Nebilol H

Uses

Essential hypertension
Use in children is not recommended.

Nebilol H is also used to associated treatment for these conditions: Acidosis, Renal Tubular, Calcium Nephrolithiasis, Cirrhosis of the Liver, Congestive Heart Failure (CHF), Diabetes Insipidus, Edema, High Blood Pressure (Hypertension), Hypertension,Essential, Hypokalemia caused by diuretics, Nephrotic Syndrome, Premenstrual tension with edema, Sodium retention, Stroke, Prophylaxis of preeclampsiaHigh Blood Pressure (Hypertension)

How Nebilol H works

Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4).

Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water.

Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water.

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

Nebilol H dosage

Once daily, preferably at the same time every day.

Side Effects

Nebivolol: Headache, Dizziness, Tiredness, Diarrhoea, Constipation, Nausea etc.

Hydrochlorothiazide: Vertigo, Itchiness, Rash, Increased sensitivity of skin to sunlight etc.

Toxicity

The oral LD₅₀ of hydrochlorothiazide is >10g/kg in mice and rats.

Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment.

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

Nebivolol: Beta-blockers should not be used in patients with untreated Congestive Heart Failure (CHF) & bradycardia. In patients with Chronic Obstructive Pulmonary Diseases (COPD), beta-blockers should be used with caution as airway constriction may be aggravated.

Hydrochlorothiazide: In patients with renal disease, thiazides may increase azotaemia. If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary. Thiazides can cause fluid or electrolyte imbalance. Thiazides may decrease urinary calcium excretion and may cause slight elevation of serum calcium in the absence of known disorders of calcium metabolism

Interaction

Nebivolol:

• Class I & III Antiarrhythmics, Calcium channel blocker (Verapamil/Diltiazem)
• Centrally-acting antihypertensives, Anaesthetics
• Antipsychotics, Antidepressants, NSAIDs

• Drugs affecting Potassium & Calcium level
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Concomitant administration of this combination with Antipsychotics, Tricyclic Antidepressants & Barbiturates may enhance the hypotensive effect and lead to postural hypotension.

Volume of Distribution

The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg.

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

An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T_max of 1-5 hours, and a C_max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C_max is 20% lower, and T_max increases from 1.6 to 2.9 hours.

The absorption of nebivolol is not affected by food. Nebivolol has a T_max 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 C_max of 2.75±1.55ng/mL, l-nebivolol has a C_max of 5.29±2.06ng/mL, both enantiomers have a C_max of 8.02±3.47ng/mL, and nebivolol glucuronides have a C_max 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

The plasma half life of hydrochlorothiazide is 5.6-14.8h.

d-nebivolol has a half life of 12 hours in CYP2D6 extensive metabolizers and 19 hours in poor metabolizers.

Clearance

The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min.

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

Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.

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

This combination is not recommended during pregnancy. It is also not recommended for mothers who are breast-feeding

Contraindication

Hypersensitivity to the active substances, Liver function impairment. Severe renal insufficiency (Creatinine clearance < 30 ml/min.), Bradycardia, Hypotension

Special Warning

Elderly: in some patients specially the elderly an initial dose of 12.5 mg daily may be sufficient.

Children: An initial dose for children has been 1 to 2 mg per kg body-weight in 2 divided doses. Infants under 6 months may need doses upto 3 mg per kg daily.

Acute Overdose

No data are available on Overdosage. Overdosage with Hydrochlorothiazide is associated with electrolyte depletion and dehydration resulting from excessive diuresis.

Storage Condition

Protect from light & moisture. Store below 30° C. Keep out of reach of children.

Innovators Monograph

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