Ethnopharmacology: Understanding Drug Response Based On Race/Ethnicity (PDF)

Ethnopharmacology: Understanding Drug Response Based on Race/Ethnicity? MOHD FUAD RAHMAT SAM (PHD) DBMS, KAHS  CONTENTS 01 02 03 Definition Race, ethnicity, Variability in Drug...

Ethnopharmacology: Understanding Drug Response Based on Race/Ethnicity? MOHD FUAD RAHMAT SAM (PHD) DBMS, KAHS  CONTENTS 01 02 03 Definition Race, ethnicity, Variability in Drug culture Response 04 05 06 CYP 450 System Genetic Polymorphism Clinical Implications  Definition Potentially Confusing Terms ALLPPT.com _ Free PowerPoint Templates, Diagrams and Charts  Definition Rivier and Bruhn: “Ethnopharmacology is a multidisciplinary area of research, concerned with the observation, description, and experimental investigation of indigenous drugs and their biological activities” (Rivier and Bruhn, 1979). Bruhn and Holmstedt: Ethnopharmacology is the “interdisciplinary scientific exploration of biologically active agents traditionally employed or observed by man” (Bruhn and Holmstedt, 1982). International Society of Ethnopharmacology: Ethnopharmacology is the “interdisciplinary study of the physiological actions of plant, animal, and other substances used in indigenous medicines of past and present cultures” (International Society of Ethnopharmacology, 2005).  Definition (cont.) Journal of Ethnopharmacology: No definition is given, but stated that the breadth of the discipline embraces “use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international convention”, as well as “the observation and experimental investigation of the biological activities of plant and animal substances”, and “particularly welcome interdisciplinary papers with an ethnopharmacological, an ethnobotanical or an ethnochemical approach to the study of indigenous drugs” (Journal of Ethnopharmacology, 2005).  Definition (cont.) Ethnopharmacology is the study of the effect of ethnicity on responses to prescribed medication, especially drug absorption, metabolism, distribution, and excretion. The field incorporates pharmacogenetics, the study of genetic variations in responses to drugs. It looks at how people’s culture and their beliefs about health issues, as well as the genetic and physiological characteristics of their ethnic group, affect the impact and effectiveness of the medications they use. It also studies how cultural attitudes and racial bias may influence the ways in which medications are prescribed. Race, culture & ethnicity Race as “a class of persons of a common lineage; in genetics, races are considered as populations having different distributions of gene frequencies”; the term generally reflects the geographic origins of ancestry. Ethnicity can refer to shared cultural bonds, a common genetic heritage, or both. Culture as an integrated system of learned beliefs, values, and customs common to a particular group of people; typically these are passed down from generation to generation (Leininger 2002). Variation in drug responses  Historically, most clinical drug trials have been conducted using white men; the results have then been generalized to all patients receiving the drugs studied. Ethnopharmacologic research has uncovered significant differences in how people in diverse ethnic groups metabolize certain drugs, with regard to both pharmacodynamics (a drug’s mechanisms of action and its effects at the target site) and pharmacokinetics (the “movement” of drugs, referring to drug absorption, metabolism, distribution, and elimination). Genetic variations in certain enzymes may cause differing drug responses. Factors such as diet and tobacco use can influence a gene’s expression, which can in turn alter a drug’s effect BIOLOGICAL FACTORS Drug absorption PSYCHOSOCIAL-CULTURAL Ethnicity Drug transporter FACTORS Age Ethnicity Gender Genetics Systemic circulation Disease Distribution Metabolism Drug transport Excretion Site of action Drug effects ENVIRONMENTAL FACTORS Ethnicity, Diet, Pollutant, Smoking, Alcohol, Drugs  Examples of ACE inhibitors Beta blockers drugs that have Warfarin Isoniazid different effects on different ethnic groups  Warfarin Warfarin is an anticoagulant drug used to prevent blood clots. Examples of ACE inhibitors Studies have shown that individuals of African and Asian Beta blockers drugs that have Isoniazid descent may require lower doses of warfarin compared to different effects individuals of European descent due to genetic variations that affect how the drug is metabolized. on different Limdi NA, Beasley TM, Baird MF, Goldstein JA. Genetic variability in the vitamin ethnic groups K pathway influences the dose effect of warfarin. Pharmacogenomics. 2008;9(7):781-793.  ACE inhibitors ACE inhibitors are drugs used to treat high blood pressure and heart failure. Studies have shown that ACE inhibitors may be less Examples of effective in African American patients compared to other Beta blockers racial/ethnic groups due to differences in genetic drugs that have Isoniazid variations that affect the renin-angiotensin-aldosterone system. different effects on different Kryzhanovskiĭ GN, Tiulpakov AN, Alieva RA, Kudriavtseva LV, Vorob'ev PA, ethnic with groups Zvenigorodskaia LA, et al. [The influence of polymorphic variants of the ACE gene on the efficacy of antihypertensive therapy with enalapril in patients arterial hypertension of different racial-ethnic groups]. Kardiologiia. 2009;49(7):5-10. Warfarin Enalapril  Beta blockers Beta blockers are drugs used to treat high blood pressure, heart failure, and other conditions. Examples of Studies have shown that beta blockers may be less drugs that have Isoniazid effective in individuals of African descent compared to individuals of European descent due to differences in different effects genetic variations that affect how the drug is metabolized. Wang JG, Staessen JA, Gong L, Liu L, Zhang SM, Wang GL, et al. Chinese trial on on different ethnic groups ACE inhibitors isolated systolic hypertension in the elderly. Systolic Hypertension in China (Syst-China) Collaborative Group. Arch Intern Med. 2000;160(2):211-220. Warfarin Propranolol  Isoniazid Isoniazid is an antibiotic used to treat tuberculosis. Studies have shown that individuals of Asian descent may Examples of be more likely to experience liver toxicity from isoniazid drugs that have compared to individuals of other racial/ethnic groups due to genetic variations that affect drug metabolism. different effects Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, et al. Cytochrome on different P450 2E1 genotype and the susceptibility to antituberculosis drug-induced ethnic groups ACE inhibitors Beta blockers hepatitis. Hepatology. 2003;37(4):924-930. Warfarin Cytochrome p-450  One group of enzymes, the cytochrome P-450 (CYP) enzymes are responsible for the phase 1 metabolism of many widely prescribed drugs. There are many CYP enzyme subgroups; these are typically identified by letters and numbers (CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc) CYP CYP450 CYP3A4 Superfamily of constitutive Enzyme that catalyzes and inducible enzymes that Family of CYP450 one of the oxidation -reduction reaction catalyze most phase I most important enzymes biotransformations involved in the metabolism Peak absorbance @450nm  Many studies have indicated that genetic abnormalities in the CYP enzymes are not only extremely common but have profound implications for drug response. It appears that the “genetic ability to produce” these enzymes “will vary by race or ethnic group”. For example, genetic changes in certain CYP enzymes, including CYP2D6, have been shown to affect the rate of drug metabolism, which in turn affects drug plasma levels at a given dosage. The CYP2D6 gene is “unique in that the gene is often duplicated or multiplied.”  A case study of a rapid metabolizer of codeine was reported in the medical literature in 2007. People who have more than two The patient was a 49-year-old man who had functional copies of the CYP2D6 gene undergone surgical removal of a nasal polyp have faster than normal enzyme and was prescribed codeine for pain management. Despite taking the prescribed activity and are known as “ultrarapid dose of codeine, the patient experienced metabolizers” severe respiratory depression and required hospitalization. Genetic testing revealed that ○ will metabolize a drug quickly, the patient was a rapid metabolizer of codeine resulting in lower serum due to genetic variations in the CYP2D6 gene. concentrations The authors of the case report highlighted the importance of considering the potential for Those with two non-functional copies altered drug response in individuals with of the gene have slower than normal genetic variations in drug-metabolizing enzyme activity and are known as enzymes, and of monitoring for adverse effects when using codeine in these individuals. “poor metabolizers” ○ metabolize the drug more slowly, Reference: Ozkokeli, U., & Coskun, U. (2007). Life-threatening respiratory resulting in higher serum levels depression due to codeine in a patient with CYP2D6*2 gene polymorphism. Journal of Anesthesia, 21(3), 445-447. doi: at the same dosage. 10.1007/s00540-007-0512-0 https://www.youtube.com/watch?v=RXmrUhSSSlo Genetic polymorphism Different does not mean mutated  Genetic polymorphism & drug metabolism A combination of the Greek words poly and morph (multiple and form), polymorphism is a term used in genetics to describe multiple forms of a single gene that exists in an individual or among a group of individuals. Inter-individual variation of drug effects. Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups in the population that differ in their ability to perform certain drug biotransformation reactions. Polymorphisms are generated by mutations in the genes for these enzymes, which cause decreased, increased, or absent enzyme expression or activity by multiple molecular mechanism.  Drug metabolism The metabolism of drugs and other xenobiotics into more hydrophilic metabolites is essential for their elimination from the body, as well as for termination of their biological and pharmacological activity. Drug metabolism or biotransformation reactions are classified as either phase I functionalization reactions or phase II biosynthetic (conjugation reactions). The enzyme systems involved in the biotransformation of drugs are localized primarily in the liver. These biotransformation reactions are carried out by CYPs (cytochrome CYP 450 isoforms) and by a variety of transferases.  Drug metabolism (cont.) Pathways of drug metabolism are classified as either: ✓ Phase I reactions: oxidation, reduction, hydrolysis ✓ Phase II reactions: acetylation, glucuronidation, sulfation, methylation Both types of reactions convert relatively lipid soluble drugs into relatively inactive and more water soluble metabolites, allowing for more efficient systemic elimination.  Polymorphisms Genetic differences in drug metabolism are the result of genetically based variation in alleles for genes that code for enzymes responsible for the metabolism of drugs. In polymorphisms, the genes contain abnormal pairs or multiples or abnormal alleles leading to altered enzyme function. Differences in enzyme activity occur at different rates according to racial group.  Genetic Polymorphisms in Genes that Can Influence Drug Metabolism – CYP 450 Isoforms Enzyme Substrate Clinical Consequence CYP1A1 Benzopyrine, phenacetin Inc. or dec. cancer risk CYP1A2 Acetaminophen, amonafide, caffeine, Decreased theophylline metabolism paraxanthine, ethoxyresorufin, propranolol, fluvoxamine CYP1B1 Estrogen metabolites Possible inc. cancer risk CYP2A6 Coumarin, nicotine, halothane Dec. nicotine metabolism and cigarette addiction CYP2B6 Cyclophosphamide, aflatozin, mephenytoin Significance unknown CYP2C8 Retinoic acid, paclitaxel Significance unknown CYP2C9 Tolbutamide, warfarin, phenytoin, NSAIDS Anticoagulant effect on warfarin Enzyme Substrate Clinical Consequence CYP2C19 Mephenytoin, omeprazole, hexobarbital, Peptic ulcer response to omeprazole mephobartibal, propranolol, proquanil, phenytoin CYP2D6 Betablockers, antidepressants, Tardive dyskinesia from antipsychotics; antipsychotics, codeine, debrisoquin, narcotic side effects, efficacy and dextromethorphan, encainide, flecanide, dependency, imipramine dose requirement; fluoxetine, guanoxan, beta blocker effects methxyamphetamine, phenacetin, propafenone, sparteine CYP2E1 Acetaminophen, ethanol Possible inc cancer risk CYP3A4/3 Macrolides, cyclosporine, tacrolimus, Tacrolimus dose requirement in pediatric A7/3A7 calcium channel blockers, midazolam, cancer patients tefrenadie, lidocaine, dapsone, quinidine, triazolam, etoposide, teniposide, loastatian, alfentanil, tamoxifen, steroids, benzo(a)pyrene Clinical implications  Careful monitoring may help Skill in communicating with prevent unnecessary increases patients from various cultures in dosage and adverse effects. is essential. It’s best to ask patients specific questions about possible adverse effects, Careful observation and rather than asking general specific questions may be questions or waiting for the necessary to elicit patient to voice concerns. important information. Need to become aware of Determining the patient’s the different terms language preferences for patients use to describe spoken and written their illnesses communication is  pharmacogenomic Pharma = drug or medicine Genomics = the study of genes *Personalized medicine tailored to your genes  Genetic differences = variable drug metabolism 4 women of the same height, weight, and age are depressed and go to the doctor. The doctor prescribes an antidepressant, Nortriptyline (at a dose of 100mg) Has an adverse reaction Nothing happens Getting better  october 30, 2045 You wake up feeling terrible, and you know it’s time to see a doctor. The doctor looks you over, listens to your symptoms, and decides to prescribe you a drug. But first, the doctor takes a look at your DNA Today vs Future Today – drugs are one size fits all Future – drugs specific for you!  In the year 2000, just 3 years shy of the completion of the Human Genome Project, artist Aaron Bacall (1939-2015) drew a cartoon featuring a woman nonchalantly handing a piece of paper to her (somewhat perplexed-looking) community pharmacist with a caption that read, “Here’s my DNA sequence”. The image was a vision of the futured the lofty goal of the tremendous international efforts underway to sequence all 3 billion base pairs of the human genome. One day, our genetic blueprint would find its way into routine medical care, and even into the hands of our local community pharmacist.  THANKS! The information presented in this power point lecture presentation is collected from various sources including Google, research articles and some book chapters from various books. Material and figures used in this presentation are gratefully acknowledged. This material is collected and presented only for teaching purpose. CREDITS: This presentation template was created by Slidesgo, including icons by Flaticon, and infographics & images by Freepik