MedChem 1-40 slides

What are the five pharmacokinetic effects of drug interaction mechanisms?
Absorption, protein binding, modified renal excretion, modified nonrenal excretion, changes in CYP450
What are the three pharmacodynamics effects of drug interaction mechanisms?
Antagonistic effects, synergistic side effects, indirect pharmacodynamics effects
What are some miscellaneous factors that affect metabolism? (six are listed)
Dietary factors, underlying disease states, circadian rhythm, sex, genes, pregnancy
What happens to a drug if the rate of metabolism decreases?
Increased intensity and duration of drug action, increased accumulation in the plasma may lead to increased probability of toxicity
What happens to a drug if the rate of metabolism increases?
Decreased intensity and duration of drug action and efficacy, toxicity may increase if the metabolite is a toxic compound and continues to circulate
What are the nomenclature guidelines for CYP450 enzymes?
CYP(cytochrome P450) #(genetic family) Letter(genetic subfamily) #(specific gene)
Define polymorphism.
Point mutations of one or more amino acids within the polypeptide
What is the primary method to eliminate drugs?
CYP450
Define pharmacogenetics factors.
Gene polymorphisms that produced a large number of CYP enzymes
How do most CYP isoenzymes arise?
Single nucleotide differences, or polymorphisms, (SNP)
How long does it take to detect CYP450 enzyme induction?
Detectable within 2 days, maximal effect within a week.
How does CYP450 enzyme induction happen?
Enzyme induction is an adaptive process by which the body perceives the overabundance of a lipid-soluble compound (a drug) that needs to be eliminated from the body, leading to a stimulation of the isoenzyme synthesis, increasing its amounts.
What are some compounds that enhance metabolism? (nine listed)
Phenobarbital (and other barbituates), glutethimide, phenylbutazone, meprobamate, ethanol, phenytoin, rifampin, griseofulvin, carbamazepine
What are the two enzyme inducer categories?
Phenobarbitol-like inducers (P450 enzymes) and polycyclic aromatic hydrocarbon-like inducers (P448 enzymes)
What are four mechanisms of enzyme inhibition?
Substrate competition, interference with protein synthesis, interference with drug metabolizing enzymes, hepatotoxicity leading to decreased metabolism
What is competitive inhibition?
The inhibitor acts as an alternate substrate for the isoenzyme
What is non-competitive inhibition?
The inhibitor inactivates the enzyme, but substrate binding remains normal for the isoenzyme
What is a suicide substrate?
A substrate that forms a covalent bond between the active site and the drug
How long does it take for CYP450 enzyme inhibition to occur?
As soon as sufficient concentration of the inhibitor is present in the bloodstream (typically 24 hours)
What are three examples of families of drug or molecular transporters?
ABC (ATP-binding cassette transporter), SLC (solute-linked carrier transporter), SLCO (solute-linked carrier organic anion transporter)
What is P-glycoprotein?
A trans-membrane protein located in many tissues that “pumps” an assortment of structurally and mechanistically unrelated compounds OUT of cells
What does a high affinity of a drug for P-gp indicate?
A smaller overall amount of drug will be absorbed into the cell and the drug is pumped out of the cell quickly following absorption
What gene is P-gp?
ABCB1 (ATP-binding cassette 1)
What are some substrates for P-gp? (eight listed)
Digoxin, fexofenadine, vincristine, indinavir, colchicine, topotecan, paclitaxel, loperamide
What are some inhibitors for P-gp? (nine listed)
ritonavir, cyclosporine, verapamil, erythromycin, ketoconazole, itraconazole, quinidine, azithromycin, valspodar
What are some inducers for P-gp? (two listed)
Rifampin, St. John’s wort
What are the two types of protein polymorphisms?
SNP (altered amino acid sequence) and silent polymorphism (coding equivalent changes in mRNA, produces a protein with identical AA sequence but different shapes)
What does a silent polymorphism in MDR1 gene change?
Substrate specificity by altering the pumps’ final tertiary structural shape (no change in AA sequence)
What gene is OCT?
SLC22A8
What are some substrates for OCT? (three listed)
Cimetidine, methotrexate, zidovudine
What are some inhibitors for OCT? (four listed)
Probenecid, cefadroxil, cefamandole, cefazolin
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