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Drug Metabolism D:
Metabolism of drugs
| Question | Answer |
|---|---|
| What is drug metabolism? | Drug metabolism is the transformation by the body of the administered drug into a different molecular entity. |
| How are drugs removed by the body? What organs are typically involved? | Drugs are eliminated by the body either by excretion of intact drug molecules (usually by kidney) or by metabolism (usually by liver). |
| Why are most drugs designed to be lipophilic? | To allow them to reach the site of action (pass through membranes) |
| Are lipophilic drugs excreted efficiently well by the kidneys? Why? | No; Because as water is extracted from tubular lumen of nephron, drug is concentrated in tubular lumen and therefore diffuses across epithelial membranes back into body. |
| What is the main route of elimination for lipophilic drugs? | DRUG METABOLISM is the main route of DRUG ELIMINATION from the body-->does so by (nearly always) metabolizing drug into hydrophilic molecule that is easily excreted by kidneys (or into bile) |
| What was evolutionary reason allowed animals to metabolize drugs for removal? Why does it matter clinically? | Animals that ate organisms with lipophilic toxins evolved metabolic machinery to eliminate toxins; different animals=different mechanisms-->lab animal metabolism poor predictor of human metabolism & explain differences metabolism across human populations |
| What are the major types of drug metabolism? | Phase I and Phase II reactions |
| What are Phase I reactions in drug metabolism? | Introduces or exposes a functionality group on parent molecule and increases water solubility. |
| What are Phase II reactions in drug metabolism? | Conjugates (attaches) a water soluble compound to functional group to further increase water solubility. |
| Is a Phase II reaction necessary for excretion via urine (or bile)? Is a phase I reaction necessary for Phase II reaction? | No, but increases solubility; USUALLY Phase I precedes Phase II; Phase I need not occur before Phase II; Phase II may also be followed by Phase I |
| What are the 3 major types of Phase I reactions? | Oxidation, reduction, and hydrolysis |
| What are the major types of oxidation reactions? | Dealkylation (N and O), hydroxylation (aliphatic or aromatic), deamination, dehydrogenation (alcohol and aldehyde), and oxidation (N, S, monoamine) |
| What are the major types of reduction reactions? | (Nitro and azo) group reduction |
| What are Cytochrome P450S? | Terminal oxidases in multi-component electron transport chain |
| What are microsomes? | In cell biology, microsomes are vesicle-like artifacts formed from the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; by definition, microsomes are not ordinarily present in living cells. |
| Describe how P450S works | In microsomes, electrons supplied by NADPH via cytochrome P450S reductase (closely associated with cytochrome P450S in lipid membrane of ER); P450S introduces single oxygen from molecular oxygen into substrate with other oxygen being reduced to H2O |
| How are CYPs classified? | According to amino acid sequence similaritie, e.g. CYP3A5: 3 = family # (40% identity within family); A = subfamily letter (55% identity within subfamily); 5=isoform #, each isoform given unique number) |
| More than 50% of all drugs are metabolized by which cytochrome family? Which groups are important due to genetic variations? | CYP3A; CYP2D6, CYP2C9, and CYP2C19 important due to genetic variations that result in inter-individual variations in rate of drug metabolism |
| What are the two major types of hydrolysis reactions in Phase I reactions? | Ester and amide hydrolysis |
| Where do Phase I reactions take place in body? In cell? | Mainly liver (though also lungs, kidneys, and GI tract); ER (also in cytosol, mitochondria, nuclear envelope, and plasma membrane) |
| What other enzymes besides cytochrome P450S can mediate phase I reactions? | Dehydrogenases, flavin containing monooxygenases, esterases, amidases |
| What results in individuals that are poor drug metabolizers? What about extensive and ultrarapid metabolizers? | Toxicity (buildup of drug) or too little active metabolites (if given pro-drug); Lack of efficacy (rapid loss of drug) or too many active metabolites |
| What is a prodrug? | Inactive parent drug that is activated by metabolism |
| Describe how codeine is metabolized | Codeine is an inactive prodrug that is metabolized by CYP2D6 to morphine; 2D6 PMs do not get pain relief from codeine-->give morphine or oxycodone (doesn't need metabolism for action) |
| What are he (6) major forms of phase II reactions? | Glucuronidation, sulfation, acetylation, glutathione, glycine, methylation |
| What is glucuronidation? | Conjugation of substrate (alcohol, carboxylic acid, amines, or thiols) with glucuronic acid via uridine diphosphate glucuronosyltransferases to give very soluble X-glucuronides (where X can be O, N, S) |
| What enzyme controls glucuronidation? | UGTs: uridine diphosphate glucuronosyltransferases |
| Where are UGTs found? | In the LIVER, intestines, kidney |
| What is sulfanation? | Conjugations with sulfate |
| What enzyme controls sulfation? Where are they found? | STs: Sulfotransferases (found in cytosol) |
| What is acetylation? | Conjugation with acetic acid |
| What enzyme mediates acetylation? Where are they found? How many isoforms are there of this enzyme? | NATs: N-acetyltransferases; cytosol; two isoforms (NAT1 and NAT2); most American are slow-acetylators |
| What is a risk of using drugs that have acetylated metabolites? | Acetylated metabolites are often less water soluble than parent drugs, and may result in crystalluria unless high urine flow rate is maintained |
| What enzyme mediates the conjugation with a glutathione? Where is it found? | GST: glutathione S-transferase; typically found in cytosol, but some are microsomial |
| What type of drug is particularly susceptible to conjugation with glutathione? | Anti-cancer drugs |
| Where do phase II reactions take place (body)? In cell? | Mainly in liver (also in lungs, kidneys, GI tract); mainly in cytosol (except for glucoronidation, which takes place in ER) |
| What are the main causes of variations in drug metabolism? | Genetic variations (change activity or expression of drug metabolizing enzymes); drug-drug interactions (can induce or inhibit metabolyzing enzymes); interactions with food, smoking, disease state, and environment |
| How does grapefruit juice interact with drug metabolism? | Inhibits CYP3A4 in gut-->increases bioavailability of drugs metabolized by this enzyme |
| How does smoking interact with drug metabolism? | Induces certain isoforms of CYPs resulting in enhanced drug metabolims-->stopping smoking may cause spike in drug levels as enzyme goes back to basal level |
| How can liver disease change drug metabolism? | Diseases that reduce liver blood flow or cause damage to hepatocytes will decrease drug metabolism |
Created by:
karkis77
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