Acetazolamide: Considerations for Systemic Administration

Ophthalmic Pearls

GLAUCOMA

by garrick chak, md, roma patel, md, mba, and r. rand allingham, md edited by sharon fekrat, md, and Ingrid u. scott, md, mph

ral acetazolamide (Diamox) usually of the calcium phosphate or is a carbonic anhydrase oxalate-based type due to reduced se- inhibitor that is commonly cretion of magnesium and citrate. used in clinical practice as Taking acetazolamide and sodium an immediate and readily bicarbonate together may increase the Oavailable option for acute reduction of risk of kidney stone formation.1 Thus, intraocular pressure (IOP). This article the ophthalmologist should consider highlights important considerations, the individual patient’s health and contraindications, and dosing adjust- medication profile when employing ments for this drug to help streamline systemic acetazolamide. ACETAZOLAMIDE. This drug can be decision making in a fast-paced office Rare, serious complications. Rarely, useful for acute reduction of intraocu- setting. acetazolamide may lead to agranulo- lar pressure, if the physician is mind- cytosis or aplastic anemia; these condi- ful of systemic considerations. Adverse Effects tions may occur suddenly and are irre- The most common side effects associ- versible.1 Therefore, if comanaged with next step to control the IOP? ated with the use of oral acetazolamide a primary care provider, the patient In the office setting, with the pa- include fatigue, paresthesias of the should have an occasional complete tient on maximum topical medica- face and extremities, metallic taste in blood count with differential, par- tion, the immediate option would be the mouth, and nausea and/or vomit- ticularly if any worrisome signs occur, to reduce IOP with a systemic drug. ing, which are related to drug-induced such as new-onset petechiae and fever. Although most cases of neovascular metabolic acidosis. Other complaints glaucoma are refractory to long-term may include dizziness, weight loss, de- Sample Case History pharmacological treatment, a drug pression, or intestinal colic. A 56-year-old patient with diabetes such as acetazolamide can be used as a Hypokalemia. If the patient presents and chronic kidney disease (CKD) temporizing measure while the physi- with several of the symptoms above, presents to the clinic with complaints cian plans a more definitive surgical the clinician should suspect hypoka- of diminished vision and pain in the approach. lemia from urinary alkalinization. It right eye. He has a history of neovas- However, is acetazolamide appro- is crucial to be aware of this because cular glaucoma from proliferative dia- priate in a patient with known CKD? hypokalemia may lead to serious mor- betic retinopathy. Examination of the Key considerations include creatinine bidity from cardiac arrhythmias. right eye is significant for visual acuity clearance; hepatic status; and history Vision changes. Patients sometimes of 20/80; IOP of 46 mmHg despite of epilepsy, drug allergy, or pulmonary report transient bilateral blurriness. use of topical latanoprost, timolol/ disease; as well as other medications It is caused by a bilateral myopic shift dorzolamide, and brimonidine; 2+ the patient may be taking. due to sulfa-related ciliary body edema nuclear sclerotic cataract; and a cup- and subsequent forward displacement to-disc ratio of 0.8. Gonioscopy reveals Creatinine Clearance of the iris-lens diaphragm. peripheral anterior synechiae for more Pharmacology. The following brief Kidney stones. A serious but less than 10 clock hours. The patient has pharmacological review may be help- common adverse effect is development recently undergone panretinal pho- ful in considering this case. Oral of kidney stones, which occurs in 1 to tocoagulation and currently has no acetazolamide is 100 percent excreted 2 percent of patients.1 The stones are active neovascularization. What’s the unchanged, which means that the drug

eyenet 35 Ophthalmic Pearls is eliminated through the kidneys and The diuresis associated with acet- disease, oral acetazolamide has been does not depend on metabolism for azolamide may be temporary due to found to reduce IOP only 50 percent as inactivation of the drug. Therefore, the high number of carbonic anhy- much as it does in healthy patients.6 creatinine clearance (CrCl) directly drase enzymes in the kidneys; this may influences the duration of action. require very high doses of the drug to Hepatic Status Acetazolamide is reportedly 90 to 98 be effective, which also exposes the Acetazolamide is contraindicated in percent protein bound; this means patient to greater risk of adverse ef- patients with liver cirrhosis because that 2 to 10 percent of the drug is ac- fects. Moreover, some patients develop it decreases ammonia clearance and tive and excreted at a given moment, drug tolerance, which may occur after increases the risk for hepatic encepha- which affects the pharmacodynamics taking the medication for one to six lopathy. In patients with mild liver of the drug such as onset of action (1- months. The tolerance is thought to disease, dose adjustment of the drug is 1.5 hours), peak effect (2-4 hours), and result from up-regulation of carbonic not necessary, since acetazolamide is elimination half-life (8-12 hours in anhydrase activity.1 not metabolized by the liver. healthy adults).1,2 Dosage adjustments in CKD. The Drug interactions. Caution must Mechanism of action. Carbonic following dosages are recommended be exercised for patients taking met- anhydrase inhibitors, including ac- for patients with renal compromise: formin or high-dose aspirin: Acet- etazolamide, impair resorption of • If CrCl > 50 mL/min: Use full dose azolamide inhibits CYP3A4 enzyme – HCO3 from the kidney’s proximal (250 mg four times a day or 500 mg activity and may enhance the adverse tubule, which osmotically leads to loss extended-release capsule [e.g., Diamox effect of these medications. Patients of Na+ and water along with bicarbon- Sequels] twice daily). on concomitant metformin and acet- ate. There is some distal compensation • If CrCl 10 to 50 mL/min: Use a half azolamide may have an increased risk of Na+ loss, so Na+ is resorbed from dose (250 mg twice daily). of developing lactic acidosis and poor tubular fluid with Cl–. Because the • If CrCl < 10 mL/min: Do not give glucose control.2 tubular fluid is negatively charged, K+ acetazolamide. For patients taking concurrent loss occurs, leading to hyperchlore- • If the patient is on hemodialysis: high-dose aspirin and acetazolamide, mic metabolic acidosis (a decrease in Use a half dose (250 mg twice daily). severe adverse effects have been re- plasma bicarbonate leads to transient • If the patient is on peritoneal dialy- ported, including coma, anorexia, metabolic acidosis), hypokalemia, and sis: Use 125 mg daily.3-5 tachypnea, and even death, likely as a depleted volume status. In patients with end-stage renal result of acute salicylate intoxication from reduced liver metabolism of sa- Common Clinical Questions licylate induced by acetazolamide. We recommend avoiding acetazolamide in Is it OK to take oral acetazolamide with food? a patient who is on high-dose aspirin 2 Yes—food does not delay the rate of absorption of the drug.1 and has renal impairment (CKD).

Does acetazolamide affect the metabolism of oral contraceptives? Epilepsy No, plasma levels of hormonal contraceptives are not affected by oral acetazol- Systemic acetazolamide is occasion- amide, since the drug does not induce CYP3A4 metabolism, so contraception ally prescribed by neurologists as an control should still be intact.1 adjunct treatment in epilepsy because Is methazolamide adjusted similarly? increased acidosis reduces the spread Although methazolamide has fewer side effects than acetazolamide and is well of seizure. However, acetazolamide tolerated by most patients, methazolamide is not removed by dialysis, and only may increase serum levels of anti- 25 percent of the drug is excreted unchanged. This indicates that methazolamide convulsants such as phenytoin or involves hepatic metabolism, unlike acetazolamide; therefore, methazolamide is carbamazepine due to inhibition of contraindicated in patients with marked renal or hepatic impairment.2 Methazol- CYP3A4 metabolism.1 Therefore, an amide is a weaker drug than acetazolamide and is metabolized slowly from the ophthalmologist who wishes to use ac- gastrointestinal tract. Methazolamide is 55 percent protein bound and has a later etazolamide in a patient with a history onset of action (2-4 hours), peak effect (6-8 hours), and elimination half-life (14 of epilepsy should do so in consulta- hours). tion with a neurologist or primary care physician. 1 Patsalos PN, Bourgeois BF (eds). Acetazolamide. In: The Epilepsy Prescriber’s In addition, caution should be exer- Guide to Antiepileptic Drugs. Cambridge, U.K.: Cambridge University Press; cised in prescribing acetazolamide to 2010:1-10. a patient on topiramate, since topira- 2 Acetazolamide: drug information. www.uptodate.com/contents/acetazolamide- mate also inhibits carbonic anhydrase, patient-drug-information. Accessed Jan. 4, 2015. which increases the risk of metabolic acidosis as well as kidney stones.1

36 march 2015 Ophthalmic Pearls

Pulmonary Disease erations mentioned above. Acetazolamide should be used with Counseling the patient is impor- caution in patients with chronic ob- tant. Encourage the patient to drink Write for us! structive pulmonary disease (COPD) additional water and supplement po- because the drug may aggravate respi- tassium intake with one banana daily. ratory acidosis. It should not be used in Although kidney stone formation may a patient who is having an acute COPD not necessarily be reduced by diet, cer- exacerbation. However, if a patient has tain foods that induce a mild metabol- Got Pearls? chronic respiratory acidosis with meta- ic alkalosis may theoretically increase Share your knowledge with your bolic compensation (mild alkalemia) urine citrate and possibly lower the colleagues! Ophthalmic Pearls at baseline, inducing additional meta- risk. (Citrate inhibits crystallization of articles provide a literature re- bolic acidosis may be acceptable and calcium salt.) view and offer helpful tips on may even stimulate respiratory drive. If the patient is on hemodialysis or disease management or proce- has severe kidney disease, appropriate dures in widespread use. History of Sulfa Allergy communication with the nephrologist When patients report a “sulfa allergy,” should be initiated. Monitor for central Are you a resident? the clinician should determine wheth- nervous system disturbances such as Authorship of an Ophthalmic er the patient developed a reaction to fatigue, lethargy, and confusion. Pearls will satisfy the RRC a sulfonamide antibiotic or a sulfon- Even though the oral acetazolamide requirements for resident amide nonantibiotic drug; the latter dosing can be adjusted in the short scholarly activity. category includes carbonic anhydrase term for patients with renal impair- inhibitors such as acetazolamide. The ment, the drug may be less effective in important distinction is that sulfon- lowering IOP in this population. These 1 amide antibiotics have structurally patients will likely need surgical inter- 2 different substituents at the N1 and N4 vention or cyclophotocoagulation, as position that may elicit a severe hyper- indicated, to better control IOP. n 3 sensitivity response, even to the point of anaphylaxis, whereas nonantibiotic 1 Patsalos PN, Bourgeois BF (eds). Acetazol- sulfonamides lack that structural con- amide. In: The Epilepsy Prescriber’s Guide to 4 figuration and, accordingly, are less Antiepileptic Drugs. Cambridge, U.K.: Cam- likely to cause severe reactions. More- bridge University Press;2010:1-10. over, cross-reactivity between sulfon- 2 Acetazolamide: drug information. www. 5 amide antibiotics and nonantibiotics is uptodate.com/contents/acetazolamide- extremely rare.2 patient-drug-information. Accessed Jan. 4, If IOP reduction via a systemic 2015. How to write an opHtHalmic route is necessary in a patient with 3 Roy LF et al. Am J Kidney Dis. 1992;20(6): pearls article a prior minor allergic reaction to a 650-652. 1. Come up with a topic, and e- sulfonamide antibiotic, the use of ac- 4 Schwenk MH et al. Pharmacotherapy. 1995; mail Peggy Denny (pdenny@aao. etazolamide or methazolamide is per- 15(4):522-527. org) to clear it before writing. missible with the patient’s informed 5 Schwenk MH et al. Adv Perit Dial. 1994; 2. Medical students, residents, consent regarding possible risk. How- 10:44-46. and fellows: Team up with a ever, even though acetazolamide ap- 6 Yue CS et al. J Pharm Pharmaceut Sci. 2013; faculty member who can provide pears to have no specific cross-reactiv- 16(1):89-98. pearls from experience. ity with sulfonamide antibiotics, it is 3. Send at least one photo or contraindicated in patients with prior Dr. Chak and Dr. Patel are glaucoma fellows, illustration. serious sulfa allergy such as Stevens- and Dr. Allingham is Barkhouser Professor 4. Use subheadings to help Johnson syndrome. and Director of Glaucoma Service at the Duke readers easily navigate your Eye Center. The authors report no related fi- 1,500-word article. Recommendations nancial interests. 5. Keep references to five or Once it is confirmed that the etiology fewer, if possible. of the high IOP is not pupillary block More About Meds and that laser peripheral iridotomy is not indicated, oral acetazolamide can Check out Focal Points 2013: SubmiSSionS be given with the appropriate adjust- Medical Treatment of Glaucoma E-mail your manuscript and art ments, as long as there are no contra- at www.aao.org/store. to [email protected]. indications, with key systemic consid-

eyenet 37