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Questions and Answers
Which organ is primarily responsible for drug metabolism?
Which organ is primarily responsible for drug metabolism?
- Intestines
- Kidneys
- Liver (correct)
- Lungs
How does drug metabolism generally affect the pharmacologic activity of metabolites compared to their parent compounds?
How does drug metabolism generally affect the pharmacologic activity of metabolites compared to their parent compounds?
- Metabolites usually have lower pharmacologic activity (correct)
- Metabolites have identical pharmacologic activity
- Metabolites are always inactive
- Metabolites have increased pharmacologic activity
What is the primary method by which most drugs are eliminated from the body?
What is the primary method by which most drugs are eliminated from the body?
- By metabolism and then urine (correct)
- By exhalation
- As unchanged compounds
- Through saliva
What concept describes the elimination of substances at a fixed rate regardless of drug concentration?
What concept describes the elimination of substances at a fixed rate regardless of drug concentration?
Which of the following drugs is eliminated via zero-order kinetics?
Which of the following drugs is eliminated via zero-order kinetics?
What is a significant factor that drug dosing depends on?
What is a significant factor that drug dosing depends on?
Which statement about drug metabolism is correct?
Which statement about drug metabolism is correct?
What type of kinetics applies when the rate of elimination is directly proportional to serum drug concentration?
What type of kinetics applies when the rate of elimination is directly proportional to serum drug concentration?
What is the classification of a patient who has little to no functional metabolic activity?
What is the classification of a patient who has little to no functional metabolic activity?
Which reaction does NOT typically occur during Phase I drug metabolism?
Which reaction does NOT typically occur during Phase I drug metabolism?
What is the role of Phase II drug metabolism?
What is the role of Phase II drug metabolism?
Which system is primarily involved in Phase I reactions?
Which system is primarily involved in Phase I reactions?
Which of the following is NOT a characteristic of Phase I drug metabolism?
Which of the following is NOT a characteristic of Phase I drug metabolism?
What is the relationship between drug concentration and the rate of metabolism for drugs under first-order kinetics?
What is the relationship between drug concentration and the rate of metabolism for drugs under first-order kinetics?
Which of the following is primarily a Phase II enzyme?
Which of the following is primarily a Phase II enzyme?
What occurs in overdoses of drugs that normally follow first-order kinetics?
What occurs in overdoses of drugs that normally follow first-order kinetics?
What is the main purpose of converting lipophilic drugs into more polar molecules during Phase I?
What is the main purpose of converting lipophilic drugs into more polar molecules during Phase I?
Which of the following is an example of a substance that follows zero-order kinetics?
Which of the following is an example of a substance that follows zero-order kinetics?
Which of the following describes an intermediate metabolizer?
Which of the following describes an intermediate metabolizer?
Where are cytochrome P450 enzymes primarily located in the body?
Where are cytochrome P450 enzymes primarily located in the body?
What effect do inducers have on drug metabolism?
What effect do inducers have on drug metabolism?
What is a potential consequence of enzyme inhibitors on drug levels?
What is a potential consequence of enzyme inhibitors on drug levels?
How can genetic variations influence drug metabolism?
How can genetic variations influence drug metabolism?
Which enzyme polymorphism is associated with altered metabolism of codeine?
Which enzyme polymorphism is associated with altered metabolism of codeine?
Which of the following is true regarding first-order kinetics?
Which of the following is true regarding first-order kinetics?
What is the consequence of being a poor metabolizer of CYP2C19 when taking clopidogrel?
What is the consequence of being a poor metabolizer of CYP2C19 when taking clopidogrel?
Which drug is a prodrug that requires metabolism by CYP2C19?
Which drug is a prodrug that requires metabolism by CYP2C19?
Which drug listed is known to affect the metabolism of multiple CYP450 enzymes?
Which drug listed is known to affect the metabolism of multiple CYP450 enzymes?
What is the effect of genetic variations on CYP450 metabolism?
What is the effect of genetic variations on CYP450 metabolism?
Which of the following drugs requires CYP2D6 for its activation?
Which of the following drugs requires CYP2D6 for its activation?
What effect does being an ultra-rapid metabolizer of CYP2D6 have on codeine?
What effect does being an ultra-rapid metabolizer of CYP2D6 have on codeine?
Which of the following drugs is considered a substrate for CYP2C9?
Which of the following drugs is considered a substrate for CYP2C9?
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Study Notes
Drug Metabolism
- Drug metabolism is the process of biotransformation, mainly occurring in the liver, that alters drugs to facilitate elimination
- Metabolites often have lower pharmacologic activity than the parent compound
- Metabolism makes drugs more polar for easier elimination
- Most drugs are eliminated by the kidneys in urine
- Some drugs are eliminated in bile, saliva, breast milk, or exhaled air
Kinetics of Metabolism
- First-order kinetics
- Rate of metabolism is proportional to the concentration of free drug
- Constant fraction of drug is metabolized per unit of time (half-life)
- t1/2 is independent of drug concentration
- Not saturable in standard doses, but can become saturable in overdoses
- Zero-order kinetics
- Constant rate of elimination regardless of drug concentration
- Examples: Ethanol, Phenytoin, Salicylates, Cisplatin, Fluoxetin, Omeprazol, Aspirin (high doses)
Cytochrome P450 (CYP450) Enzymes
- Group of enzymes mainly located in the liver and GI tract
- Important subcategories include CYP3A4, 2D6, 2C19, and 2C9
- Can be inhibited or induced by drugs
- Inducers increase drug metabolism, which can decrease or increase drug activity
- Inhibitors can lead to higher drug levels and greater potential for adverse drug reactions
- Enzymes are affected by genetic variations depending on race
Examples of CYP450 Interactions
- CYP3A4
- Inhibitors: Grapefruit juice, Clarithromycin, Erythromycin, Diltiazem, Fluconazole, Ritonavir, Verapamil, Cimetidine
- Inducers: Phenobarbital, Phenytoin, Rifampicin, St. John's Wort, Glucocorticoids
- Substrates: Clarithromycin, Erythromycin, Warfarin, Some statins (Itraconazole, Simvastatin)
- CYP2D6
- Inhibitors: Fluoxetine, Paroxetine, Bupropion, Quinidine, Amiodarone
- Inducers: Rifampicin
- Substrates: B-blockers, TCAs, Tramadol, Codeine
- Prodrug Substrate: Codeine, Tamoxifen
- CYP2C19
- Inhibitors: Lansoprazole, Omeprazole, Fluvoxamine
- Inducers: Rifampicin, Carbamazepine
- Substrates: Warfarin, Diazepam, Phenytoin
- Prodrug Substrate: Clopidogrel
- CYP2C9
- Inhibitors: Miconazole, Fluconazole
- Inducers: Rifampicin, Carbamazepine
- Substrates: Warfarin, NSAIDs
- Prodrug Substrate: Losartan
- CYP2C8
- Inhibitors: Cimetidine
- Inducers: Phenobarbital, Rifampicin
- Substrates: Diazepam
- CYP1A2
- Inhibitors: Cimetidine, Ciprofloxacin
- Inducers: Cigarette smoke
- Substrates: Theophylline
- CYP2E1
- Inhibitors: Disulfiram
- Inducers: Ethanol, Isoniazid
- Substrates: Ethanol, Halothane, Isoflurane
Genetic Variations and CYP450 Polymorphisms
- Can lead to altered metabolism of drugs
- Example: CYP2D6
- Poor metabolizers do not metabolize drugs effectively
- Ultra-rapid metabolizers metabolize drugs rapidly
- Codeine is a prodrug that is metabolized to morphine by CYP2D6
- Poor metabolizers have decreased effects from codeine
- Ultra-rapid metabolizers may experience large conversion to morphine resulting in high sensitivity
- Example: CYP2C19
- Patients with poor CYP2C19 activity have a higher risk of cardiovascular events when taking clopidogrel, an antiplatelet prodrug that relies on CYP2C19 conversion
Phenotype Classification
- Ultra-rapid metabolizer (UM): high metabolic activity
- Extensive metabolizer (EM): normal metabolic activity
- Intermediate metabolizer (IM): reduced metabolic activity
- Poor metabolizer (PM): little to no functional metabolic activity
Reactions of Drug Metabolism
- Lipophilic drugs are metabolized into more polar hydrophilic substances in the liver
- Two general sets of reactions: Phase I and Phase II
Phase I Reactions
- Occur in the liver
- Often involve the cytochrome P450 system
- Convert lipophilic drugs into more polar by introducing or unmasking a polar functional group (e.g., -OH or -NH2)
- Include reduction, oxidation, or hydrolysis
- Can increase, decrease, or have no effect on drug activity
- Phase I reactions not involving P450 include:
- Amine oxidation (e.g., oxidation of catecholamines or histamine)
- Alcohol dehydrogenation (e.g., ethanol oxidation)
- Esterases and hydrolysis
Phase II Reactions
- Occur in the liver and kidneys
- Phase II enzymes are mainly transferases
- Convert metabolites from Phase I into more water-soluble compounds via conjugation reactions
- Common substrates for conjugation include:
- Glucuronic acid
- Sulfuric acid
- Acetic acid
- Amino acids
- Major phase II enzymes:
- UDP-glucuronosyltransferases
- Sulfotransferases
- N-acetyltransferases
- Glutathione S-transferases
- Methyltransferases (mainly thiopurine S-methyl transferase and catechol O-methyl transferase)
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