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Questions and Answers
What is the principal organ responsible for drug metabolism?
Which phase of drug metabolism involves the introduction of functional groups to increase polarity?
Which of the following processes is NOT part of Phase I metabolic reactions?
What is the primary consequence of drug metabolism?
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Which type of drugs are primarily converted into hydrophilic metabolites to enhance excretion?
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Which of the following describes Phase II metabolic reactions?
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Which enzyme family is most associated with Phase I oxidation reactions?
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What is the major function of Phase I metabolism?
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What enzyme is responsible for oxidizing ethanol to acetaldehyde?
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Which substance is irreversibly inhibited by Disulphiram in the context of alcohol metabolism?
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What is the key function of Phase I reactions in drug metabolism?
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In the metabolism of paracetamol, what is the primary Phase II pathway?
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Which metabolite is produced from the oxidative dealkylation of codeine?
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What type of reaction does hydrolysis represent in drug metabolism?
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What condition leads to the saturation of the glutathione pathway when overdose occurs?
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Which of the following is not a common conjugation reaction found in Phase II metabolism?
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Which functional group does sulfonation typically target during Phase II metabolism?
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What happens to acetaldehyde when Disulphiram is administered?
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In the Phase I metabolism of ethanol, what is the product of the first enzymatic reaction?
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Chloramphenicol's mechanism in drug metabolism involves which type of reaction?
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What type of chemical reaction does glucuronidation represent in the context of drug metabolism?
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Study Notes
Drug Metabolism
- Drug metabolism is the process of transforming drugs in the body using enzymes.
- Metabolites are the products of these transformations.
- The goal of metabolism is to convert lipophilic (fat-soluble) drugs into hydrophilic (water-soluble) metabolites so they can be excreted.
- Metabolism increases renal excretion and decreases tubular re-absorption.
Consequences of Drug Metabolism
- Drugs can be converted into excretable forms.
- Drug action can be terminated.
- Drugs can be converted into metabolites with pharmacological activity.
- Inactive compounds called pro-drugs can be converted into active metabolites.
Where Drug Metabolism Happens
- The liver is the primary organ for drug metabolism.
- Other active tissues include the gastrointestinal tract, lungs, skin, and kidneys.
- Liver cells contain efficient enzymes for metabolizing foreign substances.
Phase I Metabolism
- Introduction: Phase I metabolism transforms a drug into a more polar metabolite by introducing a functional group (e.g., via oxidation, reduction, or hydrolysis).
- Oxidation Reactions: Often catalyzed by cytochrome P450 enzymes, primarily located in the endoplasmic reticulum of hepatocytes.
- Other Enzymes: Other enzymes in the body also oxidize drugs (example: xanthine oxidase, amine oxidases).
Phase I Oxidation Reactions – Oxidation / Hydroxylation
- Hydroxylation: Addition of an -OH group (a type of oxidation).
- Example — Lidocaine: Lidocaine metabolism begins with hydroxylation.
Phase I Oxidation Reactions – Oxidation / Dehydrogenation
- Dehydrogenation: Removal of two hydrogens from a molecule.
- Example — Ethanol: Most ethanol metabolism occurs in the liver. Ethanol is oxidized to ethanal (acetaldehyde) by alcohol dehydrogenase (ADH), then to acetate by aldehyde dehydrogenase (ALDH).
Disulfiram (Antabuse) — Treatment of Alcohol Abuse
- Mechanism: Disulfiram irreversibly inhibits ALDH by competing with the cofactor NAD+ for binding sites.
- Consequences: Increased acetaldehyde levels cause unpleasant side effects (hangover-like).
Phase I Oxidation Reactions – Dealkylation
- Dealkylation: Removal of an alkyl group (typically methyl).
- Example — Codeine: Codeine is converted to morphine by oxidative dealkylation, responsible for its analgesic effect.
Phase I Reactions – Reduction
- Reduction: Addition of two hydrogens to a molecule.
- Example — Chloramphenicol: A broad-spectrum antibiotic undergoes reduction.
Phase I Reactions – Hydrolysis
- Hydrolysis: Addition of water (H2O) to a molecule, breaking it into two parts.
- Examples: Aspirin hydrolysis at pH ~ 7, Procaine (local anesthetic) hydrolysis.
Phase I Summary
- Phase I reactions prepare drugs for Phase II metabolism and excretion.
- Phase II is the true "detoxification" step.
Phase II Metabolism
- Conjugation Reactions: Glucuronic acid conjugation, Sulfate conjugation, Glycine conjugation, Glutathione conjugation.
- Catalysts: Transferase enzymes and various coenzymes.
- Mechanism: Conjugation involves attaching a hydrophilic group to a functional group already present in the molecule (potentially from Phase I), making the product water-soluble for excretion in bile or urine.
Glucuronic Acid Conjugation
- Transfer: Glucuronic acid is transferred from uridine diphosphate glucuronic acid (UDP-GA) to the drug by glucuronyl transferase.
- Importance: Most common conjugation type, forming glucuronides (quantitatively the most important Phase II pathway).
- Common Drugs: Drugs with -OH, -COOH, -NH2 groups.
Sulfate Conjugation (Sulfation)
- Common for: Phenols (aromatic alcohols).
- Transfer: Sulfate is transferred from 3-phosphoadenosine-5'-phosphosulfate (PAPS) to the drug by sulfotransferase.
- Competition: Glucuronide formation and sulfation often compete for the same substrate (e.g., paracetamol).
Glycine Conjugation
- Transfer: Glycine is conjugated to -COOH groups.
Metabolism of Aspirin
- Low doses: Aspirin is primarily metabolized by glycine conjugation.
- Higher doses: Glycine conjugation pathway becomes saturated, and glucuronide conjugation predominates.
- Top doses: Saturation of conjugation pathways leads to direct urinary excretion of aspirin.
Paracetamol and its Metabolism
- Properties: Analgesic, antipyretic, but weak anti-inflammatory.
Paracetamol — Two Main Phase II Metabolic Pathways
- Glucuronidation: 45-50% of paracetamol is metabolized via glucuronidation.
- Sulfation: 45-50% of paracetamol is metabolized via sulfation.
Paracetamol — Another Minor Phase I Metabolic Pathway
- Oxidation: Paracetamol is oxidized by the P450 system to N-Acetyl-p-benzoquinone imine (NAPQI), which is toxic to the liver.
- Glutathione Conjugation: At low doses, NAPQI conjugates with glutathione (GSH) and is excreted.
Glutathione (GSH)
- Function: Reacts with harmful electrophiles produced during metabolism.
Paracetamol — Fatal at High Doses
- High doses: Saturation of glutathione pathway allows NAPQI buildup, damaging liver cells and causing fatal liver failure.
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Description
This quiz delves into the essential concepts of drug metabolism, exploring how the body transforms drugs into metabolites, the organs involved, and the phases of metabolism. Understanding these processes is crucial for comprehending drug action and pharmacology. Test your knowledge and grasp of these fundamental topics in drug metabolism.
