What Is Cilnidipine?

[Chinese alias] 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-methoxyethyl cinnamyl alcohol ester

Senidipine

Cinidipine tablets

[CAS NO.] 132203-70-4

[English name] Cilnidipine

[Molecular formula] C27H28N2O7

[Molecular weight] 492.52

[Ingredients] The main ingredient of this product is cinidipine.

[Properties] This product is a light yellow tablet.

[Pharmacology and toxicology] This product is a lipophilic dihydropyridine calcium antagonist, which can bind to the dihydropyridine site of the L-type calcium channel on the vascular smooth muscle cell membrane, and inhibit the influx of Ca2 + through the L-type calcium channel. This relaxes and dilates vascular smooth muscles and plays a role in reducing blood pressure. It can also inhibit the release of norepinephrine and sympathetic nerve activity in sympathetic nerve endings by inhibiting the influx of Ca2 + through the N-type calcium channel on the sympathetic nerve cell membrane.

[Pharmacokinetic characteristics] Studies have shown that healthy adult men take single doses of 5mg, 10mg, and 20mg of cinidipine, the blood drug concentration increases with the increase of the dosage, and the peak time is between 1.8-2.2 hours. Plasma half-life is between 2.1 and 2.5 hours. Because of its high lipophilic molecular characteristics, some drugs are stored in the lipid bilayer, and they dissociate from the cell membrane slowly, release slowly, and maintain the effective blood concentration for 23 hours. For 7 consecutive days of administration, the concentration of the original drug in the plasma (the result of the plasma concentration measurement at 23 hours after administration) did not change significantly on the 4th and 7th days after administration, suggesting that the drug has no accumulation. Neither diet nor renal function affect blood levels of cinidipine in the body. The drug is absorbed through the upper small intestine and is mainly excreted through the urine in the form of metabolites. In vivo plasma protein binding rate was 99.3%, and dialysis did not affect blood drug concentration.

[Pharmacological properties]

1. Calcium channel antagonism In the traditional patch-clamp method to evaluate the effect of cinidipine on Ca2 + channels, it was found that cinidipine effectively blocked the vascular L-type Ca2 + channels and sympathetic neuron N-type Ca2 + channels, and Ca2 + channel block effect is weak.

2. Sympathetic Inhibition

Human calcium channels include 6 types, in addition to L-type calcium channels, there are N, T, P, Q, R-type calcium channels. L-type calcium channels are mainly expressed in the heart and blood vessels, and regulate myocardial contractility, sinus node function, and vascular tone. N-type calcium channels are currently found only in the terminals of the sympathetic and central nervous systems and regulate the release of neurotransmitters. T-type calcium channels may be associated with progressive depolarization of sinus node action potentials. Blocking the L-channel can cause vasodilation and increase in reflex heart rate, while blocking the N-channel can reduce sympathetic nerve tension and blood catecholamine levels, avoiding an increase in heart rate. Furukawa et al. Used double micro-voltage clamp technology to find ten dihydropyridine calcium channel blockers (nifedipine, nilvadipine, barnidipine, nimodipine, nirendipine, amlodipine, nicardipine, shellfish (Dildipine, felodipine, and cinidipine) all have L-type calcium channel blockers, and the last five calcium channel blockers have N-type calcium channel blockers, but cinidipine blocks N-type calcium channels The effect is 10 times that of the other 4 calcium channel blockers.

Hosomo et al. Studied the effect of cinidipine on cardiovascular and neuroendocrine responses after spontaneous cold stimulation in spontaneously hypertensive rats (SHRs) and found that 3mg / kg orally of cinidipine can significantly inhibit the sympathetic excitability caused by acute cold stimulation increase. The same dose of nifedipine, nicardipine, manidipine and cinidipine have similar antihypertensive effects, but they have no inhibitory effect on the sympathetic nervous system. The antagonism of cinidipine on L-type and N-type calcium channels is shown in Figure 1.

[Clinical Research Evidence for Xinidipine]

Clinical evidence of antihypertensive effect

Sakata et al. Reported that patients with essential hypertension took orally once a dose of 5mg, 15mg, and 20mg of cilnidipine, and after 24 hours, they still reduced systolic blood pressure, diastolic blood pressure, and mean blood pressure. No circadian rhythm fluctuations in blood pressure were seen, suggesting cilnidipine The antihypertensive effect was more than 24 hours, and there was no blood pressure rebound phenomenon after stopping the drug. Cinidipine is more selective for 1,4-dihydropyridine receptors in small blood vessels of spontaneously hypertensive rats (SHR) than other tissues, which may be one of the mechanisms for the sustained antihypertensive effect of cenidipine.

Minami et al. Carried out a comparative study of patients with essential hypertension taking cilnidipine and amlodipine, taking cilnidipine (5 or 10 mg / day) and amlodipine (2.5 or 5 mg / day) for 4 weeks, respectively. The onset time and antihypertensive effect of Ping and amlodipine are similar, both have slow onset and long-lasting effects.

From 2001 to 2002, clinical studies of cinidipine (Anhui Fengyuan Pharmaceutical) registration in China showed that 109 patients with essential hypertension received cinidipine 5-10 mg / day for 8 weeks, and the average sitting systolic blood pressure decreased. 17.48mmHg, diastolic blood pressure decreased by 14.46mmHg, the total effective rate was 79.24%. Ambulatory blood pressure monitoring showed that the valley-to-peak ratio of the antihypertensive effect of cinidipine was 52.53%, suggesting that the effect of cinidipine can be effectively smoothed once a day.

A meta-analysis of the currently published studies on the antihypertensive effect of cinidipine was included in 17 randomized controlled studies (7 in Japan and 10 in China) with complete data taken longer than 8 weeks, with a total of 1476 people in the study. The drug is amlodipine, and the results show that the control effect of cinidipine on systolic blood pressure is not inferior to that of amlodipine (z = 3.97, p = 0.00), and the two drugs have the same effect on diastolic blood pressure control (z = 1.91, p = 0.06 ). Cenidipine had no effect on heart rate while lowering blood pressure (z = 1.85, p = 0.06). The main adverse reactions were dizziness, headache, palpitations, edema, drowsiness, and facial flushing. There was no statistically significant difference in adverse reaction rates between zinidipine and amlodipine (z = 0.31, p = 0.76). Cenidipine has a positive effect on blood pressure in the Central Asian population and has good safety. (Meta analysis results are shown in Table 1)

Table 1 Meta- analysis forest map of SBP and DBP improvement values after cinidipine and amlodipine treatment

2. Clinical evidence of sympathetic depression

Combined with other types of antihypertensive drugs such as diuretics, angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, cinidipine can further lower blood pressure and control heart rate.

Chen Jiangtian et al. Compared the effects of cinidipine and amlodipine on blood pressure control in patients with essential hypertension under stress, and the results showed that cinidipine could significantly control the blood pressure increase induced by the grip test. Studies by Sakata and Yamagishi have confirmed that Cinidipine has better control of morning peak hypertension and white coat hypertension related to sympathetic nerve activity. The above studies suggest that Xinidipine has a good effect on the increase of blood pressure caused by sympathetic nerve activation.

The cardiac imaging of m-iodoguanidine (MIBG) showed that MIBG intake was reduced and elution was increased, which is a manifestation of cardiac sympathetic hyperactivity. Kazuyuk et al. Performed MIBG cardiac imaging of patients with essential hypertension taking cilnidipine and amlodipine before and 3 months after taking the medication, respectively. The results showed that cilinidipine significantly increased the heart / mediastinum MIBG intake ratio Increased (P <0.05), the elution rate was significantly reduced (P <0.05); amlodipine also significantly reduced the elution rate (P <0.05), but the heart / mediastinum MIBG intake ratio did not increase. This suggests that, in patients with essential hypertension, cinidipine inhibits cardiac sympathetic hyperfunction slightly better than amlodipine.

An increase in the low-frequency / high-frequency (LF / HF) ratio of the frequency domain indicators of the ambulatory electrocardiogram indicates an increase in sympathetic excitability. Minami et al. Used a dynamic electrocardiogram to analyze the frequency-domain indicators of heart rate variability, and found that nifedipine sustained-release tablets increased the LF / HF ratio. Cinidipine had no effect on the LF / HF ratio. small.

The results of the above studies have consistently confirmed that at the same time as the removal of dilated blood vessels, cinidipine has a certain inhibitory effect on the sympathetic nervous system.

3. Target organ protection

At present, hypertension guidelines in various countries recommend strong indications based on the target organ protection of different antihypertensive drugs.

Basic and clinical studies have shown that cinidipine dilates the glomerular entering and exiting arteries at the same time, reduces the pressure in the glomerulus, and has a renal protective effect of improving renal function and reducing the rate of proteinuria excretion.

Basic research and small-scale clinical studies have shown that cinidipine also has antioxidant effects, inhibits vascular smooth muscle cell proliferation, improves left ventricular diastolic function, improves left ventricular hypertrophy, and improves insulin resistance. It may improve vascular endothelium diastolic function, improve coronary blood flow, improve cerebral blood flow, improve arterial stiffness, reduce the risk of myocardial infarction and reperfusion arrhythmia, and control the onset of angina pectoris.

[Adverse reactions] Phase I clinical trials have shown that healthy adults take 2.5-20 mg of cenidipine orally and are well tolerated, with no adverse reactions. Overdose (40mg / day) for 7 days, well tolerated, only mild headaches, runny nose and other adverse reactions, no abnormalities in blood biochemical indicators. A clinical study of cinidipine registration in China showed that only a small number of patients developed palpitations, headaches, dizziness, and flushing, suggesting that cinidipine is well tolerated.

[Indications] For the treatment of patients with hypertension.

[Usage and dosage]

(1) The starting dose is 10mg / d (equivalent to amlodipine 5mg / d). If the blood pressure does not meet the standard, the dose can be increased from 5mg / day to 20mg / d each time (the dose adjustment interval should not be shorter than 1- Two weeks).

(2) For patients with mild to moderate hypertension, this drug is the first choice. For those with significantly elevated blood pressure or other high risk factors, they can be used in combination with one or more other first-line antihypertensive drugs (diuretics, -receptor blockers, ACEI or ARB).

(3) When used in the treatment of angina pectoris, it can be used in combination with nitrate drugs or beta receptor blockers.

[Coping strategies for adverse reactions] When taking a dose of 10mg-20mg / d, patients may develop lower limb edema, headache, dizziness, facial flushing, and palpitations. If the patient has mild side effects, continue the medication under close surveillance. With the prolonged medication time, some patients' side effects may disappear by themselves.

[Contraindications] Patients who are allergic to any of the ingredients in this product are prohibited.

[Specifications] 5mg * 14 tablets 10mg * 14 tablets

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