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CARBONIC ANHYDRASE INHIBITORS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Available Forms Sources

    A) FORMS
    1) ACETAZOLAMIDE is available as: 125 and 250 mg tablets; 500 mg sustained- release capsules; 500 mg/vial for injection (Prod Info Acetazolamide extended-release oral capsules, 2008; Prod Info acetazolamide IV injection, 2008; Prod Info acetazolamide oral tablets, 2005).
    2) BRINZOLAMIDE is available as: 1% ophthalmic suspension containing 10 mg/mL brinzolamide (Prod Info AZOPT(R) ophthalmic suspension, 2010).
    3) BRINZOLAMIDE/TIMOLOL: Available as a combination product containing 10 mg/mL brinzolamide and 5 mg/mL timolol (as timolol acetate) (Prod Info AZARGA ophthalmic suspension, 2012).
    4) DICHLORPHENAMIDE is available as: 50 mg tablets (Prod Info Daranide(R), dichlorphenamide, 1996).
    5) DORZOLAMIDE is available as: 2% ophthalmic solution (containing 20 mg/mL dorzolamide) and in a combination product containing 20 mg/mL brinzolamide and 5 mg/mL timolol (Prod Info COSOPT(R) PF ophthalmic solution, 2012; Prod Info TRUSOPT(R) topical ophthalmic solution, 2009) .
    6) METHAZOLAMIDE is available as: 25 and 50 mg tablets (Prod Info NEPTAZANE(TM) oral tablets, 2010).
    B) USES
    1) AcetaZOLAMIDE is indicated for adjunctive treatment of open-angle glaucoma, secondary glaucoma, and preoperatively in acute closed-angle glaucoma where delay of surgery is indicated in order to lower intraocular pressure (Prod Info acetazolamide IV injection, 2008). It is also indicated for adjunctive treatment of drug-induced edema (Prod Info acetazolamide IV injection, 2008).
    2) Dichlorphenamide is primarily used for the treatment of glaucoma (Prod Info Daranide(R), dichlorphenamide, 1996).
    3) Methazolamide is indicated for the treatment of ocular conditions when lowering intraocular pressure is likely to be of benefit, such as chronic open-angle glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma when lowering intraocular pressure is desired before surgery (Prod Info NEPTAZANE(TM) oral tablets, 2010).
    4) Brinzolamide and dorzolamide are topical ophthalmic agents that are indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma (Prod Info AZOPT(R) ophthalmic suspension, 2010; Prod Info TRUSOPT(R) topical ophthalmic solution, 2009).
    5) BRINZOLAMIDE/TIMOLOL COMBINATION PRODUCT: Brinzolamide/timolol combination therapy is used for treatment of open-angle glaucoma or ocular hypertension in adults who did not sufficiently respond to monotherapy (Prod Info AZARGA ophthalmic suspension, 2012).
    6) Sulthiame, a carbonic anhydrase inhibitor, which is not currently available in the US, has been used as an antiepileptic in most forms of epilepsy. Initial doses of 100 mg twice daily or 50 mg three times daily up to 200 mg three times daily have been used (Sweetman, 2004).

Therapeutic Toxic Class

    A) Carbonic anhydrase inhibitors are non-bacteriostatic sulfonamides that inhibit carbonic anhydrase, thereby reducing the rate of aqueous humor formation in the eye and resulting in decreased intraocular pressure.

Specific Substances

    A) ACETAZOLAMIDE
    1) Acetazolam
    2) Acetazolamidum
    3) 5-Acetamido-1,3,4-thiadiazole-2-sulphonamide
    4) N-(5-Sulphamoyl-1,3,4-thiadiazol-2-yl) acetamide
    5) Molecular Formula: C4-H6-N4-O3-S2
    6) CAS 59-66-5
    BRINZOLAMIDE
    1) AL 4862
    DICHLORPHENAMIDE
    1) Diclofenamide
    2) Diclofenamidum
    3) 4,5-Dichlorobenzene-1,3-disulphonamide
    4) Molecular Formula: C6-H6-Cl2-N2-O4-S
    5) CAS 120-97-8
    DORZOLAMIDE
    1) L-671152
    2) MK-507
    3) (4S,6S)-4-(Ethylamino)-5,6-dihydro-6-methyl-4H-
    4) thieno[2,3-b] thiopyran-2-sulphonamide
    5) 7,7-dioxide
    6) Molecular Formula: C10-H16-N2-O4-S
    7) CAS 120279-96-1
    ETHOXZOLAMIDE
    1) Diuretic C
    2) Ethoxazolamide
    3) Ethoxyzolamide
    4) Etoxzolamide
    5) 2-Benzothiazolesulfonamide, 6-ethoxy
    6) Molecular Formula: C9-H10-N2-O3-S2
    7) CAS 452-35-7
    METHAZOLAMIDE
    1) N-(4-Methyl-2-sulphamoyl-delta(squared)-1,3,
    2) 4-thiadiazolin-5-ylidene)acetamide
    3) Molecular Formula: C5-H8-N4-O3-S2
    4) CAS 554-57-4
    SULTHIAME
    1) 4-(tetrahydro-2H-1,2-thiazin-2-yl) benzenesulphonamide S,S-dioxide
    2) Sultiame
    3) Riker-594
    4) Molecular Formula: C(10)H(14)N(2)O(4)S(2)
    5) CAS 61-56-3

    1.2.1) MOLECULAR FORMULA
    1) ACETAZOLAMIDE: C4H6N4O3S2
    2) BRINZOLAMIDE: C12H21N3O5S3
    3) DICHLORPHENAMIDE: C6H6Cl2N2O4S2
    4) DORZOLAMIDE HYDROCHLORIDE: C10H16N2O4S3.HCl
    5) METHAZOLAMIDE: C5H8N4O3S2

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Carbonic anhydrase inhibitors (CAI) are used in the treatment of glaucoma, congestive heart failure, hydrocephalus, acute mountain sickness, and seizure disorder. Agents include acetaZOLAMIDE, brinzolamide, dorzolamide, and methazolamide.
    B) PHARMACOLOGY: These agents inhibit carbonic anhydrase, an enzyme found in red blood cells and other tissues, that catalyzes the hydration of carbon dioxide and the dehydration of carbonic acid. These agents work in various ways on different organ systems
    C) . In the eye, CAI decreases the formation of bicarbonate ions, resulting in reduced sodium and fluid transport. This decrease in aqueous humor secretion reduces intraocular pressure. In the brain, CAI may decrease excessive discharge, thus raising the seizure threshold. Inhibition of carbonic anhydrase in the kidney results in bicarbonate loss, that also carries sodium, water and potassium along with it. This causes urinary alkalinization and diuresis.
    D) TOXICOLOGY: CAI causes diuresis and bicarbonate loss and can result in electrolyte, metabolic, and renal disturbances.
    E) EPIDEMIOLOGY: CAI are an uncommon poisoning that rarely result in serious toxicity.
    F) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The most common adverse effects include: paresthesias, renal calculi, metabolic acidosis, bone marrow depression, and rashes. Other more rare adverse effects include: taste disturbances, ataxia, gastritis, cholestatic hepatitis, and renal failure. Some CAI agents like acetaZOLAMIDE are basic and may be implicated in extravasation injury.
    G) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Confusion, metabolic acidosis, tachycardia, tachypnea electrolyte abnormalities (hyperkalemia and hyperchloremia) can develop.
    2) SEVERE TOXICITY: Lethargy and severe metabolic acidosis can occur.
    0.2.20) REPRODUCTIVE
    A) Carbonic anhydrase inhibitors have been classified as FDA pregnancy category C. Neoplasms and metabolic acidosis with electrolyte imbalances have been reported in infants following maternal ingestion of acetaZOLAMIDE during pregnancy. Animal studies of carbonic anhydrase inhibitors have shown congenital anomalies, including skeletal and limb defects. With dorzolamide exposure, malformations were observed at doses that caused metabolic acidosis with decreased maternal body weight gain and fetal weights. AcetaZOLAMIDE has been shown to be excreted in human milk; brinzolamide and dorzolamide have been shown to be excreted in the milk of lactating rats.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of acetaZOLAMIDE, brinzolamide, dichlorphenamide, or dorzolamide in humans.

Laboratory Monitoring

    A) Monitor serum electrolytes and renal function.
    B) Monitor liver enzymes and bilirubin, venous or arterial blood gas and urinalysis in symptomatic patients.
    C) Drug concentrations are usually not helpful in the acute setting or widely available.
    D) Consider checking acetaminophen and salicylate concentrations, if there is any uncertainty regarding the drug ingested.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Symptomatic and supportive care are usually sufficient for the treatment of mild to moderate toxicity.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is primarily symptomatic and supportive with careful attention to the airway if the patient becomes obtunded. Follow electrolytes closely and replace as these may become altered. Treat severe metabolic acidosis (pH greater than 7.1) with sodium bicarbonate (1 mEq/kg in adults and children). This may be repeated as needed at one-half the original dose every 10 minutes. Monitor ABGs closely and titrate sodium bicarbonate meticulously.
    C) DERMAL EXPOSURE
    1) Treat extravasation injury with warm compresses and elevation. Treat Stevens-Johns Syndrome with aggressive hydration and supportive care in an ICU setting.
    D) AIRWAY MANAGEMENT
    1) Administer 100% oxygen as needed for respiratory support. Intubate and provide assisted ventilation as necessary, rarely indicated.
    E) ANTIDOTE
    1) None.
    F) DECONTAMINATION
    1) PREHOSPITAL: Generally, decontamination is not indicated in the prehospital setting.
    2) HOSPITAL: Overdose is unlikely to cause severe intoxication, so activated charcoal is unnecessary. It can be used for massive ingestions or a coingestant of concern as long as the patient can tolerate charcoal.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis may be effective for the treatment of severe acetaZOLAMIDE overdose especially in the setting of renal failure, and can be used to correct severe acid base and electrolyte abnormalities, however there is no experience with the use of hemodialysis for CAI overdose and it would rarely be indicated.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients may be observed at home for small unintentional ingestions and mild symptoms, but should be evaluated for any concerning symptoms.
    2) OBSERVATION CRITERIA: Any patient who manifests signs of mild toxicity (ie, confusion, tachycardia, or tachypnea) or a large or deliberate overdose should be sent to a healthcare facility for observation. If symptoms resolve in the emergency department and the home social situation permits, the patient may be discharged after psychiatric clearance.
    3) ADMISSION CRITERIA: Patients who present with severe symptoms (ie, lethargy, severe metabolic acidosis, bone marrow depression, cholestatic hepatitis, renal failure or Stevens-Johnson Syndrome) should be admitted. In addition, if the above mild findings persist despite treatment in the emergency department, admit the patient to the appropriate level of care.
    4) CONSULT CRITERIA: Consult a medical toxicologist as needed, especially for patients admitted to the ICU.
    I) PITFALLS
    1) Failure to recognize that CAIs are sulfonamide derivatives and patients are at risk for hypersensitivity reactions if they have a prior sulfa allergy.
    J) PHARMACOKINETICS
    1) ACETAZOLAMIDE: Rapidly absorbed; onset: 60 to 90 minutes; duration: 8 to 12 hours; 70% to 90% protein bound, widely distributed, half-life 3 to 6 hours and renal elimination. BRINZOLAMIDE: Systemic absorption following topical application; 60% protein bound; widely distributed; eliminated in the urine as unchanged drug. DICHLORPHENAMIDE: Rapidly absorbed; onset: within 1 hour; duration 6 to 12 hours. METHAZOLAMIDE: More slowly absorbed; onset: 2 to 4 hours; duration: 10 to 18 hours; low protein binding; half-life 14 hours; and 15% renal elimination.
    K) TOXICOKINETICS
    1) Concomitant administration of cyclosporine and acetaZOLAMIDE can increase cyclosporine serum levels. Coadministration of salicylates and acetaZOLAMIDE may cause an increase in serum acetaZOLAMIDE levels secondary to displacement at protein binding sites by the salicylates.
    L) PREDISPOSING CONDITIONS
    1) Chronic kidney disease and advanced age predisposes patients to toxicity.
    M) DIFFERENTIAL DIAGNOSIS
    1) NSAID or COX-2 ingestions, ethylene glycol toxicity, or salicylate ingestions.

Range Of Toxicity

    A) TOXICITY: The acute toxic dose is not known. Toxicity appears variable; toxicity has occurred at levels ranging from 26 to 77 mcg/mL. A 12 month-old became ill after ingesting between 2 to 5 250-mg tablets of acetaZOLAMIDE. A 66-year-old woman died after developing renal failure, and bone marrow suppression after ingesting 50 mg daily for 11 days. A 54-year-old man died with cholestatic jaundice after ingesting 50 mg daily for 26 days.
    B) THERAPEUTIC DOSE: ADULT: ACETAZOLAMIDE: Dose ranges from 250 mg to 1 g daily, depending on the indication. BRINZOLAMIDE: Ophthalmic Solution: 1 drop in the affected eye 3 times daily. DORZOLAMIDE: Ophthalmic Solution: 1 drop in the affected eye 3 times daily. METHAZOLAMIDE: Dose ranges from 50 to 100 mg 2 or 3 times daily. PEDIATRIC: ACETAZOLAMIDE, BRINZOLAMIDE and METHAZOLAMIDE: The safety and efficacy in pediatric patients has not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Carbonic anhydrase inhibitors (CAI) are used in the treatment of glaucoma, congestive heart failure, hydrocephalus, acute mountain sickness, and seizure disorder. Agents include acetaZOLAMIDE, brinzolamide, dorzolamide, and methazolamide.
    B) PHARMACOLOGY: These agents inhibit carbonic anhydrase, an enzyme found in red blood cells and other tissues, that catalyzes the hydration of carbon dioxide and the dehydration of carbonic acid. These agents work in various ways on different organ systems
    C) . In the eye, CAI decreases the formation of bicarbonate ions, resulting in reduced sodium and fluid transport. This decrease in aqueous humor secretion reduces intraocular pressure. In the brain, CAI may decrease excessive discharge, thus raising the seizure threshold. Inhibition of carbonic anhydrase in the kidney results in bicarbonate loss, that also carries sodium, water and potassium along with it. This causes urinary alkalinization and diuresis.
    D) TOXICOLOGY: CAI causes diuresis and bicarbonate loss and can result in electrolyte, metabolic, and renal disturbances.
    E) EPIDEMIOLOGY: CAI are an uncommon poisoning that rarely result in serious toxicity.
    F) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The most common adverse effects include: paresthesias, renal calculi, metabolic acidosis, bone marrow depression, and rashes. Other more rare adverse effects include: taste disturbances, ataxia, gastritis, cholestatic hepatitis, and renal failure. Some CAI agents like acetaZOLAMIDE are basic and may be implicated in extravasation injury.
    G) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Confusion, metabolic acidosis, tachycardia, tachypnea electrolyte abnormalities (hyperkalemia and hyperchloremia) can develop.
    2) SEVERE TOXICITY: Lethargy and severe metabolic acidosis can occur.

Heent

    3.4.3) EYES
    A) ACETAZOLAMIDE: Choroidal detachment and effusion were reported in 3 patients following therapeutic topical administration of dorzolamide and oral administration of acetaZOLAMIDE. All 3 patients complained of decreased or blurred vision and 2 of the 3 patients also complained of pain in the affected eye. Symptoms resolved following discontinuation of the medications and treatment with atropine and steroids. Surgical intervention was required in 2 of the 3 patients (Fan et al, 1993; Fineman et al, 1996).
    B) BRINZOLAMIDE/TIMOLOL: During clinical trials, blurred vision, eye pain, and eye irritation were reported in up to 10% of patients receiving brinzolamide/timolol ophthalmic solution (Prod Info AZARGA ophthalmic suspension, 2012).
    3.4.6) THROAT
    A) DYSGEUSIA (altered taste sensation) of carbonated beverages was reported as a rare occurrence following acetaZOLAMIDE therapy. Taste disturbances gradually resolve within 3 days following discontinuation of acetaZOLAMIDE (Epstein et al, 1987; McMurdo et al, 1990; Miller & Miller, 1990; Martinez-Mir et al, 1997).
    1) Dysgeusia has also been frequently reported with the use of an ophthalmic brinzolamide/timolol combination product during clinical trials. It is believed that the dysgeusia is due to the passage of the eye drops in the nasopharynx via the nasolacrimal canal and is attributed to brinzolamide as the causative agent (Prod Info AZARGA ophthalmic suspension, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) CASE REPORT: Tachycardia (180 beats/minute) was reported in a 12-month-old who ingested 2 to 5 250-mg acetaZOLAMIDE tablets (Baer & Reith, 2001).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) CASE REPORT: A 60-year-old man with chronic bronchitis developed cyanosis, diaphoresis and tachypnea with diffuse expiratory and inspiratory wheezing 5 days after starting methazolamide therapy, 50 mg orally 3 times daily. An ECG showed sinus tachycardia, and arterial blood gases revealed a metabolic acidosis (pH of 7.2 and a bicarbonate level of 11 mEq/L). Methazolamide was discontinued and one hour later repeat blood gas studies showed the onset of carbon dioxide retention and combined respiratory and metabolic acidosis.
    a) The authors speculated that the metabolic acidosis induced by methazolamide precipitated respiratory failure in this patient with chronic obstructive pulmonary disease.
    b) The patient's respiratory distress was more easily controlled with intubation and resolution of the metabolic acidosis. The patient was extubated and eventually discharged 20 days after initiation of methazolamide therapy (Coudon & Block, 1976).
    B) HYPERVENTILATION
    1) Kussmaul respiration may develop in patients with metabolic acidosis of any etiology (Watson et al, 1985).
    2) Tachypnea was reported in a 12-month-old who developed mild metabolic acidosis after ingesting 2 to 5 250-mg acetaZOLAMIDE tablets (Baer & Reith, 2001).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) PARESTHESIA
    1) Paresthesias of the extremities, of the tongue, and at the mucocutaneous junction of the lips may be common occurrences following acetaZOLAMIDE therapy and will generally resolve upon discontinuation of the medication (Epstein et al, 1987; McMurdo et al, 1990; Miller & Miller, 1990; Pesin & Brandt, 1991).
    B) ATAXIA
    1) CASE REPORT: A 72-year-old woman presented with an unsteady gait 2 weeks after beginning dichlorphenamide therapy. The patient's ataxia resolved after discontinuing the medication (Ilyas, 1991).
    C) DELIRIUM
    1) Delirium and confusion is usually associated with the occurrence of metabolic acidosis following chronic administration of carbonic anhydrase inhibitors (Maisey & Brown, 1981; Rowe, 1977; Sporn et al, 1991; Wakabayashi, 1991), but delirium was also reported in the absence of a metabolic imbalance in a patient receiving methazolamide therapy (Cyr et al, 1997). The confusional states resolved following discontinuation of the medications.
    D) LETHARGY
    1) CASE REPORT: Lethargy was reported in a 12-month-old who developed mild metabolic acidosis after ingesting 2 to 5 250-mg acetaZOLAMIDE tablets (Baer & Reith, 2001).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRIC HEMORRHAGE
    1) CASE REPORT: A 65-year-old man began acetaZOLAMIDE therapy to treat elevated intraocular pressure in the left eye and, three months later, presented with anorexia, breathlessness on exertion, abdominal pain, and a weight loss of 7.5 kg. Endoscopy showed severe erosive gastritis. Twenty-six days after discontinuing acetaZOLAMIDE, the patient was asymptomatic and had gained 2 kg in weight. A repeat endoscopy was normal (Herman et al, 1980).
    2) CASE REPORT: A 66-year-old woman with chronic renal failure presented with drowsiness and acute renal function deterioration eleven days after beginning acetaZOLAMIDE therapy, 500 mg daily. Laboratory studies showed leukocyturia, thrombocytopenia, severe anemia, and tarry stools. The patient's serum acetaZOLAMIDE level was 76.5 mcg/mL( normal 12 to 17 mcg/mL), indicating acetaZOLAMIDE intoxication. Gastroscopy revealed acute hemorrhagic gastritis. Despite aggressive therapy, the patient died of disseminated intravascular coagulation and septic shock due to bone marrow suppression 6 days after hospital admission (Takeda et al, 1997).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) CASE REPORT: A 69-year-old man developed a rash, diarrhea, itching, and jaundice three weeks after beginning methazolamide therapy, 50 mg daily, for treatment of glaucoma. Laboratory tests upon admission showed elevated hepatic enzyme levels. A liver needle biopsy revealed cholestasis with bile thrombi in dilated canaliculi and intracellular bile deposits. Jaundice resolved and hepatic enzyme levels returned to normal several weeks after discontinuing methazolamide (Krivoy et al, 1981).
    2) CASE REPORT: A 54-year-old man began acetaZOLAMIDE therapy, 500 mg daily for 26 days (total amount ingested was 13 grams), and subsequently presented to the hospital with confusion, dehydration, and peripheral circulatory failure. The patient had a generalized erythematous rash and was markedly jaundiced with extreme abdominal tenderness.
    a) Despite supportive therapy, the patient became anuric and died 24 hours after admission. An autopsy revealed hepatomegaly with intracellular and canalicular cholestasis and widespread patchy fatty infiltrations, indicative of cholestatic jaundice associated with acetaZOLAMIDE administration (Kristinsson, 1967).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) CASE REPORT: A 45-year-old man was given acetaZOLAMIDE, 250 mg twice daily, to treat ocular hypertension and, 2 days later, complained of lumbar pain, nausea and vomiting, and anuria and was admitted to the hospital the next day. Creatinine plasma level rose from 87 mcmol/L, prior to beginning acetaZOLAMIDE therapy, to 975 mcmol/L 3 days after hospital admission. A renal biopsy, performed 2 days after hospital admission, showed mild and focal tubular lesions, disrupted tubular basement membranes, cellular debris, and crystal formation in the tubular lumen. Normal renal function returned following increased diuresis, and the creatinine plasma level decreased to 110 mcmol/L 6 days after hospital admission (Rossert et al, 1989).
    a) Immunofluorescence studies with monoclonal anti-Tamm-Horsfall protein (THP) antibodies showed heavy THP deposits within the glomeruli which may be due to tubular obstruction by cellular debris and crystals.
    2) Higenbottam et al (1978) reported 2 cases of acute renal failure associated with the therapeutic administration of acetaZOLAMIDE. Both patients developed anuria which was preceded by back pain and hematuria. The renal failure resolved following diuresis by ureteric catheters in one patient and by needle nephrostomy in the other patient (Higenbottam et al, 1978).
    B) KIDNEY STONE
    1) Long-term administration of carbonic anhydrase inhibitors may cause the formation of renal calculi. The calculi will generally disappear following discontinuation of the medication although surgical removal of the calculi may be necessary (Ellis, 1973; Wallace et al, 1974; Bearn, 1989; Tawil et al, 1993; Parikh et al, 1995).
    C) IMPOTENCE
    1) Epstein et al, (1987) reported 4 cases of impotence associated with therapeutic administration of carbonic anhydrase inhibitors. The impotence generally disappeared within a week after discontinuing the medications and was not associated with a decrease in libido (Epstein et al, 1987).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Hyperchloremic metabolic acidosis has been associated with chronic administration of acetaZOLAMIDE, particularly in elderly patients and patients with renal failure or diabetes (Maisey & Brown, 1981; Heller et al, 1985; Watson et al, 1985; Sporn et al, 1991). The acidosis resolved following supportive care and discontinuation of acetaZOLAMIDE therapy.
    2) CASE REPORT: Metabolic acidosis and acute respiratory failure was reported in a 60-year-old man 4 days after beginning methazolamide therapy to treat an ophthalmologic problem. Arterial blood gases revealed a pH of 7.2 and a bicarbonate level of 11 mEq/L. One hour later, repeat arterial blood gas studies showed the onset of carbon dioxide retention and a combined respiratory and metabolic acidosis. Due to the patient's deteriorating clinical status, he was intubated. The acidosis gradually resolved and the patient was extubated 48 hours later (Coudon & Block, 1976).
    3) CASE REPORT: A case of hyperchloremic and hyperkalemic metabolic acidosis occurred in an 81-year-old man 5 to 7 days after beginning dichlorphenamide therapy for the treatment of glaucoma. The patient was also receiving topical timolol. The dichlorphenamide was discontinued and the acidosis resolved following administration of sodium bicarbonate. (Wakabayashi, 1991).
    4) CASE REPORT: A 12-month-old who developed mild metabolic acidosis (pH 7.22, pCO2 39, HCO3 15, base excess -11.4 mmol/L) after ingesting 2 to 5 250-milligram acetaZOLAMIDE tablets (Baer & Reith, 2001).
    5) INCIDENCE: In a series of 27 elderly patients (mean age 63.3 years) receiving acetaZOLAMIDE 250 to 1000 mg/day for glaucoma, 4 patients (14.8%) had mild acidosis (pH 7.20 to 7.31), 10 patients (37%) had moderate acidosis (pH 7.20 to 7.29) and one patient had severe acidosis (pH 7.15) (Heller et al, 1985).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) APLASTIC ANEMIA
    1) Aplastic anemia has been reported following chronic administration of carbonic anhydrase inhibitors (Rentiers et al, 1970; Gangitano et al, 1978; Werblin et al, 1980; Krivoy et al, 1981; Moroi-Fetters et al, 1990).
    2) CASE REPORT: A 66-year-old man received approximately 116 grams of acetaZOLAMIDE over a period of 4 months and was admitted to the hospital with dry, bleeding lips, tonsillitis, and ecchymosis of the extremities. Laboratory results showed leukopenia, thrombocytopenia and bone marrow which was markedly hypoplastic with no evidence of megakaryocytes, which led to a diagnosis of aplastic anemia. Despite aggressive care, the patient died 4 days after hospital admission (Lubeck, 1970).
    B) LEUKOPENIA
    1) Leukopenia (including neutropenia and agranulocytosis) and thrombocytopenia has been reported with long-term (greater than 2 weeks) therapy with methazolamide and acetaZOLAMIDE. The WBC counts and platelet counts gradually increased to baseline levels after discontinuation of the medications (Werblin et al, 1980; Cohen et al, 1989).
    2) CASE REPORT: An 86-year-old woman, maintained on clozapine for over a year with normal WBC counts, developed leukopenia with neutropenia within 2 weeks of beginning methazolamide therapy. Her WBC count was 5600 with 73% neutrophils prior to methazolamide therapy. Eight days after beginning methazolamide therapy, her WBC count was 2200 with 30% neutrophils. Her neutropenia and leukopenia resolved within 4 days and 14 days, respectively, after discontinuing the medications (Burke & Ranno, 1994).
    C) DISSEMINATED INTRAVASCULAR COAGULATION
    1) CASE REPORT: A 66-year-old man presented to the hospital with acute renal insufficiency. The patient had been taking acetaZOLAMIDE 500 mg daily for 11 days. Laboratory studies showed leukocyturia, thrombocytopenia, severe anemia, and tarry stools. Her serum acetaZOLAMIDE level was 76.5 mcg/mL indicating acetaZOLAMIDE intoxication. Despite intensive therapy with hemodialysis and direct hemoperfusion, the patient died 6 days after hospital admission. Death was due to disseminated intravascular coagulation and septic shock from severe bone marrow depression (Takeda et al, 1997).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) STEVENS-JOHNSON SYNDROME
    1) Stevens-Johnson Syndrome, involving the eyes, oral and nasal mucosa, trunk, and extremities, was reported in several patients following chronic acetaZOLAMIDE and methazolamide therapy. In the majority of patients, the lesions resolved with steroid treatment. Despite aggressive steroid treatment and discontinuation of methazolamide, the lesions progressively spread over the entire body in 4 patients. The lesions gradually resolved with continued steroid administration (Sud & Grewal, 1981; Flach et al, 1995; Shirato et al, 1997).
    2) A case of Stevens-Johnson Syndrome occurred in a 62-year-old woman within 48 hours after ingesting 50 mg methazolamide. The patient gradually recovered with permanent changes in skin pigmentation. (Cotter, 1998)
    B) PUSTULE
    1) AcetaZOLAMIDE administration has been associated with the appearance of pustules and maculopapular rashes in 2 patients. After discontinuing the medication, the rashes cleared. On rechallenge with acetaZOLAMIDE, the pustules and maculopapular eruptions reappeared in both patients (Ogoshi et al, 1992; Kuroda et al, 1995).
    C) SKIN ULCER
    1) CASE REPORT: A 55-year-old woman received intravenous acetaZOLAMIDE, 500 mg given over 2 minutes, and developed skin ulceration around the injection site 24 hours later. It was speculated that skin ulceration developed due to acetaZOLAMIDE's pH of 9.1 (Callear & Kirkby, 1994).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) GOUT
    1) CASE REPORT: Gouty arthritis of the right great toe was reported, in a 63- year-old man following acetaZOLAMIDE therapy, 250 mg four times daily. AcetaZOLAMIDE was discontinued and lab tests revealed hyperuricemia with a serum uric acid level of 8.7 mg/100 mL and a BUN level of 17 mg/100 mL. The gout resolved following colchicine and probenecid therapy (Ferry & Lichtig, 1969).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) CASE REPORT: A 66-year-old woman developed anaphylactic shock associated with laryngeal edema and respiratory distress syndrome after ingesting 1 tablet (250 mg) of acetaZOLAMIDE. Despite intensive care, the patient subsequently died (Peralta et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) Carbonic anhydrase inhibitors have been classified as FDA pregnancy category C. Neoplasms and metabolic acidosis with electrolyte imbalances have been reported in infants following maternal ingestion of acetaZOLAMIDE during pregnancy. Animal studies of carbonic anhydrase inhibitors have shown congenital anomalies, including skeletal and limb defects. With dorzolamide exposure, malformations were observed at doses that caused metabolic acidosis with decreased maternal body weight gain and fetal weights. AcetaZOLAMIDE has been shown to be excreted in human milk; brinzolamide and dorzolamide have been shown to be excreted in the milk of lactating rats.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) ACETAZOLAMIDE
    a) Possible teratogenicity in infants includes congenital glaucoma, microphthalmia, patent ductus, and sacrococcygeal teratoma (Reiss & Oles, 1996).
    B) NEOPLASM
    1) ACETAZOLAMIDE
    a) CASE REPORT: The development of a sacrococcygeal teratoma in an infant of 27 weeks' gestation was associated with the maternal ingestion of a 750-mg daily dose of acetaZOLAMIDE during the first 5 months of pregnancy. The infant died within minutes after birth (Worsham et al, 1978).
    C) METABOLIC DISORDER
    1) ACETAZOLAMIDE
    a) The development of metabolic acidosis, hypocalcemia, and hypomagnesemia in an infant of 36 weeks gestation was associated with the maternal ingestion of acetaZOLAMIDE, 250 mg twice daily, throughout her pregnancy. Four days after birth, the infant's metabolic acidosis spontaneously disappeared (Merlob et al, 1990).
    D) ANIMAL STUDIES
    1) ACETAZOLAMIDE
    a) In animal studies, teratogenic effects (defects to the limbs) have been observed when mice, rats, hamsters, and rabbits were given IV or oral acetaZOLAMIDE (Prod Info acetazolamide IV injection, 2008; Prod Info Acetazolamide extended-release oral capsules, 2008; Prod Info acetazolamide oral tablets, 2005a).
    2) BRINZOLAMIDE
    a) RATS: Doses of oral brinzolamide in rabbits of 20, 62, and 125 times the recommended human ophthalmic dose produced a significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at the lowest and highest doses (Prod Info AZOPT(R) ophthalmic suspension, 2008).
    3) DICHLORPHENAMIDE
    a) During animal studies, teratogenic effects, including fetal limb reduction defects, were reported in animals administered oral dichlorphenamide during organogenesis at doses 17 times the maximum recommended human dose (Prod Info KEVEYIS(TM) oral tablets, 2015).
    4) DORZOLAMIDE
    a) RABBITS: Malformations of the vertebral bodies were observed when rabbits were given oral dorzolamide at dose of 2.5 mg/kg/day or greater (31 times the recommended human ophthalmic dose). The malformations were evident at doses that caused metabolic acidosis with decreased maternal body weight gain and fetal weights. There were no malformations at a dose of 1 mg/kg/day (13 times the recommended human ophthalmic dose) (Prod Info TRUSOPT(R) sterile ophthalmic solution, 2009).
    5) METHAZOLAMIDE
    a) RATS: There was teratogenicity (skeletal anomalies) in the offspring of pregnant rats that were given methazolamide doses approximately 40 times the human dose (Prod Info methazolamide oral tablets, 2007).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturers have classified ACETAZOLAMIDE, BRINZOLAMIDE, BRINZOLAMDE/BRIMONIDINE, DICHLORPHENAMIDE, DORZOLAMIDE, and METHAZOLAMIDE as FDA pregnancy category C (Prod Info KEVEYIS(TM) oral tablets, 2015; Prod Info acetazolamide IV injection, 2008; Prod Info Acetazolamide extended-release oral capsules, 2008; Prod Info SIMBRINZA(TM) ophthalmic suspension, 2013; Prod Info acetazolamide oral tablets, 2005a; Prod Info AZOPT(R) ophthalmic suspension, 2008; Prod Info TRUSOPT(R) sterile ophthalmic solution, 2009; Prod Info methazolamide oral tablets, 2007).
    B) ANIMAL STUDIES
    1) BRINZOLAMIDE
    a) RATS: Doses of oral brinzolamide in rabbits of 20, 62, and 125 times the recommended human ophthalmic dose produced maternal toxicity at the highest dose. When radioactive brinzolamide was administered to pregnant rats, the radioactivity crossed the placenta and was found in the fetal tissues and blood (Prod Info AZOPT(R) ophthalmic suspension, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) ACETAZOLAMIDE
    a) Although no harmful effects have been reported (White & White, 1984), maternal doses of 500 mg twice daily and maternal blood levels of 5.2 to 6.4 mcg/mL resulted in acetaZOLAMIDE breast milk concentrations of 1.3 to 2.1 mcg/mL (Reynolds, 1994).
    b) CASE REPORT: Plasma concentrations of 0.2 to 0.6 mcg/mL (measured 2 to 12 hours after breastfeeding) have been detected in an infant whose mother was treated with acetaZOLAMIDE. The absolute dose to the infant is estimated to be an average of 0.26 mg/kg/day, with a maximum of 0.32 mg/kg/day (Soderman et al, 1984).
    2) DICHLORPHENAMIDE
    a) Exercise caution when administering to a lactating woman (Prod Info KEVEYIS(TM) oral tablets, 2015).
    B) ANIMAL STUDIES
    1) BRINZOLAMIDE
    a) RATS: Decreases in body weight gain in offspring when female rats were given an oral dose of 15 mg/kg/day (312 times the recommended ophthalmic dose) were observed during lactation. Following administration of labeled brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in blood and plasma (Prod Info AZOPT(R) ophthalmic suspension, 2008).
    2) DORZOLAMIDE
    a) RATS: Decreases in body weight gain of 5% to 7% in offspring were observed when lactating rats were given an oral dorzolamide dose of 7.5 mg/kg/day (94 times the recommended human ophthalmic dose). There was also a slight delay in postnatal development (incisor eruption, vaginal canalization and eye openings) at this dose (Prod Info TRUSOPT(R) sterile ophthalmic solution, 2009).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) ACETAZOLAMIDE
    a) RATS: There was no effect on fertility when given as part of the diet to male and female rats at up to 4 times the recommended human dose of 1000 mg (Prod Info acetazolamide IV injection, 2008; Prod Info Acetazolamide extended-release oral capsules, 2008; Prod Info acetazolamide oral tablets, 2005a).
    2) BRINZOLAMIDE
    a) RATS: There were no adverse effects on fertility when male and female rats were given oral brinzolamide doses of up to 18 mg/kg/day (375 times the recommended human ophthalmic dose) (Prod Info AZOPT(R) ophthalmic suspension, 2008).
    3) DORZOLAMIDE
    a) RATS: There were no adverse effects on the reproductive capacity of either male or female rats given oral doses of dorzolamide of up to 188 or 94 times, respectively, the recommended human ophthalmic dose (Prod Info TRUSOPT(R) sterile ophthalmic solution, 2009).
    4) METHAZOLAMIDE
    a) There have been no long-term animal studies of the effects of methazolamide on fertility (Prod Info methazolamide oral tablets, 2007).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of acetaZOLAMIDE, brinzolamide, dichlorphenamide, or dorzolamide in humans.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of brinzolamide in humans (Prod Info AZOPT(R) ophthalmic suspension, 2008).
    2) At the time of this review, the manufacturer does not report any carcinogenic potential of dichlorphenamide in humans (Prod Info KEVEYIS(TM) oral tablets, 2015).
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturers do not report any carcinogenic potential of acetaZOLAMIDE, dichlorphenamide, or methazolamide in animals (Prod Info KEVEYIS(TM) oral tablets, 2015; Prod Info acetazolamide IV injection, 2008; Prod Info Acetazolamide extended-release oral capsules, 2008; Prod Info acetazolamide oral tablets, 2005a; Prod Info methazolamide oral tablets, 2007).
    B) URINARY BLADDER PAPILLOMA
    1) DORZOLAMIDE
    a) RATS: Urinary bladder papillomas were observed in male rats when male and female Sprague-Dawley rats were given oral dorzolamide for 2 years at the highest dose of 20 mg/kg a day (138 times higher than the lower limit of detection in human plasma following ocular administration). This effect was also observed in male rats exposed to other drugs in the carbonic anhydrase inhibitor class. There was no evidence of papillomas in rats that received the lower oral doses of 1 mg/kg/day (7 times higher than the lower limit of detection in human plasma following ocular administration). Rats are susceptible to papillomas in response to foreign bodies, compounds causing crystalluria, or diverse sodium salts (Prod Info TRUSOPT(R) ophthalmic solution, 2014).
    C) URINARY BLADDER TUMORS
    1) BRINZOLAMIDE
    a) Urinary bladder tumors were reported in male and female animals administered brinzolamide orally at doses up to 10 mg/kg/day for 2 years. Carcinogenicity appears to be secondary to urinary bladder or kidney toxicity (Prod Info AZOPT(R) ophthalmic suspension, 2015).
    D) LACK OF EFFECT
    1) DORZOLAMIDE
    a) MICE: There were no treatment-related tumors when oral dorzolamide was given to male and female mice for 21 months in doses of up to 75 mg/kg/day (582 times higher than the lower limit of detection in human plasma following ocular administration) (Prod Info TRUSOPT(R) ophthalmic solution, 2014).
    b) DOGS, MONKEYS: Bladder urothelium changes were not evident when oral dorzolamide was given to dogs for a year at a dose of 2 mg/kg/day (137 times higher than the lower limit of detection in human plasma following ocular administration) or when dorzolamide was given to monkeys topically to the eye for 1 year at a dose approximately equivalent to the human topical ophthalmic dose (Prod Info TRUSOPT(R) ophthalmic solution, 2014).

Genotoxicity

    A) ACETAZOLAMIDE
    1) AcetaZOLAMIDE was not mutagenic in a bacterial mutagenicity assay with and without metabolic activation (Prod Info acetazolamide IV injection, 2008; Prod Info Acetazolamide extended-release oral capsules, 2008; Prod Info acetazolamide oral tablets, 2005a).
    B) BRINZOLAMIDE
    1) There was no evidence of mutagenicity of brinzolamide in the following tests: in vivo mouse micronucleus assay, in vivo sister chromatid exchange assay, Ames E. coli test, and the in vitro mouse lymphoma forward mutation assay in the absence of metabolic activation (positive in the presence of metabolic activation) (Prod Info AZOPT(R) ophthalmic suspension, 2015).
    C) DORZOLAMIDE
    1) There was no evidence of mutagenicity of dorzolamide in the following tests: in vivo (mouse) cytogenetic assay, in vitro chromosomal aberration assay, alkaline elution assay, V-79 assay, and the Ames test (Prod Info TRUSOPT(R) ophthalmic solution, 2014).
    D) METHAZOLAMIDE
    1) There was no evidence of mutagenicity of methazolamide in the Ames bacterial test (Prod Info methazolamide oral tablets, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes and renal function.
    B) Monitor liver enzymes and bilirubin, venous or arterial blood gas and urinalysis in symptomatic patients.
    C) Drug concentrations are usually not helpful in the acute setting or widely available.
    D) Consider checking acetaminophen and salicylate concentrations, if there is any uncertainty regarding the drug ingested.

Methods

    A) CHROMATOGRAPHY
    1) High-performance liquid chromatography was used to determine methazolamide concentrations in human blood, plasma, and urine following oral administration (Iyer & Taft, 1998).
    2) High pressure liquid chromatography with tandem mass spectrometric detection was used to determine the presence of dorzolamide and its de-ethylated metabolite in human plasma (Constanzer et al, 1997).
    B) OTHER
    1) De Balugera et al (1994) described a differential pulse polarographic method used to determine the amount of acetaZOLAMIDE in human serum. The detection limit for acetaZOLAMIDE, using this method, was 0.111 mcg/mL (De Balugera et al, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who present with severe symptoms (ie, lethargy, severe metabolic acidosis, bone marrow depression, cholestatic hepatitis, renal failure or Stevens-Johnson Syndrome) should be admitted. In addition, if the above mild findings persist despite treatment in the emergency department, admit the patient to the appropriate level of care.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients may be observed at home for small unintentional ingestions and mild symptoms, but should be evaluated for any concerning symptoms.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist as needed, especially for patients admitted to the ICU.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient who manifests signs of mild toxicity (ie, confusion, tachycardia, or tachypnea) or a large or deliberate overdose should be sent to a healthcare facility for observation. If symptoms resolve in the emergency department and the home social situation permits, the patient may be discharged after psychiatric clearance.

Monitoring

    A) Monitor serum electrolytes and renal function.
    B) Monitor liver enzymes and bilirubin, venous or arterial blood gas and urinalysis in symptomatic patients.
    C) Drug concentrations are usually not helpful in the acute setting or widely available.
    D) Consider checking acetaminophen and salicylate concentrations, if there is any uncertainty regarding the drug ingested.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) Emesis may exacerbate fluid/electrolyte imbalance and is not recommended.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) If the ingestion is recent and substantial, consider decontamination with activated charcoal (in aqueous solution without cathartic).
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In cases of carbonic anhydrase inhibitor overdose ingestions, treatment is usually SYMPTOMATIC and SUPPORTIVE.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes and renal function.
    2) Monitor liver enzymes and bilirubin, venous or arterial blood gas and urinalysis in symptomatic patients.
    3) Drug concentrations are usually not helpful in the acute setting or widely available. Consider checking acetaminophen and salicylate concentrations. If there is any uncertainty of drug ingested.
    C) ACIDOSIS
    1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
    2) Repeat doses of no more than one-half the original amount may be given no more often than every 10 minutes if required.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Approximately 30% of an acetaZOLAMIDE dose, administered intravenously 30 minutes before dialysis, was removed by four hours of hemodialysis, despite intraerythrocytic distribution and high protein binding (Vaziri et al, 1980). Hemodialysis may be effective in the management of acetaZOLAMIDE overdoses, especially in the presence of renal failure.

Range Of Toxicity

Summary

    A) TOXICITY: The acute toxic dose is not known. Toxicity appears variable; toxicity has occurred at levels ranging from 26 to 77 mcg/mL. A 12 month-old became ill after ingesting between 2 to 5 250-mg tablets of acetaZOLAMIDE. A 66-year-old woman died after developing renal failure, and bone marrow suppression after ingesting 50 mg daily for 11 days. A 54-year-old man died with cholestatic jaundice after ingesting 50 mg daily for 26 days.
    B) THERAPEUTIC DOSE: ADULT: ACETAZOLAMIDE: Dose ranges from 250 mg to 1 g daily, depending on the indication. BRINZOLAMIDE: Ophthalmic Solution: 1 drop in the affected eye 3 times daily. DORZOLAMIDE: Ophthalmic Solution: 1 drop in the affected eye 3 times daily. METHAZOLAMIDE: Dose ranges from 50 to 100 mg 2 or 3 times daily. PEDIATRIC: ACETAZOLAMIDE, BRINZOLAMIDE and METHAZOLAMIDE: The safety and efficacy in pediatric patients has not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) ACETAZOLAMIDE
    1) Recommended daily ORAL or IV dose for GLAUCOMA, CONGESTIVE HEART FAILURE, and DRUG-INDUCED EDEMA is in the range of 250 mg to 1 g (Prod Info acetazolamide IV injection, 2008; Prod Info Acetazolamide extended-release oral capsules, 2008; Prod Info acetazolamide oral tablets, 2005a). Extended-release capsules are indicated for glaucoma, but not congestive heart failure or drug-induced edema (Prod Info Acetazolamide extended-release oral capsules, 2008).
    2) Usual total daily ORAL TABLET or IV dose for EPILEPSY is 8 to 30 mg/kg orally or IV in divided doses; optimum range is 375 to 1000 mg/day (Prod Info acetazolamide IV injection, 2008; Prod Info Acetazolamide extended-release oral capsules, 2008; Prod Info acetazolamide oral tablets, 2005a)
    3) Usual daily ORAL dose for ACUTE MOTION SICKNESS is 500 to 1000 mg, in divided doses as either tablets or extended-release capsules (Prod Info Acetazolamide extended-release oral capsules, 2008; Prod Info acetazolamide oral tablets, 2005a). IV acetaZOLAMIDE is not indicated for acute motion sickness (Prod Info acetazolamide IV injection, 2008).
    4) NOTE: The recommended doses for glaucoma and epilepsy are substantially different from that for congestive heart failure. This is due to the first two indications not being dependent upon carbonic anhydrase inhibition in the kidney. To recover from the inhibitory effect of acetaZOLAMIDE, intermittent dosages are required for congestive heart failure (Prod Info acetazolamide oral tablets, 2005a).
    B) BRIMONIDINE/BRINZOLAMIDE
    1) The recommended dose is one drop 3 times daily in the affected eye(s) (Prod Info SIMBRINZA(TM) ophthalmic suspension, 2013).
    C) BRINZOLAMIDE
    1) Recommended dose is 1 drop in the affected eye(s) 3 times daily (Prod Info AZOPT(R) ophthalmic suspension, 2008).
    D) BRINZOLAMIDE/TIMOLOL COMBINATION PRODUCT
    1) Recommended dose is 1 drop in the affected eye(s) twice daily (Prod Info AZARGA ophthalmic suspension, 2012).
    E) DICHLORPHENAMIDE
    1) Initial dosage: 50 mg orally twice daily. Adjust the dose weekly (or sooner for adverse reactions) based on individual response and tolerability. MAX dose, 200 mg/day. The decision to continue therapy based on response should be evaluated after 2 months (Prod Info KEVEYIS(TM) oral tablets, 2015).
    F) DORZOLAMIDE
    1) Dose is 1 drop in the affected eye(s) 3 times daily (Prod Info TRUSOPT(R) sterile ophthalmic solution, 2009).
    G) METHAZOLAMIDE
    1) Effective therapeutic dose is 50 to 100 mg 2 to 3 times daily, and may be given concomitantly with miotic and osmotic agents (Prod Info methazolamide oral tablets, 2007).
    7.2.2) PEDIATRIC
    A) ACETAZOLAMIDE
    1) IV and ORAL TABLETS
    a) Safety and efficacy have not been established in pediatric patients (Prod Info acetazolamide IV injection, 2008; Prod Info acetazolamide oral tablets, 2005a).
    2) ORAL EXTENDED-RELEASE CAPSULES
    a) CHILDREN 12 YEARS AND OLDER:
    1) Recommended daily dose for GLAUCOMA is in the range of 250 mg to 1 g (Prod Info Acetazolamide extended-release oral capsules, 2008).
    2) Usual daily dose for ACUTE MOTION SICKNESS is 500 to 1000 mg, in divided doses (Prod Info Acetazolamide extended-release oral capsules, 2008).
    b) CHILDREN YOUNGER THAN 12 YEARS: Safety and efficacy have NOT been established (Prod Info Acetazolamide extended-release oral capsules, 2008).
    B) BRIMONIDINE/BRINZOLAMIDE
    1) LESS THAN 2 YEARS OF AGE: Use is contraindicated (Prod Info SIMBRINZA(TM) ophthalmic suspension, 2013).
    C) BRINZOLAMIDE
    1) Safety and efficacy not established in pediatric patients. Intraocular pressure-lowering efficacy was NOT demonstrated in a 3-month trial of pediatric patients 4 weeks to 5 years of age (Prod Info AZOPT(R) ophthalmic suspension, 2008).
    D) DICHLORPHENAMIDE
    1) Safety and efficacy have not been established in pediatric patients (Prod Info KEVEYIS(TM) oral tablets, 2015).
    E) DORZOLAMIDE
    1) Safety and intraocular pressure-lowering efficacy were demonstrated in a 3-month trial of pediatric patients (Prod Info TRUSOPT(R) sterile ophthalmic solution, 2009).
    2) The adult dose is 1 drop in the affected eye(s) 3 times daily (Prod Info TRUSOPT(R) sterile ophthalmic solution, 2009).
    F) METHAZOLAMIDE
    1) Safety and effectiveness have NOT been established in pediatric patients (Prod Info methazolamide oral tablets, 2007).

Minimum Lethal Exposure

    A) ACUTE
    1) CASE REPORT: A 12-month-old developed metabolic acidosis, lethargy, tachycardia and tachypnea after ingesting between 2 and 5 250-mg tablets (Baer & Reith, 2001).
    B) CHRONIC
    1) CASE REPORT: A 66-year-old woman presented to the hospital with acute renal insufficiency. The patient had been taking acetaZOLAMIDE 500 mg daily for 11 days. Laboratory studies showed leukocyturia, thrombocytopenia, severe anemia, and tarry stools. Serum acetaZOLAMIDE concentration was 76.5 mcg/mL. Despite intensive therapy with hemodialysis and direct hemoperfusion, the patient died 6 days after hospital admission. Death was due to disseminated intravascular coagulation and septic shock due to severe bone marrow depression (Takeda et al, 1997).
    2) CASE REPORT: A 54-year-old man began acetaZOLAMIDE therapy, 500 mg daily for 26 days (total amount ingested was 13 g), and subsequently presented to the hospital with confusion, dehydration, and peripheral circulatory failure. The patient had a generalized erythematous rash and marked jaundice with extreme abdominal tenderness. Despite supportive treatment, the patient became anuric and died 24 hours after admission. An autopsy revealed hepatomegaly with intracellular and canalicular cholestasis with widespread patchy fatty infiltrations, indicative of cholestatic jaundice associated with acetaZOLAMIDE administration (Kristinsson, 1967).
    3) CASE REPORT: A 66-year-old man received approximately 116 g of acetaZOLAMIDE over a period of 4 months and was admitted to the hospital with dry, bleeding lips, tonsillitis, and ecchymosis of the extremities. Laboratory results showed leukopenia, thrombocytopenia and a markedly hypoplastic bone marrow with no evidence of megakaryocytes, which led to a diagnosis of aplastic anemia. Despite aggressive care, the patient died 4 days after hospital admission (Lubeck, 1970).
    4) CASE REPORT: A 61-year-old man developed hyperchloremic metabolic acidosis secondary to chronic acetaZOLAMIDE ingestion, 250 mg 4 times daily. Four days after his last dose, the patient's acetaZOLAMIDE levels were 26.38 mcg/mL and 38.84 mcg/mL in serum and whole blood, respectively (Watson et al, 1985).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ACETAZOLAMIDE: Therapeutic effective blood levels are commonly 5 to 10 mcg/mL (Takeda et al, 1997).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CHRONIC
    a) CASE REPORT: A 66-year-old female presented to the hospital with acute renal insufficiency. The patient had been taking acetaZOLAMIDE 500 milligrams daily for 11 days. Laboratory studies showed leukocyturia, thrombocytopenia, severe anemia, and tarry stools. Her serum acetaZOLAMIDE level was 76.5 micrograms/ milliliter (normal 12 to 17 micrograms/milliliter) indicating acetaZOLAMIDE intoxication (Takeda et al, 1997).
    b) CASE REPORT: A 61-year-old male developed hyperchloremic metabolic acidosis secondary to chronic acetaZOLAMIDE ingestion, 250 milligrams 4 times daily. Four days after his last dose, the patient's acetaZOLAMIDE levels were 26.38 micrograms/milliliter and 38.84 micrograms/milliliter in serum and whole blood, respectively (Watson et al, 1985).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ACETAZOLAMIDE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1175 mg/kg ((RTECS, 2000))
    2) LD50- (ORAL)MOUSE:
    a) 4300 mg/kg ((RTECS, 2000))
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) greater than 3 g/kg ((RTECS, 2000))
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 2750 mg/kg ((RTECS, 2000))
    B) DICHLORPHENAMIDE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 304 mg/kg ((RTECS, 2000))
    2) LD50- (ORAL)MOUSE:
    a) 1710 mg/kg ((RTECS, 2000))
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 1244 mg/kg ((RTECS, 2000))
    4) LD50- (ORAL)RAT:
    a) 10070 mg/kg ((RTECS, 2000))
    C) DORZOLAMIDE
    1) LD50- (ORAL)MOUSE:
    a) 1320 mg/kg (Prod Info Trusopt(R), dorzolamide, 2001)
    2) LD50- (ORAL)RAT:
    a) 1927 mg/kg (Prod Info Trusopt(R), dorzolamide, 2001)
    D) METHAZOLAMIDE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 2420 mg/kg (RTECS , 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) GLAUCOMA: Carbonic anhydrase, an enzyme found in red blood cells and other tissues, is primarily responsible for catalyzing the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. Carbonic anhydrase inhibitors inhibit this enzyme, in the ciliary processes of the eye, which slows the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport, thereby decreasing the aqueous humor secretion. The result is a reduction in intraocular pressure (Prod Info Trusopt(R), dorzolamide, 2001).
    B) EPILEPSY: AcetaZOLAMIDE has been shown to be useful as an adjunct in the treatment of epilepsy. It appears that inhibition of carbonic anhydrase may retard abnormal, paroxysmal, and excessive discharge from the central nervous system neurons (Prod Info Diamox(R), acetazolamide, 2002).
    C) DIURESIS: Inhibition of carbonic anhydrase in the kidney may inhibit the reversible reaction involving hydration of carbon dioxide and dehydration of carbonic acid. The result is renal loss of the bicarbonate ion which carries out sodium, water, and potassium. Therefore, alkalinization of the urine and promotion of diuresis are affected (Prod Info Diamox(R), acetazolamide, 2002).

Physicochemical

Physical Characteristics

    A) ACETAZOLAMIDE is a white to faintly yellowish white crystalline, odorless powder that is weakly acidic, very slightly soluble in water, and slightly soluble in alcohol (Prod Info acetazolamide IV injection, 2008; Prod Info Acetazolamide extended-release oral capsules, 2008).
    B) BRINZOLAMIDE is a white powder that is insoluble in water, soluble in ethanol, and very soluble in methanol. Brinzolamide has an osmolality of 300 milliosmoles/kg and a melting point of about 131 degrees C (Prod Info AZOPT(R) ophthalmic suspension, 2008).
    C) DICHLORPHENAMIDE is a white or practically white, crystalline powder that is soluble in dilute sodium carbonate or sodium hydroxide solutions and very slightly soluble in water; dilute alkaline solutions are stable at room temperature (Prod Info KEVEYIS(TM) oral tablets, 2015).
    D) DORZOLAMIDE HYDROCHLORIDE is a white to off-white, crystalline powder that is soluble in water and slightly soluble in methanol and ethanol. Dorzolamide has an osmolarity of 260 to 330 milliosmoles and a melting point of about 264 degrees C (Prod Info TRUSOPT(R) ophthalmic solution, 2014).
    E) METHAZOLAMIDE is a white crystalline powder that is weakly acidic and slightly soluble in water, alcohol, and acetone (Prod Info methazolamide oral tablets, 2007).

Ph

    A) ACETAZOLAMIDE: 9.6 (reconstituted solution for injection) (Prod Info acetazolamide IV injection, 2008)
    B) BRINZOLAMIDE: approximately 7.5 (ophthalmic suspension) (Prod Info AZOPT(R) ophthalmic suspension, 2008)
    C) DORZOLAMIDE HYDROCHLORIDE: approximately 5.6 (ophthalmic solution) (Prod Info TRUSOPT(R) ophthalmic solution, 2014)

Molecular Weight

    A) ACETAZOLAMIDE: 222.24 (Prod Info acetazolamide IV injection, 2008; Prod Info Acetazolamide extended-release oral capsules, 2008)
    B) BRINZOLAMIDE: 383.5 (Prod Info AZOPT(R) ophthalmic suspension, 2008)
    C) DICHLORPHENAMIDE: 305.16 (Prod Info KEVEYIS(TM) oral tablets, 2015)
    D) DORZOLAMIDE HYDROCHLORIDE: 360.9 (Prod Info TRUSOPT(R) ophthalmic solution, 2014)
    E) METHAZOLAMIDE: 238.26 (Prod Info methazolamide oral tablets, 2007)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Baer E & Reith DM: Acetazolamide poisoning in a toddler. J Paediatr Child Health 2001; 37:411-412.
    3) Balfour JA & Wilde MI: Dorzolamide: a review of its pharmacology and therapeutic potential in the management of glaucoma and ocular hypertension. Drugs & Aging 1997; 10:384-403.
    4) Bearn PE: Disappearance of staghorn calculi following withdrawal of treatment with acetazolamide. Br J Urology 1989; 63:329.
    5) Burke WJ & Ranno AE: Neutropenia with clozapine and methazolamide (letter). J Clin Psychopharmacol 1994; 14:357-358.
    6) Callear A & Kirkby G: Extravasation of acetazolamide (letter). Br J Ophthalmol 1994; 78:731.
    7) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    8) Cohen AM, Prialnik M, & Ben-Nissan DS: Methazolamide-associated temporary leukopenia and thrombocytopenia. DICP, The Ann Pharmacother 1989; 23:58-59.
    9) Constanzer ML, Chavez CM, & Matuszewski BK: Low level determination of dorzolamide and its de-ethylated metabolite in human plasma by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry. J Pharmaceut Biomed Anal 1997; 15:1001-1008.
    10) Cotter JB: Methazolamide-induced Stevens-Johnson syndrome: a warning!. Arch Ophthalmol 1998; 116:117.
    11) Coudon WL & Block AJ: Acute respiratory failure precipitated by a carbonic anhydrase inhibitor. Chest 1976; 69:112-113.
    12) Cyr M, Laizure SC, & daCunha CM: Methazolamide-induced delirium. Pharmacother 1997; 17:387-389.
    13) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    14) De Balugera ZG, Goicolea MA, & Barrio RJ: Joint determination of todralazine and acetazolamide in human serum by differential pulse polarography. J Pharmaceut Biomed Anal 1994; 12:883-887.
    15) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    16) Ellis PP: Urinary calculi with methazolamide therapy. Documenta Ophthalmologica 1973; 34:137-142.
    17) Epstein RJ, Allen RC, & Lunde MW: Organic impotence associated with carbonic anhydrase inhibitor therapy for glaucoma. Ann Ophthalmol 1987; 19:48-50.
    18) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    19) Fan JT, Johnson DH, & Burk RR: Transient myopia, angle-closure glaucoma, and choroidal detachment after oral acetazolamide (letter). Amer J Ophthalmol 1993; 115:813-814.
    20) Ferry AP & Lichtig M: Gouty arthritis as a complication of acetazolamide (Diamox) therapy for glaucoma. Canad J Ophthal 1969; 4:145-147.
    21) Fineman MS, Katz LJ, & Wilson RP: Topical dorzolamide-induced hypotony and ciliochoroidal detachment in patients with previous filtration surgery. Arch Ophthalmol 1996; 114:1031-1032.
    22) Flach AJ, Smith RE, & Fraunfelder FT: Stevens-Johnson syndrome associated with methazolamide treatment reported in two Japanese-American women. Ophthalmology 1995; 102:1677-1680.
    23) Gangitano JL, Foster SH, & Contro RM: Nonfatal methazolamide-induced aplastic anemia. Amer J Ophthalmol 1978; 86:138-139.
    24) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    25) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    26) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    27) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    28) Heller I, Halevy J, & Cohen S: Significant metabolic acidosis induced by acetazolamide: not a rare complication. Arch Intern Med 1985; 145:1815-1817.
    29) Herman J, Nassar F, & Dalli N: Endoscopically proved erosive gastritis due to acetazolamide. Isr J Med Sci 1980; 16:866-867.
    30) Higenbottam T, Ogg CS, & Saxton HM: Acute renal failure from the use of acetazolamide (Diamox). Postgrad Med J 1978; 54:127-128.
    31) Ilyas M: An unusual case of ataxia. J Pakistan Med Assoc 1991; 41:89-90.
    32) Iyer GR & Taft DR: Determination of methazolamide concentrations in human biological fluids using high-performance liquid chromatography. J Pharmaceut Biomed Anal 1998; 1021-1027.
    33) JEF Reynolds : Martindale: The Extra Pharmacopoeia (electronic version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    34) Kraut JA & Madias NE: Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol 2010; 6(5):274-285.
    35) Kristinsson A: Fatal reaction to acetazolamide. Br J Ophthal 1967; 51:348-349.
    36) Krivoy N, Ben-Arieh Y, & Carter A: Methazolamide-induced hepatitis and pure RBC aplasia. Arch Intern Med 1981; 141:1229-1230.
    37) Kuroda K, Kojima T, & Tanabe E: Pustular psoriasis precipitated by acetazolamide. J Dermatol 1995; 22:784-787.
    38) Kurtz S, Ashkenazi I, & Melamed S: Major depressive episode secondary to antiglaucoma drugs (letter). Am J Psychiatr 1993; 150:524-525.
    39) Lubeck MJ: Aplastic anemia following acetazolamide therapy. Amer J Ophthalmol 1970; 69:684-685.
    40) Maisey DN & Brown RD: Acetazolamide and symptomatic metabolic acidosis in mild renal failure. Br Med J 1981; 283:1527-1528.
    41) Martinez-Mir I, Badenes JN, & Larrea VP: Taste disturbance with acetazolamide (letter). Ann Pharmacother 1997; 31:373.
    42) McMurdo MET, Hutchison GL, & Lindsay G: Taste disturbance with acetazolamide (letter). Lancet 1990; 336:1190-1191.
    43) Merlob P, Litwin A, & Mor N: Possible association between acetazolamide administration during pregnancy and metabolic disorders in the newborn. Eur J Obstet Gynecol Reprod Biol 1990; 35:85-88.
    44) Miller LG & Miller SM: Altered taste secondary to acetazolamide therapy. J Fam Pract 1990; 31:199-200.
    45) Moroi-Fetters SE, Metz EN, & Chambers RB: Aplastic anemia with platelet autoantibodies in a patient after taking methazolamide. Amer J Ophthalmol 1990; 110:570-571.
    46) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    47) Ogoshi M, Yamada Y, & Tani M: Acute generalized exanthematic pustulosis induced by cefaclor and acetazolamide. Dermatology 1992; 184:142-144.
    48) Parikh JR, Nolan RL, & Bannerjee A: Acetazolamide-associated nephrocalcinosis in a transplant kidney. Transplantation 1995; 59:1742-1743.
    49) Peralta J, Abelairas J, & Fernandez-Guardiola J: Anaphylactic shock and death after oral intake of acetazolamide (letter). Amer J Ophthalmol 1992; 114:367.
    50) Pesin SR & Brandt JD: Paresthesia and numbness due to drugs: the special case of the blind (letter). J Amer Med Assoc 1991; 265:1527-1528.
    51) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    52) Product Information: AZARGA ophthalmic suspension, brinzolamide timolol ophthalmic suspension. Alcon Laboratories (UK) Ltd. (per EMA), Hemel Hempstead, Herts, United Kingdom, 2012.
    53) Product Information: AZOPT(R) ophthalmic suspension, brinzolamide 1% ophthalmic suspension. Alcon Laboratories, Inc (per FDA), Fort Worth, TX, 2015.
    54) Product Information: AZOPT(R) ophthalmic suspension, brinzolamide 1% ophthalmic suspension. Alcon Laboratories, Inc, Fort Worth, TX, 2010.
    55) Product Information: AZOPT(R) ophthalmic suspension, brinzolamide 1% ophthalmic suspension. Alcon Laboratories, Inc., Fort Worth, TX, 2008.
    56) Product Information: Acetazolamide extended-release oral capsules, Acetazolamide extended-release oral capsules. Emcure Pharmaceuticals USA, Inc, East Brunswick, NJ, 2008.
    57) Product Information: Azopt(TM), brinzolamide. Alcon Laboratories, Inc, Fort Worth, TX, 2002.
    58) Product Information: COSOPT(R) PF ophthalmic solution, dorzolamide HCl timolol maleate 2% 0.5% ophthalmic solution. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2012.
    59) Product Information: Daranide(R), dichlorphenamide. Merck & Co, Inc, West Point, PA, 1996.
    60) Product Information: Diamox(R), acetazolamide. Storz Ophthalmics, St Louis, MO, 2002.
    61) Product Information: KEVEYIS(TM) oral tablets, dichlorphenamide oral tablets. TaroPharma (per manufacturer), Hawthorne, NY, 2015.
    62) Product Information: NEPTAZANE(TM) oral tablets, methazolamide oral tablets. Fera Pharmaceuticals, LLC (per DailyMed), Locust Valley, NY, 2010.
    63) Product Information: Neptazane(R), methazolamide. Storz Ophthalmics, St Louis, MO, 2002.
    64) Product Information: SIMBRINZA(TM) ophthalmic suspension, brinzolamide 1% brimonidine tartrate 0.2% ophthalmic suspension. Alcon Laboratories, Inc. (per FDA), Fort Worth, TX, 2013.
    65) Product Information: TRUSOPT(R) ophthalmic solution, dorzolamide HCl ophthalmic solution. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2014.
    66) Product Information: TRUSOPT(R) sterile ophthalmic solution, dorzolamide hydrochloride 2% sterile ophthalmic solution. Merck & Co., Inc, Whitehouse Station, NJ, 2009.
    67) Product Information: TRUSOPT(R) topical ophthalmic solution, dorzolamide hydrochloride topical ophthalmic solution. Merck & Co., Inc., Whitehouse Station, NJ, 2009.
    68) Product Information: Trusopt(R), dorzolamide. Merck & Co, Inc, West Point, PA, 2001.
    69) Product Information: acetazolamide IV injection, acetazolamide IV injection. X-Gen Pharmaceuticals Inc, Big Flats, NY, 2008.
    70) Product Information: acetazolamide oral tablets, acetazolamide oral tablets. Taro Pharmaceuticals (per DailyMed), Hawthorne, NY, 2005.
    71) Product Information: acetazolamide oral tablets, acetazolamide oral tablets. Taro Pharmaceuticals USA,Inc, Hawthorne, NY, 2005a.
    72) Product Information: methazolamide oral tablets, methazolamide oral tablets. Sandoz Inc., Princeton, NJ, 2007.
    73) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    74) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires October/31/2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    75) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    76) Reiss WG & Oles KS: Acetazolamide in the treatment of seizures. Ann Pharmacother 1996; 30:514-519.
    77) Rentiers PK, Johnston AC, & Buskard N: Severe aplastic anemia as a complication of acetazolamide therapy. Canad J Ophthalmol 1970; 5:337-342.
    78) Reynolds JEF (Ed): Martindale: the Extra Pharmacopoeia (electronic version). Micromedex, Inc. Englewood, Colorado. 1994.
    79) Rossert J, Rondeau E, & Jondeau G: Tamm-Horsfall protein accumulation in glomeruli during acetazolamide-induced acute renal failure. Amer J Nephrol 1989; 9:56-57.
    80) Rousseau P & Fuentevilla-Clifton A: Acetazolamide and salicylate interaction in the elderly: a case report. J Amer Geriatr Soc 1993; 41:868-869.
    81) Rowe TO: Acetazolamide delirium (letter). Amer J Psychiatry 1977; 134:587-588.
    82) S Sweetman: Martindale: The Complete Drug Reference. Pharmaceutical Press. London, UK (Internet Version). Edition expires 2004; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    83) Shirato S, Kagaya F, & Suzuki Y: Stevens-Johnson syndrome induced by methazolamide treatment. Arch Ophthalmol 1997; 115:550-553.
    84) Soderman P, Hartvig P, & Fagerlund C: Acetazolamide excretion into human breast milk. Br J Clin Pharmacol 1984; 17(5):599-600.
    85) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    86) Sporn A, Scothorn DM, & Terry JE: Metabolic acidosis induced by acetazolamide. J Amer Optometr Assoc 1991; 62:934-937.
    87) Sud RN & Grewal SS: Stevens Jhonson syndrome due to Diamox. Ind J Ophthalmol 1981; 29:101-103.
    88) Tabbara KF, Al-Faisal Z, & Al-Rashed W: Interaction between acetazolamide and cyclosporine. Arch Ophthalmol 1998; 116:832-833.
    89) Takeda K, Nakamoto M, & Yasunaga C: Acute hemorrhagic gastritis associated with acetazolamide intoxication in a patient with chronic renal failure. Clin Nephrol 1997; 48:266-268.
    90) Tawil R, Moxley RT, & Griggs RC: Acetazolamide-induced nephrolithiasis: implications for treatment of neuromuscular disorders. Neurology 1993; 43:1105-1106.
    91) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    92) Vaziri ND, Saiki J, & Barton CH: Hemodialyzability of acetazolamide. South Med J 1980; 73:422-423.
    93) Wakabayashi Y: Hyperkalemia induced by carbonic anhydrase inhibitor. Br J Ophthalmol 1991; 75:176-177.
    94) Wallace MR, MacDiarmid J, & Reeder J: Exacerbation of nephrolithiasis by a carbonic anhydrase inhibitor. NZ Med J 1974; 79:687-690.
    95) Watson WA, Garrelts JC, & Zinn PD: Chronic acetazolamide intoxication. J Tox-Clin Tox 1985; 22:529-563.
    96) Werblin TP, Pollack IP, & Liss RA: Blood dyscrasias in patients using methazolamide (Neptazane) for glaucoma. Ophthalmology 1980; 87:350-354.
    97) White GJ & White M: Breastfeeding and drugs in human milk. Vet Human Toxicol 1984; 26:1-24.
    98) Worsham GF, Beckman EN, & Mitchell EH: Sacrococcygeal teratoma in a neonate: association with maternal use of acetazolamide. JAMA 1978; 240:251-252.