Enfermedades genéticas y toxicidad medicamentos

Understanding Drug Toxicity Related to Genetic Variations

Introduction to Drug-Induced Toxicity

• The lesson discusses how variations in disease-associated proteins can predispose individuals to drug toxicity, using favism (hemolytic anemia from fava bean consumption) as a primary example.

• Fava beans produce hydrogen peroxide, which is harmful to erythrocytes. Normal conditions allow for its reduction by glutathione, maintained by NADPH from glucose-6-phosphate dehydrogenase (G6PDH).

Mechanism of Erythrocyte Damage

• Low G6PDH activity leads to insufficient NADPH and reduced glutathione, resulting in the accumulation of hydrogen peroxide and subsequent hemolysis.

• This case illustrates that genetic polymorphisms in metabolic enzymes can lead to unexpected sensitivities and toxicities from drugs not directly related to their metabolism.

Examples of Drug Toxicity Due to Genetic Variations

1. Malignant Hyperthermia

• Malignant hyperthermia is characterized by increased body temperature and severe muscle rigidity due to calcium flow alterations in muscle cells.

• It is triggered by anesthetics like halothane and succinylcholine, with potential respiratory failure as a serious consequence.

2. Porphyrias

• Acute porphyrias cause neurological and gastrointestinal toxicities exacerbated by certain drugs (e.g., phenytoin), leading to fatal outcomes due to heme synthesis pathway deficiencies.

3. Hammersmith Hemoglobinopathy

• This unstable hemoglobin variant is sensitive to chemicals like nitrobenzene, causing hemolytic anemia through the separation of globin chains from heme.

4. Methemoglobinemia

• Deficiency in NADH methemoglobin reductase leads to functional loss of hemoglobin when exposed to various drugs, resulting in ineffective oxygen transport due to oxidation.