Transcript Racial Differences in the Response to Medications

Racial Differences in
Responses to
Pharmacological Treatments
Anne Chung
APAMSA National Board Retreat
January 16-18, 2004
Factors affecting
responses to medications
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Environmental
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Climate
Smoking
Alcohol consumption
Diet
Biological
– Age
– Gender
– Genetic variations
Differences in
Pharmacogenetics
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Cytochrome P450 2C19
Cytochrome P450 2A6
Cytochrome P450 2D6
N-acetyltransferase
Cytochrome P450 2C19
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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
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Drugs should be prescribed initially in lower
doses
Proton Pump Inhibitors - Helicobacter
pylori infection in peptic ulcers
100%
Cure Rate
80%
60%
100%
40%
60%
20%
0%
29%
Poor Metabolizers
Heterozygous
Homozygous Wild
Type
Ma M, Woo M, Mcleod H (2002). Genetic Basis of Drug Metabolism, American Journal of Health-System Pharmacy.
Diazepam
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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.
80
70
60
Half-Life
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50
40
30
80
64
20
10
0
20
Poor
Heterozygous Homozygous
Metabolizers
Wild Type
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.
Cytochrome P450 2A6
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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.
Cytochrome P450 2D6
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Metabolizes 20% of clinically useful drugs
Drugs metabolized by CYP2C19
– Antidepressants
– Antipsychotics
Cytochrome P450 2D6
PM
Frequency of IM
Mutation
10%
60%
8%
6%
10%
4%
2%
0%
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20%
1%
Asian
40%
Caucasian
0%
50%
2%
Asian
Caucasian
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.
Tricyclic Antidepressants
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Studies in Asian patients
have shown significantly
higher TCA concentrations
than in Caucasian patients
after a single dose.
250
200
ng/ml
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Therapeutic
Concentrations
Additionally, the incidence of
drug-related side-effects
was higher in Asians.
150
225
100
50
0
130
Asian
Caucasian
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.
Antipsychotic Drugs
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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.
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Drugs metabolized
by Nacetyltransferase
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isoniazid
sulfonamides
procainamide
hydralzaine
caffeine
Percentage Slow Metabolizers
N-acetyltransferase
60%
50%
40%
60%
30%
20%
10%
0%
20%
Asian
Caucasian
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.
Other Medications
Showing Differences
in Response
Beta-blockers
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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.
Analgesics
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Acetaminophen
– Asian patients have higher clearance rates of
acetaminophen than Caucasians.
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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.
Lower Dosage Consideration
for Asian Patients
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Omeprezole
Diazepam
Nicotine patch
TCA
Antipsychotics
Isoniazid
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Sulfonamides
Procainamide
Hydralzaine
Propranolol
Acetaminophen
Codeine/Morphine
Clinical Significance
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Physicians should incorporate genetic
factors into dosage considerations
– Toxicity
– Therapeutic levels
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Intra-racial differences as well as interracial differences exist