calcium channel blockers in hypertension

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

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

Preamble Amlodipine is a very safe and effective drug for management of HypertensionThere are some minor shortcomings with amlodipine, like pedal edema seen in some patientsSo, newer CCBs which can overcome this shortcomings are always a good option for management of Hypertension

Generations of CCBs and CilnidipineGenerationDrugsPlasma NE levelHeart rateCharact-eristicsCa 2+ channel blocked1st generationNifedipineIncreasedIncreasedRapid sympathetic activationL-type2nd generationNicardipineBenitidineIncreasedIncreasedSlow acting on L-type Ca2+ channels3rd generationAmlodipineAzelnidipineIncreasedIncreasedSlow acting on L-type of Ca2+ channels4th generationCilnidipineNo change ordecreasedNo change orDecreasedL- type and N-type Ca2+ channelL-type andN-type

Conventional CCBs fails here

Reflex tachycardiaMore incidence of Pedal EdemaElevated Proteinuria level

Looking beyond the conventional CCB

Lets care for Heart & Kidney together

CilnidipineCilnidipine is a fourth Gen. dihydropyridine (DHP) type of CCB originally developed in Japan.Unlike other calcium channel antagonists, cilnidipine blocks the influx of Ca2+ ions into bothvascular smooth muscle at the level of L-type Ca channels and neuronal cells at the level of N-type Ca channels.The blockade of N-type Ca 2+ channels affects predominantly peripheral nerve endings of sympathetic neuronsSo cilnidipine reduces sympathetic over activity in addition to reducing vascular resistance (though L type Ca2+ Channel blockage)

Tachycardia Oxidative stress Cardiac O2 consumptionPlatelet activationActivation of RASConstriction of post-glomerular vesselsEffort angina perctorisChronic heart failureMyocardial infarctionCerebral infarctionChronic renal failureGlomerular HTSympathetic OveractivityActivation of N-type Ca++ Channels

Arterial thrombosisXs glutamate releaseEffort angina perctorisChronic heart failureMyocardial infarctionCerebral infarction

Ca2+

NE

Pure L-type Ca2+ channel blockers like nifedipine, amlodipine

Ca2+VesselsVesselsHeartKidney1 adrenoceptors1 adrenoceptors1 & 1 adrenoceptorsVasoconstrictionVasoconstriction Cardiac contraction Heart rate Renal blood flow Renin secretionL-type Ca2+ channelsN-type Ca2+ channelsCilnidipine

NorepinephrineCilnidipine: Pharmacology

Superior N-Type blockade by CCBsUneyama H 1999 ; Kitahara 2004 Cilnidipine had the highest selectivity for N-type channels Ratio of IC50 (L-type & N-type Ca++ channels)

With Cilnidipine the IC50 ratio is 21 This is about 50 times more than that of Amlodipine (ratio: 0.43)

21

0.43

0.082

0.34

AMLODIPINE

CILNIDIPINE

NIMODIPINE

NISOLDIPINE

NICARDIPINEIC50 (L/N) ratio05101520250.01

In clinical trials, BP lowering efficacy of cilnidipine is equivalent to Amlodipine Cilnidipine has shown following benefits beyond BP reductions over amlodipine and other CCBsReduction in proteinuriaLess pedal edema

Shifting from other CCBs to Cilnidipine: Blood and urine catecholamines33 DM + HT patients who were on other CCBs (26 on Amlodipine) were shifted to cilnidipine for 3 months

Cilnidipine reduced blood and urine levels of catecholamines, suggesting suppression of sympathetic activityDiabetes Res Clin Pract. 2014 Dec;106(3):504-10

Shifting from other CCBs to Cilnidipine: Renal markers

Cilnidipine reduced urinary FABP and ACR, suggesting nephroprotective effectsDiabetes Res Clin Pract. 2014 Dec;106(3):504-10

Cilnidipine in BP Reduction339 subjects were randomly allocated to the cilnidipine group or amlodipine groupThe final dose was 11.575.6 mg /day in cilnidipine group 5.372.4 mg /day in amlodipine group Fujita T et al. Kidney International. 2007; 72: 15431549Cilnidipine, administered once daily effectively Reduces BP and provides 24 hour BP controlAt once daily dosing, the BP lowering effect is same as that of amlodipine

Changes in systolic and diastolic BP during12 month treatment period

13

Effect on Pulse Rate Cilnidipine Vs Amlodipine)Hoshide S, et al. Hypertens Res 2005;28: 10031008

In 110 hypertensive patients,Patients on cilnidipine have lower pulse rate Vs amlodipine

14

Cilnidipine in the Control of Early Morning BP surgeKitahara Y, et al. J Cardiovasc Pharmacol.2004;43(1):68-73

Cilnidipine administered once daily is an efficient antihypertensive drug regardless of the time of dosing, without reflex tachycardia and increase in sympathetic nervous activity, and with partial inhibition of the morning activation of the sympathetic nervous system

LF/HF -------- Low Frequency (LF), 0.040.15 Hz, and High Frequency (HF) 0.150.4 Hz.15

Effect of Cilnidipine on BP and Heart Rate: ACHIEVE ONE trialAn open label post-marketing studyTotal 2319 patients treated with cilnidipine for 12 weeks.The effects of cilnidipine on morning hypertension were examined. Patients were divided in groups as per their morning systolic BP (MSBP) and morning pulse rate (MPR)MSBP : analysed in 4 quartilesMPR : analysed in 3 quartiles

Changes in mean systolic blood pressure (MSBP) and mean pulse rate (MPR) in relation to baselinea) MSBP quartiles(b) Changes in MSBP from baseline to after 12 weeks of treatment(c) Changes in MPR from baseline to after 12 weeks of treatment

(d) Comparison of MPR between baseline and after 12 weeks of treatment(e) MPR: 6 months;Patients with normo to micro albuminuria with a urinary albumin excretion (urinary albumin/Cr ratio, UAE) of less than 300 mg/gCr

CLEARED Cilnidipine Reno protective benefits in DMP value : 0.0002P value : 0.0027Cilnidipine therapy may lower proteinuria in DM patients compared to amlodipine

Cilnidipine Vs other CCBs in Hypertension and proteinuria28 proteinuric hypertensive patients (13 men and 15 women, aged 62) who had been maintained on CCBs > 3 months were randomly assigned to a group receiving amlodipine besilate (14 patients) or a group receiving cilnidipine (14 patients).Concentrations of urine protein, urine albumin, serum and urine creatinine (Cr), and serum alpha 2-microglobulin were determined at 6 and 12 monthsHypertens Res 2004; 27: 379385

Cilnidipine Vs other CCBs in Hypertension and proteinuria

Hypertens Res 2004; 27: 379385Cilnidipine group has lower proteinuria than amlodipine group

CARTER TRIAL: RAS-I + Cilnidipine in HT + CKDIn an open label study, 339 HT + CKD patients, (on RAAS blockers), were randomly assigned to cilnidipine or amlodipine. Primary endpoint: decrease in urinary protein to creatinine ratio. Follow up: 1-year

Kidney International (2007) 72, 15431549

CARTER TRIALKidney International (2007) 72, 15431549Both Amlodipine and Cilnidipine were equally effective for BP reduction

CARTER TRIAL

Cilnidipine (added to ARB), can reduce proteinuria in HT + CKD patientsKidney International (2007) 72, 15431549

Cilnidipine Vs Amlodipine (with RAS I) in DM + HTA multicenter, randomized, active-controlled study in KoreaTotal of 74 DM + HT patients Randomized to Cilnidipine 10mg + RAS Blocker (n = 37) or Amlodipine 5mg + RAS Blocker (n = 37). Patients were assessed at baseline, 12 weeks and 24 weeks after treatmentUACR (Urinary Albumin to Creatinine Ratio) was measured at baseline and at 12 and 24 weeks

34EASD Conference Sept 2014

Cilnidipine Vs Amlodipine (with RAS I) in DM + HTIn cilnidipine group, UACR was significantly reduced after 12 weeks (-53.0 mg/g, p

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