Hydrochlorothiazide

1. Drug Name

• Generic Name: Hydrochlorothiazide

• Brand Names: HydroDIURIL, Microzide, Esidrix, Oretic, and others.

2. Drug Classification

• Class: Thiazide Diuretic

• Subclass: Thiazide-like Diuretic

3. Mechanism of Action

Hydrochlorothiazide is a thiazide diuretic that primarily acts on the distal convoluted tubule of the nephron in the kidneys. Its mechanisms of action include:

• Inhibition of Sodium and Chloride Reabsorption: Hydrochlorothiazide inhibits the sodium-chloride symporter in the distal convoluted tubule, leading to reduced sodium reabsorption. This results in increased sodium, chloride, and water excretion in urine, promoting diuresis (increased urine output).

• Potassium and Magnesium Loss: By inhibiting sodium reabsorption, hydrochlorothiazide also increases the excretion of potassium and magnesium, which can lead to hypokalemia and hypomagnesemia in some patients.

• Reduction of Blood Volume and Blood Pressure: Through its diuretic effects, hydrochlorothiazide reduces plasma volume and extracellular fluid, which lowers cardiac output and systemic vascular resistance, ultimately leading to a reduction in blood pressure.

• Calcium Retention: Unlike other diuretics, hydrochlorothiazide enhances calcium reabsorption in the distal tubules, which may be beneficial in conditions such as nephrolithiasis (kidney stones).

4. Pharmacokinetics

• Absorption: Hydrochlorothiazide is well absorbed after oral administration, with bioavailability typically ranging from 60-80%. Its absorption is not significantly affected by food.

• Distribution: It has a volume of distribution (Vd) of approximately 0.5 L/kg and is about 40-70% protein-bound, primarily to albumin.

• Metabolism: Hydrochlorothiazide is not metabolized to a significant extent. It remains largely unchanged in the body.

• Excretion: Hydrochlorothiazide is primarily excreted unchanged by the kidneys. Its half-life (t½) ranges from 5.6 to 14.8 hours, depending on individual patient factors such as renal function. It is predominantly excreted in urine, with very little renal clearance of unchanged drug.

• Special Considerations: In patients with renal impairment, hydrochlorothiazide’s renal clearance is reduced, which can increase drug levels and the risk of side effects. Adjustments in dosage may be needed.

5. Indications

• Primary Indications:

  • Hypertension: Hydrochlorothiazide is widely used for the treatment of essential hypertension, either alone or in combination with other antihypertensive agents.

  • Edema: Used in the treatment of edema associated with heart failure, chronic kidney disease, and cirrhosis, as it helps to reduce fluid retention.

• Off-Label Uses:

  • Nephrolithiasis (Kidney Stones): Hydrochlorothiazide may be used in the prevention of recurrent calcium kidney stones by enhancing calcium reabsorption and reducing urinary calcium excretion.

  • Diabetes Insipidus (Nephrogenic): It is occasionally used off-label for the treatment of nephrogenic diabetes insipidus due to its ability to concentrate urine.

• Special Populations:

  • Pediatrics: Hydrochlorothiazide is sometimes used in children to treat hypertension or edema, though it should be done with caution and under close supervision.

  • Geriatrics: Elderly patients may be more susceptible to electrolyte disturbances such as hypokalemia and hyponatremia, requiring careful monitoring.

6. Dosage and Administration

• Adult Dosing:

  • Hypertension: Typically, 12.5-25 mg orally once daily. Doses may be increased based on the patient’s response, with a maximum dose of 50 mg per day.

  • Edema: Initial dosing is typically 25-100 mg orally once daily, depending on the severity of the condition.

• Pediatric Dosing:

  • Hypertension (Children): Doses for children are typically based on body weight, ranging from 0.5 to 1 mg/kg/day (max 2 mg/kg/day).

  • Edema (Children): Dosing is typically 1-2 mg/kg/day, administered in one or two doses.

• Renal Impairment: In patients with renal impairment (CrCl <30 mL/min), the dose should be reduced to avoid excessive accumulation and electrolyte imbalances.

• Maximum Safe Dose: For hypertension, the maximum recommended dose is 50 mg/day. For edema, higher doses may be used, but the total dose should not exceed 100 mg/day unless closely monitored.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity: Known hypersensitivity to hydrochlorothiazide or sulfonamide-derived drugs.

  • Anuria: Should not be used in patients with anuria (absence of urine output), as it is ineffective in this setting.

• Relative Contraindications:

  • Renal Insufficiency: Use with caution in patients with renal impairment (CrCl <30 mL/min), as the drug is primarily excreted by the kidneys.

  • Electrolyte Imbalances: Caution is required in patients with existing electrolyte disturbances, especially hypokalemia, hyponatremia, and hypercalcemia.

8. Warnings and Precautions

• Electrolyte Imbalances: Hydrochlorothiazide can cause significant electrolyte disturbances, including:

  • Hypokalemia: Low potassium levels, which can lead to muscle weakness, cramps, and arrhythmias.

  • Hyponatremia: Low sodium levels, which can cause dizziness, confusion, and seizures.

  • Hypomagnesemia: Low magnesium levels, increasing the risk of arrhythmias.

  • Hypercalcemia: May occur due to enhanced calcium reabsorption.

• Renal Impairment: Caution is necessary in patients with pre-existing kidney conditions, as the drug can worsen renal function and lead to electrolyte disturbances.

• Gout: Hydrochlorothiazide can increase uric acid levels and precipitate gout attacks in predisposed individuals.

• Systemic Lupus Erythematosus (SLE): Thiazide diuretics may exacerbate lupus erythematosus in susceptible individuals.

• Pregnancy and Lactation: Hydrochlorothiazide is classified as Category B for pregnancy, meaning it is generally considered safe when used during pregnancy. However, it should only be used when clearly needed. It is excreted in breast milk, so caution should be exercised in nursing mothers.

9. Adverse Effects

• Common Adverse Effects:

  • Dizziness

  • Hypokalemia

  • Hypotension

  • Hyperglycemia (especially in diabetic patients)

  • Nausea

• Less Common but Clinically Significant Side Effects:

  • Gout attacks (due to elevated uric acid)

  • Erectile dysfunction

  • Photosensitivity

  • Rash

• Rare/Serious Adverse Reactions:

  • Severe electrolyte imbalances (hypokalemia, hyponatremia, hypomagnesemia)

  • Pancreatitis

  • Severe hypotension

  • Hepatitis and liver dysfunction

10. Drug Interactions

• Major Drug Interactions:

  • Lithium: Hydrochlorothiazide can increase lithium levels, leading to an increased risk of lithium toxicity.

  • ACE Inhibitors/Angiotensin Receptor Blockers (ARBs): When combined with these agents, there is an increased risk of hyperkalemia and renal dysfunction.

  • NSAIDs: Nonsteroidal anti-inflammatory drugs can reduce the diuretic and antihypertensive effects of hydrochlorothiazide.

  • Digoxin: Thiazide diuretics can increase the risk of digoxin toxicity, particularly if hypokalemia occurs.

• Food-Drug Interactions:

  • Salt Substitutes: These often contain potassium and may exacerbate hyperkalemia when used with hydrochlorothiazide, particularly if renal function is impaired.

11. Clinical Pharmacology

• Pharmacodynamics: Hydrochlorothiazide exerts its diuretic effect by inhibiting sodium and chloride reabsorption in the distal tubules of the kidney, leading to enhanced sodium and water excretion. This results in reduced blood volume and lower blood pressure.

• Additional Effects: By enhancing calcium reabsorption in the kidneys, hydrochlorothiazide may have a protective effect against the formation of calcium-based kidney stones.

12. Special Populations

• Pregnancy: Category B. Hydrochlorothiazide should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Lactation: Hydrochlorothiazide is excreted in breast milk, and its use in breastfeeding mothers should be avoided unless absolutely necessary.

• Geriatrics: Older patients are at increased risk for electrolyte disturbances, hypotension, and renal impairment, and should be monitored closely during treatment.

• Renal Impairment: Use with caution in patients with impaired renal function (CrCl <30 mL/min) as it can exacerbate renal insufficiency.

13. Therapeutic Uses

• Hypertension: Hydrochlorothiazide is a first-line treatment for mild to moderate hypertension, either alone or in combination with other antihypertensive agents.

• Edema: It is commonly used to treat edema associated with heart failure, liver cirrhosis, and kidney disease.

• Nephrolithiasis: Prevents recurrence of calcium-based kidney stones.

14. Monitoring and Follow-Up

• Lab Tests: Regular monitoring of electrolytes, renal function (serum creatinine, eGFR), and blood pressure is recommended.

• Symptoms to Monitor: Watch for symptoms of hypokalemia (muscle weakness), hypotension (dizziness, fainting), or hyperglycemia (increased thirst, urination).

15. Overdose Management

• Symptoms: Severe electrolyte imbalances, hypotension, dizziness, and dehydration.

• Treatment:

  • Supportive Care: Administration of fluids and electrolytes.

  • Hypotension: Administer IV fluids or vasopressors as necessary.

  • Electrolyte Replenishment: Correction of hypokalemia, hyponatremia, or hypomagnesemia.

16. Patient Counseling Information

• Key Points:

  • Take the medication exactly as prescribed, usually in the morning to avoid nocturnal urination.

  • Monitor blood pressure regularly.

  • Avoid excessive potassium intake from supplements or salt substitutes without consulting your doctor.

• Immediate Medical Attention: Seek medical attention if you experience dizziness, severe muscle cramps, confusion, or signs of dehydration (dry mouth, extreme thirst).