Pharmacology: Drug Distribution and Metabolism
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Questions and Answers

What is primarily responsible for the non-uniform distribution of drugs in the body?

  • The method of drug administration
  • Physiological barriers present in the body (correct)
  • Variation in metabolic rates of different tissues
  • Environmental factors surrounding the tissue

    • Which of the following factors does NOT contribute to physiological barriers affecting drug distribution?

  • Increased blood flow in certain organs (correct)
  • Physical barriers such as membranes
  • Blood-brain barrier restricting entry of certain drugs
  • Lipid solubility of the drug

    • How do physiological barriers influence drug therapy effectiveness?

  • They require higher dosages for efficacy. (correct)
  • They create a uniform drug concentration throughout all tissues.
  • They enhance the therapeutic effects of all medications.
  • They primarily affect only oral medications.

    • In the context of drug distribution, what is a likely outcome of physiological barriers?

    <p>Selective accumulation of drugs in specific tissues</p> Signup and view all the answers

    Which statement best describes the impact of physiological barriers on drug pharmacokinetics?

    <p>They play a crucial role in determining the distribution of drugs within the body.</p> Signup and view all the answers

    What factor significantly increases the hepatic concentration of mepacrine compared to its plasma level?

    <p>Chronic administration</p> Signup and view all the answers

    Which tissue is noted for having a significantly higher concentration of iodine?

    <p>Thyroid tissue</p> Signup and view all the answers

    How does the concentration of mepacrine in the liver compare to its concentration in blood plasma?

    <p>More than 200 times plasma concentration</p> Signup and view all the answers

    What is a potential consequence of chronic administration of mepacrine?

    <p>Elevated hepatic concentration</p> Signup and view all the answers

    What similarity exists between mepacrine and iodine in terms of tissue concentration?

    <p>Both are highly concentrated in specific tissues</p> Signup and view all the answers

    Which barrier allows the passage of non-ionized drugs with a high lipid/water partition coefficient to the fetus?

    <p>Placental barrier</p> Signup and view all the answers

    Which of the following substances can easily cross the blood-brain barrier (BBB)?

    <p>Thiopental sodium</p> Signup and view all the answers

    What type of diffusion process is primarily involved with the placental barrier for applicable drugs?

    <p>Simple diffusion</p> Signup and view all the answers

    Which of the following statements is true regarding the blood-brain barrier and its permeability?

    <p>Only lipid-soluble drugs can cross the BBB.</p> Signup and view all the answers

    Which drug is mentioned as having difficulty crossing the blood-brain barrier?

    <p>Dopamine</p> Signup and view all the answers

    Which types of functional groups in drugs are likely to undergo sulfate conjugation?

    <p>Hydroxyl and carboxyl groups</p> Signup and view all the answers

    What is the primary enzyme responsible for transferring sulfate groups during sulfate conjugation?

    <p>Sulfotransferase</p> Signup and view all the answers

    In which organs is sulfotransferase notably present for drug metabolism?

    <p>Liver and intestinal mucosa</p> Signup and view all the answers

    Which of the following drugs is specified as undergoing sulfate conjugation?

    <p>Phenobarbitone</p> Signup and view all the answers

    What type of chemical modification does sulfate conjugation represent in drug metabolism?

    <p>Conjugation reaction</p> Signup and view all the answers

    Why are fetuses or neonates particularly vulnerable to the toxic effects of drugs?

    <p>Their liver and metabolizing enzymes are under-developed</p> Signup and view all the answers

    What is likely to happen to the drug metabolism in elderly individuals?

    <p>It deteriorates due to declining hepatic enzymes</p> Signup and view all the answers

    In general, how does male drug metabolism compare to that of females?

    <p>Males metabolize drugs faster than females</p> Signup and view all the answers

    Which condition can significantly impair drug metabolism?

    <p>Hepatitis or cardiac disease</p> Signup and view all the answers

    What genetic factor can influence drug metabolism rates in individuals?

    <p>Being a slow acetylator</p> Signup and view all the answers

    Increased protein binding results in enhanced clearance of a drug from the body.

    <p>False</p> Signup and view all the answers

    Clearance is defined as the volume of plasma cleared of the drug by metabolism and excretion per unit time.

    <p>True</p> Signup and view all the answers

    Protein binding does not affect drug excretion through the kidneys.

    <p>False</p> Signup and view all the answers

    The process of metabolism is solely responsible for drug clearance without any role of excretion.

    <p>False</p> Signup and view all the answers

    Reduced drug clearance can lead to an accumulation of the drug in the body.

    <p>True</p> Signup and view all the answers

    Acetyl conjugation involves the enzyme acetyl transferase, which is located in the kupffer cells of the brain.

    <p>False</p> Signup and view all the answers

    Glucuronyl transferase is classified as a non-microsomal enzyme.

    <p>False</p> Signup and view all the answers

    The process of acetylation requires acetic acid to be activated by CoA to form acetyl CoA.

    <p>True</p> Signup and view all the answers

    Phenols and catechols are examples of substances involved in the acetylation process.

    <p>True</p> Signup and view all the answers

    Cytochrome P450 is a type of hydroxylase enzyme.

    <p>True</p> Signup and view all the answers

    Acetyl transferase is primarily responsible for the process of sulfation in drug metabolism.

    <p>False</p> Signup and view all the answers

    Esterases and amidase are examples of microsomal enzymes found in the cytoplasm.

    <p>False</p> Signup and view all the answers

    Dehydrogenase enzymes are primarily found in the mitochondria of different organs.

    <p>True</p> Signup and view all the answers

    Acetyl CoA can serve as a substrate in various metabolic pathways beyond conjugation.

    <p>True</p> Signup and view all the answers

    Hydrolase is a type of enzyme that aids in the breakdown of compounds through hydrolysis.

    <p>True</p> Signup and view all the answers

    The concentration of a drug in specific tissues can remain high even when its plasma concentration is low.

    <p>True</p> Signup and view all the answers

    Both alcohol and morphine have the same affinity for all organs in the body.

    <p>False</p> Signup and view all the answers

    A drug can have significant tissue concentration without a corresponding increase in its amount in the plasma.

    <p>True</p> Signup and view all the answers

    Endogenous substrates are solely derived from the body's internal processes and not from the diet.

    <p>False</p> Signup and view all the answers

    Glucuronide conjugation is considered the least common conjugation reaction of drugs.

    <p>False</p> Signup and view all the answers

    The persistence of drug concentration in tissues is unrelated to the drug's dosage or administration frequency.

    <p>False</p> Signup and view all the answers

    Nutrition has no impact on the regulation of drug conjugation.

    <p>False</p> Signup and view all the answers

    A reduced plasma concentration of a drug indicates that it has likely completely exited the body.

    <p>False</p> Signup and view all the answers

    The regulation of drug conjugation is influenced by external factors like diet and nutrition.

    <p>True</p> Signup and view all the answers

    Glucuronide conjugation is the only conjugation reaction that is essential for drug metabolism.

    <p>False</p> Signup and view all the answers

    What are the primary reactions involved in Phase-II drug metabolism?

    <p>Glucuronidation, sulfate conjugation, acetylation, glycine conjugation, and methylation reactions.</p> Signup and view all the answers

    How does acetylation facilitate drug metabolism?

    <p>Acetylation modifies drugs by adding an acetyl group, which can alter their activity and increase solubility for excretion.</p> Signup and view all the answers

    Identify the enzyme primarily responsible for glucuronidation in drug metabolism.

    <p>Glucuronyl transferase is the primary enzyme responsible for glucuronidation.</p> Signup and view all the answers

    What is the significance of sulfate conjugation in drug metabolism?

    <p>Sulfate conjugation enhances the solubility and excretion of drugs, particularly those with hydroxyl or amine groups.</p> Signup and view all the answers

    Discuss the role of endogenous substrates in drug conjugation.

    <p>Endogenous substrates are compounds produced within the body that participate in drug conjugation processes.</p> Signup and view all the answers

    How does protein binding affect drug clearance in the body?

    <p>Increased protein binding can reduce drug clearance by limiting the amount of free drug available for metabolism and excretion.</p> Signup and view all the answers

    What is the function of Cytochrome P450 in drug metabolism?

    <p>Cytochrome P450 acts as a hydroxylase enzyme that facilitates the oxidation of various substrates in drug metabolism.</p> Signup and view all the answers

    What is the mechanism through which the placental barrier allows the transfer of drugs to the fetus?

    <p>The placental barrier allows non-ionized drugs with a high lipid/water partition coefficient to transfer by simple diffusion.</p> Signup and view all the answers

    How does the permeability of the blood-brain barrier (BBB) to thiopental sodium compare to that of dopamine?

    <p>Thiopental sodium easily crosses the BBB, while dopamine does not.</p> Signup and view all the answers

    What impact does diet have on drug conjugation processes?

    <p>Diet can influence the regulation of drug conjugation by affecting enzyme activity and substrate availability.</p> Signup and view all the answers

    Explain why fetuses or neonates are more susceptible to drug toxicity.

    <p>Fetuses and neonates have underdeveloped metabolic pathways, leading to reduced ability to metabolize and clear drugs.</p> Signup and view all the answers

    Why are non-ionized drugs able to cross the placental barrier more readily than ionized drugs?

    <p>Non-ionized drugs are more lipid-soluble, allowing them to diffuse through the placental barrier more effectively.</p> Signup and view all the answers

    What is meant by glucuronide conjugation being the least common drug conjugation reaction?

    <p>Glucuronide conjugation is less frequently utilized compared to other conjugation reactions, such as sulfate conjugation, in drug metabolism.</p> Signup and view all the answers

    What role does lipid solubility play in the ability of drugs to cross both the blood-brain barrier and the placental barrier?

    <p>Lipid solubility enhances a drug's ability to cross these barriers due to easier diffusion into lipid-rich environments.</p> Signup and view all the answers

    What implication does a drug's high lipid/water partition coefficient have on its pharmacological effects during pregnancy?

    <p>A high lipid/water partition coefficient implies that the drug can easily cross the placental barrier, potentially affecting fetal development.</p> Signup and view all the answers

    What is the role of cytochrome P450 enzymes in drug metabolism, and how much of the liver’s drug metabolism is attributed to Cyp3A4?

    <p>Cytochrome P450 enzymes are involved in the oxidation and reduction of drugs during metabolism. Cyp3A4 is responsible for over 60% of the clinically prescribed drugs metabolized by the liver.</p> Signup and view all the answers

    Describe the impact of enzyme inducers on drug metabolism with an example of an inducer.

    <p>Enzyme inducers stimulate hepatic drug metabolism, accelerating the metabolism of both themselves and other drugs. An example of an inducer is phenobarbital.</p> Signup and view all the answers

    What types of drugs undergo hydrolysis, and what is the product formed from pethidine through this process?

    <p>Drugs such as atropine and acetylcholine undergo hydrolysis. Pethidine undergoes hydrolysis to form pethidinic acid.</p> Signup and view all the answers

    How does the presence of cytochrome P450 enzymes differ among body tissues, and where are they commonly found?

    <p>Cytochrome P450 enzymes differ in expression levels among tissues; they are commonly found in the GI epithelium, lung, and kidney.</p> Signup and view all the answers

    What is the significance of drug hydrolysis and which two drugs, in addition to pethidine, are mentioned as undergoing this process?

    <p>Drug hydrolysis is significant for drug activation or inactivation; atropine and acetylcholine are also mentioned as drugs undergoing hydrolysis.</p> Signup and view all the answers

    What role does acetyl transferase play in drug metabolism, particularly in the liver?

    <p>Acetyl transferase catalyzes the acetylation of drugs in the liver's kupffer cells, facilitating their metabolism and excretion.</p> Signup and view all the answers

    Explain the process by which acetic acid is involved in drug acetylation.

    <p>Acetic acid is activated by CoA to form acetyl CoA, which then conjugates with drugs during the acetylation process.</p> Signup and view all the answers

    Describe the significance of phenols and catechols in the context of acetylation.

    <p>Phenols and catechols serve as substrates that undergo acetylation, impacting their pharmacokinetic properties.</p> Signup and view all the answers

    How does the presence of acetyl CoA influence various metabolic pathways beyond conjugation?

    <p>Acetyl CoA acts as a key substrate in several metabolic pathways, including energy production and fatty acid synthesis.</p> Signup and view all the answers

    What factors influence the regulation of drug conjugation processes such as acetylation?

    <p>Factors such as diet, nutrition, and external environmental influences regulate drug conjugation processes like acetylation.</p> Signup and view all the answers

    The hepatic concentration of mepacrine is more than 200 times that of ______.

    <p>plasma level</p> Signup and view all the answers

    High concentrations of drugs may occur with ______ administration.

    <p>chronic</p> Signup and view all the answers

    Iodine is concentrated in the ______ tissue.

    <p>thyroid</p> Signup and view all the answers

    Mepacrine's concentration in the liver may reach a very high ______.

    <p>level</p> Signup and view all the answers

    In biotransformation, reactions are classified into phase-I and phase-______ reactions.

    <p>II</p> Signup and view all the answers

    The phase-I reaction converts the drug to a more ______ metabolite.

    <p>polar</p> Signup and view all the answers

    Mepacrine's concentration in the liver is significantly higher than in ______.

    <p>blood plasma</p> Signup and view all the answers

    Phase-II reactions involve the process of ______ to enhance the excretion of drugs.

    <p>conjugation</p> Signup and view all the answers

    The enzyme ______ is involved in acetyl conjugation, which is significant in drug metabolism.

    <p>acetyl transferase</p> Signup and view all the answers

    The conversion of a drug in phase-I to a polar metabolite often makes it more suitable for ______.

    <p>excretion</p> Signup and view all the answers

    The conversion of salicylic acid into ______ acid involves specific enzyme activity.

    <p>gentisic</p> Signup and view all the answers

    The enzyme ______ catalyzes the reduction of azo and nitro compounds.

    <p>reductase</p> Signup and view all the answers

    An example of a compound that undergoes reduction to form sulfonamide is ______.

    <p>prontosil</p> Signup and view all the answers

    Reduction reactions involve the conversion of compounds, such as azos and ______ compounds.

    <p>nitro</p> Signup and view all the answers

    Drug metabolism by hydrolysis is restricted to esters and ______.

    <p>amines</p> Signup and view all the answers

    The transformation from prontosil to sulfonamide is facilitated by the enzyme ______.

    <p>reductase</p> Signup and view all the answers

    The process of hydrolysis involves the splitting of a drug molecule after adding ______.

    <p>water</p> Signup and view all the answers

    Esterases and amidases are examples of enzymes found in ______.

    <p>plasma</p> Signup and view all the answers

    Hydrolysis can occur in tissues like the ______.

    <p>liver</p> Signup and view all the answers

    Hydrolysis is part of the broader category of ______ encountered in drug metabolism.

    <p>drug metabolism</p> Signup and view all the answers

    Fetuses or neonates have under-developed ______ which makes them vulnerable to toxic drug effects.

    <p>livers</p> Signup and view all the answers

    As individuals age, their hepatic ______ and other organs deteriorate, affecting drug metabolism.

    <p>enzymes</p> Signup and view all the answers

    Genetic differences such as being a slow ______ can impact drug metabolism rates.

    <p>acetylator</p> Signup and view all the answers

    Diseases such as ______ can negatively affect drug metabolism by altering blood flow to the liver.

    <p>hepatitis</p> Signup and view all the answers

    Generally, ______ metabolize drugs faster than women, which is evident with substances like alcohol.

    <p>men</p> Signup and view all the answers

    Match the following drug metabolism processes with their characteristics:

    <p>Sulfation = Involves sulfotransferase enzymes Acetylation = Requires acetic acid to form acetyl CoA Glucuronidation = Considered essential for drug metabolism Hydrolysis = Breaks down compounds through the addition of water</p> Signup and view all the answers

    Match the following factors influencing drug concentration with their descriptions:

    <p>Protein binding = Enhances clearance of a drug from the body Tissue concentration = Can remain high even with low plasma levels Endogenous substrates = Derived from the body's internal processes Reduced clearance = Leads to drug accumulation in the body</p> Signup and view all the answers

    Match the following terms with their relevant processes:

    <p>Cytochrome P450 = Type of hydroxylase enzyme Acetyl transferase = Responsible for the process of acetylation Dehydrogenase = Found primarily in the mitochondria Esterases = Examples of microsomal enzymes in cytoplasm</p> Signup and view all the answers

    Match the following statements with their implications:

    <p>Increased protein binding = Does not affect drug excretion via kidneys Chronic drug administration = May lead to concentration persistence in tissues Elderly drug metabolism = May experience reduced metabolic rates Drug metabolism factors = Can be influenced by genetic variations</p> Signup and view all the answers

    Match the following drug conjugation reactions with their characteristics:

    <p>Glucuronide conjugation = Considered the least common conjugation reaction Sulfate conjugation = Involves the transfer of sulfate groups Acetyl conjugation = Utilizes acetyl CoA as a substrate Conjugation regulation = Influenced by diet and nutrition</p> Signup and view all the answers

    Match the following types of drug conjugation with their primary characteristics:

    <p>Sulfate conjugation = Involves transfer of sulfate groups Acetylation = Requires acetic acid activation Glucuronidation = Facilitates drug excretion through glucuronides Methylation = Adds a methyl group to a drug compound</p> Signup and view all the answers

    Match the following enzymes with their primary location or function in drug metabolism:

    <p>Cytochrome P450 = Microsomal enzyme mainly for hydroxylation Acetyl transferase = Located in the liver's kupffer cells Dehydrogenase = Primarily found in the mitochondria Hydrolase = Breaks down compounds through hydrolysis</p> Signup and view all the answers

    Match the following statements about drug pharmacokinetics with their implications:

    <p>Increased protein binding = Enhances drug clearance from the body Reduced drug clearance = Can lead to drug accumulation High tissue concentration despite low plasma concentration = Indicates potential toxicity Solely metabolic drug clearance = Ignores renal excretion's role</p> Signup and view all the answers

    Match the following factors influencing drug metabolism with their effects:

    <p>Genetic factors = Influence individual metabolism rates Gender differences = Affect rates between males and females Age = Increased vulnerability in the elderly Nutritional status = Can regulate drug conjugation processes</p> Signup and view all the answers

    Match the following statements regarding drug distribution with the correct barrier or outcome:

    <p>Blood-brain barrier = Restricts many drugs from entering the brain Placental barrier = Allows non-ionized drugs with high lipid solubility Tissue concentration prevalence = Drugs may accumulate despite low plasma levels Physiological barriers = Impact the efficacy of drug therapies</p> Signup and view all the answers

    Match the following drugs with their protein binding characteristics and action duration:

    <p>Phenylbutazone = High protein binding - long acting Thiopental sodium = Low protein binding - short acting Mepacrine = High hepatic concentration - variable action Acetyl CoA = Active substrate in multiple metabolic pathways</p> Signup and view all the answers

    Match the following enzymes with their respective descriptions in drug metabolism:

    <p>Acetyl transferase = Responsible for acetylation process Glucuronyl transferase = Non-microsomal enzyme involved in conjugation Cytochrome P450 = Type of hydroxylase enzyme for drug metabolism Dehydrogenase = Primarily found in mitochondria of organs</p> Signup and view all the answers

    Match the following statements about drug clearance and metabolism:

    <p>Reduced drug clearance = Can lead to accumulation in the body Sole role of metabolism = Incorrect; excretion also plays a role Increased protein binding = Results in decreased clearance Drug concentration in tissues = Can remain high despite low plasma levels</p> Signup and view all the answers

    Match the following conjugation reactions with their characteristics:

    <p>Sulfation = Involves acetyl transferase Acetylation = Requires acetic acid activated by CoA Glucuronide conjugation = Considered least common reaction Hydrolysis = Aided by hydrolase enzyme</p> Signup and view all the answers

    Match the following statements regarding drug interactions and effects:

    <p>Endogenous substrates = Derived solely from internal processes Persistent tissue concentration = Unrelated to dosage or frequency Nutrition's impact = Regulates drug conjugation processes Affinity of alcohol and morphine = Varies among different organs</p> Signup and view all the answers

    Match the following drug metabolism processes with their respective characteristics:

    <p>First pass metabolism = Metabolism occurring as drugs cross the intestine or liver Microsomal enzymes = Enzymes present in the smooth endoplasmic reticulum of liver, kidney, and GIT Sulfate conjugation = Involves transfer of sulfate groups for drug modification Hydrolysis = Breakdown of compounds through the addition of water</p> Signup and view all the answers

    Match the following types of enzymes with their roles in drug metabolism:

    <p>Cytochrome P450 = A type of hydroxylase enzyme Acetyl transferase = Enzyme involved in acetyl conjugation Dehydrogenase = Enzymes primarily found in mitochondria Hydrolase = Enzyme that aids in the breakdown through hydrolysis</p> Signup and view all the answers

    Match the following drugs with their specific metabolic challenges:

    <p>Nitroglycerin = Undergoes first pass metabolism Penicillin = May be destroyed before absorption Mepacrine = Has a significantly higher hepatic concentration compared to plasma Iodine = Has a higher concentration in specific tissues</p> Signup and view all the answers

    Match the following statements regarding drug clearance with their implications:

    <p>Increased protein binding = Leads to reduced drug clearance Reduced drug clearance = Can cause drug accumulation in the body Solely metabolism = Not responsible for drug excretion Plasma concentration drop = Indicates the drug has likely exited the body</p> Signup and view all the answers

    Match the following conditions with their effects on drug metabolism:

    <p>Elderly individuals = Likely experience altered drug metabolism Genetic factors = Influence individual metabolism rates Nutrition = Affects drug conjugation regulation Endogenous substrates = Solely derived from internal body processes</p> Signup and view all the answers

    Match the following patient populations with their characteristics regarding drug metabolism:

    <p>Fetus or neonate = Under-developed liver and metabolizing enzymes Elderly = Deterioration of hepatic enzymes over time Men = Generally metabolize drugs faster than women Individuals with genetic differences = Examples include slow acetylators</p> Signup and view all the answers

    Match the following effects of drug metabolism with their corresponding patient characteristics:

    <p>Fetus or neonate = Increased vulnerability to toxic drug effects Elderly = Altered metabolism due to organ deterioration Diseased individuals = Impaired metabolism from conditions like hepatitis Slow acetylators = Genetically reduced drug metabolism rates</p> Signup and view all the answers

    Match the conditions affecting drug metabolism with their implications:

    <p>Hyperbilirubinemia = Can lead to encephalopathy in newborns Under-developed kidneys in neonates = Can cause jaundice due to altered excretion Deteriorating liver function in elderly = Results in decreased drug clearance Hepatitis = A disease that can impair drug metabolism</p> Signup and view all the answers

    Match the following factors with their influence on drug metabolism:

    <p>Blood brain barrier in neonates = Poorly developed leading to increased toxicity risk Genetic differences in populations = Affect rate of drug acetylation Cardiac disease = Decreased blood flow affecting liver drug metabolism Men vs women = Different metabolic rates particularly for alcohol</p> Signup and view all the answers

    Match the following statements about drug metabolism with their corresponding attributes:

    <p>Slow acetylators = Mostly found in Europeans and some black and white populations in the US First pass metabolism = Significantly affects the liver's ability to process drugs Developmental stage influences = Fetuses are particularly vulnerable to drug toxicity Gender differences = Men typically have faster drug metabolism than women</p> Signup and view all the answers

    Study Notes

    Physiological Barriers to Drug Distribution

    • Blood-Brain Barrier (BBB) prevents certain drugs from entering the central nervous system; thiopental sodium can cross, whereas dopamine cannot.
    • Placental Barrier allows non-ionized, lipid-soluble drugs to diffuse to the fetus; e.g., mepacrine's hepatic concentration can exceed plasma levels by over 200 times with chronic use.
    • Iodine concentrations in the thyroid tissue highlight selective distribution; drugs with hydroxyl, amino, or carboxyl groups (e.g., phenobarbitone) can also utilize this diffusion process.
    • Sulfate conjugation aids in drug metabolism; sulfotransferases in the liver, intestinal mucosa, and kidneys transfer sulfate groups to drug molecules.

    Variations in Drug Metabolism

    • Fetal and Neonatal Biotransformation:

      • Underdeveloped liver and enzymes increase vulnerability to drug toxicity.
      • Poorly developed blood-brain barrier increases risk for adverse effects, such as hyperbilirubinemia leading to encephalopathy.
      • Immature kidneys may impair drug excretion, resulting in jaundice.

    • Elderly Biotransformation:

      • Deterioration of hepatic enzymes and organ function with age can slow drug metabolism.

    • Sex Differences:

      • Generally, men metabolize substances like alcohol faster than women.

    • Disease Impact:

      • Certain diseases can alter drug metabolism; for example, hepatitis can impair liver function, while cardiac conditions can reduce liver blood flow.

    • Genetic Variations:

      • Genetic differences influence metabolism rates, such as the presence of slow acetylators; an autosomal recessive trait more common in individuals from Northern Europe and approximately 50% of African American and European American populations in the U.S.

    Clearance and Drug Excretion

    • Clearance refers to the volume of plasma cleared of a drug through metabolism and excretion per unit time.
    • Protein binding of drugs decreases the amount available for glomerular filtration, thus reducing drug clearance and delaying excretion.

    Drug Affinity and Tissue Concentration

    • Certain drugs, such as alcohol and morphine, may have a strong affinity for specific organs, resulting in prolonged tissue concentration even when plasma levels decline.

    Metabolism Enzymes

    • Major metabolic enzymes include glucuronyl transferase, dehydrogenase, hydroxylase, and cytochrome P450.
    • Non-microsomal enzymes are found in the cytoplasm and mitochondria of organs; examples include esterases, amidase, and hydrolase.

    Nutrition's Role in Drug Metabolism

    • Endogenous substrates for drug conjugation derive from dietary sources, highlighting the importance of nutrition in regulating drug metabolism.

    Conjugation Reactions

    • Glucuronide conjugation is the most prevalent and significant conjugation process for drugs, particularly involving phenols and catechols.
    • Acetylation involves the enzyme acetyl transferase, predominantly located in Kupffer cells of the liver, where acetic acid is conjugated to drugs via acetyl CoA activation.

    Drug Distribution Barriers

    • Blood-brain barrier (BBB) allows easy passage for thiopental sodium but does not permit dopamine.
    • Placental barrier permits non-ionized drugs with high lipid/water partition coefficients to diffuse to the fetus.

    Phase I Reactions

    • Oxidation involves the introduction of oxygen or removal of hydrogen atoms, including hydroxylation, dealkylation, or demethylation.
    • Example: Pethidine undergoes hydrolysis to form pethidinic acid; similar hydrolysis occurs with atropine and acetylcholine.
    • Cytochrome P450 is a family of isoenzymes critical for drug oxidation and reduction.

    Cytochrome P450 Enzymes

    • Found in gastrointestinal epithelium, lungs, and kidneys.
    • Cyp3A4 accounts for over 60% of drugs metabolized by the liver.

    Enzyme Induction

    • Certain drugs stimulate hepatic drug metabolism, known as enzyme induction.
    • Inducers accelerate their own metabolism and that of other drugs.
    • Examples of enzyme inducers include phenobarbital, rifampin, phenytoin, carbamazepine, griseofulvin, and compounds found in cigarette smoke.

    Acetyl Conjugation

    • Acetyl transferase enzyme, crucial for acetylation, is present in the liver's Kupffer cells.
    • Acetic acid is activated by CoA to form acetyl CoA, which conjugates to various drugs.

    Hepatic Concentration and Biotransformation

    • Mepacrine concentration in the liver exceeds plasma levels by over 200 times, indicating significant hepatic uptake.
    • Chronic administration can lead to very high concentrations of certain drugs in the liver, similar to iodine accumulation in thyroid tissue.

    Types of Biotransformation

    • Phase-I Reactions: Involve the conversion of drugs into more polar metabolites, enhancing solubility.
      • Example: Salicylic acid is metabolized to gentisic acid.
    • Reduction Reactions: Catalyzed by the enzyme reductase; involves modifications like the reduction of azo and nitro compounds.
      • Example: Prontosil is reduced to sulfonamide.
    • Hydrolysis: Metabolism process for esters and amines, facilitated by esterases and amidases found in plasma and liver.
      • Process involves adding water to split drug molecules.

    Variations in Drug Metabolism

    • Fetal and Neonatal Biotransformation:

      • Vulnerable to drug toxicity due to under-developed liver and metabolizing enzymes.
      • Poorly developed blood-brain barrier increases vulnerability to drug effects, potentially leading to hyperbilirubinemia and encephalopathy.
      • Immature kidneys may alter drug excretion and contribute to jaundice.

    • Elderly Biotransformation:

      • Age-related deterioration of hepatic enzymes and organ function can affect drug metabolism.

    • Gender Differences:

      • Metabolic rates vary, with men typically metabolizing substances like alcohol more rapidly than women.

    • Disease Impact:

      • Certain health conditions can impair drug metabolism; examples include hepatitis and cardiac issues leading to reduced liver blood flow.

    • Genetic Differences:

      • Variations such as slow acetylators, an autosomal recessive trait, are predominantly seen in populations from northern latitudes and among certain racial groups in the U.S.

    Drug Distribution and Binding

    • Active concentration is the fraction of a drug that is unbound, crucial for diffusion from plasma to the site of action.
    • High protein-binding drugs, such as phenylbutazone, exhibit prolonged action due to reduced diffusion.
    • Drugs with low protein binding, like thiopental sodium, have a shorter duration of action.

    Drug Metabolism (Biotransformation)

    • Drug metabolism refers to bodily changes in drug molecules, crucial for eliminating drugs from the body.
    • First-pass metabolism occurs as drugs cross the intestines or are processed by the liver, affecting drug efficacy (e.g., nitroglycerin).
    • Some drugs can be inactivated before absorption (e.g., penicillin).
    • Enzymes responsible for drug metabolism include microsomal enzymes located in the smooth endoplasmic reticulum of the liver, kidney, and gastrointestinal tract.

    Variations in Drug Metabolism

    • Fetuses and Neonates:

      • Vulnerable to drug toxicity due to underdeveloped liver and metabolic enzymes.
      • Poorly developed blood-brain barrier increases susceptibility to adverse effects.
      • Risks of hyperbilirubinemia leading to encephalopathy.
      • Immature kidneys affect drug excretion and contribute to jaundice.

    • Elderly:

      • Decline in hepatic enzymes and organ function reduces drug metabolism efficiency.

    • Gender Differences:

      • Men tend to metabolize drugs faster than women (example: alcohol).

    • Diseases Impacting Metabolism:

      • Conditions such as hepatitis or cardiac issues can reduce blood flow to the liver, impairing drug metabolism.
      • Pulmonary diseases can also affect the efficiency of drug processing.

    • Genetic Factors:

      • Genetic variations can lead to differences in metabolism rates, such as slow acetylators, primarily seen in individuals from high northern latitudes and among 50% of black and white populations in the US.

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    This quiz explores physiological barriers to drug distribution, including the Blood-Brain Barrier and the Placental Barrier. It also covers variations in drug metabolism, particularly in fetal and neonatal biotransformation. Test your understanding of how these factors influence drug therapy and safety.

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