"Isn’t there a pill I can take?” This is not an uncommon question from patients with glaucoma. Often, it is posed by those who are on a four-drop regimen and still experiencing progression, those who struggle with debilitating ocular surface disease, or those who lack the dexterity to instill drops reliably. Some systemic medications can effectively lower IOP, however; because of side effects, metabolic requirements, and potential toxicity, clinicians do not prescribe them as freely as they do topical therapeutics. The two classes of systemic ocular antihypertensive medication are hyperosmotic agents and carbonic anhydrase inhibitors (CAIs).

AT A GLANCE

  • Some systemic medications can effectively lower IOP; however, due to side effects, metabolic requirements, and potential toxicity, they are not prescribed as often as topical therapeutics.
  • The two classes of systemic ocular antihypertensive medication are hyperosmotic agents and carbonic anhydrase inhibitors (CAIs). The most commonly available hyperosmotic agents are mannitol and glycerol. Systemic CAIs include acetazolamide and methazolamide.
  • Hyperosmotic agents are typically used in emergent situations to lower IOP or perioperatively to reduce vitreous volume. Oral CAIs are commonly used in emergent or acute situations or as a bridge to surgery, but in the right patient, they can be used long-term for IOP control.

HYPEROSMOTIC AGENTS

The most commonly available hyperosmotic agents are mannitol and glycerol. Systemic hyperosmotic agents lower IOP primarily by increasing intravascular osmolality, which draws fluid down an osmotic gradient from the vitreous into the intravascular space and secondarily by acting on osmoreceptors in the hypothalamus. The osmotic gradient created by these agents is dictated primarily by the tonicity of the medication and the integrity of the blood-ocular barrier.1 More concentrated solutions and an intact blood ocular barrier create a greater osmotic gradient and more effectively reduce IOP.

Mannitol

Mannitol is administered intravenously in concentrations ranging from 5% to 25% at 0.5 to 2.0 g/kg body weight. Its IOP-lowering effect is seen within 5 to 10 minutes and lasts up to 6 hours.2 Due to fluid shifts and diuresis, mannitol is associated with multiple systemic adverse effects such as dehydration, electrolyte abnormalities, heart failure, and cerebral edema. For these reasons, it should not be used in patients with severe dehydration or electrolyte abnormalities, heart or kidney failure, active intracranial bleeding, or a history of hypersensitivity.3

Glycerol

Glycerol is administered orally as a 50% solution at 1.0 to 1.5 g/kg of body weight. Its IOP-lowering effect begins within 10 to 30 minutes of administration, peaks in 45 to 120 minutes, and lasts 4 to 5 hours.2 Glycerol is often mixed with a tart flavoring to improve palatability due to its natural sweetness. The agent is associated with nausea and vomiting and can precipitate ketoacidosis in patients with diabetes.

Other oral hyperosmotic agents include isosorbide and ethyl alcohol; however, isosorbide is no longer manufactured in the United States, and the use of ethyl alcohol is less practical clinically.1

Carbonic Anhydrase Inhibitors

Systemic CAIs include acetazolamide and methazolamide, which are available in intravenous and oral formulations. CAIs lower IOP primarily by altering pH in the nonpigmented ciliary epithelium, resulting in enzyme inhibition, and secondarily by creating a systemic acidosis that depresses aqueous humor production.4 Systemic CAIs are more effective than topical formulations; the former reduce aqueous humor production by 30% compared to 20% with topical CAIs.5 Systemic CAIs can produce several unique side effects, including paresthesia of the lips and digits, gastrointestinal upset, a metallic taste (particularly with consumption of carbonated beverages), nephrolithiasis, anorexia, and depression. Their sulfonamide derivation can also lead to allergic reactions such as rash and anaphylaxis and, although rare, may cause life-threatening complications such as agranulocytosis, aplastic anemia, Stevens-Johnson syndrome, and toxic epidermal necrolysis.6

Acetazolamide

Acetazolamide is available orally in 125- or 250-mg tablets, which are dosed four times per day. Its IOP-lowering effect begins within 1 to 2 hours of administration, peaks in 2 to 4 hours, and lasts about 5 hours. Slow-release acetazolamide tablets are also available in 500-mg capsules (Diamox Sequels, Teva Pharmaceuticals), which are dosed two times per day and have a more favorable systemic side effect profile. Doses of acetazolamide greater than 1,000 mg per day are not associated with greater IOP-lowering efficacy.4

Acetazolamide is excreted renally in its original form; therefore, the dose must be adjusted for patients with kidney disease to avoid toxicity.7

Methazolamide

Methazolamide is available in 25- and 50-mg tablets and dosed two or three times per day, with a maximum dose of 100 mg three times per day. As with acetazolamide, IOP begins to decrease 1 to 2 hours after administration of methazolamide; however, the peak effect occurs in 4 to 6 hours, and the duration of action is 14 hours. Methazolamide produces less metabolic acidosis and fewer side effects compared to acetazolamide, making it more suitable for longer-term therapy in a wider range of patients.8

Methazolamide is contraindicated in patients with liver disease due to primary hepatic metabolism. Because 25% of the drug is excreted renally in its original form, methazolamide must also be dose-adjusted in patients with kidney disease.9

THE RIGHT MEDICATION FOR THE PATIENT

Because of side effects and a relatively short duration of action, hyperosmotic agents are typically used only in emergent situations to lower IOP or perioperatively to reduce vitreous volume. Oral CAIs are commonly used in emergent or acute situations or as a bridge to surgery. In the right patient, CAIs can be used long-term for IOP control. Patients such as those previously described, those who cannot or will not have surgery and have no remaining options for topical therapy, or those who cannot administer eye drops may be considered for long-term treatment with oral CAIs.

1. Stamper RL, Lieberman MF, Drake MV. Hyperosmotic agents. In: Stamper RL, Lieberman MF, Drake MV, eds. Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas. Mosby; 2009.

2. Serle JB, Danias J, Gagliuso DJ. Hyperosmotic agents. In: Morrison JC, Pollack IP, eds. Glaucoma. Thieme Medical Publishers; 2003.

3. Qureshi AI, Suarez JI. Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension. Crit Care Med. 2000;28:3301-3313.

4. Stamper RL, Liberman MF, Drake MV. Carbonic anhydrase inhibitors. In: Stamper RL, Liberman MF, Drake MV, eds. Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas. Mosby; 2009.

5. Maus TL, Larsson LI, McLaren JW, Brubaker RF. Comparison of dorzolamide and acetazolamide as suppressors of aqueous humor flow in humans. Arch Ophthalmol. 1997;115:45-49.

6. Scozzafava A, Supuran CT. Glaucoma and the applications of carbonic anhydrase inhibitors. Subcell Biochem. 2014;75:349-359.

7. Acetazolamide: drug information. UpToDate. Accessed January 17, 2023. www.uptodate.com

8. Becker B. Use of methazolamide (neptazane) in the therapy of glaucoma. Am J Ophthalmol. 1960;49:1307-1311.

9. Methazolamide: drug information. UpToDate. Accessed January 17, 2023. www.uptodate.com