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Acetazolamide

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names/main trade names
   1.6 Main manufacturers/main importers
   1.7 Presentation/formulation
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailablity
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
9.0 CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    1. NAME
 
       1.1 Substance
 
           Acetazolamide
 
       1.2 Group
 
           ATC Code:  S01EC Carbonic anhydrase inhibitor
 
       1.3 Synonyms
 
           Acetamidothiadiazolesulfonamide
           Acetazolamid
           Acetazoleamide
           Acetozolamide
           Carbonic anhydrase inhibitor No. 6063
 
       1.4 Identification numbers
 
           1.4.1 CAS number
 
                  59-66-5
 
           1.4.2 Other numbers
 
                  RTECS:  AC8225000
 
       1.5 Main brand names/main trade names
 
           Acetamox; Ak-Zol; Apo-Acetazolamide; Atenezol; AZM-Tab; 
           Cidamex; Daranide; Dazamide; Defiltran; Dehydratin; Diacarb; 
           Diamox; 4-Diamox; Didoc; Diluran; Diuramid; Diureticum- 
           Holzinger; Diuriwas; Diutazol; Donmox; Duiramid; Edemox; 
           Eumicton; Fonurit; Glaupax; Glupax; MZM; Natrionex; Nephramid; 
           Nephramide; Neptazane; Phonurit; Storzolamide; Vetamox.
 
       1.6 Main manufacturers/main importers
 
           Lederle
 
       1.7 Presentation/formulation
 
           125 mg, 250 mg tablets
           
           500 mg sustained release capsules
           
           Intravenous injection 500 mg/5 cc
 
 
 
    2. SUMMARY
 
       2.1 Main risks and target organs
 
           Overdoses of diuretics are rare and problems most 
           frequently involve chronic overmedication or poor monitoring of 
           effects or drug-drug interactions that are not anticipated by 
           the clinician.  Main toxic effects are on the kidneys with 
           diuresis of water, sodium, potassium, and most importantly 
           bicarbonate with resultant dehydration.  More caution is 
           warranted with patients at higher risk for renal  abnormal 
           function including patients with any renal disease, diabetes 
           mellitus, exposure to nephrotoxic contrast agents and 
           borderline fluid and/or electrolyte status.
 
       2.2 Summary of clinical effects
 
           Patients with either acute or chronic overdosage with 
           acetazolamide may show signs of dehydration with thirst, 
           lethargy, confusion, poor skin turgor, and prolonged capillary 
           refill time, but may have a paradoxical continued diuresis. 
           Electrolyte abnormalities include hyponatremia, hypokalemia, 
           and a non-anion gap hyperchloremic metabolic acidosis in the 
           more than mild ingestion which may lead to further 
           deterioration in mental status, production of seizures, 
           electrocardiographic abnormalities, and arrhythmias.  Prior 
           renal insufficiency will lead to increased toxicity at a given 
           dose.  There are idiosyncratic reactions producing bone marrow 
           suppression with hepatic and renal insufficiency. 
           Acetazolamide may also precipitate in the renal tubules 
           producing calculi with renal colic.  Hypokalemia may lead to 
           muscular weakness, hyporeflexia, and hypochloremic metabolic 
           alkalosis.
           
           In chronic therapy, especially in geriatric patients, a chronic 
           metabolic acidosis may lead to a chronic compensatory 
           hyperventilation which increases pulmonary vascular resistance 
           and decreases left ventricular function.  This can be 
           especially significant in patients on concurrent beta-blocker 
           or calcium channel blocker therapy.  The ventricular 
           fibrillation threshold may then be reduced.
           
           Cardiac arrhythmias may occur due to potassium deficiency. 
           Abuse or overdose may result in pancreatitis.  Hyperglycemia, 
           hyperuricemia, and hyperlipidemia may occur with acute overdose 
           or in chronic use or abuse.  Hypersensitivity reactions such as 
           rash, photosensitivity, thrombocytopenia, and pancreatitis are 
           rare.
 
 
 
       2.3 Diagnosis
 
           Diagnosis should be considered in a patient that 
           demonstrates an apparently paradoxical alkaline urine in the 
           face of a metabolic acidosis or patients with unexplained 
           dehydration or hypokalemia (Spratt et al., 1982). 
           Acetazolamide levels are available at some centers but are 
           rarely useful in the acute setting.  Measurement of 
           electrolytes, urine pH, and blood gas analysis will help to 
           support the diagnosis.  Patients that may have access to 
           acetazolamide include climbers, and patients with glaucoma or 
           edematous states.
 
       2.4 First aid measures and management principles
 
           Since the complications of an overdose of strictly 
           acetazolamide are relatively rare, invasive or noxious 
           interventions such as syrup of ipecac or gastric lavage are 
           probably not warranted in most cases.  Gastrointestinal 
           decontamination with activated charcoal is probably warranted 
           if the patient presents within 1-2 hours post-ingestion, 
           especially in the face of serious underlying disease.
           
           Intervention should be targeted at replacing any fluid and 
           electrolyte abnormalities initially with intravenous isotonic 
           crystalloid solutions.  Obtaining serum electrolytes including 
           serum bicarbonate and urinalysis with urine pH is warranted 
           except in the most trivial ingestion.  Venous or arterial blood 
           gas measurement may be helpful in the severely or chronically 
           overdosed patient to better define the patient's acid-base 
           status.  Sodium bicarbonate infusion may be necessary if serum 
           pH is below 7.10 and does not respond to initial volume 
           resuscitation (Goldfrank et al, 1994).  A too rapid correction 
           may exacerbate electrolyte abnormalities.  For hypotension, 
           vigorous fluid hydration is necessary before using 
           vasopressors, and invasive monitoring with at least a central 
           venous pressure monitor is recommended.
 
    3. PHYSICO-CHEMICAL PROPERTIES
 
       3.1 Origin of the substance
 
           Acetazolamide is of synthetic origin.
 
       3.2 Chemical structure
 
           N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide; N-[5- 
           (aminosulfonyl)-1,3,4-thiadiazol-2-yl]-acetamide; 5-Acetamido- 
           1,3,4-thiadiazole-2-sulfonamide.
           
           Molecular weight: 222.2
           
           Molecular formula: C4H6N4O3S2
 
 
 
       3.3 Physical properties
 
           3.3.1 Properties of the substance
 
                  Acetazolamide exists as a white to faintly 
                  yellowish-white, odourless crystalline powder. 
                  Acetazolamide is very slightly soluble in water and only 
                  slightly soluble in ethanol (~750 g/l); it is 
                  practically insoluble in ether and chloroform.  The pH 
                  of a suspension 1g Acetazolamide in 50 ml water is 4.0 
                  to 6.0 (McEvoy, 1995).
                  
                  Acetazolamide has a melting point of about 260 C, with 
                  decomposition (Moffat, 1986).
                  
                  The pKa values are 7.2 and 9.0 (Dollery, 1991).
 
           3.3.2 Properties of the locally available formulation
 
       3.4 Other characteristics
 
           3.4.1 Shelf-life of the substance
 
                  Solutions of acetazolamide are stable for one 
                  week after reconstitution, but it is recommended to use 
                  the solution within 24 hours (McEvoy, 1995).
 
           3.4.2 Shelf-life of the locally available formulation
 
                  To be completed by each center.
 
           3.4.3 Storage conditions
 
                  Acetazolamide tablets and extended-release 
                  capsules should be stored in a well-closed container at 
                  15 to 30C.
 
           3.4.4 Bioavailablity
 
                  No data found.
 
           3.4.5 Specific properties and composition
 
                  No data found.
 
 
 
    4. USES
 
       4.1 Indications
 
           1. Preoperative management of closed-angle glaucoma, or as 
           an adjunct in the treatment of open-angle glaucoma.
           
           2. Abnormal retention of fluid: drug-induced oedema, obesity, 
           and congestive cardiac failure.
           
           3. Epilepsy
           
           4. Prevention or amelioration of acute high-altitude (mountain) 
           sickness when rapid ascent is necessary or in subjects who are 
           particularly susceptible to altitude sickness despite gradual 
           ascent.  However, this is not an approved indication for the 
           use of acetazolamide.
           
           5. Metabolic alkalaemia.
           
           6. Periodic paralysis
           (Dollery, 1991; McEvoy, 1995; Reynolds, 1993).
 
       4.2 Therapeutic dosage
 
           4.2.1  Adults
 
                  Glaucoma
                  
                  In the treatment of glaucoma the usual dose is 250 to 
                  1000 mg by mouth daily, in divided doses for amounts 
                  over 250 mg daily, or as a controlled release 
                  preparation.
                  
                  When the patient with glaucoma is unable to take oral 
                  medicine, 500 mg of acetazolamide may be administered IV 
                  or IM in adults (McEvoy, 1995).
                  
                  Abnormal retention of fluid
                  
                  For congestive heart failure, toxaemia and oedema the 
                  dose is 250-375 mg once daily in the morning.  Response 
                  may decrease with time and it may be helpful to omit the 
                  drug every third day, or to use alternate day 
                  dosage.
                  
                  For obesity the dose is 250-375 mg daily, which may be 
                  used on alternate weeks. (Dollery, 1991)
                  
                  Epilepsy
                  
 
 
 
                  Acetazolamide used in the treatment of epilepsy is 
                  administered in doses of 250 to 1000 mg daily in divided 
                  doses for amounts over 250 mg daily (Reynolds, 
                  1993).
                  
                  High-altitude sickness
                  
                  For the treatment of mountain sickness the usual dose is 
                  500 to 1000 mg daily.
                  
                  Metabolic alkalaemia
                  
                  In patients with metabolic alkalaemia acetazolamide 2.5 
                  to 5 mg per kg body-weight is administered intravenously 
                  (Berthelsen et al. as quoted in Reynolds, 1993)
 
           4.2.2  Children
 
                  Glaucoma and epilepsy
                  
                  A suggested dose for children for glaucoma or epilepsy 
                  is 8 to 30 mg per kg daily (Reynolds, 1993).  In acute 
                  glaucoma in children, 5 to 10 mg/kg may be administered 
                  IM or IV every 6 hours (McEvoy, 1995).
                  
                  Abnormal retention of fluid
                  
                  As a diuretic in children, an acetazolamide dosage of 
                  5 mg/kg or 150 mg/m2 may be administered orally or IV 
                  once daily in the morning (McEvoy, 1995).
 
       4.3 Contraindications
 
           1. Renal hyperchloraemic acidosis.
           
           2. Addison's disease and all types of suprarenal gland 
           failure.
           
           3. Conditions where there is known depletion of sodium and 
           potassium (at least until this is treated).
           
           4. Long-term administration is contraindicated in patients with 
           chronic closed angle-closure glaucoma.
           
           5. Known sensitivity to sulfonamides.
           (Dollery, 1991).
           
           6. Acetazolamide should not be used to alkalinize urine 
           following salicylate overdose since it may worsen metabolic 
           acidosis (Ellenhorn, 1988).
 
 
 
    5. ROUTES OF ENTRY
 
       5.1 Oral
 
           Acetazolamide is administered orally as tablets or 
       controlled release capsules.
 
       5.2 Inhalation
 
           Unknown
 
       5.3 Dermal
 
           Unknown
 
       5.4 Eye
 
           Unknown
 
       5.5 Parenteral
 
           When oral acetazolamide administration is impractical, 
           similar doses of acetazolamide sodium may be given by 
           intramuscular or preferably by intravenous injection.
 
       5.6 Others
 
           Unknown
 
    6. KINETICS
 
       6.1 Absorption by route of exposure
 
           Acetazolamide is well absorbed from the gastrointestinal 
           tract. Following oral administration of 500 mg of acetazolamide 
           as tablets, peak plasma concentrations are achieved within 1-3 
           hours. Low concentrations of acetazolamide are present in 
           plasma 24 hours after the drug is given.
 
       6.2 Distribution by route of exposure
 
           Acetazolamide is distributed throughout body tissues; it 
           concentrates principally in erythrocytes, plasma and kidneys 
           and to a lesser extent in liver, muscles, eyes and the central 
           nervous system. Acetazolamide does not accumulate in tissues. 
           The drug crosses the placenta in unknown  quantities (Wade, 
           1993).
           
           Acetazolamide is tightly bound to carbonic anhydrase and high 
           concentrations are present in tissues containing this enzyme 
           such as erythrocytes and the renal cortex (Reynolds, 1993).
           
           There is a small amount of irreversible binding to red cells. 
           It is 70 to 90% bound to plasma protein (Dollery, 1991).
           
 
 
 
           The volume of distribution of acetazolamide is 0.2 L/kg 
           (Dollery, 1991).
 
       6.3 Biological half-life by route of exposure
 
           Different sources have quoted different plasma half-life 
           values for acetazolamide as follows 3 to 6 hours according to 
           Reynolds (1993) whilst Dollery (1991) quotes the plasma half 
           life range as 6 to 9 hours with a mean plasma half-life of 8 
           hours.
 
       6.4 Metabolism
 
           Acetazolamide is not metabolized (Dollery, 1991)
 
       6.5 Elimination by route of exposure
 
           Acetazolamide is excreted unchanged by the kidneys via 
           tubular secretion and passive reabsorption. After 
           administration of the oral tablets 70-100% (average 90%) of the 
           dose is excreted in urine within 24-hours; 47% of the dose is 
           excreted within 24 hours following administration of the 
           controlled release tablets.
           
           There is no evidence of enterohepatic circulation although 
           small amounts of unchanged drug are eliminated in the bile 
           (Dollery, 1991).
 
    7. PHARMACOLOGY AND TOXICOLOGY
 
       7.1 Mode of action
 
           7.1.1 Toxicodynamics
 
                  Metabolic acidosis may occur with long term 
                  acetazolamide therapy due to reduced bicarbonate 
                  concentrations, and in some instances, elevated plasma 
                  chloride concentrations.
                  
                  Renal calculi have occurred, possibly due to the reduced 
                  excretion of citrate combined with unchanged or 
                  increased calcium excretion.
 
           7.1.2 Pharmacodynamics
 
                  Acetazolamide is a carbonic anhydrase inhibitor. 
                  Acetazolamide reduces the formation of hydrogen and 
                  bicarbonate ions from carbon dioxide and water by 
                  noncompetitive, reversible inhibition of the enzyme 
                  carbonic anhydrase, thereby reducing the availability of 
                  these ions for active transport into secretions.
                  
 
 
 
                  In the eye acetazolamide reduces the formation of 
                  aqueous humor so that intraocular pressure in both 
                  normal and glaucomatous eyes is reduced.
                  
                  In the kidney the inhibition of carbonic anhydrase 
                  causes a reduction in hydrogen ion concentration in the 
                  renal tubules so that there is as increased excretion of 
                  bicarbonate and, to a lesser extent, sodium and 
                  potassium. Potassium loss is particularly high during 
                  acute administration. As the reabsorption of water is 
                  reduced, the volume of urine  is increased, and the pH 
                  of the urine becomes alkaline.  The excretion  of 
                  lithium is increased whereas the excretion of ammonia, 
                  acidity, citrate and uric acid is decreased.
                  
                  The anticonvulsant activity of acetazolamide has been 
                  theorised to be caused by the production of metabolic 
                  acidosis. However, it has been postulated that a direct 
                  effect on carbonic anhydrase in the brain may result in 
                  increased carbon dioxide tension, which has been 
                  demonstrated to retard neuronal conduction; an 
                  adrenergic mechanism may be involved (McEvoy, 1995).
                  
                  For acute mountain sickness, possible mechanisms of 
                  action include increased respiratory drive secondary to 
                  induction of metabolic acidosis, and therapeutic effects 
                  through diuresis (USP DI, 1995).
 
       7.2 Toxicity
 
           7.2.1 Human data
 
                  7.2.1.1 Adults
 
                           One patient died of cholestatic 
                           jaundice after taking 13 g of acetazolamide in 
                           26 days. In one patient, fatal bone marrow 
                           depression with leukopenia, thrombocytopenia, 
                           and anemia occurred after therapy with 500 mg 
                           of acetazolamide twice daily for 14 weeks. One 
                           case of renal failure (anuria) occurred in a 
                           patient after taking 500 mg of acetazolamide 
                           twice daily for 2 weeks (McEvoy, 1995).
                           
                           According to Dollery (1991) intentional 
                           overdose has not been reported. Drowsiness and 
                           disorientation have been reported when daily 
                           doses of 1 g and 5 g have been given to 
                           patients with hepatic failure (Dollery, 
                           1991).
 
 
 
                  7.2.1.2 Children
 
                           Unknown
 
           7.2.2 Relevant animal data
 
                  Numerous animal studies have demonstrated that 
                  the toxicity of acetazolamide was very low in the 
                  species studied (mouse, dog, rat, monkey). In the mouse, 
                  the LD50 is 3000 to 6000 mg/kg (Dollery, 1991)
 
           7.2.3 Relevant in vitro data
 
                  Not relevant
 
       7.3 Carcinogenicity
 
           No data available
 
       7.4 Teratogenicity
 
           There have been no reports of congenital defects despite 
           past widespread use though one women on 750 mg per day for 
           glaucoma during the 1st and 2nd trimester had a baby with a 
           sacrococcygeal teratoma but no causal link could be made 
           (Briggs et al, 1994).
           
           Teratogenicity tests in rats and mice showed the absence of 
           fourth and fifth digits from the right forelimb in the 
           offspring of rats and mice that received 0.6% acetazolamide in 
           the diet during pregnancy (Layton and Trelstad, 1965, and 
           Holmes and Trelstad, 1979, as quoted by Dollery, 1991). There 
           were no apparent lessions in the newborn of rabbits and monkeys 
           (Scott et al, 1981, as quoted by Dollery, 1991).
           
           The drug crosses the placenta in unknown quantities (Reynolds, 
           1993).
 
       7.5 Mutagenicity
 
           No data available
 
       7.6 Interactions
 
           Potentially hazardous interactions
           
           The effects of folic acid antagonists, oral hypoglycaemic 
           agents and oral anticoagulants may be increased by 
           acetazolamide.
           
           The urinary antiseptic effect of methenamine may be prevented 
           by acetazolamide by keeping the urine alkaline. The 
           alkalinization  of the urine by acetazolamide can reduce the 
           urinary excretion of many weak bases (including amphetamine, 
 
 
 
           quinine, quinidine, and diethylcarbamazine) and thus enhance 
           their pharmacological effects. In one patient taking phenytoin 
           and acetazolamide drug-induced osteomalacia was reported 
           (Davidson, 1975, Rawlins, 1978, Richens, 1977, and Mallov, 
           1977, as quoted by Dollery, 1991).
           
           Potentially useful interactions
           
           Acetazolamide can aid the penetration of weakly acidic 
           substances across the blood/cerebrospinal fluid barrier by 
           diffusion. Acetazolamide and other carbonic anhydrase 
           inhibitors increase the effects of mercurial diuretics 
           (Dollery, 1991).
 
       7.7 Main adverse effects
 
           The incidence and severity of many adverse reactions to 
           acetazolamide are dose related and usually respond to a 
           lowering of the dosage or withdrawal of the drug.
           
           Potentially life-threatening effects
           
           Acetazolamide is a sulfonamide derivative, and some adverse 
           effects similar to those of sulfonamides have been reported. 
           The more serious effects include blood disorders, skin toxicity 
           and renal stone formation. Stevens-Johnson syndrome has not 
           been reported (Rubenstein, 1975, as quoted by Dollery, 
           1991).
           
           Symptomatic adverse effects
           
           Flushing, thirst, headache, drowsiness, dizziness, fatigue, 
           irritability, excitement, paresthesias, ataxia, hyperpnoea and 
           gastrointestinal disturbances have all been reported (Dollery, 
           1991).
           
           Interference with clinical pathology tests
           
           Sulfonamides may give false negative or decreased values for 
           urinary phenolsulfonphthalein and phenol red elimination values 
           for urinary protein, serum non-protein and for serum uric acid 
           (Dollery, 1991).
 
 
 
    9.0 CLINICAL EFFECTS
 
       9.1 Acute poisoning
 
           9.1.1 Ingestion
 
                  Oral ingestion is the usual means of exposure 
                  outside of a health care facility.  The clinical effects 
                  are those described in Section 2.2.
 
           9.1.2 Inhalation
 
                  Not relevant.
 
           9.1.3 Skin exposure
 
                  There is no appreciable dermal 
                  absorption.
 
           9.1.4 Eye contact
 
                  There is no significant absorption or local 
                  irritation.
 
           9.1.5 Parenteral exposure
 
                  Acetazolamide is used intravenously in acute 
                  volume overload states or in acute glaucoma but would 
                  not be available outside of a health care facility.  The 
                  clinical effects are those described in Section 
                  2.2.
 
           9.1.6 Other
 
                  Not relevant.
 
       9.2 Chronic poisoning
 
           9.2.1 Ingestion
 
                  As in acute poisoning.
 
           9.2.2 Inhalation
 
                  Not relevant.
 
           9.2.3 Skin exposure
 
                  As in acute poisoning.
 
           9.2.4 Eye contact
 
                  As in acute poisoning.
 
 
 
           9.2.5 Parenteral exposure
 
                  As in acute poisoning.
 
           9.2.6 Other
 
                  Not relevant.
 
       9.3 Course, prognosis, cause of death
 
           The great majority of acute overdoses especially in 
           otherwise healthy individuals are benign and with simple 
           symptomatic care should have an excellent outcome.  Patients 
           that are on chronic therapy and presenting with complications 
           thereof may have a worse prognosis especially if not suspected 
           by the clinician.  Long-term therapy with diuretics must be 
           closely monitored.  Patients on long-term therapy who present 
           with acute problems should be specifically evaluated for volume 
           status and electrolyte and acid-base abnormalities including 
           metabolic acidosis. Patients that present with arrhythmias or 
           seizures while on diuretics should be rapidly evaluated for 
           hyponatremia, hypokalemia, and hypomagnesemia.  Patients that 
           present with unexplained fluid or electrolyte abnormalities 
           should be evaluated for possible diuretic abuse.  Prognosis 
           should also be excellent in these patients if potential 
           abnormalities are rapidly evaluated and appropriately 
           treated.
           
           Acetazolamide overdoses should  be evaluated according to the 
           extent of volume depletion, the degree of electrolyte 
           abnormality or acid-base disturbance, and the severity of the 
           patient's underlying medical condition(s) and not according to 
           the amount ingested.
           
           Deaths, though rare, do occur, not directly from the drug, but 
           complications in its use or abuse, namely arrhythmias and 
           seizures from electrolyte abnormalities or cardiac or renal 
           dysfunction secondary to volume depletion, or from severe 
           metabolic acidosis.
 
       9.4 Systematic description of clinical effects
 
           9.4.1  Cardiovascular
 
                  Arrhythmias may result from hypokalemia but are 
                  usually not life-threatening unless digoxin is also 
                  being administered and are self-limited with potassium 
                  replenishment.  Myocardial function may be impaired due 
                  to hypovolemia in patients with marginal function who 
                  require high ventricular loading pressures.
                  
 
 
 
                  Chronic use may result in metabolic acidosis with a 
                  compensatory hyperventilation that can lead to increased 
                  pulmonary vascular resistance which is usually 
                  reversible with discontinuation of the 
                  medication.
 
           9.4.3  Neurological
 
                  9.4.3.1  CNS
 
                           Toxicity may be manifested as lethargy 
                           and generalized weakness due to dehydration. 
                           There may be seizures due to hyponatremia. 
                           With chronic use, paresthesias and somnolence 
                           are frequently reported (Goodman et al., 1990). 
                           Headache, confusion, depression, irritability, 
                           nervousness, vertigo, dizziness and ataxia have 
                           been reported (McEvoy, 1995).
 
                  9.4.3.2  Peripheral nervous system
 
                           May demonstrate hyporeflexia due to 
                           hypokalemia.
 
                  9.4.3.3  Autonomic nervous system
 
                           There are no known effects.
 
                  9.4.3.4  Skeletal and smooth muscle
 
                           There may be muscle weakness in both 
                           skeletal and smooth muscle due to hypokalemia 
                           and/or hypomagnesemia.  Tremor and flaccid 
                           paralysis have been reported (McEvoy, 
                           1995).
 
           9.4.4  Gastrointestinal
 
                  Gastrointestinal disturbances including anorexia, 
                  nausea, vomiting, diarrhea, constipation, and abdominal 
                  distension may occur (McEvoy, 1995).  Chronic use or 
                  abuse may result in pancreatitis which may be immune- 
                  mediated.
 
           9.4.5  Hepatic
 
                  Liver dysfunction has been reported as an 
                  idiosyncratic reaction.  A case of cholestatic jaundice 
                  was reported after ingestion of 500 mg/day for 26 days 
                  (Ellenhorn, 1988).
 
 
 
           9.4.6  Urinary
 
                  9.4.6.1  Renal
 
                           Incorrect or unmonitored use may 
                           exacerbate underlying renal insufficiency due 
                           to a multitude of conditions including diabetes 
                           mellitus, chronic hypertension, cystic kidney 
                           disease, collagen vascular disease, or gout. 
                           Acetazolamide may cause nephrolithiasis and 
                           renal colic (Ellenhorn, 1988).  Dysuria and 
                           crystalluria have been reported (McEvoy, 
                           1995).
 
                  9.4.6.2  Other
 
                           May lead to urinary incontinence in 
                           the elderly and urinary retention in patients 
                           with prostatism.
 
           9.4.7  Endocrine and reproductive systems
 
                  Hyperglycemia may result with acute or chronic 
                  use or overdose and is usually self-limited.
 
           9.4.8  Dermatological
 
                  No effects reported except allergic skin 
                  rashes.
 
           9.4.9  Eye, ear, nose, throat: local effects
 
                  Acetazolamide is used to lower IOP in acute 
                  glaucoma and also as a maintenance anti-glaucoma agent 
                  and it works by inhibiting carbonic anhydrase in the 
                  ciliary body.  Myopia has been reported and generally 
                  subsides with cessation of therapy (McEvoy, 
                  1995).
 
           9.4.10 Haematological
 
                  There have been several case reports of fatal 
                  aplastic anemia, and isolated agranulocytosis or 
                  thrombocytopenia (Kristinsson, 1966).
 
           9.4.11 Immunological
 
                  None known
 
 
 
           9.4.12 Metabolic
 
                  9.4.12.1 Acid-base disturbances
 
                           Chronic use has resulted in a 
                           hyperchloremic/hypokalemic metabolic acidosis 
                           and can be seen to a lesser extent in an acute 
                           ingestion.  41% of 27 elderly patients on 
                           chronic therapy had moderate to severe acidosis 
                           with serum pH less than 7.29  (Heller et al., 
                           1985).
 
                  9.4.12.2 Fluid and electrolyte disturbances
 
                           Acute or chronic use or abuse can 
                           result in dehydration due to free water and 
                           electrolyte loss.  Hyponatremia, hypokalemia, 
                           and hyperchloremia with bicarbonate loss may 
                           occur.  To a lesser degree and usually on a 
                           more chronic basis, significant hypomagnesemia 
                           and hypocalcemia may result.
 
                  9.4.12.3 Others
 
                           Hyperuricemia and hyperlipidemia may 
                           result following chronic use.  Patients with 
                           cirrhosis have experienced disorientation 
                           possibly due to elevation of ammonia levels 
                           with carbonic anhydrase inhibitors (McEvoy, 
                           1995).
 
           9.4.13 Allergic reactions
 
                  There have been several reports of skin rash and 
                  serum sickness hypersensivity in patients on chronic 
                  therapy (Kristinsson, 1966).  Acetazolamide is a 
                  sulfonamide derivative and shares the incidence of 
                  hypersensitivity reactions (McEvoy, 1995).  There are 
                  rare true allergic reactions reported to 
                  acetazolamide.
 
           9.4.14 Other clinical effects
 
                  The resulting hypokalemia may exacerbate 
                  underlying digoxin toxicity. There is a major potential 
                  interaction with salicylates with documented cases with 
                  significant increases in baseline salicylate levels when 
                  acetazolamide was initiated in several elderly patients 
                  (Sweeney et al, 1986).  The toxicity would also be 
                  exacerbated by metabolic acidosis induced by 
                  acetazolamide, which will increase the CNS salicylate 
                  level and resultant toxicity at a given salicylate serum 
                  level.
 
 
 
           9.4.15 Special risks
 
                  As noted above special risks with furosemide use 
                  or overdose exist in patients with pre-existing renal 
                  disease or fluid and/or electrolyte abnormalities. 
                  Acetazolamide is secreted in breast milk but in one case 
                  a nursing infant exposed for one week showed no ill 
                  results  after receiving an estimated 0.6 mg/day 
                  (approximately 0.06% of the maternal dose) (Briggs et 
                  al, 1994).
 
       9.5 Other
 
           None identified.
 
    10. MANAGEMENT
 
        10.1 General principles
 
             Since diuretic overdoses are usually benign, aggressive 
             decontamination procedures are not warranted.  Treatment is 
             symptomatic in nature and is directed at correcting any fluid 
             and/or electrolyte abnormalities.  More aggressive management 
             may be necessary in the patient with underlying abnormalities 
             including renal insufficiency, fluid and/or electrolyte 
             abnormalities, myocardial dysfunction, or taking other 
             potentially toxic medications such as digoxin or an 
             aminoglycoside antibiotic.  Treatment aggressiveness must be 
             targeted to the severity of apparent toxicity and the 
             underlying chronicity thereof.
 
        10.2 Relevant laboratory analyses
 
             10.2.1 Sample collection
 
                    Levels of diuretics are rarely available and 
                    clinically useful, with the possible exception in 
                    cases of alleged use or abuse in patients that present 
                    with unexplained fluid and/or electrolyte 
                    abnormalities or in suspected Munchausen or 
                    Munchausen-by-proxy patients.  There are acetazolamide 
                    levels available at some research centers.  There does 
                    not appear to be any additional benefit in glaucoma 
                    therapy with levels greater than 4.2 mg/ml and this is 
                    usually achieved at a dose of 63 mg four times a day 
                    at steady state (Friedland et al, 1977).
 
             10.2.2 Biomedical analysis
 
                    Analysis should be targeted to the expected 
                    electrolyte abnormalities including sodium, potassium, 
                    chloride, and bicarbonate measurements in the mildly 
                    to moderately ill patient.  Blood gas analysis may be 
                    necessary in the more severely ill patient or when one 
 
 
 
                    needs to more precisely define the acid-base 
                    disturbance that may be present.  In more chronic use 
                    or abuse, magnesium and calcium levels may be 
                    necessary to define their depletion and need for 
                    replenishment.  If drug abuse of any kind is 
                    suspected, a general urine drug screen may  be 
                    indicated.
 
             10.2.3 Toxicological analysis
 
                    Analysis would only be necessary as described 
                    above.  See Section 8 for additional detail.
 
             10.2.4 Other investigations
 
                    None relevant.
 
        10.3 Life supportive procedures and symptomatic/specific treatment
 
             Life supportive measures are usually not necessary and 
             may only be needed in potentially life-threatening 
             arrhythmias seen with hypokalemia (especially with concurrent 
             digoxin use) and with seizures secondary to hyponatremia, 
             both fairly rare complications.  Symptomatic treatment is 
             directed at fluid/electrolyte repletion, initially with 
             intravenous isotonic crystalloid solutions.  Depending on the 
             severity of volume depletion, this can be administered 
             initially as rapid boluses in the range of 1 - 2 L in the 
             adult patient or 10 - 20 mL/kg in the pediatric patient. 
             Further repletion should be based on clinical response to the 
             first bolus and definitive blood chemistry analysis.  Care 
             must be taken in bolusing patients with underlying renal or 
             cardiac insufficiency that may make them more prone to fluid 
             overload and pulmonary edema. 
             
             In cases of severe hyponatremia resulting in seizures, 
             attention must be made to assess the patient's airway, 
             breathing, and circulation status.  Seizure treatment should 
             follow standard guidelines.
             
             Arrhythmias associated with hypokalemia usually are not 
             malignant and will respond to judicious potassium 
             replacement.  If arrhythmias are malignant in nature and 
             while replenishing potassium, the usual ventricular 
             antiarrhythmic agents are utilized.  In the chronic use or 
             abuse of diuretics, hypomagnesemia may contribute to 
             ventricular arrhythmias, especially torsade de pointe, and 
             replacement therapy in an urgent manner may terminate these 
             arrhythmias without resorting to potentially detrimental 
             medications.  The dose would be magnesium sulfate 2 - 4 g 
             intravenously diluted to 100 - 250 mL over 15 - 30 minutes 
             (40 - 80 mg/kg for pediatric patients, suitably 
             diluted).
 
 
 
        10.4 Decontamination
 
             Since these ingestions are usually benign or are 
             associated with hypovolemia, specific measures such as 
             inducing vomiting or administering cathartics are 
             contraindicated.  If the patient presents early, certainly 
             less than 1 hour after ingestion, with a large ingestion or 
             with underlying cardiac, renal, or hepatic insufficiency, 
             then a dose of activated charcoal is probably indicated. 
             Certainly, in an otherwise normal child with a limited acute 
             ingestion, no GI decontamination is warranted.
 
        10.5 Elimination
 
             There is no role for enhanced elimination, but a single 
             patient study with dialysis-dependent renal failure given one 
             500 mg dose of acetazolamide pre-dialysis showed an average 
             clearance of 22 mL/minute despite its high RBC distribution 
             (Vaziri et al, 1980).
 
        10.6 Antidote treatment
 
             10.6.1 Adults
 
                    There is no antidote for any of the 
                    diuretics.
 
             10.6.2 Children
 
                    There is no antidote for any of the 
                    diuretics.
 
        10.7 Management discussion
 
             Acetazolamide ingestions are usually benign and serious 
             complications rare.  Treatment usually is limited to 
             supportive and symptomatic care.
 
    11. ILLUSTRATIVE CASES
 
        11.1 Case reports from literature
 
             A 74 year-old woman on chronic acetazolamide therapy, 
             500 mg bid, for her glaucoma presented with abdominal pain, 
             anorexia, fatigue, and a 9 kg weight loss over 3 weeks.  Her 
             heart rate was 140 per minute.  Serum electrolytes were 
             sodium 138 mEq/L, potassium 3.8 mEq/L, chloride 118 mEq/L, 
             and bicarbonate 15 mEq/L.  Arterial blood gases measurements 
             were: pH of 7.36, pO2 93 mmHg, and pCO2 26 mmHg.  Her status 
             improved markedly with withdrawal of acetazolamide (Clark and 
             Vestal, 1984).
 
 
 
        11.2 Internally extracted data on cases
 
             None available.
 
        11.3 Internal cases
 
             None available.
 
    12. ADDITIONAL INFORMATION
 
        12.1 Availability of antidotes
 
             There are no specific antidotes.
 
        12.2 Specific preventive measures
 
             There are no specific preventive measures except 
             careful monitoring of patients on chronic therapy and 
             avoiding known drug interactions.
 
        12.3 Other
 
             Not relevant.
 
    13. REFERENCES
 
        AHA (American Heart Association) (1992).  Guidelines for 
        cardiopulmonary resuscitation and emergency cardiac care.  JAMA. 
        268:2171 - 2302.
        
        Antihypertensive drugs.  In:  Ellenhorn MJ & Barceloux DG, eds. 
        Medical toxicology: diagnosis and treatment of human poisoning. 
        New York, Elsevier, pp. 279-280.
        
        Barkin RM, Rosen P, eds. (1990):  Emergency pediatrics, 3rd ed. 
        St. Louis, Mosby.
        
        Briggs GG, Freeman RK, Yaffe SJ (1994).  Drugs in pregnancy and 
        lactation, 3rd ed.  Baltimore, Williams &Wilkins, pp. 6-7.
        
        Clark BG, Vestal RE (1984). Adverse drug reactions in the elderly: 
        Case studies.  Geriatrics 39(12):53-66.
        
        Dollery CT ed. (1991). Therapeutic drugs Edinburgh, Churchill 
        Livingstone.
        
        Ellenhorn MJ, Barceloux DG (1988). Medical Toxicology : Diagnosis 
        and Treatment of Human Poisoning. New York : Elsevier.
        
        Friedland BR, Mallonee J, Anderson DR (1977).  Short-term dose 
        response characteristics of acetazolamide in man.  Arch Ophthalmol 
        95:1809-12.
        
 
 
 
        Goodman L, Gilman AG, Rall TW, Nies AS, Taylor P, eds. (1985). 
        The pharmacological basis of therapeutics, 7th ed.  New York, 
        Macmillan.  pp.716-8.
        
        Heller I, Halevy J, Cohen S, et al. (1985).  Significant metabolic 
        acidosis induced by acetazolamide:  not a rare complication.  Arch 
        Intern Med 145:1815-1817.
        
        Kristinsson A (1966).  Fatal reaction to acetazolamide.  Brit J 
        Ophthal.  51:348-9.
        
        Lewin NA (1994).  Antihypertensive agents.  In:  Goldfrank LR, 
        Weisman RS, Flomenbaum NE, Howland MA, Lewin NA, Hoffman RS. 
        Goldfrank's toxicologic emergencies 5th ed.  Norwalk, Conn., 
        Appleton & Lange, pp. 708.
        
        Reynolds JEF, ed. (1993).  Martindale: The Extra Pharmacopoeia. 
        Ass. editors Perfitt K, Parsons AN, Sweetman SC. London, The 
        Pharmaceutical Press.
        
        McEvoy GK ed. (1995).  American Hospital Formulary Service, Drug 
        information.  Bethesda, MD, American Society of Hospital 
        Pharmacists.
        
        Moffat AC(1986) Clarke's Isolation and identification of drugs in 
        pharmaceuticals, body fluids, and post-mortem material. 2nd ed. 
        (consulting editors Jackson JV, Moss MS, Widdop B) London, 
        Pharmaceutical Press.
        
        Spratt DI, Pont A (1982).  The clinical features of covert 
        diuretic use.  West J Med.  137:331-335.
        
        Sweeney KR, Chapron DJ, Brandt JL, Gomolin IH, Feig PU, Kramer PA 
        (1986).  Toxic interaction between acetazolamide and salicylate: 
        case reports and a pharmacokinetic explanation.  Clin Pharmacol 
        Ther.  40(5):518-24.
        
        USP DI (1995).  United States Pharmacopeia. 15th edition, 
        Rockville, MD, The United States Pharmacopeial Convention Inc., 
        Vol. 1, p 659.
        
        Vaziri ND< Saiki J, Barton CH, Rajudin M, Ness RL (1980). 
        Hemodialyzability of acetazolamide.  Southern Medical Journal. 
        73(4):422-3.
        
        Woo OF (1994).  Diuretics.  In:  Olson KR, ed.  Poisoning and 
        overdose handbook. Norwalk, Conn., Appleton & Lange, pp. 157- 
        158.
 
 
 
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), 
    COMPLETE ADDRESS(ES)
 
    Authors:
    
        Craig R. Warden, MD
        Jefferey L. Burgess, MD
        Washington Poison Center
        155 NE 100th St., Suite 400
    
    Reviewer:
    
        PIM panel, October 1995
    
    Initial Date:
    
        10 October 1995
 
    


    See Also:
       Toxicological Abbreviations