Week 4 - Pharmacogenetics Flashcards
Pharmacogenetics is the branch of pharmacology that involves identifying _______ ______ leading to ____-______ differences in drug response.
genetics variations, inter-individual
Pharmacogenetics refers to _______ (_____ gene) variants that affect a patient‘s ______ to a particular drug
monogenetic, single, response
Pharmacogenomics refers to the entire spectrum of _____ that are involved in determining a patient‘s _______ to a particular drug.
genes, response
The goal of the drug therapy is to produce a specific _________ _____ in a patient without producing ______ effects.
pharmacologic effect, adverse
What are the main causes of variability to drug response?
- Age
- Health or disease status
- Species
- Gender
- Breed
- Drug interactions (other drugs administered simultaneously)
- The patient‘s genome! (mutations, deletions, polymorphisms)
_________ and _____ of drugs is different from one individual to another
Effectivity, safety
Why is pharmacogenetics important?
Individual variations to drug therapy can cause
• Lack of therapeutic ______
• Unexpected ______ effects (______)
efficacy, harmful, Toxicity
Pharmacogenetics can alter both drug _______ and the likelihood of _______.
efficacy, toxicity
____________ in drug receptors, drug _______ and in drug metabolizing ______.
Polymorphisms, transporters, enzymes
Pharmacogenetics combines the areas of pharmacokinetics, how genetic differences
alter ______, and pharmacodynamics, how _____ alter ______ and _____ molecules.
ADME, genes, receptors, signal
Individualization of drug therapy has two important clinical implications:
• It can help predict those patients at _____ risk for developing drug ______. In those cases, a ______
drug dose or an ________ drug should be use.
• It can help identify those patients that are most likely to ______ from a particular drug.
high, toxicity, lower, alternative, benefit
The human genome contains approximately ___ _______ nucleotide bases, representing roughly ________ ______.
3 billion, 30,000 genes
A gene is the DNA sequence containing a series of _____ (_____ _________ nucleotide bases form a specific codon) that specify a particular _____.
codons, three, consecutive, protein
A mutation alters the ________ of nucleotide bases in a DNA molecule. This in turn alters _________ _____, creating a different ____.
sequence, transcribed RNA, codon
A silent mutation results in a _____ change that creates a codon for the _____ amino acid. There is ____ ______ in protein ______ or _____.
base, same, no change, structure, function
A mutation results in a different _____ _____, or the creation of a ____ ____, the change in protein ______ and _______ can be deleterious.
amino acid, stop codon, structure, function
At each gene locus, an individual carriers ____ _____, one from each _____.
two alleles, parent
If an individual has two identical alleles, that individual is said to have a ?
homozygous genotype
If an individual has two different alleles, that individual is said to have a ?
heterozygous genotype
The phenotype of each individual with regard to a specific gene is the _______, _______ manifestation of a given genotype. That outward ______ manifestation might be something immediately _______, or it may not be apparent until a particular _____ is administered to that individual.
outward, physical, physical, obvious, drug
Polymorphisms are _________ in a given gene may be present ______ in a population, or in relatively ______ numbers in a population.
variations, rarely, large
Polymorphisms are defined as ______ _____ occurring at a frequency of % or _____ in the population (species of interest).
genetic variations, 1, greater
In humans, many of the genes encoding cytochrome P450 enzymes are _______, whereas some inherited human diseases such as cystic fibrosis are caused by ____ _______ occurring in _____ than __% of the population.
polymorphic, rare, mutations, less, 1
For some diseases, identification of a specific mutation may be used to provide ______ ______ approaches for the patient and in the case of veterinary patients, guide ________ decisions, too.
specific treatment, breeding
Some relevant genetic defects in veterinary medicine affecting drug therapy:
- MDR1 defect
- Cytochrome P450 enzymes
- Glucuronyltransferase
- N-Acetyltransferase
MDR1 defect in dogs are caused by a ________ (__ bp) in the _____-_____ ________ gene (MDR1-gene, ______- gene) which leads to the formation of _______ protein (?).
deletion, 4, multi-drug resistance, ABCB1, shortened, P-glycoprotein
The MDR1 defect in dogs was originally described in ?
the Collie (ivermectin sensitive) and related breeds (Shetland Sheepdog, Australian Shepherd, Border Collie, mixed breeds, etc)
P-glycoprotein is a _______ protein that was first described in _____ _______ ____ cell lines. These tumor cells were ____ ______ to various _______ agents.
transmembrane, highly resistant tumor, cross resistant, anticancer
P-glycoprotein is an ____-dependent _____ which works as an _____ transporter that pumps drugs _____ of the cell and is a functional component of several body ______, such as?
ATP, carrier, efflux, out, barriers,
- Intestine
- Kidney
- Brain (blood-brain barrier)
- Testicles (blood-testis barrier)
- Placenta
- Liver (bile canaliculi)
The MDR1 defect in dogs
Expression of P-gp in dogs and relevance in drug disposition
MDR1 defect protein; green circles = all drug going to brain; left side of image only some drug entering brain
MDR1 +/+ dog
Drug can not enter
MDR1 -/- dog
Drugs able to enter brain
MDR1 +/+ dog
Images of the abdomen of dogs positioned in ventral recumbency on a gamma camera. Images were acquired 2 hours after IV injection of 99mTC-MIBI to an MDR1 WT/WT dog and to an MDR1 mut/mut dog
Intense uptake of 99mTC-MIBI in the gallbladder (arrowhead) is present in MDR1 normal dog. A void of activity in the location of the gallbladder (arrow) is present in MDR1 mutant dog
Most substrate is concentrated in the gallbladder.
MDR1 -/- dog
Images of the abdomen of dogs positioned in ventral recumbency on a gamma camera. Images were acquired 2 hours after IV injection of 99mTC-MIBI to an MDR1 WT/WT dog and to an MDR1 mut/mut dog
Intense uptake of 99mTC-MIBI in the gallbladder (arrowhead) is present in MDR1 normal dog. A void of activity in the location of the gallbladder (arrow) is present in MDR1 mutant dog
Gallbladder is almost empty and the substrate has surrounded the area.
Neurotoxicity to ivermectin in MDR1 defect
+/+ = normal, -/- = no protein present
Size is different (see bp numbers on right).
If heterozygous, will normally not show signs of toxicity; if give very high dose, will show signs of toxicity.
All breeds related to this defect.
Collie most susceptible
Humans don’t have this problem
Do we have to know this? No
Both proteins are similar in length (1,200 AA) but in the mutated MDR1, the protein is longer than in the dog but still defective.
Reduced expression of CYP1A (Same as CYP1A2) in two affected dogs (poor metabolizing, PM-Beagles)
Western Blot
Presence of enzymes in EM1 and 2, no enzyme in PM1 and PM2.
Increased concentrations of the drug AC-3933 (radequinil, a cognitive enhancer) and its metabolites in normal dogs (A, enhanced metabolizers) and CYP1A (-/-) dogs (B, poor metabolizers)
Healthy: Metabolite level reaches is not much higher than 1000.
Unhealthy: Poor metabolizer dog and the level reaches 10,000
Heinz bodies
