Efonidipine (INN) is a dihydropyridine calcium channel blocker marketed by Shionogi & Co. of Japan. It was launched in 1995, under the brand name Landel (ランデル). The drug blocks both T-type and L-type calcium channels. Drug Controller General of India (DCGI) has approved the use of efonidipine in India. It is launched under the brand name "Efnocar" (Zuventus Health care ltd, India).
Structure Activity Relationship
Efonidipine is a dual Calcium Channel Blocker (L & T-type). It has a unique chemical structure. The phosphonate moiety (Figure 1) at the C5 position of the dihydropyridine ring is considered to be important for the characteristic pharmacological profile of the drug. (figure-1)
Mechanism of action
Efonidipine, a new generation dihydropyridine (DHP) calcium channel blocker, inhibits both L-type and T-type calcium channels.
Pharmacodynamics
Efonidipine exhibits antihypertensive effect through vasodilatation by blocking L-type and T-type calcium channels. Efonidipine has a negative chronotropic effect. Working on sino atrial node cells by inhibiting T-type calcium channel activation, Efonidipine prolongs the late phase-4 depolarization of the sino atrial node action potential and suppresses an elevated HR. The negative chronotropic effect of Efonidipine decreases heart rate, myocardial oxygen demand and increases coronary blood flow. Efonidipine increases coronary blood flow by blocking L & T-type calcium channels and attenuates myocardial ischaemia. By reducing synthesis and secretion of aldosterone, Efonidipine prevents hypertrophy and remodeling of cardiac myocytes. Efonidipine increases glomerular filtration rate without increasing intra-glomerular pressure and filtration fraction. This prevents hypertension induced renal damage. Efonidipine prevents Rho-kinase and NF-κB induced renal parenchymal fibrosis and provides long term renal protection. Efonidipine enhances sodium excretion from the kidneys by suppressing aldosterone synthesis and secretion from the adrenal glands. Aldosterone induced renal parenchymal fibrosis is suppressed by Efonidipine. Efonidipine prevents NF-κB induced hypertrophy and inflammation in the renal vasculature and protects the kidneys. Efonidipine lowers blood pressure in cerebral resistance vessels and prevents hypertension induced brain damage.
Pharmacokinetics
Absorption
Peak plasma concentration is achieved in about 1.5 to 3.67 hours after administration. Half life is approximately 4 hours. The pharmacokinetic parameters of Efonidipine are depicted in Table-1.
Table 1: PK Parameters in Adult Healthy Male Subjects
Metabolism
Efonidipine is primarily metabolized in the liver. The important metabolites are N-dephenylated Efonidipine (DPH), deaminated Efonidipine (AL) and N-debenzylated Efonidipine (DBZ). DBZ and DPH exhibit 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 suggest that the majority of the pharmacological effect after oral dosing of Efonidipine hydrochloride in man is due to unchanged compound and its metabolites make a small contribution to the pharmacological effect.
Elimination
Biliary route is the main pathway of excretion. No significant amount of unchanged drug was excreted in urine. In the urine collected for 24 h after an oral dosing, 1.1 % of the dose was excreted as deaminated Efonidipine, and 0.5% as a pyridine analogue of deaminated Efonidipine.
Indications
Essential hypertension and renal parenchymal hypertension
Angina
Contraindications
Contraindicated in patients hypersensitive to Efonidipine or any of the excipients It is also contraindicated in pregnancy and lactation.
Precautions
Should be administered with caution in patients with hepatic impairment
Dose adjustment may be required in elderly as hypotension can occur
Efonidipine may worsen clinical condition in patients with sinus bradycardia, sinus arrest or sinus node dysfunction As dizziness can occur due to hypotensive action, one should be careful while operating machines, with aerial work platforms and driving of a motor vehicle Drug should not be stopped abruptly. Discontinuation should be gradual and under supervision of a qualified physician