Following topics related to Hypertension and its effective management will

be discussed in this CME Program

 Hypertension – A brief overview

 Calcium Channel Blockers
 Sympathetic overactivity
 Cilnidipine
 Cilnidipine - Clinical benefits
 Cardioprotective effect
 Renoprotective effect
 Neuroprotective effect
 Metabolic Syndrome
 Cilnidipine and other benefits
Cardiovascular diseases have emerged as an important health
concern in India

More than 2/5th of the Indian urban adult population suffers

from hypertension
CURRENT SCIENCE, VOL. 97, NO. 3, 10 AUGUST 2009
Force on Sympathetic
Arteries
overactivity
Causing
damage

Systole Diastole

Heart
Force of
at rest
Heart pumping
Causing strain

AHA* confirms that “The treatment of chronic multi-factorial disease requires a

great demand of attention from medical services”**
Ref:
* AHA – American Heart Association
**Adapted from Sing et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1190-1196
 Diuretics

 Beta-blockers

 Calcium channel blockers

 ACE Inhibitors

 Angiotensin receptor blocker

Decrease in Total Peripheral Resistance (TPR)
They are classified as:
 Dihydropyridines

• First Generation
• Second Generation
• Third Generation - Amlodipine

 Nondihydropyridines – Verapamil and Diltiazem

L – type = Long lasting
 L-type currents are long lasting (slow inactivation rate)
and are blocked by all CCBs
 They are found in Cardiac & Vascular tissues
 They are absent in Renal tissues

N – type = Neuronal
 The N-type currents are found primarily in neurons
where they initiate
neurotransmission by releasing norepinephrine from
peripheral sympathetic nerve endings
 They are also present in Renal tissue

T – type = Transiently activated

 T-type currents are transient (fast inactivation)
 They are present in Renal tissue
P or Q-type
 They are neuronal type of Calcium channels
 They were recently detected in Arterioles
Sympathetic Overactivity
primary cause of
Cardiovascular
Morbidity and Mortality
 Stress

Heart H
Y
Leads to increase in : P
Sympathetic • Cardiac output
nerve Peripheral artery  Vascular resistance E
 Na+ retention
activity
(N-type Ca++ channels)  Renin-Angiotensin System R
T
E
Leptin Kidney N
S
I
O
Obesity
Skeletal muscle Increased Insulin resistance N
Cardiovascular Therapeutics 27 (2009) 124–139
 Sympathetic overactivity
(Activation of N-type Ca++ channels)

Increased Increased Activation of

Platelet
Cardiac oxygen Tachycardia Oxidative Renin-Angiotensin
activation consumption System
stress

Arterial Thrombosis Construction of

Post-glomerular
vessels

Excessive
Glutamate release Glomerular
via activation of
N-type Ca++ channels HT

Cerebral Myocardial Effort Chronic Chronic

Infarction Infarction Angina pectoris Heart failure Renal failure

Cardiovascular Therapeutics 27 (2009) 124–139

A new star on the horizon of
Calcium Channel Blockers-

The 4th Generation CCB

 A novel and unique Dihydropyridine derivative

 Synthesized by Fujirebio Inc. (Japan) and is currently marketed in Japan, China &
Portugal under brand name – ATELEC, CINALONG & TENVASC

 It is a dual Calcium Channel Blocker - Cilnidipine

 L-type
• Lowers Blood Pressure by inhibiting L-type calcium channels which
are directly associated with vascular tone

 N-type
• Blocks N-type calcium channels which are related to sympathetic
nervous activity
25  Cellular inhibitory effects of
21 AMLODIPINE Dihydropyridines were noted on
20 rat ventricular myocytes
CILNIDIPINE
 Cilnidipine had the highest selectivity
15 NIMODIPINE
for N-type channels
NISOLDIPINE
10  Ratio of IC50 (L-type & N-type
NICARDIPINE Ca++ channels)
5
0.43
• With Cilnidipine the IC50
0.082 0.01 0.34
0 ratio is 21
IC50 (L/N) ratio
• This is about 50 times more
than that of Amlodipine
(IC50 ratio: 0.43)

Uneyama H 1999 ; Kitahara 2004

Cardioprotective Effect

Renoprotective Effect

Neuroprotective Effect

Metabolic Syndrome

Other Benefits
CARDIOPROTECTIVE EFFECT
Journal of the American Society of Hypertension (2011) 1–7
Effects of the L/N-type calcium channel antagonist
cilnidipine on morning blood pressure control and peripheral
edema formation

Conclusion
• Cilnidipine had a greater effect on MHT, without causing
significant leg edema, when administered at bedtime.
• The sympathoinhibitory action and the resulting balanced
vasodilation of arteries and veins by the L/N-type calcium
channel blocker cilnidipine are clinically useful features for
treating hypertensive patients.
 Cardioprotective Effect

 The purpose of this study was to assess the effect of Cilnidipine and Amlodipine
on ambulatory BP levels

 24 hours ambulatory BP monitoring was performed before and after the use of
Cilnidipine (n=55) and Amlodipine (n=55) as Once Daily

 110 Hypertensive patients equally divided to receive for 8 to 16 weeks:

• Cilnidipine – 10 to 20 mg/day

• Amlodipine – 2.5 to 5 mg/day

Hoshide S. Hypertens Res. 2005 Dec;28(12):1003-8

 Cardioprotective Effect

0
SBP DBP
-5  Both the drugs significantly reduced the
clinical and 24-hours Systolic BP (SBP)
and Diastolic BP (DBP) (p < 0.005)
-10 -12 -12
 However, there is 8% reduction
Diff. in BP

-15 in SBP in cilnidipine group than in

Amlodipine group.
-20
-26 AMLODIPINE
-25 -28
CILNIDIPINE
-30

-35

Hoshide S. Hypertens Res. 2005 Dec;28(12):1003-8

 Cardioprotective Effect

3
2.5 1.9
1.6 1.7
2 AMLODIPINE
1.5
CILNIDIPINE
1
24HPR DAY PR NIGHT PR
0.5
0
-0.5
-1
-1.5
-2 -1.2 -1.2
-1.6
-2.5

The 24-h, daytime and night time PR showed significantly greater decreases in the
cilnidipine group compared to amlodipine.
Hoshide S. Hypertens Res. 2005 Dec;28(12):1003-8
 Cardioprotective Effect

 Once daily administration of cilnidipine resulted in safe & more effective BP

decrease in essential hypertension without causing increase in PR

 Cilnidipine which causes N-Type blockade may decrease morning BP

 The 24-hr daytime & night time PR showed significantly greater decrease in
cilnidipine group compared to amlodipine group
 Cardioprotective Effect

N-type calcium channel blockade by Cilnidipine may not cause

Reflex Tachycardia,
and may be useful for hypertensive treatment

Hoshide S. Hypertens Res. 2005 Dec;28(12):1003-8

 Cardioprotective Effect

 Increased pulse pressure, SBP and DBP are well known characteristics of
hypertension in elderly patients

 Pulse pressure is regulated by stroke volume as well as the extensibility of elastic

arteries, which are vulnerable to arterial stiffness
 Cardioprotective Effect

 Both SBP & DBP were significantly decreased in clinidipine treated group

 The reductions in SBP & DBP were 46.8 ± 6.6 mmHg and 18.8 ± 4.2 mmHg

 As a consequence of the decrease in SBP & DBP, pulse pressure was significantly
decreased
 Cardioprotective Effect

 Decreased arterial stiffness causes positive effects on arteriosclerosis, which also

results in decrease in SBP and DBP

 Moreover, decreased pulse wave velocity associated with decreased

arteriosclerosis leads to lowering of SBP

 As a result, pulse pressure may also be decreased in elderly hypertensive patients

 Thus, the results suggest that cilnidipine reduces arteriosclerosis by decreasing

arterial stiffness in addition to exerting antihypertensive effects in elderly
hypertensives

Cilnidipine is found to be effective in the treatment

of isolated systolic hypertension (ISH)
 Cardioprotective Effect

Effects of Amlodipine & Cilnidipine on cardiac Sympathetic Nervous System (SNS)

Effect on SNS represents N-type channel blockade

 Cardioprotective Effect

 Sympathetic overactivity is the hallmark of morbidity & mortality caused

due to Hypertensive Cardiovascular disease

 Chronic activation of SNS leads to Cardiovascular (CV) events or may

advance to disease progression

Sakata K. Hypertens 1999;33:1447-1452

 Cardioprotective Effect

 47 Hypertensives were assessed using MIBG imaging (only model to evaluate

Human cardiac SNS)
• Amlodipine (n=24) – 5 to 10 mg/day
• Cilnidipine (n=23) – 10 to 20 mg/day

 MIBG (123I-metaiodobenzylguanidine)
• Radioactive isotope analog of Guanidine shares the same kinetics as
norepinephrine in the human body
• Decreased MIBG uptake is associated with unfavorable prognosis

 Cilnidipine significantly improved the MIBG kinetics representing lack of NE in the

heart tissue similar to enalapril

 However, Amlodipine had negligible effect on MIBG kinetics

Sakata K. Hypertens 1999;33:1447-1452

 Cardioprotective Effect

Cilnidipine Amlodipine

SBP  mmHg -29 -28

DBP  mmHg -22 -21

Norepinephrine  nmol/L -0.13 0.24

Heart rate  bpm -1.0 No Change

Sakata K. Hypertens 1999;33:1447-1452

 Cardioprotective Effect

Cilnidipine suppressed the enhanced cardiac sympathetic

activity, without affecting the neuro-hormonal
(SNS or Renin) status

Sakata K. Hypertens 1999;33:1447-1452

 Cardioprotective Effect

 CV events like Myocardial Infarction (MI), stroke & sudden death often occur
during morning

 During this time of the day, over-activation of sympathetic nerve increases the
TPR & therefore, the resultant CV events

 Suppression of this sympathetic nervous system (SNS) over-activation may

therefore prevent CV events

Cilnidipine’s specific effect on N-type (related to SNS activity)

results in better reduction of morning hypertension

Kitahara Y. J Cardiovasc Pharmacol 2004;43(1):68-73

 Cardioprotective Effect

 CCBs including Amlodipine are known to cause Pedal edema in upto 32% of patients
• This is primarily due to increased venular pressure after sympathetic nervous
system stimulation

 Sympathetic nerves are found in the venules. Hence the drugs that block N-type
calcium channels may possibly cause venodilation

 Cilnidipine exerts vasodilatory effect on venules by blocking the N-type channels

 This results in reduction of pressure in the venules which are peripheral to

resistance arteries upto a level which is below the oncotic pressure further
minimizing the extravasation or edema

Kushiro T. J Cardiovasc Pharmacol 2004;44:672-5

 Cardioprotective effect

Arterial Dilation
 Cardioprotective Effect

 Baroreflex control is one key mechanisms

responsible for the control of blood
pressure. Impairment of baroreflex
sensitivity is known as the predictive factor
of mortality in hypertension.

 Cilnidipine – Preferred treatment of Hypertension

amongst CCBs
• Cilnidipine decreases the sympathetic
nerve activity in the patients with
hypertension
• In this study cilnidipine did not cause
reflex tachycardia, and that cilnidipine but
not amlodipine significantly decreased the
ambulatory BP level without causing and
increase in heart rate.
 Cardioprotective Effect

 Reported not to increase the heart rate

inspite of the strong depressor effect

 Cilnidipine in the treatment for Essential

Hypertension  Significant reduction in BP
with inhibition of sympathetic nerve activity &
improvement of impaired baro-reflex control
 Cardioprotective Effect

 Left Ventricular Hypertrophy (LVH) & Diastolic dysfunction is common in

Hypertensives

 LVH is an independent risk factor for Ischemic Heart Disease (IHD), Arrhythmia,
sudden death & Congestive Heart Failure (CHF)

 Heart failure represents inability of the heart to pump blood

 This results in less blood reaching the kidneys, leading to Renin Angiotensin-
Aldosterone System (RAAS) stimulation or sympathetic stimulation

 However excessive SNS stimulation has unfavorable prognosis for heart failure

 CCBs are not ideally suited for patients with heart failure
 Cardioprotective Effect

 Comparative regressive effect of Clinidipine on left ventricular mass (LVM) with

that of Quinapril was evaluated

 Method
 60 patients with mild Essential Hypertension were randomly allocated in
two groups to receive
• Cilnidipine (n = 30) - 10 mg
• Quinapril (n = 30) - 10 mg

 Patients underwent Echocardiography & 123I-MIBG cardiac imaging

before and 12 months after drug treatment

Sakata. Drugs Exp Clin Res. 2003;29(3):117-23

 Cardioprotective Effect

-2

% Reduction in L V M I QUINAPRIL
-4
CILNIDIPINE

-6

-8 -7.6

-10
-10.6
-12

 Clinidipine produced a greater decrease in LVMI than Quinapril, probably due to

the long-term suppression of the cardiac SNS

Sakata. Drugs Exp Clin Res. 2003;29(3):117-23

 Cardioprotective Effect

 Results

• In both the groups SBP & DBP significantly decreased to similar levels

• Only in Cilnidipine group, the MIBG uptake increased significantly (p < 0.02)

• In contrast, there were no significant changes in MIBG parameters in the

Quinapril group

Sakata. Drugs Exp Clin Res. 2003;29(3):117-23

 Cardioprotective Effect

 The usefulness of Cilnidipine in patients with CHF was evaluated using MIBG
Myocardial Scintigraphy

 24 patients with stable CHF

• 12 patients were treated with ACEIs, Diuretics & Cardiotonics
• 12 patients were treated with ACEIs, Diuretics, Cardiotonics + Cilnidipine

 Symptom improvement, BP, HR, MIBG kinetic differences were noted at six months

 10 of 12 patients in Cilnidipine group showed symptom improvement

Ito K. Kaku Igaku. 2003 Nov;40(4):421-30

 Cardioprotective Effect

Degree of change Placebo Cilnidipine

BP (mm Hg) -10.8+/-9.1 - 21.2+/-8.0

Heart rate ( /min) -16.2+/-11.0 - 24.1+/-6.8

MIBG uptake 0.19+/-0.09 0.30+/-0.08

Changes observed were significantly better for Cilnidipine (p<0.05)

 Cardioprotective Effect

 Salient Features

• Increased sympathetic nervous activity has been strongly implicated in

elevated heart rate.

• The data suggests that higher the baseline heart rate, the more marked
will be the decrease in heart rate with the use of Cilnidipine

• This is the first large scale study (1008 patients) conducted in a multi-
centeric setting to evaluate the safety and efficacy of combination
therapy with an ARB and CCB - Cilnidipine

Hypertens Res Vol. 30, No. 9 (2007)

 Cardioprotective Effect

 Salient Features (Cont…)

• Present study demonstrated that the combination therapy of Cilnidipine

and an ARB can be used safely and effectively in hypertensive patients.

• Moreover, in addition to its Anti-hypertensive effect, Cilnidipine can also

decrease the heart rate, thereby protecting the heart from damage.

Hypertens Res Vol. 30, No. 9 (2007)

RENOPROTECTIVE EFFECT
 Reduces UACR

• Cilnidipine dilated afferent and efferent arterioles

in the kidney and decreased glomerular capillary
pressure, thereby reducing proteinuria and improving
glomerulosclerosis and arteriolar lesions.

• Cilnidipine reduced UACR in hypertensive patients

with normal to marginally elevated UACR independent
of its BP-lowering effect.

Clin Drug Investig 2010; 30 (10)

Less Activation of RAAS system

• Cilnidipine leads to less activation of

the RAS system compared with
conventional L-type CCB.

• Each level of all components of the

RAS including plasma aldosterone
concentration.

• Cilnidipine is superior in organ

protection in addition to the
antialbuminuric effect.
 In CRI or related diseases, there is an impaired renal blood supply leading to
increased sympathetic stimulation due to RAAS

 ACEIs slow the progression of CRI and are the preferred drugs

 Cilnidipine amongst CCBs offers:

• Greater selectivity for N-type receptors & thereby results in avoidance of
sympathetic stimulation
• Antiproliferative renoprotective effects (Inhibits TGF-beta, fibronectin)

 Cilnidipine therefore decreases the renal sympathetic activity thereby

increasing renal blood supply, This action is similar to that of ACEIs

 Role of Amlodipine therapy is controversial

(Alli 1996, Lewis 2001, AASK study-JAMA2001)

 A one year study comparing Benazepril with Cilnidipine in hypertensive patients
with benign Nephrosclerosis was conducted
• Proteinuria is a marker of Renal insufficiency & improvement with drug
therapy is desired

 20 patients randomized to receive either

• Benazepril – 5 to 10 mg/day
• Cilnidipine – 10 to 20 mg/day

 Serum Creatinine & Albuminuria were measured at 3 and 6 month intervals

respectively

While Serum creatinine levels did not change, Cilnidipine, like Benazepril,
significantly reduced SBP, DBP & Albuminuria

Rose WG. Hypertens Res 2001;24:377-83

 Disstolic Blood Pressure (mm hg)
300 120
Albuminuria (mg/day)

250 110

100
200
90
150
80
100 70

50 60
Before 6 12 months Before 3 6 12 months

Cilnidipine like Benazepril significantly reduced DBP & Albuminuria

Rose WG. Hypertens Res 2001;24:377-83

 Study comparing Cilnidipine and Amlodipine with respect to their effects on renal
function and proteinuria

 Methods:
 28 proteinuric hypertensive outpatients received either:
• Amlodipine – 5 to 10 mg/day
• Cilnidipine – 10 mg/day
 Investigations included – Urine Protein, Urine Albumin, Serum Creatinine
& Serum β2-Microglobulin

Kojima S. Hypertens Res 2004;27:379-385

  Results at 12 months:
100 87
• Amlodipine group showed
80 AMLODIPINE a significant increase of
CILNIDIPINE 87% in Proteinuria
% increase

60

40 • Increase in Proteinuria
was suppressed in
20 Cilnidipine group
4
00 • BP reduction was similar
in both the groups
Proteinuria

Kojima S. Hypertens Res 2004;27:379-385

 Clinical implications
• Effects of Cilnidipine on Proteinuria and renal function resembled those
of Renin-Angiotensin (RA) inhibitors
• Cilnidipine dilates efferent arterioles leading to lowering of glomerular
pressure
• Amlodipine dilated mainly afferent arterioles, leading to glomerular
hypertension and increase in proteinuria
• RA inhibitors also dilate efferent arterioles, but though a different
mechanism
• Combination of Cilnidipine with RA inhibitors can result in Therapeutic
Synergy on efferent arteriolar dilation or Proteinuria

Kojima S. Hypertens Res 2004;27:379-385

 Study comparing Cilnidipine and Amlodipine with respect to their effects
on Albuminuria

 Methods:

• 38 Proteinuric hypertensive outpatients received either:

• Amlodipine – 5 to 10 mg/day
• Cilnidipine – 10 mg/day

• Investigations included – Urinary Albumin Index (UAI), serum creatinine

and blood pressure measurement

Journal of Diabetes and its Complications 21 (2007): 252-257

 Findings:
• Urinary Albumin Index showed reduction with Cilnidipine treatment
• Serum creatinine excretion was increased

 Conclusion:
• In patients with Diabetic Nephropathy, blocking N-type Ca++ channels
with Cilnidipine resulted in significant reduction in Albuminuria.

Renoprotective effect of N-type Ca++ channel blockade is

seen even in combination with RAS-inhibitor

Journal of Diabetes and its Complications 21 (2007): 252-257

 Less than half of the patients respond to single drug therapy & therefore require
dual or combination therapy

 Valsartan plus Cilnidipine versus monotherapy with Valsartan was evaluated

 87 patients with Type II Diabetes showing Proteinuria (urinary protein / creatinine

ratio: 10-300 mg/g) received drugs for 1 year

 Though there was no additional reduction of BP or incidence of side effects with

dual therapy the Renoprotective effects were magnified:
• Protein/creatinine ratio was found to have decreased more markedly in the Valsartan
plus Cilnidipine combination group

Katayama K. Kidney Int. 2006 Jul;70(1):151-6.

 0
-5 -9
-10
-15 % change in protein: creatinine ratio
-20
-25
-30
-35
-40
-45
-44
Val+CIL Val

Katayama K. Kidney Int. 2006 Jul;70(1):151-6.

 CARTER - Cilnidipine versus
Amlodipine Randomized Trial for
Evaluation in Renal Disease

 Multi-centeric, open-labeled, and

randomized trial with 339 patients

 Primary Endpoint: Decrease

in urinary protein to creatinine ratio

 Duration of treatment: One year

 Patients were on RAS-inhibitors and

were given either Cilnidipine (5-20 mg
daily) or Amlodipine (2.5-7.5 mg daily)
 Findings –

• Urinary protein to creatinine ratio significantly decreased in Cilnidipine

compared to Amlodipine

• Cilnidipine exerted greater antiproteinuric effect than Amlodipine

even in subgroup whose blood pressure fell below target levels

• Conclusion: Cilnidipine is superior to Amlodipine in preventing the

progression of proteinuria in hypertensive patients when coupled with
RAS-inhibitor

Kidney Int 2007; 72: 1543- 1549

 Highlights –
• Cilnidipine significantly suppressed urinary protein/ creatinine ratio
as compared to Amlodipine
• In primary renal disease subgroup, Cilnidipine demonstrated more
Anti-proteinuric effect than Amlodipine
• Diabetic Nephropathy, the absolute value of urinary protein / creatinine
ratio is lower in Cilnidipine group compared to Amlodipine group
• Cilnidipine inhibits the sympathetic nerve activity via N-type calcium
channel blockade in chronic kidney disease patients with increased
sympathetic activity – Anti-proteinuric effect
• Significant decrease in urinary protein/creatinine ratio vs. Amlodipine
group was seen after 3 months and even after 12 months of study

Kidney Int 2007; 72: 1543- 1549

• The L/N-type CCB - Cilnidipine
categorized 4th generation according
to its effects on sympathetic function

• Pharmacological profile –
Cilnidipine, as an antihypertensive,
is equivalent. to a Comb. of pure
L- type CCB + Small dose of α &
β- adrenergic receptor antagonist

• Cilnidipine is superior to Amlodipine

in preventing the progression of
Proteinuria in patients with
Hypertension and Chronic Renal
Disease
Highlights
 Renoprotective and neuroprotective effects as well as cardioprotective action of
cilnidipine have been demonstrated in clinical practice
 The L/ N-type Ca++ channel blocker cilnidipine can be categorized as a new generation
according to its effects on sympathetic function.
 Thus, the pharmacological profile of cilnidipine as an anti hypertensive drug may be
equivalent to a combination of a pure L-type Ca++ channel blocker plus small dose of
α- and β-adrenergic receptor antagonist.
 Furthermore, cilnidipine has been clinically demonstrated to be effective for morning
hypertension and white-coat hypertension.
 Cilnidipine decreased the myocardial interstitial norepinephrine levels during ischemia
and reperfusion periods, leading to reduction of the myocardial infarct size and
incidence of ventricular premature beats.
 Clinical studies have demonstrated that cilnidipine improves left ventricular function
and produces a greater decrease in left ventricular mass than quinapril
Highlights

 Cilnidipine decreased plasma level of β-thromboglobulin, a marker of platelet

activation, which may prevent arterial thrombosis formation.

 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

 Insulin resistance improved significantly after cilnidipine treatment

 Thus, the L/ N-type Ca++ channel blocker cilnidipine can be categorized as the
fourth – generation according to its effects on sympathetic function
NEUROPROTECTIVE EFFECT
 To evaluate neuroprotective effect and
mechanisms of action of cilnidipine, a inhibitor
of L- and N-type calcium channels.

 Free radical levels and intracellular signaling

proteins were measured with the fluorescent
probe, 2',7'- dichlorodihydrofluorescein
diacetate and western blotting, respectively.

 These results indicate that cilnidipine mediates its

neuroprotective effects by reducing oxidative
stress, enhancing survival signals and inhibiting
death signals from cytochrome c release, caspase
3 activation, and PARP cleavage.

J Neurochem. 2009 Oct;111(1):90-100. Epub 2009 Jul 23

 In hypertensive Intracerebral hemorrhage, continuous infusion of Nicardipine is
often prolonged and it involves large cumulative doses.

 Discontinuation of Nicardipine may cause rebound Hypertension and re-bleeding or

intracerebral hematomoa enlargement.

 Cilnidipine does not result in decrease in the number of platelets and patients
have not demonstrated incidence of hematoma enlargement or re-bleeding

 The study results shows that when Cilnidipine is given within 3 days of
hospitalization, it can reduce the amount of intravenous Nicardipine and may also
help to maintain the BP below 80% of its initial level

Ir J Med Sci, 10 Sept 2008

Metabolic Syndrome
 Ten hypertensive patients were evaluated for effect of Cilnidipine on insulin
sensitivity

 Cilnidipine 5 -10 mg/day

 Duration of treatment – 12 weeks

 Cilnidipine – metabolically neutral

• Significantly reduced blood pressure but not any of the
parameters of glucose and lipid metabolism
• Insulin sensitivity improved by 20.8%

Yagi S. Hypertens Res 2003;26:383-87

 A cross-over study comparing the effects of Cilnidipine with Amlodipine on
Glucose and Lipid metabolism along with Renal functions in patients with
hypertension and Type II Diabetes Mellitus (DM)

 Number of subjects :77 patients (35 with DM and 42 without DM) received either:
• Amlodipine-2.5 to 7.5 mgs
• Cilnidipine-10 to 20 mgs

 Duration of each treatment: 8-9 months

 Investigations done : Serum Cholesterol, HDL-C, LDL-C, TG, Serum insulin, plasma
renin and aldosterone. Insulin resistance index (HOMA-R: homeostasis model
assessment insulin resistance index), Estimated GFR (eGFR) and the urinary
albumin/creatinine were calculated.

Cardiovasc Ther. 2010 Mar 10

Findings:

 HOMA-R* was significantly  With Amlodipine, TG was

lower with Cilnidipine than significantly higher in DM(+) group
with Amlodipine, indicating than in DM(-) group, while no such
that insulin resistance difference was noted with
improved with Cilnidipine. Cilnidipine. Thus indicating that
Cilnidipine reduces TG in
hypertensive patients with DM.
HOMA-R

3 Mg/dL Triglyceride
280
2
240
1 200
160
0 120
DM (-) DM (-)
0
Total DM(-) DM(+) Total DM(-) DM(+)
Amlodipine Cilnidipine
Amlodipine Cilnidipine

HOMA-R*: Homeostasis Model Assessment Insulin Resistance +: P < 0.05 vs DM (-)

Cardiovasc Ther. 2010 Mar 10

 In the DM(+) group eGFR was significantly higher with Cilnidipine than Amlodipine

eGFR
mL/min 1.73m2

100
+
++
80

60

40
Total DM(-) DM(+) Total DM(-) DM(+)

Amlodipine Cilndipine

Cardiovasc Ther. 2010 Mar 10

 The urinary albumin/creatinine ratio was Plasma Renin Activity
Ng/mL/h
significantly lower with Cilnidipine in the
10
DM(+) group as well as the entire population
8
compared to Amlodipine 6
4
2
 Plasma renin activity was significantly
0
lower in DM(+) group with Cilnidipine Total DM(-) DM(+) Total DM(-) DM(+)
possibly due to sympathetic suppression Amlodipine Cilndipine
(N-type channels) induced by Cilnidipine *: P < 0.05 vs amlodipine

 Conclusion: Cilnidipine is beneficial for patients with hypertension and

concomitant Diabetes Mellitus due to its effects on lipid metabolism &
renal function

Cardiovasc Ther. 2010 Mar 10

Highlights

 Cilnidipine reduces excessive excitation of the sympathetic nervous system and the
release of norepinephrine from sympathetic nerve endings, and consequently
suppresses reflective tachycardia and stress-induced blood pressure elevation

 Triglyceride in diabetes group was significantly lower with Cilnidipine than

with Amlodipine

 As regards, renal function in the diabetic group, estimated glomerular filtration rate
was significantly higher with Cilnidipine than with Amlodipine

 Urinary albumin/creatinine ratio was significantly lower with Cilnidipine than

with Amlodipine

 Using ABPM, amlodipine elevated daytime and nocturnal heart rate, while
cilnidipine reduced daytime and nocturnal heart rate
 Highlights

 HOMA-R* was significantly lower with cilnidipine than with amlodipine, indicating
that insulin resistance was improved by cilnidipine

 N-type calcium channel inhibitory action of cilnidipine is also involved in the

improvement of the lipid profile with cilnidipine

 Among CCBs, cilnidipine has been reported to reduce glomerular pressure

 Plasma renin activity was significantly lower with cilnidipine than with amlodipine

 Cilnidipine which inhibits N-type calcium channels is more useful for patients with
hypertension and diabetes mellitus from its effects on glucose and lipid metabolism
and renal function
 16 hypertensive patients were evaluated for lipid lowering effects with
Cilnidipine (5 to 10mg/d) for 3 months
 Pts had ‘high’ lipid profile - >300mg/dl

 Cilnidipine improved lipid profile & tissue plasminogen activator (t-PA)

70 % change
60
62.7
50
40
30
20
10
0 -1.6
-10 -14.1
-20
TC TG t-PA
Ahaneku JE. Pharmacol Res 2000;41(1):81-84
 Cilnidipine in these patients offers:

• Improvement in Nitric Oxide (NO) availability or endothelial dysfunction –

the initiating step for atherosclerosis

• Antiproliferative effects – inhibiting VSMC proliferation & thereby

inhibiting the progression of atherosclerotic lesion

• Antiplatelet effect

• Improves fibrinolysis or clot lysis – improves t-PA levels

OTHER BENEFITS
 Cilnidipine increases the release or bioavailability of NO

 This is a result of the elevated endothelial Ca++ ions & increased eNOS expression
or activity

 It is independent of its effect on L/N-type receptors & free radicals

 NO has antithrombotic, antiproliferative & antiatherosclerotic effects

Leung HS. Br J Pharmacol. 2006 Jan;147(1):55-63

 100  Cilnidipine is devoid DPPH* (stable
DPPH Scavenging

free radical) scavenging property

Activity (%)

*2,2-diphenyl-1-picrylhydrazyl
50

 Cilnidipine produces coronary

0 vasodilation independent of BP or
0.01 0.03 0.1 1 free radical scavenging properties
Cilnidipine (mM)

100 100

DPPH Scavenging
DPPH Scavenging

Activity (%)
Activity (%)

50 50

0 0

0.01 0.03 0.1 1 0.01 0.03 0.1 1 3 10

Nifedipine (mM) Vitamin E (mM)

Leung HS. Br J Pharmacol. 2006 ;147(1):55-63

 Antiproliferative effects

• Cilnidipine inhibits VSMC proliferation through inhibition of

DNA/RNA synthesis which is induced by growth-promoting factors

 Important implication for progression of atherosclerotic lesion

Hu WY. J Cardiovasc Pharmaco 2001;38(3):450-9

 The ability of Cilnidipine to reduce the incidence of Ventricular Premature Beat
(VPBs) was evaluated in a preclinical study

 The incidences of VPBs during ischemia and reperfusion were significantly

attenuated with Cilnidipine

 Myocardial interstitial noradrenaline levels were significantly reduced with

Cilnidipine

 The antiarrhythmic effect of Cilnidipine may be related to the attenuation of

cardiac sympathetic nerve activity

Nagai H. Hypertens Res. 2005 Apr;28(4):361-8

 Cilnidipine & Amlodipine block L/N-type Ca++ channels
• Cilnidipine is however more selective (Sakata 1999)

 The difference in potency of these CCBs was compared in a novel study

 32 patients with mild hypertension received equivalent doses of Amlodipine (5mg)

or Cilnidipine (10mg)

 Cold pressor test was performed at the end of 1st & 2nd month of treatment

 Increase in plasma norepinephrine levels was significantly higher (p<0.05) with

Amlodipine

 Consequently, platelet activation was not attenuated by Amlodipine

Tomiyama H. Hypertens Res 2001;24:679-684

 Cilnidipine prolongs vascular dilation for period of 24 hours with once-daily
administration

• Its highly Lipophilic nature compensates for short half-life

• Its plasma half-life of 2-8 hours after administration of 5-20mg

Yamagishi T.Hypertens Res 2006;29:339-344

 In clinical trials conducted with Cilnidipine, Flushing & Headache was reported, the
incidence of adverse effects were less than 0.1% to 5% compared to placebo.

Saruta, 1998 ; Tominaga et al, 1997

Indication
 Cilnidipine is used for treatment of Hypertension

Dosage & Administration

 5 to 20 mg daily with or without food

An ‘Ideal’ Anti-hypertensive drug which makes it

useful for hypertensive patients with
co-morbid conditions
 Strongest affinity for N-type channels, about 50 times compared to Amlodipine.
This ensures:

• Lesser incidence of Reflex Tachycardia or cardiac sympathetic overactivity

• Suppresses sympathetic activity in veins & therefore less potential for Pedal
edema

• Decreases renal sympathetic activity leading to efferent arteriole dilation,

increasing renal blood supply making it useful for patients with CRI where
Amlodipine role is controversial
 Improves left ventricular function, independent of BP reduction

 Improvement in Nitric Oxide availability or endothelial dysfunction – the

initiating step for atherosclerosis

 Antiproliferative effects – inhibiting VSMC proliferation & thereby preventing

the progression of atherosclerotic lesion

 Antiplatelet effect

 Improves fibrinolysis or clot lysis – improves t-PA levels

 Essential hypertension
• N-type calcium channel blockade by Cilnidipine may not cause reflex
tachycardia

 Hypertension & CHD

• Improves LV function due to its vasodilatory & sympathetic suppression

 Hypertension & Diabetes mellitus

• Neutral effect on glucose metabolism, improves insulin sensitivity

 Hypertension & Dyslipidemia

• Neutral effect on lipid metabolism, improves NO, antiproliferative,
antiplatelet, fibrinolytic properties

 Hypertension & Chronic Renal Insufficiency (CRI)

• Dilates efferent renal arteriole unlike Amlodipine
• It also reduces Proteinuria
 Slow onset
• For smooth reduction of blood pressure with less chances of hypotension

 Long Duration of Effect (24 hours)

• For better control of increased blood pressure especially during the
mornings

 Once daily administration for better compliance

 Suppresses Sympathetic Overactivity

• Less chances of Hypotension or Reflex Tachycardia

 Metabolically Neutral
• Minimal or negligible effect on glycemic or lipid metabolism for co-
administration in Diabetics and Dyslipidemic patients

 Pleiotrophic Effects
• Anti-inflammatory, antiproliferative or antioxidant properties
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