MPP Lecture 3 Principles of Pharmacology PDF

Terms: Xenobiotics: foreign substances that are not naturally found in the body drug biotransformation: The processes by which biochemical reactions alter drugs within the body are collectively called Metabolites: Metabolic products that are often less pharmacodynamically active than the parent dru...

Terms: Xenobiotics: foreign substances that are not naturally found in the body drug biotransformation: The processes by which biochemical reactions alter drugs within the body are collectively called Metabolites: Metabolic products that are often less pharmacodynamically active than the parent drug and may even be inactive P450: Important for the metabolism of many endogenouscompounds (steroids, lipids) and for the biotransformation of exogenous substances (xenobiotics) Inactive Prodrug: a drug that has to be metabolized to be an active drug and have a biological effect 1.Why is drug biotransformation necessary and where does it occur? - drugs do not possess physicochemical properties for excretion - Most drugs are lipophilic and usually strongly bound to plasma proteins - Drugs are transformed to more polar and therefore readily excreted products - Liver is the principal organ of drug metabolism - More metabolism = less drug that reaches target tissue List the four main ways drug biotransformation can alter drugs 1. An active drug may be converted to an inactive drug 2. An active drug may be converted to an active or toxic metabolite 3. An inactive prodrug may be converted to an active drug 4. An unexcretable drug may be converted to an excretable metabolite Phase I “oxidation/reduction” – convert lipophilic drugs into more polar molecules Phase II “conjugation/hydrolysis” – extra reactions to accomplish excretion Drugs already possessing an –OH, –NH2, or –COOH group may enter phase II directly and become conjugated without prior phase I metabolism Phase I Reactions Purpose: These reactions introduce or expose a functional group on the compound, often making it more polar. Mechanism: Oxidation: Addition of oxygen or removal of hydrogen. Example: The conversion of ethanol to acetaldehyde by alcohol dehydrogenase. Reduction: Removal of oxygen or addition of hydrogen. Example: The reduction of nitro compounds to amino compounds. Hydrolysis: Breakdown of compounds by water. Example: The hydrolysis of esters to form alcohols and acids. Enzymes Involved: cytochrome P450 enzymes (CYPs), P450 Reductase Outcome: The new metabolite is either further processed in Phase II biotransformation or excreted. If Phase II reactions are required, the metabolite is prepared for conjugation with additional molecules to enhance its solubility and facilitate excretion. Phase II Reactions Purpose: Many phase I metabolites are still too lipophillic to be excreted, therefore, These reactions conjugate the compound with another substance to increase its solubility and facilitate its excretion. Mechanism: Glucuronidation: Addition of glucuronic acid. Example: The conjugation of bilirubin to form bilirubin diglucuronide. Sulfation: Addition of sulfate groups. Example: The sulfation of steroids. Acetylation: Addition of acetyl groups. Example: The acetylation of aromatic amines. Methylation: Addition of methyl groups. Example: The methylation of catecholamines. Outcome: These reactions usually result in compounds that are more polar, water-soluble, and less biologically active, making them easier to excrete from the body via urine or bile. Summary Phase I reactions modify the compound to make it more reactive or polar but may not always make it more excretable. Phase II reactions conjugate the modified compound with another substance to increase its solubility and facilitate its excretion. Steps and key enzymes of Phase I metabolism Reaction Overview: 1. Substrate Binding: oxidized P450 combines with a drug substrate to form a binary complex 2. Enzyme Activation: NADPH serves as a reducing agent to donate an electron to P450 Reductase and reduce the oxidized drug complex 3. Modification Reaction: A second electron is introduced from NADPH via the same P450 reductase serves to reduce oxygen and to form an "activated oxygen"-P450-substrate complex 4. Formation of Metabolite: This complex in turn transfers activated oxygen to the drug substrate to form the oxidized product Characterize the P450 enzyme family The family name is indicated by a number that follows CYP The capital letter designates the subfamily A second number indicates the specific isozyme ○ Example: CYP3A4 P450 Inducers - P450 Inducers usually cause an increase in the gene transcription of a CYP enzyme. Consequences of increased drug metabolism include: 1. decreased plasma drug concentrations 2. decreased drug activity if the metabolite is inactive 3. increased drug activity if the metabolite is active 4. decreased therapeutic drug effect P450 Enzyme Induction 1. A drug can increase its own metabolism 2. A drug can increase the metabolism of a co-administered drug P450 Inhibtors 1. competition for the same isozyme 2. Can have serious adverse events Here are flashcards based on the provided information: Flashcard 1 Q: What are xenobiotics? A: Foreign substances that are not naturally found in the body. Flashcard 2 Q: What is drug biotransformation? A: The processes by which biochemical reactions alter drugs within the body. Flashcard 3 Q: What are metabolites? A: Metabolic products that are often less pharmacodynamically active than the parent drug and may even be inactive. Flashcard 4 Q: What role do P450 enzymes play in drug metabolism? A: They are important for the metabolism of many endogenous compounds (e.g., steroids, lipids) and for the biotransformation of exogenous substances (xenobiotics). Flashcard 5 Q: What is an inactive prodrug? A: A drug that has to be metabolized to become an active drug and have a biological effect. Flashcard 6 Q: Why is drug biotransformation necessary and where does it occur? A: It is necessary because drugs often do not possess physicochemical properties required for excretion. Most drugs are lipophilic and bound to plasma proteins. Drug biotransformation converts drugs to more polar, excretable products. The liver is the principal organ for drug metabolism. Flashcard 7 Q: List the four main ways drug biotransformation can alter drugs. A: 1. An active drug may be converted to an inactive drug. 2. An active drug may be converted to an active or toxic metabolite. 3. An inactive prodrug may be converted to an active drug. 4. An unexcretable drug may be converted to an excretable metabolite. Flashcard 8 Q: What is the purpose of Phase I drug biotransformation? A: To convert lipophilic drugs into more polar molecules. Flashcard 9 Q: What are the main mechanisms of Phase I reactions? A: Oxidation: Addition of oxygen or removal of hydrogen (e.g., ethanol to acetaldehyde). Reduction: Removal of oxygen or addition of hydrogen (e.g., nitro compounds to amino compounds). Hydrolysis: Breakdown of compounds by water (e.g., esters to alcohols and acids). Flashcard 10 Q: Which enzymes are involved in Phase I reactions? A: Cytochrome P450 enzymes (CYPs) and P450 Reductase. Flashcard 11 Q: What is the outcome of Phase I biotransformation? A: The new metabolite is either further processed in Phase II biotransformation or excreted. Flashcard 12 Q: What is the purpose of Phase II drug biotransformation? A: To conjugate the compound with another substance to increase its solubility and facilitate excretion. Flashcard 13 Q: What are the main mechanisms of Phase II reactions? A: Glucuronidation: Addition of glucuronic acid (e.g., bilirubin to bilirubin diglucuronide). Sulfation: Addition of sulfate groups (e.g., steroids). Acetylation: Addition of acetyl groups (e.g., aromatic amines). Methylation: Addition of methyl groups (e.g., catecholamines). Flashcard 14 Q: What is the typical outcome of Phase II reactions? A: These reactions usually result in compounds that are more polar, water-soluble, and less biologically active, making them easier to excrete from the body via urine or bile. Flashcard 15 Q: Summarize the roles of Phase I and Phase II reactions in drug metabolism. A: Phase I: Modifies the compound to make it more reactive or polar but may not always make it more excretable. Phase II: Conjugates the modified compound with another substance to increase its solubility and facilitate its excretion. Flashcard 16 Q: Describe the key steps and enzymes involved in Phase I metabolism. A: 1. Substrate Binding: Oxidized P450 combines with a drug substrate. 2. Enzyme Activation: NADPH donates an electron to P450 Reductase to reduce the oxidized drug complex.  3. Modification Reaction: A second electron from NADPH introduces "activated oxygen" to the P450-substrate complex. 4. Formation of Metabolite: Activated oxygen is transferred to the drug substrate to form the oxidized product. Flashcard 1 Q: How is the P450 enzyme family named? A: The family name is indicated by a number that follows "CYP". A capital letter designates the subfamily, and a second number indicates the specific isozyme. For example, CYP3A4. Flashcard 2 Q: What does "CYP" stand for in the context of P450 enzymes? A: "CYP" stands for Cytochrome P450. Flashcard 3 Q: What does the number following "CYP" represent? A: The number represents the P450 enzyme family. Flashcard 4 Q: What does the capital letter following the number in the P450 enzyme name denote? A: The capital letter designates the subfamily of the enzyme. Flashcard 5 Q: What does the second number in the P450 enzyme name indicate? A: The second number indicates the specific isozyme within the subfamily. Flashcard 6 Q: What effect do P450 inducers have on CYP enzymes? A: P450 inducers usually cause an increase in the gene transcription of a CYP enzyme. Flashcard 7 Q: What are the consequences of increased drug metabolism due to P450 inducers? A: Decreased plasma drug concentrations Decreased drug activity if the metabolite is inactive Increased drug activity if the metabolite is active Decreased therapeutic drug effect Flashcard 8 Q: Can a drug influence its own metabolism through P450 enzyme induction? A: Yes, a drug can increase its own metabolism. Flashcard 9 Q: Can a drug affect the metabolism of other drugs through P450 enzyme induction? A: Yes, a drug can increase the metabolism of a co-administered drug. Flashcard 10 Q: What is the effect of P450 inhibitors on enzyme activity? A: P450 inhibitors can compete for the same isozyme, potentially leading to the drug being less active or inactive at all. Flashcard 11 Q: What can result from competition between P450 inhibitors for the same isozyme? A: Serious adverse events may occur due to altered drug metabolism.