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:
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Lesser incidence of Reflex Tachycardia or cardiac sympathetic overactivity
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Suppresses sympathetic activity in veins & therefore less potential for Pedal edema
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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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