Which medications are used in the treatment of penetrating keratoplasty and glaucoma (PKPG)?

Updated: Dec 30, 2020
  • Author: Shibandri Das, MD; Chief Editor: Inci Irak Dersu, MD, MPH  more...
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β-Adrenergic blocking agents are the cornerstone of glaucoma treatment. They act by decreasing aqueous humor production, and they have no effect on the outflow pathways. Lass and Pavan-Langston [36]  demonstrated the efficacy of timolol in the treatment of PKPG, even in the presence of chronic angle-closure glaucoma (a type of glaucoma that results in uveoscleral and trabecular meshwork outflow obstruction). The adverse effects of β-blockers include, but are not limited to, superficial punctate keratopathy, corneal anesthesia, and damage to the ocular surface caused by a decreased aqueous layer production rate or impaired quantity and quality of the mucus layer of the tear film, resulting in a dry eye state. All of these may have an adverse effect on the graft epithelium that might compromise graft function.

Adrenergic agents can help lower the IOP but should be used with caution in patients with aphakia or pseudophakia because they can produce cystoid macular edema. Brimonidine tartrate 0.2%, a relatively selective α2-adrenergic agonist, is better tolerated than apraclonidine hydrochloride and is a safe drug for long-term control of IOP. Apraclonidine 0.5% is a potent anterior segment vasoconstrictor and more useful during the operation to both prevent anterior chamber bleeding and control the pressure spikes resulting from such a bleed.

Miotics, although used for glaucoma, should be used with caution in patients with PKPG. They can be useful in patients with open-angle glaucoma but may have very little effect in the presence of significant angle closure caused by peripheral anterior synechiae. Miotics can induce uveitis by breakdown of the blood-aqueous barrier, and this combined with the resulting inflammatory state can initiate graft rejection. In patients with aphakia, miotics can increase the risk for retinal detachment.

Topical carbonic anhydrase inhibitors (eg, dorzolamide, brinzolamide) have ocular hypotensive efficacy similar to that of betaxolol 0.5% and are not associated with clinically significant electrolyte disturbances or other systemic adverse effects seen with systemic carbonic anhydrase inhibitors. They should be used with caution in patients with PKPG, however. In those with a history of graft rejection, compromised endothelial function, and/or reduced endothelial cell counts, these agents can contribute to an irreversible corneal decompensation. [37, 38]  Systemic carbonic anhydrase inhibitors also decrease IOP by decreasing aqueous humor production. Additionally, systemic carbonic anhydrase inhibitors, such as acetazolamide, are useful in the treatment of pressure spikes in the immediate postoperative period. Their long-term use is limited because 30 to 50% of patients experience adverse effects, such as paresthesias, tinnitus, nausea, gastrointestinal disturbances, fatigue, depression, anorexia, and weight loss.

Prostaglandin analogues, such as latanoprost, appear to decrease IOP by increasing the uveoscleral outflow and can be used in conjunction with β-blockers and carbonic anhydrase inhibitors. This combination helps lower IOP by reducing aqueous humor production and increasing its outflow. During treatment with latanoprost, the most common adverse effects reported include punctate keratitis and ocular hyperemia. [39]  Additionally, latanoprost should be used with caution in patients with a history of herpes simplex keratitis because it has been reported to induce recurrent herpetic infection in humans. [40]  In patients with aphakia and pseudophakia, latanoprost has been reported to cause cystoid macular edema. [41]

No studies have been conducted on the use of latanoprostene bunod and netarsudil in PKPG; however, because of their potency, they will likely be studied specifically for PKPG in the near future and thus are discussed in the following sections.

Latanoprostene bunod (Vyzulta) has dual action as a latanoprost analogue and as butanediol mononitrate, which acts as nitric oxide. Latanoprostene bunod regulates IOP through both the trabecular outflow and uveoscleral outflow tracts. [42]  In a randomized study in which the IOP-lowering effects of latanoprostene bunod 0.024% were compared with those of timolol maleate 0.5%, mean IOP was significantly lower with latanoprostene bunod at all evaluation points within a 3-month period. [43]  This potent medical therapy for glaucoma has also been proven to significantly lower mean IOP in just 24 hours. [39]

Netarsudil acts as a rho kinase inhibitor and as a norepinephrine transporter inhibitor, which decreases IOP through various synergistic physiologic mechanisms. Netarsudil decreases the actin-myosin contraction, reducing the numbers of actin stress fibers and focal adhesions in the trabecular meshwork to improve the outflow of aqueous humor. [42]  Netarsudil has also demonstrated consistent IOP reduction across a range of baseline pressures, particularly in patients with low baseline IOP. [44]  In addition to reducing IOP via increased trabecular outflow and decreased aqueous humor production, netarsudil ophthalmic solution has been shown to decrease episcleral venous pressure, which ultimately enhances aqueous humor outflow and lowers IOP relative to baseline. [45, 46]

Ripasudil, a rho kinase inhibitor only, was found to lower IOP in patients with glaucoma poorly controlled with maximal medical therapy, and is well tolerated at up to 3 months with average IOP reduction from baseline of 2.8 mmHg [47] ; however, long-term use above 2 years does have as great of a safety profile; thus its use is still controversial. [48]

The following table documents the disadvantages of using some of the topical glaucoma medications in patients with PKPG.

Table 1. Physiologic Targets Affecting Aqueous Humor Production or Outflow and Disadvantages of the Various Glaucoma Medications in Patients with PKPG (Open Table in a new window)

Glaucoma medications 

Physiologic targets 

Potential problems in patients with PKPG 


Decrease aqueous humor production 

Superficial punctate keratitis, corneal anesthesia, dry eyes, subconjunctival fibrosis 

α2-Adrenergic agonists 

Decrease aqueous humor production and increase aqueous outflow 

Epithelial toxicity such as superficial punctate keratitis, dry eyes, and allergic reactions. Cystoid macular edema in aphakia and pseudophakia 


Increase aqueous humor outflow through contraction of ciliary muscle 

Inflammation, graft rejection, retinal detachment, subconjunctival fibrosis 

Topical carbonic anhydrase inhibitors 

Decrease aqueous humor production 

Permanent graft failure in eyes with borderline endothelial counts 

Systemic carbonic anhydrase inhibitors 

Decrease aqueous humor production 

Paresthesias, tinnitus, nausea, fatigue, depression, anorexia,  weight loss 

Prostaglandin analogues 

Increase aqueous humor outflow through the uveoscleral tract 

Uveitis, cystoid macular edema in aphakia and pseudophakia, recurrent herpes simplex infection in patients with history of herpes 

Rho kinase inhibitors 

Increase aqueous humor drainage through trabecular meshwork 

Epithelial keratopathy, reticular epithelial edema 

The benefits of pressure reduction with topical glaucoma medications should be weighed against the potential adverse effects. Apart from the specific adverse effects listed previously, topical medical therapy can have the following secondary side effects:

  • Benzalkonium chloride (BAC), the preservative used in most topical glaucoma medications, can cause severe surface toxicity. These effects include cell wall damage and destruction of the corneal epithelial microvilli, leading to increased permeability of the corneal epithelium. [49]
  • The acidic pH of some of the topical drops (eg,  Cosopt, 5.8; dorzolamide, 5.6), in addition to causing a burning sensation, may also be toxic to the corneal epithelium.

In patients who are allergic to the preservatives, preservative-free drugs, such as an Ocudose form of timolol maleate, should be used. Also, pilocarpine powder can be reconstituted with balanced salt solution by the pharmacy without any preservative.

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