=21) or other CCBs for 24 weeks Reversal of LVH is better with cilnidipine than other CCBs (including amlodipine) in HT + CKD patients Int. J. Mol. Sci. 2013, 14 , 16866-16881

43. Take Home message The newer CCB, cilnidipine inhibits both L & N type channels rather than only L channel like traditional CCBs Cilnidipine is as effective as traditional CCBs for BP reduction in HT C ilnidipine had following advantages over traditional CCBs beyond BP reduction Reduction in proteinuria Lesser risk of pedal edema Possibly better improvement in cardiac function and uric acid levels