Pharmacogenetics Flashcards
Pharmacogenetics goal for non-responders:
improve Drug Efficacy
Pharmacogenetics goal for toxic responders
improve Drug Safety
He developed the concept of chemical sensitivity
Archibald Garrod
In a sample case study, they discovered that intake of primaquine causes adverse drug reactions among African-Americans where they develop G6PD deficiency which leads to:
hemolytic anemia
The enzyme homogentisate 1,2 – dioxygenase mediates the breakdown of the amino acids:
Phenylalanin and tyrosine
alcaptonuria
excretion of homogentisic acid
homogentisic acid - (2,5 dihydroxyphenylacetic acid) an intermediate in the catabolism of aromatic amino acids such as phenylalanine and tyrosine
Mendel’s Four Principles of Inheritance
- ) Genes in pairs
- ) Dominance and Recessiveness - dominant gene will be expressed unless recessive genes are homozygous
- ) Principle of Segregation - one allele is contributed by each parent during meiosis
- ) Principle of Independent Assortment - combination of mother and father genes resulting to own individual traits
Start codon
AUG
Stop codons
UAA, UAG, UGA
Basic Patterns of Inheritance
MAXA
> Mitochondrial - ex. aminoglycoside-induced deafness
Autosomal Dominant
X-linked - ex. G6PD deficiency, Pyridoxine sensitive anemia, Vasopressin resistance
Autosomal Recessive
Factors Affecting Drug Sensitivity
Genetics, Disease, Age (geriatric, preterm, clinically ill are most sensitive), Drug-related factors (Pharmaceutical Formulation, Route of administration, Drug Interaction, Environmental Factors)
An anti-hypertensive drug used as a probe drug to identify the activity of CYP450
Debrisoquine
TRUE OR FALSE. Phenotyping can produce false results.
TRUE. Phenotyping is a direct measure of gene expression but it is subject to artifacts -> false results.
TRUE OR FALSE. Phenotyping provides a more reliable method for predicting whether or not an individual is a candidate for polymorphic metabolism.
FALSE. Molecular Genotyping is more reliable.
Polymerase chain reaction (PCR) and Restriction fragment length polymorphism mapping (RFLM) are methods for:
Molecular Genotyping
Molecular Genotyping Services are primarily driven by these three requirements:
DEPs
need to:
- DETERMINE SAFETY AND EFFICACY of an investigational new drug prior to approval
- ESTABLISH an individual’s GENETIC PREDISPOSITION to a disease state
- PROTECT patients AGAINST possible ADR’S by identifying poor metabolizers at the inception (initial laboratory studies of drug) of drug therapy.
TRUE OR FALSE. Polymorphic: frequently occurring monogenic variants occurring at a frequency < 1%.
FALSE. >1% dapat. Kung less than 1% considered insignificant ang variation.
Most common DNA Sequence Variation.
Single Nucleotide Polymorphisms (SNP)
Types of SNPs
Missense - change results in a codon that codes for a different amino acid.
Nonsense - results in a premature stop codon.
Frameshift by Addition
Frameshift by Deletion
TRUE OR FALSE. To be important SNPs must affect either function or amount of a protein
TRUE.
Goal is to determine the sequences of the 3 billion chemical base pairs that make up the human DNA.
Human Genome Project
Differentiate Pharmacogenetics from Pharmacogenomics.
Pharmacogenetics is A SUBSET of pharmacogenomics and is defined as the study of genetically controlled variations in DNA SEQUENCE as related to drug response.
Pharmacogenomics is defined as the study of variations of DNA AND RNA CHARACTERISTICS as related to drug response.
Poor metabolizers (PM) with slower than usual drug metabolism can lead to ______ blood levels causing _________.
HIGH; TOXICITY
Why does therapeutic failure happen in people who are Ultra-Fast metabolizers?
Too fast drug metabolism -> Drug excreted rapidly -> too low blood levels -> therapeutic failure
Ultra-Fast Metabolizers, when they use prodrugs:
a. Poor Efficacy
b. Adverse Drug Reaction (due to toxicity)
b.
In Ultra-Fast Metabolizers, prodrug is rapidly converted to active component eventually reaching high levels in the blood leading to toxicity. (Opposite pag normal drug. Pag normal drug, therapeutic failure naman kasi mabilis ma-metabolize and ma-excrete.)
Giving Debrisoquine among CYP2D6 Poor Metabolizers results to:
HYPOTENSION. Matagal na-metabolize ang debrisoquine kasi nga poor metabolizer so increase in blood levels leading to marked hypotension. Eventually, magllead to Delayed Toxicity (just like what happens when Poor Metabolizers use drugs even at theoretically therapeutic dose -> kaya important ang Pharmacogenetics para malaman mo kung Poor or Ultra-Fast Metabolizer ba siya.)
Pattern of Inheritance of G6PD Deficiency
X-linked
Giving Primaquine to patients with G6PD Deficiency would result to:
Hemolytic Anemia and eventually, severe pallor. (Primagquine is an anti-malarial drug)
Incidence of G6PD deficiency in Filipinos:
13%.
Micronesians - >1% Chinese - 2% African-Americans - 10% Javanese - 13% Indians-Parsees - 16%
Drugs and chemicals unequivocally demonstrated to precipitate hemolytic anemia in Subjects with G6PD
Deficiency
A-M-4N-P-4S
(Lahat ng S ay Sulfa-)
o Acetanilide
o Methylene blue
o Nalidixic Acid
o Naphthalene - accidentally ingested mothballs
o Sulfapyridine
o Sulfanilamide
o Sulfamethixazole
o Primaquine
o Sulfacetamide
o Nitrofurantoin
o Nitrates – salitre-treated meats (tocino, longganisa)
Unusual Response to Halothane:
Malignant Hyperthermia
Mutations in what receptor can result to unusual responses to the anesthetic, Halothane?
Ryanodine
Classic presentation of malignant hyperthermia following use of halothane.
rapid rise in body temperature, muscle rigidity, tachycardia, rhabdomyolysis (muscle wasting), severe acidosis, hyperkalemia - THINK EXAGG POTENTIATION OF Calcium, which is the effect of Halothane on patients with mutations.
Antidote to unusual response to halothane
L.V. Dantrolene
Patients with Warfarin (anticoagulant) resistance may require _____ times higher than the recommended therapeutic dose due to genetic defects.
7-20 times
