A Review on Properties, Application, and Analytical Methods of an Antihypertensive Drug efonidipine

INTRODUCTION

Efonidipine was launched in 1995, under the brand name of Landel, by Shionogi and Co. On August 28, 2017, the Drug Controller General of India (DCGI) granted approval of this drug in India under the brand name of Efnocar to Zuventus Healthcare Ltd.^1–3 It is chemically known as 2-(N-benzylanilino)ethyl 5-(5,5-dimethyl-2-oxo-1,3,2λ⁴-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate.

The phosphorous moiety at C5 position (Fig. 1) of the dihydropyridine ring is considered to be dominant for the pharmacological profile of the drug. About 10 and 25% of the population is expected to benefit from drug treatment of hypertension, and the exact figure depends on the cutoff value for blood pressure and the age-group considered for active treatment. In less than 95% of cases of hypertension, there is no underlying medical illness to cause high blood pressure. This is called “essential” hypertension. Hypertension is twice common in a person whose parents are suffering from hypertension, so genetic factors play a key role. It is more common in Black people of African region who are also at particular risk of stroke and renal failure. The molecular formula of efonidipine is C₃₄H₃₈N₃O₇P and molecular weight of efonidipine is 631.7 g/mol.^4–9

MECHANISM OF ACTION^10–15

Efonidipine is a new age-group dihydropyridine calcium channel blocker, which inhibits both L- and T-type of calcium channel. It is highly lipophilic drug that easily penetrate into the phospholipid-rich cell membrane and reaches the dihydropyridine binding site of the calcium channel targets, which inhibits the both L- and T-type calcium channels and leads to vasodilation and decreases the automaticity of the heart as shown in Figure 2. It exerts negative chronotropic effect. Inhibition of T-type calcium channels in the sinoatrial node prolongs the late phase-4 depolarization of SA node action potential and suppresses an elevated heart rate. Efonidipine increases the coronary blood flow by blocking L- and T-type calcium channels and attenuates myocardial ischemia. By reducing synthesis and secretion of aldosterone, it prevents hypertrophy and remodeling of cardiac myocytes. Efonidipine increases glomerular filtration rate without increasing intraglomerular pressure and filtration fraction. This prevents hypertension-induced renal damage. Efonidipine increases excretion of sodium from the kidneys by suppressing aldosterone synthesis and secretion from the adrenal glands. Renal parenchymal fibrosis is induced by aldosterone and suppressed by efonidipine. Efonidipine lowers blood pressure in cerebral resistance vessels and stops hypertension-induced brain damage.

METABOLISM¹⁶

Efonidipine is first metabolized in the liver. The relevant metabolites are N-dephenylated efonidipine (DPH), deaminated efonidipine, and N-debenzylated efonidipine (DBZ). Both DBZ and DPH expose activity as calcium antagonists. The vasodilating properties of DBZ and DPH were about two-thirds and one-third, respectively, than that of the parent compound. Results shows that the majority of the pharmacological effect after oral dosing of efonidipine hydrochloride in human is due to unchanged compound, and its metabolites make a small contribution to the pharmacological effect.

EPIDEMIOLOGY OF HYPERTENSION⁵

According to recent world health ranking in both male and female, the highest rate of hypertension patients is found in Seychelles and lowest rate in Japan as shown in Figure 3.

TREATMENT OF HYPERTENSION^4,6–8

Hypertension treatment includes different classes of drug per patient need. There are different classes such as diuretics, β-blocker, calcium antagonist, ACE inhibitor, α-blocker, angiotensin receptor blocker, and vasodilators as mentioned in Table 1.

PHYSICAL PROPERTY AND TAXONOMICAL DATA

The physical properties, taxonomical data, and pharmacokinetic parameters of efonidipine are shown in Tables 2 to 4, respectively.

CLINICAL TRIAL STUDY

Oh et al.¹⁷ reported a multicenter, prospective, open-labeled, single-armed study, where they enrolled 53 patients who were suffering from mild-to-moderate hypertension [sitting diastolic BP (SiDBP) 90–110 mm Hg). After a period of 15 days, eligible patients were treated with efonidipine (40 mg once daily for 12 weeks). The primary end point was the change in heart rate from baseline to week 12. The secondary end point included the change in trough sitting BP and 24-hour mean BP between baseline and week 12. Laboratory and clinical adverse events were examined at each study visit (4, 8, and 12 weeks). The 53 patients were included in the intention-to-treat analysis. After 12 weeks of treatment with efonidipine, the resting HR decreased significantly from baseline to week 12 (from 81.5 ± 5.3 to 71.8 ± 9.9 beats/minute (difference, −9.9 ± 9.0 beats/minute), p value < 0.0001). The trough BP [sitting systolic blood pressure (SiSBP) and SiDBP] and 24-hour mean BP also decreased significantly (SiSBP: from 144.6 ± 8.2 to 132.9 ± 13.5 mm Hg, p value < 0.0001; SiDBP: from 96.9 ± 5.4 to 88.3 ± 8.6 mm Hg, p value < 0.0001, 24-hour mean systolic BP: from 140.4±13.5 to 133.8 ± 11.6 mm Hg, p value <0.0001; 24-hour mean diastolic BP: from 91.7 ± 8.7 to 87.5 ± 9.5 mm Hg, p value < 0.0001). So, it was concluded that efonidipine was effective in controlling both HR and BP in patients with mild-to-moderate hypertension.

In research of Harada et al.,¹⁸ the influence of efonidipine hydrochloride on HR and autonomic nervous function was investigated. Using an electrocardiogram and a tonometric blood pressure measurement, autonomic nervous activity was assessed using spectral analysis of heart rate/systolic blood pressure variability.

Three agreements were used:

• A single dose of efonidipine was administered orally to healthy controls with resting heart rate values of 75 beats/minutes or more (high-HR group) and to healthy controls with resting heart rate values less than 75 beats/minutes (low-HR group);
• Efonidipine hydrochloride was newly administered to untreated patients with essential hypertension, and autonomic nervous activity was investigated after a 4 week treatment period; and
• Patients with high heart rate values (≥75 beats/minutes) who had been treated with a dihydropyridine L-type calcium channel inhibitor for 30 days or more were switched to efonidipine hydrochloride and any changes in autonomic nervous activity were examined.

In all agreement, administration of efonidipine decreased the heart rate in patients with a high heart rate, reduced sympathetic nervous activity, and increase parasympathetic nervous activity. In addition, myocardial scintigraphy with 123I-metaiodobenzylguanidine showed significant improvement in the washout rate and H/M ratio of patients who were switched from other dihydropyridine calcium antagonists to efonidipine hydrochloride.

ANALYTICAL METHODS

The various analytical methods were developed on efonidipine which are shown in (Figure 4).

CONCLUSION

The review of literature survey reveals that various analytical methods are available for the estimation of efonidipine. However, there is no report based on scientific approach using design of experiment and no method available for estimation by using HPTLC which may give better experimental parameters. There is no formulation available for efonidipine in combination with other drug (Table 5), but recently Ajanta Pharma applied for combination of efonidipine and telmisartan to treat hypertension. These chromatographic methods are rapid and far more economical. The presented information is useful for the researchers.

REFERENCES

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