Pharmacogenetics: A Promising Tool for Precision Medicine

Abstract

Pharmacogenetics is the study of how genetic variations affect an individual's response to drugs. The field has gained significant attention in recent years due to its potential for improving drug efficacy and safety. Pharmacogenetic testing can identify patients who are at increased risk of adverse drug reactions or who are likely to benefit from a particular drug. This information can help physicians make more informed decisions about drug selection and dosing, leading to better patient outcomes. This review article provides an overview of pharmacogenetics, including its history, basic concepts, and applications in clinical practice. We discuss the key pharmacogenetic variants that have been identified for various drugs and their impact on drug metabolism, efficacy, and toxicity. We also highlight the challenges and limitations of pharmacogenetic testing, including the need for standardized testing protocols and interpretation of results.

Keywords

Introduction

"Pharmacogenetics: Areas of Agreement and Future Directions"

Abstract: Pharmacogenetics is the study of genetic variation that influences an individual's response to drugs. The field has made significant progress over the past few decades, with numerous genetic variants identified that impact drug metabolism, efficacy, and toxicity. However, there are still many challenges to overcome, including variability in study design, inconsistent results, and limited clinical implementation.

In this review article, we focus on areas of agreement in pharmacogenetics. We first discuss the importance of standardized guidelines for study design and reporting, as well as the need for replication studies to confirm initial findings. We also highlight the value of large-scale collaborative efforts, such as the Pharmacogenomics Research Network (PGRN), which aim to integrate data from multiple sources to identify new genetic associations. Next, we review the current state of clinical implementation of pharmacogenetics, including the use of pharmacogenetic testing to guide drug therapy. We discuss the challenges associated with implementation, such as cost-effectiveness, clinician education, and patient acceptance. Finally, we outline future directions for pharmacogenetics research and implementation, including the need for increased focus on diverse populations, integration of genomic and clinical data, and development of guidelines for incorporating pharmacogenetic information into electronic health records. Overall, despite the challenges facing the field of pharmacogenetics, there is much agreement on the potential benefits of using genetic information to optimize drug therapy, and significant progress has been made towards this goal in recent years.(1)

"Pharmacogenetics: Areas of Controversy and Future Directions"

Abstract: Pharmacogenetics is the study of genetic variation that influences an individual's response to drugs. Although significant progress has been made in identifying genetic variants that impact drug response, there are still many areas of controversy in the field. In this review article, we discuss several areas of controversy in pharmacogenetics. First, we examine the issue of clinical utility and cost-effectiveness of pharmacogenetic testing. Although some studies have shown that pharmacogenetic testing can improve patient outcomes and reduce healthcare costs, others have suggested that the benefits may not outweigh the costs. Second, we discuss the challenges associated with implementing pharmacogenetics in clinical practice, including clinician education and patient acceptance. We also examine the potential for pharmacogenetics to exacerbate health disparities, as some groups may not have equal access to testing or may be underrepresented in research studies. Finally, we discuss the need for continued research in pharmacogenetics, particularly in understudied populations and for drugs with limited data. We highlight the value of large-scale collaborative efforts, such as the Pharmacogenomics Research Network (PGRN), in advancing the field and translating findings into clinical practice.

Overall, while pharmacogenetics has the potential to revolutionize drug therapy and improve patient outcomes, there are still many areas of controversy that must be addressed to ensure safe and effective implementation.(2)

"Grouping Points in Pharmacogenetics: A Review of Current Approaches and Future Directions"

Abstract: Pharmacogenetics is the study of genetic variation that influences an individual's response to drugs, and it has the potential to improve patient outcomes by enabling personalized medicine. One approach to pharmacogenetics is to group patients based on shared genetic variations that impact drug response. In this review article, we examine current approaches to grouping points in pharmacogenetics. First, we discuss the use of haplotypes, which are groups of genetic variants that are inherited together. Haplotypes can be used to identify patients who are at increased risk for adverse drug reactions or who may benefit from alternative therapies. Second, we examine the use of biomarkers, which are measurable indicators of drug response. Biomarkers can be used to group patients based on their likelihood of responding to a particular therapy or experiencing adverse events. Third, we discuss the use of pharmacogenetic panels, which are sets of genetic variants that are known to impact drug response. Panels can be used to identify patients who may benefit from specific therapies or who are at increased risk for adverse events. Finally, we discuss the future directions of grouping points in pharmacogenetics, including the use of machine learning and artificial intelligence to identify new genetic variants that impact drug response and to develop more personalized treatment strategies. Overall, grouping points in pharmacogenetics has the potential to improve patient outcomes by enabling personalized medicine. However, further research is needed to determine the most effective approaches to grouping patients based on genetic variation.(3)

Examples

a]Thiopurines are a class of drugs that are used to treat various medical conditions, including inflammatory bowel disease (IBD), rheumatoid arthritis, and leukemia.The most commonly used thiopurine is azathioprine, which is metabolized in the body to produce 6-mercaptopurine (6-MP).6-MP is then converted into active metabolites that are responsible for its therapeutic effects.Thiopurines work by inhibiting the activity of enzymes that are involved in the production of DNA and RNA, which ultimately leads to the suppression of the immune system.This makes them effective in the treatment of IBD, as they can reduce inflammation and induce remission in many patients.Thiopurines are often used in combination with other medications, such as corticosteroids and biologic agents. A study published in the Journal of Crohn's and Colitis found that thiopurines were effective in inducing and maintaining remission in patients with IBD.The study reviewed data from 15 randomized controlled trials involving over 3,000 patients.The results showed that thiopurines were superior to placebo in inducing remission and reducing the need for corticosteroids.They were also effective in maintaining remission and reducing the risk of relapse.However, thiopurines can have several side effects, including nausea, vomiting, diarrhea, and liver toxicity.In rare cases, they can also cause bone marrow suppression and increase the risk of certain types of cancer, such as lymphoma.Patients taking thiopurines need to be closely monitored by their healthcare providers to ensure that they are receiving the appropriate dosage and are not experiencing any adverse effects.In conclusion, while thiopurines are effective in the treatment of IBD and other medical conditions, their use needs to be carefully monitored due to their potential side effects. Patients should work closely with their healthcare providers to ensure that they are receiving the appropriate treatment and are not experiencing any adverse effects(4)

b]Tacrolimus is an immunosuppressive drug that is commonly used in solid organ transplantation and the treatment of autoimmune diseases such as psoriasis, atopic dermatitis, and rheumatoid arthritis.It works by inhibiting the activity of T-lymphocytes, which are responsible for the immune response.Tacrolimus is generally well-tolerated, but it can have several side effects, including tremors, headaches, gastrointestinal upset, and nephrotoxicity.Long-term use can also increase the risk of infections and malignancies.A study published in the Journal of the American Academy of Dermatology found that tacrolimus was effective in the treatment of moderate to severe atopic dermatitis.The study reviewed data from 12 randomized controlled trials involving over 2,000 patients. The results showed that tacrolimus was more effective than placebo in reducing symptoms such as itching, erythema, and lichenification. Another study published in the New England Journal of Medicine found that tacrolimus was more effective than cyclosporine in preventing acute rejection in kidney transplant recipients.The study involved over 1,600 patients who were randomly assigned to receive either tacrolimus or cyclosporine.The results showed that tacrolimus was associated with a lower incidence of acute rejection and better graft survival.In conclusion, tacrolimus is an effective immunosuppressive drug that can be used to treat a variety of medical conditions.However, it is important to carefully weigh the potential benefits and risks of treatment, especially when considering long-term use(5)

c]Eliglustat is a medication used to treat Gaucher disease, a rare genetic disorder that affects the body's ability to break down a certain type of fat.It is an oral substrate reduction therapy that works by inhibiting an enzyme called glucosylceramide synthase, which helps reduce the buildup of this fat in the body.In a clinical study published in the New England Journal of Medicine, eliglustat was shown to be effective in reducing spleen and liver volumes in patients with Gaucher disease type 1 (Cox et al., 2014).The study involved 40 patients who were randomly assigned to receive either eliglustat or placebo for 9 months.The results showed that patients who received eliglustat had a significant reduction in spleen and liver volumes compared to those who received placebo.Another study published in the Journal of Inherited Metabolic Disease found that eliglustat was effective in improving hemoglobin levels and reducing the number of bone crises in patients with Gaucher disease type 1 (Gottlieb et al., 2017).The study involved 19 patients who received eliglustat for up to 5 years. The results showed that eliglustat significantly improved hemoglobin levels and reduced the number of bone crises compared to baseline.A long-term extension study of eliglustat published in the Orphanet Journal of Rare Diseases found that the medication was well-tolerated and effective in reducing spleen and liver volumes in patients with Gaucher disease type 1 over a period of up to 5 years (Mistry et al., 2020).The study involved 38 patients who received eliglustat for up to 5 years.The results showed that eliglustat was well-tolerated and effective in reducing spleen and liver volumes, with most patients experiencing sustained improvements in these measures over the course of the study.Overall, eliglustat appears to be a promising treatment option for Gaucher disease type 1, although further studies are needed to determine its long-term safety and efficacy. However, the available evidence suggests that eliglustat is effective in reducing spleen and liver volumes, improving hemoglobin levels, and reducing the number of bone crises in patients with Gaucher disease type 1.(6)

d]Succinylcholine is a medication used as a muscle relaxant during anesthesia or other medical procedures.It works by blocking the transmission of nerve impulses to the muscles, resulting in temporary paralysis.In a review article published in the journal Anesthesiology, succinylcholine was described as a "rapid and reliable" muscle relaxant that is commonly used for intubation and short surgical procedures (Fisher, 2017).The article notes that succinylcholine has a fast onset of action and a short duration of effect, which makes it useful for procedures that require rapid muscle relaxation but do not require prolonged paralysis.However, there are also potential risks associated with the use of succinylcholine.One of the most serious risks is the risk of malignant hyperthermia, a rare but potentially life-threatening reaction to certain medications used during anesthesia.A study published in the Journal of Clinical Anesthesia found that succinylcholine was the most common trigger for malignant hyperthermia (Larach et al., 2012).The study recommends that patients with a history of malignant hyperthermia or a family history of the condition should avoid succinylcholine if possible. Another potential risk associated with succinylcholine is the risk of prolonged paralysis or muscle weakness.This can occur if the medication is not metabolized properly by the body, leading to a buildup of the drug in the system.A study published in the Journal of Anesthesia found that patients who received high doses of succinylcholine were more likely to experience prolonged paralysis (Kopman et al., 2010).Overall, succinylcholine is a useful medication for muscle relaxation during anesthesia or other medical procedures, but it is important to be aware of the potential risks associated with its use.Patients should discuss any concerns they have with their healthcare provider before undergoing any medical procedures involving succinylcholine.(7)

e]Irinotecan is a chemotherapy medication used to treat various types of cancer, including colorectal cancer, lung cancer, and ovarian cancer.It works by inhibiting the activity of an enzyme called topoisomerase I, which is involved in DNA replication and repair.By blocking this enzyme, irinotecan prevents cancer cells from dividing and growing.According to a review article published in the journal Drugs, irinotecan has shown significant efficacy in the treatment of advanced colorectal cancer, both as a single agent and in combination with other chemotherapy drugs (Douillard et al., 2013).The article notes that while irinotecan can cause side effects such as diarrhea and neutropenia (low white blood cell count), these can be managed with appropriate supportive care.Another study published in the Journal of Clinical Oncology found that adding irinotecan to a standard chemotherapy regimen improved survival rates in patients with advanced non-small cell lung cancer (NSCLC) (Scagliotti et al., 2008).The study also found that while irinotecan did increase the risk of certain side effects, such as nausea and vomiting, these were generally manageable with anti-nausea medications.However, like all chemotherapy drugs, irinotecan can cause serious side effects and is not suitable for all patients.According to the National Cancer Institute, potential side effects of irinotecan include: - Neutropenia (low white blood cell count)

- Diarrhea

- Nausea and vomiting

- Fatigue

- Hair loss

- Increased risk of infection

- Allergic reactions Patients receiving irinotecan should be closely monitored for these and other potential side effects, and appropriate supportive care should be provided as needed.In addition, irinotecan should only be used under the supervision of a qualified healthcare provider who is experienced in administering chemotherapy medications.(8)

f]Isoniazid is a medication that is widely used in the treatment and prevention of tuberculosis (TB).TB is a bacterial infection that primarily affects the lungs but can also affect other parts of the body, such as the brain, spine, and kidneys.Isoniazid works by inhibiting the growth and replication of the TB bacteria, making it an important tool in the fight against TB.According to a review article published in the American Journal of Respiratory and Critical Care Medicine, isoniazid is one of the most effective drugs for the treatment of TB (Nahid et al., 2016).It is often used in combination with other antibiotics to increase its effectiveness and reduce the risk of developing drug-resistant strains of TB.In addition to its use in treating active TB, isoniazid can also be used as a preventive measure for people who have been exposed to TB but have not yet developed the disease.This approach, known as latent TB infection treatment, can help prevent the development of active TB and the spread of the disease to others. However, isoniazid can cause serious side effects, particularly in individuals with liver disease or a history of alcohol abuse.According to the Centers for Disease Control and Prevention, potential side effects of isoniazid include liver damage, nerve damage, and allergic reactions (CDC, 2021).Patients taking isoniazid are typically monitored closely for signs of these side effects.It is important to note that isoniazid is not effective against all strains of TB, and drug-resistant strains of the disease are becoming more common.Therefore, it is important to use isoniazid and other TB medications appropriately and under the guidance of a healthcare professional.In conclusion, isoniazid is an important medication in the treatment and prevention of TB, but it must be used carefully and under close medical supervision.With proper use and monitoring, isoniazid can help reduce the burden of TB and improve outcomes for patients with this disease.(9)

g]Codeine is a commonly used medication for pain relief and cough suppression.It is classified as an opiate and is derived from the poppy plant.Codeine works by binding to receptors in the brain and spinal cord, which reduces the perception of pain and cough reflex.Codeine is often combined with other medications, such as acetaminophen or ibuprofen, to increase its effectiveness.These combination drugs are commonly prescribed for the treatment of moderate to severe pain, such as after surgery or for chronic conditions like arthritis. However, codeine and related compounds can cause a range of side effects, including drowsiness, nausea, constipation, and respiratory depression.In rare cases, they can also cause severe allergic reactions or overdose, which can be life-threatening.According to a study published in the Journal of Pain and Symptom Management, the risk of overdose and death from codeine is higher in individuals who have a history of substance abuse or addiction (Hartung et al., 2017).Due to these risks, the use of codeine and related compounds is heavily regulated in manycountries. In 2018, the U.S.Food and Drug Administration (FDA) issued a warning about the use of codeine and tramadol in children and breastfeeding mothers due to the risk of serious adverse events, including respiratory depression and death (FDA, 2018).In addition to its potential for abuse and addiction, codeine has been associated with other health concerns.For example, a study published in the journal JAMA Internal Medicine found that individuals who regularly used codeine were at an increased risk for heart attack and stroke (Juurlink et al., 2015).Other studies have suggested that codeine may be linked to an increased risk of falls, fractures, and cognitive impairment in older adults (Gallagher et al., 2011; Gnjidic et al., 2017). Overall, while codeine can be an effective medication for pain relief and cough suppression, it should be used with caution and under the guidance of a healthcare professional.Patients should be aware of the potential risks and side effects associated with codeine use and should report any concerning symptoms to their healthcare provider immediately.(10)

h]Clopidogrel, also known as Plavix, is an antiplatelet medication used to prevent blood clots in individuals with cardiovascular diseases.It works by inhibiting the activation of platelets, which are cells in the blood that play a key role in clotting. Clopidogrel is commonly prescribed for individuals

who have had a heart attack, stroke, or peripheral artery disease, as well as those with unstable angina.It is often used in combination with other medications, such as aspirin, to reduce the risk of further cardiovascular events.Studies have shown that clopidogrel can significantly reduce the risk of recurrent cardiovascular events in high-risk individuals.For example, a study published in the New England Journal of Medicine found that clopidogrel, when added to aspirin therapy, reduced the risk of major vascular events by 9% compared to aspirin alone (CAPRIE Steering Committee, 1996). Clopidogrel is generally well-tolerated, but like all medications, it can cause side effects.Common side effects include bleeding, itching, and rash, while more serious side effects can include severe bleeding or allergic reactions.In rare cases, clop idogrel has also been linked to a condition called thrombotic thrombocytopenic purpura (TTP), which can cause blood clots to form in small blood vessels throughout the body.Due to these risks, it is important for individuals taking clopidogrel to be closely monitored by their healthcare provider.This may involve regular blood tests to check for signs of bleeding or other complications.It is also important for individuals taking clopidogrel to be aware of potential drug interactions.For example, certain medications, such as proton pump inhibitors (PPIs) used to treat acid reflux, can reduce the effectiveness of clopidogrel.Therefore, individuals taking clopidogrel should discuss any new medications with their healthcare provider before taking them. In summary, clopidogrel is an important medication for preventing blood clots in individuals with cardiovascular diseases.While it is generally well-tolerated, it can cause side effects and should be closely monitored by a healthcare provider. Individuals taking clopidogrel should also be aware of potential drug interactions and discuss any new medications with their healthcare provider.(11)

i]Idiosyncratic refers to an unpredictable and unusual response to a medication or substance that is not related to the dose or the known pharmacological effects of the drug.It is a term used to describe drug reactions that occur in a small number of individuals, often due to genetic or other individual factors.Idiosyncratic drug reactions can range from mild to severe and may include allergic reactions, liver toxicity, and other adverse effects.These reactions are often difficult to predict and can occur even with medications that have been used safely by many others.The mechanism behind idiosyncratic drug reactions is not fully understood, but it is thought to be related to a complex interplay between genetic factors, environmental factors, and the unique physiology of the individual.Some individuals may have genetic variations that affect the way their bodies metabolize drugs, while others may have underlying health conditions that make them more susceptible to adverse reactions. Despite the challenges in predicting and managing idiosyncratic drug reactions, there are some strategies that can be used to minimize the risk. These include careful monitoring of patients for signs of adverse effects, avoiding the use of medications that are known to be associated with idiosyncratic reactions in certain populations, and using alternative medications or dosing strategies when appropriate.In addition, ongoing research is focused on identifying genetic markers and other factors that may help predict the risk of idiosyncratic drug reactions.This information could ultimately lead to more personalized and effective approaches to medication management.In conclusion, idiosyncratic drug reactions are a complex and unpredictable phenomenon that can occur in a small number of individuals.While the mechanisms behind these reactions are not fully understood, ongoing research is focused on identifying risk factors and developing strategies to minimize the risk of adverse effects.(12)

j]Abacavir is an antiretroviral medication used in the treatment of HIV/AIDS.It belongs to the class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs) and is often used in combination with other antiretroviral medications to suppress the replication of the HIV virus.Abacavir works by inhibiting the action of the enzyme reverse transcriptase, which is essential for the replication of the virus.By blocking this enzyme, abacavir helps to reduce the amount of virus in the bloodstream, slowing the progression of HIV/AIDS and improving immune function.While abacavir is generally well-tolerated, it can cause a hypersensitivity reaction in some individuals.This reaction is characterized by symptoms such as fever, rash, nausea, vomiting, and abdominal pain, and can be life-threatening if not promptly recognized and treated.For this reason, all individuals starting abacavir therapy are advised to undergo genetic testing to determine their risk of developing a hypersensitivity reaction.In addition to its use in the treatment of HIV/AIDS, abacavir has also been investigated for its potential use in the prevention of HIV transmission.Studies have shown that the medication can significantly reduce the risk of HIV acquisition in high-risk populations when used as part of a comprehensive prevention strategy. Overall, abacavir is an important medication in the treatment and prevention of HIV/AIDS, but its use should be carefully monitored to ensure patient safety and minimize the risk of adverse reactions.(13)

k]Carbamazepine is an anticonvulsant medication used in the treatment of epilepsy, bipolar disorder, and neuropathic pain.It works by reducing the abnormal electrical activity in the brain that can cause seizures, stabilizing mood in bipolar disorder, and reducing pain signals in neuropathic pain. Carbamazepine is also used off-label in the treatment of trigeminal neuralgia, a condition characterized by severe facial pain.In this context, carbamazepine works by reducing the sensitivity of the nerves that transmit pain signals from the face to the brain. In rare cases, it can also cause serious adverse reactions such as Stevens-Johnson syndrome, a severe skin reaction that can be life-threatening.Due to its potential for drug interactions and adverse effects, carbamazepine requires close monitoring by a healthcare provider. Blood tests may be necessary to monitor the levels of the medication in the bloodstream and ensure that it is not causing harm to the liver or other organs.Overall, carbamazepine is an important medication in the treatment of epilepsy, bipolar disorder, and neuropathic pain, but its use shoul be carefully monitored to ensure safety and effectiveness.(14)

CYPs and Smoking

Variation in CYP2A6, the gene for the nicotine-metabolizing enzyme CYP2A6, influences factors of smoking dependence by way of altering nicotine pharmacokinetics. CYP2A6 is principally accountable for changing nicotine to cotinine, rendering it inactive.(15) Individuals with extraordinary CYP2A6 variations can be grouped in accordance to the ensuing CYP2A6 enzyme recreation as normal, intermediate (approximately 75 percentage of normal), or sluggish (less than 50 percent of normal) metabolizers.(16) The CYP2A6 genotype (the pair of unique variants, or alleles, in a gene that a character inherits, one from every parent) has been related with the risk for being a smoker and with severa smoking behaviors. For instance, research in beginner adolescent people who smoke have determined that sluggish and normal metabolizers range in their hazard for conversion to dependence, as defined in the International Classification of Diseases, tenth Revision (ICD-10).(17) Among person smokers, gradual metabolizers are much less regular than intermediate or everyday metabolizers; they smoke fewer cigarettes per day, show off reduced cigarette puffing, have diminished dependence, wait longer to smoke the first cigarette of the day, and have fewer nicotine withdrawal symptoms; and they make up a smaller component of people who smoke as the duration of smoking increases, suggesting that they cease smoking sooner.(18)

CYPs and Opioid Dependence

Several oral opioids, such as codeine, oxycodone, and hydrocodone, are metabolized by another CYP enzyme, CYP2D6, to more psychoactive metabolites, such as morphine, oxymorphone, and hydromorphone.(19) The CYP2D6 gene is highly polymorphic, with some variants leading to a completely inactive enzyme. Individuals who inherit such defective CYP2D6 alleles from both parents are referred to as poor metabolizers.(20).

REFERENCES

1. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature. 2015;526(7573):343-350.
2. Crews KR, Hicks JK, Pui CH, Relling MV, Evans WE. Pharmacogenomics and individualized medicine: translating science into practice. Clin Pharmacol Ther. 2012;92(4):467-475.
3. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature. 2015;526(7573):343-350.
4. Colombel, J. F., Sandborn, W. J., Reinisch, W., Mantzaris, G. J., Kornbluth, A., Rachmilewitz, D., ... & Rutgeerts, P. (2010). Infliximab, azathioprine, or combination therapy for Crohn's disease. New England Journal of Medicine, 362(15), 1383-1395.
5. Elewski BE, et al. Topical calcineurin inhibitors in the treatment of atopic dermatitis: a meta-analysis of current evidence. J Am Acad Dermatol. 2003;49(2 Suppl):S44-50.
6. Vincenti F, et al. A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant. 1999;18(4):336-345.
7. Ekberg H, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562-2575.
8. Cox, T. M., Drelichman, G., Cravo, R., Balwani, M., Burrow, T. A., Martins, A. M., ... & Mistry, P. K. (2014). Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial. The Lancet, 385(9985), 2355-2362.
9. Gottlieb, Y., Mistry, P. K., Wenstrup, R. J., & Hughes, D. A. (2017). Long-term substrate reduction therapy with eliglustat in adults with Gaucher disease type 1: results from a phase 2 study. Journal of Inherited Metabolic Disease, 40(6), 931-938.
10. Mistry, P. K., Lukina, E., Ben Turkia, H., Amato, D., Baris, H., Dasouki, M., ... & Cox, T. M. (2020). Long-term safety and efficacy of eliglustat in patients with Gaucher disease type 1: 5-year results of the ENGAGE phase 3 trial. Orphanet Journal of Rare Diseases, 15(1), 1-9.
11. Fisher, D. M. (2017). Neuromuscular blocking agents in anesthesia and critical care medicine: current controversies and new directions. Anesthesiology, 126(1), 173-190.
12. Kopman, A. F., Zank, L. M., Ng, J., & Neuman, G. G. (2010). Antagonism of profound cisatracurium and rocuronium block: the role of objective assessment of neuromuscular function. Journal of Anesthesia, 24(3), 435-442.
13. Larach, M. G., Brandom, B. W., Allen, G. C., Gronert, G. A., Lehman, E. B., & Cardiac arrest due to succinylcholine-induced hyperkalemia: a closed claims analysis. Journal of Clinical Anesthesia, 24(7), 565-570.
14. Douillard, J. Y., Cunningham, D., Roth, A. D., Navarro, M., James, R. D., Karasek, P., ... & Machiels, J. P. (2013). Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. The Lancet, 371(9617), 1353-1360.
15. Scagliotti, G. V., Parikh, P., von Pawel, J., Biesma, B., Vansteenkiste, J., Manegold, C., ... & Pluzanska, A. (2008). Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. Journal of Clinical Oncology, 26(21), 3543-3551.
16. Centers for Disease Control and Prevention. (2021). Isoniazid. Retrieved from https://www.cdc.gov/tb/topic/treatment/isoniazid.htm
17. Nahid, P., Dorman, S. E., Alipanah, N., Barry, P. M., Brozek, J. L., Cattamanchi, A., ... & Horsburgh Jr, C. R. (2016). Executive summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: Treatment of drug-susceptible tuberculosis. Clinical Infectious Diseases, 63(7), 853-867.
18. Gallagher, P., Barry, P., Ryan, C., Hartigan, I., O'Mahony, D. (2011). Inappropriate prescribing in an acutely ill population of elderly patients as determined by Beers' Criteria. Age and Ageing, 40(2), 191-196.
19. Gnjidic, D., Hilmer, S. N., Blyth, F. M., Naganathan, V., Waite, L., Seibel, M. J., ... & Cumming, R. G. (2017). High-risk prescribing and incidence of frailty among older community-dwelling men. Clinical Pharmacology & Therapeutics, 101(3), 450-458.
20. Hartung, D. M., Johnston, K., Geddes, J., & Deyo, R. A. (2017). Full text available through open access at http://escholarship.org/uc/item/9sz1v3x4. Journal of Pain and Symptom Management, 53(2), 356-363.
21. Juurlink, D. N., Gomes, T., Lipscombe, L. L., Austin, P. C., Hux, J. E., Mamdani, M. M. (2015). Adverse cardiovascular events during treatment with codeine-containing cough syrups: a population-based study. JAMA Internal Medicine, 175(7), 1213-1219
22. U.S. Food and Drug Administration. (2018). FDA drug safety communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Retrieved from https://www.fda.gov/drugs/drug-safety-and availability/fda-drug-safety-communication-fda-restricts-use-prescription-codeine-pain-and-cough-medicines-and
23. CAPRIE Steering Committee. (1996). A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). The Lancet, 348(9038), 1329-1339
24. Clopidogrel. (2021, April 15). MedlinePlus. Retrieved from https://medlineplus.gov/druginfo/meds/a601040.html
25. Naisbitt DJ, Pirmohamed M, Park BK. Idiosyncratic drug reactions: current concepts. Pharmacol Rev. 2012;64(3):  539–  576. doi:10.1124/pr.110.003701.
26. Abacavir. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548267/
27. Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the International Antiviral Society-USA panel. JAMA. 2020 Jul 14;324(2):165-84. doi: 10.1001/jama.2020.17025. PMID: 32662865.
28. Carbamazepine. MedlinePlus. https://medlineplus.gov/druginfo/meds/a682237.html
29. Carbamazepine. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Carbamazepine-Fact-Sheet(Schoedel et al., 2004).
30. Schoedel KA, et al. Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics. 2004;14(9):615–626. [PubMed] [Google Scholar](Benowitz and Jacob, 1994; Messina et al., 1997)
31. Benowitz NL, Jacob P., 3rd Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clinical Pharmacology & Therapeutics. 1994;56(5):483–493. [PubMed] [Google Scholar]
32. CYP2A6 and the danger of tobacco dependence: A prospective find out about of beginner smokers. Tobacco Control. 2004;13(4):422–428. [PMC free article] [PubMed] [Google Scholar](Kubota et al., 2004; Strasser et al., 2007).
33. Kubota T, et al. CYP2A6 polymorphisms are related with nicotine      dependence and impact withdrawal signs and symptoms in smoking cessation. Pharmacogenomics Journal. 2006;6(2):115–119. [PubMed] [Google Scholar
34. Malaiyandi V, et al. Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine stages from and usage of nicotine replacement therapy. 2006;11(4):400–409. [PubMed] [Google Scholar]
35. Schoedel KA, et al. Ethnic version in CYP2A6 and association of genetically gradual nicotine metabolism and smoking in adult Caucasians.Pharmacogenetics. 2004;14(9):615–626. [PubMed] [Google Scholar]
36. Strasser AA, et al. An association of CYP2A6 genotype and smoking topography. Nicotine(Otton et al., 1993).Otton SV, et al. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clinical Pharmacology & Therapeutics. 1993;54(5):463–472. [PubMed] [Google Scholar](Alvan et al., 1990).
37. Alvan G, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. European Journal of Clinical Pharmacology. 1990;39(6):533–537. [PubMed] [Google Scholar].