An Introduction to An Introduction to EthnopharmacologyEthnopharmacology

John McFadden, CRNAJohn McFadden, CRNA Program Administrator &Program Administrator & Assistant Professor of Assistant Professor of AnesthesiologyAnesthesiology Barry University, Miami Shores, Barry University, Miami Shores, FLFL

Who do you think needs Who do you think needs a higher dose of a higher dose of propofol? Or desflurane?propofol? Or desflurane?

Which of these patients requires Which of these patients requires more anesthetic agent? For more anesthetic agent? For example, more desflurane or example, more desflurane or lidocaine as a local?lidocaine as a local?

Who will probably be Who will probably be discharged quicker?discharged quicker?

Which of these three will Which of these three will need more PACU time?need more PACU time?

Toxic Reaction

Hmmm...No Effect

Oops!Oops!

Too Much Too Little

Dose Dose

No effect

DoseDose

Still Toxic side effects…

What is What is “Ethnopharmacology”“Ethnopharmacology”?? Study of substances used as Study of substances used as

medicines by various ethnic medicines by various ethnic groups.groups.

The International Society of The International Society of EthnopharmacologyEthnopharmacology

Journal of EthnopharmacologyJournal of Ethnopharmacology

Ethnopharmacology Ethnopharmacology vsvsEthnic pharmacologyEthnic pharmacology

The effect of ethnicity on The effect of ethnicity on responses to drugs.responses to drugs.

Two distinct concepts:Two distinct concepts:– GeneticsGenetics– Culture and environmentCulture and environment

Clearing up the Clearing up the definitions…definitions…

RaceRace – a class of persons with a common – a class of persons with a common lineage; a group of people who have lineage; a group of people who have different distributions of gene frequenciesdifferent distributions of gene frequencies

CultureCulture – a group of people with an – a group of people with an integrated system of learned beliefs, values integrated system of learned beliefs, values and customs.and customs.

EthnicityEthnicity – shared common cultural bonds, – shared common cultural bonds, or common genetic heritage.or common genetic heritage.

African American?African American?

Pharmacogenetics and Pharmacogenetics and

PharmacogenomicsPharmacogenomics

The effects of genetic variation on The effects of genetic variation on drug action.drug action.

Correlation of drug-specific traits Correlation of drug-specific traits with genome-wide DNA sequence with genome-wide DNA sequence variationsvariations

Culture and Environment: Culture and Environment: Linked to pharmacokinetics and Linked to pharmacokinetics and

pharmacodynamics?pharmacodynamics?

Enzymes and Enzymes and Pathways Pathways in Drug Metabolismin Drug Metabolism

Phase IPhase I OxidationOxidation ReductionReduction HydrolysisHydrolysis

Phase IIPhase II ConjugatioConjugatio

n n

for for eliminationelimination

The CYP 450 EnzymesThe CYP 450 Enzymes

CYP = cytochrome P 450 familyCYP = cytochrome P 450 family– CYP 1 A 2CYP 1 A 2– CYP 2 D 6CYP 2 D 6

Smoking and Smoking and AnesthesiaAnesthesia

Induces CYP Induces CYP enzymesenzymes

Decreased Decreased potency of potency of aminosteroids aminosteroids MRsMRs

No impact on No impact on inhalation agentsinhalation agents

More opioids?More opioids?

AlcoholAlcohol

Barash, P.G., Cullen, B.F., Stoelting, R.K. Barash, P.G., Cullen, B.F., Stoelting, R.K. Clinical AnesthesiaClinical Anesthesia (5 (5thth ed.). 2006. ed.). 2006. Philadelphia: Lippincott. p.397-398.Philadelphia: Lippincott. p.397-398.– ““..no single mechanism explains ..no single mechanism explains

alterations in MAC…”alterations in MAC…”– Chronic alcoholism = increase MAC due Chronic alcoholism = increase MAC due

to upregulation from chronically to upregulation from chronically depressed neurotransmitter levelsdepressed neurotransmitter levels

– Acute alcohol intoxication = decrease Acute alcohol intoxication = decrease MACMAC

Cruciferous VegetablesCruciferous Vegetables

Increase CYP 1A2 Increase CYP 1A2 activityactivity

Decreased Decreased therapeutic action therapeutic action of verapamil, of verapamil, haldol, haldol, odansetron, odansetron, ropivicaineropivicaine

CoffeeCoffeeBlackBlack and and GreenGreen teas teas

Induce CYP 1A2 Induce CYP 1A2 and CYP 2Band CYP 2B

PhytochemicalPhytochemical Major SourceMajor Source CYP 450CYP 450

Anthraflavic AcidAnthraflavic Acid RhubarbRhubarb CYP1ACYP1A

Diallyl disulphide & Diallyl disulphide &

Diallyl sulfideDiallyl sulfideCoffee and TeaCoffee and Tea CYP1A2, CYP2BCYP1A2, CYP2B

GlycyrrhizinGlycyrrhizin LiquoriceLiquorice CYP1A2, CYP2A1, CYP1A2, CYP2A1, CYP2B, CYP2C11, CYP2B, CYP2C11, CYP3ACYP3A

HyperforinHyperforin St. John’s wortSt. John’s wort CYP3A4CYP3A4

MentholMenthol MintMint CYP2BCYP2B

TangeretinTangeretin Citrus FruitCitrus Fruit CYP1A1, CYP1A2, CYP1A1, CYP1A2, CYP2B1, CYP2B2CYP2B1, CYP2B2

Adapted from: Ioannides, C. (2003). Drug–phytochemical Adapted from: Ioannides, C. (2003). Drug–phytochemical interactions.interactions. InflammopharmacologyInflammopharmacology, , 11 (1), 7-4211 (1), 7-42

Phytochemicals that up-regulate

CYP 450 enzymes in vivo

PhytochemicalPhytochemical Major SourceMajor Source CYP 450CYP 450

BergamottinBergamottin GrapefruitGrapefruit CYP3A4CYP3A4

CapsaicinCapsaicin Coffee and TeaCoffee and Tea CYP1A2, CYP2BCYP1A2, CYP2B

PiperinePiperine PepperPepper CYP2E1CYP2E1

SulphoraphaneSulphoraphane BroccoliBroccoli CYP2E1, CYP3A4CYP2E1, CYP3A4

Adapted from: Ioannides, C. (2003). Drug–phytochemical Adapted from: Ioannides, C. (2003). Drug–phytochemical interactions.interactions. InflammopharmacologyInflammopharmacology, , 11 (1), 7-4211 (1), 7-42

Phytochemicals that inhibit

CYP 450 enzymes in vivo

Krasowski MD, McGehee DS, Moss J. Natural inhibitors of cholinesterase: Krasowski MD, McGehee DS, Moss J. Natural inhibitors of cholinesterase: implications for adverse reactions.Can J Anaesth 1997:44(Pt5):1525–1534.implications for adverse reactions.Can J Anaesth 1997:44(Pt5):1525–1534.

“…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.

How recent is this How recent is this trend?trend?

1800s WWII 1950s 1960s 1990

The Basics of GeneticsThe Basics of Genetics

45 human chromosomes45 human chromosomes 2 meters of DNA2 meters of DNA 3 billion DNA subunits3 billion DNA subunits

– The bases: A,T, C, GThe bases: A,T, C, G Approximately 30,000 genes code Approximately 30,000 genes code

for proteins that perform most life for proteins that perform most life functionsfunctions

The Basics of GeneticsThe Basics of Genetics

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 ScienceState of the Science

Serum Cholinesterase activitySerum Cholinesterase activity CYP variant effect on proton pump CYP variant effect on proton pump

inhibitorsinhibitors Psychotropic DrugsPsychotropic Drugs AntihypertensivesAntihypertensives G6PDG6PD BronchodilationBronchodilation Opioid ResponsivenessOpioid Responsiveness Gender and AnesthesiaGender and Anesthesia

State of the ScienceState of the Science

Serum Cholinesterase activitySerum Cholinesterase activity CYP variant effect on proton pump CYP variant effect on proton pump

inhibitorsinhibitors Psychotropic DrugsPsychotropic Drugs AntihypertensivesAntihypertensives G6PDG6PD BronchodilationBronchodilation Opioid ResponsivenessOpioid Responsiveness Gender and AnesthesiaGender and Anesthesia

State of the ScienceState of the Science

Serum Cholinesterase activitySerum Cholinesterase activity CYP variant effect on proton pump CYP variant effect on proton pump

inhibitorsinhibitors Psychotropic DrugsPsychotropic Drugs AntihypertensivesAntihypertensives G6PDG6PD BronchodilationBronchodilation Opioid ResponsivenessOpioid Responsiveness Gender and AnesthesiaGender and Anesthesia

CYP 2D6: CYP 2D6: Poor Metabolizer or Poor Metabolizer or Ultra Rapid Metabolizer?Ultra Rapid Metabolizer? Affected MedicationsAffected Medications

– AntidepressantsAntidepressants– AntipsychoticsAntipsychotics– Beta adrenergic antagonistsBeta adrenergic antagonists– CodeineCodeine– DextromethorphanDextromethorphan– AmphetamineAmphetamine

State of the ScienceState of the Science

Serum Cholinesterase activitySerum Cholinesterase activity CYP variant effect on proton pump CYP variant effect on proton pump

inhibitorsinhibitors Psychotropic DrugsPsychotropic Drugs AntihypertensivesAntihypertensives G6PDG6PD BronchodilationBronchodilation Opioid ResponsivenessOpioid Responsiveness Gender and AnesthesiaGender and Anesthesia

State of the ScienceState of the Science

Serum Cholinesterase activitySerum Cholinesterase activity CYP variant effect on proton pump CYP variant effect on proton pump

inhibitorsinhibitors Psychotropic DrugsPsychotropic Drugs AntihypertensivesAntihypertensives G6PDG6PD BronchodilationBronchodilation Opioid ResponsivenessOpioid Responsiveness Gender and AnesthesiaGender and Anesthesia

Who needs more Who needs more anesthesia?anesthesia?

Liem, E.B., et al. (2004). Anesthetic requirements is increased in redheads. Anesthesiology 2004; 101:279-283.

State of the ScienceState of the Science

Serum Cholinesterase activitySerum Cholinesterase activity CYP variant effect on proton pump CYP variant effect on proton pump

inhibitorsinhibitors Psychotropic DrugsPsychotropic Drugs AntihypertensivesAntihypertensives Warfarin activityWarfarin activity G6PDG6PD BronchodilationBronchodilation Opioid ResponsivenessOpioid Responsiveness Gender and AnesthesiaGender and Anesthesia

State of the ScienceState of the Science

Serum Cholinesterase activitySerum Cholinesterase activity CYP variant effect on proton pump CYP variant effect on proton pump

inhibitorsinhibitors Psychotropic DrugsPsychotropic Drugs AntihypertensivesAntihypertensives Warfarin activityWarfarin activity G6PDG6PD BronchodilationBronchodilation Opioid ResponsivenessOpioid Responsiveness Gender and AnesthesiaGender and Anesthesia

Gender and AnesthesiaGender and Anesthesia

Gan, T.J. et al. (1999). Women emerge from Gan, T.J. et al. (1999). Women emerge from general anesthesia with general anesthesia with propofol/alfentanil/nitrous oxide faster than propofol/alfentanil/nitrous oxide faster than men. men. Anesthesiology:90(5).Anesthesiology:90(5). 1283-1287. 1283-1287.

Buchanan, F.F. et al (2006). Gender and Buchanan, F.F. et al (2006). Gender and recovery after general anesthesia combined recovery after general anesthesia combined with neuromuscular blocking drugs. with neuromuscular blocking drugs. Anesthesia & Analgesia 102Anesthesia & Analgesia 102: 291-297.: 291-297.

Ethnicity and Ethnicity and AnesthesiaAnesthesia Ortolani, O. et al (2001). The recovery of Ortolani, O. et al (2001). The recovery of

Senegalese African Blacks from Senegalese African Blacks from intravenous anesthesia with propofol and intravenous anesthesia with propofol and remifentanyl is slower than that of remifentanyl is slower than that of Caucasians. Caucasians. Anesthesia & Analgesia, 93 Anesthesia & Analgesia, 93 (5):(5): 1222-1226. 1222-1226.

Ortolani, O. et al (2004). Ethnic differences Ortolani, O. et al (2004). Ethnic differences in propofol and fentanyl response: A in propofol and fentanyl response: A comparison among Caucasians, Kenyan comparison among Caucasians, Kenyan Africans and Brazilians. Africans and Brazilians. European Journal European Journal of Anesthesiology 2004, 21:of Anesthesiology 2004, 21: 314 - 315 314 - 315

What are the What are the implications of ethnic implications of ethnic

pharmacology?pharmacology? Linking health disparities with Linking health disparities with

biologic and genetic factors?biologic and genetic factors? Discriminatory practices?Discriminatory practices? Marketing?Marketing? Research?Research?

So…So…