Pharmacology: Paracetamol and P450 Enzymes

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Questions and Answers

Which cytochrome P450 isoform is involved in the metabolism of more than 75% of drugs?

CYP2C19

CYP1A2

CYP2D6

CYP3A4/5 (correct)

What is a prodrug primarily used for?

To increase drug potency immediately upon administration

To serve as a direct active drug without any transformation

To overcome drug instability (correct)

To reduce side effects of active drugs

Which factor contributes to unexpected adverse drug reactions?

High drug dosage

Administration route of the drug

Increased metabolic pathways

Person-person variation in CytP450 genes (correct)

What is the primary role of phase I reactions in relation to prodrugs?

To activate the pharmacologically inert prodrug Signup and view all the answers

What percentage of patients do not benefit from codeine due to null activity of CYP2D6?

10% Signup and view all the answers

What is the main metabolite produced from the hydroxylation of lidocaine?

Unknown Signup and view all the answers

Which enzyme is responsible for the oxidation of acetaldehyde to acetate in ethanol metabolism?

Aldehyde dehydrogenase (ALDH) Signup and view all the answers

What type of reaction is oxidative dealkylation considered?

Phase I reaction Signup and view all the answers

Disulfiram primarily affects which step in ethanol metabolism?

Conversion of acetaldehyde to acetate Signup and view all the answers

In chronic alcohol consumption, which metabolic system becomes induced?

Microsomal ethanol-oxidizing system (MEOS) Signup and view all the answers

What are the common side effects caused by acute disulfiram administration in alcoholics?

Facial flushing, nausea, and vomiting Signup and view all the answers

What percentage of paracetamol undergoes oxidation to form the toxic metabolite benzoquinoneimine?

5% Signup and view all the answers

Which of the following compounds is NOT a product of aspirin metabolism?

Chloramphenicol Signup and view all the answers

Which metabolic pathway of paracetamol becomes important when intake far exceeds therapeutic doses?

P450-dependent GSH conjugation Signup and view all the answers

What is the role of glutathione in paracetamol metabolism?

It combines with benzoquinoneimine to prevent liver injury. Signup and view all the answers

What happens when large amounts of ethanol are consumed regarding the alcohol dehydrogenase system?

The system becomes saturated Signup and view all the answers

What is the recommended antidote for paracetamol overdose when administered within 8-16 hours?

N-acetylcysteine Signup and view all the answers

How does alcohol consumption affect the metabolism of paracetamol?

It induces CYP450 enzymes, increasing paracetamol toxicity. Signup and view all the answers

Which of the following statements about human P450 enzyme systems is true?

P450 systems help in drug metabolism and understanding drug interactions. Signup and view all the answers

What happens to glutathione stores during paracetamol overdose?

They are depleted, resulting in liver injury. Signup and view all the answers

What is the role of methanoic acid in relation to cefamandole sulfate?

It serves as a stabilizing agent by forming a pure and stable ester. Signup and view all the answers

Why can't 5-aminosalicylic acid (5-ASA) be administered directly for treating ulcerative colitis?

It is absorbed in the stomach and small intestine before it can act. Signup and view all the answers

What is the mechanism by which sulfasalazine delivers 5-ASA to the colon?

By linking 5-ASA to sulfapyridine via an azo linkage that is cleaved by azoreductases. Signup and view all the answers

What type of link is present between sulfapyridine and 5-ASA in sulfasalazine?

Azo linkage Signup and view all the answers

Which characteristic of cefamandole sulfate contributes to its therapeutic effectiveness after administration?

The breakdown of its ester form by esterases in the blood. Signup and view all the answers

What is the main advantage of diamorphine over morphine?

It crosses the blood-brain barrier more easily. Signup and view all the answers

Why is Enalaprilat poorly absorbed in comparison to Enalapril?

Enalapril is less polar than Enalaprilat. Signup and view all the answers

What is the role of esterase enzymes in the metabolism of prodrugs?

They convert prodrugs into their active forms. Signup and view all the answers

How does Haloperidol decanoate provide prolonged antipsychotic activity?

It is converted to Haloperidol slowly over time. Signup and view all the answers

What characteristic of sulfioxazole acetyl makes it more desirable for patient use?

It is tasteless compared to sulfioxazole. Signup and view all the answers

What can be inferred about the necessity of prodrugs in psychopharmacology?

Prodrugs can improve patient compliance through reduced dosing frequency. Signup and view all the answers

Which functional groups in diamorphine enhance its lipophilicity?

Acetyl groups. Signup and view all the answers

Which factor is critical for the therapeutic efficacy of Haloperidol decanoate?

Slow release and conversion to active drug. Signup and view all the answers

Which of the following statements accurately describes the role of cytochrome P450 enzymes in drug metabolism?

They contribute to the metabolism of the majority of clinically used drugs. Signup and view all the answers

What is a common advantage of using prodrugs in pharmacotherapy?

They can enhance drug stability and delivery. Signup and view all the answers

Which of the following is NOT a potential reason for the development of prodrugs?

To ensure it only requires phase II metabolic reactions. Signup and view all the answers

In terms of metabolic pathways, what distinguishes CYP3A4/5 from other isoforms?

They play a major role in drug interactions due to broad substrate specificity. Signup and view all the answers

What is a key factor contributing to the variability in response to the drug codeine?

Differences in the activity of the CYP2D6 enzyme. Signup and view all the answers

Which of the following describes a consequence of drug metabolism?

It can convert a drug to an excretable form. Signup and view all the answers

What role does the liver play in drug metabolism?

It is the principal site of drug metabolism. Signup and view all the answers

What occurs during Phase I drug metabolism?

Functional groups are introduced or unmasked in the drug molecule. Signup and view all the answers

What is the primary consequence of depleting glutathione stores in relation to paracetamol metabolism?

Increased formation of benzoquinoneimine leading to liver injury Signup and view all the answers

Which statement regarding cytochrome P450 is accurate?

It participates in hydroxylation of xenobiotics and endogenous compounds. Signup and view all the answers

Which of the following statements accurately describes the effect of alcohol on paracetamol metabolism?

Enhanced induction of CYP450 enzymes increases the conversion of paracetamol to toxic metabolites Signup and view all the answers

What is the significance of Phase II drug metabolism?

It increases the water solubility of metabolites for easier excretion. Signup and view all the answers

Which of the following is a possible result of drug metabolism?

Formation of a toxic metabolite can occur. Signup and view all the answers

Which metabolite is primarily responsible for hepatotoxicity due to paracetamol overdose?

Benzoquinonamine Signup and view all the answers

Which organ besides the liver is also significantly involved in drug metabolism?

Lungs Signup and view all the answers

Which of the following is a characteristic of GSH in the context of paracetamol metabolism?

GSH normally combines with reactive metabolites to prevent liver injury Signup and view all the answers

How does drug metabolism impact inactive pro-drugs?

They can be converted to active drugs through metabolism. Signup and view all the answers

When paracetamol intake far exceeds therapeutic doses, which pathway becomes increasingly significant for metabolism?

P450-dependent pathway Signup and view all the answers

What percentage of paracetamol is typically oxidized to produce the toxic metabolite benzoquinoneimine?

5% Signup and view all the answers

What is the primary role of cytochrome P450 enzymes in drug metabolism?

To convert lipophilic substances into hydrophilic metabolites Signup and view all the answers

Which statement best represents the relationship between paracetamol and alcohol in terms of liver metabolism?

Chronic alcohol consumption can enhance the production of toxic paracetamol metabolites. Signup and view all the answers

What is the primary purpose of Phase II metabolism in drug metabolism?

To convert lipophilic substances into hydrophilic forms for excretion. Signup and view all the answers

Which of the following conjugation reactions is MOST common for drugs containing -OH groups?

Glucuronic acid conjugation Signup and view all the answers

Which reaction is catalyzed by sulfotransferase during drug metabolism?

Sulfate conjugation Signup and view all the answers

What type of drug metabolism products are generated from conjugation with glutathione?

Detoxification products containing sulfur Signup and view all the answers

Which of the following conjugation reactions predominantly utilizes glucuronic acid?

Glucuronic acid conjugation Signup and view all the answers

Which statement best describes glycine conjugation?

It is common for drugs containing -COOH groups. Signup and view all the answers

What is the result of sulfation during drug metabolism?

Detoxification through the introduction of sulfur groups. Signup and view all the answers

Which reaction competes directly with glucuronide formation for the same substrate like paracetamol?

Sulfation Signup and view all the answers

What role does the ethyl ester play in Enalapril compared to Enalaprilat?

It enhances the absorption of the drug. Signup and view all the answers

Which characteristic makes Haloperidol decanoate beneficial for patients requiring long-term medication?

It allows for intramuscular injection. Signup and view all the answers

How does the acetylation of morphine in diamorphine improve its pharmacokinetics?

It enhances its ability to cross the blood-brain barrier. Signup and view all the answers

What is the primary reason sulfioxazole acetyl is used in treatment instead of sulfioxazole itself?

It has a tasteless profile for better patient compliance. Signup and view all the answers

What is the mechanism by which Haloperidol decanoate maintains its antipsychotic effect?

Slow hydrolysis into its active form over time. Signup and view all the answers

Which of the following describes the primary use of diamorphine in medical practice?

As a prodrug to deliver morphine to systemic circulation. Signup and view all the answers

Why is 5-ASA not administered directly for treating ulcerative colitis?

It cannot reach the target site efficiently. Signup and view all the answers

Study Notes

Paracetamol Metabolism

Paracetamol metabolism involves two primary pathways: glucuronidation and sulfation, which account for 95% of the excreted metabolites.
The remaining 5% is metabolized by a P450-dependent pathway that produces benzoquinoneimine, a highly reactive substance that can lead to hepatotoxicity.
When glutathione stores are depleted, free benzoquinoneimine binds to hepatic proteins, causing liver damage.
Alcohol abuse increases paracetamol toxicity due to the induction of CYP1A2, CYP2E1 and CYP3A4 enzymes by ethanol, which ultimately leads to increased formation of the toxic benzoquinonamine.

Cytochrome P450 Enzymes

Cytochrome P450 enzymes are a family of proteins responsible for oxidizing various compounds, including drugs.
There are approximately 60 human P-450 enzyme systems that play a crucial role in drug metabolism and drug interactions.

Phase I Oxidation Reactions

Oxidative dealkylation is a common Phase I reaction involving the removal of an alkyl group.
Codeine is dealkylated to morphine, producing a significant analgesic effect.
Dehydrogenation is another Phase I reaction involving the removal of hydrogen atoms.
Ethanol is primarily metabolized by the liver through oxidation to acetaldehyde, followed by further oxidation to acetate.

Disulfiram and Alcohol Metabolism

Disulfiram inhibits aldehyde dehydrogenase, leading to a buildup of acetaldehyde, which causes unpleasant side effects like facial flushing, nausea, vomiting, and headache.
Alcohol is metabolized by alcohol dehydrogenase, and then by aldehyde dehydrogenase.

Microsomal Ethanol-Oxidizing System (MEOS)

MEOS is involved in ethanol metabolism and primarily utilizes NADPH and CYP450 enzymes like 2E1, 1A2, and 3A4.
When ethanol consumption is high, alcohol dehydrogenase becomes saturated, and MEOS activity increases.

Phase I and Phase II Reactions

Phase I reactions typically involve oxidation, reduction, or hydrolysis, often introducing polar groups to make the drug more water-soluble.
Phase II reactions involve conjugation, where a molecule is attached to the drug, further increasing its water solubility for excretion.

Prodrugs

Prodrugs are pharmacologically inactive precursors that are converted into active drugs in the body.
Activation of a prodrug usually involves a Phase I reaction.
Codeine is a prodrug that is metabolized by CYP2D6 to morphine, but some individuals lack this enzyme, making codeine ineffective.

Reasons for Using Prodrugs

Prodrugs can overcome drug instability, improve physicochemical properties, promote site-specific drug delivery, prolong drug release, and enhance patient acceptance.

Specific Examples of Prodrugs

Cefamandole sulfate-methanoic acid ester: This ester is a stable prodrug of cefamandole sulfate, which is unstable and difficult to purify.
Sulfasalazine: This prodrug contains 5-aminosalicylic acid (5-ASA), an active drug for ulcerative colitis, linked to sulfapyridine. The azo linkage is broken down in the colon, releasing 5-ASA.
Diamorphine (heroin): This prodrug delivers morphine to the CNS after being converted by esterases.
Enalapril: This prodrug is a less polar ester form of enalaprilat, an ACE inhibitor, resulting in better absorption.
Haloperidol decanoate: This prodrug is injected intramuscularly and slowly releases haloperidol, providing extended antipsychotic activity.
Sulfioxazole acetyl: This tasteless prodrug is converted to the bitter-tasting active drug sulfioxazole.

Aspirin Metabolism

Aspirin is metabolized in the liver.
Aspirin is converted to salicylic acid.

Paracetamol Metabolism

Paracetamol is metabolized by the liver.
Majority of the drug is converted to non-toxic metabolites through glucuronidation and sulfation.
5% of the drug is converted to a toxic metabolite, benzoquinoneimine, by CYP450 enzymes.
Benzoquinoneimine is usually detoxified by binding to glutathione.
When glutathione stores are depleted, benzoquinoneimine binds to liver proteins, leading to liver injury.
Alcohol abuse increases the activity of CYP450 enzymes, potentially increasing the formation of benzoquinoneimine.
This increases the risk of paracetamol toxicity in alcohol abusers.

Cytochrome P450

Cytochrome P450 enzymes are responsible for drug metabolism.
They are a family of proteins present in the liver and other organs.
There are approximately 60 different P450 enzymes in humans with very different substrate specificities.
They can convert drugs to inactive metabolites.
They can convert drugs to active metabolites.
They can convert drugs to toxic metabolites.

Site of Drug Metabolism

The liver is the primary site of drug metabolism.
Liver cells contain enzymes that metabolize foreign substances (xenobiotics).
Other tissues, such as the gastrointestinal tract, lungs, skin, and kidneys, also contribute to drug metabolism.

Consequences of Drug Metabolism

Drug metabolism converts drugs to forms that can be easily excreted by the kidneys.
Drug metabolism can terminate drug action.
Drug metabolism can convert an inactive compound (pro-drug) into an active drug.
Drug metabolism can convert a drug into a metabolite that has its own pharmacological effect.

Phase I Metabolism

Introduces or unmasks functional groups (e.g. -ОН, -NH2, -COOH) into the drug molecule.
Makes the drug more water-soluble and prepares it for Phase II metabolism

Phase II Metabolism

Conjugates hydrophilic groups, like glucuronic acid, to the drug molecule, increasing its water solubility and ease of excretion.
Major reactions include:
- Glutathione conjugation
- Glucuronic acid conjugation
- Sulfate conjugation
- Glycine conjugation
- Acetylation

Glucuronic Acid Conjugation

Most common type of conjugation.
Converts drugs with -OH, -COOH, -NH2 groups into glucuronides.
Glucuronic acid is transferred from UDP-glucuronic acid by glucuronyl transferase.

Sulfate Conjugation

Common for phenols.
Sulfate is transferred from 3-phosphoadenosine-5’-phosphosulfate (PAPS) by sulfotransferase.
Glucuronide formation and sulfation often compete for the same substrate, like paracetamol.

Glutathione Conjugation

Detoxifies toxic compounds.
Sulfur atoms derived from glutathione are added to the drug molecule.
Forms mercapturate as the end product.
Common for aromatic nitro, halogenated compounds, and products of polycyclic hydrocarbons.

Glycine Conjugation

Common for drugs with -COOH groups.
CYP3A4/5 and UGT*:
These enzymes are involved in the metabolism of more than 75% of drugs.

Prodrug

A prodrug is an inactive precursor to an active drug.
Usually activated by a Phase I reaction.
Example: Codeine is a prodrug that is converted to morphine by CYP2D6.

Reasons for using a prodrug

To overcome drug instability.
Site-specific drug delivery.
Improved physicochemical properties.
Prolonged drug release.
To encourage patient acceptance.

Prodrug Examples:

Sulfasalazine: Prodrug for 5-aminosalicylic acid (5-ASA) to treat inflammatory bowel disease. Sulfapyridine is a carrier responsible for adverse effects.
Diamorphine (Heroin): Prodrug used to deliver morphine to the central nervous system. More fat-soluble than morphine, crosses the blood-brain barrier more readily. Acetyl groups are removed in the CNS to give morphine.
Enalapril: Prodrug for enalaprilat, an ACE inhibitor. Enalapril is better absorbed due to its lower polarity and is metabolized to the active enalaprilat in vivo.
Haloperidol decanoate: Long-acting prodrug of haloperidol, an antipsychotic. Injected intramuscularly and provides antipsychotic activity for 1 month due to slow conversion to haloperidol. Used for schizophrenia treatment.
Sulfioxazole acetyl: Prodrug for sulfioxazole, a sulfa drug, that is tasteless to improve patient acceptance.

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Description

This quiz covers the metabolism of paracetamol and the role of Cytochrome P450 enzymes in drug metabolism. It discusses the pathways involved, the implications of alcohol on toxicity, and insights into Phase I oxidation reactions. Test your knowledge on these critical pharmacological concepts.