Topic 1 of 79 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 22 sections, about 1,005 words (8 min of reading), with 26 flashcards.
In this note
Pharmacogenetics and pharmacogenomics. Polymorphic monogenic pharmacogenetic defects. CYP450 superfamily variants: CYP2D6, CYP2C9, CYP2C19, CYP3A4. FGD in individuals with genetic diseases.
I. GENERAL OVERVIEW
II. CYP450 SUPERFAMILY – GENERAL CHARACTERISTICS
III. CYP2D6
IV. CYP2C9
V. CYP2C19
VI. CYP3A4
VII. COMPARISON OF MAJOR CYP VARIANTS
VIII. FGD – PHARMACOGENETICS IN INDIVIDUALS WITH GENETIC DISEASES
Conventional therapy of genetic diseases. Orphan drugs.
I. GENERAL CONCEPT OF THERAPY IN GENETIC DISEASES
II. PRINCIPLES OF CONVENTIONAL THERAPY OF GENETIC DISEASES
III. DIETARY AND METABOLIC THERAPY
IV. ENZYME AND PROTEIN REPLACEMENT THERAPY
V. HORMONE AND FACTOR REPLACEMENT
VI. PHARMACOLOGICAL MODULATION OF PATHWAYS
VII. SYMPTOMATIC AND SUPPORTIVE THERAPY
VIII. PREVENTIVE THERAPY AND EARLY INTERVENTION
IX. ORPHAN DRUGS
X. TYPES OF ORPHAN DRUGS USED IN GENETIC DISEASES
XI. CHALLENGES OF ORPHAN DRUG THERAPY
XII. ROLE OF GENETIC COUNSELING IN THERAPY
I. GENERAL OVERVIEW
Many clinically important differences in drug response are caused by polymorphisms in genes encoding cytochrome P450 (CYP450) enzymes. These enzymes are responsible for the phase I metabolism of most commonly used drugs.
Because these polymorphisms are common in the population, they represent polymorphic monogenic pharmacogenetic defects.
II. CYP450 SUPERFAMILY – GENERAL CHARACTERISTICS
What is the CYP450 system?
The cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases, primarily located in the liver, that catalyze:
oxidation,
reduction,
hydroxylation of drugs and xenobiotics.
Why CYP polymorphisms matter
Genetic variation in CYP genes leads to different metabolic phenotypes, which directly affect:
plasma drug levels,
efficacy,
toxicity,
risk of adverse drug reactions.
Metabolizer Phenotypes
III. CYP2D6
CYP2D6 metabolizes ~25% of commonly prescribed drugs, despite representing a small proportion of hepatic CYP enzymes.
Drugs Metabolized by CYP2D6
Antidepressants (TCAs, SSRIs)
Antipsychotics
Beta-blockers
Opioids (codeine, tramadol)
Antiarrhythmics
Genetic Variability
Gene deletions → poor metabolizers
Gene duplications → ultrarapid metabolizers
Pathophysiology
CYP2D6 activity determines drug activation or inactivation.
Poor metabolizers accumulate parent drug → toxicity.
Ultrarapid metabolizers clear drug rapidly or overproduce active metabolites.
Clinical Examples
Codeine:
PM → inadequate analgesia
UM → excessive morphine production → toxicity
Antidepressants → increased side effects in PMs
Continue reading free
The whole note, all 22 sections, is free with an AceMed account, with its 26 flashcards. Premium adds flashcard recall, highlights and Ask AI.
