Glaucoma is a neurodegenerative disease leading to irreversible blindness in millions of people worldwide [1]. Raised Intraocular pressure (IOP) is usually considered the major modifiable risk factor to prevent further progression. According to recommendations of the American Academy of Ophthalmology, a 25% reduction in IOP from the baseline is the basic objective of the initial treatment in primary open-angle glaucoma (POAG) [2]. Primarily treatment starts with topical antiglaucoma drugs but when medications fail to control IOP, then ophthalmologists consider patients for trabeculectomy or laser trabeculoplasty to minimize disease progression [3].

Several risk factors including cardiovascular diseases, Hypertension, Diabetes, Myopia, and Smoking have been found to be associated with glaucoma [4]. These multimorbid patients face the problems of polypharmacy while physicians, on the other hand, face challenges as they are more focused on individual disease and may overlook or pay little attention to other diseases and drugs [5]. Concomitant use of antiglaucoma and systemic drugs to treat comorbidities can cause drug interactions and serious side effects [6] , as well as the non-affordability and inconvenience of therapy, may result in failure to achieve its goals. Moreover, it may have a negative impact on the efficacy of prescribed drugs and ophthalmologists may tend to change the therapy unnecessarily [7]. On the basis of the above facts and as per estimations, only 50% of patients adhere to their treatments in developed countries and this problem can be expected to be more worse in developing countries [8].

Pharmacoepidemiology is a new branch of clinical pharmacology that provides insight to investigate drug utilization in real- life conditions. It is the study of the interaction of drugs and society [9]. Monitoring drug utilization is an important tool to determine the drug’s impact on evidence-based prescribing and healthcare system decisions. Auditing of prescription patterns can identify the gaps in providing quality health care by physicians through proper feedback and awareness about appropriate drug utilization [10]. Therefore hospital, as well as population-based epidemiological studies of drugs with respect to their clinical usage, interactions, and side effects, are necessary to enhance better understanding of the rationale, cost-effectiveness, and adherence in order to achieve treatment objectives.

Pakistan is a developing country and there is a lack of such types of studies. So, to update our physicians and for better understanding to optimize rational drug therapy in real-life conditions, we decided to conduct an extensive pharmacoepidemiological study of drugs in multimorbid glaucoma patients with special emphasis on hypertension and diabetes mellitus type 2. The objective of this study was to evaluate the prescription pattern and utilization of drugs in glaucoma patients with comorbidities like hypertension and diabetes mellitus type 2. We also checked any change in the drug regimen of patients after visiting the glaucoma specialist (Pre and Post visit).

A descriptive, cross-sectional study was conducted in the outpatient department of glaucoma, Al-Shifa trust eye hospital, Rawalpindi Pakistan from April 2021 to October 2021. The study was performed in full compliance with the declaration of Helsinki 1964 and formal permission was obtained from ethical committees of Al-Shifa Trust Eye Hospital & University of Malakand before the commencement of this study.

All patients presenting at glaucoma clinics with ages between 20 years and above, irrespective of gender, were included in the study. Patients who refused to take part in the study were excluded from the study. A non-probability convenience sampling technique was employed to recruit participants.

Data regarding patients’ clinical history, presenting complaints, history of glaucoma in the family, and other socio-demographics were recorded in a predesigned proforma. Comorbidities including Hypertension and Diabetes type 2 and detailed medication history were also recorded. Patients were asked about any side effects they experienced while using ophthalmic drugs in combination with antihypertensive and antidiabetic medications. The collected medication data was reorganized and rearranged by taking help from a privately published quick drug reference book PharmaGuide Pakistan (28th Edition, 2019-20) for active ingredients, company name, pharmacological drug group, and market price. Percent utilization of total ophthalmic, antiglaucoma, antihypertensive, and antidiabetic drugs was calculated. Percent occurrence of side effects, comparative utilization of antiglaucoma drugs in hypertensive and diabetic patients, and Prescription of antiglaucoma drugs pre and post-visit to glaucoma specialist was also compared. Different dosage forms and status of change in drug regimen were also noted.

All of the data was evaluated by using SPSS 25 software and descriptive statistics were presented. Mean, standard deviation, the maximum limit, and percentage were calculated for the variables.

During the prescribed period 876 patients were interviewed. Table 1 indicates 74% (n=648) of patients were treated free of cost (Charity/Zakat), 511 (58.3%) were males, collectively more than 50% belonged to the age group of 50-70 years and 219 (25%) were addicted to tobacco use. Comorbidities data indicates that 238 (27%) and 165 (18.8%) glaucoma patients were hypertensive and diabetic respectively. Out of hypertensive patients, 143 (60.1%) were females while diabetes mellitus distribution in males 84 (50.9%) and females 81 (49.1%) was almost equal. Eighty-three (9.47%) patients were having both hypertension and diabetes while 194 (22%) patients were suffering from other systemic diseases like Asthma, Depression, Arthritis, Tuberculosis, Gastric issues, Cardiovascular problems, etc.

Out of 876 patients, 82 (9.4%) were glaucoma suspects. Amongst the rest, 687 (78.3%) and 92 (10.5%) had open-angle glaucoma and angle closure glaucoma respectively. Amongst hypertensive and diabetic patients, the prevalence of open-angle (>70%) and angle closer-glaucoma (>12%) was almost the same. Besides glaucoma, other ocular diseases were found in 22.9% of total glaucoma patients but this occurrence was a little higher in hypertensive (23.1%) than in diabetic (17%). Cup disc ratio (CDR) was >0.8 in 868 (49.54%) of eyes in total glaucoma patients while this ratio was 0.6 to 0.8 in 34.24% and 43.64% of eyes in hypertensive and diabetic patients respectively. Visual fields defects limits were outside normal in 33% eyes of all glaucoma patients with equal occurrence in hypertensive and diabetic patients.

The prescription pattern of ophthalmic drugs, dosage form, and post-visit status are explained in Table 2. In the majority of patients, 1 or 2 ophthalmic medications (Including Antiglaucoma) were prescribed (29.3% and 27.9% respectively). In 634 (72.4%) patients topical antigalaucoma drugs were prescribed and eye drops were the most commonly prescribed dosage form1505 (97%). In 50% of patients, ophthalmologists decided not to change the drugs but in 41% of patients, they decided to change (either added, deleted, or changed the existing drug) the prescription for glaucoma patients. 100% of drugs were prescribed by their brand name.

The percent utilization of ophthalmic medication in glaucoma patients with comorbidities is exhibited in Table 3. Antiglaucoma drugs were equally prescribed in hypertensive 229 (71.02%) and diabetic 220 (72.85%) patients as compared to total glaucoma patients 1138 (73.23%). Artificial tears were prescribed in hypertensive and diabetic patients in 9.98% and 6.29% respectively along with antiglaucoma drugs. During post visit, a decrease was noted in lubricants, an increase in antiallergics, and almost no change in antiglaucoma drug prescriptions.

The percent utilization of different groups of antiglaucoma drugs is shown in Table 4. Fixed-dose combinations (FDCs) were the most prescribed drugs in all glaucoma patients 380 (33.39%) including hypertensive 102 (34.11%) and diabetic 81 (36.82%) patients followed by prostaglandin analogs 331 (29.09%) prescribed in all glaucoma patients including 83 (27.76%) and 62 (28.18%) in hypertensive and diabetic patients respectively. Latanoprost (67.74%) was more prescribed in diabetics while travoprost (37.35%) was more prescribed in hypertensive patients. The above 80% prescribed fixed-dose combination was Dorzolamide + Timolol maleate in all glaucoma patients as well as in hypertensive and diabetic patients. Beta-blockers were the least prescribed drugs in all groups. Alpha 2 agonists and CAIs were prescribed in 19.07% and 10.81% respectively of all glaucoma patients. Brimonidine tartrate was the only alpha 2 agonist equally prescribed in all groups. Amongst antiglaucoma drugs, beta-blockers were prescribed slightly less in number in post-visit 59 (5%) as compared to pre-visit 81 (7.12%). An increase was noted in the prescription of brinzolamide eye drops in post-visit (from 87.8% to 98.50%) while utilization of acetazolamide (oral tablets) was decreased to 1.5% from 12.20%. The use of latanoprost was slightly decreased in post-visit as compared to travoprost.

The percent utilization of systemic antihypertensive and antidiabetic drugs in glaucoma patients is shown in Table 5. Beta-blockers 46 (27.2%) were the most utilized antihypertensive drugs followed by Angiotensin 2 receptor Antagonists 37 (21.9%) and calcium channel blockers 34 (20.1%). Sulfonylureas 69 (45.39%) were the most utilized hypoglycemic agents followed by biguanides 55 (36.18%) and combinations of various drugs 16 (10.53%). Only seven patients with DMT2 were using subcutaneous insulin. 60.1% and 81.21% of hypertensive and diabetic patients were aware of their systemic drugs respectively.

The frequency of adverse effects of ophthalmic medications among the patients is illustrated in Figure 1. Amongst a total of 1554 eye medication utilized only 54 (3.47%), side effects were noted. Burning of eyes 15 (28%) was the most prominent side effect noted followed by ocular allergy or itching 9 (17%) and lacrimation 7 (13%).

Figure 1: Frequency of Side Effects of Ophthalmic Medications in Glaucona Patients (Total eye medication utilized=1554, Total side effects noted=54, Precentincidence=3.47%)

Out of 876, 27% and 18.8% of glaucoma patients were hypertensive and diabetic respectively, 9.27% were suffering from both hypertension and diabetes mellitus type 2 while 22% were having other systemic diseases. Like glaucoma other comorbidities especially hypertension and diabetes mellitus also need to treat for a long-life period. Due to the use of multiple therapies, there are chances to develop drug-induced glaucoma and other ocular disorders [11]. There is a scarcity of local literature pertaining to the topic however, our study findings are in accordance with previously published international literature. For instance, a study was done by Talaat et al. [12] concerning the comorbidities and types of glaucoma in Jeddah, Saudi Arabia. Hypertension was one of the most common comorbidities associated with glaucoma (61%) followed by diabetes mellitus (58%) and dyslipidemia (33.6%). However several studies argue that a higher rate of hyperlipidemia is seen with glaucoma [13, 14]. Previous studies also argue (Chen et al.) about increased cases of glaucoma seen in patients who were prescribed statins [15].

We found that antiglaucoma medications were prescribed to both hypertensive and diabetic patients without any difference in the dosage and pharmacological group. All the drugs were prescribed by their brand names. Although it is a routine practice of prescribing drugs in Pakistan and there is no law available to prescribe generic medicines. However, currently, there is an emphasis on the prescription of drugs by their generic names worldwide and the Pakistani Government also highlighted to use of generic medicine to cope with the high medication costs [16].

Eye drops were the most commonly prescribed dosage form (97%) and in the majority of patients, 1 or 2 ophthalmic drugs were prescribed. Our results were almost consistent with an Indian study where eye drops were prescribed the most (77%) but per prescription drugs were 2 or 3 in the majority of cases [17]. Similar results were also found in a study conducted in Dhaka, Bangladesh [18]. During the visit of patients, ophthalmologists decided not to change the therapy in 50% cases which mean patients were stable and doctors were satisfied with the outcome of therapy. On the other hand, in 41% of patients depending upon their glaucoma profile, comorbidities, and treatment outcomes, drugs were either deleted, added, or substituted with another antiglaucoma drug.

To the best of our knowledge, this is the first study conducted in Pakistan with such extensive pharmacoepidemiology among glaucoma patients with comorbidities like hypertension and diabetes mellitus type 2.

In our study, Combinations of fixed doses of drugs were the most prescribed drugs (>30%) and given to all glaucoma patients irrespective of comorbidity. It was similar to other countries where fixed-dose combinations (FDC) are frequently prescribed as they lower the number of drops, improve treatment adherence, [19] provide dose regimen simplicity, avoidance of washout effect [20], and ultimately the cost of treatment. Dorzolamide and Timolol were given most of the time (>80% of FDCs) as a fixed-dose combination in hypertensive, diabetic, and glaucoma patients. It was in contrast to a study in India where Brimonidine + timolol was prescribed in 81.48% and Dorzolamide in 22.31% [21]. In our study, Brinzolamide (>87%) was the most prescribed drug among carbonic anhydrase inhibitors. After FDCs, prostaglandin analogs were equally the most prescribed drugs as a single agent in hypertensive (27.76%), diabetic (28.18%), and all glaucoma patients (29.09%). Amongst them, latanoprost was a highly prescribed antiglaucoma drug (>60% of its class). Beta-blockers were the least prescribed drugs amongst all antiglaucoma groups (up to 7%) and the most commonly prescribed beta blocker was Timolol maleate in all patients with glaucoma. These findings were in contrast to another Indian study where prostaglandin analogs were prescribed in 17.88% and amongst them, bimatoprost was prescribed more as compared to latanoprost. Beta-blockers were the most prescribed antiglaucoma as a single drug [22]. A study conducted in Nigeria also showed very different results of antiglaucoma drug utilization. They concluded that 34.6% of utilization of CAIs flowed by beta blockers (31.9%) and Prostaglandin analogs (26.2%) [23].

Systemic antihypertensive drugs are potentially associated with the progression of glaucoma. So these must be considered in relevant patients [24]. In our current study systemic beta-blockers were being used the most (27.4%) by glaucoma patients with comorbid hypertension. As it is documented, co-prescribing topical beta-blockers in patients already taking systemic beta-blockers is inappropriate. So, it is obvious that our prescribers are well aware of this interaction. That’s why they have prescribed very low (7%) topical beta blockers to control glaucoma. As stated in a study conducted in Australia and authors concluded that prescribing topical beta-blockers in patients using systemic beta blockers is totally inappropriate and it affects patients, especially the elderly. So awareness programs regarding increased side effects and reduced efficacy for health care providers and patients must be arranged [25]. Another valid reason for low prescribing beta-blockers may be the availability of more effective and safer drugs like prostaglandin analogs as depicted in our study. According to Yen et al. [26] beta-blockers now don’t remain the first choice for the treatment of glaucoma as compared to prostaglandin analogs because of their higher systemic side effects and lower efficacy. But, as a second-line treatment especially in FDCs, beta blockers are still prescribed. However, the selection of appropriate antiglaucoma drug as a first choice is dependent upon the patient’s ocular and systemic comorbidities [26]. Alpha 2 agonists were equally prescribed to both diabetic patients and hypertensive patients. Brimonidine Tartrate was the only alpha 2 agonist, however, prescribed in glaucoma patients.

Only a 3.47% incidence of side effects of ophthalmic drugs was noted in our study. Burning of the eyes was seen as the most common side effect (28%) followed by ocular itching (17%) and lacrimation (13%). Surprisingly, a study of only 50 patients in India indicates the occurrence of side effects of ophthalmic drugs in 50% of patients [27].

Association between diabetes mellitus type 2 and glaucoma always remained a question. Several controversies are present in the literature. Oral hypoglycemic agents were frequently studied in context with the progression of glaucoma, as a higher trend of increased IOP in patients using Sulfonylureas was stated in both SEED and EPIC Norfolk Eye Studies. An increased IOP was reported in diabetics as compared to non-diabetics in the rotterdam eye study [28]. In our current study sulfonylureas were used the most (45.39%) in glaucoma patients with comorbid diabetes mellitus type 2 followed by biguanides (36.18%). As per The Singapore Epidemiology of Eye Diseases Study, diabetes was declared amongst the major risk for glaucoma, and hypoglycemic agents like sulfonylureas and biguanides were associated with an increase in IOP (>1mmHg) which translated into a 14% greater risk to induce glaucoma. Sulfonylureas belong to sulfonamides (Sulfa drugs) and may have the potential to induce side effects similar to other sulfa drugs because of structural similarities [29]. Carbonic anhydrase inhibitors (CAIs) like acetazolamide, dorzolamide and brinzolamide are another groups of antiglaucoma drugs, also belonged to sulfonamides [30]. So the concomitant use of sulfonylureas and CAIs may potentiate the systemic side effects of each other. In our current study, CAIs were prescribed to up to 11% of glaucoma patients with comorbid diabetes mellitus type 2 whereas prostaglandins were prescribed the most after FDCs. The CAIs were prescribed less in diabetics as compared to hypertensive patients. It showed the ethical approach of our prescribers while treating glaucoma patients by keeping in mind the comorbidities and systemic medications.

We also compared the percent utilization of antiglaucoma drugs pre- and post-visit of patients to ophthalmologists and we found no prominent difference between the two except brinzolamide. It means our glaucoma patients were stable and prescribers were satisfied with the outcomes of the treatment given to them. So, no significant change in the drug regimen of the patients took place during their visit to the ophthalmologist.

A study was conducted in Ghana on the clinical prevention of glaucoma in a referral facility and its impact on public health [31]. The authors advocated screening of personnel in the workplace since many patients were employed and were unaware of the disease and its treatment. This was similar to our study where 39.9% of hypertensive patients were unaware of their systemic drugs while 81.21% of diabetic patients know about their drugs was quite encouraging. So, the knowledge about systemic drugs is crucial both for patients as well as for ophthalmologists and this can be improved by maintaining a proper history of patients.

Using combinations of multiple drugs poses a serious problem among glaucoma patients with multiple comorbidities is that they are at risk of non-adherence and show non-compliance towards the treatment regime. The risk of adverse effects and drug-to-drug interactions is also increased [32]. Therefore, an adequate amount of pharmacological knowledge of drugs, particularly pharmacodynamics, adverse reactions, and interactions is a must for a practicing ophthalmologist. Therefore, it is advised that health policies should be developed that facilitate the increasing awareness of both physicians and patients about the drugs prescribed and their possible interactions with the systemic medications. It is also important to take a thorough history of comorbidities and medications. As most patients do not remember the name of the medications they are taking, the prescriber should request the patient to bring the name of the medicines on the next follow-up.

The current study highlights the need for rational prescribing of antiglaucoma drugs in multimorbid patients to avoid the hazards of polypharmacy and the importance of creating awareness of pharmacological actions, drug interactions, and side effects of drugs among physicians. Further studies should explore the factors causing non-adherence to antiglaucoma medication among patients using multiple drug therapies.

We highly acknowledge the cooperation and support of Glaucoma department, Al-Shifa trust eye hospital, Rawalpindi Pakistan to conduct this study.

This research paper received no external funding.

The authors declare no conflicts of interest.

Muhammad Sadiq (Concept, Design, Data collection, Data analysis, Literature review, Manuscript writing). Mahmood Ali (Manuscript writing, Data collection, Design, Data analysis). Waqar Ahmad (Review, Supervision, Design). Mir Azam Khan (Concept, Review, Manuscript writing). Farah Akhtar (Review, Supervision, Data collection)

Informed consent was obtained from all participates in the study as needed.

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