Metabolism

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Questions and Answers

What is a potential disadvantage of drug metabolism?

Production of toxic metabolites (correct)

Increased drug efficacy

Facilitation of drug absorption

Conversion of prodrugs to active metabolites

Which enzyme family accounts for approximately 75% of drug metabolism?

Cyclooxygenases

Dehydrogenases

Cytochrome P450s (correct)

Transferases

What is first pass metabolism primarily associated with?

Enhancement of drug stability in the gastrointestinal tract

Increased bioavailability of drugs

Alteration of drugs before they enter systemic circulation (correct)

Direct metabolism in the muscle tissues

Which formulation would not bypass first pass metabolism?

Oral capsule Signup and view all the answers

What could potentially happen if a patient takes a CYP3A4 inducer?

Lower levels of the affected drug in the system Signup and view all the answers

Which of the following is included in Phase II metabolism?

UDP-glucuronosyl transferases Signup and view all the answers

What main factor can affect drug metabolism?

Age of the patient Signup and view all the answers

What is a significant consequence of an increased first pass effect?

Decreased effective oral drug absorption Signup and view all the answers

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

They convert drugs into more hydrophilic metabolites for easier excretion Signup and view all the answers

What is the primary purpose of drug metabolism?

To convert drugs into more polar and water-soluble forms for excretion Signup and view all the answers

Which of the following organs is NOT typically involved in drug metabolism?

Pancreas Signup and view all the answers

What role do cytochrome P450 (Cyp) enzymes play in drug metabolism?

Oxidizing drugs and facilitating their conjugation Signup and view all the answers

What is a prodrug?

An inactive form of a drug that becomes active after metabolism Signup and view all the answers

Which of the following factors can significantly affect drug metabolism?

Genetic variations in enzymes Signup and view all the answers

What is one implication of the first-pass effect?

Oral drugs can be inactivated by liver metabolism before reaching circulation Signup and view all the answers

What could be a consequence of a toxic metabolite?

Increased risk of adverse effects Signup and view all the answers

Which phase of drug metabolism typically involves conjugation reactions?

Phase II Signup and view all the answers

Which enzyme is primarily responsible for the metabolism of ethanol?

CYP2E1 Signup and view all the answers

What is the primary outcome of Phase 1 metabolism?

Increased water solubility Signup and view all the answers

Which of the following reactions is not commonly associated with Phase 1 metabolism?

Sulfation Signup and view all the answers

Which enzyme is primarily responsible for oxidation reactions in Phase 1 metabolism?

Cytochrome P450 (CYP) Signup and view all the answers

In Phase 2 metabolism, what is the most common conjugation reaction?

Glucuronidation Signup and view all the answers

Which of the following is a true statement about hydrolysis in metabolism?

It involves the breakdown of esters and amides. Signup and view all the answers

What does N-dealkylation in Phase 1 metabolism involve?

Loss of an alkyl group attached to nitrogen, oxygen, or sulfur Signup and view all the answers

Which factor is least likely to affect drug metabolism?

Color of the drug capsule Signup and view all the answers

Sulfation in Phase 2 metabolism is especially important for which drugs?

Steroid hormones Signup and view all the answers

Which of these is typically a result of Phase 2 metabolism?

Decreased drug action Signup and view all the answers

What is one of the main functions of Phase 1 metabolism?

To introduce polar functional groups Signup and view all the answers

What enzyme is primarily responsible for the oxidation of losartan?

CYP3A4 Signup and view all the answers

What is the potency of metabolite EXP-3174 compared to losartan?

10- to 40-fold more potent Signup and view all the answers

What clinical consideration should be taken into account when prescribing losartan to a patient on ketoconazole?

Inhibition of losartan metabolism Signup and view all the answers

In the context of hypertensive treatment, what is the involvement of losartan and its metabolite?

Both losartan and EXP-3174 contribute to antihypertensive effects Signup and view all the answers

Which factor is NOT mentioned as affecting drug metabolism?

Diet Signup and view all the answers

If a patient has normal kidney function, what is the recommended course of action regarding losartan after a diagnosis of severe liver dysfunction?

Continue losartan at the current dosage Signup and view all the answers

What does the term 'first pass metabolism' refer to?

The initial metabolism of a drug before it reaches systemic circulation Signup and view all the answers

Which enzyme is also involved in the metabolism of losartan but to a lesser extent?

CYP2C9 Signup and view all the answers

What is a primary reason for a patient who is unresponsive to lisinopril to consider switching to losartan?

Losartan and its metabolite provide potent antihypertensive effects Signup and view all the answers

Which of the following factors is implied to affect the metabolism of medications involving losartan?

Lifestyle choices Signup and view all the answers

Study Notes

Metabolism Definition

The process where a xenobiotic or endobiotic is enzymatically transformed into a more polar, water-soluble, excretable form.

Metabolism Sites

Hepatic microsomal enzymes: Responsible for oxidation and conjugation.
Extrahepatic microsomal enzymes: Also responsible for oxidation and conjugation.
Hepatic non-microsomal enzymes: Responsible for acetylation, sulfation, glutathione conjugation, alcohol/aldehyde dehydrogenase, hydrolysis, and oxidation/reduction.
Extrahepatic locations: Intestine, brain, lungs, skin, heart, kidneys, GIT, and blood.

Fate of a Drug

An active drug can be metabolized into an inactive, active, or toxic metabolite.
Prodrugs that are not yet active can be metabolized into an active form.

Activity and Toxicity Implications

Active metabolites: Can have the same, better, altered, or less activity than the original drug.
Inactive metabolites: Drugs are pharmacologically inactive.
Toxic metabolites: Can be toxic.

Advantages and Disadvantages of Metabolism

Advantages:*
Prevents prolonged effects of drugs in the body.
Detoxifies drugs.
Allows for prodrug strategies.
Disadvantages:*
Can produce side effects and toxic effects.
Can lead to loss of drug activity.
Can alter therapeutic effects.

Clinical Significance of Metabolism

Impacts drug therapy for metabolic, genetic, and environmentally-related illnesses.
Can cause problems with long-term therapy due to toxicity and/or active metabolites.
Contributes to drug-drug or drug-food interactions.
Aids in assessing drug efficacy, safety, and designing dosage regimens.
Provides insight into toxic processes like carcinogenesis and tissue necrosis.
Helps understanding enzymes involved in drug metabolism, which are important for metabolizing endogenous substances.

Enzymes Involved in Metabolism

Cytochrome P450s (Cyps): The most important and major enzymes involved in metabolism.
- CYP3A4, CYP2E1, CYP2D6, CYP2C9, and CYP2C19 account for 75% of drug metabolism.
Other enzymes:
- UDP-glucuronosyl transferases (UGTs)
- Glutathione-S-transferases (GSTs)
- Sulfotransferases (STs)
- N-acetyl transferases (NATs)
- Catechol-O-methyltransferase (COMT)

Types of Metabolism

First-pass metabolism: When a drug is metabolized in the liver before it reaches the general circulation (mostly by CYP3A4).
- Highly lipophilic drugs are more susceptible to this.
- Can impact the bioavailability of drugs.
- Alternating routes of administration can be used (IV, topical, rectal).
Phase I Metabolism: Includes reactions like oxidation, reduction, and hydrolysis.
Phase II Metabolism: Includes conjugation reactions with various molecules, including glucuronidation, sulfation, amino acid conjugation, glutathione conjugation, acetylation, and methylation.

Factors Affecting Metabolism

Internal Factors:*
Genetics: Enzyme variability impacting metabolism (e.g., poor metabolizers, intermediate metabolizers, extensive metabolizers, ultrarapid metabolizers).
Ethnicity: Can influence enzyme activity.
Age: Enzyme activity changes with age.
Gender: Some metabolic enzymes have sex-based differences.
Disease States: Liver and kidney disease can significantly impact metabolism, as can diseases like heart failure or chronic obstructive pulmonary disease.
External Factors:*
Drugs: Can be enzyme inducers or inhibitors.
Diet: Some foods may influence metabolism.
Environment: Exposure to chemicals or toxins can impact metabolic processes.

Clinical Significance of Metabolism: Cases

Enzyme Inducers: Drugs or other factors that increase enzyme activity (can lead to lower levels of other drugs being metabolized and require dose adjustments).
Enzyme Inhibitors: Drugs or other factors that decrease enzyme activity (can lead to higher levels of other drugs being metabolized and require dose adjustments).
Liver Diseases: Can reduce enzyme activity and affect drug metabolism.
Kidney Diseases: Can reduce drug excretion and lead to drug accumulation.

First Pass Metabolism Exercise

First Pass metabolism can be avoided by transdermal patches (I) and buccal (II) formulations. (Correct answer: D.)
Propranolol given IV will still undergo first pass metabolism in the liver, but its bioavailability will not be significantly reduced because it has already entered circulation. (Correct answer: B.)

Phase I & Phase II Metabolism Exercise

Oxidation, reduction, hydrolysis are Phase I reactions. Sulfation is a Phase II reaction. (Correct answer: B.)
The example shows a hydroxylation reaction, which is a Phase I metabolic reaction. (Correct answer: Phase I)

Water Solubility and Phase II Reactions

Methylation is the only reaction that would decrease water solubility (not glucuronidation, hydroxylation, N-dealkylation, or hydrolysis). (Correct answer: E.)

Clinical Significance of Metabolism: Exercise

Mr. X should NOT be given Losartan because Ketoconazole is a strong CYP3A4 inhibitor, which will lead to increased Losartan levels (likely causing toxicity). (Correct answer: B.)
Mr. X should NOT continue Losartan because he has severe liver dysfunction, which impairs drug metabolism. (Correct answer: B.)

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Description

Test your knowledge on the metabolic processes of drugs, including the transformation of xenobiotics and endobiotics. This quiz covers metabolic sites, fates of drugs, and the implications of active and inactive metabolites. Challenge yourself and enhance your understanding of pharmacological metabolism.