Drug metabolism involves the conversion of drugs from one chemical form to another through enzymatic processes. [1] Metabolism renders lipid-soluble compounds more water-soluble so they can be excreted from the body. [2] The major site of drug metabolism is the liver through enzyme systems like cytochrome P450. [3] Metabolism can inactivate drugs, activate prodrugs, or change a drug's pharmacological effects.
1. Metabolism, or biotransformation, is the process by which enzymes convert lipid-soluble compounds into water-soluble compounds so they can be excreted from the body.
2. The major site of drug metabolism is the liver, through phase I (functionalization) and phase II (conjugation) reactions. Phase I reactions involve oxidation, reduction, and hydrolysis, while phase II reactions conjugate compounds to make them more hydrophilic through glucuronidation, methylation, sulfation, and other processes.
3. Cytochrome P450 enzymes and UDP-glucuronyl transferases are among the most important enzyme families involved in drug metabolism. Metabolism can
Drug metabolism involves two main phases: Phase I involves reactions like oxidation, reduction and hydrolysis that make the drug more polar. This is mainly done by cytochrome P450 enzymes in the liver. Phase II involves conjugating reactions like glucuronidation, sulfation and acetylation to make the drug more water soluble for excretion. Cytochrome P450 isoenzymes like CYP3A4 metabolize many drugs. Understanding drug metabolism is important in drug discovery and development.
Metabolic Changes of Drugs and Related Organic Compounds describes the human metabolic processes of various functional groups found in therapeutic agents.
The importance of a chapter on metabolism lies in the fact that drug interactions are based on these processes.
For pharmacists, it is necessary for them to understand why certain drugs are contraindicated with other drugs.
This chapter attempts to describe the various phases of drug metabolism, the sites where these biotransformation will occur, the role of specific enzymes, metabolism of specific functional groups, and several examples of the metabolism of currently used therapeutic agents.
The document discusses various Phase II biotransformation reactions. It describes conjugation reactions like conjugation with glucuronic acid, sulphate moieties, alpha amino acids, and glutathione. Conjugation with glucuronic acid is the most common reaction where glucuronic acid is attached to form glucuronides. Conjugation with sulphate occurs less frequently. Amino acid conjugation forms amide bonds between carboxylic acids and amino acids like glycine. These conjugation reactions make compounds more polar and water soluble for excretion.
This document summarizes factors that affect drug metabolism. It discusses how drug metabolism occurs primarily in the liver through enzymatic and non-enzymatic processes. The key metabolic enzymes are microsomal and nonmicrosomal enzymes. Metabolism can inactivate drugs, produce active metabolites, or activate prodrugs. Factors that influence metabolism include chemical factors like enzyme induction/inhibition, biological factors like age, sex, diet; and physicochemical properties of drugs. Specifically, it notes how induction increases and inhibition decreases metabolic rates, and how rates vary between species, strains, ages and sexes.
Cytochrome P450 enzymes (CYP450) play an important role in metabolizing drugs and other xenobiotic substances. There are many CYP450 isoenzymes, with CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4 being the most clinically significant in humans. These isoenzymes metabolize many psychiatric drugs and can be induced or inhibited by other drugs, foods, or substances, leading to potential drug-drug interactions. Careful consideration of a patient's complete medication regimen and lifestyle factors is important when prescribing drugs metabolized by CYP450 enzymes.
1. Metabolism, or biotransformation, is the process by which enzymes convert lipid-soluble compounds into water-soluble compounds so they can be excreted from the body.
2. The major site of drug metabolism is the liver, through phase I (functionalization) and phase II (conjugation) reactions. Phase I reactions involve oxidation, reduction, and hydrolysis, while phase II reactions conjugate compounds to make them more hydrophilic through glucuronidation, methylation, sulfation, and other processes.
3. Cytochrome P450 enzymes and UDP-glucuronyl transferases are among the most important enzyme families involved in drug metabolism. Metabolism can
Drug metabolism involves two main phases: Phase I involves reactions like oxidation, reduction and hydrolysis that make the drug more polar. This is mainly done by cytochrome P450 enzymes in the liver. Phase II involves conjugating reactions like glucuronidation, sulfation and acetylation to make the drug more water soluble for excretion. Cytochrome P450 isoenzymes like CYP3A4 metabolize many drugs. Understanding drug metabolism is important in drug discovery and development.
Metabolic Changes of Drugs and Related Organic Compounds describes the human metabolic processes of various functional groups found in therapeutic agents.
The importance of a chapter on metabolism lies in the fact that drug interactions are based on these processes.
For pharmacists, it is necessary for them to understand why certain drugs are contraindicated with other drugs.
This chapter attempts to describe the various phases of drug metabolism, the sites where these biotransformation will occur, the role of specific enzymes, metabolism of specific functional groups, and several examples of the metabolism of currently used therapeutic agents.
The document discusses various Phase II biotransformation reactions. It describes conjugation reactions like conjugation with glucuronic acid, sulphate moieties, alpha amino acids, and glutathione. Conjugation with glucuronic acid is the most common reaction where glucuronic acid is attached to form glucuronides. Conjugation with sulphate occurs less frequently. Amino acid conjugation forms amide bonds between carboxylic acids and amino acids like glycine. These conjugation reactions make compounds more polar and water soluble for excretion.
This document summarizes factors that affect drug metabolism. It discusses how drug metabolism occurs primarily in the liver through enzymatic and non-enzymatic processes. The key metabolic enzymes are microsomal and nonmicrosomal enzymes. Metabolism can inactivate drugs, produce active metabolites, or activate prodrugs. Factors that influence metabolism include chemical factors like enzyme induction/inhibition, biological factors like age, sex, diet; and physicochemical properties of drugs. Specifically, it notes how induction increases and inhibition decreases metabolic rates, and how rates vary between species, strains, ages and sexes.
Cytochrome P450 enzymes (CYP450) play an important role in metabolizing drugs and other xenobiotic substances. There are many CYP450 isoenzymes, with CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4 being the most clinically significant in humans. These isoenzymes metabolize many psychiatric drugs and can be induced or inhibited by other drugs, foods, or substances, leading to potential drug-drug interactions. Careful consideration of a patient's complete medication regimen and lifestyle factors is important when prescribing drugs metabolized by CYP450 enzymes.
Biotransformation involves the chemical alteration of drugs in the body through phase 1 and phase 2 reactions. Phase 1 reactions like oxidation, reduction and hydrolysis activate or expose functional groups on drugs. Phase 2 reactions like conjugation make drugs more polar and excretable. The liver is the primary site of biotransformation through cytochrome P450 enzymes and UDP-glucuronyltransferases. First pass metabolism can decrease oral bioavailability. Drug interactions can occur through enzyme induction, increasing metabolism of other drugs, or enzyme inhibition, decreasing metabolism of other drugs.
1. Drug metabolism involves enzymatic modification of drugs by the body with the goal of making them more water soluble and easier to excrete.
2. Metabolism can occur in many tissues like the liver, kidneys, lungs, and intestines and is primarily carried out by the cytochrome P450 enzyme system.
3. Metabolism can result in inactive, active, or more active drug metabolites and influences the drug's pharmacokinetic and pharmacodynamic properties. Certain drugs are able to induce or inhibit the cytochrome P450 enzyme system, altering metabolism of other drugs metabolized by the same enzymes.
This document discusses the different types of receptors:
1) Ligand-gated ion channels directly open ion channels in response to neurotransmitters.
2) G-protein coupled receptors activate intracellular second messenger systems through G-proteins.
3) Kinase-linked receptors activate intracellular protein kinases.
4) Nuclear receptors regulate gene transcription by binding to DNA response elements as dimers.
Factors affecting biotransformation of drugsZubia Arshad
The biotransformation of drugs can be affected by various chemical, biological, physiological, temporal, and environmental factors. Chemical factors include enzyme induction and inhibition, which can increase or decrease the metabolism of drugs. Biological factors like age, gender, genetics, diet, and disease states can impact drug metabolism rates. Physiological changes during pregnancy, with hormonal imbalances, or disease states can also alter drug biotransformation. Additional influencing factors are temporal variations, the route of drug administration, and environmental exposures. Careful consideration of all these potential factors is important for safe and effective drug therapy.
This document discusses drug excretion pathways and mechanisms. It states that excretion involves the irreversible transfer of drugs and metabolites from the internal to external environment through renal and non-renal routes. The principal organs of excretion are the kidneys, bile, lungs, saliva, milk, and sweat. The kidneys are the primary route of excretion, utilizing glomerular filtration, tubular secretion, and reabsorption to eliminate compounds under 500 Da. Bile actively secretes hydrophilic drugs and metabolites over 500 Da, while the lungs passively diffuse gases and volatile substances.
The document discusses drug excretion from the body through various routes. It describes the principal organs involved in excretion as the kidneys, lungs, biliary system, intestines, saliva, and milk. Renal excretion through the kidneys is the primary route for water soluble drugs and involves glomerular filtration, tubular secretion, and tubular reabsorption. Other routes include biliary excretion into the feces, pulmonary excretion of volatile substances through the lungs, and excretion into saliva, sweat, and breast milk in small amounts for some drugs. Factors like a drug's molecular size, charge, lipid solubility, and degree of protein binding determine which excretion pathways it undergoes.
University Institute of Pharmaceutical Sciences is a flag bearer of excellence in Pharmaceutical education and research in the country. Here is another initiative to make study material available to everyone worldwide. Based on the new PCI guidelines and syllabus here we have a presentation dealing with pharmacokinetics : concept of linear and non-linear compartment models.
Thank you for reading.
Hope it was of help to you.
UIPS,PU team
Drug distribution involves the reversible transfer of drugs between compartments like blood and tissues. Several factors affect how drugs are distributed, including tissue permeability, organ size and blood flow, and binding to tissue components. Drugs with certain physicochemical properties like small molecular size and appropriate lipophilicity more easily pass through barriers and cell membranes into tissues. Additionally, tissues with greater blood flow and perfusion rates allow for faster drug distribution. Finally, the extent to which drugs bind to proteins and other components in blood and tissues impacts their distribution.
This document provides an overview of pharmacokinetics, which is the quantitative study of how the body acts on drugs. It describes the four main components of pharmacokinetics - absorption, distribution, metabolism, and excretion. Absorption refers to how drugs enter the bloodstream, distribution is how drugs spread to tissues, metabolism is how drugs are chemically altered, and excretion is how drugs and their metabolites leave the body. Key factors that determine a drug's pharmacokinetic properties and how it behaves in the body are also discussed.
The phenomenon of complex formation of drug with protein is called as Protein drug binding. The proteins are particularly responsible for such an interaction. A drug can interact with several tissue components.
Expt. 1 Introduction to in vitro pharmacology and physiological salt solutionsVISHALJADHAV100
This document provides an overview of in-vitro pharmacology experiments using isolated tissues and physiological salt solutions (PSS). It defines pharmacology and drugs, describes the aims of experimental pharmacology as finding therapeutic agents, studying toxicity and mechanisms of action. It also discusses types of experiments, equipment like organ baths and levers for recording tissue responses, and PSS compositions and roles. PSS are artificial solutions that maintain isolated tissues by resembling extracellular fluid composition. Selection of the appropriate PSS depends on the tissue being studied.
The document discusses biotransformation, which is the chemical alteration of drugs in the body. The body treats drugs as foreign substances and converts them into more polar, water soluble compounds through biotransformation so they can be excreted through the kidneys. Biotransformation occurs primarily in the liver and involves two phases - phase I reactions change the drug through processes like oxidation and phase II involves conjugating the drug to make it inactive so it can be excreted. Factors like other drugs, food, and an individual's characteristics can impact the biotransformation of drugs through inhibition or induction of the enzymes involved.
This document discusses drug elimination, which involves biotransformation (metabolism) and excretion of drugs from the body. It describes zero-order and first-order elimination kinetics, drug metabolism pathways including phase I and II reactions, and factors that influence renal excretion of drugs such as physicochemical properties and plasma concentration. Renal clearance is defined as the volume of plasma cleared of drug per unit time by the kidneys. Non-renal routes of excretion include biliary, pulmonary, dermal and gastrointestinal excretion.
This document discusses biotransformation, or the metabolism, of drugs in the body. It defines biotransformation as the chemical conversion of drugs from one form to another. The major organs involved in drug metabolism are the liver, lungs, kidneys, intestine, and placenta. The enzymes responsible for drug metabolism are divided into microsomal and non-microsomal enzymes. Drug metabolism occurs in two phases - phase I involves processes like oxidation and hydrolysis, while phase II involves conjugation reactions like glucuronidation and sulfation. Factors like the drug's physicochemical properties, genetic factors, age, and diet can influence a drug's metabolism in the body.
The cytochrome P450 system (CYP) is a large family of heme-containing enzymes that catalyze the oxidation of organic substances, including drugs and toxins. CYP enzymes are primarily located in the liver and intestine and are responsible for metabolizing approximately 75% of clinically used drugs. Variability in CYP gene expression between individuals can significantly impact drug metabolism and response. Drug interactions occur when one drug inhibits or induces the activity of a CYP enzyme, altering the metabolism of other drugs that are CYP substrates and potentially causing toxic effects. Careful consideration of a patient's complete medication regimen is important to avoid dangerous drug-drug interactions mediated by the CYP system.
This document discusses drug metabolism and phase I reactions. It defines drug metabolism as enzymatic chemical reactions that convert drugs into metabolites within the body. Drug metabolism is divided into two phases: phase I and phase II reactions. Phase I reactions introduce or expose functional groups through oxidation, reduction, and hydrolysis, making the drug more polar and susceptible to phase II reactions. Some examples of phase I reactions discussed are aromatic hydroxylation, oxidation of olefins, benzylic carbons, carbon atoms next to carbonyl groups, and aliphatic carbons. Reduction and hydrolytic reactions during phase I are also summarized.
Bioassays are quantitative procedures that use a living system's functional response to assess the concentration or potency of physical, chemical, or biological agents. They compare the magnitude of response of an unknown preparation to a standard under standard conditions. Bioassays are useful for identifying compounds, quantifying screening procedures, and producing drugs like antibiotics. They must be reliable, sensitive, reproducible, and minimize errors from biological variation and methodology. Common sources of error include animal-to-animal biological variation and faulty methodology or experimental errors.
This document discusses bioavailability and methods for assessing it. Bioavailability refers to the rate and extent that an unchanged drug is absorbed and available at its site of action. It depends on pharmaceutical, patient, and route of administration factors. Methods for assessing bioavailability include plasma drug concentration-time profiles, urinary excretion studies, acute pharmacological response methods, and therapeutic response methods. The concept of equivalence is also introduced, which examines the relationship between different drug products.
The document discusses prodrugs, which are pharmacologically inactive derivatives of active drugs designed to improve drug properties like solubility, absorption, and site-specific delivery. It covers basic prodrug concepts and classifications like carrier-linked prodrugs and bioprecursors. Approaches for prodrug design include using carriers, linkers, and multi-drug systems. Applications of prodrugs include improving patient acceptability by modifying taste, odor or irritation, enhancing solubility and dissolution for better absorption, and enabling site-specific or sustained drug delivery. The document provides examples of prodrug linkages and enzymes involved in their hydrolysis.
Circadian rhythms are biological processes that display an approximately 24-hour cycle. The document discusses the history and types of biological rhythms, focusing on circadian rhythms which are regulated by the suprachiasmatic nucleus in the brain. It describes how circadian rhythms influence many physiological functions and the absorption, distribution, metabolism, and elimination of drugs. Timed or chronotherapy aims to deliver drugs at times that synchronize with the body's natural rhythms to maximize efficacy and minimize side effects.
The document discusses the key aspects of pharmacokinetics including absorption, distribution, metabolism, and excretion of drugs in the body. It describes how drugs are absorbed via mechanisms like passive diffusion, active transport, and endocytosis. Factors like molecular weight, concentration gradients, and membrane permeability influence absorption rates. Most drug absorption occurs in the small intestine. Distribution of drugs depends on blood flow, ability to cross membranes, and plasma protein binding. The liver plays a major role in drug metabolism through phase I and phase II reactions, converting lipophilic drugs into more polar and water-soluble compounds that can be excreted.
Pharmacokinetics - drug absorption, drug distribution, drug metabolism, drug ...http://neigrihms.gov.in/
A power point presentation on general aspects of Pharmacokinetics suitable for undergraduate medical students beginning to study Pharmacology. Also suitable for Post Graduate students of Pharmacology and Pharmaceutical Sciences.
Biotransformation involves the chemical alteration of drugs in the body through phase 1 and phase 2 reactions. Phase 1 reactions like oxidation, reduction and hydrolysis activate or expose functional groups on drugs. Phase 2 reactions like conjugation make drugs more polar and excretable. The liver is the primary site of biotransformation through cytochrome P450 enzymes and UDP-glucuronyltransferases. First pass metabolism can decrease oral bioavailability. Drug interactions can occur through enzyme induction, increasing metabolism of other drugs, or enzyme inhibition, decreasing metabolism of other drugs.
1. Drug metabolism involves enzymatic modification of drugs by the body with the goal of making them more water soluble and easier to excrete.
2. Metabolism can occur in many tissues like the liver, kidneys, lungs, and intestines and is primarily carried out by the cytochrome P450 enzyme system.
3. Metabolism can result in inactive, active, or more active drug metabolites and influences the drug's pharmacokinetic and pharmacodynamic properties. Certain drugs are able to induce or inhibit the cytochrome P450 enzyme system, altering metabolism of other drugs metabolized by the same enzymes.
This document discusses the different types of receptors:
1) Ligand-gated ion channels directly open ion channels in response to neurotransmitters.
2) G-protein coupled receptors activate intracellular second messenger systems through G-proteins.
3) Kinase-linked receptors activate intracellular protein kinases.
4) Nuclear receptors regulate gene transcription by binding to DNA response elements as dimers.
Factors affecting biotransformation of drugsZubia Arshad
The biotransformation of drugs can be affected by various chemical, biological, physiological, temporal, and environmental factors. Chemical factors include enzyme induction and inhibition, which can increase or decrease the metabolism of drugs. Biological factors like age, gender, genetics, diet, and disease states can impact drug metabolism rates. Physiological changes during pregnancy, with hormonal imbalances, or disease states can also alter drug biotransformation. Additional influencing factors are temporal variations, the route of drug administration, and environmental exposures. Careful consideration of all these potential factors is important for safe and effective drug therapy.
This document discusses drug excretion pathways and mechanisms. It states that excretion involves the irreversible transfer of drugs and metabolites from the internal to external environment through renal and non-renal routes. The principal organs of excretion are the kidneys, bile, lungs, saliva, milk, and sweat. The kidneys are the primary route of excretion, utilizing glomerular filtration, tubular secretion, and reabsorption to eliminate compounds under 500 Da. Bile actively secretes hydrophilic drugs and metabolites over 500 Da, while the lungs passively diffuse gases and volatile substances.
The document discusses drug excretion from the body through various routes. It describes the principal organs involved in excretion as the kidneys, lungs, biliary system, intestines, saliva, and milk. Renal excretion through the kidneys is the primary route for water soluble drugs and involves glomerular filtration, tubular secretion, and tubular reabsorption. Other routes include biliary excretion into the feces, pulmonary excretion of volatile substances through the lungs, and excretion into saliva, sweat, and breast milk in small amounts for some drugs. Factors like a drug's molecular size, charge, lipid solubility, and degree of protein binding determine which excretion pathways it undergoes.
University Institute of Pharmaceutical Sciences is a flag bearer of excellence in Pharmaceutical education and research in the country. Here is another initiative to make study material available to everyone worldwide. Based on the new PCI guidelines and syllabus here we have a presentation dealing with pharmacokinetics : concept of linear and non-linear compartment models.
Thank you for reading.
Hope it was of help to you.
UIPS,PU team
Drug distribution involves the reversible transfer of drugs between compartments like blood and tissues. Several factors affect how drugs are distributed, including tissue permeability, organ size and blood flow, and binding to tissue components. Drugs with certain physicochemical properties like small molecular size and appropriate lipophilicity more easily pass through barriers and cell membranes into tissues. Additionally, tissues with greater blood flow and perfusion rates allow for faster drug distribution. Finally, the extent to which drugs bind to proteins and other components in blood and tissues impacts their distribution.
This document provides an overview of pharmacokinetics, which is the quantitative study of how the body acts on drugs. It describes the four main components of pharmacokinetics - absorption, distribution, metabolism, and excretion. Absorption refers to how drugs enter the bloodstream, distribution is how drugs spread to tissues, metabolism is how drugs are chemically altered, and excretion is how drugs and their metabolites leave the body. Key factors that determine a drug's pharmacokinetic properties and how it behaves in the body are also discussed.
The phenomenon of complex formation of drug with protein is called as Protein drug binding. The proteins are particularly responsible for such an interaction. A drug can interact with several tissue components.
Expt. 1 Introduction to in vitro pharmacology and physiological salt solutionsVISHALJADHAV100
This document provides an overview of in-vitro pharmacology experiments using isolated tissues and physiological salt solutions (PSS). It defines pharmacology and drugs, describes the aims of experimental pharmacology as finding therapeutic agents, studying toxicity and mechanisms of action. It also discusses types of experiments, equipment like organ baths and levers for recording tissue responses, and PSS compositions and roles. PSS are artificial solutions that maintain isolated tissues by resembling extracellular fluid composition. Selection of the appropriate PSS depends on the tissue being studied.
The document discusses biotransformation, which is the chemical alteration of drugs in the body. The body treats drugs as foreign substances and converts them into more polar, water soluble compounds through biotransformation so they can be excreted through the kidneys. Biotransformation occurs primarily in the liver and involves two phases - phase I reactions change the drug through processes like oxidation and phase II involves conjugating the drug to make it inactive so it can be excreted. Factors like other drugs, food, and an individual's characteristics can impact the biotransformation of drugs through inhibition or induction of the enzymes involved.
This document discusses drug elimination, which involves biotransformation (metabolism) and excretion of drugs from the body. It describes zero-order and first-order elimination kinetics, drug metabolism pathways including phase I and II reactions, and factors that influence renal excretion of drugs such as physicochemical properties and plasma concentration. Renal clearance is defined as the volume of plasma cleared of drug per unit time by the kidneys. Non-renal routes of excretion include biliary, pulmonary, dermal and gastrointestinal excretion.
This document discusses biotransformation, or the metabolism, of drugs in the body. It defines biotransformation as the chemical conversion of drugs from one form to another. The major organs involved in drug metabolism are the liver, lungs, kidneys, intestine, and placenta. The enzymes responsible for drug metabolism are divided into microsomal and non-microsomal enzymes. Drug metabolism occurs in two phases - phase I involves processes like oxidation and hydrolysis, while phase II involves conjugation reactions like glucuronidation and sulfation. Factors like the drug's physicochemical properties, genetic factors, age, and diet can influence a drug's metabolism in the body.
The cytochrome P450 system (CYP) is a large family of heme-containing enzymes that catalyze the oxidation of organic substances, including drugs and toxins. CYP enzymes are primarily located in the liver and intestine and are responsible for metabolizing approximately 75% of clinically used drugs. Variability in CYP gene expression between individuals can significantly impact drug metabolism and response. Drug interactions occur when one drug inhibits or induces the activity of a CYP enzyme, altering the metabolism of other drugs that are CYP substrates and potentially causing toxic effects. Careful consideration of a patient's complete medication regimen is important to avoid dangerous drug-drug interactions mediated by the CYP system.
This document discusses drug metabolism and phase I reactions. It defines drug metabolism as enzymatic chemical reactions that convert drugs into metabolites within the body. Drug metabolism is divided into two phases: phase I and phase II reactions. Phase I reactions introduce or expose functional groups through oxidation, reduction, and hydrolysis, making the drug more polar and susceptible to phase II reactions. Some examples of phase I reactions discussed are aromatic hydroxylation, oxidation of olefins, benzylic carbons, carbon atoms next to carbonyl groups, and aliphatic carbons. Reduction and hydrolytic reactions during phase I are also summarized.
Bioassays are quantitative procedures that use a living system's functional response to assess the concentration or potency of physical, chemical, or biological agents. They compare the magnitude of response of an unknown preparation to a standard under standard conditions. Bioassays are useful for identifying compounds, quantifying screening procedures, and producing drugs like antibiotics. They must be reliable, sensitive, reproducible, and minimize errors from biological variation and methodology. Common sources of error include animal-to-animal biological variation and faulty methodology or experimental errors.
This document discusses bioavailability and methods for assessing it. Bioavailability refers to the rate and extent that an unchanged drug is absorbed and available at its site of action. It depends on pharmaceutical, patient, and route of administration factors. Methods for assessing bioavailability include plasma drug concentration-time profiles, urinary excretion studies, acute pharmacological response methods, and therapeutic response methods. The concept of equivalence is also introduced, which examines the relationship between different drug products.
The document discusses prodrugs, which are pharmacologically inactive derivatives of active drugs designed to improve drug properties like solubility, absorption, and site-specific delivery. It covers basic prodrug concepts and classifications like carrier-linked prodrugs and bioprecursors. Approaches for prodrug design include using carriers, linkers, and multi-drug systems. Applications of prodrugs include improving patient acceptability by modifying taste, odor or irritation, enhancing solubility and dissolution for better absorption, and enabling site-specific or sustained drug delivery. The document provides examples of prodrug linkages and enzymes involved in their hydrolysis.
Circadian rhythms are biological processes that display an approximately 24-hour cycle. The document discusses the history and types of biological rhythms, focusing on circadian rhythms which are regulated by the suprachiasmatic nucleus in the brain. It describes how circadian rhythms influence many physiological functions and the absorption, distribution, metabolism, and elimination of drugs. Timed or chronotherapy aims to deliver drugs at times that synchronize with the body's natural rhythms to maximize efficacy and minimize side effects.
The document discusses the key aspects of pharmacokinetics including absorption, distribution, metabolism, and excretion of drugs in the body. It describes how drugs are absorbed via mechanisms like passive diffusion, active transport, and endocytosis. Factors like molecular weight, concentration gradients, and membrane permeability influence absorption rates. Most drug absorption occurs in the small intestine. Distribution of drugs depends on blood flow, ability to cross membranes, and plasma protein binding. The liver plays a major role in drug metabolism through phase I and phase II reactions, converting lipophilic drugs into more polar and water-soluble compounds that can be excreted.
Pharmacokinetics - drug absorption, drug distribution, drug metabolism, drug ...http://neigrihms.gov.in/
A power point presentation on general aspects of Pharmacokinetics suitable for undergraduate medical students beginning to study Pharmacology. Also suitable for Post Graduate students of Pharmacology and Pharmaceutical Sciences.
The document discusses various aspects of drug metabolism including:
1. Drug metabolism can lead to termination of drug action, activation of prodrugs, bioactivation and toxication, carcinogenesis, and teratogenesis.
2. Phase I and Phase II metabolic pathways are discussed in detail along with the enzymes involved such as cytochrome P450 and factors affecting drug metabolism.
3. Specific drug examples are provided to illustrate different metabolic pathways and implications like the interaction between grapefruit juice and CYP3A4 inhibiting drugs.
Biotransformation refers to the chemical alteration of substances within living organisms, typically involving enzymatic reactions. These reactions make compounds more water-soluble so they can be more easily excreted from the body. Biotransformation occurs in three phases - Phase I involves oxidation, reduction, and hydrolysis reactions; Phase II involves conjugating reactions like glucuronidation and sulfation; Phase III involves transport of conjugated compounds out of cells and organs. The liver is a major site of biotransformation, with cytochrome P450 enzymes and conjugating enzymes playing important roles in Phase I and Phase II reactions. Biotransformation is vital for the metabolism of drugs and other xenobiotics in the body.
1. Drug metabolism involves two phases - phase I involves reactions like oxidation and reduction that can make the drug more active or toxic. Phase II involves conjugation reactions that make the drug inactive.
2. The liver is the main organ where drug metabolism occurs, though some drugs are metabolized in other tissues like the lungs or intestines. Liver enzymes involved in metabolism are located on the smooth endoplasmic reticulum.
3. The metabolites produced from phases I and II are excreted from the body primarily through urine or bile, with factors like protein binding and drug properties affecting clearance.
First-pass metabolism refers to the process where a drug administered orally is absorbed through the gastrointestinal tract and transported to the liver via the portal vein, where it is metabolized before reaching systemic circulation. As a result, only a small proportion of the active drug reaches the intended target tissue. Notable drugs like morphine, propranolol, and lidocaine experience significant first-pass metabolism through the liver. Administering drugs via routes other than oral can bypass first-pass metabolism and increase bioavailability.
This document discusses the absorption of drugs and the first pass effect. It describes how drugs are absorbed through the gastrointestinal tract via passive diffusion, active transport, endocytosis, or exocytosis. It then lists factors that affect drug absorption related to the drug itself and factors related to the body, such as area of absorptive surface and vascularity. Finally, it explains that the first pass effect greatly reduces bioavailability as drugs are metabolized by the liver before reaching systemic circulation.
Golden rice is a genetically engineered variety of rice that produces beta-carotene, a precursor to vitamin A, in the edible parts of the rice grain. It was developed to help address vitamin A deficiency in parts of the world where rice is a staple crop. The goals are to provide a sustainable source of vitamin A through a staple food that is accessible and can be grown locally by farmers to consume and sell. The rice was engineered by introducing two new genes that activate the biosynthetic pathway to produce beta-carotene in the endosperm of the rice grain.
The major organs involved in drug excretion are the kidneys and liver. The kidneys excrete drugs through glomerular filtration, tubular secretion, and tubular reabsorption in the nephron. The liver excretes some drugs and their metabolites into bile. Pulmonary excretion eliminates gaseous and volatile substances through expiration.
The document discusses the process of excretion in the human body. Medications are eliminated from the body through excretion, which primarily occurs through the kidneys. The kidneys filter waste from the blood through glomerular filtration and either reabsorb or actively secrete drugs and other molecules into the urine through tubular transport processes for excretion from the body.
The document discusses drug excretion and elimination from the body. It describes the various routes of excretion including renal, biliary, pulmonary, salivary, dermal and gastrointestinal. The key organs involved in excretion are the kidneys and liver. Drugs can be excreted unchanged or as metabolites, through glomerular filtration, tubular secretion or reabsorption in the kidneys. Non-renal routes depend on the drug's physicochemical properties and include biliary excretion of conjugated metabolites. Factors like urine pH, blood flow and drug interactions can influence renal excretion. Clearance is the volume from which the drug is completely removed per unit time and includes renal, hepatic and total body clearance
1. Distribution is the dispersion of a drug among various organs and tissues of the body after administration.
2. Key factors that determine a drug's distribution include its physicochemical properties, binding to plasma and tissue proteins, blood flow rates to different organs, and barriers like the blood-brain barrier.
3. Disease states can also impact a drug's distribution by altering barriers or blood flow. The rate and extent of a drug's distribution determines its access to sites of action, metabolism, and excretion.
Factors affecting biotransformation of drugsvincyv88
Factors affecting biotransformation of drugs include physicochemical properties of the drug, chemical factors like induction or inhibition of drug-metabolizing enzymes, and biological factors like species, strain, sex, age, diet, and physiological state differences. Drug biotransformation can be studied using in vitro methods with human liver microsomes, hepatocytes, or cDNA-expressed enzymes, or in vivo by collecting and analyzing samples from urine, feces, blood, or tissues to identify drug metabolites.
Drug biotransformation involves the chemical alteration of drugs within the body, primarily in the liver, kidney, and intestine, through Phase I and Phase II reactions. Phase I reactions introduce or expose functional groups on drugs through oxidation, reduction, hydrolysis, or other reactions. This makes the drugs more polar and able to undergo Phase II conjugation reactions. Phase II reactions conjugate drugs to molecules like glucuronic acid, glutathione, sulfate, or glycine, which allows for excretion in urine or bile. Biotransformation can activate prodrugs, terminate drug action by making them more polar, produce active or toxic metabolites, and lead to enterohepatic recycling of some drugs.
This document discusses protein drug binding, including the mechanisms, classes, and factors that influence it. It begins by introducing protein drug binding and defining it as the formation of a complex between a drug and a protein. This binding can be reversible or irreversible. There are several mechanisms of binding including hydrogen bonds, hydrophobic bonds, ionic bonds, and Van der Waals forces. Protein drug binding is important as it influences the absorption, distribution, metabolism, and excretion of drugs. The extent of protein binding is affected by characteristics of the drug and protein as well as disease states and interactions between drugs. In summary, this document provides an overview of the topic of protein drug binding, including the key concepts and significance.
The document discusses compartment modeling and one compartment open models. It describes how the body can be represented as a single well-mixed compartment and outlines the assumptions of compartmental models. It then covers one compartment open models for intravenous bolus administration, intravenous infusion, and extravascular administration. For intravenous bolus administration, the elimination phase can be characterized by parameters like elimination rate constant, half-life, and clearance. Intravenous infusion allows for constant rate input into the compartment. Extravascular administration models absorption as either zero-order or first-order kinetics.
Biotransformation, or metabolism, of drugs involves enzymatic reactions that make the drugs more polar so they can be more easily excreted from the body. These reactions are divided into two phases: phase I introduces functional groups through reactions like oxidation, and phase II involves conjugating these groups to endogenous compounds. Cytochrome P450 enzymes are a major catalyst of phase I reactions, introducing groups like hydroxyl that then undergo conjugation. Factors like other drugs, diet, age and liver function can influence a drug's biotransformation.
This document discusses compartment modeling in pharmacokinetics. It begins by defining a mathematical model and compartment model. Compartmental models divide the body into compartments and use first-order kinetics to describe the movement of drugs between compartments. Common compartment models include one-compartment open models for intravenous bolus, intravenous infusion, and extravascular administration. Determination of pharmacokinetic parameters like absorption rate, elimination rate constant, and half-life are also covered.
This document discusses pharmacokinetic models used to mathematically represent how drugs move through the body over time. It covers one compartment models, which assume rapid equilibrium between blood and tissues. For intravenous bolus administration, drug concentration decreases exponentially according to first-order kinetics. Key parameters include elimination rate constant, half-life, volume of distribution, and clearance. Compartmental modelling is useful for predicting drug concentrations, determining dosing schedules, and understanding drug interactions.
Drug metabolism involves the biochemical modification of pharmaceutical substances by living organisms through specialized enzyme activity. There are four main stages: absorption, distribution, metabolism, and elimination. Drugs are metabolized to make them more hydrophilic so they can be excreted from the body. The two main phases of drug metabolism are phase I, which introduces functional groups to drugs through reactions like oxidation, and phase II, which involves conjugating drugs to make them more polar and excretable through conjugation reactions. Cytochrome P450 enzymes are largely responsible for phase I reactions. Factors like genetics, age, sex, disease states, and environmental exposures can impact an individual's drug metabolism capacity and response.
pharmacology consist to main part that its pharmacodynamic and pharmacokinatic, pharmacokinatic consist of four stages that is absorbtion, distrbution, metabolism and elimination.
this presentation is about metabolism its very short disicription about metabolism of drug in the body.
This document discusses drug metabolism, which involves the conversion of drugs from one chemical form to another through biotransformation reactions. It describes the two main phases of metabolism - Phase I and Phase II reactions. Phase I reactions involve oxidation, reduction, and hydrolysis and functionalize lipid-soluble drugs. Phase II reactions involve conjugating these functionalized drugs or their metabolites with endogenous compounds like glucuronic acid or sulfate, forming water-soluble drug conjugates that can be readily excreted. The key enzymes and reactions involved in each phase are discussed in detail.
Drug metabolism Introduction and TypesDrParthiban1
This document provides an overview of drug metabolism. It defines drug metabolism as the biochemical modification of chemicals occurring through specialized enzyme systems. Drug metabolism involves two phases: phase I reactions functionalize drugs through oxidation, reduction or hydrolysis, making them more polar; phase II or conjugation reactions then conjugate these functionalized drugs to other molecules like glucuronic acid, making them water soluble and excretable. The liver is the primary site of drug metabolism, though other tissues also metabolize drugs. First-pass metabolism by the liver can deactivate drugs before they reach systemic circulation. Drug metabolism transforms lipophilic drugs into more polar, excretable metabolites to prevent accumulation and toxicity.
Drug metabolism involves biochemical changes that convert lipophilic compounds into more polar, water soluble compounds that can be readily excreted. This occurs mainly through two phases - phase I involves oxidation, reduction, and hydrolysis while phase II involves conjugating metabolites with glucuronic acid, sulfate, glycine or glutathione. Many factors can influence drug metabolism, including a drug's chemical structure, species differences, physiological state, genetics, dosage, nutrition, age, gender, route of administration, and interactions with metabolic enzymes. Understanding these factors is important for predicting a drug's effects in the body.
Medicinal chemistry -l-Second year-Fourth semester --Medichem drug metabolism...manjusha kareppa
This document provides an overview of drug metabolism. It discusses that drug metabolism involves altering drug molecules through phase I and phase II reactions to make them more polar and excretable from the body. Phase I reactions introduce functional groups through oxidation, reduction, or hydrolysis. Phase II reactions conjugate phase I metabolites with molecules like glucuronic acid, glutathione, or sulfate to further increase polarity. Several factors can influence a drug's metabolism, including its physicochemical properties, the presence of enzyme inhibitors or inducers, and biological factors like age, diet, or disease state. The document aims to explain the basic process of drug metabolism and some key concepts.
xenobiotics chemistry and drug metabolismKimEliakim1
Xenobiotics are compounds foreign to the body that are subject to biotransformation. Biotransformation involves two phases: Phase I uses enzymes like cytochrome P450 to introduce functional groups, making compounds slightly more hydrophilic. Phase II involves conjugating compounds with endogenous molecules like glutathione and glucuronic acid, greatly increasing hydrophilicity and facilitating excretion. Biotransformation can activate or inactivate compounds, and is influenced by genetic and environmental factors. The liver is the primary site of biotransformation, though other tissues play roles.
This document provides an overview of metabolism and biotransformation. It defines key terms like metabolism, biotransformation, and xenobiotics. It describes the major sites of drug metabolism as the liver and secondary sites like the kidneys, lungs, and intestines. It outlines the two phases of biotransformation - phase I involving oxidation, reduction, and hydrolysis, and phase II involving conjugation reactions. Several examples of phase I and II enzyme systems and reactions are provided. The document also discusses enzyme induction and inhibition and their clinical importance in drug metabolism.
Metabolism is essential for eliminating drugs and other foreign substances from the body. Phase I metabolism makes compounds more polar through reactions like oxidation and hydrolysis. Phase II metabolism further increases polarity through conjugation. The liver is the primary site of metabolism, with cytochrome P450 enzymes performing many Phase I reactions. Metabolism inactivates most compounds but can also activate prodrugs. Factors like induction, inhibition, disease, age, sex and genetics can impact an individual's drug metabolism. Proper metabolism and excretion of compounds and their metabolites terminates their biological activity.
Xenobiotics are chemical substances found within an organism that are not naturally produced or expected to be present. They can produce various biological effects including pharmacological responses, toxicity, immunological responses, and cancers. Xenobiotics undergo two-phase metabolism - phase 1 involves reactions like hydroxylation and phase 2 involves conjugating the phase 1 products to make them more polar and excretable. The overall goal is to detoxify and eliminate xenobiotics from the body.
Drug metabolism involves the modification of drugs by the body to make them more water soluble and easier to excrete. Drugs undergo two main phases of metabolism: Phase I involves reactions like oxidation, reduction and hydrolysis that introduce or expose functional groups. Phase II involves conjugating functional groups with molecules like glucuronic acid to facilitate excretion. Understanding a drug's metabolic pathways is crucial for predicting its effects, toxicity and interactions with other drugs.
By the end of this lecture, students should:
Explain why drug metabolism is essential
Describe the phases of drug metabolism
Explain the role of cytochrome p 450 enzyme system in drug metabolism
Definition
Chemical reactions which occur in the body to change drugs from nonpolar lipid soluble forms to polar water soluble forms that are easily excreted by the kidney.
Drug metabolism involves biochemical changes that drugs undergo in the body, converting them into metabolites with different effects. The liver is a major site of drug metabolism. Metabolism is needed to make non-polar compounds more polar and water soluble so they can be excreted. Metabolites can be inactive, retain similar activity, have different activity, or be bioactivated prodrugs. Metabolism occurs through phase I and phase II reactions. Phase I involves oxidation, reduction, and hydrolysis. Phase II involves conjugation through addition of molecules like glucuronic acid or sulfate to make compounds more polar. Factors like an individual's genetics and health, the drug's chemical structure, and concurrent medications can impact drug metabolism.
Drug metabolism involves the biochemical modification of pharmaceutical substances by specialized enzymatic activity, usually in the liver. This generates more polar, water-soluble and inactive metabolites that can be readily excreted. Phase I metabolism uses enzymes like cytochrome P450 to functionalize drugs, while Phase II conjugates them to allow elimination. Factors like environmental chemicals, diseases, age, sex and genetics can influence an individual's drug metabolism capacity and effects.
This document provides an overview of metabolism, including definitions, types of metabolism reactions, and factors that affect metabolism. It discusses the two phases of metabolism - phase I and phase II reactions. Phase I reactions include oxidation, reduction, and hydrolysis and introduce polar groups to make compounds more water-soluble for excretion. Phase II reactions involve conjugating compounds with endogenous molecules like glucuronic acid and sulfate to form conjugates that are highly polar and excretable. The liver is the primary organ of metabolism, but other organs like the lungs, kidneys, and intestines can also carry out metabolic reactions.
Biotransformation, also called drug metabolism, refers to the chemical alteration of drugs inside living organisms. The liver is the main site where drugs are metabolized, converting lipid-soluble and unionized compounds into more water-soluble and ionized forms that can be readily excreted by the kidneys. There are two phases of drug metabolism: phase I involves oxidation, reduction, and hydrolysis reactions, while phase II involves conjugation reactions that further increase water solubility to allow for excretion. Repeated drug use can induce the synthesis of metabolic enzymes, while some drugs inhibit enzyme activity.
This document discusses drug metabolism, which occurs in two phases: Phase I and Phase II reactions. Phase I reactions introduce functional groups like hydroxyl groups and involve oxidation, reduction, and hydrolysis. This is done primarily by cytochrome P450 enzymes in the liver. Phase II reactions conjugate these metabolites to make them more polar and water soluble, through glucuronidation, sulfation, methylation, acetylation, and conjugation with amino acids like glycine. Together, these two phases of metabolism convert lipophilic drugs into more hydrophilic forms that can be more readily excreted from the body. The rate and pathway of a drug's metabolism can be affected by its physicochemical properties as well as environmental and
1) Biotransformation, or metabolism, involves the biochemical conversion of active drugs into inactive forms that can be readily excreted from the body, usually by transforming lipid-soluble drugs into water-soluble forms.
2) The main sites of drug metabolism are the liver, kidneys, intestines, lungs, and plasma, with the liver being the primary site. Metabolism converts drugs into more polar, water-soluble compounds to facilitate their elimination through urine.
3) The two main types of metabolic reactions are non-synthetic (phase 1) reactions like oxidation, reduction, and hydrolysis, and synthetic (phase 2) reactions like conjugation that combine drugs with small molecules like glucur
The document discusses drug metabolism and excretion. It describes how drugs are metabolized in two phases - phase I involves reactions like oxidation, reduction and hydrolysis that make the drug more polar. Phase II involves conjugating the drug or its metabolites to make them water soluble, such as by glucuronidation, sulfation or glutathione conjugation. The major site of drug metabolism is the liver, specifically the microsomal enzyme systems. Cytochrome P450 enzymes play a key role in phase I reactions like oxidation. Making drugs more polar allows them to be excreted in urine or bile.
This document discusses drugs used to treat joint diseases like rheumatoid arthritis (RA), osteoarthritis (OA), and gout. For RA, treatments include NSAIDs, synthetic and biologic DMARDs, and glucocorticoids. DMARDs work to reduce inflammation and slow disease progression. Biologics target cytokines like TNF-α. For OA, treatments focus on pain relief and include NSAIDs, topical NSAIDs, corticosteroid injections, glucosamine sulfate, and hyaluronic acid injections. Gout is treated by ending acute flares with NSAIDs, colchicine or steroids, and preventing future flares with allopurinol or probenecid to decrease
Trypanocidal drugs like diminazene aceturate, phenanthridium compounds, and quinapyramine compounds act through various mechanisms to inhibit the growth and replication of trypanosomes. Diminazene aceturate binds to DNA and interferes with DNA formation while phenanthridium compounds cleave kinetoplast DNA. These drugs are administered intramuscularly or subcutaneously and distributed widely throughout tissues. Common side effects include local reactions at the injection site and potential hepatotoxicity or neurotoxicity.
HISTORY pharmacology DRUG NOMENCLATURE CLINICAL TRIALS.PDFsuniu
Pharmacology is the study of drugs and their effects on living systems. It deals with how chemicals interact with the body. Drugs can come from natural sources like plants, animals, and minerals, or be synthesized chemically. A drug is defined as any substance used for diagnosis, prevention, or treatment of disease, or to affect the body's structure or function. Drugs must undergo testing to prove they are safe and effective before being approved for medical use. The development of new drugs is a long, complex, and costly process.
NSAIDs are commonly used analgesic, antipyretic and anti-inflammatory drugs. They work by inhibiting cyclooxygenase (COX) enzymes, decreasing synthesis of prostaglandins. There are two main COX isoforms, COX-1 and COX-2. NSAIDs can be nonselective inhibitors of both isoforms or selective inhibitors of COX-2. The main pharmacological effects of NSAIDs are analgesia, antipyresis and reduction of inflammation by decreasing prostaglandin levels. However, they also carry risks of adverse gastrointestinal, renal and platelet effects due to inhibition of the constitutive COX-1 isoform.
The document discusses the molecular mechanisms of action of drugs. It describes four main ways drugs produce effects in the body: 1) by acting on receptors, 2) by inhibiting carriers, 3) by modulating or blocking ion channels, and 4) by inhibiting enzymes. It focuses on describing the different types of protein targets for drug action, including receptors, ion channels, enzymes, and carrier molecules. It provides details on the structure and function of receptors, the main types of receptor families, and concepts such as receptor heterogeneity, subtypes, and the actions of agonists and antagonists.
The document discusses key concepts related to dose-response relationships for drugs. It defines important terms like dose, response, and dose-response curves. It explains that the dose-response relationship depends on multiple factors and describes the difference between main and side effects. Additionally, it provides details about graded and quantal dose-response curves and their characteristics. Metrics like potency, efficacy, slope, and variability that are used to analyze dose-response relationships are also outlined.
Drugs interact with receptors through various forces like hydrogen bonding, ionic interactions, and hydrophobic interactions. This interaction forms a drug-receptor complex that can dissociate. The affinity and stability of this complex determines the drug's potency and efficacy. Several theories have attempted to explain how drug-receptor binding leads to a biological response, such as occupation theory, induced fit theory, and two-state receptor model. The two-state model proposes that receptors exist in two conformations - active and inactive - and drugs can shift the equilibrium to elicit different responses.
Xenosensors are ligand-activated receptors that induce the expression of xenobiotic-metabolizing enzymes like cytochrome P450s in response to exposure to foreign compounds. The main xenosensors are the aryl hydrocarbon receptor, pregnane X receptor, constitutive androstane receptor, and peroxisome proliferator-activated receptors. Activation of these receptors by drugs and other ligands can lead to auto-induction of the drug's own metabolism and drug-drug interactions by inducing drug-metabolizing enzymes and transporters. Species differences exist in the specific ligands that activate these xenosensors.
Chromatography is a laboratory technique used to separate mixtures by distributing components to separate between two phases, one stationary and one mobile. It works based on how substances partition between the phases and move through the system at different rates. Common techniques include column chromatography, thin layer chromatography, gas chromatography, and high performance liquid chromatography. Chromatography is used in analytical chemistry to identify unknown substances and quantify components in a mixture.
Immunodiffusion techniques such as radial immunodiffusion, Ouchterlony double diffusion, and immunoelectrophoresis can be used to detect and quantify antigens and antibodies through the formation of precipitin lines. These techniques utilize the diffusion of antigens and antibodies through a semi-solid medium like agar to form visible precipitin lines where the antigens and antibodies combine. They can be used to diagnose diseases, detect immunodeficiencies, and assess the purity and concentration of antigens and antibodies.
Ultrasonography uses high frequency sound waves to non-invasively image soft tissues. It is used for both diagnostic purposes like organ imaging and measurement as well as therapeutic purposes like HIFU and lithotripsy. Ultrasound has a range above human hearing and most diagnostic instruments use 1-10 MHz. It provides greyscale images based on tissue density and is useful for visualizing soft tissue structures and blood flow.
Spectrophotometry uses the principle that molecules absorb specific wavelengths of light. A spectrophotometer directs a beam of light through a sample and measures the amount of light absorbed. It contains a light source, wavelength selector like a prism or grating to produce monochromatic light, sample holders, a detector to measure transmitted light intensity, and a readout device. It works based on Beer's law, where absorbance is directly proportional to concentration, molar absorptivity, and path length. This allows spectrophotometry to quantify the concentration of an analyte by its optical properties.
Electron microscopy provides high resolution imaging of nanoscale structures using electron beams. There are two main types: transmission electron microscopy (TEM) and scanning electron microscopy (SEM). TEM uses transmitted electrons to image ultra thin samples, allowing visualization of structures less than an angstrom in size. SEM scans a focused electron beam across a sample to generate topographical and compositional information from electron interactions within microns of the surface. Both techniques require specialized sample preparation and equipment to produce high quality images for research applications across biology, materials science, and other fields.
The document discusses drug excretion through various organs and processes. The kidneys are the primary organ for water-soluble drug removal through glomerular filtration, tubular secretion, and reabsorption. Biliary excretion also plays a role in removing some drugs through active transport into bile. Drug conjugates are more readily excreted in bile. Enterohepatic recirculation can prolong a drug's presence as it is absorbed and secreted between the liver and intestines.
This document summarizes various drugs used in veterinary gastroenterology, including:
1) Appetite stimulants, emetics, antiemetics, antiulcer drugs, prokinetics, and drugs for diarrhea treatment.
2) Details are provided on specific drug classes like H2 blockers, proton pump inhibitors, cytoprotective drugs, and motility regulators.
3) Cathartics and treatments for ruminal issues are also outlined, along with antifoaming agents and rumen modifiers.
This document summarizes various poisonous plants of veterinary importance in India. It discusses the toxic principles in plants, factors affecting toxicity, clinical signs of acute and chronic poisoning, diagnosis, and treatment approaches. Some of the key poisonous plants mentioned include Abrus precatorius, Datura stramonium, Parthenium hysterophorus, and Strychnos nux-vomica. The summary provides an overview of the types of toxins present in plants and their effects on animal health.
This document summarizes the clinical pharmacology of anti-neoplastic drugs used to treat tumors. It discusses the characteristics of tumors and principles of anti-neoplastic therapy, including considering the type and stage of tumor and the patient's condition. It outlines safe handling practices for anti-neoplastic agents and their classification into groups like alkylating agents, antimetabolites, antibiotic antineoplastics, and mitotic inhibitors. For each group, it briefly describes the mechanism of action and example drugs. It also mentions biologic response modifiers that enhance the host's anti-tumor defenses.
This document summarizes the potential toxicity of various common household substances. It describes substances like soaps, detergents, corrosives, disinfectants, solvents, batteries, glues, matches, mothballs, over-the-counter drugs, insecticides and more. For each substance or class, it outlines the sources of exposure, signs of toxicity, and recommended treatment approaches. The goal is to provide veterinarians with essential information on managing pet poisonings from accidental ingestions of everyday products.
This document summarizes different generations of cephalosporin and penem group of antibiotics. It discusses their mechanism of action, spectrum of activity, beta-lactamase stability, and uses. First, second, third, and fourth generation cephalosporins have increasing spectrum and stability against gram-negative bacteria. Specific antibiotics mentioned include cefazolin, cefuroxime, ceftriaxone, cefotaxime, ceftazidime, cefepime, and ceftiofur.
This document summarizes different types of antifungal drugs, including their mechanisms of action, spectra of activity, pharmacokinetics, indications, and side effects. It discusses several major classes: polyenes like amphotericin B; azoles like fluconazole and itraconazole; 5-flucytosine; echinocandins; allylamines like terbinafine; and others occasionally used topically. It provides details on antifungal drug properties, interactions, resistance issues, and therapeutic uses to treat various fungal infections.
Leveraging Generative AI to Drive Nonprofit InnovationTechSoup
In this webinar, participants learned how to utilize Generative AI to streamline operations and elevate member engagement. Amazon Web Service experts provided a customer specific use cases and dived into low/no-code tools that are quick and easy to deploy through Amazon Web Service (AWS.)
This document provides an overview of wound healing, its functions, stages, mechanisms, factors affecting it, and complications.
A wound is a break in the integrity of the skin or tissues, which may be associated with disruption of the structure and function.
Healing is the body’s response to injury in an attempt to restore normal structure and functions.
Healing can occur in two ways: Regeneration and Repair
There are 4 phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This document also describes the mechanism of wound healing. Factors that affect healing include infection, uncontrolled diabetes, poor nutrition, age, anemia, the presence of foreign bodies, etc.
Complications of wound healing like infection, hyperpigmentation of scar, contractures, and keloid formation.
How to Make a Field Mandatory in Odoo 17Celine George
In Odoo, making a field required can be done through both Python code and XML views. When you set the required attribute to True in Python code, it makes the field required across all views where it's used. Conversely, when you set the required attribute in XML views, it makes the field required only in the context of that particular view.
The chapter Lifelines of National Economy in Class 10 Geography focuses on the various modes of transportation and communication that play a vital role in the economic development of a country. These lifelines are crucial for the movement of goods, services, and people, thereby connecting different regions and promoting economic activities.
This presentation was provided by Rebecca Benner, Ph.D., of the American Society of Anesthesiologists, for the second session of NISO's 2024 Training Series "DEIA in the Scholarly Landscape." Session Two: 'Expanding Pathways to Publishing Careers,' was held June 13, 2024.
Level 3 NCEA - NZ: A Nation In the Making 1872 - 1900 SML.pptHenry Hollis
The History of NZ 1870-1900.
Making of a Nation.
From the NZ Wars to Liberals,
Richard Seddon, George Grey,
Social Laboratory, New Zealand,
Confiscations, Kotahitanga, Kingitanga, Parliament, Suffrage, Repudiation, Economic Change, Agriculture, Gold Mining, Timber, Flax, Sheep, Dairying,
Walmart Business+ and Spark Good for Nonprofits.pdfTechSoup
"Learn about all the ways Walmart supports nonprofit organizations.
You will hear from Liz Willett, the Head of Nonprofits, and hear about what Walmart is doing to help nonprofits, including Walmart Business and Spark Good. Walmart Business+ is a new offer for nonprofits that offers discounts and also streamlines nonprofits order and expense tracking, saving time and money.
The webinar may also give some examples on how nonprofits can best leverage Walmart Business+.
The event will cover the following::
Walmart Business + (https://business.walmart.com/plus) is a new shopping experience for nonprofits, schools, and local business customers that connects an exclusive online shopping experience to stores. Benefits include free delivery and shipping, a 'Spend Analytics” feature, special discounts, deals and tax-exempt shopping.
Special TechSoup offer for a free 180 days membership, and up to $150 in discounts on eligible orders.
Spark Good (walmart.com/sparkgood) is a charitable platform that enables nonprofits to receive donations directly from customers and associates.
Answers about how you can do more with Walmart!"
How to Setup Warehouse & Location in Odoo 17 InventoryCeline George
In this slide, we'll explore how to set up warehouses and locations in Odoo 17 Inventory. This will help us manage our stock effectively, track inventory levels, and streamline warehouse operations.
LAND USE LAND COVER AND NDVI OF MIRZAPUR DISTRICT, UPRAHUL
This Dissertation explores the particular circumstances of Mirzapur, a region located in the
core of India. Mirzapur, with its varied terrains and abundant biodiversity, offers an optimal
environment for investigating the changes in vegetation cover dynamics. Our study utilizes
advanced technologies such as GIS (Geographic Information Systems) and Remote sensing to
analyze the transformations that have taken place over the course of a decade.
The complex relationship between human activities and the environment has been the focus
of extensive research and worry. As the global community grapples with swift urbanization,
population expansion, and economic progress, the effects on natural ecosystems are becoming
more evident. A crucial element of this impact is the alteration of vegetation cover, which plays a
significant role in maintaining the ecological equilibrium of our planet.Land serves as the foundation for all human activities and provides the necessary materials for
these activities. As the most crucial natural resource, its utilization by humans results in different
'Land uses,' which are determined by both human activities and the physical characteristics of the
land.
The utilization of land is impacted by human needs and environmental factors. In countries
like India, rapid population growth and the emphasis on extensive resource exploitation can lead
to significant land degradation, adversely affecting the region's land cover.
Therefore, human intervention has significantly influenced land use patterns over many
centuries, evolving its structure over time and space. In the present era, these changes have
accelerated due to factors such as agriculture and urbanization. Information regarding land use and
cover is essential for various planning and management tasks related to the Earth's surface,
providing crucial environmental data for scientific, resource management, policy purposes, and
diverse human activities.
Accurate understanding of land use and cover is imperative for the development planning
of any area. Consequently, a wide range of professionals, including earth system scientists, land
and water managers, and urban planners, are interested in obtaining data on land use and cover
changes, conversion trends, and other related patterns. The spatial dimensions of land use and
cover support policymakers and scientists in making well-informed decisions, as alterations in
these patterns indicate shifts in economic and social conditions. Monitoring such changes with the
help of Advanced technologies like Remote Sensing and Geographic Information Systems is
crucial for coordinated efforts across different administrative levels. Advanced technologies like
Remote Sensing and Geographic Information Systems
9
Changes in vegetation cover refer to variations in the distribution, composition, and overall
structure of plant communities across different temporal and spatial scales. These changes can
occur natural.
2. METABOLISM OR BIOTRANSFORMATION
The conversion from one chemical form of a substance to another.
The term metabolism is commonly used probably because products of drug
transformation are called metabolites.
Metabolism is an essential pharmacokinetic process, which renders lipid soluble and
non-polar compounds to water soluble and polar compounds so that they are
excreted by various processes.
This is because only water-soluble substances undergo excretion, whereas lipid
soluble substances are passively reabsorbed from renal or extra renal excretory sites
into the blood by virtue of their lipophilicity.
Metabolism is a necessary biological process that limits the life of a substance in the
body.
Biotransformation: It is a specific term used for chemical transformation of
xenobiotics in the body/living organism.
• a series of enzyme-catalyzed processes—that alters the physiochemical properties of
foreign chemicals (drug/xenobiotics) from those that favor absorption across biological
membranes (lipophilicity) to those favoring elimination in urine or bile (hydrophilicity )
3. Metabolism : It is a general term used for chemical
transformation of xenobiotics and endogenous
nutrients (e.g., proteins, carbohydrates and fats) within
or outside the body.
Xenobiotics : These are all chemical substances that
are not nutrient for body (foreign to body) and which
enter the body through ingestion, inhalation or dermal
exposure.
They include :
drugs, industrial chemicals, pesticides, pollutants,
plant and animal toxins, etc.
4. Functions of Biotransformation
It causes conversion of an
active drug to inactive or
less active metabolite(s)
called as pharmacological
inactivation.
It causes conversion of an
active to more active
metabolite(s) called as
bioactivation or
toxicological activation.
• It causes conversion of an
inactive to more active
toxic metabolite(s) called
as lethal synthesis
5. Functions of Biotransformation….contd
• It causes conversion of an
inactive drug (pro-drug) to
active metabolite(s) called
as pharmacological
activation
• It causes conversion of an
active drug to equally active
metabolite(s) (no change in
pharmacological activity)
• It causes conversion of an
active drug to active
metabolite(s) having
entirely different
pharmacological activity
(change in pharmacological
activity)
6. Site/Organs of drug metabolism
The major site of drug metabolism is the liver
(microsomal enzyme systems of hepatocytes)
Secondary organs of biotransformation
• kidney (proximal tubule)
• lungs (type II cells)
• testes (Sertoli cells)
• skin (epithelial cells); plasma. nervous tissue
(brain); intestines
7. Sites of Biotransformation…contd
Liver
The primary site for metabolism of almost all drugs because it is relatively
rich in a large variety of metabolising enzymes.
Metabolism by organs other than liver (called as extra-hepatic metabolism)
is of lesser importance because lower level of metabolising enzymes is
present in such tissues.
Within a given cell, most drug metabolising activity is found in the smooth
endoplasmic reticulum and the cytosol.
Drug metabolism can also occur in mitochondria, nuclear envelope and
plasma membrane.
A few drugs are also metabolised by non-enzymatic means called as non-
enzymatic metabolism.
For example, atracurium, a neuromuscular blocking drug, is inactivated in
plasma by spontaneous non-enzymatic degradation (Hoffman elimination)
in addition to that by pseudocholinesterase enzyme.
9. Drug Metabolising Enzymes
A number of enzymes in animals are capable of metabolising
drugs. These enzymes are located mainly in the liver, but may
also be present in other organs like lungs, kidneys, intestine,
brain, plasma, etc.
Majority of drugs are acted upon by relatively non-specific
enzymes, which are directed to types of molecules rather than
to specific drugs.
The drug metabolising enzymes can be broadly divided into two
groups: microsomal and non-microsomal enzymes.
10. Microsomal enzymes: The endoplasmic reticulum (especially
smooth endoplasmic reticulum) of liver and other tissues
contain a large variety of enzymes, together called microsomal
enzymes
(microsomes are minute spherical vesicles derived from
endoplasmic reticulum after disruption of cells by
centrifugation, enzymes present in microsomes are called
microsomal enzymes).
They catalyse glucuronide conjugation, most oxidative
reactions, and some reductive and hydrolytic reactions.
The monooxygenases, glucuronyl transferase, etc are
important microsomal enzymes.
11. Non-microsomal enzymes: Enzymes occurring in
organelles/sites other than endoplasmic reticulum
(microsomes) are called non-microsomal enzymes.
These are usually present in the cytoplasm, mitochondria, etc.
and occur mainly in the liver, Gl tract, plasma and other tissues.
They are usually non-specific enzymes that catalyse few
oxidative reactions, a number of reductive and hydrolytic
reactions, and all conjugative reactions other than
glucuronidation.
None of the non-microsomal enzymes involved in drug
biotransformation is known to be inducible.
14. Factors Affecting Drug Metabolism
1. Species differences : eg in phenylbutazone, procaine and
barbiturates.
2. Genetic differences – variation exist with species
3. Age of animal –feeble in fetus,aged, newborn.
4.sex: under the influence of sex hormones.
5. Nutrition: starvation and malnutrition
6. Patholigical conditions: Liver/Kidney dysfunction
15. TYPES OF BIOTRANSFORMATION
Phase 1 reaction. (Non synthetic phase). Phase II reaction. (Synthetic phase)
• a change in drug molecule. generally • Last step in detoxification reactions
results in the introduction of a and almost always results in loss of
functional group into molecules or the biological activity of a compound.
exposure of new functional groups of • May be preceded by one or more of
molecules phase one reaction
: Phase I (non-synthetic or non- • Involves conjugation of functional
conjugative phase) includes reactions groups of molecules with hydrophilic
which catalyse oxidation, reduction and endogenous substrates- formation
hydrolysis of drugs. of conjugates - is formed with (an
endogenous substance such as
carbohydrates and amino acids. )with
In phase I reactions, small polar
drug or its metabolites formed in
functional groups like-OH, -NH2. -SH, -
phase 1 reaction.
COOH, etc. are either added or
unmasked (if already present) on the Involve attachment of small polar
lipid soluble drugs so that the resulting endogenous molecules like glucuronic
products may undergo phase II acid, sulphate, methyl, amino acids,
reactions. etc., to either unchanged drugs or
phase I products.
• result in activation, change or
inactivation of drug. Products called as 'conjugates' are
water-soluble metabolites, which are
readily excreted from the body.
16. • Phase I metabolism is sometimes called a • Phase II metabolism includes what are known
“functionalization reaction,”
as conjugation reactions.
• Results in the introduction of new
hydrophilic functional groups to compounds. • Generally, the conjugation reaction with
• Function: introduction (or unveiling) of endogenous substrates occurs on the
functional group(s) such as –OH, –NH2, –SH, metabolite( s) of the parent compound after
–COOH into the compounds. phase I metabolism; however, in some cases,
• Reaction types: oxidation, reduction, and the parent compound itself can be subject to
hydrolysis phase II metabolism.
• Function: conjugation (or derivatization) of
• Enzymes: functional groups of a compound or its
• Oxygenases and oxidases: Cytochrome P450 (P450 metabolite(s) with endogenous substrates.
or CYP), flavincontaining
• Reaction types: glucuronidation, sulfation,
• monooxygenase (FMO), peroxidase, monoamine
oxidase(MAO), alcohol dehydrogenase, aldehyde glutathione-conjugation, Nacetylation,
dehydrogenase, and xanthine 0xidase. Reductase: methylation and conjugation with amino acids
Aldo-keto reductase and quinone reductase. (e.g., glycine, taurine, glutamic acid).
• Hydrolytic enzymes: esterase, amidase, aldehyde
oxidase, and alkylhydrazine
• Enzymes: Uridine diphosphate-Glucuronosyltransferase
(UDPGT): sulfotransferase (ST), N-acetyltransferase,
• oxidase.
glutathione S-transferase (GST),methyl transferase, and
• Enzymes that scavenge reduced oxygen: amino acid conjugating enzymes.
Superoxide dismutases, catalase,
• Glucuronidation by uridine diphosphate-
• glutathione peroxidase, epoxide hydrolase, y- glucuronosyltransferase; Sulfation by sulfotransferase
glutamyl transferase,
• 3. Acetylation by N-acetyltransferase; Glutathione
• dipeptidase, and cysteine conjugate β-lyase conjugation by glutathione S-transferase;. Methylation by
methyl transferase; Amino acid conjugation
17. PHASE I BIOTRANSFORMATION
Oxidation
• Oxidation by cytochrome P450 isozymes (microsomal mixed-
functionoxidases).
• Oxidation by enzymes other than cytochrome P450s—most of these
• (a) oxidation of alcohol by alcohol dehydrogenase,
• (b) oxidation of aldehyde by aldehyde dehydrogenase,
• (c) N-dealkylation by monoamineoxidase.
18. Phase I Reactions
Oxidation :
• Oxidative reactions are most important metabolic reactions, as
energy in animals is derived by oxidative combustion of organic
molecules containing carbon and hydrogen atoms.
• The oxidative reactions are important for drugs because they
increase hydrophilicity of drugs by introducing polar functional
groups such as -OH.
• Oxidation of drugs is non-specifically catalysed by a number of
enzymes located primarily in the microsomes. Some of the
oxidation reactions are also catalysed by non-microsomal enzymes
(e.g., aldehyde dehydrogenase, xanthine oxidase and monoamine
oxidase).
19. The most important group of oxidative enzymes are microsomal
monooxygcnases or mixed function oxidases (MFO).
These enzymes are located mainly in the hepatic endoplasmic
reticulum and require both molecular oxygen (02) and reducing
NADPH to effect the chemical reaction.
Mixed function oxidase name was proposed in order to
characterise the mixed function of the oxygen molecule, which is
essentially required by a number of enzymes located in the
microsomes.
20. The term monooxygenses for the enzymes was proposed as they
incorporate only one atom of molecular oxygen into the organic substrate
with concomitant reduction of the second oxygen atom to water.
The overall stoichiometry of the reaction involving the substrate RH which
yields the product ROH, is given by the following reaction:
MFO
RH+02+NADPH+H+ ----------------► R0H+H20+NADP+
The most important component of mixed function oxidases is the
cytochrome P-450 because it binds to the substrate and activates oxygen.
The wide distribution of cytochrome P-450 containing MFOs in varying
organs makes it the most important group of enzymes involved in the
biotransformation of drugs.
24. The cytochrome P-450 ENZYMES
• Superfamily of haem-thiolate proteins that are widely distributed
across all living creatures.
• The name given to this group of proteins because their reduced
form binds with carbon monoxide to form a complex, which has
maximum absorbance at 450 nm.
• Depending upon the extent of amino acid sequence homology, the
cytochrome P-450 (CYP) enzymes superfamily contains a number of
isoenzymes, the relative amount of which differs among species and
among individuals of the same species.
• These isoenzymes are grouped into various families designated by
Arabic numbers 1, 2, 3 (sequence that are greater than 40% identical
belong to the same family), each having several subfamilies
designated by Capital letter A, B, C, while individual isoenzymes are
again allotted Arabic numbers 1.2,3 (e.g., CYP1A1, CYP1A2, etc.).
25.
26. ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISM
In human beings, of the 1000 currently known cytochrome P-450s, about 50 are functionally
active. These are categorised into 17 families, out of which the isoenzymes CYP3A4 and CYP2D6
carry out biotransformation of largest number of drugs.
RELATIVE HEPATIC CONTENT % DRUGS METABOLIZED
OF CYP ENZYMES BY CYP ENZYMES
CYP2E1
CYP2D6 7%
2%
CYP 2C19
11%
CYP 2C9
CYP 2C 14%
CYP2D6
17%
23%
OTHER
36%
CYP 1A2
CYP 1A2 14%
12%
CYP 3A4-5 CYP2E1
CYP 3A4-5
26% 5%
33%
27.
28. Participation of the CYP Enzymes in Metabolism of Some
Clinically Important Drugs
CYP Enzyme Examples of substrates
1A1 Caffeine, Testosterone, R-Warfarin
1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin
2A6 17 -Estradiol, Testosterone
2B6 Cyclophosphamide, Erythromycin, Testosterone
2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S-
Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin,
Zidovudine (2C8,9,19);
2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6 Acetaminophen, Codeine, Debrisoquine
3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine,
Cortisol, Erythromycin, Cyclophosphamide, S- and R-
Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine
29. 2. Reduction :
Reduction
Enzymes responsible for reduction of xenobiotics require NADPH as a cofactor.
Substrates for reductive reactions include azo- or nitrocompounds, epoxides,
heterocyclic compounds, and halogenated hydrocarbons:
(a) Azo or nitroreduction by cytochrome P450;
(b) Carbonyl (aldehyde or ketone) reduction by aldehyde reductase, aldose
reductase, carbonyl reductase, quinone reductase
(c) other reductions including disulfide reduction, sulfoxide reduction, and
reductive dehalogenation.
30. The acceptance of one or more electron(s) or their equivalent from another
substrate.
Reductive reactions, which usually involve addition of hydrogen to the drug
molecule, occur less frequently than the oxidative reactions.
Biotransformation by reduction is also capable of generating polar functional
groups such as hydroxy and amino groups, which can undergo further
biotrans-formation.
Many reductive reactions are exact opposite of the oxidative reactions
(reversible reactions) catalysed cither by the same enzyme (true reversible
reaction) or by different enzymes (apparent reversible reactions).
Such reversible reactions usually lead to conversion of inactive metabolite
into active drug, thereby delaying drug removal from the body.
31.
32. 3. Hydrolysis :
Esters, amides, hydrazides, and carbamates can be hydrolyzed by
various
enzymes.
The hydrolytic reactions, contrary to oxidative or reductive
reactions, do not involve change in the state of oxidation of the
substrate, but involve the cleavage of drug molecule by taking up
a molecule of water.
The hydrolytic enzymes that metabolise drugs are the ones that
act on endogenous substances, and their activity is not confined
to liver as they are found in many other organs like kidneys,
intestine, plasma, etc.
A number of drugs with ester, ether, amide and hydrazide
linkages undergo hydrolysis. Important examples are
cholinesters, procaine, procainamide, and pethidine.
33.
34. PHASE II REACTIONS
Phase II or conjugation (Latin, conjugatus = yoked together)
reactions involve combination of the drug or its phase I
metabolite with an endogenous substance to form a highly polar
product, which can be efficiently excreted from the body.
In the biotransformation of drugs, such products or metabolites
have two parts:
Exocon, the portion derived from exogenous compound or
xenobiotic,
Endocon, the portion derived from endogenous substance.
Conjugation reactions have high energy requirement and they
often utilise suitable enzymes for the reactions.
35. The endogenous substances (endocons) for conjugation
reactions are derived mainly from carbohydrates or amino acids
and usually possess large molecular size.
They are strongly polar or ionic in nature in order to render the
substrate water-soluble. The molecular weight of the conjugate
(metabolite) is important for determining its route of excretion.
High molecular weight conjugates are excreted predominantly in
bile (e.g., glutathione exclusively, glucuronide mainly),
while low molecular weight conjugates are excreted mainly in the
urine.
As the availability of endogenous conjugating substance is limited,
saturation of this process is possible and the unconjugated
drug/metabolite may precipitate toxicity.
36. 1. Conjugation with glucuronic a./ Glucuronidation
Conjugation with glucuronic acid (glucuronide conjugation or
glucuroni-dation) is the most common and most important
phase II reaction in vertebrates, except cats and fish.
The biochemical donor (cofactor) of glucuronic acid is uridine
diphosphate«-D-glucuronicacid (UDPGA) and the reaction is
carried out by enzyme uridine diphosphate-glucuronyl
transferase (UDP-giucuronyl transferase; glucuronyl
transferase).
Glucuronyl transferase is present in microsomes of most
tissues but liver is the most active site of glucuronide
synthesis.
37. Glucuronidation can take place in most body tissues because
the glucuronic acid donor UDPGA is present in abundant
quantity in body, unlike donors involved in other phase II
reactions.
In cats, there is reduced glucuronyl transferase activity, while
in fish there is deficiency of endogenous glucuronic acid donor.
The limited capacity of this metabolic pathway in cats may
increase the duration of action, pharmacological response and
potential of toxicity of several lipid-soluble drugs (e.g., aspirin)
in this species.
38. A large number of drugs undergo glucuronidation including
morphine, paracetamol and desipramine. Certain endogenous
substances such as steroids, bilirubin, catechols and thyroxine
also form glucuronides.
Deconjugaiion process: Occasionally some glucuronide
conjugates that are excreted in bile undergo deconjugation
process in the intestine mainly mediated by β glucuronidase
enzyme.
This releases free and active drug in the intestine, which may be
reabsorbed and undergo entero-hepatic cycling.
Deconjugation is an important process because it often prolongs
the pharmacological effects of drugs and/or produces toxic
effects.
39. 2. Conjugation with sulphate/ Sulphation:
Conjugation with sulphate (sulphate conjugation,
sulphoconjugation orsulphation) is similar to glucuronidation
but is catalysed by non-microsomal enzymes and occurs less
commonly.
The endogenous donor of the sulphate group is 3'-
phosphoadenosine-5'-phosphosulphate (PAPS), and enzyme
catalysing the reaction is sulphotransferase
40. The conjugates of sulphate are referred to as sulphate ester
conjugates or ethereal sulphates. Unlike glucuronide
conjugation, sulphoconjugation in mammals is less important
because the PAPS donor that transfers sulphate to the substrate
is easily depleted.
Capacity for sulphate conjugation is limited in pigs. However
in cats, where glucuronidation is deficient, sulphate conjugation
is important. Functional groups capable of forming sulphate
conjugates include phenols, alcohols, arylamines, N-
hydroxylamines and N-hydroxyamides.
Drugs undergoing sulphate conjugation include
chloramphenicol, phenols, and adrenal and sex steroids.
41. 3. Conjugation with methyl group/ Methylation :
Conjugation with methyl group (methyl conjugation or
methylation) involves transfer of a methyl group (-CH3) from the
cofactor S-adenosyl methionine (SAM) to the acceptor substrate
by various methyl transferase enzymes.
Methylation reaction is of lesser importance for drugs, but is
more important for biosynthesis (e.g., adrenaline, melatonin)
and | Inactivation (e.g., histamine) of endogenous amines.
Occasionally, the metabolites formed are not polar or water-
soluble and may possess equal or greater activity than the
parent compound (e.g., adrenaline synthesised from
noradrenaline).
42. 4. Conjugation with glutathione and mercapturic acid formation.
Conjugation with glutathione (glutathione conjugation) and mercapturic acid formation
is a minor but important metabolic pathway in animals.
Glutathione (GSH, G=glutathione and SH = active-SH group) is a tripeptide having
glutamic acid, cysteine and glycine.
It has a strong nucleophilic character due to the presence of a -SH (thiol) group in its
structure. Thus, it conjugates with electrophilic substrates, a number of which are
potentially toxic compounds, and protects the tissues from their adverse effects.
The interaction between the substrate and the GSH is catalysed by enzyme glutathione-
S-transferase, which is located in the soluble fraction of liver homogenates.
The glutathione conjugate either due to its high molecular weight is excreted as such in
the bile or is further metabolised to form mercapturic acid conjugate that is excreted in
the urine.
43. 5. Conjugation with acetyl group/ Acetylation :
Conjugation with acetyl group (acetylation) is an important
metabolic pathway for drugs containing the amino groups.
The cofactor for these reactions is acetyl coenzyme A and the
enzymes are non-microsomal N-acetyl transferases, located in
the soluble fraction of cells of various tissues.
Acetylation is not a true detoxification process because
occasionally it results in decrease in water solubility of an amine
and. thus, increase in its toxicity (e.g., sulphonamides).
44. Acetylation is the primary route of biotransformation of
sulphonamide compounds. Dogs and foxes do not acetylate
the aromatic amino groups due to deficiency of arylamine
acetyltransferase enzyme.
Conjugation with amino acids : Conjugation with amino acids
occurs to a limited extent in animals because of limited
availability of amino acids. The most important reaction
involves conjugation with glycine.
Conjugation with other amino acids like glutamine in man and
ornithine in birds is also seen.
Examples of drugs forming glycine or glutamine conjugates are
salicylic acid, nicotinic acid and cholic acid.
45. Conjugation with thiosulphate : Conjugation with thiosulphate is
an important reaction in the detoxification of cyanide. Conjugation
of cyanide ion involves transfer of sulphur atom from the
thiosulphate to the cyanide ion in presence of enzyme rhodancse
to form inactive thiocyanate.
Thiocyanate formed is much less toxic than the cyanide (true
detoxification) and it is excreted in urine.
46.
47.
48. INDUCTION OF METABOLISM
Administration of certain xenobiotics sometimes results in a
selective increase in the concentration of metabolizing enzymes in
both phase I and II metabolism, and thereby in their activities
Enzyme induction becomes important especially when
polypharmacy involves drugs with narrow therapeutic windows, since
the induced drug metabolism could result in a significant decrease in
its exposure and therapeutic effects.
In addition, enzyme induction may cause toxicity, associated with
increased production of toxic metabolites.
Mechanisms of Induction
Stimulation of transcription of genes and/or translation of proteins,
and/or stabilization of mRNA and/or enzymes by inducers, resulting in
elevated enzyme levels.
49. Stimulation of preexisting enzymes resulting in apparent
enzyme induction without an increase in enzyme synthesis (this
is more common in vitro than in vivo).
In many cases, the details of the induction mechanisms are
unknown.
TWO receptors have been identified for CYPlA1/2 and
CYP4A1/2induction:
(a) Ah (aromatic hydrocarbon) receptor in cytosol, which
regulates enzyme (CYP1 A1 and 1A2) induction by polycyclic
aromatic hydrocarbon (PAH)-type inducers;
(b) Peroxisome proliferator activated receptor (PPAR), where
hypolipidemic agents cause peroxisome proliferation in rats
(CYP4A1 and 4A2);-humans have low PPAR and show no
effects from hypolipidemic agents.
50. Characteristics of Induction
Induction is a function of intact cells and cannot be achieved by treating
isolated cell fractions such as microsomes with inducers.
Evaluation of enzyme induction is usually conducted in ex vivo experiments,
ie., treating animals in vivo with potential inducers and measuring enzyme
activities in vitro or in cell-based in vitro preparations such as hepatocytes, liver
slices, or cell lines.
Recent studies have demonstrated that primary cultures of hepatocytes can
be used for studying the inducibility of metabolizing enzymes such as P450 under
certain incubation conditions
Enzyme induction is usually inducer-concentration–dependent. The extent of
induction increases as the inducer concentration increases; however, above
certain values, induction starts to decline.
In general, inducers increase the content of endoplasmic reticulum within
hepatocytes as well as liver weight.
In some cases, an inducer induces enzymes responsible for its own
metabolism (so-called “autoinduction”).
51. Induction of Drug Metabolising Enzymes
Several drugs and chemicals have ability to increase the drug
metabolising activity of enzymes called as enzyme induction.
These drugs known as enzyme inducers mainly interact with DNA and
increase the synthesis of microsomal enzyme proteins, especially
cytochrome P-450 and glucuronyl transferase.
As a result, there is enhanced metabolism of endogenous substances
(e.g., sex steroids) and drugs metabolised by microsomal enzymes.
Some drugs (e.g., carbamazepine and rifampicin) may stimulate their
own metabolism, the phenomenon being called as auto-induction or
self induction.
52. Since different cytochrome P450 isoenzymes are involved in the
metabolism of different drugs, enzyme induction by one drug affects
metabolism of only those drugs, which are substrate for the induced
isoenzyme.
However, some drugs like Phenobarbitone may affect metabolism of a
large number of drugs because they induce isoenzymes like CYP3A4 and
CYP2D6 which act on many drugs.
Enzyme inducers are generally lipid-soluble compounds with relatively long
plasma half-lives.
Repeated administration of inducers for a few days (3 to 10 days) is often
required for enzyme induction, and on stoppage of drug administration,
the enzymes return to their original value over 1 to 3 weeks.
Non-microsomal enzymes are not known to be induced by any drug or
chemical.
53.
54. Clinical importance of enzyme induction
It reduces efficacy and potency of drugs metabolised by these
enzymes.
It reduces plasma half-life and duration of action of drugs.
It enhances drug tolerance.
It increases drug toxicity by enhancing concentration of
metabolite, if metabolite is toxic.
It increases chances of drug interactions.
It alters physiological status of animal due to altered metabolism
of endogenous compounds like sex steroids.
55. Inhibition of Drug Metabolising Enzymes
Contrary to metabolising enzyme induction, several drugs or
chemicals have the ability to decrease the drug metabolising activity of
certain enzymes called as enzyme inhibition.
Enzyme inhibition can be either non-specific of microsomal enzymes
or specific of some non-microsomal enzymes (e.g., monoamine oxidase,
cholinesterase and aldehyde dehydrogenase).
The inhibition of hepatic microsomal enzymes mainly occurs due to
administration of hepatotoxic agents,
which cause either rise in the rate of enzyme degradation (e.g., carbon
tetrachloride and carbon disulphide) or fall in the rate of enzyme synthesis
(e.g., Puromycin and Dactinomycin).
56. Nutritional deficiency, hormonal imbalance or hepatic
dysfunction, etc.also inhibit microsomal enzymes indirectly.
Inhibition of non-microsomal enzymes with specific function
usually results when Structurally similar compounds compete for
the active site on the enzymes.
Such an inhibition is usually rapid (a single dose of inhibitor
may be sufficient) and clinically more important than the non-
specific microsomal enzyme inhibition.
Enzyme inhibition generally results in depressed metabolism
of drugs.
As a result, the plasma hall-life, duration of action, and efficacy
as well toxicity of the object drug (whose metabolism has been
inhibited) are significantly enhanced.
57. In case the drug undergoes hepatic first-pass effect, the
bioavailability and toxicity Of the drug will be markedly increased
in presence of enzyme inhibition. Enzyme inhibition may also
produce undesirable drug interactions.
In therapeutics, some specific enzyme inhibitors like
monoamine oxidase inhibitors, cholinesterase inhibitors and
angiotensin converting enzyme (ACE) inhibitors are purposely
used for producing desirable pharmacological actions
58. Inducing Agents
In general, enzyme inducers are lipophilic at physiological pH and
exhibit relatively long t 1/2 with high accumulation in the liver.
Different classes of enzyme inducers.
1. Barbiturates: Phenobarbitone, Phenobarbital.
2. Polycyclic aromatic hydrocarbons (PAH): 3-methylcholanthrene (3-MC),
2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD), β-naphthoflavone β ( -NF).
3. Steroids: Pregnenalone 16-α -carbonitrile (PCN), Dexamethasone.
4. Simple hydrocarbons with aliphatic chains: Ethanol (chronic), Acetone,
5. Hypolipidemic agents: Clofibrate, lauric acids.
6. Macrolide antibiotics: Triacetyloleandomycin (TAO).
7. A wide variety of structurally unrelated compounds: e.g., Antipyrine,
Carisoniazid. Bamazepine, Phenytoin, and Rifampicin
59.
60.
61.
62.
63. EXTRAHEPATIC METABOLISM
Most tissues have some metabolic activity; however,
quantitatively the liver is by far the most important organ for drug
metabolism.
Important organs for extrahepatic metabolism include the
intestine (enterocytes and intestinal microflora), kidney, lung,
plasma, blood cells, placenta, skin, and brain.
In general, the extent of metabolism in the major extrahepatic
drug-metabolizing organs such as the small intestine, kidney, and
lung is approximately 10–20% of the hepatic metabolism.
Less than 5% of extrahepatic metabolism compared to hepatic
metabolism can be considered low with negligible
pharmacokinetic implications
64. First-Pass Effect/First-Pass Metabolism
First-pass effect (first-pass metabolism or pre-systemic metabolism) may be defined
as the loss of drug through biotransformation before it enters systemic circulation.
This may occur during passage of drug for first time (therefore called first-pass
effect/metabolism) through intestine or liver after oral administration.
Intestinal first-pass effect: In this type, drugs are metabolised in the gastrointestinal
tract by enzymes present in either gut mucosa or gut lumen before they are
absorbed
Recent studies have indicated that P450 isoforms such as CYP2C19 and 3A4 in
enterocytes might play an important role in the presystemic intestinal metabolism of
drugs and the large interindividual variability in systemic exposure after oral
administration
The cytochrome P450 content of the intestine is about 35% of the hepatic content
in the rabbit, but accounts for only 4% of the hepatic content in the mouse.
Cytochrome P450 levels and activities are highest in the duodenum near the
pyrolus, and then decrease toward the colon
A similar trend in regional activity levels along the intestine has been observed for
glucuronide, sulfate, and glutathione conjugating enzymes.
65. Microorganisms present in the GI tract also inactivate some drugs.
Such drugs are not suitable by oral administration due to poor
bioavailability (e.g., catecholamines).
Hepatic first-pass effect: In this type, drugs are suitably absorbed
across the GI tract and enter portal circulation, but they are rapidly
and significantly metabolised during the first passage through the
liver.
(Normally, when a drug is absorbed across GI tract, it first enters the
portal vein and passes through liver before it reaches the systemic
circulation).
Such drugs are also not/less suitable by oral administration due to
their poor bioavailability. Examples of drugs undergoing significant
hepatic first-pass effect include Propranolol, Lignocaine and
Nitro-glycerine.
66. The rate and extent of first-pass intestinal metabolism of a drug
after oral administration are dependent on various physiological
factors
1. Site of absorption: If the absorption site in the intestine is different
from the metabolic site, first-pass intestinal metabolism of a drug
may not be significant.
2. Intracellular residence time of drug molecules in enterocytes: The
longer the drug molecules stay in the enterocytes prior to entering
the mesenteric vein, the more extensive the metabolism.
3. Diffusional barrier between splanchnic bed and enterocytes: The
lower the diffusibility of a drug from the enterocytes to the
mesenteric vein, the longer its residence time.
4. Mucosal blood flow: Blood in the splanchnic bed can act as a sink
to carry drug molecules away from the enterocytes, which reduces
intracellular residence time of drug in the enterocytes
67. Renal Metabolism
In addition to physiological functions of homeostasis in water and
electrolytes and the excretion of endogenous and exogenous compounds
from the body, the kidneys are the site of significant biotransformation
activities for both phase I and phase II metabolism.
The renal cortex, outer medulla, and inner medulla exhibit different
profiles of drug metabolism, which appears to be due to heterogeneous
distribution of metabolizing enzymes along the nephron.
Most metabolizing enzymes are localized mainly in the proximal tubules,
although various enzymes are distributed in all segments of the nephron
The pattern of renal blood flow, pH of the urine, and the urinary
concentrating mechanism can provide an environment that facilitates the
precipitation of certain compounds, including metabolites formed within the
kidneys.
The high concentration or crystallization of xenobiotics and/or their
metabolites can potentially cause significant renal impairment in specific
regions of the kidneys.
68. Metabolism in Blood
Blood contains various proteins and enzymes.
As metabolizing enzymes, esterases, including cholinesterase,
arylesterase, and carboxylesterase, have the most significant effects
on hydrolysis of compounds with ester, carbamate, or phosphate
bonds in blood .
Esterase activity can be found mainly in plasma, with less activity in
red blood cells.
Plasma albumin itself may also act as an esterase under certain
conditions.
For instance, albumin contributes about 20% of the total hydrolysis
of aspirin to salicylic acid in human plasma.
The esterase activity in blood seems to be more extensive in small
animals such as rats than in large animals and humans. Limited, yet
significant monoamine oxidase activities can be also found in blood.