Introduction
Glaucoma is currently one of the major irreversible causes of blindness in the world. Elevated intraocular pressure is a major risk factor for optic nerve damage during the development of glaucoma. Although laser and surgical treatments for glaucoma have made great strides, drug therapy remains the most important and fundamental treatment. The main way drugs lower IOP is by reducing atrial aqueous production or increasing atrial aqueous drainage, or both.
In the past 20 years, significant progress has been made in the research of anti-glaucoma drugs, and many new drugs are available for clinical application, but there is another problem, that is, various drugs have different efficacy and side effects. At the same time, because each patient has different sensitivity to drugs and there are obvious differences in the pharmacokinetics and pharmacodynamics of drugs among different individuals, the dose and interval of drug administration should be different from one person to another, and accordingly, the concept of individualized medicine is proposed. The following is a review of individualized medicine for glaucoma.
1. Classification of glaucoma drugs
1.1 Adrenergic receptor blockers
The main β-adrenergic receptor blockers that are widely used in clinical practice are timolol and betaxolol. Their mechanism of lowering IOP is through the inhibition of atrial fluid production. Their side effects mainly include bronchoconstriction and heartbeat slowing, blepharoconjunctivitis, and causing or aggravating dry eye symptoms.
1.2 Cholinomimetics
These drugs have a pupil constricting effect, the clinical application is commonly known as pupil constricting agents. The mechanism of action is to open the anterior atrial aqueous drainage pathway and expand the trabecular meshwork, improving the ease of atrial aqueous outflow. The side effects are mainly headache, decreased visual acuity, and long-term use can lead to post-iris adhesions and even cause more serious fibrinoid iritis.
1.3 Prostaglandins
This type of drug is a new type of anti-glaucoma drug, currently clinically used mainly latanoprost and travoprost. The mechanism of action is mainly to increase the ease of atrial aqueous outflow and increase the outflow of atrial aqueous from the sclera and uvea. The side effects are rare, but mild conjunctival congestion, allergic symptoms and thickening and lengthening of eyelashes are occasionally seen.
1.4 Sympathomimetic drugs
They are adrenergic agonists that excite alpha and beta receptors and can effectively lower IOP. Its mechanism of hypotensive action is to increase atrial aqueous discharge and also partially reduce atrial aqueous production. The main drugs used clinically are colistin and akathisia. Its common side effects include local congestion, lacrimation and dry mouth, while systemic side effects may include tachycardia, arrhythmias and hypertension.
1.5 Topical carbonic anhydrase inhibitors
The main systemic oral drugs are vinpocetine tablets and the main local drugs are brinzolamide. The mechanism of action is to inhibit carbonic anhydrase related to atrial fluid secretion, thus reducing atrial fluid secretion. Long-term oral administration of this drug may lead to adverse reactions such as numbness of hands and feet, gastrointestinal dysfunction, etc. Local adverse reactions in the eyes are commonly burning sensation, stinging and lacrimation.
1.6 Systemic therapeutic drugs
Mainly hypertonic dehydrating agents, and mannitol as the representative, through increasing the plasma colloid osmotic pressure to reduce intraocular pressure. Excessive or prolonged application of these drugs may cause dehydration and electrolyte disorders.
1.7 Neuroprotective drugs
The main clinically used drugs are erythropoietin, Memantine, neurotrophic factor, Betuxol and Niprolol. Most of the optic neuroprotective pathways and agents of these drugs are still at the stage of animal experiments or in vitro experiments, and their side effects need to be further studied.
2.Pharmacogenomics
The response of the organism to drugs is related to the cause and extent of the disease, drug interactions, individual age and nutritional conditions, liver and kidney function and co-morbidities. In recent years, it has been found that genetic variation, i.e. single nucleotide polymorphism (SNP), plays a significant role in drug effects. SNP refers to the phenomenon that the majority of nucleotide sequences in the same chromosome or nucleotide sequence of the same locus in different individuals are the same, but only one of the bases is different, mainly manifested as SNPs can also occur in genes that are not identical.
SNPs can also occur in regions other than the protein-coding region of a gene and affect the function of the gene by altering the regulation of the gene in question. Pharmacogenomics refers to the entire spectrum of genes that determine drug performance and sensitivity, but it is often customarily defined as the narrower spectrum of genes that determine drug metabolism and distribution. Thus, it can be said that the basis of pharmacogenomics research is SNPs.
The earliest records of individual diversity in drug response date back to the 1850s. It is now clearly known that many drug metabolizing enzymes, targets of action, and transporters have genetic polymorphisms, and the clinical significance of many of these has been elucidated. For example, the effects and toxic responses of many drugs are closely related to drug metabolizing enzymes and drug sites of action (e.g., receptors). Thus, the ultimate goal of pharmacogenomic research is to be able to select the appropriate drug and dose for each patient based on genetic differences in metabolism, excretion, and response to the drug in each patient.
3. SNPs and drug effects and toxicity
3.1 β1 receptors and SNPs
β1 receptor blockers are widely used to treat various types of glaucoma, but the ineffectiveness of these drugs in some patients remains a clinical headache. β1 receptor is a cell surface receptor encoding the gene ADRB1, which is localized on chromosome 10q24-26. Stephen GS et al [12] studied the response to betaxolol hydrochloride in 48 volunteers and found that the coding gene of β1 receptor gene polymorphisms significantly affected the individual response to the drug. This study identified two prevalent SNPs: Ser49Gly and Gly389Arg.
The study suggests that Gly389Arg is strongly associated with the efficacy of betaxolol and may play an important role in the prevalence of glaucoma in African Americans. It was concluded that Arg389 pure-identical volunteers had higher basal intraocular pressure and a more pronounced IOP-lowering response to betaxolol hydrochloride than Gly389 carriers and was independently associated with basal intraocular pressure and the response to betaxolol hydrochloride pressure reduction.
3.2 β2 receptors and SNP
The distribution density of β2 receptors is higher in the iris and ciliary body than that of β1 receptors; therefore, their utility in regulating atrial aqueous dynamics is dominant and thus more clinically significant than that of β1 receptor SNPs. catherine AM et al. identified two SNPs encoding the gene ADRB2: Arg16Gly and Gln27Glu. by regression analysis, it was found that The CC-type gene in Gln27Glu achieved a statistically significant IOP-lowering effect of 20% or more. the opposite conclusion reached by Gabriele FM et al. may be related to the fact that the study was conducted in a normal population and other influencing factors. Since these drugs are the cheapest topical ophthalmic antihypertensive drugs, efficacy studies on these drugs can greatly reduce medical costs and the financial burden on patients.
3.3 β3 receptor and SNP
Catherine AM et al. identified a β3 receptor SNP: Trp64Arg. No differences in drug response were found among the three genotypes CC, CT and TT encoding this gene. Therefore, the real β3 receptor SNP that determines the drug response needs to be further investigated.
3.4 PGF2α receptors and SNPs
Prostaglandin (PG) drugs exert their IOP-lowering effects mainly by binding to prostaglandin receptors in the eye. PGF2α receptors are found in many ocular tissues, such as corneal epithelium, ciliary epithelium and ciliary muscle Latanoprost is a PGF2α analogue that binds to the PGF2α receptor. The gene encoding this receptor is localized at 1p31.1. Sakurai M et al. identified 10 SNPs of the PGF2α receptor by studying 100 healthy volunteers in response to prostaglandins.
Two of these SNPs-rs3766355 and rs3753380-were associated with short-term therapeutic effects of latanoprost and may have contributed to the different responses to latanoprost in the volunteers. peng Hoh-Boon et al. identified a novel by studying 76 glaucoma patients in Malaysia This mutation may create a new SNP and its effect on the efficacy of prostaglandin therapy needs to be further investigated.
3.5 Drug metabolizing enzymes and SNPs
Timolol has been used as a first-line agent in open-angle glaucoma since its use to lower IOP in the late 1870s, with a maximum effective concentration of 0.5%. It is metabolized in the liver by cytochrome oxidase P450 (CYP2D6), which is classified as fast-, intermediate-, and slow-metabolizing in the population. The two SNPs were analyzed and found to be statistically insignificantly different in terms of their IOP-lowering effects. However, the Arg296Cys SNP was associated with either a heart rate slowing side effect or a weak IOP lowering effect of timolol: the CC genotype of Arg296Cys had a role in preventing the occurrence of heart rate slowing side effects of timolol.
3.6 Drug toxicity and SNPs
Drug metabolizing enzyme polymorphisms determine individual blood levels, while polymorphisms in receptor genes determine the natural response of individuals to drugs. It can be inferred from this that drug toxicity is non-specific. However, certain apparent toxic responses are still associated with drug receptor SNPs. Therefore, for those individuals with purely conforming wild-type (non-mutant) drug-metabolizing enzymes and receptor genotypes, the drug will produce the greatest therapeutic effect and the least toxic response. Today, drug toxicity can be classified into two types: type A and type B. Type A toxicity is associated with blood levels and may be a single gene-determined, non-specific response. Lennard MS et al. found that the activity of timolol correlated with the phenotype of isoquinoguanidine oxidase – fast versus slow metabolizers. For individuals with slow metabolism, timolol will be more likely to produce side effects associated with blood levels.
4. Prospects of pharmacogenomics in individualized therapy
The core of rational drug use is to design clinical individualized drug regimen according to the relationship between individual variation and pharmacological differences in order to give full play to the effect of drugs on the organism, which not only increases the effectiveness of the first dose prescription, but also reduces the toxic side effects of patients and lowers the cost of drug use. Based on the continuous development of genetic analysis technology, molecular diagnostic technology and drug proteomics knowledge, combined with the consideration of the influence of environmental factors such as age, weight, diet, smoking and alcohol, so as to develop a reasonable individualized drug administration scheme.
5.Outlook
The genetic structure of the patient, especially the mutated genetic structure, is used to select the drug and give the appropriate dose to the patient, which is called the “gene-directed drug use model”. The physician can take targeted pharmacogenomic tests according to the characteristics of the patient’s disease, so as to create the patient’s “individual medication business card” and take targeted drug treatment, which can improve the efficacy of drugs, reduce drug toxicity, shorten the treatment time and improve the quality of life of the patient.
Although the current application of pharmacogenomics has shortcomings such as insufficient pharmacogenetic database, unknown drug response mechanism, huge workload and high cost, with the progress of science, it is believed that in the near future, with the change of drug treatment model, gene-oriented individualized drug use will provide an important way for safer, more effective and more economical rational use of drugs.