Pharmacogenetics Flashcards
what can genetic variability cause in respect to drugs?
adverse drug reactions: excessive drug concentrations
treatment failures: inadequate drug concentrations
what can be a single nucleotide polymorphism (SNP)?
amino acid change
premature stop codon
mRNA splicing error
amount of mRNA transcription
what sites affect drug disposition?
drug transporters
drug metabolizing enzymes
what are some causes of variability between species?
low feline glucuronidation capacity
dogs lack acetylation enzymes
deficient pig sulfation
what is the most famous drug transporter?
P-glycoprotein
where is P-glycoprotein located?
blood-brain barrier
intestinal and bronchial epithelium
renal tubules and liver canaliculi
what gene mutation is important in P-glycoprotein?
multiple drug resistance gene ABCB1 (MDR1) mutation
what is the role of P-glycoprotein?
limit oral absorption
restricts entry into CNS
facilitates renal and liver excretion
what are two analgesic/tranquilizer P-glycoprotein substrates?
butorphanol
acepromazine
what are some non-analgesic/tranquilizer P-glycoprotein substrates?
ivermectin
emodepside
anticancer agents (vincristine and doxorubicin)
loperamide (imodium AD)
anything that impacts action is as well: predisone and spinosad
what percent of cats has feline ABCB1 nonsense mutation?
5% of those studied
phenotype is same as ABCB1-1delta mutation in dogs
what is the clinical significance of the ABCB1-1delta mutation?
excessive neurotoxicity
excessive drug effect causing sedation
impaired drug excretion leading to toxicity
are morphine, buprenorphine, and fentanyl known to cause excessive sedation in susceptible dogs?
no reports
butorphanol dosing recommendations: 3/4 dose for heterozygotes and 1/2 for homozygotes
what can you use to reverse opioids?
nalaxone
true/false: ivermectin is safe for dogs with ABCB1-1delta at the normal heartworm dose
true
only when overdoses
what drug inhibits P-glycoprotein and can therefore make normal dogs behave like mutant dogs pharmacologically?
spinosad
also is a substrate
what breeds of dogs have a high prevalence of ABCB1-1delta?
australian shepherds (also minis)
collie (not so much border collies)
longhaired whippet
what are the breeding recommendations for reducing the amount of dogs with ABCB1-1delta?
avoid breeding homozygous ABCB1-1delta dogs
ideally breed only wildtype ABCB1 dogs
ensure one parent is unaffected at least
how does prednisone affect P-glycoprotein?
upregulates it
more than 7 days of prednisone will decrease impact of chemotherapy
is there variation by species with the cytochrome P450 enzyme system?
yes- significant
where is the cytochrome P450 enzyme system?
most important is liver
what does the cytochrome P450 enzyme system do?
inactivates most drugs
what is special about greyhounds?
reduced activity of 2B11 in the liver
prolonged action of thiobarbiturates
