Download The Future of Hypertension Management: Pharmacogenetics

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/
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.”
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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 4050% 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
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
A Solution on the Horizon…
Pharmacogenetics!
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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
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
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
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 6phosphate dehydrogenase
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
acetylate isoniazid; “slow acetylators” more likely
to develop toxicity
• 1959 Friedrich Vogel coined the term
pharmacogenetics
Current Treatment Reflects Genetic
Component
• General treatment of hypertension is trialand-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
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
Pharmacogenetics Applied to
Hypertension
• Locations for genetic variation in drug
response:
1. Drug receptors
2. Response pathway of activated
receptors
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
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 αsubunit of Gs-protein, which pairs β-adrengeric
receptor activation to cAMP production
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
Angiotensin II Blockers
• 6 possible SNP’s isolated in one study
• Angiotensin converting enzyme and
angiotensinogen gene
Calcium Channel Blockers
• Preferential effectiveness in African Americans
suggests genetic component
• Future study on polymorphisms of saltsensitivity hypertension due to actions of
vasodilation and natriuresis
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
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
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
So, how well do you remember
your genetics?
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