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Racial Differences in Responses to Pharmacological Treatments

Racial Differences in Responses to Pharmacological Treatments. Anne Chung APAMSA National Board Retreat January 16-18, 2004. Factors affecting responses to medications. Environmental Climate Smoking Alcohol consumption Diet Biological Age Gender Genetic variations.

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Racial Differences in Responses to Pharmacological Treatments

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  1. Racial Differences in Responses to Pharmacological Treatments Anne Chung APAMSA National Board Retreat January 16-18, 2004

  2. Factors affecting responses to medications • Environmental • Climate • Smoking • Alcohol consumption • Diet • Biological • Age • Gender • Genetic variations

  3. Differences in Pharmacogenetics • Cytochrome P450 2C19 • Cytochrome P450 2A6 • Cytochrome P450 2D6 • N-acetyltransferase

  4. Cytochrome P450 2C19 • Metabolizes 15% of clinically useful drugs • 15-30% incidence of poor metabolizers of CYP2C19 in Asians vs. 3-6% incidence of PMs in Caucasians • Drugs metabolized by CYP2C19 • Omeprazole • Diazepam • Drugs should be prescribed initially in lower doses

  5. Proton Pump Inhibitors - Helicobacter pylori infection in peptic ulcers Ma M, Woo M, Mcleod H (2002). Genetic Basis of Drug Metabolism, American Journal of Health-System Pharmacy.

  6. Diazepam • It has been noted that Hong Kong physicians normally prescribe smaller doses of diazepam for Chinese than for Caucasians. • Poor metabolizers of CYP2C19 may be at higher risk for diazepam toxicity. • Differences in amount of body fat could also affect need for higher dosage. Ma M, Woo M, Mcleod H (2002). Genetic Basis of Drug Metabolism, American Journal of Health-System Pharmacy. Ghoneim MM, Korttila K, Chiang C-K, et al. (1981) Diazepam effects and kinetics in Caucasians and Orientals. Clinical Pharmacology and Therapeutics, 29,749-756.

  7. Cytochrome P450 2A6 • Responsible for metabolizing nicotine. • Involved in activating several carcinogens in tobacco smoke. • Chinese patients have lower activity than Latinos and Caucasians. • Implications • May explain lower rates of lung cancer in Chinese smokers. • Also important in determining proper doses for nicotine patches.

  8. Cytochrome P450 2D6 • Metabolizes 20% of clinically useful drugs • Drugs metabolized by CYP2C19 • Antidepressants • Antipsychotics

  9. Cytochrome P450 2D6 • Drug oxidation capacity of the IM phenotype is severely reduced and may be comparable to that of PMs, especially under conditions of long-term treatment.

  10. Tricyclic Antidepressants • Studies in Asian patients have shown significantly higher TCA concentrations than in Caucasian patients after a single dose. • Additionally, the incidence of drug-related side-effects was higher in Asians. Yamashita I & Asano Y. (1979) Tricyclic antidepressants: therapeutic plasma level. Psychopharmacology Bulletin, 15, 40-41. Hu WH, Lee CF, Yang YY, et al. (1983) Imipramine plasma levels and clinical response. Bulletin of Chinese Society of Neurology and Psychiatry, 9, 40-49. Lewis P, Rack PH, Vadadi KS, et al. ( 1980) Ethnic differences in drug response. Postgraduate Medical Journ, 56(Suppl. 1),46-49.

  11. Antipsychotic Drugs • Asian patients require lower doses of antipsychotic drugs and appear to develop toxicity and side effects at lower doses compared to Caucasians. • Haloperidol • Chinese patients were shown to produce 40-50% higher plasma haloperidol concentrations compared to non-Chinese patients (Caucasians and Blacks). • Potkin SG, Shen Y, Pardes H, et al. ( 1984) Haloperidol concentrations elevated in Chinese patients. Psychiatry • Research, 12,167-172.

  12. N-acetyltransferase • Drugs metabolized by N-acetyltransferase • isoniazid • sulfonamides • procainamide • hydralzaine • caffeine Price Evans DA. N-acetyltransferase in pharmacogenetics of drug metabolism. In Kalow W, ed. Pharmacogenetics of drug metabolism. International encyclopedia of pharmacology and therapeutics. New York: Pergamon Press, 1992: 43:95-178.

  13. Other MedicationsShowing Differences in Response

  14. Beta-blockers • Propranolol is more effective in reducing blood pressure and heart rate in Chinese than in Caucasians. • Patients in China are prescribed much lower doses of propranolol than patients in the US and Europe. • Paradoxically, Chinese patients metabolize propranolol more rapidly than Caucasian patients. • Total blood clearance for Chinese patients is 76% greater.

  15. Analgesics • Acetaminophen • Asian patients have higher clearance rates of acetaminophen than Caucasians. • Codeine • Both Asian and Caucasian men transform codeine into morphine similarly, but Asian men experience significantly weaker effects from the drug. • Morphine cleared faster and increased metabolism of codeine through enzymes other than CYP2D6 in Asian men Wood, A.J.J. 1997. Pharmacogenetic and ethnic differences in opiate response. Meeting of the American Chemical Society. Las Vegas.

  16. Omeprezole Diazepam Nicotine patch TCA Antipsychotics Isoniazid Sulfonamides Procainamide Hydralzaine Propranolol Acetaminophen Codeine/Morphine Lower Dosage Consideration for Asian Patients

  17. Clinical Significance • Physicians should incorporate genetic factors into dosage considerations • Toxicity • Therapeutic levels • Intra-racial differences as well as inter-racial differences exist

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