Cilacar Cme Final 23-8-2010 4s1bc

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 Arteries Causing damage

Sympathetic overactivity

Systole

Force of Heart pumping Causing strain

Diastole

Heart at rest

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

Sympathetic nerve activity

Peripheral artery

(N-type Ca++ channels)

Leptin

Obesity

Leads to increase in : • Cardiac output  Vascular resistance  Na+ retention  Renin-Angiotensin System

Kidney

Skeletal muscle

Increased Insulin resistance

H Y P E R T E N S I O N

Cardiovascular Therapeutics 27 (2009) 124–139

Sympathetic overactivity (Activation of N-type Ca++ channels)

Platelet activation

Increased Cardiac oxygen consumption

Tachycardia

Increased Oxidative stress

Activation of Renin-Angiotensin System

Construction of Post-glomerular vessels

Arterial Thrombosis

Excessive Glutamate release

Glomerular HT

via activation of N-type Ca++ channels

Cerebral Infarction

Myocardial Infarction

Effort Angina pectoris

Chronic Heart failure

Chronic 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 21

AMLODIPINE

20

CILNIDIPINE

15

NIMODIPINE NISOLDIPINE

10

NICARDIPINE

5 0.43

0

0.082 0.01 0.34

IC50 (L/N) ratio

 Cellular inhibitory effects of Dihydropyridines were noted on rat ventricular myocytes  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 (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 istered 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

-5

SBP

-12 -12

-10

Diff. in BP

DBP

 Both the drugs significantly reduced the clinical and 24-hours Systolic BP (SBP) and Diastolic BP (DBP) (p < 0.005)  However, there is 8% reduction in SBP in cilnidipine group than in Amlodipine group.

-15 -20

-25

-26

AMLODIPINE -28

CILNIDIPINE

-30 -35

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

Cardioprotective Effect

3 2.5 2 1.5 1 0.5 0 -0.5 -1 -1.5 -2 -2.5

1.9

1.7

1.6

AMLODIPINE CILNIDIPINE 24HPR

-1.2

DAY PR

-1.6

NIGHT PR

-1.2

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 istration 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 AngiotensinAldosterone 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

% Reduction in L V M I

0 -2 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 multicenteric 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)

Albuminuria (mg/day)

300 250 200

150 100 50

Before

6

12 months

120 110 100 90

80 70 60

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:

% increase

100

87

80

AMLODIPINE

60

CILNIDIPINE

40 20

4

00 Proteinuria

• Amlodipine group showed a significant increase of 87% in Proteinuria

• Increase in Proteinuria was suppressed in Cilnidipine group • BP reduction was similar in both the groups

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 -10 -15 -20 -25 -30 -35 -40 -45

-9 % change in protein: creatinine ratio

-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 reninangiotensin 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 lower with Cilnidipine than with Amlodipine, indicating that insulin resistance improved with Cilnidipine. HOMA-R 3

 With Amlodipine, TG was significantly higher in DM(+) group than in DM(-) group, while no such difference was noted with Cilnidipine. Thus indicating that Cilnidipine reduces TG in hypertensive patients with DM. Mg/dL

Triglyceride

280

2

240

1

200 160

0 DM (-) Amlodipine

DM (-) Cilnidipine

HOMA-R*: Homeostasis Model Assessment Insulin Resistance

120 0

Total DM(-) DM(+) Amlodipine

Total

DM(-) DM(+) Cilnidipine

+: 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(+)

Amlodipine

Total

DM(-) DM(+)

Cilndipine

Cardiovasc Ther. 2010 Mar 10

 The urinary albumin/creatinine ratio was Ng/mL/h significantly lower with Cilnidipine in the 10 DM(+) group as well as the entire population 8 compared to Amlodipine 6

Plasma

Renin

Activity

4





Plasma renin activity was significantly lower in DM(+) group with Cilnidipine possibly due to sympathetic suppression (N-type channels) induced by Cilnidipine

2 0 Total

DM(-) DM(+)

Amlodipine

Total DM(-) DM(+)

Cilndipine

*: 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 60 50 40 30 20 10 0 -10 -20

% change 62.7

-1.6

-14.1

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

 Cilnidipine is devoid DPPH* (stable free radical) scavenging property

DPPH Scavenging Activity (%)

100

*2,2-diphenyl-1-picrylhydrazyl

50

0 0.01

0.03 0.1 1 Cilnidipine (mM)

100

DPPH Scavenging Activity (%)

100

DPPH Scavenging Activity (%)

 Cilnidipine produces coronary vasodilation independent of BP or free radical scavenging properties

50

0 0.01

0.03 0.1 Nifedipine (mM)

1

50

0 0.01 0.03 0.1 1 3 Vitamin E (mM)

10

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 istration • Its highly Lipophilic nature compensates for short half-life • Its plasma half-life of 2-8 hours after istration 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 & istration  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 istration 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 coistration in Diabetics and Dyslipidemic patients



Pleiotrophic Effects • Anti-inflammatory, antiproliferative or antioxidant properties

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