Usage
- Cilnidipine + Nebivolol is prescribed for the treatment of essential hypertension (high blood pressure).
- Pharmacological classification: This is a combination drug containing a calcium channel blocker (Cilnidipine) and a beta-blocker (Nebivolol), both classified as antihypertensives.
- Mechanism of Action: Cilnidipine blocks calcium channels in blood vessels, causing vasodilation (widening of blood vessels). Nebivolol is a cardioselective beta-blocker, meaning it primarily affects the heart, decreasing heart rate and cardiac output. It also has vasodilating properties by stimulating nitric oxide release. The combination of these two actions leads to a synergistic effect in lowering blood pressure.
Alternate Names
- Cilnidipine and Nebivolol is often referred to as a fixed-dose combination (FDC). There are no internationally recognized alternate names for the combination itself.
- Brand Names: Some brand names for this fixed-dose combination include Nebicard LN, Cilneb, Cinod N and LN Beta.
How It Works
- Pharmacodynamics: Cilnidipine acts on L-type and N-type calcium channels in vascular smooth muscle, leading to vasodilation and reduced peripheral resistance. Nebivolol is a β1-selective adrenergic receptor blocker, reducing heart rate and myocardial contractility, hence decreasing cardiac output. Nebivolol also has a vasodilating effect mediated by nitric oxide. The combined effect results in a significant reduction in blood pressure.
- Pharmacokinetics:
- Absorption: Both drugs are orally absorbed. Food does not significantly affect the absorption of either.
- Metabolism: Nebivolol is extensively metabolized by the liver, primarily by CYP2D6. Cilnidipine is also metabolized in the liver.
- Elimination: Both Cilnidipine and Nebivolol metabolites are eliminated through renal (kidney) and fecal (stool) routes.
- Mode of Action: Cilnidipine inhibits calcium influx into vascular smooth muscle cells, preventing contraction and promoting relaxation. Nebivolol blocks β1-adrenergic receptors in the heart, leading to a decrease in heart rate and force of contraction. Nebivolol’s nitric oxide-mediated vasodilation further enhances the antihypertensive effect.
- Receptor binding/Enzyme inhibition: Cilnidipine binds to and blocks L-type and N-type calcium channels. Nebivolol binds to and blocks β1-adrenergic receptors. Nebivolol is a CYP2D6 substrate, meaning it is metabolized by this enzyme. Drugs that inhibit or induce CYP2D6 may affect Nebivolol’s plasma concentration.
- Elimination pathways: Both are metabolized by the liver, with subsequent elimination in urine and feces.
Dosage
Standard Dosage
Adults:
- The typical starting dose is one tablet containing Cilnidipine 10 mg + Nebivolol 2.5 mg or 5 mg once daily. The dose may be titrated upwards at intervals of at least 2 weeks to a maximum of Cilnidipine 10 mg + Nebivolol 10mg or as directed by a physician, based on individual patient response.
- It’s best taken at the same time each day, with or without food.
Children:
- This combination is not recommended for use in children and adolescents below 18 years of age due to lack of data on safety and efficacy.
Special Cases:
- Elderly Patients: Start with the lower dose (Cilnidipine 10 mg + Nebivolol 2.5 mg) and increase cautiously as needed, with careful monitoring of blood pressure.
- Patients with Renal Impairment: For patients with mild to moderate renal impairment (Creatinine clearance (CrCl) 30-60 mL/min) the recommended initial dose is Nebivolol 2.5 mg. The maximum dose in this group is generally 20 mg. For patients with severe renal impairment (CrCl < 30 mL/min) use is contraindicated. Close monitoring of creatinine and potassium levels is recommended.
- Patients with Hepatic Dysfunction: Cilnidipine + Nebivolol should be used with caution in patients with mild to moderate hepatic impairment. For patients with severe liver impairment, use is contraindicated.
- Patients with Comorbid Conditions: Use with caution in patients with asthma, chronic bronchitis, diabetes, or peripheral vascular disease (Raynaud’s).
Clinical Use Cases
The provided sources mainly focus on the use of Cilnidipine + Nebivolol in the context of outpatient hypertension management. There is no specific dosing information available for clinical use cases like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. In these settings, blood pressure management is often individualized based on the patient’s overall condition and hemodynamic stability, often with intravenous medications.
Dosage Adjustments
Dosage adjustments are necessary for patients with renal or hepatic dysfunction and elderly patients, as outlined above. Dosage should also be adjusted based on individual patient’s response to therapy.
Side Effects
Common Side Effects:
- Headache
- Dizziness
- Fatigue
- Nausea
- Constipation
- Slow heart rate (bradycardia)
- Peripheral edema (swelling in the ankles and feet)
- Flushing
Rare but Serious Side Effects:
- Severe hypotension (low blood pressure)
- Worsening of heart failure
- Bronchospasm (difficulty breathing)
- Heart block
- Severe allergic reactions (angioedema, anaphylaxis)
Long-Term Effects:
- The long-term effects of this combination are primarily related to its intended effect of lowering blood pressure, which can reduce the risk of cardiovascular complications such as stroke, heart attack, and kidney disease. However, some side effects, such as peripheral edema, may persist with long-term use.
Adverse Drug Reactions (ADR):
- Clinically significant ADRs include severe hypotension, bradycardia, heart block, and bronchospasm. These require immediate medical intervention.
Contraindications
- Severe bradycardia
- Second or third-degree heart block
- Cardiogenic shock
- Decompensated heart failure
- Severe hepatic impairment (Child-Pugh class C)
- Sick sinus syndrome (unless a permanent pacemaker is present)
- Hypersensitivity to Cilnidipine or Nebivolol
Drug Interactions
- Cilnidipine interacts with strong CYP3A4 inhibitors/inducers like ketoconazole, erythromycin, rifampicin, and phenytoin.
- Nebivolol interacts with CYP2D6 inhibitors like fluoxetine, paroxetine, quinidine and thioridazine.
- This combination also interacts with other antihypertensives (additive effect), digoxin (increased risk of bradycardia), and calcium antagonists (increased risk of hypotension).
- Alcohol can increase the hypotensive effect of this combination.
- Grapefruit juice can increase cilnidipine levels and hence the risk for side effects.
Pregnancy and Breastfeeding
- Pregnancy: Cilnidipine + Nebivolol is generally contraindicated during pregnancy due to the potential for fetal harm. Beta-blockers can cause intrauterine growth restriction, bradycardia, and hypoglycemia in the newborn.
- Breastfeeding: Nebivolol is excreted in breast milk and is generally not recommended during breastfeeding. It is unknown whether cilnidipine is excreted in breast milk. Safer alternatives should be considered.
Drug Profile Summary
- Mechanism of Action: Cilnidipine: Calcium channel blocker (L-type and N-type); Nebivolol: Beta-1 blocker. Both have vasodilating properties.
- Side Effects: Headache, dizziness, fatigue, nausea, constipation, bradycardia, hypotension, edema.
- Contraindications: Severe bradycardia, heart block, cardiogenic shock, decompensated heart failure, severe hepatic impairment, hypersensitivity, pregnancy, and breastfeeding.
- Drug Interactions: CYP3A4 and CYP2D6 inhibitors/inducers, other antihypertensives, digoxin, calcium antagonists, alcohol.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Cilnidipine 10 mg + Nebivolol (2.5mg or 5mg) once daily. Titrate upwards as needed.
- Monitoring Parameters: Blood pressure, heart rate, ECG, potassium levels, renal and liver function tests.
Popular Combinations
This medication itself is a popular combination. Combining it with other antihypertensives may be clinically beneficial in certain cases, but should be done under strict medical supervision, considering the potential for additive hypotensive effects and drug interactions.
Precautions
- General Precautions: Monitor blood pressure, heart rate, and ECG regularly. Assess renal and hepatic function before and during treatment.
- Specific Populations: Avoid in pregnancy and breastfeeding. Use with caution in the elderly and those with renal or hepatic impairment. Not recommended for children.
- Lifestyle Considerations: Patients should adopt a healthy lifestyle including a low-sodium diet, regular exercise, weight management, and limit alcohol intake. Driving may be impaired due to side effects like dizziness, and patients should be cautioned accordingly.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Cilnidipine + Nebivolol?
A: The usual starting dose is one tablet of Cilnidipine 10 mg + Nebivolol 2.5 mg or 5 mg once daily. The dose can be titrated upwards at intervals of 2 weeks or more to a maximum of Cilnidipine 10 mg + Nebivolol 10 mg per day as directed by the physician, according to the patient’s individual response.
Q2: Can Cilnidipine + Nebivolol be taken with food?
A: Yes, it can be taken with or without food.
Q3: What are the most common side effects?
A: Common side effects include headache, dizziness, fatigue, nausea, constipation, bradycardia (slow heart rate), and peripheral edema (swelling in the ankles and feet).
Q4: Is Cilnidipine + Nebivolol safe during pregnancy or breastfeeding?
A: No, it’s contraindicated during pregnancy and generally not recommended during breastfeeding due to potential risks to the fetus or infant.
Q5: Who should not take Cilnidipine + Nebivolol?
A: Patients with severe bradycardia, heart block, cardiogenic shock, decompensated heart failure, severe hepatic impairment, or hypersensitivity to Cilnidipine or Nebivolol should not take this medication.
Q6: What should I do if I miss a dose?
A: Take the missed dose as soon as you remember, unless it is almost time for your next dose. Do not double the dose to catch up.
Q7: Does Cilnidipine + Nebivolol interact with other medications?
A: Yes, it can interact with several medications, including other antihypertensives, certain antidepressants, antifungals, antibiotics, and digoxin. It is crucial to inform your doctor about all other medications you are taking, including over-the-counter drugs and supplements.
Q8: Can I drink alcohol while taking Cilnidipine + Nebivolol?
A: Alcohol can increase the hypotensive effect of this combination, potentially leading to dizziness or lightheadedness. It is advisable to limit alcohol consumption.
Q9: Are there any dietary restrictions while taking this medication?
A: While no specific foods are prohibited, maintaining a healthy, balanced diet, including a low-sodium diet, is recommended for managing hypertension effectively. Grapefruit juice may increase the blood levels of Cilnidipine; concomitant use is generally not recommended.
Q10: How long does it take for Cilnidipine + Nebivolol to start working?
A: The full blood pressure-lowering effects are typically attained within 2 weeks of starting treatment or changing the dose.
