Pharmacology ch 4 - Drug Biotransformation

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Questions and Answers

What is the effect of enzyme induction on the pharmacologic action of the inducer and co-administered drugs?

Has no effect on the pharmacologic action of the inducer.

Increases the potency of the inducer and co-administered drugs.

Only affects drug substrates that are not metabolically transformed.

Decreases the pharmacologic action of the inducer and co-administered drugs. (correct)

How do imidazole-containing drugs affect cytochrome P450 enzyme activity?

They activate other substrates that compete for metabolism.

They have no impact on cytochrome P450 enzymes.

They bind to the heme iron and reduce metabolism of certain drugs. (correct)

They enhance the metabolism of all endogenous substrates.

What type of drugs are metabolized by CYP3A and reduced through competitive inhibition?

Imidazole drugs like cimetidine.

Non-steroidal anti-inflammatory drugs.

Macrolide antibiotics such as troleandomycin and erythromycin. (correct)

Macrolide antibiotics such as penicillin.

Which substance is known to induce P450 enzymes and potentially exacerbate toxicity?

Benzo[a]pyrene. Signup and view all the answers

What mechanism do compounds like proadifen utilize to inhibit enzyme activity?

Binding to the heme iron rendering it inactive. Signup and view all the answers

What is the primary purpose of phase I reactions in drug biotransformation?

Convert the parent drug to a more polar metabolite Signup and view all the answers

Which of the following statements about phase II reactions is true?

Phase II reactions often involve endogenous substrates Signup and view all the answers

Where do the majority of metabolic biotransformations occur?

In the liver Signup and view all the answers

What is a possible outcome of phase I metabolic reactions?

Generation of inactive metabolites Signup and view all the answers

What characterizes phase I metabolites in terms of elimination?

Phase I metabolites are often more polar and can be excreted Signup and view all the answers

What role do endogenous substrates play in phase II reactions?

They conjugate with phase I metabolites Signup and view all the answers

What is the main consequence of drug acetylation during biotransformation?

Creation of a hepatotoxic metabolite Signup and view all the answers

Which functional groups are typically involved in phase I metabolic reactions?

–NH2, –OH, –SH Signup and view all the answers

Which of the following substances undergoes cytochrome P450-dependent oxidation?

Carbon tetrachloride Signup and view all the answers

What is the primary product when ethanol is oxidized?

Acetaldehyde Signup and view all the answers

Which of the following reactions is classified as a reduction?

Nitro reduction of nitrobenzene Signup and view all the answers

What type of enzyme is flavin monooxygenase most closely associated with?

Oxidoreductase Signup and view all the answers

Which compound is associated with hydrolysis involving the formation of a carboxylic acid and an alcohol?

Procaine Signup and view all the answers

Which of the following drugs is NOT involved in azo reduction?

Clonazepam Signup and view all the answers

What occurs during the ammonia formation in amine oxidation?

Dehydrogenation Signup and view all the answers

Which of the following substances is a substrate for carbonyl reduction?

Naloxone Signup and view all the answers

Which drug is known to quasi-irreversibly inactivate an enzyme, inhibiting the metabolism of potential substrates?

Parathion Signup and view all the answers

What type of reaction involves the hydrolysis of amides?

Hydrolysis Signup and view all the answers

What does a higher metabolic activation of prodrugs indicate for individuals with the CYP2C19*17 allele?

Enhanced effectiveness of certain medications Signup and view all the answers

What is the designation for individuals with MR values greater than 12.6?

Poor metabolizers (PM) Signup and view all the answers

Which of the following drugs is associated with improved outcomes when metabolized by carriers of the CYP2C19*17 allele?

Tamoxifen Signup and view all the answers

What is the consequence of having high levels of parent APAP in the body?

Potential liver failure Signup and view all the answers

At what time post-ingestion is the patient's APAP blood level considered dangerously high?

1 hour Signup and view all the answers

Which type of conjugation primarily uses UDP glucuronic acid as a reactant?

Glucuronidation Signup and view all the answers

What is the reason for the conversion of parent APAP into a toxic product?

Phase I P450 enzyme activity Signup and view all the answers

What does the presence of APAP-sulfate and APAP-glucuronide in urine imply?

Effective detoxification processes Signup and view all the answers

What is the main substrate type for N-Acetyltransferase during acetylation?

Amines Signup and view all the answers

Which enzyme is responsible for glutathione conjugation?

GSH-S-transferase Signup and view all the answers

What is a potential risk associated with clopidogrel metabolism?

Higher risk of bleeding Signup and view all the answers

Which type of conjugation occurs in the mitochondria?

Glycine conjugation Signup and view all the answers

What is the function of sulfotransferase in drug metabolism?

To sulfate phenols and alcohols Signup and view all the answers

What type of substance does transmethylase primarily act upon?

Catecholamines Signup and view all the answers

Which of the following substrates can undergo water conjugation?

Arene oxides Signup and view all the answers

Which type of conjugation occurs through the use of phosphoadenosyl phosphosulfate?

Sulfation Signup and view all the answers

Which of the following compounds is NOT an example of a substrate for glucuronidation?

Dapsone Signup and view all the answers

What type of conjugation is primarily associated with the modification of catecholamines?

Methylation Signup and view all the answers

What is the role of P450 enzymes in drug metabolism?

They are responsible for approximately 75% of phase I drug metabolism. Signup and view all the answers

Which of the following statements about genetic polymorphisms in P450 enzymes is true?

They can affect pharmacokinetics and drug response. Signup and view all the answers

What is a critical time frame for administering N-acetylcysteine after acetaminophen overdose?

Within 8–16 hours. Signup and view all the answers

Why is the administration of GSH ineffective in treating acetaminophen toxicity?

It does not penetrate cell membranes effectively. Signup and view all the answers

Which metabolite of acetaminophen is known to be particularly reactive and toxic?

An electrophilic metabolite. Signup and view all the answers

What percentage of physiologic drug biotransformation is attributed to the P450 enzymes mentioned?

60% Signup and view all the answers

Which of the following statements about cysteamine and N-acetylcysteine is correct?

Both serve as antidotes for acetaminophen toxicity. Signup and view all the answers

What is the role of NADPH in the P450 enzyme system?

It donates electrons for the reduction of P450. Signup and view all the answers

What is a significant consequence of reactive oxygen species (ROS) generation in relation to acetaminophen?

They promote oxidative stress and hepatotoxicity. Signup and view all the answers

Which genetic polymorphism is specifically associated with debriquin-sparteine oxidation?

CYP2D6 polymorphism. Signup and view all the answers

Which substance is known to alter the rates of drug metabolism by inducing CYP1A enzymes?

2,3,7,8-tetrachlorodibenzo-p-dioxin Signup and view all the answers

What characteristic is shared by substrates for the P450 enzyme complex?

High lipid solubility Signup and view all the answers

What is the overall impact of P450 genetic polymorphisms on patient care?

They necessitate individualized dose adjustments. Signup and view all the answers

Which step in the P450 enzyme system involves the introduction of a second electron from NADPH?

Reduction of molecular oxygen Signup and view all the answers

What process increases the synthesis of cytochrome P450 enzymes?

Enhanced transcription and translation Signup and view all the answers

What is the result of the oxidation process in the P450 enzyme system?

Conversion of drug substrate to an oxidized product Signup and view all the answers

What type of receptor is identified as a cytoplasmic receptor for polycyclic aromatic hydrocarbons?

AhR Signup and view all the answers

What component is notably a cofactor required for the P450 enzyme activity?

Heme Signup and view all the answers

Which of the following statements about substrate specificity in the P450 enzyme complex is true?

It exhibits very low substrate specificity. Signup and view all the answers

What is the first step in the process of drug biotransformation by P450?

Combination of P450 with the drug substrate Signup and view all the answers

What is the likely consequence of O-Demethylation of codeine in individuals classified as UM?

Increased metabolic activation to morphine and thus increased risk of respiratory depression Signup and view all the answers

What is the effect of O-Demethylation of tramadol in PM individuals?

Reduced therapeutic efficacy due to increased clearance Signup and view all the answers

How does hydroxylation affect the therapeutic action of tamoxifen?

It reduces metabolic activation to the active endoxifen Signup and view all the answers

What might be required to avoid potential drug-drug interactions involving drugs metabolized by CYP3A4?

Dose adjustment to accommodate metabolic changes Signup and view all the answers

What is the impact of N-Demethylation on nortriptyline in UM individuals?

Reduced therapeutic efficacy due to increased clearance of the drug Signup and view all the answers

What is the primary organ responsible for drug metabolism?

Liver Signup and view all the answers

Which phase II metabolic reaction commonly involves the formation of a conjugate?

Glucuronidation Signup and view all the answers

What characterizes drugs after they undergo phase I metabolic reactions?

They may have modified activity. Signup and view all the answers

Which process allows some drugs to be absorbed intact from the small intestine?

Phase I metabolism Signup and view all the answers

What is formed when an amino acid combines with a functional group during phase II metabolism?

Highly polar conjugate Signup and view all the answers

Which of the following tissues displays considerable drug metabolism activity?

Skin Signup and view all the answers

What happens to the lipophilic drugs as a result of phase II reactions?

They form highly polar conjugates. Signup and view all the answers

Which of the following statements about conjugation reactions in drug metabolism is true?

They transform lipophilic drugs into more hydrophilic forms. Signup and view all the answers

What is the effect of the CYP1A2 enzyme being classified as an extensive metabolizer (EM) in cigarette smokers?

Increased caffeine metabolism Signup and view all the answers

Which of the following consequences is associated with poor metabolizers (PM) of nicotine?

Greater tendency for nicotine addiction Signup and view all the answers

What clinical consequence is linked to PM of CYP2B6 involved with efavirenz?

Increased risk of adverse drug reactions (ADRs) Signup and view all the answers

Which enzyme defect leads to an increased risk of bleeding when using anticoagulants like coumarin?

CYP2A6 (PM) Signup and view all the answers

What is the impact of PM status on the metabolism of paclitaxel?

Enhanced risk of drug accumulation and ADRs Signup and view all the answers

Which therapeutic use is associated with PM individuals metabolizing caffeine?

Decreased CNS stimulation Signup and view all the answers

In terms of smoking habits, how does EM status of CYP2A6 affect nicotine metabolism?

Enhanced craving for regular smoking Signup and view all the answers

How does the PM status of CYP2C8 influence the use of repaglinide?

Reduced drug clearance and more ADRs Signup and view all the answers

What is one potential clinical consequence of having PM status for CYP2C8 when using rosiglitazone?

Higher potential for drug interactions Signup and view all the answers

Which drug is linked with an enhanced risk of adverse drug reactions in PM with respect to cyclophosphamide?

Efavirenz Signup and view all the answers

Study Notes

Biotransformation in Drug Disposition

Biotransformations primarily occur between drug absorption into circulation and renal excretion, with some happening in the intestinal lumen or wall.
Two major categories of biotransformation are Phase I and Phase II reactions.
Phase I reactions alter the parent drug to create more polar metabolites by introducing functional groups (e.g., –OH, –NH2, –SH).
Phase I metabolites may be inactive, but can sometimes have modified or even enhanced activity.
Phase II reactions involve conjugation with endogenous substrates (e.g., glucuronic acid, sulfuric acid) resulting in increased polarity for easier excretion.
Phase II reactions can precede Phase I reactions in some instances.

Enzyme Inhibition and Induction

Certain drugs inhibit cytochrome P450 enzyme activity, affecting drug metabolism and pharmacologic action.
Drugs like cimetidine and ketoconazole bind to P450 heme iron, reducing the metabolism of endogenous substrates like testosterone.
Drugs can also induce certain P450 isoforms, increasing substrate metabolism and potentially leading to altered effects for co-administered medications.
Environmental chemicals, such as benzo[a]pyrene from tobacco, can induce P450 enzymes, further complicating metabolism pathways.

Phase I Reactions

Include cytochrome P450-dependent oxidations (e.g., hydrocarbons, amine oxidations).
Non-P450 oxidations involve flavin monooxygenase, and reductions include azo and nitro reductions.
Hydrolysis includes the breakdown of esters and amides, influencing the activity and elimination of various drugs.

Phase II Reactions (Conjugations)

Glucuronidation utilizes UDP glucuronic acid for substrates like alcohols and phenols.
Acetylation via N-acetyltransferase targets amines such as sulfonamides and isoniazid.
Glutathione conjugation detoxifies compounds, while glycine, sulfation, and methylation also modify drug metabolism.
Water conjugation occurs with epoxide hydrolase, detoxifying reactive intermediates.

Clinical Relevance of Drug Metabolism

Individual differences in metabolism and drug distribution affect therapeutic blood levels, requiring personalized dosing.
Genetic variations, such as the presence of the CYP2C19*17 allele, enhance prodrug activation, influencing therapy efficacy and risk profiles.
Example: Higher conversion of tamoxifen in carriers associated with lower breast cancer relapse rates and increased bleeding risk with certain antimalarials.
Monitoring APAP (acetaminophen) levels illustrates the balance between therapeutic effects and potential liver toxicity, dependent on metabolism pathways and conjugation efficiency.

Drug Metabolism Overview

Phase II metabolism involves conjugation of amino acids with functional groups, creating a highly polar conjugate to enhance solubility and elimination.
The liver is the primary organ for drug metabolism, although other tissues, including the gastrointestinal tract, lungs, skin, kidneys, and brain, also play significant roles.

Absorption and Elimination

After oral administration, many drugs, including isoproterenol, meperidine, pentazocine, and morphine, are absorbed intact from the small intestine.
Phase I reactions involve drug modification, while Phase II reactions produce conjugates from these modified drugs.
The goal of these metabolic pathways is to convert lipophilic drugs into hydrophilic compounds for easier excretion.

Cytochrome P450 and Drug Metabolism

Cytochrome P450 enzymes form a binary complex with drug substrates, initiating the oxidative metabolism of various drugs.
NADPH is crucial for the reduction of oxidized P450-drug complexes, allowing for the transfer of activated oxygen to drug substrates.
This process can create reactive O2 species (ROS), increasing oxidative stress, which can contribute to acetaminophen toxicity.

Genetic Factors in Drug Metabolism

Human liver P450 enzymes 3A4, 2C9, 2D6, 2C19, 1A2, and 2B6 are responsible for approximately 75% of clinically relevant Phase I drug metabolism.
Genetic polymorphisms in P450 enzymes can significantly affect an individual’s drug metabolism, resulting in variations in therapeutic response and drug clearance.

Acetaminophen Overdose and Treatment

The reactive metabolite of acetaminophen can lead to hepatotoxicity, but effective antidotes like N-acetylcysteine (NAC) can reduce this risk if administered within 8–16 hours post-overdose.
GSH is ineffective for treating acetaminophen toxicity due to poor cell membrane permeability.

Examples of Genetic Polymorphisms in Phase I and Phase II

CYP1A2:
- Extensive Metabolizers (EM) metabolize caffeine more rapidly, leading to reduced CNS stimulation.
- Poor Metabolizers (PM) experience enhanced CNS stimulation due to slower metabolism.
CYP2A6:
- PM leads to nicotine toxicity and increased craving for cigarettes.
- EM results in increased nicotine metabolism and decreased craving.
CYP2B6:
- PM can reduce clearance of drugs like cyclophosphamide and increase the risk of adverse drug reactions (ADRs).
CYP3A4:
- This enzyme's polymorphisms can affect the clearance of many drugs, possibly necessitating dosage adjustments to prevent drug-drug interactions.

Conclusion on Drug Metabolism

Understanding the biotransformation processes, including the role of P450 enzymes and genetic variations, is critical for optimizing drug therapy and minimizing adverse effects.

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Description

Explore the intricate role of biotransformation in drug disposition, focusing on acetylation of macromolecules and isonicotinic acid. Understand how biotransformation mechanisms influence drug metabolism and interaction. This quiz challenges your knowledge on biochemical processes involved in pharmacology.