Traditionally, emergency responses were largely focused on accident or trauma-related incidents. However, an ageing and more sedentary population, often presenting with comorbidities, make adverse drug reactions (ADRs) and drug interactions (DIs) an increasingly likely cause. Rapid developments in the pharmaceutical industry also associate presentations with poly-pharmacy incidents. Therefore, the healthcare industry is seeing a changing paradigm in causes for emergency calls, often including the complexities of pharmacology (Martin, 2012).
Medications in the UK have clear regulatory laws that are governed by the Medicines and Healthcare Products Regulatory Agency (MHRA). This is an executive agency of the Department of Health (MHRA, 2014). The formal regulation of medical devices began in the 1990s by a European-wide initiative. This was instigated by the medication thalidomide, used to treat morning sickness; however, it had severe unpredicted birth defects. Now medications must first be considered safe, i.e. the benefits outweigh the side effects caused, and then licensed or given marketing authorisation (MHRA, 2014). Licences for medicines are granted only when a product meets high standards of safety, quality and works for the purpose intended. The regulatory system also imposes rigorous standards on medicines manufacturers and wholesale dealers who trade in them (MHRA, 2012).
These medications are closely monitored via the General Practice Research Database (GPRD). The GPRD is an internationally recognised database which is used to research safety and effectiveness issues of licensed medicines, as well as improve the understanding of disease. The database contains the anonymised records of patients registered at more than 480 general practices across the UK, making it the largest and most validated population-based database in the world, which details illness, investigations, and treatment.
Patients have the choice of allowing their records to be used in this way, and all access to the data and research is strictly regulated (MHRA, 2012). The MHRA's Defective Medicines Report Centre (DMRC) issues alerts to healthcare professionals, for example informing them when a medicine is being recalled or when there are concerns about the quality affecting its safety or effectiveness. The MHRA provides a clear, complete and regularly updated list of prescription only medications (POMs), including the substance, maximum strength, route, limitations and maximum quantity of the substance (MHRA, 2010). Also included is guidance provided for pharmacists and the regulatory body, the General Pharmaceutical Council, ensuring high standards are maintained.
In comparison to the United Arab Emirates (UAE), there is no continuity across areas. Each location, such as Abu Dhabi and Dubai, have differing legislations as there are two differing governing bodies, the Health Authority Abu Dhabi and the Ministry of Health. There is no obvious clear list of POMs available, forcing pharmacists to draw on experience and decide what they sell. Therefore, should you visit two different pharmacies within Abu Dhabi, one may refuse to sell you a medication without a prescription whereas the other will.
In this review, a patient purchased metformin, glipizide and simvastatin without a prescription and therefore having never seeing a physician, thus avoiding a diagnosis as well as the necessary education required to maintain their health.
On the other hand, there are stricter regimes in place for the purchase of controlled drugs in the UAE. For example, codeine may be purchased over the counter in the UK at certain doses; however, it cannot at all in the UAE without prescription. Again though there is no clear list, the pharmacist is not updated on this but formulates a list based on how difficult it was to purchase from a wholesaler. This therefore can cause logistical difficulties for ambulance services in the country where pain medications such as fentanyl are administered. Referencing this information is difficult due to the lack of regulation, this information has therefore been gathered from pharmacists employed in the area. Further research and documentation is required in pharmaceutical safety in the UAE.
Medications reviewed
Details of the medications reviewed in this article can be found in Box 1.
Adverse drug reactions
Adverse drug reactions (ADRs) are an important public health issue (Lee, 2006). When drugs are taken and distributed, their effects are unlikely to be restricted to the target receptors. They may fit other receptors which can produce unwanted effects (British Medical Association, 2008). ADRs are ‘unwanted or harmful reactions experienced after the administration of a drug, or combination of drugs’ (Lee, 2006). They can be divided into two groups: the predictable reactions (Type A), and the more rare and abnormal reactions (Type B). The predictable reactions are relatively common, usually not serious and can be resolved through reducing dosages. Rarer reactions are unrelated to the drugs normal pharmacology, but tend to be more serious. Stopping and avoiding the drug is the only method to resolve these reactions (Rawlins and Thompson, 1991). The specified medication regime (mostly unprescribed) was reviewed and researched, with the possible ADRs recorded (see Appendix 3).
The most significant potential ADR found is lactic acidosis, a metabolic non-hypoxic acidosis caused by metformin build up. Although unlikely in healthy adults, if renally impaired it is a severe and possible ADR (Wilson, 1997). However, if appropriately prescribed, the risk of this ADR would be minimal (Bailey et al, 1992).
Metformin is a biguanide, which lowers blood glucose by reducing its absorption from the digestive tract into the blood stream. It reduces glucose production in the liver and kidneys, and increases sensitivity of cells to insulin so glucose is absorbed more effectively (British Medical Association, 2008). It is the preferred treatment of insulin resistant (type II diabetes) overweight patients because of its additional benefit of lowering plasma triglyceride levels (Simonsen et al, 2006), and therefore a promising treatment for this patient. Unlike sulfonylureas, metformin is not bound to plasma proteins so it is not metabolised, increasing its half-life and allowing it to be eliminated rapidly by the kidneys (Bailey et al, 1992). If the kidneys are not functioning effectively metformin builds up, leading to acidosis (Bailey et al, 1992).
Metformin increases anaerobic metabolism even in the presence of oxygen by decreasing the activity of the enzyme, pyruvate dehydrogenase, and the transport of mitochondrial reducing agents. This non oxygen-dependent hypoxia, in the presence of insulin, increases production for the tricarboxylic acid cycle (Price, 2003). This includes the inhibition of the pyruvate dehydrogenase channels, forcing the body to convert pyruvate in to lactate (Fitzgerald et al, 2009). Renal impairment causes the reduced elimination of metformin as well as lactate, therefore increasing acidosis, which if unrecognised can have severe consequences. This patient may be more susceptible to this ADR as the patient may not suffer with low levels of insulin, and so encouraging the tricarboxylic acid cycle further. Metformin in itself, when used appropriately, is not a high risk medication (British Medical Association, 2008). However, if a healthy individual takes the drug long term it will still act on the body, lowering blood glucose levels, which in turn suggests that hypoglycaemia will be a more significant ADR in this case study.
Drug interactions
Drug interactions (DIs) ‘occur when the pharmacological profile of one drug is altered by the administration of another drug, resulting in weakened, enhanced or altered effects’ (Simonsen et al, 2006). This may be due to a pharmacodynamic interaction (i.e. acting on the same receptors), or a pharmacokinetic interaction (i.e. alterations in their concentration level). However, should an unexpected effect occur when several drugs are being taken simultaneously, a polypharmaceutical interaction is likely (Simonsen et al, 2006). This pharmacodynamic interaction increases in likelihood with the more medications taken. DIs are higher risk in patients with renal or hepatic impairment (Simonsen et al, 2006). Specifically in the described regime, oral hypoglycaemics act on the central nervous system and therefore may exhibit pharmacokinetic interactions.
Due to the medication regime being adhered to, the most significant potential DI discovered is the pharmacokinetic effect of liraglutide on the absorption of medications that pass through the gastrointestinal (GI) tract, i.e. all oral medications including metformin, simvastatin and candesar.
Liraglutide is a long-acting, glucagon like peptide-1 receptor agonist (Kanoski et al, 2011). It is a class of insulinotropic hormones which are secreted from the GI tract by enteroendocrine cells in response to the oral ingestion of glucose. Insulin secretion is increased due to the hormones action on the pancreatic b cells. This is known as the incretin effect, one of the postprandial insulin responses (Doyle and Egan, 2007). GLP-1 inhibits gastric secretion and motility delaying carbohydrate absorption, contributing to a satiating effect. Postprandial plasma levels of GLP-1 nearly eradicate antral and duodenal contractile activity (Schirra et al, 1997). The purpose is to maximise the extraction of carbohydrates from food ingested. As well as inhibiting mobility this peptide hinders gastric acid and pancreatic enzyme secretion (Schirra et al, 1997). This hormone has a strong vagal cholinergic effect, and so the administration of the drug Liraglutide mimics this effect (Fehmann et al, 1995). In type II diabetes gastric emptying is accelerated, which may be caused by insufficient volumes of this hormone, leading to inadequate uptake of carbohydrates (Frank et al, 1995). Therefore the administration of liraglutide helps delay this but in turn will influence the absorption of successive drugs such as metformin (Simonsen et al, 2006). Plasma concentrations of this drug will be lower than if liraglutide was not taken. It will cause an interaction affecting all the medications taken by the patient orally. On the other hand, if there is no clinical need for the patient to be administering these oral medications a delay in the effects will not immediately be a detriment. The native GLP-1 actions suppressing appetite and energy intake in both normal-weight and obese individuals may benefit some as it is shown to cause weight loss and decreased food intake (Astrup et al, 2009). The underlying mechanisms that mediate the effects of weight reduction of liraglutide are most probably a combination of effects on the GI tract and brain (Astrup et al, 2009).
Evidence for use of medications in type II diabetes
A randomised control trial based on number needed to treat by Nauck et al (2009) was carried out into the efficacy and safety of adding liraglutide to the primary medication of metformin in the treatment of type II diabetes over a 6-month period. Adult subjects with diagnosed type II diabetes were assessed using the HbA1c test. The HbA1c is the primary test in diabetes management, a blood test measuring the amount of glycosylated blood (Rothman et al, 2003). Subjects scoring between 7 and 11%, with a BMI of less than or equal to 40 kg/m2 were included. This investigation concluded pro use of liraglutide in conjunction with metformin in the treatment of type II diabetes, again suggesting that the patient under review is taking an effective medication for treatment of type II diabetes.
After undergoing screening criteria the study consisted of 1 087 subjects, randomly divided into five treatment groups. However, this could not be done evenly, therefore would this effect the validity of the results? The groups consisted of 0.6 mg, 1.2 mg and 1.8 mg once daily liraglutide, once daily 4 mg glimepiride and the placebo. Over a 26-week time period there was a decrease in the mean HbA1c values of subjects in all liraglutide groups compared to an increase in the glimipiride group. This suggests that liraglutide is a more effective treatment method. The most significant results were 0.1% decrease in mean HbA1c in both 1.2 mg and 1.8 mg once daily liraglutide groups, concluding that these values are optimal drug concentrations for glycaemic control. As you would expect the incidence of minor ADRs, such as nausea and vomiting, increased with dose concentration. However, these incidences decreased 2 weeks into the study, again suggesting liraglutide to be an effective and safe treatment.
Using the BMI as subject criteria reduces the risk of obesity in subjects and this effect on the pharmacokinetics of medications, therefore making the results of the trial more reliable and relevant to this review. The measurement of HbA1c in this investigation was the end point, following standards set by the National Glycohemoglobin Standardisation Program (NGSP) for the United Kingdom Prospective Diabetes Study (UKPDS) (NGSP, 2014). Secondary end points included changes in body weight, fasting plasma glucose, seven-point plasma glucose profiles (before each meal, 90 minutes after breakfast, lunch and dinner, and at bedtime), and beta-cell function based on fasting insulin, fasting C-peptide, and fasting proinsulin to insulin ratio. Increasing the number of end points improves the reliability of final results, provides an exclusion criterion for anomalous results, and allows analysis on the intent to treat population.
HbA1c levels were also the end point of the UKPDS (1977–1997), one of the largest scale studies into type II diabetes with a subject number of 5 102. The scale of this study increases its reliability. This study showed a positive correlation between HbA1c levels and the risk of developing diabetic complications, therefore standardising HbA1c as a measurement criteria in diabetes. Although now outdated, it has still provided a single reference standard for risk assessment in type I and type II diabetes (The Oxford Centre for Diabetes, Endocrinology and Metabolism, 1997).
The evidence supporting the conclusion from Nauck et al (2009) consists of statistical analysis of the subjects recorded HbA1c levels. The results were obtained through carrying out a double blind quantitative study, reducing the risk of bias and interference. The constants were that each subject was treated with metformin and went through the same assessment structure before selection: they met a certain criteria, for example 7–11% HbA1c levels, ensuring consistency. The results were analysed using an analysis of covariance model with treatment, country, and previous treatment as fixed effects and baseline as the covariate. However, the baseline characteristics appeared consistent across each treatment group.
Conclusions
Overall, the medication regime may be effective in treating type II diabetes; however, the risk of possible ADRs and DIs is increased when self-prescribing medications. A general practitioner plays a large role in monitoring your medication regime and underlying condition. However, due to lack of clear legislation, self-medicating is a regular occurrence in the UAE. A more uniformed and clear list similar to that of Europe and the UK needs to be put in place as well as clear guidance for those in the pharmaceutical industry.