Lacidipine

Lacidipine (Caldine®, Lacimen®, Lacipil®, Midotens®, Motens®) is a once-daily, orally-administered, lipophilic dihydropyridine calcium antagonist with an intrinsically slow onset of activity, resulting in a lack of reflex tachycardia. It has a long duration of action and a high degree of vascular selectivity. In addition to calcium channel-modulated vasodilation, lacidipine displays antioxidant activity greater than that of other dihydropyridine calcium antagonists.

In randomised, well-controlled trials, lacidipine 2–6mg orally once daily had antihypertensive efficacy similar to that of other long-acting dihydropyridine calcium antagonists, thiazide diuretics, atenolol (a β-blocker) and enalapril (an ACE inhibitor). Lacidipine was effective in elderly patients (including those with isolated systolic hypertension), African Nigerian patients and patients with concurrent type 2 diabetes mellitus.

During long-term treatment for 4 or 5 years in patients with isolated systolic hypertension or essential hypertension, the incidence of cardiovascular events and mortality with lacidipine was similar to that with chlorthalidone or atenolol.

The European Lacidipine Study on Atherosclerosis (ELSA), in which 2334 patients with hypertension were randomised to 4 years of therapy with lacidipine 4–6 mg/day or the β-blocker atenolol 50–100 mg/day, demonstrated significantly lower atherosclerotic progression and plaque formation with lacidipine compared with atenolol in patients completing the full 4 years of the study. Between-group differences in favour of lacidipine for the primary efficacy variable (mean change in carotid artery intima-media thickness) did not reach statistical significance in the intent-to-treat population.

The tolerability profile of lacidipine (headache, flushing, pedal oedema, dizziness and palpitations) is similar to that of other dihydropyridine calcium antagonists, but with a lower incidence of peripheral oedema. Data from the ELSA study suggest that the incidence of serious adverse events during long-term lacidipine therapy is similar to that with atenolol.

Lacidipine is a once-daily, orally-administered lipophilic 1,4-dihydropyridine calcium antagonist with an intrinsically slow onset of activity and long duration of action. The lipophilic nature of the drug results in the accumulation of lacidipine in membrane lipid bilayers from which it is slowly and continuously released. Lacidipine blocks voltage-dependent L-type calcium channels, producing vasodilation, and thereby reduces total peripheral vascular resistance, resulting in a reduction in blood pressure (BP). In addition, lacidipine has antioxidant activity that is considered to play a role in reducing endothelial dysfunction induced by oxidative stress. The antioxidant activity of lacidipine is greater than that of other dihydropyridine calcium antagonists.

The onset of the antihypertensive effect occurs 0.5–1.0 hours post-dose, and is maintained throughout a 24-hour period during multiple dosing. Lacidipine administration once daily in the morning reduces BP over 24 hours as demonstrated by ambulatory BP monitoring, although night-time BP is reduced to a lesser extent than day-time BP. Trough to peak plasma concentration ratios of 65% or more are commonly observed, indicating that once-daily administration is appropriate. The slow onset of activity means that lacidipine causes little or no reflex tachycardia or sympathetic activation during long-term administration. The high vascular selectivity of lacidipine results in little or no cardiodepression. Lacidipine also improves left ventricular function and, in animal models, exhibits vasoprotective properties in both the cardiovascular and cerebrovascular circulation.

Lacidipine has natriuretic and diuretic effects and is metabolically neutral, having no adverse effects on glucose or lipid metabolism. Lacidipine displays some renal protective properties in animal models, but to a lesser extent than inhibitors of the renin-angiotensin system.

After single-dose oral administration of lacidipine 2–6mg to healthy volunteers, mean peak plasma concentrations (Cmax) of 1.2–6.9 μg/L occurred at a median time of 1.0–1.8 hours post-dose, with high inter-individual variability. Administration of lacidipine 2–6mg once daily for 8 days produced mean steady-state Cmax values of 1.2–5.2 μg/L. Plasma concentrations are increased in the elderly and in patients with hepatic impairment. Lacidipine undergoes extensive first-pass hepatic metabolism and has a mean absolute bioavailability of approximately 10% (range 3–59%). Lacidipine is >90% bound to plasma proteins, mainly albumin. During multiple-dose administration, the terminal elimination half-life of lacidipine 2–6 mg/day was 13.2–18.7 hours. Lacidipine is completely metabolised in the liver by cytochrome P450 3A4 (CYP3A4) to pharmacologically inactive metabolites that are mainly eliminated by the biliary route and excreted in the faeces. Despite being metabolised by CYP3A4, pharmacokinetic interactions with grapefruit juice, simvastatin and digoxin are not considered clinically significant.

Dose-response studies have demonstrated that the effective therapeutic antihypertensive range of lacidipine is 2–6mg once daily, while dose-titration studies have shown that ≥77% of patients with mild-to-moderate hypertension achieve satisfactory BP control with this dose range.

In randomised, controlled trials, the antihypertensive efficacy of lacidipine 2-6mg once daily for 1–48 months in patients with mild-to-moderate essential hypertension was similar to that of other long-acting dihydropyridine calcium antagonists (sustained-release nifedipine, nifedipine gastrointestinal therapeutic system, sustained-release isradipine, nitrendipine, felodipine, amlodipine, manidipine and lercanidipine), the thiazide diuretic hydrochlorothiazide, the β-blocker atenolol and the ACE inhibitor enalapril, without affecting heart rate. Lacidipine was as effective as chlorthalidone and hydrochlorothiazide in the treatment of elderly patients with isolated systolic hypertension. In addition to its use as firstline therapy, lacidipine has value as add-on therapy in patients whose BP is inadequately controlled by other antihypertensive therapies. Lacidipine further reduced BP in patients whose hypertension was uncontrolled by β-blockers, thiazide diuretics or ACE inhibitors. Lacidipine is also effective in African Nigerians with hypertension, and in hypertensive patients with concurrent type 2 diabetes mellitus.

The European Lacidipine Study on Atherosclerosis (ELSA), the largest study of its kind to date, was designed to compare the effects of lacidipine 4–6 mg/day with those of atenolol 50–100 mg/day for 4 years on the progression of carotid artery intima-media thickness (IMT) as an index of atherosclerosis in patients with hypertension. After 4 years of therapy, the mean change in IMT was lower in lacidipine- than atenolol-treated patients, but the difference did not reach statistical significance in the intent-to-treat (ITT) population. However, the mean change in JMT was significantly (p < 0.01) lower in lacidipine-than atenolol-treated patients for the population of patients completing the full 4 years of the study (completers). Analysis of estimated treatment effect (lacidipine minus atenolol) showed significant (p < 0.0001) differences favouring lacidipine for both the ITT and completer populations. Plaque formation was also significantly (p < 0.05) less frequent in the lacidipine-treated patients.

In the long-term treatment of elderly patients with isolated systolic hypertension, the incidence of cardiovascular events (stroke, sudden death, myocardial infarction, congestive heart failure or transient ischaemic attacks) with lacidipine was similar to that with chlorthalidone over 5 years. Similarly, in the ELSA study, there was no significant difference between the lacidipine and atenolol treatment groups in the incidence of cardiovascular events and death during 4 years of treatment.

The tolerability profile of lacidipine is similar to that of other dihydropyridine calcium antagonists; although, in some studies, the incidence of pedal oedema was lower with lacidipine than with other dihydropyridine calcium antagonists. The most common adverse effects are generally attributable to the drug’s vasodilatory actions and consist of headache, flushing, pedal oedema, dizziness and palpitations. Overall, approximately 32% of patients reported adverse events in controlled therapeutic trials. Adverse events tend to occur in the first 6 months of therapy and diminish during long-term use. In the ELSA study, the incidence of serious adverse events during long-term therapy with lacidipine was small and was similar to that seen with atenolol.

Although the most common effective oral dosage of lacidipine in clinical trials has been 4 mg/day, the recommended starting dose in the UK and many European countries in which the drug is approved is usually 2mg orally once daily, increased after 3–4 weeks to 4mg once daily. If necessary, the dosage may be further increased to 6mg once daily. However, in other countries, such as France, the recommended starting dosage is 4mg once daily, increasing to 6mg once daily after 6 weeks if BP is not adequately controlled with the starting dosage. Lacidipine should be taken at the same time each day, preferably in the morning.

The recommended initial dosage in elderly hypertensive patients is 2mg once daily. Dosage adjustment is not required in patients with renal impairment in France, but the manufacturer does not recommend the use of lacidipine in patients with severe renal impairment. Caution is required in patients with hepatic impairment and those with cardiac conduction abnormalities or reduced cardiac reserve.