Genetics · MU Sofia

14. Pharmacogenetics and genomics: pharmacogenetics and adverse drug reactions.

Inside: 23 sections · 31 labelled pictures · 5 tables · 29 flashcards · 12 min

Topic 14 of 79 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 23 sections, about 1,516 words (12 min of reading), with 29 flashcards.

In this note

  1. Pharmacogenetics and pharmacogenomics. Polymorphic monogenic pharmacogenetic defects. G6PD-deficiency; deficiency of: TPMT, DPYD, NAT1, and NAT2; alcohol dehydrogenase and aldehyde dehydrogenase deficiency.
  2. I. GENERAL CONCEPT
  3. II. G6PD DEFICIENCY
  4. III. TPMT DEFICIENCY (THIOPURINE METHYLTRANSFERASE)
  5. IV. DPYD DEFICIENCY (DIHYDROPYRIMIDINE DEHYDROGENASE)
  6. V. NAT1 AND NAT2 DEFICIENCY (N-ACETYLTRANSFERASES)
  7. VI. ALCOHOL DEHYDROGENASE (ADH) AND ALDEHYDE DEHYDROGENASE (ALDH) DEFICIENCY
  8. Pharmacogenetics and pharmacogenomics. Rare monogenic pharmacogenetic defects. Мalignant hyperthermia, atypical butyrylcholine esterase.
  9. I. PHARMACOGENETICS
  10. II. PHARMACOGENOMICS
  11. III. RARE MONOGENIC PHARMACOGENETIC DEFECTS
  12. IV. MALIGNANT HYPERTHERMIA (MH)
  13. V. ATYPICAL BUTYRYLCHOLINESTERASE DEFICIENCY
  14. VI. CLINICAL SIGNIFICANCE OF PHARMACOGENETICS
  15. Pharmacogenetics and pharmacogenomics. Polymorphic monogenic pharmacogenetic defects. CYP450 superfamily variants: CYP2D6, CYP2C9, CYP2C19, CYP3A4. FGD in individuals with genetic diseases.
  16. I. GENERAL OVERVIEW
  17. II. CYP450 SUPERFAMILY – GENERAL CHARACTERISTICS
  18. III. CYP2D6
  19. IV. CYP2C9
  20. V. CYP2C19
  21. VI. CYP3A4
  22. VII. COMPARISON OF MAJOR CYP VARIANTS
  23. VIII. FGD – PHARMACOGENETICS IN INDIVIDUALS WITH GENETIC DISEASES

I. GENERAL CONCEPT

What is meant by polymorphic pharmacogenetic defects?

Polymorphic monogenic pharmacogenetic defects are caused by common genetic variants (polymorphisms) in single genes that influence:

  • drug metabolism,
  • drug efficacy,
  • risk of adverse drug reactions.

Unlike rare pharmacogenetic disorders, these variants are frequent in the general population and explain inter-individual differences in drug response.

Pharmacogenetic Mechanisms

  1. Altered enzyme activity (reduced, absent, or increased).
  2. Changes in drug clearance.
  3. Accumulation of toxic metabolites.
  4. Increased sensitivity or resistance to drugs.

II. G6PD DEFICIENCY

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a pharmacogenetic disorder characterized by increased susceptibility to oxidative stress, leading to hemolytic anemia after exposure to certain drugs or substances.

Inheritance

  • X-linked recessive
  • Males more severely affected
  • Females may be carriers or variably affected due to lyonization

Normal Function of G6PD

G6PD is a key enzyme of the pentose phosphate pathway, producing NADPH, which:

  • maintains glutathione in reduced form,
  • protects red blood cells from oxidative damage.

RBCs are especially vulnerable because they lack mitochondria.

Pathophysiology

  1. G6PD activity is reduced.
  2. NADPH production decreases.
  3. Reduced glutathione cannot neutralize oxidative stress.
  4. Oxidative damage to hemoglobin and RBC membrane occurs.
  5. Hemolysis is triggered after exposure to oxidant drugs or infections.

Triggering Agents

  • Antimalarials (e.g., primaquine)
  • Sulfonamides
  • Nitrofurantoin
  • Certain antibiotics
  • Fava beans
  • Infections

Clinical Features

  • Acute hemolytic anemia
  • Jaundice
  • Dark urine
  • Fatigue
  • Neonatal jaundice (severe cases)

Clinical Importance

G6PD deficiency is one of the most important pharmacogenetic conditions worldwide and a classic example of drug-induced hemolysis.

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