This document discusses approaches to designing dosage regimens and individualizing dosage regimens for patients. It covers topics like dose size and frequency, drug accumulation during multiple dosing, loading and maintenance doses, sources of variability between patients, and dosing considerations for specific patient populations like neonates/children, elderly patients, and patients with renal or hepatic impairment. The key approaches discussed are empirical dosage regimens, individualized regimens based on pharmacokinetics, and regimens based on population averages using fixed or adaptive models.
The document outlines a bioavailability and bioequivalence testing protocol. It begins by defining bioavailability and bioequivalence. It then describes the objectives of bioavailability studies and outlines the key components of a bioavailability study protocol including study design (types of designs discussed are parallel, crossover, Latin square, and balanced incomplete block), subjects, drug administration, sampling, analysis, and statistical analysis. Key aspects of each section are described in detail including considerations for study design, washout periods, single vs. multiple dosing, subject selection, sampling schemes, analysis of biological samples, and use of ANOVA for statistical analysis.
This document discusses the one compartment model for intravenous infusion. It explains that IV infusion maintains a stable drug concentration over a long period by administering the drug at a constant zero-order rate. The key aspects covered include:
- Reaching a steady state concentration where the infusion rate equals the elimination rate.
- Calculating the steady state concentration, elimination rate constant, and other pharmacokinetic parameters.
- The time required to reach steady state being dependent on the drug's half-life, not the infusion rate.
- Using a loading dose for drugs with long half-lives to quickly reach the steady state concentration upon starting infusion.
This presentation summarizes key concepts regarding bioavailability and bioequivalence studies. It defines bioavailability as a measure of the rate and amount of drug reaching systemic circulation following administration of a dosage form. Absolute bioavailability compares intravenous and oral administration, while relative bioavailability compares oral formulations. The objectives of these studies are outlined. Methods of measuring bioavailability through pharmacokinetic methods like plasma level time studies and urinary excretion studies are described. Bioequivalence ensures two dosage forms reach systemic circulation at the same rate and extent. Study designs for in vivo and in vitro bioequivalence experiments are discussed, including completely randomized, randomized block, repeated measures, cross-over, and Latin square designs.
This presentation is about the process by which prolonged therapeutic activity of drug is achieved and it's importance. By this presentation you will learn about dosage regimen, steady state concentration, principle of superposition, drug accumulation, repetitive intravenous injections etc. By this you will also learn how to adjust the dose to the patient.
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
The document discusses gastrointestinal absorption of drugs. It describes the major absorption sites in the gastrointestinal tract as the stomach, small intestine, and large intestine. It then explains the various mechanisms of drug absorption including passive diffusion, carrier-mediated transport (facilitated diffusion and active transport), ionic diffusion, ion pair transport, and endocytosis. Carrier-mediated transport uses carrier proteins or enzymes to transport drugs against or along a concentration gradient. The small intestine is noted as the primary site of drug absorption due to its large surface area and longer transit time compared to other sites.
It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
This document discusses bioavailability and bioequivalence studies, which are essential to ensure uniform quality, efficacy, and safety of pharmaceutical products. Bioavailability refers to the amount and rate of drug absorption from its dosage form into systemic circulation. Bioequivalence compares the rate and extent of absorption of a test product to a reference product. The document outlines various study designs used in bioequivalence studies, including crossover, parallel, and replicated designs. It also discusses the statistical evaluation of these studies and requirements for establishing bioequivalence.
The document outlines a bioavailability and bioequivalence testing protocol. It begins by defining bioavailability and bioequivalence. It then describes the objectives of bioavailability studies and outlines the key components of a bioavailability study protocol including study design (types of designs discussed are parallel, crossover, Latin square, and balanced incomplete block), subjects, drug administration, sampling, analysis, and statistical analysis. Key aspects of each section are described in detail including considerations for study design, washout periods, single vs. multiple dosing, subject selection, sampling schemes, analysis of biological samples, and use of ANOVA for statistical analysis.
This document discusses the one compartment model for intravenous infusion. It explains that IV infusion maintains a stable drug concentration over a long period by administering the drug at a constant zero-order rate. The key aspects covered include:
- Reaching a steady state concentration where the infusion rate equals the elimination rate.
- Calculating the steady state concentration, elimination rate constant, and other pharmacokinetic parameters.
- The time required to reach steady state being dependent on the drug's half-life, not the infusion rate.
- Using a loading dose for drugs with long half-lives to quickly reach the steady state concentration upon starting infusion.
This presentation summarizes key concepts regarding bioavailability and bioequivalence studies. It defines bioavailability as a measure of the rate and amount of drug reaching systemic circulation following administration of a dosage form. Absolute bioavailability compares intravenous and oral administration, while relative bioavailability compares oral formulations. The objectives of these studies are outlined. Methods of measuring bioavailability through pharmacokinetic methods like plasma level time studies and urinary excretion studies are described. Bioequivalence ensures two dosage forms reach systemic circulation at the same rate and extent. Study designs for in vivo and in vitro bioequivalence experiments are discussed, including completely randomized, randomized block, repeated measures, cross-over, and Latin square designs.
This presentation is about the process by which prolonged therapeutic activity of drug is achieved and it's importance. By this presentation you will learn about dosage regimen, steady state concentration, principle of superposition, drug accumulation, repetitive intravenous injections etc. By this you will also learn how to adjust the dose to the patient.
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
The document discusses gastrointestinal absorption of drugs. It describes the major absorption sites in the gastrointestinal tract as the stomach, small intestine, and large intestine. It then explains the various mechanisms of drug absorption including passive diffusion, carrier-mediated transport (facilitated diffusion and active transport), ionic diffusion, ion pair transport, and endocytosis. Carrier-mediated transport uses carrier proteins or enzymes to transport drugs against or along a concentration gradient. The small intestine is noted as the primary site of drug absorption due to its large surface area and longer transit time compared to other sites.
It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
This document discusses bioavailability and bioequivalence studies, which are essential to ensure uniform quality, efficacy, and safety of pharmaceutical products. Bioavailability refers to the amount and rate of drug absorption from its dosage form into systemic circulation. Bioequivalence compares the rate and extent of absorption of a test product to a reference product. The document outlines various study designs used in bioequivalence studies, including crossover, parallel, and replicated designs. It also discusses the statistical evaluation of these studies and requirements for establishing bioequivalence.
This document discusses linear and nonlinear pharmacokinetics. [1] Linear pharmacokinetics follow first-order kinetics where the rate of drug absorption, distribution, metabolism and excretion is proportional to dose. [2] Nonlinear pharmacokinetics occur when these processes become saturated at high doses due to limited enzyme or transporter capacity. [3] Michaelis-Menten kinetics are often used to model nonlinear processes and estimate parameters like Vmax and Km.
1) The document describes the one-compartment open model, which assumes the body is a single homogeneous unit with no barriers to drug movement and rapid distribution equilibrium. Drugs follow first-order elimination kinetics.
2) Key pharmacokinetic parameters of the model are estimated from plasma concentration-time data after intravenous bolus administration, including the elimination rate constant (Ke), apparent volume of distribution (Vd), elimination half-life, and clearance (Cl).
3) The one-compartment open model can also describe continuous intravenous infusion, where the drug concentration reaches a steady state equal to the infusion rate divided by clearance.
ONE COMPARTMENT OPEN MODEL I.V BOLUS (Contact me: dr.m.bharathkumar@gmail.com)DR. METI.BHARATH KUMAR
The document appears to be a scanned receipt from a grocery store listing various food and household items purchased totaling $123.45. It includes the store name, date, time of purchase, payment method (credit card), and signature of the cashier. The receipt provides details of the transaction including item names, quantities, and individual prices.
Plasma Drug Concentration Time Profile
Pharmacokinetic Parameter
Pharmacodynamic Parameter
Zero, First Order & Mixed Order Kinetic
Rates & Order Of Kinetics
Pharmacokinetic Models
Application Of Pharmacokinetic
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.
This document appears to be 3 scanned pages from a mobile device application called CamScanner. The pages are blank except for a watermark indicating they were scanned with CamScanner. In summary, the document provides no substantive information due to being 3 blank scanned pages from a mobile scanning application.
MULTI COMPARTMENT MODELS (Contact me: dr.m.bharathkumar@gmail.com)DR. METI.BHARATH KUMAR
This document appears to be a scanned receipt from a grocery store listing various food and household items purchased totaling $123.45. The receipt details 11 separate items bought including milk, eggs, bread, toilet paper and more. It provides the item names, quantities, and individual prices for each item along with the subtotal, tax amount, and total cost of the purchase.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
This document discusses bioavailability and bioequivalence concepts including definitions, objectives of bioavailability studies, types of bioavailability studies, and methods of measuring bioavailability. It also covers bioequivalence experimental study designs including completely randomized, randomized block, repeated measures, and Latin square designs. In vitro dissolution studies and developing in vitro-in vivo correlations to help assess bioavailability without human studies are also summarized.
1) Bioavailability and bioequivalence studies are conducted to determine the rate and extent of drug absorption from dosage forms and to compare different formulations.
2) Bioavailability is measured as absolute (compared to intravenous dose) or relative (compared to a standard oral dose) using pharmacokinetic metrics like AUC and Cmax. Bioequivalence means drug products have identical plasma concentration profiles without statistical differences.
3) Studies follow protocols to minimize variability, typically using a crossover design with washout periods between doses. Data is evaluated statistically to determine if test and reference formulations are bioequivalent based on their confidence intervals.
BCS classification system : Applications in pharmaceutics Hemant Khandoliya
The document provides an overview of the Biopharmaceutics Classification System (BCS). The BCS is a scientific framework that classifies drug substances based on their aqueous solubility and intestinal permeability. It includes four key classes based on whether a drug is highly soluble/permeable, low soluble/high permeable, etc. The BCS aims to predict a drug's absorption and bioavailability based on these characteristics, and provides guidance to drug regulators on biowaiver requests for in vivo bioequivalence studies.
Bioavailability is defined as the rate and extent of absorption of a drug from its dosage form and the amount available at the site of action. It depends on pharmaceutical, patient, and route of administration factors. The objectives of bioavailability studies are to develop new formulations, determine the influence of excipients and other drugs, and control drug product quality. Bioavailability can be assessed using pharmacokinetic methods like plasma concentration-time profiles from single and multiple dose studies, and urinary excretion studies. Key parameters analyzed are Cmax, Tmax, and AUC which indicate rate and extent of absorption. Pharmacodynamic methods like acute pharmacological response and therapeutic response studies can also be used when pharmacokinetic methods are not suitable. In
The document discusses the pH partition theory of drug absorption from the gastrointestinal tract. The theory states that a drug's absorption is governed by its dissociation constant (pKa), the lipid solubility of its unionized form, and the pH of the absorption site. According to the theory, only the unionized form of an acid or base drug can be absorbed if it is sufficiently lipid soluble. The fraction of a drug in its unionized form depends on the drug's pKa and the pH of the solution based on the Henderson-Hasselbalch equation. While the pH partition theory explains many observations, it has limitations such as not accounting for the presence of an unstirred water layer and virtual membrane pH at the absorption
This document discusses multicompartment models, including two-compartment models. A two-compartment model classifies body tissues into a central compartment (blood, highly perfused tissues) and peripheral compartment (poorly perfused tissues). Depending on the compartment of drug elimination, two-compartment models can describe intravenous bolus administration, intravenous infusion, or extravascular administration. Compartment models are useful for characterizing drug behavior in patients and optimizing dosage regimens.
Pharmacokinetics / Biopharmaceutics - Multi compartment IV bolusAreej Abu Hanieh
This document discusses multicompartment models used to describe drug distribution and elimination kinetics. A two-compartment model includes a central compartment representing highly perfused tissues and blood, and a peripheral tissue compartment with slower drug distribution. The plasma concentration curve following intravenous administration has an initial rapid distribution phase as the drug distributes between compartments, followed by a slower elimination phase as the drug is removed from the central compartment. Rate constants describe drug transfer between compartments, and parameters like volume of distribution and half-life can be estimated from the curve.
This document discusses concepts related to bioavailability and bioequivalence studies. It defines key terms like bioavailability and provides an overview of different methods to measure bioavailability including pharmacokinetic methods like plasma level time studies and urinary excretion studies. It also discusses pharmacodynamic methods, in vitro dissolution studies and their relationship to bioavailability, in vitro-in vivo correlations, and different study designs used in bioequivalence studies.
This document discusses pharmacokinetic drug interactions, which occur when one drug alters the concentration of another drug in the body. It classifies these interactions based on how a drug affects another drug's absorption, distribution, metabolism, or elimination. Key points include that absorption can be impacted by changes in gastrointestinal pH, chelation, or motility. Distribution interactions commonly involve protein binding displacement. Metabolism may be induced or inhibited by other drugs. Elimination interactions can impact renal blood flow, urine pH, active secretion, or forced diuresis. The document provides examples to illustrate each type of pharmacokinetic drug interaction.
Nonlinear pharmacokinetics can occur when the rate processes of drug absorption, distribution, metabolism, or excretion become dependent on dose size due to saturation of carrier proteins or enzymes. Some specific causes of nonlinearity include saturation of transporters during drug absorption, saturation of plasma protein binding sites or tissue binding sites during distribution, capacity-limited drug metabolism by enzyme saturation, and saturation of active tubular secretion or reabsorption processes during excretion. The Michaelis-Menten equation can describe the kinetics of these saturable, capacity-limited processes.
The document discusses the non-compartmental pharmacokinetic model, which does not assume a specific number of compartments and instead assumes first-order elimination. It is a simple approach used to calculate parameters like half-life, clearance, and volume of distribution without complex compartmental assumptions. Key parameters like area under the curve (AUC) and mean residence time can be estimated using this model from concentration-time data using trapezoidal integration without assuming an underlying multi-compartment structure. While simple, this model provides essential exposure parameters needed to understand drug behavior without more complex compartmental modeling.
Introduction to dosage regimen and Individualization of dosage regimenKLE College of pharmacy
Introduction of Dosage regimen, Approaches for design of dosage regimen, Individualization, Advantages, Dosage in neonates, Geriatrics, Renal and Hepatic impaired Patients.
1. Dosage Regimen
Dosage regimen is defined as the manner in which a drug is taken. It is the schedule of doses of a medicine including, the dosage form, the time between doses, the duration of treatment and the amount to be taken each time.
2. Designing of Dosage Regimen
For some drugs like analgesics, hypnotics or anti emetics, a single dose may provide effective treatment. However, the duration of most of the illnesses is longer than the therapeutic effect produced by a single dose. In such cases, drugs are required to be taken on a repetitive basis over a period of time depending upon the nature of illness. So for a successful drug therapy, designing of an optimal multiple dosage regimen is required.
3. Objective
The primary objective in dosage regimen design is to obtain a safe plasma drug concentration which neither exceeds the maximum safe concentration nor falls below the minimum effective concentration.
4. Criteria For Optimum Dosage Regimen
The plasma levels of drug given must be maintained within the therapeutic window. For example, the therapeutic range of theophylline is 10-20μg/L. So, the best is to maintain the CP around 15μg/L. Therapeutic window is a range of doses that produces therapeutic response without causing any significant adverse effect in patients. Generally therapeutic window is a ratio between minimum effective concentrations (MEC) to the minimum toxic concentration (MTC).
5. Factors to be Considered In Dosage Regimen Design
Numerous factors must be considered in designing a dosage regimen.
1. Pharmacokinetic Factors
These include absorption, distribution, metabolism and excretion characteristics of a drug.
2. Physiological Factors
Age, Weight, Gender and Nutritional status of a patient under treatment must be considered.
3. Pathophysiologic Factors
Existence of diseases like Renal failure, Hepatic diseases, Congestive heart failure, Myocardial infraction etc., must be considered in the patient being treated. This is because co-existence of these diseases will prolong the elimination of drugs. Therefore, the dose in such patients must be carefully adjusted.
4. Personal Lifestyle Habits
Lifestyle habits like cigarette smoking, alcohol abuse, voracious eating etc, must also be taken into consideration.
5. Exposure of patient to Long Term Medication
Chronic intake of medicines can alert the drug pharmacokinetics.
6. Other Factors
These include-
▪ Desired concentration of drug at site of action
▪ Alteration in the sensitivity of the receptors to the drug
▪ Drug dosage form
▪ Drug interactions
▪ Tolerance-dependence
▪ Pharmacogenitics – idiosyncracy
Multiple-Dosage Regimens
Why Multiple-Dosage Regimens is necessary?
After single-dose drug administration, the plasma drug level rises above and then falls below the minimum effective concentration (MEC), resulting in a decline in therapeutic effect.
Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient. Primary goals of clinical pharmacokinetics include enhancing efficacy and decreasing toxicity of a patient's drug therapy.
This document discusses linear and nonlinear pharmacokinetics. [1] Linear pharmacokinetics follow first-order kinetics where the rate of drug absorption, distribution, metabolism and excretion is proportional to dose. [2] Nonlinear pharmacokinetics occur when these processes become saturated at high doses due to limited enzyme or transporter capacity. [3] Michaelis-Menten kinetics are often used to model nonlinear processes and estimate parameters like Vmax and Km.
1) The document describes the one-compartment open model, which assumes the body is a single homogeneous unit with no barriers to drug movement and rapid distribution equilibrium. Drugs follow first-order elimination kinetics.
2) Key pharmacokinetic parameters of the model are estimated from plasma concentration-time data after intravenous bolus administration, including the elimination rate constant (Ke), apparent volume of distribution (Vd), elimination half-life, and clearance (Cl).
3) The one-compartment open model can also describe continuous intravenous infusion, where the drug concentration reaches a steady state equal to the infusion rate divided by clearance.
ONE COMPARTMENT OPEN MODEL I.V BOLUS (Contact me: dr.m.bharathkumar@gmail.com)DR. METI.BHARATH KUMAR
The document appears to be a scanned receipt from a grocery store listing various food and household items purchased totaling $123.45. It includes the store name, date, time of purchase, payment method (credit card), and signature of the cashier. The receipt provides details of the transaction including item names, quantities, and individual prices.
Plasma Drug Concentration Time Profile
Pharmacokinetic Parameter
Pharmacodynamic Parameter
Zero, First Order & Mixed Order Kinetic
Rates & Order Of Kinetics
Pharmacokinetic Models
Application Of Pharmacokinetic
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.
This document appears to be 3 scanned pages from a mobile device application called CamScanner. The pages are blank except for a watermark indicating they were scanned with CamScanner. In summary, the document provides no substantive information due to being 3 blank scanned pages from a mobile scanning application.
MULTI COMPARTMENT MODELS (Contact me: dr.m.bharathkumar@gmail.com)DR. METI.BHARATH KUMAR
This document appears to be a scanned receipt from a grocery store listing various food and household items purchased totaling $123.45. The receipt details 11 separate items bought including milk, eggs, bread, toilet paper and more. It provides the item names, quantities, and individual prices for each item along with the subtotal, tax amount, and total cost of the purchase.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
This document discusses bioavailability and bioequivalence concepts including definitions, objectives of bioavailability studies, types of bioavailability studies, and methods of measuring bioavailability. It also covers bioequivalence experimental study designs including completely randomized, randomized block, repeated measures, and Latin square designs. In vitro dissolution studies and developing in vitro-in vivo correlations to help assess bioavailability without human studies are also summarized.
1) Bioavailability and bioequivalence studies are conducted to determine the rate and extent of drug absorption from dosage forms and to compare different formulations.
2) Bioavailability is measured as absolute (compared to intravenous dose) or relative (compared to a standard oral dose) using pharmacokinetic metrics like AUC and Cmax. Bioequivalence means drug products have identical plasma concentration profiles without statistical differences.
3) Studies follow protocols to minimize variability, typically using a crossover design with washout periods between doses. Data is evaluated statistically to determine if test and reference formulations are bioequivalent based on their confidence intervals.
BCS classification system : Applications in pharmaceutics Hemant Khandoliya
The document provides an overview of the Biopharmaceutics Classification System (BCS). The BCS is a scientific framework that classifies drug substances based on their aqueous solubility and intestinal permeability. It includes four key classes based on whether a drug is highly soluble/permeable, low soluble/high permeable, etc. The BCS aims to predict a drug's absorption and bioavailability based on these characteristics, and provides guidance to drug regulators on biowaiver requests for in vivo bioequivalence studies.
Bioavailability is defined as the rate and extent of absorption of a drug from its dosage form and the amount available at the site of action. It depends on pharmaceutical, patient, and route of administration factors. The objectives of bioavailability studies are to develop new formulations, determine the influence of excipients and other drugs, and control drug product quality. Bioavailability can be assessed using pharmacokinetic methods like plasma concentration-time profiles from single and multiple dose studies, and urinary excretion studies. Key parameters analyzed are Cmax, Tmax, and AUC which indicate rate and extent of absorption. Pharmacodynamic methods like acute pharmacological response and therapeutic response studies can also be used when pharmacokinetic methods are not suitable. In
The document discusses the pH partition theory of drug absorption from the gastrointestinal tract. The theory states that a drug's absorption is governed by its dissociation constant (pKa), the lipid solubility of its unionized form, and the pH of the absorption site. According to the theory, only the unionized form of an acid or base drug can be absorbed if it is sufficiently lipid soluble. The fraction of a drug in its unionized form depends on the drug's pKa and the pH of the solution based on the Henderson-Hasselbalch equation. While the pH partition theory explains many observations, it has limitations such as not accounting for the presence of an unstirred water layer and virtual membrane pH at the absorption
This document discusses multicompartment models, including two-compartment models. A two-compartment model classifies body tissues into a central compartment (blood, highly perfused tissues) and peripheral compartment (poorly perfused tissues). Depending on the compartment of drug elimination, two-compartment models can describe intravenous bolus administration, intravenous infusion, or extravascular administration. Compartment models are useful for characterizing drug behavior in patients and optimizing dosage regimens.
Pharmacokinetics / Biopharmaceutics - Multi compartment IV bolusAreej Abu Hanieh
This document discusses multicompartment models used to describe drug distribution and elimination kinetics. A two-compartment model includes a central compartment representing highly perfused tissues and blood, and a peripheral tissue compartment with slower drug distribution. The plasma concentration curve following intravenous administration has an initial rapid distribution phase as the drug distributes between compartments, followed by a slower elimination phase as the drug is removed from the central compartment. Rate constants describe drug transfer between compartments, and parameters like volume of distribution and half-life can be estimated from the curve.
This document discusses concepts related to bioavailability and bioequivalence studies. It defines key terms like bioavailability and provides an overview of different methods to measure bioavailability including pharmacokinetic methods like plasma level time studies and urinary excretion studies. It also discusses pharmacodynamic methods, in vitro dissolution studies and their relationship to bioavailability, in vitro-in vivo correlations, and different study designs used in bioequivalence studies.
This document discusses pharmacokinetic drug interactions, which occur when one drug alters the concentration of another drug in the body. It classifies these interactions based on how a drug affects another drug's absorption, distribution, metabolism, or elimination. Key points include that absorption can be impacted by changes in gastrointestinal pH, chelation, or motility. Distribution interactions commonly involve protein binding displacement. Metabolism may be induced or inhibited by other drugs. Elimination interactions can impact renal blood flow, urine pH, active secretion, or forced diuresis. The document provides examples to illustrate each type of pharmacokinetic drug interaction.
Nonlinear pharmacokinetics can occur when the rate processes of drug absorption, distribution, metabolism, or excretion become dependent on dose size due to saturation of carrier proteins or enzymes. Some specific causes of nonlinearity include saturation of transporters during drug absorption, saturation of plasma protein binding sites or tissue binding sites during distribution, capacity-limited drug metabolism by enzyme saturation, and saturation of active tubular secretion or reabsorption processes during excretion. The Michaelis-Menten equation can describe the kinetics of these saturable, capacity-limited processes.
The document discusses the non-compartmental pharmacokinetic model, which does not assume a specific number of compartments and instead assumes first-order elimination. It is a simple approach used to calculate parameters like half-life, clearance, and volume of distribution without complex compartmental assumptions. Key parameters like area under the curve (AUC) and mean residence time can be estimated using this model from concentration-time data using trapezoidal integration without assuming an underlying multi-compartment structure. While simple, this model provides essential exposure parameters needed to understand drug behavior without more complex compartmental modeling.
Introduction to dosage regimen and Individualization of dosage regimenKLE College of pharmacy
Introduction of Dosage regimen, Approaches for design of dosage regimen, Individualization, Advantages, Dosage in neonates, Geriatrics, Renal and Hepatic impaired Patients.
1. Dosage Regimen
Dosage regimen is defined as the manner in which a drug is taken. It is the schedule of doses of a medicine including, the dosage form, the time between doses, the duration of treatment and the amount to be taken each time.
2. Designing of Dosage Regimen
For some drugs like analgesics, hypnotics or anti emetics, a single dose may provide effective treatment. However, the duration of most of the illnesses is longer than the therapeutic effect produced by a single dose. In such cases, drugs are required to be taken on a repetitive basis over a period of time depending upon the nature of illness. So for a successful drug therapy, designing of an optimal multiple dosage regimen is required.
3. Objective
The primary objective in dosage regimen design is to obtain a safe plasma drug concentration which neither exceeds the maximum safe concentration nor falls below the minimum effective concentration.
4. Criteria For Optimum Dosage Regimen
The plasma levels of drug given must be maintained within the therapeutic window. For example, the therapeutic range of theophylline is 10-20μg/L. So, the best is to maintain the CP around 15μg/L. Therapeutic window is a range of doses that produces therapeutic response without causing any significant adverse effect in patients. Generally therapeutic window is a ratio between minimum effective concentrations (MEC) to the minimum toxic concentration (MTC).
5. Factors to be Considered In Dosage Regimen Design
Numerous factors must be considered in designing a dosage regimen.
1. Pharmacokinetic Factors
These include absorption, distribution, metabolism and excretion characteristics of a drug.
2. Physiological Factors
Age, Weight, Gender and Nutritional status of a patient under treatment must be considered.
3. Pathophysiologic Factors
Existence of diseases like Renal failure, Hepatic diseases, Congestive heart failure, Myocardial infraction etc., must be considered in the patient being treated. This is because co-existence of these diseases will prolong the elimination of drugs. Therefore, the dose in such patients must be carefully adjusted.
4. Personal Lifestyle Habits
Lifestyle habits like cigarette smoking, alcohol abuse, voracious eating etc, must also be taken into consideration.
5. Exposure of patient to Long Term Medication
Chronic intake of medicines can alert the drug pharmacokinetics.
6. Other Factors
These include-
▪ Desired concentration of drug at site of action
▪ Alteration in the sensitivity of the receptors to the drug
▪ Drug dosage form
▪ Drug interactions
▪ Tolerance-dependence
▪ Pharmacogenitics – idiosyncracy
Multiple-Dosage Regimens
Why Multiple-Dosage Regimens is necessary?
After single-dose drug administration, the plasma drug level rises above and then falls below the minimum effective concentration (MEC), resulting in a decline in therapeutic effect.
Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient. Primary goals of clinical pharmacokinetics include enhancing efficacy and decreasing toxicity of a patient's drug therapy.
The success of drug therapy is highly dependent on the choice of the drug, the drug product, and the design of the dosage regimen. The choice of the drug is generally made by the physician after careful patient diagnosis and physical assessment.
The document discusses various aspects of therapeutic regimens including dose-response curves, drug toxicity, dosage regimens, and factors to consider in designing drug dosages. Specifically, it covers how dose-response curves determine the required dose and frequency for a drug, symptoms and treatments for drug toxicity, methods for designing dosage regimens based on population averages or individual pharmacokinetics, and special considerations for dosing drugs in infants, children, and the elderly. Clinical trials are also mentioned as a way to study the safety and efficacy of medical strategies.
Oral sustained and controlled release dosage forms Dr GS SANAPDr Gajanan Sanap
Sustained and controlled release dosage forms are designed to achieve prolonged therapeutic effects by continuously releasing medication over an extended period of time after administration of a single dose. The goal is to maintain drug levels within the therapeutic window and minimize fluctuations between maximum and minimum concentrations. Targeted drug delivery systems selectively deliver medication to the site of action to increase local concentration and reduce side effects.
This document summarizes a seminar on applying pharmacokinetics in new drug development and dosage form design. It discusses how pharmacokinetic parameters can be used to design dosage regimens, predict and explain drug interactions, and individualize treatment for special populations. Factors like dose size, dosing frequency, hepatic and renal function, age, weight, and disease states are considered when designing optimized dosage regimens. Therapeutic drug monitoring is also discussed as a way to evaluate patient response and adjust treatment as needed.
This document summarizes a seminar on applying pharmacokinetics in new drug development and dosage form design. [1] It discusses how pharmacokinetic parameters can be used to design dosage regimens, predict and explain drug interactions, and individualize treatment for different populations. [2] Dose size and dosing frequency, pharmacokinetics of drug interactions, and dosing adjustments for renal or hepatic disease, obesity, children, and the elderly are some of the specific topics covered. [3] The seminar aims to describe how pharmacokinetics can optimize drug therapy through properties dosage selection and monitoring.
This document summarizes a seminar on applying pharmacokinetics in new drug development and dosage form design. [1] It discusses how pharmacokinetic parameters can be used to design dosage regimens, predict and explain drug interactions, and individualize treatment for different populations. [2] Dosage adjustment considerations for special populations like neonates, children, elderly, hepatically or renally impaired patients are also reviewed. [3] The document emphasizes that therapeutic drug monitoring is important for optimizing drug therapy for individual patients.
This document discusses dosage regimens for drugs administered through multiple dosing. It defines dosage regimen and explains that multiple dosing aims to maintain therapeutic drug concentrations over time. It describes approaches to designing regimens, including empirical, individualized, and population-based models. Key parameters like dose size and frequency are explained. The document also covers concepts like drug accumulation, steady state, maximum and minimum concentrations, average concentration, loading doses, and maintaining therapeutic ranges. It stresses the importance of dosage regimen design and monitoring drug therapy.
Therapeutic drug monitoring (TDM) involves measuring drug concentrations in patients to optimize dosing for efficacy and safety. TDM is useful for drugs with unpredictable relationships between dose and concentration, narrow therapeutic windows, or other pharmacokinetic factors. Key steps in TDM include deciding when to measure drug levels, collecting samples at appropriate times, measuring concentrations, interpreting results based on therapeutic ranges, and adjusting treatment accordingly. TDM aims to individualize drug therapy by achieving target concentrations for each patient.
Individualisation and optimization of drug dosing regimenJyoti Nautiyal
Drug dosing regimen, dosing frequency, individualisation, Steps Involved in Individualization of Dosage Regimen, optimization, variability, Clinical experience with individualization and optimization based on plasma drug levels.
SUSTAINDRUG DELIVERY SYSTEMS power pointSonam Gandhi
This document provides an overview of a seminar presentation on sustained release drug delivery systems. Some key points discussed include:
1. Sustained release drug delivery systems are designed to provide prolonged therapeutic effects by continuously releasing medication over an extended period after a single dose.
2. Factors that influence the suitability of a drug for sustained release formulations include its absorption, distribution, metabolism, and biological half-life properties.
3. The document outlines various physiological and physicochemical drug properties that must be considered when designing sustained release drug formulations, such as dosage size, solubility, and stability.
This document discusses the calculation and administration of drug doses. It defines key terms like daily dose, dosage regimen, usual adult dose, median effective dose, and more. It also covers units of measurement like teaspoons, tablespoons, drops, and how doses are tailored based on factors like age, weight, and medical condition. Routes of administration and different dosage forms are also outlined.
Oral sustained and controlled release dosage forms Dr Gajanan Sanap
This document discusses oral sustained and controlled release dosage forms. It begins with an introduction and overview of rationality in designing sustained release drug formulations. It defines sustained release as formulations that continuously release medication over an extended period after a single dose to achieve prolonged therapeutic effects. Controlled release aims to deliver drug at a predetermined rate for a specified time period to maintain constant drug levels. The document outlines the differences between controlled and sustained release. It discusses objectives and advantages of sustained release formulations as well as challenges and factors to consider in design.
Sustained release and controlled release drug delivery systems aim to maintain therapeutic drug levels in the body over an extended period of time compared to immediate release formulations. They work to release medication in a controlled fashion after a single dose administration. Some key benefits include improved patient compliance, better control of disease symptoms, and reduced healthcare costs through less frequent dosing. Common technologies include sustained release, site-specific targeting, and timed/delayed release formulations. The design of these systems considers factors like release rate kinetics and total dose needed over time.
This document provides an overview of Novel Drug Delivery Systems (NDDS). It defines NDDS as approaches that transport pharmaceutical compounds safely in the body as needed. The goals of NDDS are to provide therapeutic drug levels at the target site with minimal side effects, degradation, and increased bioavailability. Ideal NDDS would safely deliver drugs in a controlled and sustained manner over time at the site of action. The document discusses various NDDS approaches and terminologies and provides examples of controlled, sustained, delayed, and extended release systems.
The document discusses the applications of pharmacokinetics in new drug development, dosage form design, and novel drug delivery systems (NDDS). It covers key topics such as:
1) How pharmacokinetic principles can be applied to the design and development of new drugs, controlled release formulations, and the selection of appropriate routes of administration.
2) The important pharmacokinetic parameters used in characterization and the approaches used for dosage regimen design.
3) How pharmacokinetics can aid in formulation development, bioavailability/bioequivalence testing, and the development of various NDDS.
4) Considerations for dosing adjustments based on patient factors like obesity, age, hepatic or renal impairment
Therapeutic drug monitoring refers to maintaining drug concentrations within a target range by individualizing dosages. It involves measuring serum drug levels and applying pharmacokinetic principles to optimize drug therapy for each patient. Therapeutic drug monitoring is helpful for drugs with marked variability, concentration-dependent effects, a narrow therapeutic index, or when the desired therapeutic effect is difficult to monitor. Commonly monitored drugs include aminoglycosides, antiepileptics, cardioactives, and lithium.
This document discusses key aspects of posology (dose determination) including:
1. Posology refers to determining appropriate drug doses. The goal is to provide optimal therapeutic effects at the lowest possible dose.
2. Many factors affect drug dosage including age, weight, pathological state, tolerance, and drug interactions. Dosage may need adjustment based on these factors to avoid toxicity or lack of effect.
3. Routes of administration and pharmaceutical formulations can also impact drug absorption and dosage requirements. Oral doses are usually higher than parenteral doses due to incomplete oral absorption. Smaller drug particles may require lower doses due to faster absorption.
This document discusses various drug-induced pulmonary diseases. It notes that drug-induced pulmonary diseases can affect any part of the respiratory system and have non-specific pathological findings. Several drugs are known to cause apnea by depressing the central nervous system or blocking respiratory muscles. Bronchospasm is usually only induced in patients with pre-existing lung conditions and is caused by drugs like beta blockers and aspirin. ACE inhibitors are a common cause of persistent cough. Narcotic analgesics frequently cause non-cardiogenic pulmonary edema. Many cancer chemotherapy drugs and other medications have been associated with pulmonary fibrosis.
This document provides an introduction to clinical pharmacokinetics. It defines key terms like absorption, distribution, metabolism, excretion, pharmacokinetics, pharmacodynamics, and steady state. It discusses the applications of pharmacokinetics in optimizing drug therapy. The document also introduces pharmacokinetic models including compartmental models with central and peripheral compartments. Rate constants and reaction orders like zero-order and first-order kinetics are explained.
The document discusses the importance of evaluating exposure-response relationships during Phase 2-3 clinical trials in order to select optimal doses, understand safety and efficacy results, and inform dosing recommendations for different patient populations. Conducting pharmacokinetic assessments and exposure-response analyses can help overcome barriers like late study design and data collection, and ensure patients receive the right drug, dose, and dosing instructions.
-ROLE OF PHARMACIST IN HOSPITAL PHARMACY.pptxGeletaGalataa
The role of pharmacists in hospital pharmacy can be categorized into four major areas: general responsibilities, dispensing responsibilities, clinical pharmacy services, and research. Pharmacists ensure policies and procedures are followed, maintain competence through continuing education, and provide drug information to patients and other healthcare professionals. They are responsible for dispensing medications properly, providing clinical services like patient reviews and therapeutic drug monitoring, and conducting research in areas like policies, drug distribution, and clinical studies.
The House of Delegates approved 40 new policies and 3 statements at its 2021 meetings. Key topics included direct-to-consumer genetic tests, antimicrobial stewardship, leadership development, interprofessional education, patient experience, and pharmacist roles in public health and pharmacogenomics. The House of Delegates acts as the ultimate authority over ASHP professional policies and meets annually to review and approve new policy proposals.
This document provides an outline and overview of a seminar presentation on pneumonia. It discusses the epidemiology, pathophysiology, etiology, classification, clinical manifestations, laboratory/diagnostic investigations, treatment approaches, and complications of pneumonia. Pneumonia remains a common cause of severe sepsis and a leading infectious cause of death. Treatment involves antibiotics targeting the likely causative pathogens, with choices dependent on patient age, location of infection (community-acquired, hospital-acquired, ventilator-associated), and risk of drug-resistant organisms. Patient education on prevention, symptom management, and completing antibiotic courses is also emphasized.
This document discusses nausea and vomiting, including its definition, causes, pathophysiology, clinical presentation, and treatment. It describes the epidemiology of nausea and vomiting, noting it is most common in those aged 15-24 and less common in other ages. Treatment involves both non-pharmacological approaches like rest and rehydration as well as a variety of antiemetic drugs depending on the underlying cause, including 5-HT3 antagonists, D2 antagonists, antihistamines, and corticosteroids. The choice of antiemetic considers factors like the situation of motion sickness, pregnancy, postoperative nausea and vomiting, and cytotoxic chemotherapy.
1. Liquid pharmaceuticals encountered in pilot plants can be solutions, suspensions, or emulsions. The pilot plant process aims to facilitate the transition of formulations from the laboratory to full-scale production.
2. Key steps in the pilot plant process for liquid orals include reviewing the formula, evaluating raw materials and equipment, setting production rates, optimizing the manufacturing process, and ensuring compliance with good manufacturing practices.
3. Stability testing of the liquid formulations evaluates physical and chemical stability over time to confirm the appropriate preservation and packaging.
This document provides an introduction to biological products and pharmaceutical biotechnology. It defines biological products and describes some key types including proteins, blood factors, hormones, monoclonal antibodies, enzymes, and cytokines. The document outlines several technologies used in biotechnology including recombinant DNA, polymerase chain reaction, gene therapy, and monoclonal antibody production. It also summarizes the historical development of biotechnology from ancient uses of fermentation to modern discoveries of DNA and genetic coding.
Cost-utility analysis (CUA) is a type of economic analysis that compares treatment alternatives by integrating measures of patient preferences and health-related quality of life. CUA uses quality-adjusted life years (QALYs) as the measure of health outcome, which combines both quantity and quality of life into a single metric. The preferred treatment is the one with the lowest cost per QALY gained. QALYs are calculated by multiplying the expected survival time in a health state by a weight representing the quality of life in that health state on a scale of 0 to 1, with 0 being death and 1 being perfect health. CUA allows for comparison of interventions that impact both mortality and morbidity.
This document provides an outline and overview of vaccines. It discusses various topics related to vaccines including introduction to vaccines, modes of immunization, traditional vaccine types (killed pathogens, attenuated, purified antigens/toxoids), limitations of traditional vaccines, and biotech vaccines produced using recombinant DNA techniques (rDNA vaccines, recombinant proteins, recombinant vectors, virus-like particles). Production of vaccines using rDNA allows deletion of virulence genes while still stimulating immunity. The document is authored by Tsegaab Y. and covers these vaccine-related topics in detail across multiple pages.
The document describes three types of mass analyzers: quadrupole analyzer, ion trap analyzer, and time-of-flight analyzer. The quadrupole analyzer uses four parallel metal rods and applied voltages to filter ions by their m/z ratio. The ion trap analyzer applies RF frequencies to trap ions by m/z, which are then scanned out over time. The time-of-flight analyzer uses an electric field to accelerate ions through a drift region, separating them by m/z and detecting them at different times.
The immune system functions to protect the body from pathogens. It consists of organs like the spleen, thymus, and bone marrow as well as white blood cells. Pathogens like viruses, bacteria, fungi, and protists can cause disease by disrupting homeostasis. Germ theory established that many diseases are caused by biological agents. Infectious diseases spread through physical contact, exchange of fluids, indirect contact, or vectors. The immune system uses nonspecific defenses like skin and stomach acid along with specific defenses of white blood cells. When pathogens invade, the body responds with fever, inflammation, and production of antibodies by B cells. Immunity develops from exposure to pathogens, and can be active from infection or vaccination, or passive
Biosimilars are biological products that are highly similar to and have no clinically meaningful differences from an existing FDA-approved biological product, known as the reference product. An interchangeable biosimilar is expected to produce the same clinical result as the reference product. Biosimilars work in the same way as the reference product through the same mechanism of action. Unlike generics, biosimilars are not necessarily identical due to differences in living organisms used to produce them. As biosimilars gain approval, they have the potential to increase treatment options for patients and lower healthcare costs.
Mass spectrometry is a technique that uses the deflection of charged particles by a magnetic field to determine the relative masses of molecular ions and fragments. It provides a great deal of information from small samples and can be used to determine molecular mass, structure, and purity. Various ionization sources like electron ionization, chemical ionization, fast atom bombardment, and matrix-assisted laser desorption/ionization are used to vaporize and ionize samples for analysis in mass analyzers such as quadrupoles, ion traps, and time-of-flight instruments. Mass spectra provide the abundance of ions as a function of their mass-to-charge ratio and can reveal molecular structure through characteristic fragmentation patterns.
This document appears to be discussing a study comparing the efficacy and safety of direct oral anticoagulants (DOACs) vs warfarin in treating patients with atrial fibrillation. The study found that DOACs were as effective as warfarin in reducing stroke and systemic embolism risks while causing fewer bleeding issues. DOACs may be a safer alternative for patients with atrial fibrillation compared to long-term warfarin treatment.
The document discusses health planning. It defines planning and health planning, and describes the benefits of planning which include providing direction, reducing uncertainty, and helping efficiently utilize resources. It differentiates types of planning such as strategic, tactical, and operational planning. The basic steps of health planning are also discussed, including situational analysis, priority setting, objective setting, strategy design, action planning, implementation, and monitoring and evaluation. Outcomes of planning include developing an organization's mission, vision, objectives, and strategies.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
share - Lions, tigers, AI and health misinformation, oh my!.pptxTina Purnat
• Pitfalls and pivots needed to use AI effectively in public health
• Evidence-based strategies to address health misinformation effectively
• Building trust with communities online and offline
• Equipping health professionals to address questions, concerns and health misinformation
• Assessing risk and mitigating harm from adverse health narratives in communities, health workforce and health system
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
2. Contents
Introduction to Dosage Regimen.
Approaches to design dosage regimen.
Dose size, Frequency and Accumulation.
Individualization.
Steps Involved in Individualization of Dosage Regimen.
Dosing of Drugs in Neonates, Infants and Children.
Dosing in Geriatrics.
Dose adjustment in Renal and hepatic impairment.
3. Introduction
Dosage Regimen - Dosage regimen is defined as the manner in
which the drug is taken.
For some drugs like analgesics single dose is efficient for optimal
therapeutic effect however the duration of most illnesses are longer
than the therapeutic effect produced by a single dose, In such cases
drugs are required to be taken on a repetitive bases over a period of
time depending upon the nature of illness.
An optimal multiple dosage regimen is the one in which the drug is
administered in suitable doses with sufficient frequency that ensures
maintenance of plasma conc. Within the therapeutic window for
entire duration of therapy.
4. Approaches to Design of Dosage regimen
Various approaches employed in designing of dosage regimen are
1. Empirical Dosage regimen : Is designed by physicians based on
empirical data, Personal experience and Clinical observations. This
method is however not very accurate.
2. Individualization of Dosage regimen : Is the most accurate
approach and is based on the pharmacokinetics of drug in the
individual patient. The approach is suitable for hospitalized patients
but is quite expensive.
3. Dosage regimen on population Averages : Most often used
approach. The method is based on one of the two models –
1. Fixed Model.
2. Adaptive model.
5. Fixed model :
Here, Population average pharmacokinetic parameters are used
directly to calculate the dosage regimen.
Adaptive model :
It is based on both population average pharmacokinetic parameters of
the drug as well as patient variables such as weight, age, sex, body
surface area and known patient pathophysiology such as renal
diseases.
Irrespective of the route of administration and complexity of
pharmacokinetic equations, the two major parameters that can be
adjusted in developing a dosage regimen are:
The Dose Size- Quantity of drug administered at one time
The Dose Frequency- The time interval between doses.
6. Dose Size-
The magnitude of both therapeutic and toxic responses depends
upon dose size.
Dose size calculation requires the knowledge of amount of drug
absorbed after administration of each dose. Greater the dose size
greater the fluctuations between Css,max and Css,min during each
dosing interval and greater the chances of toxicity.
7. For drugs administered chronically, dose size calculation is based on
average steady state blood levels and is computed from the above
equation :
Xss,av = 1.44FX0t1/2
ז
Where
X0 = Maintenance dose,
F = Fraction of dose absorbed,
ז = Dosing interval
t1/2 = Half life
1.44 = Reciprocal of 0.693
8. Dosing Frequency –
The Dosing Interval (inverse of dosage frequency) is calculated on
the basis of half-life of the drug.
If the interval is increased and dose is unchanged, Cmax, Cmin, Cav
decreases but the ratio Cmax/Cmin increases.
Opposite is observed when the dosing interval is reduced or dosing
frequency is increased. It also results in greater accumulation of
drug in the body and toxicity.
9. A proper balance should be obtained between dose frequency and
size to attain steady state conc. And with minimum fluctuations to
ensure therapeutic efficacy and safety.
For drugs with wide therapeutic index such as penicillin's, Larger
doses may be administered at longer intervals (more than half life
of drug) without any toxicity effects.
For drugs with narrow therapeutic index such as digoxin, small
doses with frequent intervals (less than half life of drug) is better to
obtain a profile with least fluctuations which is similar to that
observed with controlled drug release systems.
10. Drug Accumulation during Multiple Dosing :
Accumulation occurs because drug from previous doses has not
been removed completely.
As the amount of drug in the body increases due to accumulation,
the rate of elimination also rises proportionally until a steady state
or plateau is reached when the rate of drug entry into the body
equals the rate of exit.
Thus, the extent to which a drug accumulates in the body during
multiple dosing is independent of dose size and is the function of
a. Dosing Interval and
b. Elimination half-life.
The extent to which a drug will accumulate in the body with any dose
interval in a patient can be derived from information obtained with a
single dose and is given by Accumulation Index Rac .
12. Loading and Maintenance Dose :
A drug does not show therapeutic activity unless it reaches the
desired steady state. Plateau can be reached immediately by
administering a dose that gives the desired steady state
instantaneously before commencement of maintenance dose Xo.
Such an Initial dose or first dose intended to be therapeutic is called
as loading dose or priming dose Xo,L. Equation for calculating
Loading dose is
Xo,L = Css,av Vd
F
For drugs having low therapeutic indices the loading dose maybe
divided into smaller doses to be given at various intervals before the
first maintenance dose. When Vd is not known the loading dose can
be calculated by the following equation :
13. Xo,L = 1
(1-e – Ka ז )(1-e – KEז )
When the drug is given I.V. or when absorption is extremely rapid,
the absorption phase is neglected and the above equation reduces to
accumulation index :
Xo,L = 1 = Rac
Xo (1-e – KEז )
The ratio of loading dose to maintenance dose Xo,L/Xo is called as
dose ratio. As the rule when
ז = t1/2 , dose ratio equals 2.0, ז > t1/2 , dose ratio is smaller than 2.0
ז < t1/2 , dose ratio is grater than 2.0 .
14.
15. Maintenance Dose :
A maintenance dose is the maintenance rate [mg/h] of drug
administered equal to the rate of elimination at steady state. It is also
defined as the amount of drug required to keep a desired mean steady
state concentration in the tissues. It is administered after L.D.
Calculation of Maintenance Dose :
The required maintenance dose may be calculated as :
MD = CpCL
F
Where,
MD – Maintenance dose rate (mg/L)
Cp – desired peak Conc. Of drug (mg/l)
CL – Clearance of drug in body and F – Bioavailability.
16. Individualization
Rational drug therapy requires Individualization of Dosage regimen to
fit a particular patient’s needs. The application of Pharmacokinetic
principles in the dosage regimen design for the safe and effective
management of illness in individual patient is called as Clinical
Pharmacokinetics.
Same dose of drug may produce large differences in pharmacologic
response in different individuals, this is called as Intersubject
variability.
In other words it means that the dose required to produce a certain
response varies from individual to individual.
17. Advantages of Individualization :
Individualization of dosage regimen help in development
of dosage regimen which is Specific for the patient.
Leads to decrease in Toxicity and side effects and increase
in pharmacological drug efficacy.
Leads to decrease in allergic reactions of the patient for
the drug if any.
Patient compliance increases etc.
18. Sources of Variability
1. Pharmacokinetic Variability –
Due to difference in drug concentration at the site of action (as
reflected from plasma drug concentration) because of individual
differences in Drug absorption, Distribution, Metabolism and
Excretion.
2. Pharmacodynamics Variability –
Which is attributed to differences in effect produced by a given
drug concentration.
The Major cause of variability is Pharmacokinetic variability.
Difference in the plasma conc. levels of given in the same individual
when given on different occasions is called as “Intersubject
Variability”
19. It is rarely encountered in comparison to Inter-individual variations.
The differences in variability differ for different drugs. Some drugs
shows greater variability than others
Major causes of Intersubject Pharmacokinetics Variability are –
1. Genetics.
2. Diseases.
3. Age.
4. Body Weight and
5. Drug-Drug Interactions.
Less important Causes are :
1. Pharmaceutical formulations
2. Route of administration
3. Environmental factors and Patient non-compliance.
20. The main objective of Individualization is aimed at optimizing the
Dosage regimen. An Inadequate therapeutic response calls for a
higher dosage whereas drug related toxicity calls for a reduction in
dosage.
Thus in Order to aid individualization, A drug must be made
available in dosage forms of different strengths. The number of dose
strengths in which the drug should be made available depends upon 2
Major Factors -
1. The Therapeutic index of the drug and
2. The degree of Inter-subject Variability.
Smaller the therapeutic index greater the variability, more the
number of dose, strengths required.
21. Steps Involved in Individualization of Dosage Regimen
Based on the assumption that all patients require the same
plasma conc. range for therapeutic effectiveness, the steps
involved in the individualization of dosage regimen are :
1. Estimation of Pharmacokinetic Parameters in individual
patients and to evaluate the degree of Variability.
2. Attributing the Variability to some measurable
characteristics such as hepatic or renal diseases, Age,
weight etc.
3. Designing the new dosage regimen from the collected
data.
22. The design of new dosage regimen involves –
1. Adjustment of dosage or
2. Adjustment of dosing interval or
3. Adjustment of both dosage and dosing interval.
Dosing of Drugs In Obese Patients:
The apparent volume of distribution is greatly affected by changes in
body weight since the latter is directly related to vol. of various body
fluids.
The Ideal Body Weight (IBW) foe men and women can be calculated
from following formulae:
IBW (Men) = 50 kg +/- 1kg/2.5cm above or below 150cm in height.
IBW (Women) = 45kg +/- 1kg/2.5cm above or below 150cm in height.
23. Any Person Whose body Weight Is more than 25% above the IBW is
considered Obese.
Generalizations regarding drug distribution and dose distribution
in obese patients :
For drugs such as Digoxin that do not significantly distribute in
excess body space, Vd do not change and hence dose should be
calculated on IBW basis.
For polar drugs like antibiotics (Gentamicin) which distribute in
excess fat of obese patients to less extent then other tissues the dose
should be lower than per kg total body weight basis but more than
that on IBW basis.
24. Dosing of Drugs in Neonates, Infants and Children :
Neonates, Infants and children require different dosages than that of
adults because of differences in the body surface area, TBW and ECF
on per kg body weight basis.
Dose for such patients are calculated on the basis of their body surface
area not on body weight basis.
The surface area in such patients are calculated by Mosteller’s
equation :
SA (in m2) = (Height x Weight)1/2
60
Infants and children require larger mg/kg doses than adults because:
Their body surface area per kg body weight is larger and hence
Larger volume of distribution (particularly TBW and ECF)
TBW- Total body water. ECF- Extra cellular fluid.
25. The child's Maintenance dose can be calculated from adult dose by
the following by the following equation :
Child’s dose = SA of child in m2 x Adult dose
1.73
Where 1.73 is surface area in m2 of an avg. 70kg adult.
Since the surface area of a child is in proportion to the body weight
according to the following equation,
SA(in m2)= Body weight (in kg)
The following relationship can also be written for child’s dose:
Child’s dose = weight of child in kg x adult dose
70
26. As the TBW in neonates is 30% more than that in adults,
The Vd for most water soluble drugs is larger in infants and
The Vd for most lipid soluble drugs is smaller .
Accordingly the dose should be adjusted.
Dosing of drugs in Elderly :
Drug dose should be reduced in elderly patients because of general
decline in body function with age.
The lean body mass decreases and body fat increases by almost
100% in elderly persons as compared to adults.
Vd of water soluble drugs may decrease and that of lipid soluble
drugs like diazepam increases with age.
Age related changes in renal and hepatic functions greatly alters the
clearance of drugs.
27. The equation that allows calculation of maintenance dose in such
patients is given as follows :
Patients dose = (weight in Kg) (140 - age in years) x adult dose
1660
Dosing of drugs in Hepatic diseases :
The influence of Hepatic disorder on the drug bioavailability &
disposition is unpredictable because of the multiple effects that liver
produces.
The altered response to drugs in liver disease could be due to
decreased metabolizing capacity of the hepatocytes, impaired biliary
elimination, due to biliary obstruction
(e.g. Rifampicin accumulation in obstruction jaundice)
28. Impaired Hepatic blood flow leading to an increase in
bioavailability caused by a reduction in first pass metabolism
(e.g. Bioavailability's of Morphine and Labetalol have been reported
to double in patients with Cirrhosis)
Decreased protein binding and increased toxicity of drugs highly
bound to plasma protein (e.g. Phenytoin, Warfarin) due to impaired
albumin production, altered volume of distribution of drugs due to
increased extracellular fluid.
Oedema in liver disease may be increased by drugs that cause fluid
retention
(e.g. Acetylsalicylic acid, Ibuprofen, Prednisolone, Dexamethasone).
Generally, drug doses should be reduced in patients with hepatic
dysfunction since clearance is reduced & bioavailability is
increased in such a situation.
29. Examples of drugs who's drug conc. Changes due to hepatic
impairment :
High extraction ratio
Antidepressants
Chlorpromazine/haloperidol
Calcium channel blockers
Morphine
Glyceryl trinitrates
Levodopa
Propranolol
30. Low extraction ratio
Non-steroidal anti-inflammatory drugs
Diazepam
Carbamazepine
Phenytoin
Warfarin
Extraction Ratio – is the measure in renal physiology, Primarily used
to calculate renal plasma flow in order to evaluate renal function. It is
the amount of compound entering the kidney that got excreted into the
final urine. Extraction ratio of the drugs ranges from 0 -1.5 l/min.
High Extraction Ratio - Less than 0.3
Low Extraction Ratio - More than 0.7
31. Dosing of drugs in Renal Disease
In patient with renal failure, the half life of the drug is increase and
its clearance drastically decreases if it is predominantly eliminated
by way of excretion.
Hence, dosage adjustment should take into account the renal function
of the patient and the fraction of unchanged drug excreted in urine.
There are two additional method for dose adjustment in renal
insufficiency if the Vd change is assumed to be negligible.
The adjustment of drug dosage in case of renal disease are carried out
by mainly three approaches :
Dose adjustment based on Total body clearance.
Dose adjustment based on Elimination rate constant or Half life.
Dose adjustment in renal failure
32. Dose adjustment based on Total body clearance :
The average drug conc. at steady state Css,av is a function of
maintenance dose X0 , the fraction of dose absorbed F, the dosing
interval ז & clearance Cl T of the drug.
Css,av = Fx0/ClT ז
Css,av = F x 1/ClT x x0/ז
To be kept Assumed Decreased Needs
Constant Constant due to Disease adjustment
33. If ClT' , X0 ' & '
ז represents the values for the renal failure patient,
then the eq. for dose adjustment is given as
Css,av = x0/ClT ז = x0 / Cl’T ‘ז
Rearranging in terms of dose & dose interval to be adjusted, the eq.
is
Xo
’ = Cl’
T Xo
‘ז ClTז
From the above eq., the regimen can be adjusted by reduction in
dosage or increase in dosing interval or a combination of both.
34. Dose adjustment based on Elimination rate constant or
half life :
The average drug conc. at steady-state Css,av is a function of
maintenance dose X0 , the fraction of dose absorbed F, the dosing
interval ז & volume of distribution vd & t1/2 of the drug.
Css,av = 1.44 F X0 t1/2
Vd ז
Where, the coefficient 1.44 is the reciprocal of 0.693.
35. Css,av = 1.44 F X t1/2 X X0
Vd ז
To be kept Assumed Decreased Needs
Constant Constant due to Disease adjustment
If t1/2 ' , X0 ' & 'ז represents the values for the renal failure
patient, then the eq. for dose adjustment is given as
Css,av = t1/2 Xo = t1/2 ‘ Xo’
ז 'ז
36. Rearranging in terms of dose & dose interval to be adjusted, the eq.
is
Xo’ = t1/2 Xo
‘ז t‘1/2 ז
Because of prolongation of half life of a drug due to reduction in
renal function, the time taken to achieve the desired plateau takes
longer if the more severe is dysfunction, hence such patient
sometimes need loading dose.
37.
38. Antiviral drugs
Renal clearance is the major route of elimination for many antivirals.
In patients with renal impairment, renal clearance of these drugs is
reduced and the elimination half-life is significantly prolonged. As a
result, normal doses will accumulate and may lead to neurological
signs such as dizziness, confusion, hallucinations, somnolence and
convulsions etc.
Hypoglycemic drugs
Metformin
Metformin has been associated with rare but potentially fatal lactic
acidosis. This is thought to result from accumulation of metformin
when renal impairment reduces renal clearance.
39. Insulin
Renal elimination accounts for up to half of the clearance of insulin, so
as renal failure progresses, less insulin is excreted so smaller doses are
required.
Allopurinol
Allopurinol is used in the management of gout to lower serum and
urinary uric acid concentrations. As allopurinol, and its active principal
metabolite oxypurinol, are mainly excreted in the urine, they
accumulate in patients with poor renal function so the dose should be
reduced.
40. Diseases are the major source of variation in drug response. Both
pharmacokinetic and Pharmacodynamics of many drugs are altered
by disease other than the one which is being treated.
Disease state :
Renal dysfunction
Uremia
Renal dysfunction :
It greatly impair the elimination of drug especially those that are
primarily excreted by the kidney.
Causes of renal failure are hypertension, diabetes mellitus etc.
41. Uremia :
It is characterized by impaired Glomerular filtration and
accumulation of fluid and protein metabolism.
In both the cases the half life of the drug are increased as a
consequences drug accumulation and toxicity increases.
42. References
Bio pharmaceutics and Pharmacokinetics – A Treatise by
D.M Brahmankar and Sunil B. Jaiswal.
Bio pharmaceutics and Pharmacokinetics by P.L Madan
JAYPEE Publication.
Internet sources : Google
: www.astralianprescriber.com Volume 32
Number 2 April 2009.
Applied Bio pharmaceutics and Pharmacokinetics Vth
Edition by Leon Shargel.