Hypotensive lipids fall into three subcategories: prostaglandin analogues (PGAs) which include latanoprost (Xalatan 0.005 %) and travoprost (Travatan and Travatan Z, both 0.004 %; Izba which is travoprost 0.003 %), prostamide which includes bimatoprost (Lumigan 0.03 % and 0.01 %), and the deconsanoid class which is represented by unoprostone isopropyl (Rescula 0.15 %). They are all derivatives of prostaglandin F2 alpha, based on pioneering work by Bito, Stjernschantz, and Camras (Bito 2001; Camras et al. 1989).

PGAs increase both trabecular meshwork and uveoscleral outflow (Lim et al. 2008) and are less affected by circadian variations in aqueous production than the beta-blockers (Walters et al. 2004). Although these drugs have dual mechanism of action, most of the increased outflow facility can be attributed to their effects on the pressure-independent uveoscleral outflow pathway.

Variations in the PGF2 alpha molecule result in changes in potency and side effects. Latanoprost was the first one to be developed commercially (by Pharmacia, now Pfizer). In order to reduce the hyperemia associated with PGF2 alpha, the unsaturated (double) bond between carbons 13 and 14 was saturated. This resulted in some loss of potency, but by reducing hyperemia made the drug cosmetically acceptable to patients. Because there is no major clinical difference in IOP-lowering efficacy whether this class of drugs is dosed daytime or nighttime, it has become customary to prescribe them at bedtime, so that the majority of the immediate hyperemia associated with drug dosing occurs while the patient is asleep. These drugs do have some “chronic” hyperemia that tends to subside over several months of use. Occasionally patients prefer morning dosing, which is acceptable from an efficacy perspective. Clinical IOP-lowering efficacy is better with OD dosing rather than BID dosing (Alm and Stjernschantz 1995). Systemic half-life of the drugs is brief (e.g., latanoprost 17 min). There is little effect of the drugs on the IOP of the contralateral eye when dosed unilaterally (Sjoquist and Stjernschantz 2002).

To improve efficacy, Alcon Laboratories modified the PGF2 alpha molecule to create travoprost by adding a CF3 on the unsaturated benzene ring. This allows for a tighter bonding of the travoprost free acid to the FP receptors (Sharif et al. 2003). This results in a longer-duration, clinically useful, IOP-lowering effect of both original travoprost and the BAK-free version, Travatan Z (Gross et al. 2008). This could be important in patients who occasionally miss doses.

Most of the hyperemia associated with the HLs results from dilated conjunctival vessels in response to direct activation of FP receptors found in the vasculature muscle walls. Bimatoprost has a six- to eightfold greater concentration than other hypotensive lipids. This may be related to the clinical observation that bimatoprost causes more red eye than the other two products (Stewart et al. 2003).

The three hypotensive lipids lower IOP on average between 25 and 30 %. These drugs have relatively flat IOP curves over 24 h, demonstrating both low circadian IOP fluctuation and, unlike the beta-blockers, effective diurnal and nocturnal IOP control (Konstas et al. 2005). They do not evidence short-term escape or long-term drift (Goldberg 2001; Cohen et al. 2004; Bayer et al. 2004).

Latanoprost is subject to deterioration when exposed to heat over 100 °F for longer than 8 days (Xalatan package insert, Pfizer, NY). The other hypotensive lipids seem to be somewhat more stable at temperatures likely to be found in most natural settings. All agents may deteriorate at an accelerated pace when exposed to direct sunlight.

Topical beta-blockers were considered the gold standard initial treatment for open-angle glaucoma for nearly two decades, from 1978 to 1996, when the first prostaglandin analogue was granted approval by the FDA. Hypotensive lipids (prostaglandin analogues) are more potent IOP-lowering drugs than timolol and other beta-blockers. However, this fact does not mean that beta-blockers cannot be used as a first-line agent. This class of medication still remains efficacious, tolerated, and cost-effective.

Beta-blockers antagonize beta 1 and beta 2 receptors in the ciliary body’s nonpigmented epithelium and thereby reduce secretion of the aqueous humor through an incompletely understood mechanism, which in turn lowers IOP. Action on the ciliary microvasculature may reduce the ultrafiltration component of aqueous secretion.

One drop of timolol maleate 0.25 or 0.50 % has its peak effect, 2 h following administration, and may last for 24 h. Some residual effect of timolol on IOP may be detected for as long as 2–3 weeks, and beta blockade can be detected up to 1 month after discontinuation of the drug.

Nonselective beta-blockers lower IOP 20–30 %. However, IOP reduction may be as high as 50 % and last greater than 24 h in some individuals. In up to 20 % of cases, the initial IOP reduction can be lost within 2–3 weeks. This has been called short-term escape and most likely reflects an upregulation in the number of ocular beta receptors after initial complete blockade (Boger 1983). For this reason, it is recommended to wait at least 4 weeks following initiation of therapy before assessing IOP effect.

Beta-blocker treatment can maintain control of IOP for years. However, in some patients IOP control may be lost after many years of therapy or even within 3 months (Gieser et al. 1996). This phenomenon is called long-term drift and may be the result of drug tolerance or progression of the trabecular meshwork outflow problems.

Selective beta 1 blockers are less potent at reducing IOP than their nonselective counterparts, which can make them less attractive in patients who need a bigger IOP reduction.

The advantage of selective beta 1 blockers is that they have less effect on the beta 2 receptors found predominantly in the pulmonary system, making them more tolerable in patients with the potential for bronchospasm. Among nonselective beta-blockers, there are no differences in terms of IOP-lowering efficacy.

Patients under treatment with systemic beta-blockers may experience a reduced effect of topical administration and increased side effects (Allingham et al. 2005).

There are ocular, cardiovascular, pulmonary, metabolic, and central nervous system side effects. In general, beta-blockers are well tolerated when applied topically; however, there are reports of ocular discomfort due to burning, hyperemia, toxic keratopathy, punctate keratopathy, periocular contact dermatitis, and dry eye (Dunham et al. 1994).

Chronic administration of benzalkonium chloride (BAK) used as preservative in most beta-blocker solutions may play a role in ocular toxicity. The use of preservative-free timolol may help identify preservative as the source of local side effects. Timolol is available as a solution and in a gel-forming preparation. Gel-forming preparations allow longer permanence on the ocular surface for a sustained effect, and the once-daily administration can lead to fewer side effects. Gel-forming solution is also less likely to reach the nasolacrimal duct, lessening the potential for systemic side effects.

Beta-blockers are absorbed via the nasolacrimal system by the nasal and oral mucosa, thus bypassing the first-pass effect in the liver (Sharif et al. 2003). Direct access to the blood stream explains many systemic side effects and contralateral IOP lowering. Systemic side effects must be thoroughly searched for by a careful medical history since patients often overlook their eyedrops as a potential cause of systemic symptoms.

Beta 1 receptor blockade lowers blood pressure and heart rate, which can cause severe bradycardia, especially in patients with advanced age or underlying medical conditions, such as greater than first-degree heart block (a contraindication for the use of beta-blockers). They also cause decrease myocardial contractility, which is a relative contraindication for beta-blockers in patients affected by heart insufficiency. Exercise-induced tachycardia may be blocked in healthy individuals.

Beta-2 receptor blockade may cause severe asthma attacks. Nonselective beta-blockers are contraindicated in asthmatic patients. They also may exacerbate airway disease in a previously controlled asthma patient or trigger airway disease in a previously undetected or asymptomatic patient. Betaxolol, a beta 1-receptor blocker, has been successfully used in patients with pulmonary disease, but it is not entirely free of potential side effects (Fechtner 1999). A trial of once-daily dosing at the lowest available concentration of an agent (preferably in one eye) would be a good way to start. Only then, if indicated, should the frequency and concentration be increased.

Beta-blockers have been observed to alter the blood lipid profile negatively and could increase the risk of coronary heart disease. They may also mask the symptoms of hypoglycemia, such as tachycardia, in diabetics.

Central nervous system side effects are often subjective in nature and rarely attributed to eyedrops by patients. It is prudent to directly question patients about symptoms of fatigue, lethargy, confusion, memory loss, sleep disturbance, and dizziness. If present, a lower dosage of beta-blocker or replacement with another class of drug should be discussed.

The selective alpha-agonist agents used to treat glaucoma are modifications of the clonidine molecule (similar to the development of the hypotensive lipids that were derived from PGF2 alpha).

Two topical alpha-adrenergic agonists are available for glaucoma therapy, apraclonidine which is relatively nonselective for alpha 1 and alpha 2 receptors and brimonidine (Alphagan and generic) that is more selective for alpha 2 than alpha 1 receptors. These drugs work by preventing the release of norepinephrine at presynaptic terminals. They both decrease aqueous production, and they may have some effect on episcleral venous pressure as well as uveoscleral outflow (Reitsamer et al. 2006; Toris et al. 1999). Brimonidine may also affect conventional outflow in a positive manner. These drugs lower IOP between 20 and 25 %.

Apraclonidine (a) does not lower IOP in about 1/3 of patients, (b) has extreme tachyphylaxis (loss of effect) within about 90 days in about 1/3 of patients, and finally (c) causes blepharoconjunctivitis with red eyes, conjunctival follicles, pruritus, and periorbital dermatitis in about 1/3 of patients. Pupil dilation and lid retraction may also occur in a significant fraction of patients (Yuksel et al. 1992).

The newer lower concentrations of Alphagan-P, which contain the preservative purite instead of BAK, seem to be better tolerated, with a decreased incidence of allergy and almost as good intraocular pressure control as with the higher (0.2 %) concentration of the original drug (Whitson et al. 2006).

The pharmacokinetics of topically administered brimonidine requires that it be dosed three times per day, similar to the topical CAIs.

Brimonidine must be used with caution in neonates, young children, and the frail and elderly. With very young patients, brimonidine has resulted in apnea and coma (Mungan et al. 2003). Brimonidine can cause fatigue in elderly. Patients should specifically be queried about the presence of this important side effect. In these groups of patients, the drug seems to cross the blood–brain barrier in sufficient concentration to cause these severe side effects.

Alpha-adrenergic agonists should not be used in patients taking monoamine oxidase inhibitors (MAOIs) because they may precipitate a hypertensive crisis. They are also contraindicated in patients taking tricyclic antidepressants because of an increased risk of central nervous system (CNS)-mediated depression (Schuman 2002). These drugs cause symptoms of dry mouth (and dry nose) when drained through the nasolacrimal duct into the throat.

There are at least 14 known varieties of the alpha-carbonic anhydrases (a-CA) whose main function is the hydration of CO2 to bicarbonate (HCO−). Two of these enzymes are important for the production of the aqueous humor by the epithelium of the ciliary processes, cytoplasmic CA II and membrane-bound CA IV (Matsui et al. 1996). Part of aqueous production involving active secretion relies on the formation of bicarbonate by these enzymes to correct the imbalance caused by the ATPase-fueled transport of sodium into the space between the nonpigmented ciliary epithelial cells.

Patients should be specifically asked about breathing difficulties and skin reactions (Turtz and Turtz 1958), which are the most common form of allergic manifestations to sulfonamide antibiotics.

CAIs can be used topically or systemically. Topical CAIs are remarkably free from side effect and effective. They are the most effective class to use in combination with a prostaglandin analogue (Scozzafava and Supuran 2014). Systemic CAIs are also effective, but should be used with full knowledge of the frequency and severity of their side effects.

The parasympathomimetic medications are the oldest form of eyedrops used to treat glaucoma. Since they all act on the iris sphincter muscle to make the pupil smaller, we shall use the simpler name “miotics” when referring to these agents. The miotics are subdivided into two classes based on mechanism of action, the direct-acting cholinergic agents like pilocarpine and carbachol and the indirect-acting anticholinesterase agents like echothiophate iodide.