Nebula D
Nebula D Uses, Dosage, Side Effects, Food Interaction and all others data.
Indapamide is a diuretic antihypertensive. It appears to cause vasodilation, probably by inhibiting the passage of calcium and other ions (sodium, potassium) across membranes. It has an extra-renal antihypertensive action resulting in a decrease in vascular hyperreactivity and a reduction in total peripheral and arteriolar resistance.
Classified as a sulfonamide diuretic, indapamide is an effective antihypertensive agent and by extension, has shown efficacy in the prevention of target organ damage.Administration of indapamide produces water and electrolyte loss, with higher doses associated with increased diuresis. Severe and clinically significant electrolyte disturbances may occur with indapamide use - for example, hypokalemia resulting from renal potassium loss may lead to QTc prolongation. Further electrolyte imbalances may occur due to renal excretion of sodium, chloride, and magnesium.
Other indapamide induced changes include increases in plasma renin and aldosterone, and reduced calcium excretion in the urine. In many studies investigating the effects of indapamide in both non-diabetic and diabetic hypertensive patients, glucose tolerance was not significantly altered. However, additional studies are necessary to assess the long term metabolic impacts of indapamide, since thiazide related impaired glucose tolerance can take several years to develop in non-diabetic patients.
Nebivolol is a β-adrenergic receptor blocking agent. Nebivolol is a racemate of two enantiomers, d-Nebivolol and l-Nebivolol. Nebivolol exhibits high selectivity for β1-adrenergic receptors and has vasodilating activity due to a direct action on the endothelium, involving nitric oxide release. It lacks intrinsic sympathomimetic and membrane-stabilising activity.
Nebivolol is a selective beta-1 adrenergic receptor antagonist that decreases vascular resistance, increases stroke volume and cardiac output, and does not negatively affect left ventricular function. It has a long duration of action as effects can be seen 48 hours after stopping the medication and a wide therapeutic window as patients generally take 5-40mg daily. Patients should not abruptly stop taking this medication as this may lead to exacerbation of coronary artery disease. Diabetic patients should monitor their blood glucose levels as beta blockers may mask signs of hypoglycemia.
| Trade Name | Nebula D |
| Generic | Nebivolol + Indapamide |
| Weight | 5mg |
| Type | Tablet |
| Therapeutic Class | |
| Manufacturer | Zydus Cadila Healthcare Ltd |
| Available Country | India |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Indapamide is used for the treatment of essential hypertension . It is effective in treating hypertension in patients with renal function impairment, although its diuretic effect is reduced. Indapamide is also used for the treatment of salt and fluid retention associated with congestive heart failure.
Nebivolol is used for the treatment of essential hypertension and adjunct in stable mild to moderate heart failure in patients over 70 years.
Nebula D is also used to associated treatment for these conditions: High Blood Pressure (Hypertension), Recurrent Nephrolithiasis, Sodium and fluid retentionHigh Blood Pressure (Hypertension)
How Nebula D works
Indapamide acts on the nephron, specifically at the proximal segment of the distal convoluted tubule where it inhibits the Na+/Cl- cotransporter, leading to reduced sodium reabsorption. As a result, sodium and water are retained in the lumen of the nephron for urinary excretion. The effects that follow include reduced plasma volume, reduced venous return, lower cardiac output, and ultimately decreased blood pressure.
Interestingly, it is likely that thiazide-like diuretics such as indapamide have additional blood pressure lowering mechanisms that are unrelated to diuresis. This is exemplified by the observation that the antihypertensive effects of thiazides are sustained 4-6 weeks after initiation of therapy, despite recovering plasma and extracellular fluid volumes.
Some studies have suggested that indapamide may decrease responsiveness to pressor agents while others have suggested it can decrease peripheral resistance. Although it is clear that diuresis contributes to the antihypertensive effects of indapamide, further studies are needed to investigate the medication’s ability to decrease peripheral vascular resistance and relax vascular smooth muscle.
Nebivolol is a highly selective beta-1 adrenergic receptor antagonist with weak beta-2 adrenergic receptor antagonist activity. Blocking beta-1 adrenergic receptors by d-nebivolol leads to decreased resting heart rate, exercise heart rate, myocardial contracility, systolic blood pressure, and diastolic blood pressure. The selectivity of d-nebivolol limits the magnitude of beta blocker adverse effects in the airways or relating to insulin sensitivity. Nebivolol also inhibits aldosterone, and beta-1 antagonism in the juxtaglomerular apparatus also inhibits the release of renin. Decreased aldosterone leads to decreased blood volume, and decreased renin leads to reduced vasoconstriction. l-nebivolol is responsible for beta-3 adrenergic receptor agonist activity that stimulates endothelial nitric oxide synthase, increasing nitric oxide levels; leading to vasodilation, decreased peripheral vascular resistance, increased stroke volume, ejection fraction, and cardiac output. The vasodilation, reduced oxidative stress, and reduced platelet volume and aggregation of nebivolol may lead to benefits in heart failure patients.
Dosage
Nebula D dosage
One tablet daily preferably in the morning. In more sever case Indapamide can be combine with other categories of anti-hypertensive agent. The safety and effectiveness in pediatric patients have not been established
Adults: 5 mg daily, maximum recommended dose 40 mg once daily.
Renal Impairment: In patients with severe renal impairment the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed.
Hepatic Impairment: In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed.
Geriatric Patients: It is not necessary to adjust the dose in the elderly.
Pediatric Use: Safety and effectiveness of Nebivolol in pediatric patients have not been established.
Side Effects
Side effects of Indapamide include headache, anorexia, gastric irritation,nausea, vomiting, constipation, diarrhoea etc.
The most common side effects are headache, nausea and bradycardia.
Toxicity
Indapamide overdose symptoms may include but are not limited to nausea, vomiting, gastrointestinal disorders, electrolyte disturbances and weakness. Other signs of overdose include respiratory depression and severe hypotension. In cases of overdose, supportive care interventions may be necessary to manage symptoms. Emesis and gastric lavage may be recommended to empty the stomach; however, patients should be monitored closely for any electrolyte or fluid imbalances.
Patients experiencing an overdose may present with bradycardia, hypotension, cardiac failure, dizziness, hypoglycemia, fatigue, vomiting, bronchospasm and heart block. Treat overdose with general supportive measures including intravenous atropine for bradycardia, vasopressors and intravenous fluids for hypotension, isoproterenol infusion for heart block, digitalis glycosides and diuretics for congestive heart failure, bronchodilators for bronchospasm, and intravenous glucose for hypoglycemia.
Precaution
Monitoring of potassium and uric acid serum levels is recommended, especially in subjects with a predisposition or sensitivity to hypokalemia and in patients with gout. Although no allergic manifestations have been reported during clinical trials, patients with a history of allergy to sulfonamide derivatives should be closely monitored.
Patients with inadequate cardiac function, well-compensated heart failure, myasthenia gravis. Patients undergoing major surgery involving general anaesth. May mask signs and symptoms of hypoglycaemia and hyperthyroidism. Abrupt withdrawal may exacerbate angina symptoms and/or precipitate MI and ventricular arrhythmias in patients with coronary artery disease. Pregnancy and lactation.
Interaction
Other antihypertensive: Indapamide may add to or potentiate the action of other antihypertensive drugs.
Norepinephrine: Indapamide like thiazides, may decrease arterial responsiveness to norepinephrine.
Lithium: In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity.
Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.), Do not use Nebivolol with other β-blockers, both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia, Nebivolol can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (verapamil and diltiazem), or antiarrhythmic agents, such as disopyramide.
Volume of Distribution
Some sources report an apparent volume of distribution of 25 L for indapamide, while others report a value of approximately 60 L.
For a 20mg dose, d-nebivolol has an apparent volume of distribution of 10,290.81±3911.72L, l-nebivolol has an apparent volume of distribution of 8,066.66±4,055.50L, and both enantiomers together have a volume of distribution of 10,423.42±6796.50L.
Elimination Route
The bioavailability of indapamide is virtually complete after an oral dose and is unaffected by food or antacids. Indapamide is highly lipid-soluble due to its indoline moiety - a characteristic that likely explains why indapamide’s renal clearance makes up less than 10% of its total systemic clearance. The Tmax occurs approximately 2.3 hours after oral administration. The Cmax and AUC0-24 values are 263 ng/mL and 2.95 ug/hr/mL, respectively.
The absorption of nebivolol is not affected by food. Nebivolol has a Tmax of 1.5-4 hours. Bioavailability can range from 12-96% for extensive to poor CYP2D6 metabolizers. For a 20mg dose, d-nebivolol has a Cmax of 2.75±1.55ng/mL, l-nebivolol has a Cmax of 5.29±2.06ng/mL, both enantiomers have a Cmax of 8.02±3.47ng/mL, and nebivolol glucuronides have a Cmax of 68.34±44.68ng/mL. For a 20mg dose, d-nebivolol has an AUC of 13.78±15.27ng*h/mL, l-nebivolol has an AUC of 27.72±15.32ng*h/mL, both enantiomers have an AUC of 41.50±29.76ng*h/mL, and nebivolol glucuronides have an AUC of 396.78±297.94ng*h/mL.
Half Life
Indapamide is characterized by biphasic elimination. In healthy subjects, indapamide's elimination half-life can range from 13.9 to 18 hours. The long half-life is conducive to once-daily dosing.
d-nebivolol has a half life of 12 hours in CYP2D6 extensive metabolizers and 19 hours in poor metabolizers.
Clearance
Indapamide's renal and hepatic clearance values are reported to be 1.71 mL/min and 20-23.4 mL/min, respectively.
For a 20mg dose, the clearance of d-nebivolol is 1241.63±749.77L/h, l-nebivolol is 435.53±180.93L/h, and both enantiomers is 635.31±300.25L/h.
Elimination Route
An estimated 60-70% of indapamide is eliminated in the urine, while 16-23% is eliminated in the feces.
In extensive CYP2D6 metabolizers, 38% is eliminated in the urine and 44% in the feces. In poor CYP2D6 metabolizers, 67% is eliminated in the urine and 13% in the feces. 5
Pregnancy & Breastfeeding use
There are no adequate and well-controlled studies in pregnant women and so Indapamide is not recommended. Mothers taking Indapamide should not breast feed.
Pregnancy category C and not recommended during nursing.
Contraindication
This drug must not be taken in the following conditions:
- Hypersensitivity to sulfonamides
- Severe renal failure
- Hepatic encephalopathy or severe hepatic failure
- Hypokalaemia
Nebivolol is contraindicated in the following conditions: severe bradycardia, heart block greater than first degree, patients with cardiogenic shock, decompensated cardiac failure, sick sinus syndrome, patients with severe hepatic impairment, patients who are hypersensitive to any component of this product.
Acute Overdose
Symptoms: These could include: allergies, skin rashes, epigastric pain, nausea, photosensitivity, dizziness, weakness and paraesthesia.Treatment: Treatment is supportive and symptomatic, directed at correcting the electrolyte abnormalities.
Symptoms: Bradycardia, hypotension, cardiac failure, dizziness, fatigue, hypoglycaemia, vomiting, bronchospasm, heart block.
Management: Symptomatic and supportive treatment. IV atropine may be given for bradycardia, if it persists, admin IV isoproterenol cautiously. For hypotension, admin IV fluids and vasopressors. IV glucagon may also be useful. A β2-agonist and/or aminophylline for bronchospasm. Admin IV glucose for hypoglycaemia and an IV cardiac glycoside and diuretic may be used for CHF.
Storage Condition
Store in a cool and dry place. Protect from light and moisture.
Store between 20-25° C. Protect from light. Keep out of the reach of children.
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