Test 1 Flashcards
(36 cards)
Receptor types (ie I, II, III)
I - plasma membrane
II - cytoplasm
III - nucleus
How many half lives does it take to get to a drug’s steady state concentration?
4-6
Restrictive vs Non-restrictive hepatic clearance
Restrictive - The clearance of a drug by hepatocytes is related only to binding and metabolism. The liver is saturated and it doesn’t matter how much drug is presented. ex Warfarin and phenytoin
Non-restrictive - The clearance of a drug by the liver is related to the amount of drug that is delivered. The liver has the capacity to get rid of as much drug as is brought to it, so more blood flow = more clearance. ex Lidocaine and propranolol
Cyp2D6
20-25% of all drugs, but inactive in 2-10% of the population.
Tricyclic antidepressants, antiarrhythmics, beta-blockers, and neuroleptics
Cyp2C9
15% of all drugs. 40% of population is heterozygous, 1% are deficient entirely.
Warfarin
Cyp2C19
5% of all drugs. Common inactive allele.
Clopidogrel (Plavix) (can’t digest if patient is Cyp2C19*2
Cyp3A4
50% of all drugs. No inactivating polymorphisms.
Grapefruit juice, though, will coat the enzyme and decrease its activity.
N-acetyltransferase (NAT)
Phase II metabolism. Some people have a “slow acetylator phenotype,” so their NAT’s take longer to metabolize drug products.
Isoniazid, hydralazine, sulfonamides.
Vitamin K epoxide reductase (VKORC1)
Target of warfarin. Polymorphisms in this gene account for about 25% of warfarin’s variability, and together with Cyp2C9 polymorphisms it accounts for about 60% of warfarin’s variability.
hERG
Potassium channel (Ikr) that many compounds interact with, leading to elongated QT intervals. All new drugs are tested for interactions with this channel.
Acetaminophen metabolism
Normally, Phase II reactions convert it and that leads to its elimination. Also metabolized slightly via a phase I reaction by CYP2E1 into NAPQI. This slight amount is then reacted with GSH in a phase II reaction and then excreted. If GSH is overwhelmed, either via overdose or alcohol consumption (alcohol increases CYP2E1 amount because it is trying to metabolize the alcohol), then NAPQI binds to proteins and leads to cell death.
Red Man Syndrome
Drugs act directly on mast cells (not IgE receptors) leading to degranulation.
Steven-Johnsons syndrome
Blistering and separation of the epidermis from the dermis.
Potency
Concentration of drug needed to elicit 50% of the maximal response.
Maximal Efficacy
The maximal response produced by the drug.
Therapeutic index
The distance between the median effective dose and the median lethal dose on a Quantal-dose response curve.
Therapeutic window
The distance between the minimum effective therapeutic dose and the minimum lethal dose. More useful in determining the safety of a drug.
Ligand regulated transmembrane enzymes
Protein tyrosine kinases, when activated they phosphorylate tyrosines or serines.
Ex insulin, ANF, EGF
Cytokine receptors
Similar to ligand regulated transmembrane receptors, but the phosphorylated subunit (STAT, phosphorylated by JAK) is not intrinsic to the membrane and detaches upon phosphorylation. They then travel to the nucleus to initiate transcription.
Ligand-gated channel receptors
Fast. Pentamer with 4 subunits. Ach bind alpha subunits inducing a conformational change and opening of a channel.
Ex is nicotinic cholinergic receptor.
G-protein linked receptors
7 pass transmembrane protein. N-terminus is extracellular, C-terminus is intracellular and has serines available for phosphorylation that results in regulation. 3rd intracellular loop interacts with G proteins inside the cell.
Ex. dopamine, norepinephrine, 5-HT (serotonin), and Acetylcholine.
G-proteins activate adenyl cyclase to make cAMP–>PKA–>response amplification
PIP2–>IP3 and DAG.
IP3 –> Ca2+ release–>CAM kinases–>amplification of reponse
DAG –> PKC–>amplification of response
G proteins activate what second messengers?
adenyl cyclase to make cAMP–>PKA–>response amplification
PIP2 activates what?
PIP2–>IP3 and DAG.
IP3 –> Ca2+ release–>CAM kinases–>amplification of reponse
DAG –> PKC–>amplification of response
Tachyphylaxis
Rapid development of a diminished drug response
