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
1st
generation
Nifedipine Increased Increased
Rapid
sympathetic
activation
L-type
2nd
generation
Nicardipine
Benitidine
Increased Increased
Slow acting on
L-type Ca2+
channels
3rd
generation
Amlodipine
Azelnidipine
Increased Increased
Slow acting on
L-type of Ca2+
channels
4th
generation
Cilnidipine
No change or
decreased
No change or
Decreased
L- type and N-
type Ca2+
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

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 Ca2+ 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 O2
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. Ca2+
NE
Pure L-type Ca2+
channel blockers like
nifedipine, amlodipine
Ca2+
Vessels Vessels Heart Kidney
α1 adrenoceptors β1 adrenoceptors
α1 & β1
adrenoceptors
•VasoconstrictionVasoconstriction •↑ Cardiac contraction
•↑ Heart rate
• ↓ Renal blood flow
• Renin secretion
L-type Ca2+
channels
N-type Ca2+
channels
Cilnidipine
Norepinephrine
Cilnidipine: Pharmacology

9. 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
0
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 otherCCBs 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 otherCCBs to Cilnidipine:
Renalmarkers
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 RateCilnidipine 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 HeartRate:
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 Indian
study ESC2014
• A prospective randomized study in Amritsar, Punjab
• 120 HT patients were divided in 2 groups of 60 each
• Treated with – 10 mg Cilnidipine or 5 mg Amlodipine
• Change in SBP were compared in both the groups
• Follow up: 3 months
European Heart Journal ( 2014 ) 35 ( Abstract Supplement ), 66
14
22
0 5 10 15 20 25
Fall in SBP (mm Hg) Cilnidipine
Amlodipine
Conclusion: Cilnidipine offers greater reduction of BP
and preventing of ankle edema in HT patients
• Ankle edema with amlodipine (6) Vs cilnidipine (0)

20. RAAS overactivation
Ang II increases
AT1 receptor
NaCl retention
Water Retention
Decreases renal blood flow
Vasoconstriction
Kidney
Sympathetic
Nervous
Overactivity
PODOCYTE
INJURY

21. Destruction of the podocytes can lead to massive proteinuria where
large amounts of protein are lost from the blood.
GLOMERULOSCLEROSIS
Podocyte
injury
Podocyte
stress
Podocyte
apoptosis
Podocin,
Nephrin
Protein loss
Proteinuria
ESRD
Podocyte Damage

22. CILNIDIPINE
Reduces
Ca++
overload
Reduces
excess NE
release
Reduces
overactivation of
RAAS
Reduces excess
Renin release
Reduces AngII level
Vasodilation
Reduces oxidative
stress by reducing
superoxide
production
(produced by AngII)
Reduces the
Podocyte Loss
Reduces
Podocin,
nephrin
excretion
Prevents
Proteinuria
N-type Ca++ channels
on podocytes
Cilnidipine & Podocyte

23. Cilnidipine & Podocyte

25. Renoprotectionby 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.
• 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

26. 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

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

28. CLEARED–CilnidipineRenoprotectivebenefitsin
DM
25.6
38.9
23.2
0
5
10
15
20
25
30
35
40
45
baseline L type CCB cilnidipine (6 months)
Urine Albumin excretion (UAE) (mg/gCr)
P value : 0.0002 P value : 0.0027
Cilnidipine therapy may lower proteinuria in DM patients
compared to amlodipine

29. 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).
• Concentrations 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

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

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

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

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

34. CilnidipineVs Amlodipine (withRAS –I)
inDM + 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

35. CilnidipineVs Amlodipine (withRAS –I)
inDM+ 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

36. CCB induced pedal edema : Mechanism
Amlodipine dilates only arterioles
(and not the venules)
Increased capillary pressure
and capillary permeability
Expulsion of fluid into
the surrounding tissue
Pedal edema
Dilates Arterioles Does not
dilate venules

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

38. Indian Study on Safetyand Tolerabilityto
Cilnidipine
• A prospective open label study on 27 HT patients
with amlodipine-induced edema
• Amlodipine was substituted with cilnidipine.
• Ankle 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.

39. Indian Study on Safetyand Tolerabilityto
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.

40. • 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

41. 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).
• No 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

42. Effectof CilnidipineVs Amlodipineon cardiac
functionand uric acid: 2016study
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

43. Cilnidipine vs OtherCCBs^ WithRAS-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

44. 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
• Cilnidipine 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