URAZIDE COMBINATION PRODUCT TABLET

Indications

• Oedema
• Heart failure
• Hypertension
• Adjunct to thiazide or loop diuretics for potassium conservation

Dosage

Children: Child 1 month–11 years: 100–200 micrograms/kg twice daily; maximum 20 mg per day.

Adults: 5-10 mg once daily; dose may be adjusted based on clinical response.

Mechanism of action

Amiloride acts by inhibiting sodium reabsorption in the distal convoluted tubule and the collecting ducts of the kidneys, thereby promoting diuresis while conserving potassium.

Pharmacodynamics

As a potassium-sparing diuretic, amiloride enhances the excretion of sodium and water while reducing potassium loss, making it useful in conditions where hypokalemia may be a concern.

Pharmacokinetics

Amiloride is well absorbed from the gastrointestinal tract, with peak plasma concentrations reached within 1-2 hours. It is primarily excreted unchanged in the urine. The half-life is approximately 6-9 hours.

Contra-indications

• Addison’s disease
• anuria

Adverse effects

• Appetite decreased
• erectile dysfunction
• gastrointestinal discomfort
• hyperglycaemia
• rash

Interactions

• thiazide diuretics
• potassium-sparing diuretics

Precautions

• Diabetes mellitus

Pregnancy

Refer to BNF for specific guidance on use during pregnancy.

Breast-feeding

Refer to BNF for specific guidance on use during breastfeeding.

Storage

Store at room temperature, protected from light and moisture.

Formulations

• Amiloride hydrochloride 1 mg per 1 ml oral suspension
• Amiloride 5 mg/5 ml oral solution sugar-free
• Amiloride hydrochloride 5 mg tablets

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

• Hypertension
• Congestive heart failure
• Edema associated with conditions such as nephrotic syndrome

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations in paediatric patients.

Adults: Refer to the BNF for specific dosing recommendations based on the condition being treated.

Mechanism of action

Amiloride works by inhibiting sodium reabsorption in the distal convoluted tubules and collecting ducts of the kidneys. It binds to amiloride-sensitive sodium channels, resulting in increased sodium and water excretion while preventing potassium loss. Unlike aldosterone antagonists, amiloride's effects are evident even in the absence of aldosterone.

Pharmacodynamics

As a potassium-sparing diuretic, amiloride reduces blood pressure and aids in the management of fluid overload in patients with heart failure. It has a unique chemical structure that distinguishes it from other diuretics. Its potassium-sparing property can lead to hyperkalemia, particularly when used in conjunction with ACE inhibitors or other potassium-retaining medications.

Pharmacokinetics

Amiloride is administered orally and is absorbed well from the gastrointestinal tract. It has a half-life that allows for once-daily dosing in many cases. The drug is excreted primarily through the kidneys, and its pharmacokinetics can be affected by renal function. Adjustments may be necessary in patients with renal impairment.

Contra-indications

• Severe renal impairment
• Hyperkalemia
• Anuria

Adverse effects

• Hyperkalemia
• Hypotension
• Gastrointestinal disturbances
• Dizziness
• Headache

Interactions

• Increased risk of hyperkalemia with ACE inhibitors
• Increased risk of hyperkalemia with potassium supplements
• Increased risk of hyperkalemia with potassium-sparing diuretics like spironolactone
• May enhance the effects of other antihypertensive medications

Precautions

• Monitor renal function regularly
• Monitor serum potassium levels, particularly in high-risk patients
• Use cautiously in patients with hepatic impairment
• Caution in patients with a history of electrolyte imbalances

Pregnancy

Amiloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Amiloride is excreted in breast milk; caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets
• Oral solution

Mechanism of action

Amiloride works by inhibiting sodium reabsorption in the distal convoluted tubules and collecting ducts in the kidneys by binding to the amiloride-sensitive sodium channels. This promotes the loss of sodium and water from the body, but without depleting potassium. Amiloride exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. Amiloride is not an aldosterone antagonist and its effects are seen even in the absence of aldosterone.

Pharmacodynamics

Amiloride, an antikaliuretic-diuretic agent, is a pyrazine-carbonyl-guanidine that is unrelated chemically to other known antikaliuretic or diuretic agents. It is an antihypertensive, potassium-sparing diuretic that was first approved for use in 1967 and helps to treat hypertension and congestive heart failure. The drug is often used in conjunction with thiazide or loop diuretics. Due to its potassium-sparing capacities, hyperkalemia (high blood potassium levels) are occasionally observed in patients taking amiloride. The risk is high in concurrent use of ACE inhibitors or spironolactone. Patients are also advised not to use potassium-containing salt replacements.

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.