An Introduction to Pharmacogenomics for Behavioral Health Nurses

This program has been approved for one contact hour for nurses by the Really Important Contact Hour Approver

This course is valid for two years and expires 8/31/2013

Objectives

• Define pharmacogenomics

• Discuss how the application of pharmacogenomics principles can lead to safer, individualized health care

• Apply the principles of pharmacogenomics to safe medication administration, using the medication venlafaxine as an example

Background

• Genome: An organism’s complete set of DNA, including its genes

• DNA made up of 4 chemicals, called bases– Abbreviated A, C, T, & G

– Human genome has 3 billion pairs of bases

– Particular order of these chemicals critical

• DNA in humans arranged into 24 chromosomes– Chromosomal abnormalities (duplication, breaks) can

cause disease

Source: The Human Genome Project Information, http://www.ornl.gov/sci/techresources/Human_Genome/project/info.shtml

Background

• Genes– Many per

chromosome

– Basic unit of heredity

– Specific sequences of bases that encode instructions on how to make proteins

– 99.9% of bases the same in all people

Source: The Human Genome Project Information, http://www.ornl.gov/sci/techresources/Human_Genome/project/info.shtml

The Human Genome Project

• Begun in 1990, finished in 2003• Goals

– identify all the approximately 20,000-25,000 genes in human DNA,

– determine the sequences of the 3 billion chemical base pairs that make up human DNA,

– store this information in databases,

– improve tools for data analysis,

– transfer related technologies to the private sector, and

– address the ethical, legal, and social issues (ELSI) that may arise from the project.

Source: The Human Genome Project Information, http://www.ornl.gov/sci/techresources/Human_Genome/project/about.shtml

SNPs

• Single nucleotide polymorphisms– DNA sequence variations that occur when a single

base (A,T,C,or G) in the genome sequence is altered

• Example: AAGGCTAA to ATGGCTAA

– For variation to be considered a SNP, must occur in at least 1% of population

– Evolutionarily stable

– Can influence the likelihood of developing a disease

• Alzheimer’s

• Heart disease

• Diabetes

Source: The Human Genome Project Information, http://www.ornl.gov/sci/techresources/Human_Genome/faq/snps.shtml

SNPs and Pharmacogenomics

• Pharmacogenomics– The study of how an individual's genetic inheritance

affects the body's response to drugs

• Cytochrome P450 (CYP)– Family of liver enzymes responsible for metabolizing

more than 30 different classes of drugs

• SNPs in this cytochrome can cause the body to break down drugs more rapidly, or to break them down more slowly

– If rapid, may have subtherapeutic response– If slowed, may become toxic

Source: The Human Genome Project Information, http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml

Drugs that undergo metabolism by CYP2D6

• Other medical conditions– Carvedilol – Chlorpheniramine – Dextromethorphan – Diltiazem – Metoclopramide – Metoprolol – Ondansetron – Tramadol

• Drugs with abuse potential– Amphetamine – Codeine – Oxycodone

• Psychotropics– Amitriptyline – Aripiprazole – Donepezil – Duloxetine – Fluoxetine – Haloperidol– Iloperidone – Imipramine – Mirtazapine – Nortriptyline – Sertraline – Venlafaxine Source: Mayo Clinic Laboratories,

http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/83180

SNPs and Pharmacogenomics

• Four drugs now require genetic testing prior to administration– abacavir (Ziagen)

• Used in treatment of HIV– trastuzumab (Herceptin)

• Used in treatment of breast cancer– mercaptopurine (Purinethol)

• For acute lymphoblastic leukemia– irinotecan (Camptosar)

• For colon cancer• So why don’t we use pharmacogenomics to

customize medication selection for all patients?

Source: National Human Genome Research Institute, http://www.genome.gov/27530645

Pharmacogenomics in Prescribing

• Advantages– Better, safer drugs

the first time

– More accurate methods of determining dosages

• Barriers– Complexity of SNPs

– Limited drug alternatives

– Drug companies targeting majority genotype

– Educating health care providers

– Lack of laboratories, slowed treatment?

Source: The Human Genome Project Information, http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml

Pharmacogenomics and Venlafaxine

• Venlafaxine– Brand name Effexor, Effexor-ER

– Antidepressant

• Serotonin-norepinephrine reuptake inhibitor (SNRI)

– Higher fatal toxicity index than selective serotonin reuptake inhibitors (SSRIs, like Prozac/Celexa)

– Higher suicide frequency compared to other antidepressants

Pharmacogenomics and Venlafaxine

• Venlafaxine– Depression predisposes to suicidal behavior

– Venlafaxine more effective than SSRIs or tricyclic antidepressants in the treatment of resistant depression (Launiained, Rasanen, Vuori, and Ojanpera, 2011)

• Therefore, often prescribed to those at highest risk

• Can we apply the principles of pharmacogenomics to determine which patients should and should not receive this medication?

Pharmacogenomics and Venlafaxine

• Four out of five studies reviewed indicated a relationship between CYP2D6 polymorphism and adverse reaction to Venlafaxine– Piatkov, Jones, and Van Vuuren (2011) studied 11

patients who had committed suicide while on venlafaxine

• 10 of 11 had polymorphisms; several had more than one

• 8 patients had other medications in their bloodstream, including prescribed medications, illicit drugs and/or alcohol

Pharmacogenomics and Venlafaxine

• Other studies– McAlpine, O'Kane, Black, and Mrazek (2007)

• Examined medical records of those who had been prescribed venlafaxine for side effects

• Patients who lacking active CYP2D6 may not tolerate venlafaxine or may only tolerate the minimal dosage

– Shams et al. (2006)

• A polymorphism in CYP2D6 that leads to poor metabolism increases the risk of side effects, including GI symptoms and hyponatremia

Pharmacogenomics and Venlafaxine

• Other studies– Whyte et al. (2006)

• Geriatric population

• Genetic testing may help screen for those with polymorphisms for whom venlafaxine can cause adverse drug reactions, especially those with cardiac or renal issues

– Launiained, Rasanen, Vuori, and Ojanpera (2011)

• Inherent CYP2D6 activity was not a factor in toxicity

• Adverse drug interactions, inhibiting CYP2D6 activity, is a significant factor contributing to toxicity

What conclusions can we draw?

• 4 out of 5 studies indicate that genetic testing to identify those with the polymorphism that would lead to side-effects– Side-effects may even include an increased risk for

suicide

• All five studies note the negative effect of co-administration of other medications dependent on the CYP2D6 pathway for metabolism

What conclusions can we draw?

• McAlpine et al. (2007) recommend “start low and go slow” – What are the risks of this approach?

• Despite its high fatal toxicity index, Venlafaxine is not an inherently “bad drug”, but it may be the wrong drug for some people

Implications for clinicians

• In the near future, genetic testing will be a part of the prescribing regimen for many medications, including many psychotropic medications

• In the meantime, when administering venlafaxine:– Minimize co-administration of other drugs

metabolized by the CYP2D6 pathway when possible

– Carefully consider the appropriateness of this medication for patients with a known history of illicit drug use

– Carefully consider the appropriateness of this medication for patients whose past history indicates poor compliance with follow-up monitoring

References – Understanding Pharmacogenomics

• Mayo Clinic Laboratories. (2011). Unit code 83180: Cytochrome P450 2D6 genotype. Retrieved August 2, 2011, from http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/83180

• National Human Genomics Research Institute. (2011). Frequently asked questions about pharmacogenomics. Retrieved from http://www.genome.gov/27530645

• National Institutes Of Health. (2010). Could genetics improve warfarin dosing? Retrieved from http://www.genome.gov/27530277

References – Understanding Pharmacogenomics

• US Department Of Energy Office of Science. (2008). Human Genome Project information:

– The science behind the Human Genome Project. Retrieved from http://www.ornl.gov/sci/techresources/Human_Genome/project/info.shtml

– About the Human Genome Project. Retrieved from http://www.ornl.gov/sci/techresources/Human_Genome/project/about.shtml

– Pharmacogenomics. Retrieved from http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml

References – Venlafaxine Studies

• Launiained, T., Rasanen, I., Vuori, E., & Ojanpera, I. (2011). Fatal venlafaxine poisonings are associated with a high prevalence of drug interactions. International Journal of Legal Medicine, 125, 349-358. doi:10.1007/s00414-010-0461-5

• McAlpine, D. E., O'Kane, D. J., Black, J. L., & Mrazek, D. A. (2007). Cytochrome P450 2D6 genotype variation and venlafaxine dosage. Mayo Clinic Proceedings, 82, 1065-1068. Retrieved from http://www.mayoclinicproceedings.com/

• Piatkov, I., Jones, T., & Van Vuuren, R. J. (2011). Suicide cases and venlafaxine. Acta Neuropsychiatrica 2011, 23, 156-160. doi:10.1111/j.1601-5215.2011.00566.x

References – Venlafaxine Studies

• Shams, M. E., Arneth, B., Hiemke, C., Dragicevic, A., Muller, M. J., Kaiser, R.,...Hartter, S. (2006). CYP2D6 polymorphism and clincal effect of the antidepressant venlafaxine. Journal of Clinical Pharmacy and Therapeutics, 31, 493-502. Retrieved from http://ezproxy.sjcme.edu:2279/bw/journal.asp?ref=0269-4727

• Whyte, E. M., Romkes, M., Mulsant, B. H., Kirshne, M. A., Begley, A. E., Reynolds, C., Pollock, B. (2006). CYP2D6 genotype and venlafaxine. International Journal of Geriatric Psychiatry, 21, 542-549. doi:10.1002/gps.1522