The Future of Hypertension Management: Pharmacogenetics

1. The Future of Hypertension Management: Pharmacogenetics Beth McElroy Hill April 3, 2008 PAS 646 Dr. Doris Rapp, Pharm D., PA-C http://www.pharmacogeneticsinpsychiatry.com/

2. The Hypertension Epidemic • American Heart Association reports 65 million+ American with hypertension (≥140/90 mm Hg) • This equals roughly 1 in 4 adults • Another ¼ of American adults are prehypertensive (120-139/80-89 mm Hg) • WHO identifies hypertension as the “number one attributable risk for death worldwide.” http://khomsah1.multiply.com/journal/item/615

3. Control • AHA reports reducing systolic blood pressure by 10 mm Hg is associated with a 50-60% decrease in risk of death from stroke and a 40-50% decrease in risk of death from cardiovascular disease and other vascular causes • Framingham Heart Study determined that only 1/3 of hypertensive patients are controlled to blood pressure ≤ 140/90

4. Obstacles to Control • Generally asymptomatic condition • Lack of understanding of patients of importance of control leads to poor compliance • Patients have unique responses to medications leading to trial-and-error approach to treatment, which takes time and money

5. A Solution on the Horizon… Pharmacogenetics! http://www.waynewhitecoop.com/system/images/Light%20Bulb.jpg

6. Pharmacogenetics • “a biotechnological science that combines the techniques of medicine, pharmacology, and genomics and is concerned with developing drug therapies to compensate for genetic differences in patients which cause varied responses to a single therapeutic regimen” -Merriam-Webster • In other words, pharmacogenetics matches a person’s unique genetic profile with complementary drugs

7. Is it really necessary? • 30% of patients are not benefitting from prescribed medications they are currently taking • Every year in the US 2.2 million adverse reactions to drugs occur • Over 100,000 deaths per year are attributed to reactions to prescription drugs • Genetics are estimated to account for 20-95% of variation in individual responses to drugs

8. History • Early 1900’s Sir Archibald E. Garrod noted, “Even against chemical poisons taken by mouth, or by other channels, there are some means of defence. Every active drug is a poison, when taken in large enough doses; and in some subjects a dose which is innocuous to the majority of people has toxic effects, whereas others show exceptional tolerance of the same drug.” Meyer 2004

9. History • World War II: American soldiers administered doses of antimalarial agent primaquine • Significant number of soldiers developed acute hemolytic crises • Reaction traced to deficiency of glucose 6-phosphate dehydrogenase

10. History • Succinylcholine, an adjunct anesthetic led to prolonged apnea in some patients, which was traced to a deficiency in pseudocholinesterase • 1952, is using isoniazid therapy for tuberculosis, researchers noted great variation in amount of unchanged drug in the urine due to ability to acetylateisoniazid; “slow acetylators” more likely to develop toxicity • 1959 Friedrich Vogel coined the term pharmacogenetics

11. Current Treatment Reflects Genetic Component • General treatment of hypertension is trial-and-error, although there are a few loose guidelines 1. Renin Profile 2. Age-race Profile • In general, African Americans respond better to diuretics and calcium channel blockers, while Caucasians respond better to beta blockers and ACE-inhibitors

12. Genetic Basis of Hypertension • Montreal Adoption Study: stronger correlation between biological siblings blood pressures • Many physiological systems (and genes) at work: renal, neuronal, endocrine, vascular • Current study of candidate genes: is one allele more common in the disease state than another? • Family Blood Pressure Program identified candidate gene SLC4A5 on chromosome 2 • Much study needed but AHA believes that 50% of variation in blood pressure has a genetic cause

13. Pharmacogenetics Applied to Hypertension • Locations for genetic variation in drug response: 1. Drug receptors 2. Response pathway of activated receptors

14. Diuretics • Thiazides currently first-line treatment, available, cheap • Adducin Paradigm: single nucleotide polymorphism(SNP) at ADD1Gly460Trp on the alpha chain of the adducin protein result in substitution of Trp for Gly; this SNP enhances renal tubular absorption of sodium, leading to increased blood volume, which leads to salt-sensitive hypertension, for which diuretics are most effective • Also studies on insertions and deletions of angiotensin converting enzyme with mixed results

15. Beta-Blockers • Areas of study: genes involved in the synthesis of proteins for the adrenergic receptors and that code for G proteins involved in signal transduction • Possibilities: 1. SNP of gene for angiotensinogen could result in better blood pressure control with atenolol 2. Substitution of Arg instead of Gly at site 389 of the gene for protein of the β1 adrenergic receptor linked to increased affinity for receptor agonist binding 3. Silent polymorphism on exon 5 of gene for α- subunit of Gs-protein, which pairs β-adrengeric receptor activation to cAMP production

16. ACE-Inhibitors • SNP’s altering RAAS function could lead to enhanced response to ACE-inhibitors • Insertion/deletion polymorphisms of angiotensin converting enzyme; similar responses to ACE-inhibitors

17. Angiotensin II Blockers • 6 possible SNP’s isolated in one study • Angiotensin converting enzyme and angiotensinogen gene

18. Calcium Channel Blockers • Preferential effectiveness in African Americans suggests genetic component • Future study on polymorphisms of salt-sensitivity hypertension due to actions of vasodilation and natriuresis

19. Barriers to use in Clinical Practice • Takes time to sort through all the genes at work in regulation of blood pressure and drug response • Education of practitioners on genetics and application to clinical practice • Lack of evidence-based results due to observational nature of this field • Genetic testing is expensive and not well standardized

20. The Future • More SNP’s are being studied and in time will be sorted out as to their effect on blood pressure and drug response • Studies on populations will need to control for environmental factors influencing hypertension such as age, gender, race, and diet before they can be generalized the society • Large scale studies are needed with more accessible screening tests

21. Conclusions • Current cost of antihypertensive agents per year is $7-$15 billion • Fatal comorbidities accompany uncontrolled hypertension • Current treatments are not effective as only 1/3 are controlled • Pharmacogenetics will save lives, money, time • Allow for implementation of new drugs

22. So, how well do you remember your genetics?

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