Cilnidipine

What Is Blood Pressure ?

Blood pressure is the amount of force on the walls of the arteries as the blood circulates around the body.

Blood PressureBP = pressure exerted on the vessel wall by bloodBP = cardiac output ( CO) x PVR where CO isCO = stroke volume x Heart rate

BP = ( SV X HR ) X PVR

BLOOD PRESSURE Peripheral Vascular Resistance depends on :

- Lumen diameter of peripheral arterioles

- dilatation of peripheral arterioles decreases PVR & lowers BP

- Contraction of peripheral arterioles increases PVR & BP

Hypertension

JNC-7

Causes of HypertensionPrimary / Essential hypertension: - No identifiable causeMost common causeAccounts for 93 % of cases

Secondary Hypertension: (Due to other diseases)Renal HypertensionEndocrine Hypertension etc.

Harmful effects of High Blood PressureHardening of the arteries-atherosclerosis

Stroke

Heart attack

Kidney damage-kidney failure

Blindness

Benefits of lowering BP

Condition

Percent reduction

Stroke

34-40%

MI

20-25 %

Heart Failure

50%

Goals of therapyBP < 140/90 mmHg

In diabetics or in patients with chronic renal disease: 50 years:

Ideal Antihypertensive drugGood efficacy-should provide 24-hr control of BP with once daily doseMinimal or no serum glucose imbalanceMinimal or no electrolyte imbalanceMinimal or no lipid profile imbalanceImprove quality of life - Physical activity, sleep, sexual functions.Dosage compliance

Major Antihypertensives1. Diuretics: Hydrochlorothiazide2. Beta blockers : Atenolol, nebivolol, metoprololACE inhibitors : - Enalapril, Lisinopril, Ramipril etc4. AT1 receptor antagonists: - Losartan, valsartan, telmisartan etcCalcium antagonists : - Cilnidipine, Amlodipine, Nifedipine, DiltiazemAlpha blockers : - Prazosin,terazosin,doxazosin

Calcium AntagonistsAlso called calcium channel blockers-Dilate arterioles- decrease PVR & BP 3 groups:

1.Dihydropyridine derivatives: Nifedipine, felodipine, amlodipine, cilnidipine etc

2.Benzothiazepines: Diltiazem

3.Phenylalkylamines: Verapamil

CCBs block the L type calcium channels present within blood vessels- prevent entry of calcium ions into vascular smooth muscle fibers

relaxing large and small arteries and reducing peripheral resistance( PVR )

Reduce force of contraction of myocardium

Calcium Antagonists

Calcium Channel BlockersIndications

Hypertension

Angina

CCBs are commonly used to treat hypertension because:Very well tolerated,compliance is high, They dont have any adverse effect on quality of lifeDo not alter carbohydrate or lipid Metabolism

often used in combination with beta-blocker therapy

Calcium antagonists

Averse Drug Reactions:FlushingHeadacheAnkle oedemaReflex tachycardia

Calcium antagonists

Renin Angiotensin Aldosterone System (RAAS)Plays an essential role in regulation of blood pressure, blood volume, electrolyte balance and glomerular filtration rate (GFR)

RAASAngiotensinogen Renin(kidney) Angiotensin I

Non ACE ACE Pathway

Angiotensin II

AT1 receptors AT2 receptors

Vasoconstriction Aldosterone Stimulation Cell growth (PVR) release of SNS salt & water retention (preload)

RAASAT1 receptors:Responsible for virtually all the known actions of Angiotensin II AT1 receptors are present in the blood vesselsadrenal glandheartkidney brain & liver

RAASVasoconstriction:Angiotensin II is the most potent vasoconstrictor in the body Produces constriction of arterioles as well as veinsConstriction of peripheral arterioles results in increased Peripheral Vascular Resistance (PVR)

RAASInappropriately elevated levels of angiotensin II have following adverse effects:

Constriction of peripheral arterioles leads to increased PVR (afterload)

Angiotensin II leads to aldosterone secretion from adrenal cortex

Aldosterone causes sodium & water retention in the body, thus increasing blood volume (preload)

RAASAll these actions of angiotensin II are seen after it has combined with AT1 receptors

RAAS - InhibitionTwo different groups of drugs that inhibit the RAAS are:ACE inhibitors e.g. Enalapril, Lisinopril, Ramipril AT1 receptor blockers (ARBs) e.g. Losartan, Valsartan, Telmisartan

Block the AT1 receptors

Reduce afterload & preload e.g. Losartan, candesartan, valsartan, telmisartan etc

Better tolerated than ACE inhibitors- - do not produce dry coughAngiotensin-II Receptor Blockers

Beta BlockersMode of actionBlock Beta receptors present in heart :Decrease CO-decrease heart rate & force of contraction-negative chronotropic & negative inotropic effects

Decrease in Renin release from the Kidneys

Central action - reduction in Sympathetic tone

Beta blockersClassification :1.Non-selective: Block both beta1 & beta2 receptors (Propranolol )

2.Cardio-selective: Block only beta1 receptors (Atenolol, Metoprolol, Nebivolol )

3. Combined beta & alpha blocker: Block both beta1 & beta2 + alpha1 receptors ( carvedilol )

Beta BlockersIndications

Hypertension Angina Post-MI

Beta BlockersSide effectsBradycardiaAV block- not safe in heart blockFatigueBronchospasm- not safe in asthmaLoss of LibidoImpotenceDyslipidemia

Not at Goal Blood Pressure (100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)Stage 1 Hypertension (SBP 140159 or DBP 9099 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.Without Compelling IndicationsAlgorithm for Treatment of HypertensionStage 2 Hypertension (SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)Stage 2 Hypertension (SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)

Cilnidipine

Cilnidipine was administered orally once daily at an initialdose of 10 mg for 4 weeks

Treatment: 10 mg Cilnidipine for 7 daysCilnidipine is effective as a once-daily antihypertensive agent and causeslittle infuence on heart rate and the autonomic nervous system in patients with mild tomoderate essential hypertension

Study designed to compare the effects of 12-month blood pressure (BP) control using cilnidipine and telmisartan on vascular damage in untreated hypertensive patients

One hundred patients were randomly assigned to either a cilnidipine group or a telmisartan group

The extent of vascular damage was assessed before and after treatment by measuring urinary albumin excretion (UAE)pulse wave velocity (PWV)intima-media thickness (IMT) of the carotid arteries

Both drugs similarly decreased BP Both UAE and PWV were significantly improved in both groups, but IMT was significantly reduced only in the cilnidipine group.

Study compared cilnidipine and amlodipine with respect to their effects on renal function and proteinuria

Twenty-eight proteinuric hypertensive outpatients (13 men and 15 women, aged 62.2 years) who had been maintained on CCBsfor more than 3 months were randomly assigned to a group receiving amlodipine besilate (14 patients) or a group receiving cilnidipine (14 patients)

Before and at 6 and 12 months after randomization, the concentrations of urine protein, urine albumin, serum and urine creatinine (Cr), and serum 2-microglobulin were determine

Amlodipine group showed a significant increase in proteinuria, while the increase was suppressed in the cilnidipine group

Conclusion: cilnidipine results in a greater suppression of the increase in proteinuria and greater reduction in glomerular filtration rate than amlodipine, and that these effects are similarbetween cilnidipine and RA inhibitors

The study was a prospective, randomized, open label comparison45 patients received 5-10mg Amlodipine and other 55 patients of same age groups received 10-20mg Cilnidipine.

Both the drug significantly reduced both systolic (SBP) and diastolic blood pressure (DSP)Amlodipine group the pulse rate (PR) after treatment tended to be higher than those before treatmentCilnidipine group there was decrease in PR after treatmentUnlike Amlodipine, Cilnidipine decreased urinary protein excretion and in diabetic patients reduced serum triglyceride

Unlike Amlodipine, Cilnidipine which inhibits L-and N-type calcium channels will be useful for patients with hypertension and cardiovascular disease, diabetes mellitus or renal disease and proves to be a better alternative to existing calcium channel blockers

Evaluated the antialbuminuric advantage of cilnidipine,L/N type Calcium channel blocker (CCB), compared with L-type CCBs in diabetic patients with normoalbuminuria and microalbuminuria.

Participants were 90 type 2 diabetic patients exhibiting either normo- or microalbuminuria, and undergoing CCB treatment for 6 months prior to study entry.

The CCB at the time of entry was continued for the first 6 months (Period 1). Treatment was subsequently switched from cilnidipine to an L-type CCB, or vice versa, for the second 6-month observation period (Period 2). During Period 1, the L-type CCB group showed a significant increase of urinary albumin excretion (UAE) over time, while the cilnidipine group showed no significant elevation.During Period 2, switching of the treatment from the L-type CCB to cilnidipine resulted in significant reduction of the UAE, whereas switching from cilnidipine to the L-type CCB resulted in no significant change in the UAE.

This study demonstrated that the antialbuminuric effect of Cilnidipine, but not the L-type CCBs, was sustained even in patients treated for a long time. In addition, the antialbuminuric effect can be anticipated after switching from an L-type CCB to cilnidipine, but not vice versa.

Conclusion: In Treatment Period of L-type CCB there was increase in Urinary Protein Excretion while in Treatment Period of Cilnidipine there was reduction in Urinary Protein Excretion.

Cilnidipine offers Reno-protection

Hypertens Res 2006; 29: 339-44Fifty-eight subjects diagnosed with both essential hypertension and morning hypertension (43 currently being treated, 15 new patients) were prescribed cilnidipine at a dosage of 1020 mg per day for 8 weeks

After addition of or a change to cilnidipine, the morning systolic blood pressure (SBP) was controlled to less than 135 mmHg in 25 (58%) out of the 43 patients currentlyreceiving antihypertensive medication

Office SBP in 24 out of those 25 patients was also maintained under 140 mmHg

In the 15 newly treated patients, the morning SBP of 12 patients (80%) was controlled to less than 135 mmHg after administration of cilnidipine

J Clin Hypertens 2013; 15: 133The authors examined 2319 patients treated with cilnidipine for 12 weeks

Clinic systolic BP (SBP) decreased by 19.6 mm Hg from 155.0 mm Hg, whereas morning SBP decreased by 17.0 mm Hg from 152.9 mm Hg after 12-week cilnidipine treatment

Cilnidipine significantly reduced BP and Pulse Rate (PR) in hypertensive patients at the clinic and at home, especially with higher BP and PR in the morning

J Hyper 2007; 25: 2178- 218350 patients with untreated essential hypertension were randomized to receive 5mg of amlodipine (n=25) or 10mg of cilnidipine (n=25)once daily in the morning for 24 weeks

Patients were evaluated before and after the therapy to assess changes in renal function, flow-mediated vasodilation (a parameter of vascular endothelial function), and brachial-ankle pulse wave velocity (a parameter of arterial stiffness)

After treatment, urinary albumin excretion was decreased significantly in the cilnidipine group compared with the amlodipine group, andthe decrease of brachial-ankle pulse wave velocity was significantly larger in the cilnidipine group than in the amlodipine group

Conclusion:These results suggest that cilnidipine is more effective than amlodipine at improving renal function and arterial stiffness in patients with essential hypertension

Kidney International 2007; 72:1543-49339 patients, already receiving reninangiotensin system inhibitor treatment, were randomly assigned to cilnidipine or amlodipine

Primary endpoint was a decrease in the urinary protein to creatinine ratio

After 1-year of treatment, systolic and diastolic blood pressures were significantly reduced in both groups which did not differ between them

The urinary protein to creatinine ratio significantly decreased in the cilnidipine compared to the amlodipine group

Cilnidipine exerted a greater antiproteinuric effect than amlodipine even in the subgroup whose blood pressure fell below the target level.Study suggests that cilnidipine is superior to amlodipine inpreventing the progression of proteinuria in hypertensive patients when coupled with a reninangiotensin system inhibitor

Excellent Tolerability of Cilnidipine in Patients with Amlodipine induced Edema27 patients with Amlodipine induced edemaTreatment with Cilnidipine 10 mg for 4 weeksEdema resolved in all patientsSignificant decrease in bilateral ankle circumference and body weight (p< 0.001)

Before TreatmentAfter TreatmentAnkle Circumference Rt (cm)2623.7-2.3p