Pharmacogenetics

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Pharmacogenetics

• Dr, P Derakhshandeh, PhD

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Pharmacogenetics
genetic variations in drug response
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• Among normal subject maximum rate of reaction
  of drug-metabolizing enzymes often differ widely
• drug elimination rates measured in vivo vary by
  fourfold to more than fortyfold
• depending on the drug and population studied

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• Numerous twin and family studies have shown that
  genetic factors are mainly responsible for these
  large interindividual variations.

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Pharmacogenetics

• has clinical consequences and biologic
  significance

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• ?

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• the inherent capacity to clear a drug may differ
  among patients
• A patient with rapid metabolism may require
  larger, more frequent doses to achieve
  therapeutic concentrations
• a patient with slow metabolism may need lower,
  less frequent doses
• to avoid toxicity, particularly for drugs with a
  narrow margin of safety.

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• Many environmental and developmental factors
  can interact with each other and with genetic
  factors to affect drug response

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Genetic, environmental, and developmental factors
that can interact, causing variations in drug
response among patients.

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(No Transcript)
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• PHARMACOKINETIC VARIATION

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Acetylation

• In about 50 of the U.S. population,drug
  inactivation
• by hepatic N-acetyltransferase
• Such persons (slow acetylators) require a longer
  time to metabolize drugs that are acetylated
• therefore they are more susceptible to adverse
  effects of such drugs (eg, peripheral
  isoniazid,)

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• In the rest of the population, acetylation is
  rapid
• Compared with slow acetylators, such persons
  require larger or more frequent doses of drugs
  that are acetylated (eg, isoniazid)
• to obtain the desired therapeutic response

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Oxidation

• In about 5 to 10 of whites in North America and
  Europe
• oxidative biotransformation of debrisoquin is
  decreased
• if such persons take debrisoquin for hypertension
• they are at increased risk of toxicity

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Aldehyde dehydrogenase-2

• About 50 of Japanese, Chinese, and other Asian
  populations
• lack aldehyde dehydrogenase-2
• an enzyme involved in ethanol metabolism
• In such persons, alcohol ingestion results in
  marked elevations of blood acetaldehyde
• in adverse effects (eg, facial flushing,
  increased heart rate, muscle weakness)

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Glucose-6-phosphate dehydrogenase (G6PD)
deficiency

• G6PD is essential for RBC reduction reactions
• maintain cytoskeletal integrity.
• 10 of black males, are at increased risk of
  developing hemolytic anemia when given oxidant
  drugs, such as antimalarials (eg, chloroquine,
  pamaquine,primaquine), aspirin, and vitamin K.

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G6PD
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• it is located at the q28 locus (Pai et al.,
  1980).
• All X-linked genetic conditions, such as G6PD
  deficiency, are more likely to affect males than
  females
• to have over 400 variant alleles

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• Different populations have different types of
  mutations, but within a specific population,
  common mutations are usually shared.
• For example, in Egypt there exists only one type
  of allele, called the "Mediterranean" variant,

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demographics of G6PD deficiency
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• most of the affected individuals reside in
  Africa, the Middle East, and Southeast Asia.
  African Americans and some isolated tribes in
  Africa and Southeast Asia exhibit the highest
  frequency of incidence for any given population
• a defective enzyme can be found in as many as
  one in four people among these populations
  (Scriver et al., 1995).

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CLINICAL ASPECTS OF G6PD DEFICIENCY

• red blood cell can no longer transport oxygen
  effectively throughout the body
• hemolytic anemia arises
• neonatal jaundice, abdominal and/or back pain,
  dizziness, headache, dyspnea (irregular
  breathing), and palpitations (Cecil, 1992)

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NEONATAL JAUNDICE

• Neonatal jaundice is a yellowish discoloration of
  the whites of the eyes and skin
• a direct result of insufficient activity of the
  G6PD enzyme in the liver
• In some cases, the neonatal jaundice is severe
  enough to cause death or permanent neurologic
  damage (Beutler, 1994).

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HEMOLYTIC ANEMIA

• An anemic response can be induced in affected
  individuals by certain oxidative drugs, fava
  beans, or infections (Beutler, 1994).
• Death if the hemolytic episode is not properly
  treated

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Glutathione synthetase deficiency

• In patients with RBC glutathione synthetase
  deficiency (much rarer than G6PD deficiency)
• oxidant drugs cause hemolytic anemia
• in hepatocytes are at increased risk of liver
  damage if given such drugs as acetaminophen.

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Cytochrome P450s

• a multigene family of enzymes
• in the liver
• for the metabolic elimination of most of the
  drugs currently used in medicine
• Individuals that are poor metabolisers of the
  genes encoding specific cytochrome P450s often
  have mutations which have inactivated the enzyme
  and severely compromised the ability to
  metabolize the
• drug of interest

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CYP2D6

• One example the cytochrome P450 CYP2D6
• a highly polymorphic gene that is inactive in
  about 6 of Caucasians
• Many drugs which are used for the treatment of
  psychiatric, neurological, and cardiovascular
  disease are metabolized by the product of this
  gene

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CYP2D6

• In one variant of the gene
• tandem repeat causing individuals to metabolize
  the substrate so quickly that a therapeutic
  effect cannot be achieved by conventional doses.

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CYP2D6

• Also, individuals that are poor metabolisers of
  CYP2D6 cannot convert codeine to the analgesic
  morphine and do not achieve the desired effect.