The document provides an overview of key concepts in pharmacology including:
- Pharmacodynamics describes the site and mode of action of drugs. Pharmacokinetics describes how drug concentration changes over time through absorption, distribution, metabolism and excretion.
- Drugs act by binding to receptors like ion channels, enzymes, or DNA to produce their effects. Specific binding allows for fewer side effects.
- Agonists mimic endogenous ligands while antagonists block the action. Drugs can be classified based on their binding properties and ability to be reversed.
- Multiple factors influence drug absorption, distribution, metabolism and excretion including pH, lipid solubility, plasma protein binding and liver/kidney function.
- Adverse drug
Therapeutic objective (prevention of DVT) Choose drug & dosing regimen (warfarin od) Monitor therapeutic and toxic response (INR and bleeding) PK PD Initiation and management of drug therapy
Drug levels can be monitored to ensure they remain within a therapeutic range. This involves repeated dosing to maintain steady state levels between a lower limit for adequate effect and an upper limit to avoid toxicity for drugs with a narrow therapeutic index or variable pharmacokinetics. Factors like liver or kidney function and drug interactions can impact drug clearance and require dosing adjustments.
The document discusses therapeutic drug monitoring (TDM), including choosing a drug and dosing regimen for a therapeutic objective, monitoring the therapeutic and toxic response, and managing drug therapy. It provides examples of TDM for various drugs, noting their therapeutic ranges, toxicity risks, and factors that influence pharmacokinetics and clearance. Close monitoring of drug levels is especially important for drugs with a low therapeutic index or highly variable pharmacokinetics.
Midterm [CH4] Psychopharmacology by Sujit Kumar Kar MD.pptTristanBabaylan1
This document discusses psychopharmacology and the effects of drugs on affect, cognition, and behavior. It covers topics like pharmacokinetics, drug effectiveness, routes of drug administration, tolerance and sensitization, synaptic transmission, and drug actions on synaptic transmission. It also summarizes different classes of psychotropic drugs like antipsychotics, antidepressants, mood stabilizers, anxiolytics, and others. It discusses objectives of treatment, reasons for using medications, phases of treatment, potential adverse effects, and principles of prescribing and managing treatment failure.
This document discusses psychopharmacology and the effects of drugs on affect, cognition, and behavior. It covers topics like pharmacokinetics, drug effectiveness, routes of drug administration, tolerance and sensitization, synaptic transmission, and drug actions on synaptic transmission. It also summarizes different classes of psychotropic drugs like antipsychotics, antidepressants, mood stabilizers, anxiolytics, and others. It discusses objectives of treatment, reasons for using medications, phases of treatment, potential adverse effects, and principles of prescribing and managing treatment failure.
Psychopharmacology Dr. Sujit Kumar kar.pptSaqibTeli1
This document discusses psychopharmacology and the effects of drugs on affect, cognition, and behavior. It covers topics like pharmacokinetics, drug effectiveness, routes of drug administration, tolerance and sensitization, synaptic transmission, and drug actions on synaptic transmission. It also summarizes different classes of psychotropic drugs like antipsychotics, antidepressants, mood stabilizers, anxiolytics, and others. It discusses objectives of treatment, reasons for using medications, phases of treatment, potential adverse effects, and principles of prescribing and managing treatment failure.
This document discusses drug interactions, which can occur via pharmacokinetic or pharmacodynamic mechanisms. Pharmacokinetic interactions involve effects on absorption, distribution, metabolism, or excretion of one drug by another drug. Common examples include inhibition of cytochrome P450 enzymes, alteration of gut motility, and displacement from plasma protein binding sites. Pharmacodynamic interactions involve direct effects on physiological systems or receptor sites, and can result in synergism, antagonism, or unexpected toxicity. It is important for clinicians to be aware of potential drug interactions due to their impact on treatment outcomes and patient safety.
PHARMACOKINETICS all about metabolism included.pptxmahadan07
Pharmacokinetics studies the absorption, distribution, metabolism, and excretion of drugs in the body. Absorption involves passage of drugs through membranes to reach sites of action by diffusion, active transport, or endocytosis. Distribution involves transport of drugs throughout tissues, determined by factors like volume of distribution. Metabolism involves chemical breakdown of drugs by enzymes, especially in the liver. Excretion removes drugs from the body, primarily through the kidneys by glomerular filtration, tubular reabsorption, and tubular secretion. Pharmacokinetic properties determine dosing strategies to achieve therapeutic drug concentrations.
This document provides an overview of the three phases of drug action: the pharmaceutic phase, pharmacokinetic phase, and pharmacodynamic phase. It describes the processes involved in each phase, including drug absorption, distribution, metabolism, and excretion in the pharmacokinetic phase. Key concepts like therapeutic index, drug interactions, and the five rights of drug administration are also summarized. The document is intended as an introduction to pharmacology and the processes that determine a drug's effects in the body.
Therapeutic objective (prevention of DVT) Choose drug & dosing regimen (warfarin od) Monitor therapeutic and toxic response (INR and bleeding) PK PD Initiation and management of drug therapy
Drug levels can be monitored to ensure they remain within a therapeutic range. This involves repeated dosing to maintain steady state levels between a lower limit for adequate effect and an upper limit to avoid toxicity for drugs with a narrow therapeutic index or variable pharmacokinetics. Factors like liver or kidney function and drug interactions can impact drug clearance and require dosing adjustments.
The document discusses therapeutic drug monitoring (TDM), including choosing a drug and dosing regimen for a therapeutic objective, monitoring the therapeutic and toxic response, and managing drug therapy. It provides examples of TDM for various drugs, noting their therapeutic ranges, toxicity risks, and factors that influence pharmacokinetics and clearance. Close monitoring of drug levels is especially important for drugs with a low therapeutic index or highly variable pharmacokinetics.
Midterm [CH4] Psychopharmacology by Sujit Kumar Kar MD.pptTristanBabaylan1
This document discusses psychopharmacology and the effects of drugs on affect, cognition, and behavior. It covers topics like pharmacokinetics, drug effectiveness, routes of drug administration, tolerance and sensitization, synaptic transmission, and drug actions on synaptic transmission. It also summarizes different classes of psychotropic drugs like antipsychotics, antidepressants, mood stabilizers, anxiolytics, and others. It discusses objectives of treatment, reasons for using medications, phases of treatment, potential adverse effects, and principles of prescribing and managing treatment failure.
This document discusses psychopharmacology and the effects of drugs on affect, cognition, and behavior. It covers topics like pharmacokinetics, drug effectiveness, routes of drug administration, tolerance and sensitization, synaptic transmission, and drug actions on synaptic transmission. It also summarizes different classes of psychotropic drugs like antipsychotics, antidepressants, mood stabilizers, anxiolytics, and others. It discusses objectives of treatment, reasons for using medications, phases of treatment, potential adverse effects, and principles of prescribing and managing treatment failure.
Psychopharmacology Dr. Sujit Kumar kar.pptSaqibTeli1
This document discusses psychopharmacology and the effects of drugs on affect, cognition, and behavior. It covers topics like pharmacokinetics, drug effectiveness, routes of drug administration, tolerance and sensitization, synaptic transmission, and drug actions on synaptic transmission. It also summarizes different classes of psychotropic drugs like antipsychotics, antidepressants, mood stabilizers, anxiolytics, and others. It discusses objectives of treatment, reasons for using medications, phases of treatment, potential adverse effects, and principles of prescribing and managing treatment failure.
This document discusses drug interactions, which can occur via pharmacokinetic or pharmacodynamic mechanisms. Pharmacokinetic interactions involve effects on absorption, distribution, metabolism, or excretion of one drug by another drug. Common examples include inhibition of cytochrome P450 enzymes, alteration of gut motility, and displacement from plasma protein binding sites. Pharmacodynamic interactions involve direct effects on physiological systems or receptor sites, and can result in synergism, antagonism, or unexpected toxicity. It is important for clinicians to be aware of potential drug interactions due to their impact on treatment outcomes and patient safety.
PHARMACOKINETICS all about metabolism included.pptxmahadan07
Pharmacokinetics studies the absorption, distribution, metabolism, and excretion of drugs in the body. Absorption involves passage of drugs through membranes to reach sites of action by diffusion, active transport, or endocytosis. Distribution involves transport of drugs throughout tissues, determined by factors like volume of distribution. Metabolism involves chemical breakdown of drugs by enzymes, especially in the liver. Excretion removes drugs from the body, primarily through the kidneys by glomerular filtration, tubular reabsorption, and tubular secretion. Pharmacokinetic properties determine dosing strategies to achieve therapeutic drug concentrations.
This document provides an overview of the three phases of drug action: the pharmaceutic phase, pharmacokinetic phase, and pharmacodynamic phase. It describes the processes involved in each phase, including drug absorption, distribution, metabolism, and excretion in the pharmacokinetic phase. Key concepts like therapeutic index, drug interactions, and the five rights of drug administration are also summarized. The document is intended as an introduction to pharmacology and the processes that determine a drug's effects in the body.
Pharmacogenomics is the study of how an individual's genetic inheritance affects their body's response to drugs. Certain cytochrome P450 enzymes are involved in drug metabolism and can impact how drugs are absorbed, distributed, metabolized and excreted from the body. Single nucleotide polymorphisms (SNPs) in genes that encode these enzymes or drug targets can help explain inter-individual variability in drug responses. Pharmacogenomic testing may help optimize drug therapy for conditions like cancer, cardiovascular disease, and asthma by matching patients with medications based on their genetic profile.
The purpose of studying pharmacokinetics and pharmacodynamics is to understand the drug action, therapy, design, development and evaluation.
PHARMACOKINETIC: It is a branch of Pharmacology which deals with the study of Absorption, Distribution, Metabolism, Excretion / Elimination.
Pharmacokinetics is the study of “What the body does to the drug”
PHARMACODYNAMIC:
Pharmacodynamics is the study of biochemical and physiologic effect of drug. It is the study of “What the drug does to the body”
This document provides an overview of pharmacokinetics, specifically focusing on absorption. It defines pharmacokinetics as the study of what the body does to drugs. The four main processes are absorption, distribution, metabolism, and excretion (ADME). Absorption is defined as the passage of drugs through cell membranes to reach the site of action. The main mechanisms of absorption are described as simple diffusion, active transport, facilitated diffusion, and pinocytosis. Factors that influence absorption, such as drug properties and gastrointestinal factors, are also discussed.
This document discusses various factors that can modify drug action, including genetic and non-genetic factors. Body size, age, sex, species, race, and genetics can impact drug pharmacokinetics and dosing requirements. Route of administration, environmental factors, psychological states, concurrent diseases, and drug interactions can also influence drug effects both quantitatively and qualitatively. Tolerance can develop with repeated drug use due to changes in disposition or receptor sensitivity. These modifying factors are important to consider for safe and effective use of medications.
Drug Distribution is a Process where by an absorbed drug moves away from the site of absorption to other area of body where it had no drug initially, conc gradient being in the direction of plasma to tissues.
Determines the transport of drugs to their site of action, to other sites and to organs of metabolism and excretion.
& it is Non-uniform due to various factors.Difference in regional blood flow Factors affecting the Drug distibution:
-Physico-chemical charecteristics of the drug.
-Lipid solubility
Capillary permeability
-Ionization at physiological pH
-Extent of binding to plasma & tissue proteins
-Disease
Special compartments and barrier
-Presence of tissue specific transporters
-Tissue volume &
-Age
This document discusses the pharmacokinetics of drugs, which refers to what the body does to a drug. It covers the absorption, distribution, metabolism and excretion of drugs. Key points include that absorption transfers a drug to the bloodstream, distribution passes a drug to tissues, metabolism chemically alters drugs to aid excretion, and excretion removes drugs from the body. Factors like a drug's properties, dosage, and the body's clearance rate determine its behavior and effects over time. Understanding pharmacokinetics helps optimize drug therapy and dosing.
Basic knowledge about Pharmacology which will be helpful in Academic and for GPAT exam. Brief description about Pharmacokinetics and Pharmacodynamic, clinical trials and some important definitions. Different types of drug administration.
Therapeutic drug monitoring (TDM) involves measuring drug concentrations in a patient's bloodstream to optimize dosage regimens. TDM is used for drugs with narrow therapeutic ranges, marked pharmacokinetic variability, or difficult-to-monitor target concentrations. A drug's absorption, distribution, and elimination are based on its route of administration, protein binding, volume of distribution, and clearance. TDM guides dosing of drugs like digoxin, lithium, antibiotics, antiepileptics, immunosuppressants, and some antineoplastics to ensure concentrations remain within therapeutic ranges and avoid toxicity.
The document discusses drug elimination and kinetics. It covers:
- Drug elimination occurs through metabolism and excretion.
- Drugs can be eliminated through first or zero-order kinetics. Most drugs follow first-order kinetics where a constant fraction is eliminated per unit time.
- Drugs are mainly eliminated through the kidneys and liver, with other routes including the lungs, bile, sweat and milk.
- Key processes for renal elimination include glomerular filtration, tubular secretion and reabsorption. pH changes can impact drug ionization and reabsorption.
- The half-life of a drug describes the time for its concentration to reduce by half and impacts dosing adjustments. Drug accumulation can occur if
Therapeutic drug monitoring (TDM) involves analyzing drug concentrations in blood to ensure dosage is therapeutic and not toxic. TDM is indicated when the therapeutic index is narrow, drug effects vary between patients, or changes in a patient's condition could affect drug levels. Common drugs monitored include cardiac medications, antibiotics, antiepileptics, psychotherapeutics, and immunosuppressants. Factors like absorption, distribution, metabolism, and excretion influence circulating drug concentrations.
Prescribing in physiological and pathological conditionsDrSahilKumar
This document discusses factors that modify drug action and prescribing in physiological and pathological conditions. It covers topics like:
- Individuals can differ in how they absorb, distribute, metabolize, and excrete drugs due to genetic and environmental factors. This impacts the dosage needed.
- Physiological states like age, pregnancy, organ function, and disease states can significantly impact drug pharmacokinetics and pharmacodynamics. Changes in absorption, distribution, metabolism, and excretion often require dosage adjustments.
- Prescribing for special populations like pediatrics, elderly, and those with organ dysfunction requires special consideration of altered physiology to ensure safety and efficacy. Close monitoring is important with high risk drug classes.
Drug interactions are an important consideration in psychiatry. Several types of interactions can occur, including pharmaceutical, pharmacokinetic, and pharmacodynamic. Pharmacokinetic interactions can affect absorption, distribution, metabolism, and excretion of drugs. Many psychiatric medications are substrates, inhibitors, or inducers of cytochrome P450 enzymes, particularly CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. Recognition of interactions is important to avoid adverse effects or lack of efficacy. Management may require dosage adjustments or choosing alternative medications.
Basics of Pharmacology general pharmacology.....pptxMosaHasen
This document discusses the general pharmacology concepts of absorption, distribution, metabolism, and excretion (ADME) of drugs in the body. It explains that ADME processes determine the fate of drugs administered, influencing their effectiveness and safety. Absorption moves drugs into circulation, distribution carries drugs throughout tissues, metabolism biotransforms drugs to more polar compounds, and excretion eliminates drugs and metabolites from the body. Understanding these processes is important for optimizing drug dosing regimens to achieve therapeutic effects while avoiding adverse reactions.
Pharmacokinetic aspects of Drug Interactionsaarushi grover
This document discusses pharmacokinetic drug-drug interactions, which involve processes of drug absorption, distribution, metabolism and excretion. It describes how interactions can affect gastric pH and drug absorption in the gastrointestinal tract. It also explains how drugs may interact by displacing each other from plasma protein binding sites or by inhibiting or inducing cytochrome P450 drug metabolizing enzymes in the liver. Inhibition of these enzymes can increase drug levels and toxicity risks, while induction can decrease drug levels and efficacy. Careful consideration of these pharmacokinetic drug interaction mechanisms is important for safe polypharmacy in patients.
Drug distribution & drug elimination pharmacologyVishnu Priya
This document discusses drug distribution and elimination in the body. It covers topics like absorption, distribution, protein binding, volume of distribution, clearance and elimination routes. Absorption involves movement of drugs from the site of administration to tissues. Distribution is the reversible process by which drugs enter tissues, depending on factors like blood flow and lipid solubility. Drugs are eliminated from the body through various routes like the kidneys, liver, lungs and intestines. Key elimination processes involve glomerular filtration, tubular secretion and reabsorption in the kidneys. The rates of drug distribution and elimination determine properties like half-life and whether kinetics are first-order or zero-order.
This document provides an overview of pharmacokinetic and pharmacodynamic principles including absorption, distribution, metabolism, excretion, and factors that influence drug response and adverse reactions.
It begins with definitions of pharmacokinetics as the processes by which drugs are absorbed, distributed, metabolized and excreted by the body. It then summarizes the key components of absorption, distribution, metabolism and excretion. Several factors that influence drug absorption such as drug properties, formulation, and patient factors are outlined. The document also discusses protein binding, distribution to tissues, phases of drug metabolism, and routes of drug excretion.
In 3 sentences or less, this document summarizes important pharmacokinetic and pharmacodynamic concepts
The binding of cosmological structures by massless topological defectsSérgio Sacani
Assuming spherical symmetry and weak field, it is shown that if one solves the Poisson equation or the Einstein field
equations sourced by a topological defect, i.e. a singularity of a very specific form, the result is a localized gravitational
field capable of driving flat rotation (i.e. Keplerian circular orbits at a constant speed for all radii) of test masses on a thin
spherical shell without any underlying mass. Moreover, a large-scale structure which exploits this solution by assembling
concentrically a number of such topological defects can establish a flat stellar or galactic rotation curve, and can also deflect
light in the same manner as an equipotential (isothermal) sphere. Thus, the need for dark matter or modified gravity theory is
mitigated, at least in part.
Pharmacogenomics is the study of how an individual's genetic inheritance affects their body's response to drugs. Certain cytochrome P450 enzymes are involved in drug metabolism and can impact how drugs are absorbed, distributed, metabolized and excreted from the body. Single nucleotide polymorphisms (SNPs) in genes that encode these enzymes or drug targets can help explain inter-individual variability in drug responses. Pharmacogenomic testing may help optimize drug therapy for conditions like cancer, cardiovascular disease, and asthma by matching patients with medications based on their genetic profile.
The purpose of studying pharmacokinetics and pharmacodynamics is to understand the drug action, therapy, design, development and evaluation.
PHARMACOKINETIC: It is a branch of Pharmacology which deals with the study of Absorption, Distribution, Metabolism, Excretion / Elimination.
Pharmacokinetics is the study of “What the body does to the drug”
PHARMACODYNAMIC:
Pharmacodynamics is the study of biochemical and physiologic effect of drug. It is the study of “What the drug does to the body”
This document provides an overview of pharmacokinetics, specifically focusing on absorption. It defines pharmacokinetics as the study of what the body does to drugs. The four main processes are absorption, distribution, metabolism, and excretion (ADME). Absorption is defined as the passage of drugs through cell membranes to reach the site of action. The main mechanisms of absorption are described as simple diffusion, active transport, facilitated diffusion, and pinocytosis. Factors that influence absorption, such as drug properties and gastrointestinal factors, are also discussed.
This document discusses various factors that can modify drug action, including genetic and non-genetic factors. Body size, age, sex, species, race, and genetics can impact drug pharmacokinetics and dosing requirements. Route of administration, environmental factors, psychological states, concurrent diseases, and drug interactions can also influence drug effects both quantitatively and qualitatively. Tolerance can develop with repeated drug use due to changes in disposition or receptor sensitivity. These modifying factors are important to consider for safe and effective use of medications.
Drug Distribution is a Process where by an absorbed drug moves away from the site of absorption to other area of body where it had no drug initially, conc gradient being in the direction of plasma to tissues.
Determines the transport of drugs to their site of action, to other sites and to organs of metabolism and excretion.
& it is Non-uniform due to various factors.Difference in regional blood flow Factors affecting the Drug distibution:
-Physico-chemical charecteristics of the drug.
-Lipid solubility
Capillary permeability
-Ionization at physiological pH
-Extent of binding to plasma & tissue proteins
-Disease
Special compartments and barrier
-Presence of tissue specific transporters
-Tissue volume &
-Age
This document discusses the pharmacokinetics of drugs, which refers to what the body does to a drug. It covers the absorption, distribution, metabolism and excretion of drugs. Key points include that absorption transfers a drug to the bloodstream, distribution passes a drug to tissues, metabolism chemically alters drugs to aid excretion, and excretion removes drugs from the body. Factors like a drug's properties, dosage, and the body's clearance rate determine its behavior and effects over time. Understanding pharmacokinetics helps optimize drug therapy and dosing.
Basic knowledge about Pharmacology which will be helpful in Academic and for GPAT exam. Brief description about Pharmacokinetics and Pharmacodynamic, clinical trials and some important definitions. Different types of drug administration.
Therapeutic drug monitoring (TDM) involves measuring drug concentrations in a patient's bloodstream to optimize dosage regimens. TDM is used for drugs with narrow therapeutic ranges, marked pharmacokinetic variability, or difficult-to-monitor target concentrations. A drug's absorption, distribution, and elimination are based on its route of administration, protein binding, volume of distribution, and clearance. TDM guides dosing of drugs like digoxin, lithium, antibiotics, antiepileptics, immunosuppressants, and some antineoplastics to ensure concentrations remain within therapeutic ranges and avoid toxicity.
The document discusses drug elimination and kinetics. It covers:
- Drug elimination occurs through metabolism and excretion.
- Drugs can be eliminated through first or zero-order kinetics. Most drugs follow first-order kinetics where a constant fraction is eliminated per unit time.
- Drugs are mainly eliminated through the kidneys and liver, with other routes including the lungs, bile, sweat and milk.
- Key processes for renal elimination include glomerular filtration, tubular secretion and reabsorption. pH changes can impact drug ionization and reabsorption.
- The half-life of a drug describes the time for its concentration to reduce by half and impacts dosing adjustments. Drug accumulation can occur if
Therapeutic drug monitoring (TDM) involves analyzing drug concentrations in blood to ensure dosage is therapeutic and not toxic. TDM is indicated when the therapeutic index is narrow, drug effects vary between patients, or changes in a patient's condition could affect drug levels. Common drugs monitored include cardiac medications, antibiotics, antiepileptics, psychotherapeutics, and immunosuppressants. Factors like absorption, distribution, metabolism, and excretion influence circulating drug concentrations.
Prescribing in physiological and pathological conditionsDrSahilKumar
This document discusses factors that modify drug action and prescribing in physiological and pathological conditions. It covers topics like:
- Individuals can differ in how they absorb, distribute, metabolize, and excrete drugs due to genetic and environmental factors. This impacts the dosage needed.
- Physiological states like age, pregnancy, organ function, and disease states can significantly impact drug pharmacokinetics and pharmacodynamics. Changes in absorption, distribution, metabolism, and excretion often require dosage adjustments.
- Prescribing for special populations like pediatrics, elderly, and those with organ dysfunction requires special consideration of altered physiology to ensure safety and efficacy. Close monitoring is important with high risk drug classes.
Drug interactions are an important consideration in psychiatry. Several types of interactions can occur, including pharmaceutical, pharmacokinetic, and pharmacodynamic. Pharmacokinetic interactions can affect absorption, distribution, metabolism, and excretion of drugs. Many psychiatric medications are substrates, inhibitors, or inducers of cytochrome P450 enzymes, particularly CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. Recognition of interactions is important to avoid adverse effects or lack of efficacy. Management may require dosage adjustments or choosing alternative medications.
Basics of Pharmacology general pharmacology.....pptxMosaHasen
This document discusses the general pharmacology concepts of absorption, distribution, metabolism, and excretion (ADME) of drugs in the body. It explains that ADME processes determine the fate of drugs administered, influencing their effectiveness and safety. Absorption moves drugs into circulation, distribution carries drugs throughout tissues, metabolism biotransforms drugs to more polar compounds, and excretion eliminates drugs and metabolites from the body. Understanding these processes is important for optimizing drug dosing regimens to achieve therapeutic effects while avoiding adverse reactions.
Pharmacokinetic aspects of Drug Interactionsaarushi grover
This document discusses pharmacokinetic drug-drug interactions, which involve processes of drug absorption, distribution, metabolism and excretion. It describes how interactions can affect gastric pH and drug absorption in the gastrointestinal tract. It also explains how drugs may interact by displacing each other from plasma protein binding sites or by inhibiting or inducing cytochrome P450 drug metabolizing enzymes in the liver. Inhibition of these enzymes can increase drug levels and toxicity risks, while induction can decrease drug levels and efficacy. Careful consideration of these pharmacokinetic drug interaction mechanisms is important for safe polypharmacy in patients.
Drug distribution & drug elimination pharmacologyVishnu Priya
This document discusses drug distribution and elimination in the body. It covers topics like absorption, distribution, protein binding, volume of distribution, clearance and elimination routes. Absorption involves movement of drugs from the site of administration to tissues. Distribution is the reversible process by which drugs enter tissues, depending on factors like blood flow and lipid solubility. Drugs are eliminated from the body through various routes like the kidneys, liver, lungs and intestines. Key elimination processes involve glomerular filtration, tubular secretion and reabsorption in the kidneys. The rates of drug distribution and elimination determine properties like half-life and whether kinetics are first-order or zero-order.
This document provides an overview of pharmacokinetic and pharmacodynamic principles including absorption, distribution, metabolism, excretion, and factors that influence drug response and adverse reactions.
It begins with definitions of pharmacokinetics as the processes by which drugs are absorbed, distributed, metabolized and excreted by the body. It then summarizes the key components of absorption, distribution, metabolism and excretion. Several factors that influence drug absorption such as drug properties, formulation, and patient factors are outlined. The document also discusses protein binding, distribution to tissues, phases of drug metabolism, and routes of drug excretion.
In 3 sentences or less, this document summarizes important pharmacokinetic and pharmacodynamic concepts
The binding of cosmological structures by massless topological defectsSérgio Sacani
Assuming spherical symmetry and weak field, it is shown that if one solves the Poisson equation or the Einstein field
equations sourced by a topological defect, i.e. a singularity of a very specific form, the result is a localized gravitational
field capable of driving flat rotation (i.e. Keplerian circular orbits at a constant speed for all radii) of test masses on a thin
spherical shell without any underlying mass. Moreover, a large-scale structure which exploits this solution by assembling
concentrically a number of such topological defects can establish a flat stellar or galactic rotation curve, and can also deflect
light in the same manner as an equipotential (isothermal) sphere. Thus, the need for dark matter or modified gravity theory is
mitigated, at least in part.
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...University of Maribor
Slides from talk:
Aleš Zamuda: Remote Sensing and Computational, Evolutionary, Supercomputing, and Intelligent Systems.
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Inter-Society Networking Panel GRSS/MTT-S/CIS Panel Session: Promoting Connection and Cooperation
https://www.etran.rs/2024/en/home-english/
ESPP presentation to EU Waste Water Network, 4th June 2024 “EU policies driving nutrient removal and recycling
and the revised UWWTD (Urban Waste Water Treatment Directive)”
EWOCS-I: The catalog of X-ray sources in Westerlund 1 from the Extended Weste...Sérgio Sacani
Context. With a mass exceeding several 104 M⊙ and a rich and dense population of massive stars, supermassive young star clusters
represent the most massive star-forming environment that is dominated by the feedback from massive stars and gravitational interactions
among stars.
Aims. In this paper we present the Extended Westerlund 1 and 2 Open Clusters Survey (EWOCS) project, which aims to investigate
the influence of the starburst environment on the formation of stars and planets, and on the evolution of both low and high mass stars.
The primary targets of this project are Westerlund 1 and 2, the closest supermassive star clusters to the Sun.
Methods. The project is based primarily on recent observations conducted with the Chandra and JWST observatories. Specifically,
the Chandra survey of Westerlund 1 consists of 36 new ACIS-I observations, nearly co-pointed, for a total exposure time of 1 Msec.
Additionally, we included 8 archival Chandra/ACIS-S observations. This paper presents the resulting catalog of X-ray sources within
and around Westerlund 1. Sources were detected by combining various existing methods, and photon extraction and source validation
were carried out using the ACIS-Extract software.
Results. The EWOCS X-ray catalog comprises 5963 validated sources out of the 9420 initially provided to ACIS-Extract, reaching a
photon flux threshold of approximately 2 × 10−8 photons cm−2
s
−1
. The X-ray sources exhibit a highly concentrated spatial distribution,
with 1075 sources located within the central 1 arcmin. We have successfully detected X-ray emissions from 126 out of the 166 known
massive stars of the cluster, and we have collected over 71 000 photons from the magnetar CXO J164710.20-455217.
Unlocking the mysteries of reproduction: Exploring fecundity and gonadosomati...AbdullaAlAsif1
The pygmy halfbeak Dermogenys colletei, is known for its viviparous nature, this presents an intriguing case of relatively low fecundity, raising questions about potential compensatory reproductive strategies employed by this species. Our study delves into the examination of fecundity and the Gonadosomatic Index (GSI) in the Pygmy Halfbeak, D. colletei (Meisner, 2001), an intriguing viviparous fish indigenous to Sarawak, Borneo. We hypothesize that the Pygmy halfbeak, D. colletei, may exhibit unique reproductive adaptations to offset its low fecundity, thus enhancing its survival and fitness. To address this, we conducted a comprehensive study utilizing 28 mature female specimens of D. colletei, carefully measuring fecundity and GSI to shed light on the reproductive adaptations of this species. Our findings reveal that D. colletei indeed exhibits low fecundity, with a mean of 16.76 ± 2.01, and a mean GSI of 12.83 ± 1.27, providing crucial insights into the reproductive mechanisms at play in this species. These results underscore the existence of unique reproductive strategies in D. colletei, enabling its adaptation and persistence in Borneo's diverse aquatic ecosystems, and call for further ecological research to elucidate these mechanisms. This study lends to a better understanding of viviparous fish in Borneo and contributes to the broader field of aquatic ecology, enhancing our knowledge of species adaptations to unique ecological challenges.
Travis Hills' Endeavors in Minnesota: Fostering Environmental and Economic Pr...Travis Hills MN
Travis Hills of Minnesota developed a method to convert waste into high-value dry fertilizer, significantly enriching soil quality. By providing farmers with a valuable resource derived from waste, Travis Hills helps enhance farm profitability while promoting environmental stewardship. Travis Hills' sustainable practices lead to cost savings and increased revenue for farmers by improving resource efficiency and reducing waste.
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
Authoring a personal GPT for your research and practice: How we created the Q...Leonel Morgado
Thematic analysis in qualitative research is a time-consuming and systematic task, typically done using teams. Team members must ground their activities on common understandings of the major concepts underlying the thematic analysis, and define criteria for its development. However, conceptual misunderstandings, equivocations, and lack of adherence to criteria are challenges to the quality and speed of this process. Given the distributed and uncertain nature of this process, we wondered if the tasks in thematic analysis could be supported by readily available artificial intelligence chatbots. Our early efforts point to potential benefits: not just saving time in the coding process but better adherence to criteria and grounding, by increasing triangulation between humans and artificial intelligence. This tutorial will provide a description and demonstration of the process we followed, as two academic researchers, to develop a custom ChatGPT to assist with qualitative coding in the thematic data analysis process of immersive learning accounts in a survey of the academic literature: QUAL-E Immersive Learning Thematic Analysis Helper. In the hands-on time, participants will try out QUAL-E and develop their ideas for their own qualitative coding ChatGPT. Participants that have the paid ChatGPT Plus subscription can create a draft of their assistants. The organizers will provide course materials and slide deck that participants will be able to utilize to continue development of their custom GPT. The paid subscription to ChatGPT Plus is not required to participate in this workshop, just for trying out personal GPTs during it.
ESR spectroscopy in liquid food and beverages.pptxPRIYANKA PATEL
With increasing population, people need to rely on packaged food stuffs. Packaging of food materials requires the preservation of food. There are various methods for the treatment of food to preserve them and irradiation treatment of food is one of them. It is the most common and the most harmless method for the food preservation as it does not alter the necessary micronutrients of food materials. Although irradiated food doesn’t cause any harm to the human health but still the quality assessment of food is required to provide consumers with necessary information about the food. ESR spectroscopy is the most sophisticated way to investigate the quality of the food and the free radicals induced during the processing of the food. ESR spin trapping technique is useful for the detection of highly unstable radicals in the food. The antioxidant capability of liquid food and beverages in mainly performed by spin trapping technique.
The debris of the ‘last major merger’ is dynamically youngSérgio Sacani
The Milky Way’s (MW) inner stellar halo contains an [Fe/H]-rich component with highly eccentric orbits, often referred to as the
‘last major merger.’ Hypotheses for the origin of this component include Gaia-Sausage/Enceladus (GSE), where the progenitor
collided with the MW proto-disc 8–11 Gyr ago, and the Virgo Radial Merger (VRM), where the progenitor collided with the
MW disc within the last 3 Gyr. These two scenarios make different predictions about observable structure in local phase space,
because the morphology of debris depends on how long it has had to phase mix. The recently identified phase-space folds in Gaia
DR3 have positive caustic velocities, making them fundamentally different than the phase-mixed chevrons found in simulations
at late times. Roughly 20 per cent of the stars in the prograde local stellar halo are associated with the observed caustics. Based
on a simple phase-mixing model, the observed number of caustics are consistent with a merger that occurred 1–2 Gyr ago.
We also compare the observed phase-space distribution to FIRE-2 Latte simulations of GSE-like mergers, using a quantitative
measurement of phase mixing (2D causticality). The observed local phase-space distribution best matches the simulated data
1–2 Gyr after collision, and certainly not later than 3 Gyr. This is further evidence that the progenitor of the ‘last major merger’
did not collide with the MW proto-disc at early times, as is thought for the GSE, but instead collided with the MW disc within
the last few Gyr, consistent with the body of work surrounding the VRM.
The ability to recreate computational results with minimal effort and actionable metrics provides a solid foundation for scientific research and software development. When people can replicate an analysis at the touch of a button using open-source software, open data, and methods to assess and compare proposals, it significantly eases verification of results, engagement with a diverse range of contributors, and progress. However, we have yet to fully achieve this; there are still many sociotechnical frictions.
Inspired by David Donoho's vision, this talk aims to revisit the three crucial pillars of frictionless reproducibility (data sharing, code sharing, and competitive challenges) with the perspective of deep software variability.
Our observation is that multiple layers — hardware, operating systems, third-party libraries, software versions, input data, compile-time options, and parameters — are subject to variability that exacerbates frictions but is also essential for achieving robust, generalizable results and fostering innovation. I will first review the literature, providing evidence of how the complex variability interactions across these layers affect qualitative and quantitative software properties, thereby complicating the reproduction and replication of scientific studies in various fields.
I will then present some software engineering and AI techniques that can support the strategic exploration of variability spaces. These include the use of abstractions and models (e.g., feature models), sampling strategies (e.g., uniform, random), cost-effective measurements (e.g., incremental build of software configurations), and dimensionality reduction methods (e.g., transfer learning, feature selection, software debloating).
I will finally argue that deep variability is both the problem and solution of frictionless reproducibility, calling the software science community to develop new methods and tools to manage variability and foster reproducibility in software systems.
Exposé invité Journées Nationales du GDR GPL 2024
Deep Software Variability and Frictionless Reproducibility
Memorizing notes.pdf
1. Memorizing notes- Pharmacology 1
Intro into pharmacology (Module 1)
- Pharmacodynamics: Site of action and mode of action
- Pharmacokinetics: Way in which the drug
concentration changes with time (ADME, quantitively
pharmacokinetics).
- Osmotic diuretics (mannitol) or osmotic laxatives
(sorbitol) will bind to water (TARGET) in the kidney
- Antacids will bind to acid (TARGET) in the stomach
- Unscheduled drugs can be sold through other retail
outlets
- Receptors are macromolecular structures in or on the cell surface with which drugs interact to
produce effects:
o Change in structure can change activity of drug
o The type of chemical interaction with the receptor can influence the action of the drug
o A high degree of specificity can result in fewer toxic side effects.
- Receptor example: sensing elements for chemical communication (hormone, neurotransmitter,
nonhormones)
o D2 dopamine: agonist dopamine, antagonist: chlorpromazine
- Ion channels: may be blocked by a drug or the gating operation may be modulated
o Local anesthetics: physically block the voltage gated sodium channel
o Benzodiazepines bind to a region of the GABA receptor/chloride channel complex
- Enzymes: drugs may be competitive or non-competitive
- Pumps: Drugs may inhibit the action of carrier molecules: proton pump inhibitors
- Binding to DNA: some anti-tumor alkylating drugs
- Counterfeit substrates: Antihypertensive agent alpha-methyldopa substitutes for normal
substrates in the synthesis of noradrenaline resulting in a less active end product.
- Potency: Inherent ability of drug to combine with receptors. Important for dosage but
unimportant for clinical purposes
- ED50 is a measure of potency
- Emax measure of efficacy
2. 2
Agonists, antagonist and drug toxicity (Module 1)
- Bethanechol mimics action of Ach- muscarinic Ach receptors
- Atropine competitively inhibits the action of ACH at the muscarinic receptors
- Agonists- affinity and intrinsic activity
- Antagonists- affinity but lack intrinsic activity
- Buprenorphine (partial agonist at μ opioid receptor) produces less analgesia than morphine (full
agonist)
- Reversible competitive: increased concentration agonist can reverse blockade. ED50 increased
o Atropine
- Irreversible: antagonist dissociates slowly or not at all. Blockade cannot be reverses
o ED50 same, Emax decreased
o Methysergide (5-HTreceptorantagonist) used in Rx of migraine
o Neurotoxins from snake venom (nicotinic receptor antagonist)
- Non-competitive: ED50 increased Emax decreases
o Suxamethonium (depolarizing muscle relaxant) desensitizes nicotinic receptor ion
channel
Calcium antagonists (e.g. verapamil and nifedipine) non-specific block of contractions by
other drugs
- Physiological antagonism: Blockade of effect due to production of an effect in the opposite
direction, opposing receptors.
o In gut - ACh contraction mediated through muscarinic receptor antagonised by
noradrenaline (Nad) relaxation mediated through beta receptor
- Desensitization and tachyphylaxis: a drug effect which gradually diminishes over a few seconds to
minutes. Caused:
o Change in receptors: Receptor resulting in tight binding of agonist without opening of
ion channel
o Exhaustion of mediators: secondary messengers
o Increased metabolic degradation
o Physiological adaptation: side effects
o Translocation of receptors: Receptor may be internalized by endocytosis: EG:
gonadotrophin-releasing hormone inhibits gonadotropin release by continuous receptor
simulation used in prostatic cancer.
- LD50/ED50 gives an idea of the relative margin of safety of a drug
- Greater this ratio the safer the drug
3. 3
Drug admiration and absorption (Module 2)
- Low lipid solubility- poorly absorbed from gut
- Most drugs or their salts are weak acids/bases
- Ionized drugs are not very lipid soluble, only non-
ionized form of drug crosses membrane readily
- If pKa= pH, compound is 50% ionized and 50%
non-ionized
- Gastric pH=3
- Plasma pH=7.4
- Urine pH=8
- Drugs cross lipid membranes mainly by passive diffusion
- Only the uncharged species (the protonated form for a
weak acid, the unprotonated form for a weak base) can
diffuse across lipid membranes; this gives rise to pH
partition.
- Weak acids tend to accumulate in compartments of
relatively high pH
- Oral route: most common
o First pass metabolism: Thus, drugs that are
highly metabolised by the liver may attain very low circulating levels relative to those
attained after parenteral administration
o Drugs taken orally are absorbed in stomach and small intestine
o Blood vessels take the drug directly to the liver
o Drug passes through liver before being distributions round the body
o Irregular absorption: delayed gastric emptying, alter stomach pH due to food,
decreased splanchnic blood flow in heart failure, complex formation
o Gastrointestinal irritation
o Low pH may inactive certain drugs
o Particle size
o Require patient compliance
- Oral bioavailability: Fraction of orally administered drug that reaches the systemic circulation
- Sublingual- avoids first pass metabolism, rapid absorption
- Intravenous
- IM and subcutaneous
- Rectal
- Spinal
- Topical
4. 4
Drug distribution, metabolism and excretion (module 3)
- Drug distribution depends on: permeability across barriers,
binding within compartments, pH portion, fat: water portion
- If the free fraction (FF, unbound) is <10% apparently slight
variations in FF can have important consequences: potential
for drug interactions
- As FF becomes larger (eg 10-25%) binding becomes less important
- If 2 drugs compete for the same site, then stronger affinity will transiently displace weaker affinity
- Phenylbutazone displaces warfarin and also inhibits warfarin
metabolism → internal bleeding
- aspirin displaces methotrexate and also reduces its renal secretion → GIT and kidney toxicity
Quinidine/verapamil/amiodarone displace digoxin and reduce
its renal excretion → severe dysrhythmias
-
Loading dose = target plasma conc. x Volume of distribution (Vd)
1. The drug must be instantaneously distributed, and no metabolism should have occurred
2. No portion of the drug should have been excreted
3. No portion of the drug should have been sequestered (thiopentone, being lipid
soluble is sequestered into fat)
- Ionised drugs (which are filtered or actively secreted in proximal tubule) undergo little
reabsorption and are excreted
- POINT TO METABOLISM IS TO MAKE THE COMPOUND MORE WATER NOT
LIPID SOLUBLE
- Lipophilic drugs diffuse back (reabsorbed) into blood
therefore not eliminated
- Drugs bound to plasma proteins are unable to be
filtered but are subject to tubular secretion (eg.
penicillin)
Aspirin undergoes phase 1 and phase 2 glucuronidation
Paracetamol undergoes phase 2 only
5. 5
Renal excretions
- Nearly all drugs cross the glomerular filter
freely
- They will be efficiently excreted (ie. remain in
tubular fluid) unless they are lipid soluble and
can be re-absorbed into the blood
- The key function of metabolism is to make the drug molecule less lipid soluble (more water
soluble/more charged)
- Drugs excreted unchanged: digoxin gentamicin, methotrexate
6. 6
Quantitative pharmacokinetics (module 4)
- Clearance (CL) is the volume of plasma cleared of drug
per unit time (L/hr)
- Relates rate of drug elimination to its plasma
concentration (Cp) (mg/L)
- Rate of drug elimination = Cp x CL (mg/hr)
- For most individuals at therapeutic concs CL is the same
at different drug doses (Q) (NB: not in overdose)
Small or large volume of distribution, results in the
same clearance
7. 7
- 2 opposing forces at work
- Patient compliance
- Fluctuations in plasma concentration- less often the
drug is given, greater the fluctuation in Cp
2 compartment model
- A fast and slow phase of loss of drug from plasma is noted
- The fast phase is characterized as distribution from plasma to the
tissue
- The slow phase equates to elimination from the plasma
- Most drugs are described by a 2-compartment model
8. 8
- Rate of eliminated is independent of drug starting concentration
- t1/2 is dependent on drug starting concentration
- Eg. Ethanol = 4 mmol/hr
- Once the Cp producing the maximal rate of metabolism is exceeded, the Cp will, in principle,
increase indefinitely and a steady state Cp will not be reached
- Therefore, Cp should be regularly measured
9. 9
Adverse drug reactions
- Noxious and unintended and that occurs at doses normally used in humans
- The TGA evaluates therapeutic goods before they are marketed and monitors products once on
the market
- All serious ADRs are documented by the time a drug is marketed
- It is difficult to determine if a drug is responsible
- ADRs should only be reported if absolutely certain
- One reported case can’t make a difference
Main causes of variability are:
- Age (neonatal vs adult vs elderly)
- Pharmacogenetics (genetic factors)
- Disease (kidney or liver disease)
- Idiosyncratic reactions (rare fatal reactions)
Age
- Cardiac output decreases with a decreased proportion of blood flow to kidney/liver
- GFR decreases with age with a reduced creatine clearance rate
- [Albumin] decline with age so less plasma protein binding and greater free drug
- GFR in the newborn is 20% of adults
- Decrease in GFR not reflected in plasma [creatinine] as creatinine synthesis decline with age.
- Enzymes have low activity in neonates and elderly
- Includes: CYP450, glucuronyltrasferase, acetyltransferase, plasma ChE
- Slow hepatic conjugation of:
o Chloramphenicol in babies –‘grey baby’ syndrome
o Morphine during labour –respiratory depression in newborns
- The same plasma drug concentration can cause different effects in young and old:
- Benzodiazepines produce more confusion and less sedation in elderly than in young patients
- Hypotensive drugs cause postural hypotension more commonly in elderly than in young adults
Pharmacogenetics
- Administered to dizygotic twins (fraternal) and monozygotic (identical) twins. Much less
variation in the half-life in identical twins. First evidence for the role of genes in drug
metabolism (pharmacokinetics)
- People with an inherited deficiency in the enzyme glucose-6-dehydrogenase (G6PD) can develop
haemolytic anaemia after eating broad beans (Phythagoras)
10. 10
- A large amount of individual variability to drugs is genetically determined
o Half-life of antipyrine and warfarin are 6-22 times less variable
in identical than in fraternal twins
- Gene polymorphisms can affect an individuals susceptibility to ADRs
o Pharmacokinetic (eg. polymorphisms in genes encoding
CYP450)
o Pharmacodynamic (eg. polymorphisms in drug targets such as receptors and enzymes)
Abacavir- Hla gene test
- Is a reverse transcriptase inhibitor that is highly effective in treating HIV infection.
- Its use has been limited by severe rashes.
- Susceptibility to this adverse effect is closely linked to the human leukocyte antigen (HLA)
variant HLAB*5701,
- Testing for this variant is used widely
Trastuzumab
- Is a monoclonal antibody that antagonises epidermal growth factor (EGF) by binding to one of
its receptors (human epidermal growth factor receptor 2 – HER2) which can occur in tumour
tissue
- It is used in patients with breast cancer whose tumour tissue overexpresses this receptor. Other
patients do not benefit from it.
- Liver and kidney disease: Prolonged drug effects –
toxicity: Reduction in protein binding, liver/kidney blood
flow, liver capacity
- Migraine and diabetic neuropathy: Slowed drug absorption
due to gastric stasis
- Heart failure: Reduced liver perfusion – toxicity: Mucosal
oedema – reduced absorption
- Hyperthyroidism: Increased sensitivity to pethidine (mechanism?)
- Hypothermia: Reduced drug clearance
11. 11
Idiosyncratic reactions
- Harmful, sometimes fatal, reactions that occur in a small minority of individuals
o Qualitatively abnormal
o Rare
o eg. Chloramphenicol induced aplastic anemia (bone marrow
depression) in ~1 in 50,000 patients
- Reactions may occur with low doses
- Sometimes genetic factors may be responsible
o Primaquine, dapsone, doxorubicin, some sulfonamides and
Vicia fava beans cause severe anemia in G6PD deficient
Afro-Carribean men (deficiency in the antioxidant glutathione)
-
CYP2Cs
- Major substrates include some nonsteroidal anti-inflammatory drugs, warfarin, phenytoin, PPIs
- Dramatic interracial polymorphism e.g. CYP2C19
12. 12
o CYP2C19 activity is genetically determined, and its genetic polymorphism shows marked
interracial difference.
o The incidence of the poor metaboliser phenotype is markedly higher in Asian
populations (13–23%) than in white populations (2–5%)
- Substrate in relation to metabolism refers to a drug which
undergoes metabolism by a specific enzyme (e.g.
CYP3A4)
- However, a drug can be a substrate to multiple enzymes
- fluoxetine (substrate) is metabolized by both CYP2D6
and CYP3A4
- warfarin is a substrate for 1A2, 2A6, 2C19, 3A4
- One enzyme has many different substrates and these will
compete with one another
- Drugs can be substrates and inducers or inhibitors
concurrently
- 3A4 and 2D6 are the isoenzymes responsible for the
metabolism of most commonly used drugs
13. 13
Drugs in pregnancy (Module 6)
- Plasma volume increases (increased Vd)
- Maternal plasma albumin concentration is reduced to 70-80%-decreased protein binding
(albumin conc. Rises in fetus)
- Cardiac output is increased-increased GFR-increased clearance of free drug
- Hormones alter liver enzymes
- Gastric pH increases
- Smaller molecules transfer across the placenta faster. Greater than 1000 Da will not cross
- Lipophilic drugs cross faster
- Foetal pH more acidic-so weak acids and bases will become more ionized and tend to accumulate
- 40% of drugs are taken during the critical period
- Teratogenesis=the production of gross physical malformations
- Teratogen- toxic agent that increase the occurrence of a structural defect/abnormality
- Effect varies depending upon amount and length of exposure, genetic factors, additive effects of
- Effect of agents on somatic cells
- Lack toxicity in the mother but produce malformations in fetus
- Blastocyst formation: cytotoxic drugs and alcohol; resistant to teratogenic effects- may cause
miscarriage
- Organogenesis: Teratogens
- Histogenesis and functional maturation: Miscellaneous drugs
- Probability of structural defect is greatest during organogenesis
- Structural organisation of fetus occurs in a sequence: Brain, Heart and major vessels, Skeleton
and limbs, Ears and eyes, Palate, Genitourinary system
- Type of malformation depends on time of exposure
- Drugs enter embryonic bloodstream by passive diffusion
- Fetal liver has 20-40% of adult activity for phase 1 reaction
- Category A: taken by many women-no evidence of causing malformation. Controlled studies
- Category B: Divided into 3 groups (B1, B2, B3) with all having only been taken by limited
number of women (pregnant or childbearing age) with no increased incidence of malformation
or effects on fetus. Differences range from no effects in animals (B1) to evidence of fetal damage
in animals (B3)
- Category C: No data available or suspected harmful effects
- Category D: suspected increased incidence of malformation- benefits may be acceptable despite
risk. Category x: high risk
- Most medications are assigned to category C
- Thalidomide: sedative, was originally deemed safe, amelia, phocomelia
o Lesson: low maternal toxicity and low toxicity in animals may have high teratogenic
potential
14. 14
Drug receptors
- Ligand gated ion channel: trigger is agonist binding
- Location: membrane
- Effector: ion channel
- Coupling: direct
- Examples: Nicotinic acetylcholine (ACh), g-Aminobutyric
acid (GABA), Excitatory amino acids (eg. NMDA,
aspartate),Glycine
- Timescale: extremely rapid cell activation with a time scale
of milliseconds
- 2 ACH molecules is needed
- Voltage gated: trigger is change in membrane potential
- G-protein-couple receptors:
- Location: membrane
- Effector: channel or enzyme
- Coupling: G-protein (affinity for guanyl nucleotides (GDP/GTP)
- Examples: Muscarinic Ach Adrenoceptors
- Timescale: slow cell activation with a time scale of seconds
- Amplification of signal: one receptor can activate many G-proteins
- Active G-proteins can cause effector enzymes to produce many intracellular second messengers
- Principal second messengers: 1. Cyclic adenosine monophosphate (cAMP), 2. Ca2, 3.
phosphoinositides (eg IP3 and DAG)
- Active=GTP bound
- Inactive= GDP bound
- G-proteins provide link between ligand-activated receptor and effector
- G-proteins have intrinsic GTPase activity which spontaneously hydrolyses bound GTP to bound
GDP
- Gi=inhibitory. Gs=stimulatory
- Kinase-linked receptor:
- Location: membrane
- Effector: protein kinases
- Coupling: direct
- Examples: Insulin Growth factors eg.Epidermal growth
factor (EGF), nerve growth factor, platelet derived growth
factor (PDGF)
Cytokine receptors eg. interferon-gamma (IFN-g)
- Timescale: cell activation with a time scale of minutes to hours
15. 15
- Enzyme is usually a protein tyrosine kinase, but can be a protein serine kinase, a protein
threonine kinase or guanyl cyclase (activation of receptor by phosphorylation)
- Nuclear receptors:
- Location: intracellular
- Effector: gene transcription
- Coupling: via DNA
- Examples: Sex steroids, eg. Testosterone, Glucocorticoids eg cortisol, Mineralocorticoids eg
aldosterone, Hormones and vitamins eg. Vitamin D and thyroid
hormone
- Timescale: cell activation with a time scale of hours
- Agonist-receptor complex acting on DNA resulting in
- 1. transcription and translation of mediator proteins or
- 2. repression of expression of certain genes with inhibition of production of specific proteins
16. 16
Precision Medicine
- Assumption that one size fits all: disease subtypes, clinical features, risk profiles for particular
groups and demographics, environmental effects, socio-economic effects and the use of
biomarkers
- Precision medicine includes: Genomics and Omics (e.g. proteomics), Lifestyle, Preferences,
Compliance, Health History, Medical Records, Other exogenous factors
- Karyotyping is extremely valuable
- Single nucleotide polymorphisms: changes in the nucleotide sequence
- The CFTR protein is composed of 1,480 amino acids—the building blocks of all proteins—and
is located on the surface of many cells in the body
- It plays an important role in transporting chloride ions in and out of the cell
- This is caused when a defective in CTFR, obstructs the normal flow of water and mineral ions in
and out of cells.
- When this occurs in the sweat glands, it prevents sodium from being reabsorbed into cells and
causes chloride to accumulate in the sweat ducts. As the excessive amounts of sodium and
chloride get pushed close to the surface of the skin, they combine to form salt.
1. Find a mutation that influence the activity of a protein
2. Obtain cells with the desired mutation
3. Develop a high-throughput screening method for protein activity
4. Screen thousands of compounds and look for activity in cell lines
5. Check if it works in patients through clinical trials
- F508del mutations lead to little to no trafficking of the CFTR, but of the small amount of protein
that gets to the surface is like G551D and non-functional.
- Augmentation therapy is the use of alpha-1 antitrypsin protein (AAT) from the blood plasma of
healthy human donors to augment (increase) the alpha-1 levels circulating in the blood and lungs
of AATD patients diagnosed with emphysema.
- AATD patient survival after lung transplantation who received augmentation therapy prior show
worse 10-year survival rates relative to AATD without prior augmentation as well as to those
with general COPD.
- Despite being on inhaled corticosteroids treatment is able to further reduce the inflammation by
restoring AAT activity.
- Depending on the AATC genotype augmentation therapy may or may not help
Protospacer Adjacent Motif (PAM)-is a short DNA sequence (~3 base pairs) that follows the DNA
region targeted for cleavage by the CRISPR system.
• CRISPR RNAs (crRNA)- transcribed from this CRISPR locus matching the virus sequence
• (TracrRNA)- partially complementary to pairs with a pre-crRNA forming an RNA duplex.