The major cause of blindness in glaucoma is damage to the optic nerve, of which IOP is the only known and effectively controllable risk factor for optic nerve damage and visual field loss. Therefore, the main clinical goal of current glaucoma pharmacotherapy is to lower IOP. The ultimate goal of glaucoma pharmacotherapy is to achieve a safe IOP level at which further optic nerve and visual field damage is less likely to occur. The main pathways of glaucoma medication can include 2 aspects, namely reducing atrial aqueous production and increasing atrial aqueous drainage. They can be divided into the following categories.
Systemic medications
1. Hypertonic dehydrating agents
The mechanism of hypertonic dehydrating agents is to lower the pressure mainly by increasing the plasma osmolarity, and the intraocular tissues are in a relatively hypotonic state. The elevated plasma osmolarity causes causes the water of the intraocular tissues to migrate to the intraocular vessels, mainly the water of the vitreous and atrial aqueous to the vessels of the retina and choroid, so that the water of the intraocular tissues penetrates into the plasma, making the volume of the vitreous cavity smaller and the IOP decreases. As the volume of the vitreous cavity decreases, it allows the iris and crystalloid septum to move back, causing the anterior chamber to deepen, the atrial angle to reopen, atrial water circulation to improve, and IOP to decrease.
Hypertonic dehydrating agents include two types: those used intravenously and those used orally, mainly mannitol for intravenous use and glycerol for oral use.
Mannitol, when injected intravenously, can rapidly increase plasma osmolarity and provide a rapid hypotensive effect. The dose is usually 250ml or 500ml, and the effect can start in about 10-30 minutes and reach the minimum level in 1-2 hours, and the effect can be maintained for 3-4 hours. The drug may cause electrolyte disorders, mainly manifested as low potassium, low sodium, pulmonary edema, heart failure, etc. The drug is mainly metabolized by the renal tubules and has the risk of causing renal failure. Therefore, when using it, it is important to pay attention to the patient’s heart and kidney function. In addition to this, mannitol may cause adverse reactions such as headache, dizziness, nausea and vomiting.
After oral administration, mannitol can be absorbed by the gastrointestinal tract and enter the body, where it is distributed in the extracellular fluid, creating a plasma-atrial water osmotic pressure difference and creating a hypotensive effect. The generally used dose is 1-2g/kg, which is given orally at once and can be repeatedly administered after 6 hours. The antihypertensive effect of oral glycerol is relatively slow. The common adverse effect is nausea and vomiting.
2.Carbonic anhydrase inhibitor
Carbonic anhydrase is distributed in many places throughout the body, and its main function is to maintain the acid-base balance in blood and other tissue fluids. In the eye, carbonic anhydrase is mainly distributed in the epithelial cells of the ciliary body, and is secreted into the atrial fluid by catalyzing the formation of bicarbonate from CO2 and H2O, causing increased secretion of Na+ into the atrial fluid and leading to secretion of water into the anterior chamber. Carbonic anhydrase inhibitors (CAIs) reduce atrial water secretion by inhibiting carbonic anhydride in the ciliary epithelium.
Commonly used systemic carbonic anhydrase inhibitors are oral formulations, including acetazolamide and acetazolamide (nimex). The recommended dose of acetazolamide is 500 mg for the first time, followed by 250 mg twice daily. The recommended dose of acetazolamide is 50-100mg for the first time and 25-50mg twice daily thereafter. Reduce or discontinue the drug as appropriate depending on the IOP. It is important to note that these drugs are sulfonamide derivatives and should be used with caution in those with sulfonamide allergy. Acetazolamide can cause electrolyte disorders, and long-term use may result in symptoms such as sensory numbness, abnormal hearing, loss of appetite, and nausea, which can be combined with sodium bicarbonate and potassium citrate during treatment.
Topical medication
1, adrenoceptor blockers: This is the most widely used and the oldest topical anti-glaucoma drug. beta receptors in the eye are mainly distributed in the ciliary epithelium, stroma and ciliary vessels. The ciliary body produces atrial fluid through blood ultrafiltration and active secretion by the ciliary epithelium. When beta receptors are blocked, such secretion is reduced, so atrial fluid production decreases and intraocular pressure falls. The general topical use of beta-blocker eye drops results in a decrease in IOP at 30-60 minutes, with the maximum effect occurring 3-4 hours after the drop.
The main types are timolol maleate, carteolol (Mechelon), levobunolol (Betagen), betaxolol (Betuxol), etc. These drugs can be absorbed into the body circulation and produce certain systemic side effects. Therefore, care should be taken when using these drugs in patients with co-morbid systemic diseases. They can induce bronchospasm, so patients with asthma or chronic obstructive pneumonia should use them with caution. Patients with severe heart disease need to be tested for signs of heart failure and have their heart rate checked. Because beta-blockers may mask the signs and symptoms of hypoglycemia, use with caution in patients with spontaneous hypoglycemia and unstable diabetes. In addition, beta-blockers may mask signs of hyperthyroidism, aggravate variant angina pectoris, lead to severe peripheral and central circulatory disturbances, and hypotension, so they also need to be used with caution in such patients. It is worth mentioning that betaxolol is a selective beta-blocker, which has minimal side effects on the whole body and is therefore relatively safe for use in patients with a combination of the aforementioned neoplastic diseases.
Another characteristic of the topical use of these drugs is the phenomenon of drift. After continuous use of these drugs, their effectiveness in lowering blood pressure decreases as the time of use increases. For example, the effect of antihypertensive effect is significantly weakened or even disappeared after 1 year of use of Tiamoxinan. At this time can be replaced by other types of drugs instead, after a period of time to reuse beta-blockers, can regain good antihypertensive effect.
2, cholinergic drugs: parasympathetic nerve can innervate the pupillary sphincter and ciliary muscle, cholinergic drugs can act on its M receptors, can produce pupil contraction and reduce the effect of intraocular pressure, such drugs are also known as pupil reduction agents. These drugs lower IOP mainly by stimulating the ciliary muscle that is connected to the scleral eminence and trabecular meshwork, causing the scleral eminence to move back, pulling the trabeculae, enlarging the trabecular meshwork, undergoing morphological changes, and increasing the outflow of discharge water. The main main type of clinical use is trichothecene. Its side effects are mainly to cause regulatory spasm, headache orbital pain, etc. This drug also has a pupil constricting effect, so it can cause significant vision loss in patients with central lens opacities and posterior subcapsular opacities, and can lead to posterior iris adhesions and corneal banding degeneration after long-term use. In patients with spherical crystals, this drug not only does not lower IOP, but can be aggravated by the formation of pupillary block.
These drugs are thought to have the potential to reduce the uveoscleral pathway, so this class of drugs is not recommended to be used in combination with prostaglandins.
3. Carbonic anhydrase inhibitors: Topical medications include brinzolamide eye drops (Perimin eye drops). The mechanism of action, as mentioned above, can be to inhibit atrial aqueous production. Long-term use of such drugs can lead to low potassium, can lead to numbness in the hands and feet, gastrointestinal disorders and other adverse reactions. Local use of the eye can produce burning sensation, stinging and tearing and other discomfort.
4, alpha agonists: the main clinical drugs are colistin and brimonidine tartrate (Alfagen). Brimonidine can activate the α2 receptors in the ciliary body, inhibit cAMP synthesis and reduce atrial fluid production. The main mechanism of its hypotensive effect is to increase atrial fluid drainage and decrease atrial fluid production. Its common local side effects include congestion, lacrimation and dry mouth, and systemic side effects include tachycardia, tardive dyskinesia and hypertension. The drug has a dual mechanism for lowering IOP, as well as potential optic nerve protection, and the lowest rate of visual field progression occurred when used and followed up in a large population of hypo-cyanotic individuals. This class of drugs has the least cardiovascular side effects compared to timothyroxine.
This is a relatively new class of anti-glaucoma drugs, currently used in 0.005% latanoprost eye drops (Silyta), 0.004% travoprost eye drops (Suvetan), 0.03% bemiprost eye drops (Lumigan), etc. PGs are a class of unsaturated 20-carbon fatty acids derived mainly from arachidonic acid via the cyclooxygenase pathway. The main mechanism of action of PGs is to reduce IOP by acting on matrix metalloproteinases in the non-ciliary muscle and scleral-vitreous membrane channels, resulting in relaxation of the ciliary muscle and an increase in the muscle gap, as well as an increase in matrix metalloproteinase activity, which reduces the resistance to atrial outflow and leads to outflow of atrial water through the scleral-vitreous membrane channels. These drugs were approved by the US FDA to enter the clinic in 1996 and are currently the most prescribed anti-glaucoma drugs in Europe and America. In China, due to economic factors, this drug is often used as a second-line drug. With the development of China’s economic level and the improvement of patients’ medical payment ability, the prescription amount of prostaglandins in China is gradually increasing and becoming a common drug for glaucoma clinical treatment. Completed clinical studies have confirmed that prostaglandin-based eye drops can effectively lower intraocular pressure, and are effective for open-angle glaucoma, chronic angle-closure glaucoma, pigment-spreading glaucoma, atrial angle recession, resting uveitis, and exfoliation syndrome, but not for active uveitis or Sturgeon-Weber syndrome. Its common side effects include conjunctival congestion, eyelash growth, and deepening of iris pigmentation.
Combinations of topical agents
The combination preparations that have been used are latanoprost eye drops, also known as Silygar: this drug is a combination of latanoprost and timolol maleate. Each 1ml of latanoprost eye drops contains 50ug of latanoprost and 6.8mg of timolol. It is indicated for patients in whom conventional beta-blocker therapy is not effective. The precautions for its use are the same as those described previously, and attention needs to be paid to the side effects of beta-blockers on the respiratory and cardiovascular systems.