Transcript Pharmacogenetics

An Introduction to
Ethnopharmacology
John McFadden, CRNA
Program Administrator &
Assistant Professor of Anesthesiology
Barry University, Miami Shores, FL
Who do you think needs a
higher dose of propofol? Or
desflurane?
Which of these patients requires more
anesthetic agent? For example, more
desflurane or lidocaine as a local?
Who will probably be
discharged quicker?
Which of these three will
need more PACU time?
Oops!
Toxic
Reaction
Hmmm...
No Effect
Too Much
Dose
Too Little
Dose
Still Toxic side
effects…
Dose
No effect
Dose
What is
“Ethnopharmacology”?
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Study of substances used as medicines
by various ethnic groups.
The International Society of
Ethnopharmacology
Journal of Ethnopharmacology
Ethnopharmacology vs
Ethnic pharmacology
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The effect of ethnicity on responses
to drugs.
Two distinct concepts:
– Genetics
– Culture and environment
Clearing up the
definitions…
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Race – a class of persons with a common
lineage; a group of people who have different
distributions of gene frequencies
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Culture – a group of people with an integrated
system of learned beliefs, values and customs.
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Ethnicity – shared common cultural bonds, or
common genetic heritage.
African American?
Pharmacogenetics and
Pharmacogenomics
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The effects of genetic variation on
drug action.
Correlation of drug-specific traits with
genome-wide DNA sequence variations
Culture and Environment:
Linked to pharmacokinetics and
pharmacodynamics?
Enzymes and Pathways
in Drug Metabolism
Phase I
 Oxidation
 Reduction
 Hydrolysis
Phase II
 Conjugation
for
elimination
The CYP 450 Enzymes
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CYP = cytochrome P 450 family
– CYP 1 A 2
– CYP 2 D 6
Smoking and Anesthesia
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Induces CYP
enzymes
Decreased potency
of aminosteroids
MRs
No impact on
inhalation agents
More opioids?
Alcohol
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Barash, P.G., Cullen, B.F., Stoelting, R.K.
Clinical Anesthesia (5th ed.). 2006.
Philadelphia: Lippincott. p.397-398.
– “..no single mechanism explains
alterations in MAC…”
– Chronic alcoholism = increase MAC due
to upregulation from chronically
depressed neurotransmitter levels
– Acute alcohol intoxication = decrease
MAC
Cruciferous Vegetables
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Increase CYP 1A2
activity
Decreased
therapeutic action
of verapamil,
haldol, odansetron,
ropivicaine
Coffee
Black and Green teas
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Induce CYP 1A2
and CYP 2B
Phytochemicals that up-regulate
CYP 450 enzymes in vivo
Phytochemical
Major Source
CYP 450
Anthraflavic Acid
Rhubarb
CYP1A
Diallyl disulphide &
Diallyl sulfide
Coffee and Tea
CYP1A2, CYP2B
Glycyrrhizin
Liquorice
CYP1A2, CYP2A1, CYP2B,
CYP2C11, CYP3A
Hyperforin
St. John’s wort
CYP3A4
Menthol
Mint
CYP2B
Tangeretin
Citrus Fruit
CYP1A1, CYP1A2,
CYP2B1, CYP2B2
Adapted from: Ioannides, C. (2003). Drug–phytochemical interactions.
Inflammopharmacology, 11 (1), 7-42
Phytochemicals that inhibit
CYP 450 enzymes in vivo
Phytochemical
Major Source
CYP 450
Bergamottin
Grapefruit
CYP3A4
Capsaicin
Coffee and Tea
CYP1A2, CYP2B
Piperine
Pepper
CYP2E1
Sulphoraphane
Broccoli
CYP2E1, CYP3A4
Adapted from: Ioannides, C. (2003). Drug–phytochemical interactions.
Inflammopharmacology, 11 (1), 7-42
“…foods that are rich in solanaceous
glycoalkaloids (SGAs) such as tomatoes,
potatoes, and eggplants, delay recovery from
anesthesia and recommended restricting these
foods a few days before surgery. The SGAs are
reported to inhibit cholinesterases…”
Loizou, G.D.. & Cocker, J., The effects of alcohol and daily sulphide on CYP2E1
activity in humans: a phenotyping study using chlorzoxazone. Human &
Experimental Toxicology (2001) 20, 321 – 327.
Krasowski MD, McGehee DS, Moss J. Natural inhibitors of cholinesterase:
implications for adverse reactions.Can J Anaesth 1997:44(Pt5):1525–1534.
How recent is this trend?
1800s
WWII
1950s
1960s
1990
The Basics of Genetics
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45 human chromosomes
2 meters of DNA
3 billion DNA subunits
– The bases: A,T, C, G
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Approximately 30,000 genes code for
proteins that perform most life
functions
The Basics of Genetics
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Variant alleles
Genetic polymorphisms
The search is on to identify variant
alleles that yield polymorphisms.
It may be that a single nucleotide
polymorphism or “SNP” can be
associated with a specific drug or
group of drugs.
State of the Science
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Serum Cholinesterase activity
CYP variant effect on proton pump inhibitors
Psychotropic Drugs
Antihypertensives
G6PD
Bronchodilation
Opioid Responsiveness
Gender and Anesthesia
State of the Science
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Serum Cholinesterase activity
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CYP variant effect on proton pump inhibitors
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Psychotropic Drugs
Antihypertensives
G6PD
Bronchodilation
Opioid Responsiveness
Gender and Anesthesia
State of the Science
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Serum Cholinesterase activity
CYP variant effect on proton pump inhibitors
Psychotropic Drugs
Antihypertensives
G6PD
Bronchodilation
Opioid Responsiveness
Gender and Anesthesia
CYP 2D6:
Poor Metabolizer or
Ultra Rapid Metabolizer?
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Affected Medications
– Antidepressants
– Antipsychotics
– Beta adrenergic antagonists
– Codeine
– Dextromethorphan
– Amphetamine
State of the Science
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Serum Cholinesterase activity
CYP variant effect on proton pump inhibitors
Psychotropic Drugs
Antihypertensives
G6PD
Bronchodilation
Opioid Responsiveness
Gender and Anesthesia
State of the Science
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Serum Cholinesterase activity
CYP variant effect on proton pump inhibitors
Psychotropic Drugs
Antihypertensives
G6PD
Bronchodilation
Opioid Responsiveness
Gender and Anesthesia
Who needs more anesthesia?
Liem, E.B., et al. (2004). Anesthetic requirements is increased in
redheads. Anesthesiology 2004; 101:279-283.
State of the Science
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Serum Cholinesterase activity
CYP variant effect on proton pump inhibitors
Psychotropic Drugs
Antihypertensives
Warfarin activity
G6PD
Bronchodilation
Opioid Responsiveness
Gender and Anesthesia
State of the Science
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Serum Cholinesterase activity
CYP variant effect on proton pump inhibitors
Psychotropic Drugs
Antihypertensives
Warfarin activity
G6PD
Bronchodilation
Opioid Responsiveness
Gender and Anesthesia
Gender and Anesthesia
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Gan, T.J. et al. (1999). Women emerge
from general anesthesia with
propofol/alfentanil/nitrous oxide faster than
men. Anesthesiology:90(5). 1283-1287.
Buchanan, F.F. et al (2006). Gender and
recovery after general anesthesia combined
with neuromuscular blocking drugs.
Anesthesia & Analgesia 102: 291-297.
Ethnicity and Anesthesia
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Ortolani, O. et al (2001). The recovery of
Senegalese African Blacks from intravenous
anesthesia with propofol and remifentanyl is
slower than that of Caucasians. Anesthesia
& Analgesia, 93 (5): 1222-1226.
Ortolani, O. et al (2004). Ethnic differences
in propofol and fentanyl response: A
comparison among Caucasians, Kenyan
Africans and Brazilians. European Journal of
Anesthesiology 2004, 21: 314 - 315
What are the implications
of ethnic pharmacology?
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Linking health disparities with biologic
and genetic factors?
Discriminatory practices?
Marketing?
Research?
So…