Clinical pearls: Race-conscious and personalized medicine — What pharmacists can do to acknowledge race-based and genetic variations that affect drug therapy
March 14, 2022
Written by Bhawani Jain
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We all have different genetics and backgrounds, so why should everyone receive identical medical treatment for a diagnosis or condition? Personalized medicine is on the rise, with medical treatments tailored to a patient’s unique characteristics, such as genetic differences and environmental conditions. Genetic testing for every patient may not always be necessary, and it can be difficult to achieve due to cost and a lack of resources. Nevertheless, for hospital pharmacists it is important to understand that drug treatments may not work universally for all patients. Quality patient care can sometimes require hospital pharmacists to consider genetic variations that may impact medication therapy. As such, this article examines three genetic variations that are prevalent among specific populations, and how these differences may influence the pharmacists’ choice of drug treatment.
Aldehyde Dehydrogenase 2 mutation (ALDH2*2) among East Asian individuals
Approximately 45% of people of East Asian descent (about 560 million people and 8% of the global population) have the genetic variation ALDH2*2.1,2 The aldehyde dehydrogenase 2 (ALDH2) enzyme is important for metabolizing toxic and reactive aldehydes in the body to non-reactive carboxylic acids.1 A loss-of-function point mutation in this enzyme (ALDH2*2) results in an inability to metabolize these toxic aldehydes, which then accumulate in the person’s body. For example, rather than being metabolized via the ALDH2 enzyme, alcohol is converted into acetaldehyde in the liver. Those with ALDH2*2 accumulate acetaldehyde in their body after consuming alcohol, causing facial flushing as well as nausea and tachycardia.3
Along with the metabolism of aldehydes, ALDH2 also metabolizes nitroglycerin to nitric oxide, a vasodilator used to prevent and treat angina and acute myocardial infarctions (heart attacks), among other uses.2 The conversion to nitric oxide by ALDH2 is important for vasodilation. Compared to someone without the mutation, those with ALDH2*2 are 10 times less able to convert nitroglycerin to nitric oxide, and they require about 40% more nitroglycerin to achieve the same therapeutic response as someone without the mutation.4 Hospital pharmacists should be aware of the effect of ALDH2 on metabolism of nitroglycerin. This may impact decisions regarding the use and dosage of nitroglycerin in multiple settings, including cardiology, emergency medicine, and obstetrics (where nitroglycerin is used to relax the uterus). It is important for hospital pharmacists to gauge the efficacy of nitroglycerin for these patients. They may also consider dose increases or alternative medications, such as nitroprusside, that are not affected by ALDH2.4
Individuals with ALDH2*2 who consume alcohol also have an increased risk of diabetes, osteoporosis, reactive airway disease, lung cancer, and cardiovascular disease (including myocardial infarctions, coronary artery disease, and cardiac ischemia), among other health risks.4 Furthermore, those with ALDH2*2 who smoke and drink frequently have a 189-fold risk of developing esophageal cancer due to the accumulation of toxic aldehydes from these activities.4 As a result, it is important to speak to patients with ALDH2*2 about the increased health implications of frequent drinking and smoking.
Clinicians can initiate a conversation with patients to screen for ALDH2*2, asking if they are of East Asian descent, and if they experience facial flushing after consuming alcohol, especially within the first few years after they began drinking.3 If the patient is a child, the question can be directed to their parents to determine the likelihood of the child having the genetic variation.
Glucose-6-phosphate Dehydrogenase (G6PD) deficiency among Kurdish Jewish individuals
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that protects red blood cells from being damaged by oxidizing agents. Red blood cells use hemoglobin to transport oxygen in the body. Reactions between hemoglobin and oxygen produce oxidizing agents such as superoxide anion (O2-) and hydrogen peroxide.5 These chemicals can damage and kill red blood cells. G6PD prevents this from happening, as it produces agents that reduce the oxidant nature of the oxidizing agent. For example, G6PD is involved in a cascade of reactions that help convert hydrogen peroxide to water. In those who are genetically deficient in G6PD, an accumulation of oxidizing agents can occur and lead to hemolysis, also known as hemolytic anemia.5 Hospital pharmacists should be alert for ways to prevent hemolysis in individuals with G6PD deficiency.
G6PD deficiency is particularly prevalent among Kurdish Jews, with about 70% of this population having G6PD deficiency. G6PD deficiency is also prevalent in Nigerians (22%), Thai people (17%) and African Americans (12%).6 G6PD deficiency is an X-linked condition, meaning it is passed down via the X chromosome. Since males only have one X chromosome, if they inherit this mutation, G6PD deficiency affects all of their red blood cells. Females are not usually affected by the deficiency, as females have two X chromosomes. If a female inherits mutation from one parent, half of their red blood cells would have the normal G6PD gene, while the other half wouldn’t. If a female inherits the mutation from both parents, she would be affected, though this is very rare.6 There are over 200 different variants of G6PD, and the World Health Organization has divided these variants into classes based on severity of hemolysis and amount of enzyme deficiency.7 Most people with G6PD deficiency live a healthy life with no symptoms. However, these individuals are at risk for an episode of acute hemolysis if they experience oxidant injury from medications, illness, or food.6
One study noted that 46% of acute hemolysis episodes in patients with G6PD deficiency were caused by medication.6 Hospital pharmacists must be aware of the medications that could potentially precipitate an acute hemolytic episode.6,8 Among others, such medications include: chlorpropamide, dapsone, fluoroquinolones, methylene blue, nitrofurantoin, phenazopyridine, primaquine, rasburicase, and sulfonylureas. Hospital pharmacists, as part of a care team, can proactively recommend medication alternatives. For example, in treating urinary tract infections, fosfomycin tromethamine can serve as an alternative therapy to nitrofurantoin, ciprofloxacin, and sulfamethoxazole/trimethoprim.6,9 It is also important for hospital pharmacists to review home medications upon hospital admission to ensure that G6PD-deficient patients are not taking any medications that could precipitate an acute hemolytic episode. If a patient with G6PD deficiency is taking a medication that could cause harm, an intervention can be made to switch to a different medication. Patients in this population should also be told to avoid eating fava beans, which can cause hemolysis; they contain compounds that are metabolised to potent oxidizing agents.6
Hospital pharmacists should be proactive in screening a patient’s demographic characteristics and medical history for G6PD deficiency. Patients can be asked about their ethnic background when it is medically relevant. If the patient identifies as Kurdish Jewish, for instance, they should be screened for G6PD deficiency using laboratory testing. Furthermore, newborn babies with G6PD deficiency may experience jaundice within the first few days after birth.6 Patients and parents can be asked if they themselves or their children experienced jaundice as a newborn prior to initiating testing. These screening methods are important to prevent acute hemolytic episodes in people with suspected G6PD deficiency, especially if the care team is considering using a medication that could be problematic. It is also important to counsel patients about what it means to have G6PD deficiency, what medications to void, and what they can do to prevent acute hemolytic episodes.
Response to Angiotensin-Converting Enzyme (ACE) inhibitors among Black individuals
Angiotensin-converting enzyme (ACE) inhibitors are a class of medications that are used to treat hypertension and heart failure after a heart attack, and to reduce the likelihood of heart attacks and stroke in patients at risk. For patients with uncomplicated hypertension, diabetes, heart disease, a recent heart attack, heart failure, or chronic kidneys, the drug class of choice is ACE inhibitors such as ramipril.10 However, compared to other populations, studies show that Black patients tend to respond poorly to ACE inhibitors, angiotensin receptor blockers, and some beta blockers when these drugs are used as monotherapy. According to several studies, when using either medication in these classes, Black patients have a smaller blood pressure reduction compared to other patient populations.11,12 The cause of this is uncertain; some studies point to a genetic factor indicating that Black individuals’ bodies tend to retain more salt, which can also put this population at a greater risk for hypertension.13
The prevalence of hypertension is highest among Black individuals relative to any other patient population.14 This highlights the need for hospital pharmacists to be aware that Black patients may respond differently to first-line anti-hypertensive medications, and that alternative regimens should be considered. If a Black patient was recently diagnosed with hypertension, the American College of Cardiology and the American Heart Association recommends that the patient be given a dihydropyridine calcium channel blocker (such as diltiazem) or thiazide diuretic (such as chlorthalidone).11,14 Black patients with hypertension tend to respond favourably to these classes of anti-hypertensives. If a combination of drugs is required, an ACE inhibitor can be combined with a dihydropyridine calcium channel blocker. A diuretic such as chlorthalidone can be used if this treatment does not work.11,15,16 Although ACE inhibitors are not typically first-line treatment for uncomplicated hypertension, they can be used in combination with other antihypertensives for Black patients with proteinuric chronic renal disease and hypertensive nephrosclerosis.11, 17 In an interprofessional care team, hospital pharmacists can highlight the difference in response to ACE inhibitors among Black populations to influence decisions regarding drug treatment and to improve health outcomes.
Along with drug therapy, hospital pharmacists can counsel patients about lifestyle modifications to lower the risk of developing hypertension and to lower blood pressure for those who have hypertension. Such modifications include reducing dietary salt consumption, increasing exercise, avoiding excess alcohol, and, in case of obesity, weight loss. One study noted that regular exercise along with medication reduced blood pressure more than medication alone.11,18 To determine if a person should use an ACE inhibitor or another class of anti-hypertensives, a clinician or pharmacist can ask the patient about their ethnic background, and state that evidence shows race-based differences in response to certain medications.
Being cognizant of ethnic and genetic differences that affect patients’ response to medications can help clinicians make better medical decisions and improve health outcomes, both for chronic health conditions such as hypertension, and for emergent situations such as acute hemolysis and angina attacks. Pharmacogenetic testing is not always readily available, especially in emergent situations, so it is wise to respectfully ask patients about their ethnic background to identify the ways their genes might affect their reactions to drug therapies. It is also important to educate patients about the implications of their ethnic and genetic characteristics. Hospital pharmacists can discuss with patients which health conditions they may be at higher risk for, recommend lifestyle changes as appropriate, and proactively work with the patient to take preventative measures.
- Chen CH, Ferreira JCB, Joshi AU, Stevens MC, Li SJ, Hsu JH, et al. Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes' toxicity. EBioMedicine. 2020;55:102753. doi: 10.1016/j.ebiom.2020.102753.
- Gross ER, Zambelli VO, Small BA, Ferreira JC, Chen CH, Mochly-Rosen D. A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant. Annu Rev Pharmacol Toxicol. 2015;55:107-27. doi: 10.1146/annurev-pharmtox-010814-124915.
- Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Med. 2009;6(3):e50. doi: 10.1371/journal.pmed.1000050.
- McAllister SL, Sun K, Gross ER. Developing precision medicine for people of East Asian descent. J Biomed Sci. 2016;23(1):80. doi: 10.1186/s12929-016-0299-3.
- Glader B. Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency. UpToDate [Internet]. 18 September 2020 [cited 13 March 2022]. Available from: https://www.uptodate.com/contents/genetics-and-pathophysiology-of-glucose-6-phosphate-dehydrogenase-g6pd-deficiency
- Glader B. Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency. UpToDate [Internet]. 17 March 2021 [cited 13 March 2022]. Available from: https://www.uptodate.com/contents/diagnosis-and-management-of-glucose-6-phosphate-dehydrogenase-g6pd-deficiency
- Glucose-6-phosphate dehydrogenase deficiency. WHO Working Group. Bull World Health Organ. 1989;67(6):601-11.
- Bubp J, Jen M, Matuszewski K. Caring for Glucose-6-Phosphate Dehydrogenase (G6PD)-Deficient Patients: Implications for Pharmacy. P T. 2015;40(9):572-4.
- Nicolle L. Urinary Tract Infection | CPS [Internet]. Canadian Pharmacists Association. 12 April 2021 [cited 13 March 2022].
- Padwal R, Gibson P, Tsuyuki RT. Hypertension. [Internet]. Canadian Pharmacists Association. 21 April 2021 [cited 13 March 2022].
- Egan BM. Treatment of hypertension in Black individuals. UpToDate [Internet]. 6 April 2021 [cited 13 March 2022]. Available from: https://www.uptodate.com/contents/treatment-of-hypertension-in-black-individuals
- Mann JFE. Choice of drug therapy in primary (essential) hypertension. UpToDate [Internet]. 5 August 2021 [cited 13 March 2022]. Available from: https://www.uptodate.com/contents/choice-of-drug-therapy-in-primary-essential-hypertension
- Spence JD, Rayner BL. Hypertension in Blacks: Individualized Therapy Based on Renin/Aldosterone Phenotyping. Hypertension. 2018;72(2):263-269. doi: 10.1161/HYPERTENSIONAHA.118.11064.
- Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):1269-1324. doi: 10.1161/HYP.0000000000000066.
- Ojji DB, Mayosi B, Francis V, Badri M, Cornelius V, Smythe W, et al. Comparison of Dual Therapies for Lowering Blood Pressure in Black Africans. N Engl J Med. 2019;380(25):2429-2439. doi: 10.1056/NEJMoa1901113.
- Flack JM, Sica DA, Bakris G, Brown AL, Ferdinand KC, Grimm RH Jr., et al. Management of high blood pressure in Blacks: an update of the International Society on Hypertension in Blacks consensus statement. Hypertension. 2010;56(5):780-800. doi: 10.1161/HYPERTENSIONAHA.110.152892.
- Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-72. doi: 10.1001/jama.289.19.2560.
- Kokkinos PF, Narayan P, Colleran JA, Pittaras A, Notargiacomo A, Reda D, et al. Effects of regular exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension. N Engl J Med. 1995;333(22):1462-7. doi: 10.1056/NEJM199511303332204.