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

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

Generations of CCBs and Cilnidipine

Generation DrugsPlasma NE

levelHeart rate

Charact-eristics

Ca 2+ channel blocked

1st generation Nifedipine Increased Increased

Rapid sympathetic

activation

L-type2nd generation

NicardipineBenitidine Increased Increased

Slow acting on L-type Ca2+ channels

3rd generation

AmlodipineAzelnidipine Increased Increased

Slow acting on L-type of Ca2+

channels

4th generation Cilnidipine No change or

decreasedNo change or

Decreased

L- type and N-type Ca2+ channel

L-type andN-type

Conventional CCB’s fails here…

• Reflex tachycardia• More incidence of Pedal Edema• Elevated Proteinuria level

Looking beyond the conventional CCB

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)

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 OveractivityActivation of N-type Ca++ Channels

Arterial thrombosis

Xs glutamate

release

Effort angina

perctoris

Chronic heart failure

Myocardial

infarctionCerebral infarction

Ca2+

NE

Pure L-type Ca2+

channel blockers like nifedipine, amlodipine

Ca2+

Vessels Vessels Heart Kidney

α1 adrenoceptors β1 adrenoceptorsα1 & β1

adrenoceptors

•VasoconstrictionVasoconstriction •↑ Cardiac contraction•↑ Heart rate

• ↓ Renal blood flow• Renin secretion

L-type Ca2+ channels

N-type Ca2+ channelsCilnidipine

Norepinephrine

Cilnidipine: Pharmacology

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) ratio0

5

10

15

20

25

0.01

• 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

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

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

Cilnidipine in BP Reduction

• 339 subjects were randomly allocated to the cilnidipine group or amlodipine groupThe 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 during12 month treatment period

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

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

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

• 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

• (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 .

Cilnidipine Vs Amlodipine : An Indian 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 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

Fall in SBP (mm Hg)

0 5 10 15 20 25

1422

CilnidipineAmlodipine

Conclusion: Cilnidipine offers greater reduction of BP and preventing of ankle edema in HT patients

• Ankle edema with amlodipine (6) Vs cilnidipine (0)

RAAS overactivationAng II increasesAT1 receptorNaCl retentionWater RetentionDecreases renal blood flowVasoconstriction

Kidney

PODOCYTE INJURY

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 lossProteinuria

ESRD

Podocyte Damage

CILNIDIPINE

Reduces Ca++ overloadReduces excess NE release

Reduces overactivation of RAASReduces excess Renin release

Reduces AngII levelVasodilationReduces 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

Cilnidipine & Podocyte

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.

Effer

ent a

rterio

les

Afferen

t arte

rioles

• 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

Afferent arteriole Efferent arteriole

Glomerulus

Afferent arteriole dilated

Efferent arterioleconstricted

Glomerulus

Afferent arteriole dilated

Efferent arterioledilated

Glomerulus

Conventional L-type CCBs on afferent and efferent arterioles

Cilnidipine on afferent and efferent arterioles

Increased Glomerular pressure

Balanced VasodilationNo increase in glomerular

pressure

Cilnidipine: In Reno-protection: A hypothesis

CLEARED– Cilnidipine Reno protective benefits in DM

• Multicenter, Cross over open label trial • T2DM Patients treated continuously with a CCB for > 6 months;• Patients with normo to micro albuminuria with a urinary albumin

excretion (urinary albumin/Cr ratio, UAE) of less than 300 mg/gCr

CLEARED– Cilnidipine Reno protective benefits in DM

baseline L type CCB cilnidipine (6 months)

0

5

10

15

20

25

30

35

40

45

25.6

38.9

23.2

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

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

Cilnidipine Vs other CCBs in Hypertension and proteinuria

Hypertens Res 2004; 27: 379–385

Cilnidipine group has lower proteinuria than amlodipine group

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. Primary endpoint: decrease in urinary protein to creatinine ratio. Follow up: 1-year

Kidney International (2007) 72, 1543–1549

CARTER TRIAL

Kidney International (2007) 72, 1543–1549

Both Amlodipine and Cilnidipine were equally effective for BP reduction

CARTER TRIAL

Cilnidipine (added to ARB), can reduce proteinuria in HT + CKD patients

Kidney International (2007) 72, 1543–1549

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 Conferenc

e Sept 2014

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 Conferenc

e Sept 2014

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

Cilnidipine in pedal edema

“Cilnidipine effectively controls BP without causing significant Leg edema”

The JASH and NAJMs states….

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. • 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.

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.

• 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

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

Effect of Cilnidipine Vs Amlodipine on cardiac function and uric acid: 2016 study

HEART AND VESSELS · JANUARY 2016 DOI: 10.1007/s00380-016-0796-zLAVI: 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

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

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