Acetazolamide

Acetazolamide is a well-established carbonic anhydrase inhibitor with an extensive range of clinical applications. It plays a vital role in modern medicine, not only for common conditions like glaucoma and epilepsy but also for niche uses such as managing altitude sickness and idiopathic intracranial hypertension. With the constant evolution of clinical guidelines and practices, a deep understanding of how Acetazolamide functions, its therapeutic applications, dosing strategies, safety profile, and drug interactions is increasingly important for healthcare professionals.

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Brief Description

Acetazolamide, a sulphonamide derivative, exerts its primary pharmacological effect by inhibiting the enzyme carbonic anhydrase. This enzyme is present in various tissues, including the renal tubules, the eye, and the central nervous system. Carbonic anhydrase is responsible for catalysing the conversion of carbon dioxide and water into carbonic acid, which dissociates into hydrogen and bicarbonate ions. Inhibition of this enzyme by Acetazolamide leads to decreased bicarbonate reabsorption, promoting diuresis and altering systemic acid-base balance. This effect proves beneficial across a wide spectrum of medical conditions. Its availability in oral and intravenous formulations makes it suitable for both outpatient therapy and emergency interventions.

Uses of Acetazolamide

Acetazolamide’s versatility stems from its ability to influence various physiological systems:

• Glaucoma: Acetazolamide is highly effective in reducing intraocular pressure, particularly in open-angle and secondary glaucoma, by decreasing aqueous humour production.

• Altitude sickness: It is widely used for the prevention and treatment of acute mountain sickness (AMS), helping the body adapt to high altitudes by inducing mild acidosis, which stimulates ventilation.

• Epilepsy: As an adjunctive treatment, Acetazolamide is useful in managing refractory or difficult-to-control seizures, especially absence seizures.

• Congestive heart failure: It is occasionally used as a mild diuretic in patients who cannot tolerate other diuretics or who require pH modulation.

• Periodic paralysis: Especially in cases of hypokalaemic periodic paralysis, Acetazolamide reduces the frequency and severity of paralytic episodes.

• Drug-induced oedema: It may be used to counteract fluid retention caused by certain medications such as corticosteroids or oestrogens.

• Idiopathic intracranial hypertension (IIH): A key indication where Acetazolamide helps reduce cerebrospinal fluid (CSF) production, alleviating symptoms like headaches and visual disturbances.

Dosage and Administration

Dosing varies according to the condition being treated, age of the patient, renal and hepatic function, and other individual factors:

• Glaucoma: Typical dosage ranges from 250 mg to 1000 mg daily, divided into two to four doses.

• Altitude sickness: Usually 250 mg twice daily, starting 1–2 days prior to ascent and continuing for 2–3 days at altitude.

• Epilepsy: Can be used in doses up to 1000 mg per day, usually in divided doses.

• Idiopathic intracranial hypertension: Initial dose is often 500 mg to 1 g/day; titrated based on response and tolerability.

• IV administration: In emergencies or when oral intake is not possible, 500 mg to 1 g/day intravenously in divided doses may be given.

It is critical to individualise dosage and monitor patients closely to avoid adverse effects.

Dose Adjustment in Specific Conditions

Renal Impairment:

• Contraindicated in patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m²) due to the risk of drug accumulation and metabolic acidosis.

• In mild to moderate impairment, dose reductions may be necessary, with careful electrolyte and acid-base monitoring.

Hepatic Impairment:

• Should be avoided in severe hepatic disease as it may precipitate hepatic encephalopathy.

• In moderate impairment, caution is required due to the drug’s potential to disrupt ammonia metabolism and worsen neurological status.

Pregnancy:

• Classified as Pregnancy Category C. Acetazolamide crosses the placenta and can be detected in foetal tissues. Although animal studies show adverse effects, there is limited human data. Use only when potential benefits justify potential risk to the foetus.

Lactation:

• Small amounts are excreted in breast milk. Caution advised, especially for neonates and preterm infants.

Effects and Side Effects

Common side effects:

• Tingling or numbness in extremities (paresthesia)

• Increased frequency of urination (polyuria)

• Gastrointestinal upset including nausea, diarrhoea

• Taste alterations, especially metallic taste

• Drowsiness or fatigue

Less common but significant adverse effects:

• Kidney stone formation due to changes in urinary pH

• Electrolyte imbalances, particularly hypokalaemia and hyponatraemia

• Metabolic acidosis from bicarbonate loss

Serious adverse effects:

• Aplastic anaemia and other blood dyscrasias

• Stevens-Johnson syndrome and toxic epidermal necrolysis

• Hepatic encephalopathy in susceptible individuals

Regular monitoring of renal function, electrolytes, and full blood count is recommended for long-term users.

How Acetazolamide Works

Acetazolamide's main mechanism is the inhibition of carbonic anhydrase, resulting in decreased formation of hydrogen and bicarbonate ions. In the renal tubules, this leads to increased excretion of bicarbonate, sodium, potassium, and water, thus producing a diuretic effect. In the eye, it reduces aqueous humour secretion, which lowers intraocular pressure. Additionally, Acetazolamide induces mild systemic acidosis, which can stimulate ventilation and help with high-altitude adaptation. It also exhibits anticonvulsant properties by altering neuronal excitability and modulating synaptic transmission.

Drug Combinations and Infusion Considerations

Acetazolamide may be combined with other medications to enhance therapeutic efficacy:

• With loop diuretics: For synergistic diuresis in refractory fluid retention.

• With antiepileptic drugs: May enhance seizure control in refractory epilepsy when used adjunctively.

Infusion guidelines:

• Reconstitute 500 mg vial with 10–20 mL sterile water for injection.

• Administer via slow IV injection to avoid local irritation or thrombophlebitis.

• Monitor vital signs, acid-base status, and renal and hepatic function during prolonged IV use.

Presentation and Dosage Forms

Form	Strength	Route
Tablet	250 mg	Oral
Extended-release cap.	500 mg	Oral
Injection	500 mg vial	Intravenous
Oral suspension	Compounded	Oral

Extended-release capsules offer the advantage of twice-daily dosing, enhancing compliance.

Pharmacokinetics and Pharmacodynamics

• Absorption: Nearly complete after oral administration; onset of action within 1–2 hours

• Distribution: Widely distributed; crosses the placental barrier and is present in breast milk

• Metabolism: Minimal liver metabolism; largely remains unchanged

• Excretion: Primarily via kidneys through tubular secretion

• Half-life: Ranges between 10 and 15 hours, enabling twice-daily dosing

Although Acetazolamide does not possess direct antibacterial properties, its urinary pH modulation can influence the efficacy of urinary tract antimicrobials and change the spectrum of bacterial flora in the genitourinary tract.

Drug Interactions

• Salicylates (e.g., aspirin): May exacerbate acidosis

• Lithium: Decreased lithium reabsorption may reduce efficacy

• Cyclosporine: Enhanced risk of nephrotoxicity

• Phenytoin and barbiturates: Additive CNS depressant effects

• Corticosteroids and diuretics: Enhanced risk of hypokalaemia when used concurrently

Regular drug reconciliation is necessary, especially in patients on polypharmacy.

Comparison with Similar Drugs

Drug	Mechanism	Primary Use	Major Concerns
Acetazolamide	Carbonic anhydrase inhibitor	Glaucoma, AMS, IIH, epilepsy	Acidosis, electrolyte imbalance
Furosemide	Loop diuretic	Oedema, hypertension	Hypokalaemia, volume depletion
Hydrochlorothiazide	Thiazide diuretic	Hypertension, oedema	Hyperglycaemia, hyperuricaemia
Mannitol	Osmotic diuretic	Cerebral oedema, AKI	Electrolyte shifts, dehydration
Brinzolamide	Topical carbonic anhydrase inhibitor	Glaucoma	Ocular irritation, allergy

Precautions and Special Considerations

• Regular monitoring of serum electrolytes, renal function, and acid-base status is essential.

• Use cautiously in the elderly, paediatric patients, and those with respiratory or liver impairment.

• Contraindicated in sulphonamide hypersensitivity.

• Ensure patients maintain adequate hydration to minimise the risk of kidney stone formation.

• Educate patients on recognising signs of electrolyte disturbances such as muscle cramps, confusion, and fatigue.

Toxicity and Overdose

Symptoms:

• Confusion, lethargy, dizziness

• Hyperventilation or respiratory depression

• Severe metabolic acidosis

• Seizures and cardiac arrhythmias

Management:

• Immediate discontinuation

• Supportive therapy with IV fluids and electrolyte replacement

• Activated charcoal (if recent ingestion)

• Haemodialysis in severe or unresponsive cases

Recent Updates and Guidelines

• The BNF 2025 recommends baseline and periodic kidney function tests for all long-term Acetazolamide users.

• NICE 2025 guidelines for AMS now prefer lower prophylactic doses (125 mg BD) to reduce adverse effects while maintaining efficacy.

• New studies suggest greater benefit of Acetazolamide in early-stage idiopathic intracranial hypertension compared to placebo.

• Ongoing trials are evaluating Acetazolamide’s potential benefits in certain neurodegenerative disorders due to its impact on neuronal excitability.

Facts to Remember

• Acetazolamide is not typically a first-line diuretic but is invaluable in specialised conditions.

• Alters acid-base balance and urinary pH.

• May cause unusual side effects like metallic taste and finger tingling.

• Must be used with ongoing lab monitoring.

• Available in both oral and IV forms, suitable for diverse clinical settings.

Did You Know?

Acetazolamide was introduced in the 1950s and remains one of the few pharmacological options available for managing idiopathic intracranial hypertension and hypokalaemic periodic paralysis. Its role in space medicine has also been explored, as it may help astronauts manage fluid shifts and intracranial pressure during long-duration missions.

References

1. British National Formulary (BNF), 2025 edition

2. NICE Guidelines for Glaucoma and Altitude Sickness, 2025

3. Martindale: The Complete Drug Reference, Pharmaceutical Press

4. WHO Model List of Essential Medicines, 2024 update

5. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th Edition

6. British Medical Journal (BMJ), Clinical Review, February 2025

7. Journal of Neuro-Ophthalmology, April 2025 Edition