Acetazolamide

S01E - Antiglaucoma preparations and miotics ATC S01EC01 Small molecule approved 1953 Oral Parenteral Natural product Black-box warning

JFDA label: Acetazolamide 250 mg tab

⚠ Black-Box Warning

Mechanism of Action

Inhibitor of Carbonic anhydrase 1 — Carbonic anhydrase I inhibitor; Inhibitor of Carbonic anhydrase 2 — Carbonic anhydrase II inhibitor; Inhibitor of Carbonic anhydrase 12 — Carbonic anhydrase XII inhibitor; Inhibitor of Carbonic anhydrase 4 — Carbonic anhydrase IV inhibitor

Target	Action	Gene / class
Carbonic anhydrase 1 efficacy	INHIBITOR	CA1
Carbonic anhydrase 12 efficacy	INHIBITOR	CA12
Carbonic anhydrase 2 efficacy	INHIBITOR	CA2
Carbonic anhydrase 4 efficacy	INHIBITOR	CA4

Indications

Off-label

Familial periodic paralysis
Hydrocephalus, normal-pressure
Metabolic alkalosis
Prevention of cystine renal calculi (adjunctive therapy)
Respiratory stimulant in stable hypercapnic COPD

Contraindications

Source: Lexicomp

Hypersensitivity to acetazolamide, sulfonamides, or any component of the formulation Absolute
adrenocortical insufficiency Absolute
decreased sodium and/or potassium levels Absolute
hyperchloremic acidosis Absolute
long-term use in noncongestive angle-closure glaucoma Note: Although the FDA approved product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See “Warnings/Precautions” for more detail Absolute
marked hepatic disease or insufficiency Absolute
severe renal disease or dysfunction Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Not Known Flushing

Nervous system disorders (12)

Not Known Ataxia · confusion · convulsions · depression · dizziness · drowsiness · excitement · fatigue · flaccid paralysis · headache · malaise · paresthesia

Hepatobiliary disorders (4)

Not Known Abnormal hepatic function tests · cholestatic jaundice · fulminant hepatic necrosis · hepatic insufficiency

Renal and urinary disorders (4)

Not Known Crystalluria · hematuria · Polyuria · renal failure

Blood and lymphatic system disorders (5)

Not Known Agranulocytosis · aplastic anemia · leukopenia · thrombocytopenia · thrombocytopenic purpura

Immune system disorders (1)

Not Known Anaphylaxis

Metabolism and nutrition disorders (7)

Not Known Electrolyte imbalance · growth retardation (children) · hyperglycemia · hypoglycemia · hypokalemia · hyponatremia · metabolic acidosis

Gastrointestinal disorders (7)

Not Known Decreased appetite · diarrhea · dysgeusia · glycosuria · melena · nausea · vomiting

Skin and subcutaneous tissue disorders (5)

Not Known Allergic skin reaction · skin photosensitivity · Stevens-Johnson syndrome · toxic epidermal necrolysis · urticaria

Eye disorders (1)

Not Known Myopia

Ear and labyrinth disorders (2)

Not Known Auditory disturbance · tinnitus

General disorders and administration site conditions (2)

Not Known Fever · Pain at injection site

Dosing

Source: Lexicomp

Note: IM administration is not recommended because of pain secondary to the alkaline pH. Altitude illness: Oral: Manufacturer's labeling: 500 to 1,000 mg/day in divided doses every 8 to 12 hours (immediate release tablets) or divided every 12 to 24 hours (extended release capsules). These doses are associated with more frequent and/or increased side effects. Alternative dosing has been recommended: Prevention: 125 mg twice daily; beginning either the day before (preferred) or on the day of ascent; may be discontinued after staying at the same elevation for 2 to 3 days or if descent initiated (Basnyat 2006; Luks 2010). Note: In situations of rapid ascent (such as rescue or military operations), 1,000 mg/day is recommended by the manufacturer. The Wilderness Medical Society recommends consideration of using dexamethasone in addition to acetazolamide in these situations (Luks 2010). Treatment: 250 mg twice daily. Note: With high altitude cerebral edema, dexamethasone is the primary treatment; however, acetazolamide may be used adjunctively with the same treatment dose (Luks 2010). Edema: Oral, IV: 250 to 375 mg once daily Epilepsy: Oral: 8 to 30 mg/kg/day in divided doses. A lower dosing range of 4 to 16 mg/kg/day in 1 to 4 divided doses has also been recommended; maximum dose: 30 mg/kg/day or 1 g/day (Oles 1989; Reiss 1996). Note: Minimal additional benefit with doses >16 mg/kg/day. Extended release capsule is not recommended for treatment of epilepsy. Familial periodic paralysis (off-label use): Oral: 125 mg 3 times daily (Links 1988) or 250 mg once daily (Venance 2004) or 250 mg every 6 hours (Hoskins 1974). Additional data may be necessary to further define the role of acetazolamide in the treatment of this condition. Glaucoma: Oral, IV: Chronic simple (open-angle): 250 mg 1 to 4 times/day or 500 mg extended release capsule twice daily Secondary or acute (closed-angle): Initial: 250 to 500 mg; maintenance: 125 to 250 mg every 4 hours (250 mg every 12 hours has been effective in short-term treatment of some patients). Hydrocephalous, normal pressure (off-label use): Oral: Initial: 125 mg/day; may increase dose up to 375 mg/day (Alperin 2014). Metabolic alkalosis (off-label use): IV: 500 mg as a single dose; reassess need based upon acid-base status (Marik 1991; Mazur 1999) Prevention of cystine renal calculi (adjunctive therapy) (off-label use): Oral: 500 mg daily at bedtime in combination with potassium citrate and captopril (Sterrett 2008) Respiratory stimulant in stable hypercapnic COPD (off-label use): Oral: 250 mg twice daily (Wagenaar 2003)

(For additional information see "Acetazolamide: Pediatric drug information") Note: IM administration is not recommended because of pain secondary to the alkaline pH. Edema: Limited data available: Infants, Children, and Adolescents: Oral (immediate release), IV: 5 mg/kg/dose every other day in the morning (Pagliaro 2002). Epilepsy: Oral: Refer to adult dosing. Altitude illness: Oral: Prevention: 2.5 mg/kg/dose every 12 hours started either the day before (preferred) or on the day of ascent and may be discontinued after staying at the same elevation for 2-3 days or if descent initiated; maximum dose: 125 mg/dose (Luks 2010). Note: The International Society for Mountain Medicine does not recommend prophylaxis in children except in the rare circumstance of unavoidable rapid ascent or in children with known previous susceptibility to acute mountain sickness (Pollard 2001). Treatment: 2.5 mg/kg/dose every 8-12 hours; maximum dose: 250 mg/dose. Note: With high altitude cerebral edema, dexamethasone is the primary treatment; however, acetazolamide may be used adjunctively with the same treatment dose (Luks 2010; Pollard 2001).

Refer to adult dosing. Oral: Initial doses should begin at the low end of the dosage range.

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling. Severe impairment: Use is contraindicated. Hemodialysis: Dialyzable. Avoid use unless dose is reduced and serum concentrations can be monitored; monitor patients closely for CNS toxicity (Schwenk 1995). Peritoneal dialysis: Supplemental dose is not necessary (Schwenk 1994).

Use is contraindicated in patients with cirrhosis or marked liver disease or dysfunction.

Warnings & Precautions

Source: Lexicomp

CNS effects

Impairment of mental alertness and/or physical coordination may occur.

Sulfonamide (“sulfa”) allergy

The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes. Disease-related concerns:

Diabetes

Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control.

Hepatic impairment

Use with caution in patients with hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.

Respiratory acidosis

Use with caution in patients with respiratory acidosis; may worsen acidosis. Concurrent drug therapy issues:

Aspirin (high dose)

Use with caution or avoid in patients taking high-dose aspirin concurrently; may lead to severe adverse effects including tachypnea, anorexia, lethargy, coma, and death. Special populations:

Elderly

Use with caution in the elderly; may be more sensitive to side effects. Other warnings/precautions:

Appropriate use

Increasing the dose does not increase diuresis and may increase the incidence of drowsiness and/or paresthesia; often results in a reduction of diuresis.

IM administration

Painful because of the alkaline pH of the drug; use by this route is not recommended.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have been observed in animal reproduction studies. Limited data is available following the use of acetazolamide in pregnant women for the treatment of idiopathic intracranial hypertension (Falardeau 2013; Kesler 2013). Pregnant women exposed to acetazolamide during pregnancy for the treatment of seizure disorders are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at aedpregnancyregistry.org

Lactation

Acetazolamide is excreted into breast milk. In a case report, low concentrations of acetazolamide were detected in the breast milk and the infant serum following a maternal dose of acetazolamide 500 mg twice daily. Acetazolamide concentrations in the breast milk were 1.3 to 2.1 mcg/mL, 1 to 9 hours after the dose. Acetazolamide concentrations in the infant serum were 0.2 to 0.6 mcg/mL, 2 to 12 hours after nursing. Maternal plasma concentrations were 5.2 to 6.4 mcg/mL, 1 to 7 hours after the dose

Monitoring

Clinical pearl	Intraocular pressure; serum electrolytes, periodic CBC with differential; monitor growth in pediatric patients

Chemistry & Properties

Formula	C4H6N4O3S2
Molecular weight	222.25 g/mol
IUPAC name	N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
CAS	59-66-5
PubChem CID	1986
InChIKey	`BZKPWHYZMXOIDC-UHFFFAOYSA-N`
logP	-0.86 (XLogP -0.3)
Polar surface area	115.04 Å²
H-bond acceptors / donors	6 / 2
Drug-likeness (QED)	0.63
Lipinski violations	0

SMILES

CC(=O)Nc1nnc(S(N)(=O)=O)s1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB -0.52)

Enzyme interactions

Enzyme	Role	Detail
CYP3A4	Substrate	—

Receptor binding (top 6)

Target	Action	Affinity
carbonic anhydrase 7 (CA7)	Inhibitor	pKi 8.6
carbonic anhydrase 12 (CA12)	Inhibitor	pKi 8.2
Carbonic Anhydrase Isozymes, CA II	Binding	pKi 7.9
Carbonic Anhydrase Isozymes, CA IX	Binding	pKi 7.6
Carbonic Anhydrase Isozymes, CA I	Binding	pKi 6.6
carbonic anhydrase 1 (CA1)	Inhibitor	pKi 6.6

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OAT1 (Inhibitor)OAT2 (Inhibitor)OAT3 (Inhibitor)OAT4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)OAT (Substrate)OAT2 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acetylsalicylic acid	major
Aminolevulinic acid	major
Arsenic trioxide	major
Cisapride	major
Metformin	major
Salicylic acid (sodium)	major
Acarbose	moderate
Acetohexamide	moderate
Albiglutide	moderate
Aldesleukin	moderate
Alogliptin	moderate
Aminolevulinic acid (topical)	moderate
Amphotericin B	moderate
Amphotericin B (cholesteryl sulfate)	moderate
Amphotericin B (lipid complex)	moderate
Amphotericin B (liposomal)	moderate
Beclomethasone dipropionate	moderate
Betamethasone	moderate
Bisacodyl	moderate
Canagliflozin	moderate
Castor oil	moderate
Chloroquine	moderate
Chlorpropamide	moderate
Corticotropin	moderate
Cyclosporine	moderate
Dapagliflozin	moderate
Deflazacort	moderate
Dexamethasone	moderate
Diatrizoate	moderate
Dulaglutide	moderate
Empagliflozin	moderate
Epoprostenol	moderate
Ertugliflozin	moderate
Exenatide	moderate
Fludrocortisone	moderate
Formoterol	moderate
Glimepiride	moderate
Glipizide	moderate
Glyburide	moderate
Glycerin	moderate

Showing 40 of 100+.

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Acetazolamide	Tablet 250 mg	30 tab	JAWEDA INT. DRUD STORE	4.190