BILAMCAR 16MG/10MG Hard capsule

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II receptor blockers (ARBs) and calcium channel blockers; ATC code: C09DB07. Bilamcar is a combination of two antihypertensive substances with complementary mechanisms of action that control blood pressure in patients with essential hypertension: the angiotensin II receptor antagonist candesartan cilexetil and the dihydropyridine calcium channel blocker amlodipine. The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater extent than either component administered alone. Candesartan cilexetil Mechanism of action Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension, heart failure, and other cardiovascular disorders. It also plays a role in the pathogenesis of target organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis, and stimulation of cell growth, are mediated through the type 1 (AT1) receptor. Candesartan cilexetil is a prodrug suitable for oral administration. It is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan belongs to the group of AIIRAs selective for the AT1 receptor, with tight binding to the receptor and slow dissociation. It has no agonist activity. Pharmacodynamic effects Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. It has no effect on ACE and does not potentiate the effects of bradykinin or substance P. In controlled clinical trials comparing candesartan with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not bind to receptors of other hormones or to ion channels known to be important for cardiovascular regulation. Antagonism of angiotensin II (AT1) receptors results in dose-related increases in plasma renin, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentrations. Clinical efficacy and safety Hypertension In hypertension, candesartan causes a dose-dependent, long-lasting reduction in arterial blood pressure. The antihypertensive effect is due to decreased systemic peripheral resistance without reflex increase in heart rate. There has been no evidence of severe or excessive first-dose hypotension or rebound effect after cessation of treatment. Following a single dose of candesartan cilexetil, the onset of the antihypertensive effect is generally observed within 2 hours. With continued treatment, the majority of blood pressure reduction at any dose is generally achieved within four weeks and is sustained during long-term treatment. According to a meta-analysis, the mean additional effect of increasing the dose from 16 mg to 32 mg once daily was only small. However, taking into account the inter-individual variability, a greater than average effect can be expected in some patients. Once daily dosing of candesartan cilexetil provides an effective and smooth blood pressure reduction over a full 24 hours, with a small difference between peak and trough effects during the dosing interval. The antihypertensive effect and tolerability of candesartan and losartan were compared in two randomised double-blind studies in a total of 1,268 patients with mild to moderate hypertension. Trough blood pressure reduction (systolic/diastolic) was 13.1/10.5 mmHg with candesartan cilexetil 32 mg once daily and 10.0/8.7 mmHg with losartan potassium 100 mg once daily (difference in blood pressure reduction was 3.1/1.8 mmHg, p<0.0001/p<0.0001). When candesartan cilexetil is used with hydrochlorothiazide, the blood pressure reduction is additive. An enhanced antihypertensive effect is also observed when candesartan cilexetil is combined with amlodipine or felodipine. Medicinal products that block the renin-angiotensin-aldosterone system have a less pronounced antihypertensive effect in black patients (who usually have low renin levels) than in patients of other ethnic groups. The same applies to candesartan. In an open-label clinical study in 5,156 patients with diastolic hypertension, the blood pressure reduction during candesartan treatment was significantly less in black patients than in patients of other ethnic groups (14.4/10.3 mmHg versus 19.0/12.7 mmHg, p<0.0001/p<0.0001). Candesartan increases renal blood flow and either has no effect on or increases glomerular filtration rate, while renal vascular resistance and filtration fraction are reduced. In a 3-month clinical study in patients with hypertension who had type 2 diabetes mellitus and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion (albumin/creatinine ratio, mean value 30%, 95% confidence interval 15–42%). There are currently no data available regarding the effect of candesartan on the progression of diabetic nephropathy. The effects of candesartan cilexetil 8–16 mg (mean dose 12 mg) once daily on cardiovascular morbidity and mortality were evaluated in a randomised clinical trial with 4,937 elderly patients (aged 70–89 years; 21% were aged 80 years and over) with mild to moderate hypertension, followed for a mean period of 3.7 years (Study on Cognition and Prognosis in the Elderly). Patients received candesartan cilexetil or placebo, with other antihypertensive therapy added as needed. Blood pressure decreased from 166/90 to 145/80 mmHg in the candesartan group and from 167/90 to 149/82 mmHg in the control group. The primary endpoint, i.e. major cardiovascular events (cardiovascular mortality, non-fatal stroke, and non-fatal myocardial infarction), showed no statistically significant differences. In the candesartan group, 26.7 events per 1,000 patient-years were observed, compared to 30.0 events per 1,000 patient-years in the control group (relative risk 0.89; 95% confidence interval 0.75 to 1.06, p=0.19). Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Two large randomised controlled clinical trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) examined the use of a combination of an ACE inhibitor with an angiotensin II receptor blocker. The ONTARGET study was conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with evidence of target organ damage. The VA NEPHRON-D study was conducted in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies showed no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension was observed compared with monotherapy. Given the similarity of pharmacodynamic properties, these results are also relevant to other ACE inhibitors and angiotensin II receptor blockers. ACE inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. The ALTITUDE study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was designed to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke were numerically more frequent in the aliskiren group than in the placebo group, and adverse events and serious adverse events of interest (hyperkalaemia, hypotension, and renal dysfunction) were more frequently reported in the aliskiren group compared with the placebo group. Amlodipine Mechanism of action Amlodipine is an inhibitor of calcium ion influx into the cell of the dihydropyridine group (slow channel blocker or calcium ion antagonist), which inhibits the transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle cells. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The exact mechanism by which amlodipine relieves angina pectoris has not been fully elucidated, but amlodipine reduces total ischaemic burden by the following two actions: Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload) against which the heart works. Since heart rate remains stable, this reduction in cardiac workload reduces myocardial energy consumption and oxygen requirements. The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina). Pharmacodynamic effects In patients with hypertension, once daily dosing provides clinically significant blood pressure reductions in both supine and standing positions throughout the 24-hour period. Due to the slow onset of action, acute hypotension does not occur with the administration of amlodipine. In patients with angina pectoris, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1 mm ST-segment depression, and decreases both the frequency of angina attacks and glyceryl trinitrate tablet consumption. Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipid levels and is suitable for use in patients with asthma, diabetes, and gout.