NEBTAS H

Indications

• Hypertension
• Edema associated with congestive heart failure
• Edema due to renal dysfunction

Dosage

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

Adults: 2.5 mg daily, taken in the morning for hypertension; higher doses may be used for other indications.

Mechanism of action

Hydrochlorothiazide is transported into epithelial cells of the distal convoluted tubule via organic anion transporters OAT1, OAT3, and OAT4. It inhibits the sodium-chloride symporter (SLC12A3), preventing sodium reabsorption. This action reduces the concentration gradient that promotes water reabsorption, leading to increased urine production.

Pharmacodynamics

Hydrochlorothiazide increases the excretion of sodium and water, thereby promoting diuresis. It is effective in lowering blood pressure and has a wide therapeutic range, with doses typically ranging from 25 to 100 mg. The drug exhibits a greater antihypertensive effect at lower doses due to enhanced vasodilation, while higher doses primarily exert their effects through diuresis. Caution is advised in patients with renal or hepatic impairment.

Pharmacokinetics

Hydrochlorothiazide is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1-2 hours post-administration. It has a half-life of about 6-15 hours, depending on individual patient factors. The drug is primarily excreted unchanged in the urine. Dosage adjustments may be necessary in patients with renal impairment due to the risk of accumulation.

Contra-indications

• History of hypersensitivity to sulfonamides
• Acute porphyrias
• Severe renal impairment

Adverse effects

• Angina pectoris
• Arrhythmias
• Arthralgia
• Asthenia
• Chest pain
• Confusion
• Dry mouth
• Haemolytic anaemia
• Hepatic disorders
• Hyperkalaemia
• Hypokalemia
• Nausea
• Rhabdomyolysis
• Syncope
• Vertigo

Interactions

• Potassium-sparing diuretics
• Other antihypertensives
• Lithium
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Corticosteroids

Precautions

• Diabetes mellitus
• Elderly patients
• Basal cell carcinoma
• Cutaneous lupus erythematosus
• Patients with hepatic impairment
• Monitoring of electrolytes

Pregnancy

Hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is advisable to avoid use, especially during the first trimester.

Breast-feeding

Hydrochlorothiazide is present in breast milk; however, the amount is probably too small to be harmful. Caution is advised as large doses may suppress lactation.

Storage

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

Formulations

• Tablets: 12.5 mg, 25 mg
• Oral solution
• Combination products with amiloride

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.