An Introduction to Ethnopharmacology John McFadden, CRNA Program Administrator & Program Administrator & Assistant Professor of Anesthesiology Assistant Professor of Anesthesiology Barry University, Miami Shores, FL 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?

Toxic Reaction Hmmm... No Effect Oops! Too Much Too Little  Dose  Dose No effect  Dose  Dose Still Toxic side effects…

What is “Ethnopharmacology”? Study of substances used as medicines by various ethnic groups. Study of substances used as medicines by various ethnic groups. The International Society of Ethnopharmacology The International Society of Ethnopharmacology Journal of Ethnopharmacology Journal of Ethnopharmacology

Ethnopharmacology vs Ethnic pharmacology The effect of ethnicity on responses to drugs. The effect of ethnicity on responses to drugs. Two distinct concepts: Two distinct concepts: –Genetics –Culture and environment

Clearing up the definitions… Race – a class of persons with a common lineage; a group of people who have different distributions of gene frequencies Race – a class of persons with a common lineage; a group of people who have different distributions of gene frequencies Culture – a group of people with an integrated system of learned beliefs, values and customs. Culture – a group of people with an integrated system of learned beliefs, values and customs. Ethnicity – shared common cultural bonds, or common genetic heritage. Ethnicity – shared common cultural bonds, or common genetic heritage.

African American?

Pharmacogenetics and Pharmacogenomics The effects of genetic variation on drug action. The effects of genetic variation on drug action. Correlation of drug-specific traits with genome-wide DNA sequence variations 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 Oxidation Reduction Reduction Hydrolysis Hydrolysis Phase II Conjugation Conjugation for elimination

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

Smoking and Anesthesia Induces CYP enzymes Induces CYP enzymes Decreased potency of aminosteroids MRs Decreased potency of aminosteroids MRs No impact on inhalation agents No impact on inhalation agents More opioids? More opioids?

Alcohol Barash, P.G., Cullen, B.F., Stoelting, R.K. Clinical Anesthesia (5 th ed.) Philadelphia: Lippincott. p Barash, P.G., Cullen, B.F., Stoelting, R.K. Clinical Anesthesia (5 th ed.) Philadelphia: Lippincott. p –“..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 Increase CYP 1A2 activity Increase CYP 1A2 activity Decreased therapeutic action of verapamil, haldol, odansetron, ropivicaine Decreased therapeutic action of verapamil, haldol, odansetron, ropivicaine

Coffee Black and Green teas Induce CYP 1A2 and CYP 2B Induce CYP 1A2 and CYP 2B

Phytochemical Major Source CYP 450 Anthraflavic Acid RhubarbCYP1A Diallyl disulphide & Diallyl sulfide Coffee and Tea CYP1A2, CYP2B GlycyrrhizinLiquorice CYP1A2, CYP2A1, CYP2B, CYP2C11, CYP3A Hyperforin St. John’s wort CYP3A4 MentholMintCYP2B Tangeretin Citrus Fruit CYP1A1, CYP1A2, CYP2B1, CYP2B2 Adapted from: Ioannides, C. (2003). Drug–phytochemical interactions. Inflammopharmacology, 11 (1), 7-42 Phytochemicals that up-regulate CYP 450 enzymes in vivo

Phytochemical Major Source CYP 450 BergamottinGrapefruitCYP3A4 Capsaicin Coffee and Tea CYP1A2, CYP2B PiperinePepperCYP2E1 SulphoraphaneBroccoli CYP2E1, CYP3A4 Adapted from: Ioannides, C. (2003). Drug–phytochemical interactions. Inflammopharmacology, 11 (1), 7-42 Phytochemicals that inhibit CYP 450 enzymes in vivo

Krasowski MD, McGehee DS, Moss J. Natural inhibitors of cholinesterase: 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 trend? 1800s WWII 1950s 1960s 1990

The Basics of Genetics 45 human chromosomes 45 human chromosomes 2 meters of DNA 2 meters of DNA 3 billion DNA subunits 3 billion DNA subunits –The bases: A,T, C, G Approximately 30,000 genes code for proteins that perform most life functions Approximately 30,000 genes code for proteins that perform most life functions

The 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 Science Serum Cholinesterase activity Serum Cholinesterase activity CYP variant effect on proton pump inhibitors CYP variant effect on proton pump inhibitors Psychotropic Drugs Psychotropic Drugs Antihypertensives Antihypertensives G6PD G6PD Bronchodilation Bronchodilation Opioid Responsiveness Opioid Responsiveness Gender and Anesthesia Gender and Anesthesia

State of the Science Serum Cholinesterase activity Serum Cholinesterase activity CYP variant effect on proton pump inhibitors CYP variant effect on proton pump inhibitors Psychotropic Drugs Psychotropic Drugs Antihypertensives Antihypertensives G6PD G6PD Bronchodilation Bronchodilation Opioid Responsiveness Opioid Responsiveness Gender and Anesthesia Gender and Anesthesia

State of the Science Serum Cholinesterase activity Serum Cholinesterase activity CYP variant effect on proton pump inhibitors CYP variant effect on proton pump inhibitors Psychotropic Drugs Psychotropic Drugs Antihypertensives Antihypertensives G6PD G6PD Bronchodilation Bronchodilation Opioid Responsiveness Opioid Responsiveness Gender and Anesthesia Gender and Anesthesia

CYP 2D6: Poor Metabolizer or Ultra Rapid Metabolizer? Affected Medications Affected Medications –Antidepressants –Antipsychotics –Beta adrenergic antagonists –Codeine –Dextromethorphan –Amphetamine

State of the Science Serum Cholinesterase activity Serum Cholinesterase activity CYP variant effect on proton pump inhibitors CYP variant effect on proton pump inhibitors Psychotropic Drugs Psychotropic Drugs Antihypertensives Antihypertensives G6PD G6PD Bronchodilation Bronchodilation Opioid Responsiveness Opioid Responsiveness Gender and Anesthesia Gender and Anesthesia

State of the Science Serum Cholinesterase activity Serum Cholinesterase activity CYP variant effect on proton pump inhibitors CYP variant effect on proton pump inhibitors Psychotropic Drugs Psychotropic Drugs Antihypertensives Antihypertensives G6PD G6PD Bronchodilation Bronchodilation Opioid Responsiveness Opioid Responsiveness Gender and Anesthesia Gender and Anesthesia

Who needs more anesthesia? Liem, E.B., et al. (2004). Anesthetic requirements is increased in redheads. Anesthesiology 2004; 101:

State of the Science Serum Cholinesterase activity Serum Cholinesterase activity CYP variant effect on proton pump inhibitors CYP variant effect on proton pump inhibitors Psychotropic Drugs Psychotropic Drugs Antihypertensives Antihypertensives Warfarin activity Warfarin activity G6PD G6PD Bronchodilation Bronchodilation Opioid Responsiveness Opioid Responsiveness Gender and Anesthesia Gender and Anesthesia

State of the Science Serum Cholinesterase activity Serum Cholinesterase activity CYP variant effect on proton pump inhibitors CYP variant effect on proton pump inhibitors Psychotropic Drugs Psychotropic Drugs Antihypertensives Antihypertensives Warfarin activity Warfarin activity G6PD G6PD Bronchodilation Bronchodilation Opioid Responsiveness Opioid Responsiveness Gender and Anesthesia Gender and Anesthesia

Gender and Anesthesia Gan, T.J. et al. (1999). Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology:90(5) Gan, T.J. et al. (1999). Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology:90(5) Buchanan, F.F. et al (2006). Gender and recovery after general anesthesia combined with neuromuscular blocking drugs. Anesthesia & Analgesia 102: Buchanan, F.F. et al (2006). Gender and recovery after general anesthesia combined with neuromuscular blocking drugs. Anesthesia & Analgesia 102:

Ethnicity and Anesthesia 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): 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): 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: 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:

What are the implications of ethnic pharmacology? Linking health disparities with biologic and genetic factors? Linking health disparities with biologic and genetic factors? Discriminatory practices? Discriminatory practices? Marketing? Marketing? Research? Research?

So…