NEBTAS-H

Indications

• Hypertension
• Edema associated with congestive heart failure
• Edema due to liver cirrhosis
• Edema related to renal disorders

Dosage

Children: For children, the dosage should be individualized and is generally based on the child's weight and condition

Adults: Typically, the initial adult dose is 12.5 mg to 25 mg once daily, which may be adjusted based on response, up to a maximum of 100 mg per day.

Mechanism of action

Hydrochlorothiazide is transported into epithelial cells of the distal convoluted tubule through organic anion transporters OAT1, OAT3, and OAT4. It inhibits the sodium-chloride symporter (SLC12A3) in the proximal region of the distal convoluted tubule, which reduces sodium and water reabsorption. This inhibition leads to increased sodium and water excretion in urine, thereby reducing blood volume and blood pressure.

Pharmacodynamics

The primary pharmacodynamic effect of hydrochlorothiazide is its ability to prevent the reabsorption of sodium and water from the distal convoluted tubule. This results in increased urine output and decreased blood pressure. The drug is noted for its wide therapeutic window, allowing for individualized dosing, typically ranging from 25 to 100 mg. Caution is advised in patients with impaired renal or hepatic function.

Pharmacokinetics

Hydrochlorothiazide is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. The drug has a half-life of approximately 6 to 15 hours, allowing for once-daily dosing in most cases. It is primarily excreted unchanged in the urine, with a small portion undergoing hepatic metabolism. The diuretic effect typically begins within 2 hours, peaking at about 4 to 6 hours and lasting for up to 12 hours.

Contra-indications

• Hypersensitivity to hydrochlorothiazide or other sulfonamide-derived drugs
• Anuria
• Severe renal impairment

Adverse effects

• Electrolyte imbalances (hyponatremia, hypokalemia)
• Hypotension
• Dizziness
• Headache
• Gastrointestinal disturbances (nausea, vomiting)
• Skin rashes
• Hyperuricemia
• Increased blood glucose levels

Interactions

• NSAIDs may reduce the antihypertensive effect
• Corticosteroids may increase the risk of hypokalemia
• Lithium levels may increase leading to toxicity
• Antidiabetic medications may require dosage adjustment due to altered glycemic control

Precautions

• Use with caution in patients with liver disease, diabetes mellitus, or gout
• Monitor electrolyte levels regularly
• Assess renal function prior to initiation and periodically during treatment
• May cause sensitivity to sunlight

Pregnancy

Hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution is advised.

Breast-feeding

Hydrochlorothiazide is excreted in breast milk. Caution is advised when administered to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets (12.5 mg, 25 mg, 50 mg)
• Oral solution (available in some regions)

Indications

• Essential hypertension
• Migraine prophylaxis
• Hypertension in patients with renal impairment
• Adjunct treatment in stable mild to moderate heart failure
• Management of arrhythmias during anesthesia

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations.

Adults: Initially 5 mg once daily, with a maximum of 40 mg daily depending on clinical response and tolerance.

Mechanism of action

Nebivolol selectively antagonizes beta-1 adrenergic receptors, leading to decreased heart rate, myocardial contractility, and blood pressure. Additionally, it stimulates beta-3 adrenergic receptors, causing increased nitric oxide production and subsequent vasodilation. This reduces vascular resistance and enhances cardiac output while minimizing adverse effects commonly associated with non-selective beta blockers.

Pharmacodynamics

Nebivolol decreases vascular resistance and increases stroke volume and cardiac output without negatively impacting left ventricular function. Its effects can persist for up to 48 hours after discontinuation of the drug. It possesses a wide therapeutic window, with typical doses ranging from 5 to 40 mg daily. Patients, especially those with coronary artery disease, should not stop treatment abruptly as this may exacerbate their condition. Additionally, diabetic patients should monitor blood glucose levels, as nebivolol may mask hypoglycemic symptoms.

Pharmacokinetics

Nebivolol is well absorbed and undergoes extensive first-pass metabolism. It has a half-life that allows for once-daily dosing, making it convenient for patient adherence. The drug is primarily metabolized by the liver, and its elimination is influenced by renal function. The pharmacokinetic profile supports its use in various patient populations, including the elderly, who may require dose adjustments.

Contra-indications

• Acute or decompensated heart failure requiring intravenous inotropes
• Severe bradycardia
• Heart block (greater than first degree) unless a functioning pacemaker is present
• Cardiogenic shock
• Severe hepatic impairment

Adverse effects

• Constipation
• Oedema
• Postural hypotension
• Dyspepsia
• Flatulence
• Skin reactions
• Palpitations
• Alopecia
• Arrhythmia
• Conjunctivitis
• Dry eyes
• Fatigue
• Thrombocytopenia
• Sexual dysfunction

Interactions

• Propafenone: Severe (increases exposure)
• Dacomitinib: Severe (increases exposure)
• Berotralstat: Moderate (increases exposure)
• Fedratinib: Moderate (increases exposure)
• Givosiran: Moderate (increases exposure)
• Panobinostat: Moderate (increases exposure)
• Bupropion: Unknown (increases exposure)
• Cinacalcet: Unknown (increases exposure)
• Terbinafine: Unknown (increases exposure)
• Ropeginterferonalfa: Unknown (increases exposure)

Precautions

• Use with caution in patients with diabetes, as beta-blockers may mask signs of hypoglycemia
• Monitor blood pressure and heart rate regularly
• Taper off the medication gradually to avoid exacerbation of coronary artery disease
• Caution in patients with a history of bronchospastic disease

Pregnancy

Use only if the benefits outweigh the risks, as safety in pregnancy has not been established.

Breast-feeding

Manufacturers advise avoidance due to potential effects on the infant.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Nebivolol 1.25 mg tablet
• Nebivolol 5 mg tablet
• Nebivolol 10 mg tablet
• Nebivolol solution for injection

Mechanism of action

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.

Pharmacodynamics

Hydrochlorothiazide prevents the reabsorption of sodium and water from the distal convoluted tubule, allowing for the increased elimination of water in the urine. Hydrochlorothiazide has a wide therapeutic window as dosing is individualized and can range from 25-100mg. Hydrochlorothiazide should be used with caution in patients with reduced kidney or liver function.

Mechanism of action

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.

Pharmacodynamics

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.