Although the dysfunction and degeneration of reti- nal ganglion cells and their projections are what cause blindness in glaucoma, existing therapies tar- get lowering IOP through medication or surgery [ 18 ]. Currently, fi rst-line treatment for glaucoma is the topical use of eyedrops to reduce IOP [ 19 ].
There are fi ve main classes of IOP- lowering drugs, all of which either reduce the production of AH (by reducing activity of the ciliary body) or increase AH outfl ow (by action on the drainage canals in the iridocorneal angle, Table 1 ). Interestingly, lowering IOP often slows the progression of vision loss even in patients with normal IOP [ 20 ].
AH production can be reduced with drugs tar- geting the adrenergic system, antagonizing β- and activating α-receptors (e.g., timolol or brimoni- dine, respectively), or with carbonic anhydrase inhibitors (e.g., dorzolamide), presumably by slowing the formation of bicarbonate ions with subsequent reduction in Na + and fl uid transport.
S.D. Crish and C.M. Dengler-Crish
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Alternatively, AH outfl ow can be increased by prostaglandin analogs (e.g., latanoprost, a prosta- glandin F analog) or agonists of adrenergic and cholinergic signaling (e.g., carbachol).
Patients who are unresponsive to these medica- tions or have other issues can undergo surgery to physically increase AH outfl ow by creating new drainage canals in the eye. Shunts or cannulae used as drainage devices may also be implanted.
Infl uence of Treatment on Metabolism
Pharmacological treatment of glaucoma typically does not affect systemic metabolism to a large degree. The most common side effects impact the eye itself and may include irritation or discomfort due to corneal dryness, infl ammation, or allergic reaction. However, some of the topical drugs
Blood pressure
Retinal blood flow
OPP Metabolic risk factors:
- Obesity - Orbital fat - Blood lipid profile - Blood viscosity
IOP
RGC metabolic dysfunction
Mechanical effects on RGC axons
Ca2+ dysregulation Oxidative stress
RGC damage
Fig. 1 Relationship between conditions associated with metabolic syndrome, diabetes, and glaucoma. Different factors act to (1) increase intraocular pressure ( IOP ) or (2) reduce blood fl ow to the retina (due to either low blood pressure or microvascular changes). Either of these effects will reduce ocular perfusion pressure ( OPP ), leading to a decrease in retinal blood supply. Ultimately, this impairs
retinal function and leads to retinal ganglion cell ( RGC ) damage and degeneration through specifi c (Ca 2+ -activated degenerative cascades) and nonspecifi c (oxidative stress- induced damage) mechanisms. Another major factor in glaucoma is age. Terms highlighted in framed boxes change with age in a way that age increases the prevalence and severity of the disease
Table 1 Classes and examples of the most important glaucoma treatments
Drug class Examples AH production AH outfl ow
Prostaglandin analogs Latanoprost, travoprost
β-Blockers Timolol, carteolol
α-Agonists Brimonidine, apraclonidine
Carbonic anhydrase inhibitors Dorzolamide, brinzolamide
Cholinergic agonists Pilocarpine, carbachol
AH aqueous humor Glaucoma
76
used to treat glaucoma do cause systemic effects upon entering the circulation through the nasal mucosa by way of the lacrimal ducts (Fig. 2 ).
Drugs targeting β-adrenergic receptors can decrease systemic blood pressure (see chapter
“ Hypertension ”) and pulse rate (see chapters
“ Atherosclerotic heart disease ” and “ Heart fail- ure ”), as well as cause bronchospasm and nega- tively affect blood glucose levels and lipid profi le, the latter through impairing low- density lipoprotein and triglyceride metabolism by inhibiting lipoprotein lipase (LPL, see chapter
“ Hyperlipidemia ”) [ 19 ]. Confl icting research on the safety of topical β-blockers exist: several studies have found no increase in cardiovascu- lar events [ 21 ] or respiratory issues in elderly populations [ 22 ], but others found an increased risk of developing airway obstruction [ 23 ].
Perspectives
The relationship between metabolism and glau- coma is murky as most of the links examine the connection between metabolism and elevated IOP, a risk factor for glaucoma, rather than glau- coma itself. Given the variety of glaucomas, the variability in disease progression, the intricate relationships between the risk factors, and the specifi c mechanisms proposed to contribute to the pathology, it is very likely that several meta- bolic changes can impact the development or progression of the disease.
An area of great interest in glaucoma research is the development of a “complete therapy,”
where mechanisms of neurodegeneration are addressed in addition to lowering IOP [ 18 ]. At present, there are no dedicated neuroprotective
[LPL]
Heart rate
Blood pressure
Bronchospasm Airway obstruction
LDL
Serum triglycerides HDL
Eyedrops
b-BLOCKERS Lacrimal puncta
Fig. 2 Effects of topical β-blocker treatment (eyedrops) on systemic function. Eyedrops travel through the lacri- mal puncta and enter systemic circulation through the nasolacrimal duct. Common intraocular pressure-lower- ing drugs that inhibit the adrenergic system can decrease
heart rate, lower blood pressure, impair respiratory func- tion, and produce unfavorable blood lipid profi les through inhibition of lipoprotein lipase ( LPL ) in heart, muscle, and adipose tissue. LDL low-density lipoprotein, HDL high-density lipoprotein
S.D. Crish and C.M. Dengler-Crish
77
agents used for the treatment of glaucoma (although some of the existing IOP-lowering drugs such as brimonidine are thought to have neuroprotective effects). Researchers are cur- rently exploring a number of avenues—some of which could potentially have effects on metabo- lism—such as drugs affecting hemodynamics, mitochondrial function, or Ca 2+ dynamics. With a projected increase in glaucoma prevalence, this avenue represents one of the best hopes for reduc- ing disease burden in the future.
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