timolol twice daily and latanoprost once daily has been shown to further decrease IOP (on average 1.2 mmHg) than the fixed combination products. The advantage of using a CAI twice daily with a prostaglandin analog may be a stronger IOP lowering effect [13, 17, 25].

Summary for the Clinician

››Beta blockers can be used in combination with any other class of drug. Fixed combinations with CAIs may be slightly more effective than using the two medications separately.

››Prostaglandin analogs can also be used in combination with any other class of drug. CAIs may offer a slight edge over beta blockers.

24.4  Should Miotics Still Be Used?

Miotics are seldom used today because there now exist more effective topical medication classes requiring less frequent administration and causing fewer side effects. Of 2,775 patients receiving monotherapy in one series, only 21 were treated with miotics [31]. Pilocarpine, which increases outflow, remains useful in combination with beta blockers and with prostaglandin analogs [1]. Its low cost makes it attractive when cost is an issue. Miotics are indicated in the management of some cases of acute angle-closure glaucoma, aphakic and pseudophakic glaucoma, and in presbyopic patients. They are contraindicated in uveitic or neovascular glaucoma.

Pilocarpine and other miotics are associated with many ocular side effects because of their effect on muscarinic cholinergic receptors present in the iris and ciliary body muscles. The indirect-acting miotics act by inhibiting cholinesterase and they can affect systemic cholinesterase, which prolongs the effect of succinylcholine during general anesthesia.

Summary for the Clinician

››Despite their efficacy, miotics are seldom used today because of the availability of drugs with easier dosing regimens and fewer side effects.

››Miotics remain a useful medication where cost is an issue.

››Miotics are useful in combination with beta blockers and prostaglandin analogs.

References

 1. Airaksinen PJ, Valkonen R, Stenborg T, et al. (1987) A dou- ble-masked study of timolol and pilocarpine combined. Am J Ophthalmol 104:587–590.

 2. Allingham RR, Damji K, Freedman S, et al. (2005) Adrenergic receptor antagonists. In: Shield’s Textbook of Glaucoma. Lippincott Williams and Wilkins, Philadelphia.

 3. Allingham RR, Damji K, Freedman S, et al. (2005) Prosta­ glandins and hypotensive lipids. In: Shield’s Textbook of Glaucoma. Lippincott Williams and Wilkins, Philadelphia.

 4. Boger WP III (1983) Short term “escape” and long term “drift”: the dissipation effects of the beta adrenergic agents. Surv Ophthalmol 28suppl:235–242.

 5. Camras CB, Hedman K, US Latanoprost Study Group (2003) Rate of response to latanoprost or timolol with ocular hypertension or glaucoma. J Glaucoma 12:466–469.

 6. Caprioli J, Sears M, Bausher L, et al. (1984) Forskolin lowers intraocular pressure by reducing aqueous inflow. Invest Ophthalmol Vis Sci 25:268–277.

 7. Choudhri S, Wand M, Shields MB (2000) A comparison of dorzolamide-timolol combination versus the concomitant drugs. Am J Ophthalmol 130:832–833.

 8. Coleman AL, Diehl DLC, Jampel HD, et al. (1990) Topical timolol decreases plasma high-density lipoprotein cholesterol level. Arch Ophtalmol 108:1260–1263.

 9. Cvenkel B, Stewart JA, Nelson LA, et al. (2008) Dorzolamide/ timolol fixed combination versus latanoprost/timolol fixed combination in patients with primary open-angle glaucoma or ocular hypertension. Curr Eye Res 33:163–168.

10.Dunham CN, Spaide RF, Dunham G (1994) The contralateral reduction of intraocular pressure by timolol. Br J Ophthalmol 78:38–40.

11.Fechtner RD (1999) Beta blockers. In: Netland PA, Allen RC (eds),GlaucomaMedicalTherapyPrinciplesandManagement. The Foundation of the American Academy of Ophthalmology, San Francisco.

12.Feghali JG, Kaufman PL (1985) Decreased intraocular pressure in the hypertensive human eye with betaxolol, a b1 – adrenergic antagonist. Am J Ophthalmol 100:777–782.

13.Feldman RM, Tanna AP, Gross RL, et al. (2007) Comparison of the ocular hypotensive efficacy of adjunctive brimonidine 0.15% or brinzolamide 1% in combination with travoprost 0.004%. Ophthalmology 114:1248–1254.

14.Gieser SC, Juzych M, Robin AL, et al. (1996) Clinical pharmacology of adrenergic drugs. In: Ritch R, Shields MB, Krupin T (eds), The Glaucomas. Mosby, St. Louis

15.Goethals M (1989) Ten year follow-up of timolol-treated open angle glaucoma. Surv Ophthalmol 33 Suppl:463–464.

16.Hejkal TW, Toris CB, Camras CB (1999) Prostaglandin analogs. In: Netland PA, Allen RC (eds), Glaucoma Medical Therapy Principles and Management. The Foundation of the American Academy of Ophthalmology, San Francisco.

17.Hommer A, Ganfort Investigators Group I (2007) A doublemasked, randomized, parallel comparison of a fixed combination of bimatoprost 0.03%/timolol 0.5% with non-fixed combination use in patients with glaucoma or ocular hipertensión. Eur J Ophthalmol 17:53–62.

18.Kass MA, Heuer DK, Higginbotham EJ, et al. (2002)The Ocular Hypertension Treatment Study Group. The Ocular Hypertension­ Treatment Study: a randomized trial determines

that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 120:701–713.

19.Konstas AG, Nakos E, Tersis I, et al. (2002) A comparison of once daily morning vs evening dosing of concomitant latanoprost/timolol. Am J Ophthalmol 133:753–757.

20.Konstas AG, Katsimpris IE, Kaltsos K, et al. (2008) Twenty- four-hour efficacy of the brimonidine/timolol fixed combination versus therapy with the unfixed components. Eye 22:1391–1397.

21.Konstas AG, Kozobolis VP, Tsironi S, et al. (2008) Comparison of the 24 hour intraocular pressure-lowering effects of latanoprost and dorzolamide/timolol fixed combination after 2 and 6 months of treatment. Ophthalmology 115:99–103.

22.Lama PJ (2002) Systemic adverse effects of beta-adrenergic blockers: an evidence based assessment. Am J Ophthalmol 134:749.

23.McCannel CA, Heinrich SR, Brubacker RF (1992) Acetazolamide­ but not timolol lowers aqueous humor flow in sleeping humans. Graefes Arch Clin Exp Ophthalmol 230:513–520.

24.Mittag TW (1996) Adrenergic and Dopaminergic Drugs in Glaucoma. In: Ritch R, Shields MB, Krupin T (eds), The Glaucomas. Mosby, St. Louis.

25.O’Connor DJ, Martone JF, Mead A (2002) Additive intraocular pressure lowering effect of various medications with latanoprost. Am J Ophthalmol 133:836–837.

26.Rylander NR, Vold SV (2008) Cost analysis of glaucoma medications. Am J Ophthalmol 145:106–113.

27.Van Buskirk EM, Fraunfelder FT (1984) Ocular beta-blockers and systemic effects. Am J Ophthamol 98:623–624.

28.Zimmerman TJ, Kaufman HE (1977) Timolol dose response and duration of action. Arch Ophthalmol 95:605–607.

29.Zimmerman TJ, Shrir M, Nardin GF, et al. (1992) Therapeutic index of pilocarpine, carbachol and timolol with nasolacrimal Occlusion. Am J Ophthalmol 114:1–7.

30.Zimmerman TJ (1993) Topical ophthalmic beta blockers: a comparative review. J Ocular Pharm 9:373–384.

31.Zimmerman TJ, Stewart WC and the Latanoprost Axis Study Group (2003) Intraocular pressure, safety, and quality of life in glaucoma patients switching to latanoprost from monotherapy treatments. J Ocular Pharmacol Ther 16:557–564.

Core Messages

››There is no high level evidence for the fetal effects of medications used to treat glaucoma.

››Risks that topical and systemic medications pose to the fetus and neonate must be balanced against the risk of vision loss in the mother.

››All glaucoma medications should be avoided during the first trimester of pregnancy, if possible; systemic carbonic anhydrase inhibitors and prostaglandin analogs should be avoided absolutely.

››Some topical medications are deemed compatible with lactation by the American Academy of Pediatrics, however, caution should still be practiced.

25.1  Which Glaucoma Medications

Are Safe to Use in Pregnancy?

The management of glaucoma in pregnant women and during lactation is controversial, challenging, and full of conflicting advice [1, 2]. No clinical studies exist on the fetal effects of commonly used medications, and it is unlikely that trials will be performed. Trials to establish “safety and efficacy” of ophthalmic solutions are seldom performed in children or pregnant women because of medicolegal constraints, limited sample

T. Zeyen ( )

Department of Ophthalmology, University UZ Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium

e-mail: thierry.zeyen@uzleuven.be

size, and low financial incentives to drug companies evaluating products in these populations [3]. Therefore, we must rely on the information gathered from case reports and animal studies.

Table 25.1 summarizes the U.S. FDA’s categories of safety for medications during pregnancy. There are no glaucoma medications that fall into category A. Brimonidine is a category B drug, but it has been shown to cross the placenta and could potentially cause apnea in neonates if used through parturition. Beta blockers, CAIs, prostaglandin analogs, and parasympathomimetics are classified as category C. There have been reports of fetal complications from topical beta blockers, however, none have been seen with low dose timolol in gel formulation. Fetal complications have also been reported with systemic acetazolamide. There is only one case report of complications with topical CAIs [4] in a neonate who also had low birth weight and impaired kidney function. Prostaglandins are known to stimulate uterine contraction and may cross the blood–placental barrier; prostaglandin analogs should be avoided during pregnancy to minimize risk of premature labor.

Childbearing plans should be addressed with all women of reproductive age who have glaucoma. The risks and benefits of glaucoma treatment to the fetus versus vision loss in the mother must be discussed. Also, it is probably a good practice to remind would-be mothers that a certain percentage of pregnancies will be anomalous by chance despite glaucoma treatment. As the greatest risk of medication to the developing fetus is in the first trimester, when organ systems develop, discontinuation of medications should occur prior to conception and through the first trimester. If a woman has advanced glaucoma and elevated pressures or if she is taking multiple medications, serious consideration should be given to surgery before conception.

Table 25.1  Medication safety during pregnancy according to the U.S. FDA

Category A: safety established using human studies Category B: presumed safety based on animal studies

Category C: uncertain safety; no human studies; animal studies show adverse effect

Category D: unsafe; evidence of risk that in certain clinical circumstances may be justifiable

If the patient has early glaucoma or is only a suspect, stopping medications for a number of months should not pose any great risk to vision. Intraocular pressure (IOP) tends to decrease during pregnancy in healthy patients, especially during the second and third trimesters. However, in one retrospective review, almost 30% of pregnant glaucoma patients experienced an increase in IOP during pregnancy [5].

If pregnancy is established and treatment is necessary, laser trabeculoplasty (LTP) is probably the best initial therapy and a good alternative to medication. If medications cannot be stopped then the use of beta blockers, cholinergics, topical CAIs, and alpha agonists can be continued. However, beta blockers and alpha agonists should be discontinued after the 8th month of pregnancy, to avoid betaor alpha-blockade in the neonate (see Chapter 51 for effects in infants and children). Beta blockers have a long track record and are occasionally used by obstetricians for systemic hypertension during pregnancy. Timolol 0.1% gel once daily is probably a safe option, due to the low dosage and low systemic absorption. If necessary it can be combined with dorzolamide or brinzolamide twice daily. Systemic CAIs are potentially teratogenic but topical CAIs appear to be safe.

Filtering surgery can be considered if glaucoma is progressive and an adequate IOP cannot be obtained with LTP or with the medications mentioned above. Peribulbar or sub-tenon lidocaine appears to be safe for the fetus. It is desirable to defer surgery until the second trimester of pregnancy to reduce the fetus’ exposure to potentially teratogenic anesthetic agents. The patient should be positioned with the uterus displaced laterally so as to avoid aortic and vena caval compression by the gravid uterus [6]. Postoperatively, topical erythromycin and steroids in ointment or in drops using punctal occlusion are safe. Antimetabolites, such as 5-FU or mitomycin C, should not be used on a pregnant woman for medicolegal reasons. Pregnant surgeons may also want to avoid handling these agents as occupational medicine does not allow the pregnant

surgeons to handle MMC or 5-FU. Diode laser cyclodestruction can be a valuable alternative to filtering surgery [7]. Both the obstetrician and pediatrician should coordinate and provide the necessary care.

Questions about the safety of vaginal delivery in a woman with glaucoma occasionally arise. There is no literature which addresses these questions. The theoretical risks of vision loss from elevated eye pressure and decreased blood flow to the optic nerve during the pushing phase of labor should be discussed with the mother and may depend on the stage of the glaucoma. These concerns may also need to be addressed with the obstetrician.

Summary for the Clinician

››Evidence of glaucoma medication safety in pregnancy is largely derived from case reports and animal studies.

››Address glaucoma management prior to conception in women of childbearing age.

››IOP tends to decrease during pregnancy in healthy women, but has been reported to increase in up to one-third of pregnant glaucoma patients.

››Avoid prostaglandin analogs during pregnancy to minimize risk of premature labor.

››Avoid all medications during the first trimester of pregnancy to minimize possible teratogenic effects.

››In the second and third trimesters, beta blockers, alpha agonists, and miotics have been safely used but consider stopping the first two listed prior to childbirth to avoid complications in the newborn infant.

››If surgery is necessary during pregnancy, postpone it until the second trimester and avoid antimetabolite use.

25.2  What Medications Are Safe to Use in a Nursing Mother?

Again, a thorough discussion of the risks and benefits to the infant vs. those to the nursing mother should be discussed. Beta blockers are concentrated in breast milk and should be avoided while nursing, despite the American Academy of Pediatrics statement that beta