Drug Metabolism Overview

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Questions and Answers

What is a characteristic of prodrugs?

They can be eliminated without any transformation.

They require a phase II reaction for activation.

They are pharmacologically inert precursors to active drugs. (correct)

They are always active upon administration.

Which of the following statements about cytochrome P450 (CYP) enzymes is true?

CYP3A4/5 and UGT are involved in less than 50% of drug metabolism.

CYP2D6 is responsible for nearly all drug metabolization.

All CYP isoforms have narrow substrate specificity.

Genetic variation in CytP450 genes can lead to unexpected drug reactions. (correct)

What is a primary reason for using prodrugs?

To improve physicochemical properties. (correct)

To ensure immediate release of the active drug.

To enhance drug instability.

To make the drug less effective.

What role does CYP2D6 play in drug metabolism?

It results in no benefit in about 10% of patients using codeine. Signup and view all the answers

Which of the following CYP isoforms is involved in the metabolism of a significant percentage of drugs?

CYP3A4/5 Signup and view all the answers

What characteristic of cefamandole sulfate is primarily challenged due to its instability?

It is difficult to purify. Signup and view all the answers

How does the ester formed from cefamandole sulfate and methanoic acid become the active drug?

It is cleaved by esterases in the blood. Signup and view all the answers

Which drug is specifically designed to reach the colon by circumventing absorption in previous sites?

Sulfasalazine Signup and view all the answers

What is the role of azoreductases in the context of sulfasalazine?

They break down the azo linkage in the colon. Signup and view all the answers

What active therapeutic moiety does sulfasalazine release in the colon?

5-aminosalicylic acid Signup and view all the answers

What is the main product formed when glucuronic acid conjugates with a drug?

Glucuronide Signup and view all the answers

Which of the following represents a common reaction for drugs containing -OH, -COOH, and -NH2 groups during Phase II metabolism?

Glucuronic acid conjugation Signup and view all the answers

Which transferase enzyme is responsible for transferring glucuronic acid from UDP-glucuronic acid to a drug?

Glycuronyl transferase Signup and view all the answers

What is the primary purpose of pharmacokinetics?

To understand how the body affects drugs Signup and view all the answers

Which conjugation reaction is primarily used for compounds containing phenols?

Sulfate conjugation Signup and view all the answers

Which of the following best describes phase I drug metabolism?

Oxidation, reduction, and hydrolysis reactions Signup and view all the answers

What is the detoxification product resulting from glutathione conjugation?

Mercapturate Signup and view all the answers

What is a potential risk associated with high doses of paracetamol?

Toxicity due to metabolic overload Signup and view all the answers

Which of the following conjugation methods would be common for drugs with -COOH functional groups?

Glycine conjugation Signup and view all the answers

What rare feature of glutathione that aids in detoxification is mentioned?

Cysteine-containing tripeptide Signup and view all the answers

What defines a prodrug?

A compound that is inactive until metabolized Signup and view all the answers

Which type of drug-drug interaction is most likely to lead to increased toxicity?

Competitively inhibiting the same metabolic enzyme Signup and view all the answers

Which Phase II metabolic reaction often competes with glucuronide formation for the same substrate, particularly for paracetamol?

Sulfation Signup and view all the answers

What is the primary pathway for paracetamol metabolism under normal therapeutic doses?

Glucuronidation and sulfation Signup and view all the answers

What percentage of paracetamol is metabolized through the P450-dependent pathway under normal conditions?

5% Signup and view all the answers

What condition can lead to increased hepatotoxicity in alcohol abusers when taking paracetamol?

Depletion of glutathione Signup and view all the answers

Which of the following statements about the metabolism of paracetamol is true?

Alcohol can induce CYP450 enzymes that increase toxicity. Signup and view all the answers

What antidote is used for paracetamol overdose and is effective within 8–16 hours?

Cysteamine Signup and view all the answers

What is the primary reaction that leads to hepatotoxicity from paracetamol overdose?

Oxidation to benzoquinoneimine Signup and view all the answers

Which cytochrome P450 isoforms are primarily responsible for the oxidation of paracetamol?

CYP1A2, CYP2E1, CYP3A4 Signup and view all the answers

Which factor contributes to the lower threshold for paracetamol overdose in alcohol abusers?

Induction of specific P450 enzymes Signup and view all the answers

Which of the following statements best describes the role of CYP3A4/5 in drug metabolism?

It is involved in the metabolism of more than 75% of drugs in use. Signup and view all the answers

What is the main reason prodrugs are used in drug development?

They help to improve drug stability and site-specific delivery. Signup and view all the answers

What proportion of patients does not receive any benefit from codeine due to CYP2D6 variation?

Approximately 10% Signup and view all the answers

Which of the following pathways is NOT typically involved in the metabolism of drugs?

Amine oxidase (AO) Signup and view all the answers

What is a characteristic of many cytochrome P450 enzymes regarding drug metabolism?

They exhibit broad substrate specificity. Signup and view all the answers

What best describes the role of drug metabolism in the body?

To enhance the water solubility of drugs for renal excretion Signup and view all the answers

Which Phase I reaction is primarily responsible for the oxidation of drug substrates?

Hydroxylation Signup and view all the answers

What is the mechanism of action of disulfiram in alcohol metabolism?

Inhibits acetaldehyde dehydrogenase Signup and view all the answers

Why can paracetamol be toxic at high doses?

It forms reactive metabolites through a pathway involving cytochrome P450 Signup and view all the answers

What role does renal excretion play in drug metabolism?

Facilitates the detoxification of polar metabolites before elimination Signup and view all the answers

Why is sulfasalazine effective for treating ulcerative colitis?

It contains 5-ASA linked to sulfapyridine by an azo linkage. Signup and view all the answers

What is the role of methanoic acid in the formulation of cefamandole sulfate?

It forms a stable ester with cefamandole sulfate. Signup and view all the answers

What specifically cleaves the azo linkage in sulfasalazine to release its therapeutic component?

Azoreductases Signup and view all the answers

What is a major challenge associated with cefamandole sulfate as an antibiotic?

It is difficult to purify and unstable. Signup and view all the answers

What characteristic of the active drug released from cefamandole sulfate is a result of blood enzyme activity?

It is converted from a prodrug form. Signup and view all the answers

What consequence does disulfiram have on the metabolism of alcohol?

It prevents acetaldehyde from being oxidized to acetate. Signup and view all the answers

Which Phase I reaction primarily contributes to the formation of morphine from codeine?

Oxidative Dealkylation Signup and view all the answers

What role does aldehyde dehydrogenase (ALDH) play in ethanol metabolism?

It oxidizes acetaldehyde to acetate. Signup and view all the answers

What is a common result of chronic alcohol consumption regarding metabolism?

Induction of MEOS activity. Signup and view all the answers

Which product is formed following the complete metabolism of ethanol?

Acetate Signup and view all the answers

What type of reaction does chloramphenicol undergo during Phase I metabolism?

Reduction Signup and view all the answers

What is a significant side effect of increased acetaldehyde levels due to disulfiram?

Facial flushing and nausea Signup and view all the answers

Which enzyme is primarily responsible for ethanol metabolism in the liver?

Alcohol dehydrogenase Signup and view all the answers

What is the main function of acetyl groups in diamorphine?

To facilitate cross the blood-brain barrier Signup and view all the answers

Why is Enalapril considered more effective than Enalaprilat in terms of absorption?

It has a less polar ethyl ester Signup and view all the answers

How does Haloperidol decanoate provide therapeutic effects for a prolonged period?

It is converted slowly to Haloperidol after injection Signup and view all the answers

What is the advantage of using sulfioxazole acetyl over sulfioxazole?

It is tasteless and more palatable Signup and view all the answers

What is the primary mechanism by which esterase enzymes contribute to the activation of Enalapril?

By hydrolyzing it to release the active Enalaprilat Signup and view all the answers

Which property primarily distinguishes diamorphine from morphine?

Lipophilicity due to acetylation Signup and view all the answers

What is a key characteristic of prodrugs in psychotic treatment?

They allow for prolonged drug release Signup and view all the answers

What is the significance of the polarity of Enalaprilat in its pharmacological use?

It limits its absorption through the gastrointestinal tract Signup and view all the answers

Study Notes

Drug Metabolism

Metabolism is the process by which drugs undergo transformations by enzymes.
Drugs generally start lipophilic and are transformed into hydrophilic metabolites, becoming more excretable.
Increased water solubility results in increased renal excretion and decreased tubular reabsorption.
Alcohol consumption results in significant increases in ethanol metabolism and clearance of other drugs eliminated by the cytochrome P450 system.
Genetic deficiencies in the ALDH enzyme, common in East Asians, are linked to "Genetic Disulfiram".

Phase I Metabolism

Generally involves oxidation, reduction, or hydrolysis reactions.
Often introduces polar groups like hydroxyl, carboxyl, or amine.
Can generate more reactive metabolites.

Phase II Metabolism

Involves conjugation reactions where a hydrophilic group is conjugated to the molecule, giving a water-soluble product.
Often, phase I metabolism provides a conjugation site (e.g., OH).

Main Conjugation Reactions:

Glutathione Conjugation: Common for aromatic nitro- and halogenated compounds.
Glucuronic Acid Conjugation: Most common form of conjugation, common for drugs with -OH, -COOH, -NH2 groups.
Sulfate Conjugation: Common for phenols.
Glycine Conjugation: Common for drugs with -COOH groups.
Acetylation: Common for drugs with -NH2 groups.

Metabolism and Toxicity

Paracetamol: Normally undergoes glucuronidation and sulfation, making up 95% of excreted metabolites.
Hepatotoxicity: Occurs because 5% of paracetamol is oxidized to benzoquinoneimine, a highly reactive substance.
When glutathione stores are depleted: Benzoquinoneimine combines with hepatic proteins and causes liver injury.
Alcohol abuse and paracetamol toxicity: Ethanol induces CYP1A2, CYP2E1, and CYP3A4, which oxidize paracetamol to benzoquinonamine.
Alcohol abusers have higher levels of these enzymes: This leads to increased conversion of paracetamol to benzoquinonamine, increasing risk of toxicity at lower doses.

Cytochrome P450

Family name: CYP (Cytochrome P450)
Subfamily: Specific protein
Different allelic forms: Account for person-to-person variability in drug metabolism.
Knowledge of the P450 system: Essential for understanding drug metabolism and drug interactions.

Learning Objectives:

Define pharmacokinetics and describe the main purpose of drug metabolism.
Describe the types of reactions involved in phase I and phase II drug metabolism with examples.
Describe the metabolism of ethanol and the mechanism of action of disulfiram.
Describe the metabolism of aspirin and paracetamol and explain why some drugs are toxic at high doses.
Define prodrugs and recall situations in which these are used.
Describe drug-drug interactions.

Pharmacokinetics:

“What the body does to the drug”

Key components:
- Administration
- Distribution
- Metabolism
- Elimination

Prodrugs:

Pharmacologically inert precursor to an active drug.
Activation usually involves a phase I reaction.

Reasons to use a prodrug:

Overcome drug instability
Site-specific drug delivery
Improve physicochemical properties
Prolonged drug release
Encourage patient acceptance

Prodrug example:

Cefamandole sulfate: A broad-spectrum antibiotic that is difficult to purify and unstable.
Cefamandole sulfate-methanoic acid ester: A stable prodrug formed by reacting cefamandole sulfate with methanoic acid. It is cleaved by esterases in the blood to release the active drug.

Site-specific drug delivery example:

Sulfasalazine: The drug of choice for ulcerative colitis.
5-aminosalicylic acid (5-ASA): The active therapeutic moiety.
Azo linkage: 5-ASA is linked to sulfapyridine by an azo linkage.
Azoreductases: These enzymes break down the azo linkage in the colon, releasing 5-ASA for targeted delivery.

Drug-drug interactions:

CYP3A4/5 and UGT: Involved in the metabolism of more than 75% of drugs in use.
Person-person variation in CytP450 genes: Responsible for many unexpected adverse drug reactions.

Pharmacokinetics

Pharmacokinetics is the study of how drugs move into, around and out of the body.
It focuses on what the body does to the drug.
It comprises four key components:
- Administration
- Distribution
- Metabolism
- Elimination

Drug Metabolism

Drug metabolism is the process by which drugs undergo transformations catalyzed by enzymes.
The products of these transformations are called metabolites
Drug metabolism generally converts lipophilic drugs into hydrophilic metabolites, which are easier to excrete.
Many of the enzymes involved in drug metabolism have broad substrate specificity, meaning they can act on a variety of drugs.

Phase I Reactions

Phase I drug metabolism typically involves oxidation, reduction, or hydrolysis reactions.
Examples:
- Oxidative dealkylation: Codeine is de-alkylated to morphine.
- Reduction: Chloramphenicol undergoes reduction.
- Hydrolysis: Aspirin is hydrolyzed to salicylate and acetate.
The enzymes involved in these reactions are often referred to as mixed-function oxidases, or cytochrome P450 enzymes.

Phase II Reactions

Phase II drug metabolism involves conjugation reactions where a drug molecule is coupled with a polar molecule.
This process typically increases the water solubility of the drug, facilitating excretion.
Examples:
- Glucuronidation
- Sulfation
- Acetylation
- Methylation

Ethanol Metabolism

Most ethanol is metabolized by the liver.
Main enzymes involved:
- Alcohol dehydrogenase (ADH): Converts ethanol to acetaldehyde.
- Aldehyde dehydrogenase (ALDH): Converts acetaldehyde to acetate.
Disulfiram: Is an irreversible inhibitor of ALDH.
This leads to an accumulation of acetaldehyde and causes unpleasant side effects such as flushing, nausea, vomiting, dizziness, and headache.

Prodrugs

A prodrug is a pharmacologically inactive precursor to an active drug.
Activation of a prodrug generally involves a phase I reaction.
They are often utilized to:
- Overcome drug instability
- Achieve site-specific drug delivery
- Improve physicochemical properties
- Prolong drug release
- Encourage patient acceptance

Drug-Drug Interactions

Drug-drug interactions can occur when two or more drugs are taken simultaneously.
One drug can influence the metabolism of another drug, leading to altered plasma concentrations and potential adverse effects.
The cytochrome P450 enzymes are highly involved in drug-drug interactions.
This is a primary reason for monitoring patients' responses to drug therapy and implementing individual drug adjustments.

CYP3A4/5 and UGT Enzymes

These enzymes are involved in the metabolism of over 75% of drugs in use.
They play a crucial role in the detoxification and elimination of a wide range of medications.
Individual variations in these enzyme activities can lead to significant differences in drug responses among patients.

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Description

This quiz covers the essential processes of drug metabolism, including Phase I and Phase II reactions. It examines how metabolic transformations affect drug excretion and the role of genetic factors in metabolism. Test your knowledge on the principles of metabolism and its implications in pharmacology.