Lec 3.3-hepatic elimination( first pass effect)
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The document discusses the first-pass effect and hepatic elimination of orally administered drugs. It defines the first-pass effect as the rapid metabolism of a drug by the liver or intestinal mucosa before it reaches systemic circulation. This results in lower bioavailability compared to intravenous administration. The liver extraction ratio measures the liver's efficiency in eliminating a drug from the bloodstream during a single pass through the liver. It can be estimated from a drug's oral bioavailability and provides information about the liver's extraction of the drug and implications for oral dosing. Drugs with high liver extraction require higher oral doses to achieve equivalent effects as intravenous administration due to the first-pass effect.
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For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
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These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
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IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
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INTRODUCTION
• Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
• Results in 100% bioavailability as the absorption process is bypassed.
• The absolute bioavailability of a drug, when administered by an extra vascular route is usually less than one (i.e. F<100%).> Oral > Rectal > Topical.
A systematic approach to ensure bioavailability of pharmaceutical products:
BIOAVAILABILITY
It the degree to which, or the rate at which, a medication or other substance is absorbed or becomes available at the targeted place in the body. Bioavailability can be influenced by inactive ingredients (see Excipients) in the drug such as additives that prevent the medication from dissolving in the stomach. If a medication that is intended to be taken on an empty stomach is taken instead with food, this can also change the absorption rate and affect the bioavailability of the active ingredient
BIO AVAILABILITY FRACTION (F):
Bio available fraction it refers to the fraction of administered dose that enters the systemic circulation.
*100
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Bioavailability
1) Bioavailability refers to the proportion of an administered drug dose that reaches systemic circulation and is available at the site of action. It depends on pharmaceutical, patient, and route of administration factors.
2) Bioavailability studies are important in drug development to determine the influence of excipients and formulations as well as compare availability between dosage forms.
3) Bioavailability can be measured using pharmacokinetic methods like plasma concentration-time profiles and urinary excretion studies or pharmacodynamic methods like acute pharmacological responses and therapeutic effects. Pharmacokinetic methods are more direct but pharmacodynamic methods may be needed if other methods can't be used.
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Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
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Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
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IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
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2. AUC is important for assessing drug exposure in toxicology, comparing drug products, and determining pharmacokinetic parameters like clearance and elimination rate.
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INTRODUCTION
• Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
• Results in 100% bioavailability as the absorption process is bypassed.
• The absolute bioavailability of a drug, when administered by an extra vascular route is usually less than one (i.e. F<100%).> Oral > Rectal > Topical.
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It the degree to which, or the rate at which, a medication or other substance is absorbed or becomes available at the targeted place in the body. Bioavailability can be influenced by inactive ingredients (see Excipients) in the drug such as additives that prevent the medication from dissolving in the stomach. If a medication that is intended to be taken on an empty stomach is taken instead with food, this can also change the absorption rate and affect the bioavailability of the active ingredient
BIO AVAILABILITY FRACTION (F):
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*100
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DRUG-DOSE ADJUSTMENT IN PATIENTS WITH HEPATIC DISEASES
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dosage adjustment in renal and hepatic failure for medical student
dosage adjustment in renal and hepatic failure for medical student
Pharmacokinetics / Biopharmaceutics - Drug Elimination
Pharmacokinetics / Biopharmaceutics - Drug Elimination
Similar to Lec 3.3-hepatic elimination( first pass effect)
Bioavailability
1) Bioavailability refers to the proportion of an administered drug dose that reaches systemic circulation and is available at the site of action. It depends on pharmaceutical, patient, and route of administration factors.
2) Bioavailability studies are important in drug development to determine the influence of excipients and formulations as well as compare availability between dosage forms.
3) Bioavailability can be measured using pharmacokinetic methods like plasma concentration-time profiles and urinary excretion studies or pharmacodynamic methods like acute pharmacological responses and therapeutic effects. Pharmacokinetic methods are more direct but pharmacodynamic methods may be needed if other methods can't be used.
BIOAVAILABILITY BIOEQUIVALENCE THERAPEUTIC INDEX
This document discusses key topics related to pharmacology including bioavailability, bioequivalence, and therapeutic index. It provides background on how bioavailability was studied initially due to toxicity issues with certain drugs. Factors that influence bioavailability include pharmaceutical factors like formulation, patient factors like metabolism, and route of administration. Bioequivalence compares the bioavailability of two drugs to determine if they are therapeutically equivalent. The therapeutic index is the ratio of toxic to therapeutic doses - a higher index is preferable as it means toxicity occurs at a much higher dose level.
Drug absorption
The document discusses first-pass effects, which refers to the metabolism of drugs in the liver and gut before they reach systemic circulation. It describes the theory behind first-pass effects and the various systems like digestive enzymes, bacterial enzymes, and hepatic enzymes that can metabolize drugs and affect bioavailability. It also discusses methods to estimate bioavailability and prevent or take advantage of first-pass effects. Evaluation techniques include in silico, physicochemical, in vitro, in situ, and cell-based methods like the Caco-2 cell model.
EFFECT OF HEPATIC DISEASE ON PHARMACOKINETICS.pptx
The document discusses the effect of hepatic (liver) disease on drug pharmacokinetics. Hepatic diseases can alter how drugs are metabolized, distributed, and eliminated from the body. This can lead to drug accumulation, changes in active metabolites formed, and altered protein binding. Several factors are relevant when considering drug dosing in patients with hepatic impairment, including changes in enzyme activity and blood flow. Tests are used to assess liver function and severity of disease, but do not fully capture changes to drug metabolism. Drugs may require dose adjustments in patients with hepatic impairment depending on the fraction of the drug metabolized by the liver.
1. Pk Absorption
This document discusses pharmacokinetics and the processes the body undergoes to metabolize drugs. It covers the four main aspects of pharmacokinetics: absorption, distribution, metabolism, and excretion. Specifically, it focuses on drug absorption, explaining the sites it occurs through the gastrointestinal tract, and factors that can modify absorption such as solubility, pH, lipid solubility, blood flow, and food intake. It also defines bioavailability as the fraction of unchanged drug reaching systemic circulation by any administration route.
Effects of liver diseases on pharmacokinetics
Hepatic disease can significantly alter the pharmacokinetics and pharmacodynamics of drugs due to changes in drug metabolism and clearance in the liver. The degree of liver function impairment is commonly assessed using the Child-Pugh score, with higher scores indicating more severe impairment. For drugs that undergo significant hepatic metabolism or clearance, dosage reductions may be necessary in patients with liver disease to avoid drug accumulation, decreased formation of active metabolites, and increased risk of adverse effects. The need for dosage adjustment depends on the fraction of the drug metabolized by the liver and the severity of liver function impairment.
A PPT on Non-linear Pharmacokinetics
This document discusses non-linear pharmacokinetics and pharmacodynamics. It begins by defining basic kinetic parameters like absorption and elimination rate constants, volume of distribution, and bioavailability fraction. It then explores possible causes of non-linearity, including saturation of absorption, distribution, metabolism and excretion processes. Non-linear binding due to saturation of plasma protein binding sites is also covered. The document concludes by giving an example of non-linear pharmacological responses with phenytoin, where capacity-limited metabolism leads to fluctuating clearance and half-life with changing plasma concentrations.
Basics of Pharmacology general pharmacology.....pptx
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.
Bioavailabity.pharmacology lecture.pp tx
Bioavailability is defined as the fraction of an administered dose of a drug that reaches systemic circulation in an unchanged form. It is measured as the area under the curve obtained by plotting drug concentration versus time. Bioavailability is considered 100% for intravenous administration but is often less than 100% for other routes due to factors such as incomplete absorption, first-pass metabolism, drug properties like lipophilicity, and efflux pumps. The bioavailability of a drug depends on its absorption, formulation, route of administration, and metabolism. Two drug products are considered bioequivalent if they exhibit equal bioavailability and similar time to reach peak plasma concentrations.
Pharmacokinetics: An overiew
Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, through, and out of the body—the time course of its absorption, bioavailability, distribution, metabolism, and excretion.
Concept of clearance & factors affecting renal excretion
This document discusses the concept of renal clearance. It defines renal clearance as the volume of blood or plasma completely cleared of unchanged drug by the kidney per unit time. Renal clearance is calculated as the rate of urinary excretion divided by the plasma drug concentration. Several factors can affect renal clearance, including the physiochemical properties of the drug, plasma drug concentration, distribution and binding characteristics, urine pH, blood flow to the kidneys, biological factors, drug interactions, and disease states. Renal clearance is an important concept for understanding how drugs are eliminated from the body through the kidneys.
Drug Elimination
This document discusses drug elimination through excretion. It defines excretion as the process of transferring drugs and metabolites from the internal to external environment. The principal organs of excretion are the kidneys, through which drugs are excreted via renal excretion. Other routes of non-renal excretion include the lungs, biliary system, intestines, and sweat glands. The key processes determining renal excretion are glomerular filtration, tubular secretion, and tubular reabsorption. Drugs can be cleared from the body through renal clearance or non-renal clearance via routes like biliary, pulmonary, salivary, dermal and gastrointestinal excretion.
Drug absorption
This document provides an overview of pharmacokinetics and drug absorption. It defines key terms like bioavailability, discusses factors that influence drug absorption like lipid solubility and ionization, and mechanisms of drug transport including passive diffusion. Specific topics covered include the first-pass effect, importance of drug and environmental pH on absorption, and how molecular weight impacts absorption. Measurement of areas under the curve is presented as a method for assessing bioavailability.
Practice 4(1)_General Pharmacology.ppt
The document discusses various concepts related to pharmacodynamics and pharmacokinetics. It defines key terms like agonism, antagonism, transmembrane signaling, receptor regulation, drug permeation and distribution, routes of administration, drug elimination, loading dose, maintenance dose, half-life, therapeutic window, bioavailability, drug metabolism, and toxic metabolism. It provides examples of different transmembrane signaling mechanisms and discusses graded vs quantal responses, efficacy vs potency. The document concludes with sample exam questions related to these concepts.
nihms-691736
The document discusses a non-invasive test called the dual cholate test that can quantify liver function. It measures the clearance of two cholate substrates (given orally and intravenously) to assess hepatic perfusion from both the portal and systemic circulations, as well as portal-systemic shunting. A disease severity index (DSI) derived from these cholate clearance measurements provides a direct link to clinical outcomes of patients. The DSI appears to outperform measures of fibrosis like biopsy or liver stiffness in predicting risks for future clinical events. The dual cholate test and DSI may offer accurate, minimally-invasive ways to monitor liver function and disease progression.
pharmacokinetics & pharmacodynamics- seminar- magdum sir.pptx
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”
Pharmacokinetics of drugs , detailes of drug ADME.pptx
Pharmacokinetics of drugs , detailes of drug Absorption, Distribution, Metabolism, and Excretion.
Pharma Co Kinetics Filtration by Kidney
Pharma Co Kinetics Filtration by KidneyPKLI University- Institute of Nursing and Allied Health Sciences Lahore , Pakistan.
Pharma co kinetics includes 1:Renal excretion (Major )
2:Biliary Excretion
3:Pulmonary Excretion
4:Salivary Excretion
5:Sweat Excretion
6:Mamamry Excretion
Introduction of hepatic impairment study 29 jul
This document provides an introduction to hepatic impairment studies. It discusses the role of the liver in pharmacokinetics including absorption, distribution, metabolism and excretion of drugs. Common liver diseases and their effects on pharmacokinetics are also described. The objectives and recommended designs of hepatic impairment studies are outlined, including categorization of impairment using the Child-Pugh score and dose adjustment recommendations based on area under the curve comparisons. Both single-dose and multiple-dose study designs are discussed.
Drug excretion lecture 10
The major organs involved in drug excretion are the kidneys and liver. The kidneys excrete drugs through glomerular filtration, tubular secretion, and tubular reabsorption in the nephron. The liver excretes some drugs and their metabolites into bile. Pulmonary excretion eliminates gaseous and volatile substances through expiration.
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EFFECT OF HEPATIC DISEASE ON PHARMACOKINETICS.pptx
EFFECT OF HEPATIC DISEASE ON PHARMACOKINETICS.pptx
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Concept of clearance & factors affecting renal excretion
Concept of clearance & factors affecting renal excretion
pharmacokinetics & pharmacodynamics- seminar- magdum sir.pptx
pharmacokinetics & pharmacodynamics- seminar- magdum sir.pptx
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Pharmacokinetics of drugs , detailes of drug ADME.pptx
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Lec 3.2-hepatic elimination (clearance of protien bound drugs) (1)
Hepatic clearance is the volume of blood cleared of a drug by the liver per unit time. It is a component of total body clearance along with renal clearance. Hepatic clearance of a protein-bound drug can be restrictive or nonrestrictive. Restrictive clearance means the protein-bound portion of the drug is not easily metabolized, while the free portion is. Nonrestrictive clearance means the liver extracts the drug regardless of its bound or free state. The relationship between hepatic clearance, blood flow, and intrinsic clearance depends on whether the drug exhibits restrictive or nonrestrictive clearance.
Skeleton
The human skeleton is made up of 206 bones that form a protective framework for muscles and soft tissues. There are two main types of skeleton - the axial skeleton which includes the skull and vertebral column, and the appendicular skeleton which includes the shoulders, pelvis and limbs. Bones provide structure, movement, protection and mineral storage. There are many different bone types distributed throughout the body. Joints connect bones and allow movement, with different joint types providing varying degrees of mobility and stability.
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Lec 3.3-hepatic elimination( first pass effect)
- 1. LEC:3.3 Hepatic Elimination: FIRST PASS EFFECT
- 2. First Pass Effect DEFINITION EVIDENCE OF FIRST-PASS EFFECT LIVER EXTRACTION RATIOS DETERMINATION OF EXTRACTION RATIO 2
- 3. Definition 3 The rapid metabolism of an orally administered drug before reaching the general circulation is termed first-pass effect or presystemic elimination Drugs that are highly metabolized by the liver or by the intestinal mucosal cells demonstrate poor systemic availability when given orally
- 4. 4 Evidence of First-Pass Effects 1. From experimental findings in animals, first-pass effects may be assumed if the intact drug appears in a cannulated hepatic portal vein but not in general circulation. 2. In another approach first pass effect can be established by lesser 𝑨𝑼𝑪 𝟎 ∞ oral < 𝑨𝑼𝑪 𝟎 ∞ IV
- 5. For a drug to be 100% bioavailable after oral administration (F=1) 𝑨𝑼𝑪 𝟎 ∞ oral = 𝑨𝑼𝑪 𝟎 ∞ IV Therefore, the absolute bioavailability (F) may reveal evidence of drug being removed by the liver due to first-pass effects as follows: For drugs that undergo first-pass effects 𝑨𝑼𝑪 𝟎 ∞ oral < 𝑨𝑼𝑪 𝟎 ∞ IV and F < 1. Examples of drugs that undergo significant first pass effect and have F values less than 1 include propranolol, morphine, and nitroglycerin 5
- 6. Liver Extraction Ratio The extraction ratio of an organ of elimination can be described as the measure of the organ's relative efficiency in eliminating the drug from the systemic circulation over a single pass through the organ 𝑬𝑹 = 𝑪 𝒂 − 𝑪 𝒗 𝑪 𝒂 where C a is the drug concentration in the blood entering the liver C v is the drug concentration leaving the liver 6
- 7. 7 Because C a is usually greater than C v, ER is usually less than 1. For example, for propranolol, ER is about 0.7 about 70% of the drug is actually removed by the liver before it is available for general distribution to the body.
- 8. Determination of Extraction Ratio 8 Liver ER provides a measurement of liver extraction of a drug orally administered. Unfortunately, sampling of drug from the hepatic portal vein and artery is difficult and performed mainly in animals. Animal ER values may be quite different from those in humans.
- 9. 9 The following relationship between bioavailability and liver extraction enables a rough estimate of the extent of liver extraction: Where F is the fraction of bioavailable drug, ER is the drug fraction extracted by the liver, F″ is the fraction of drug removed by non-hepatic process. If F″ is assumed to be negligible—that is, there is no loss of drug due to chemical degradation, gut metabolism, and incomplete absorption—ER may be estimated from
- 10. This can be rearranged as OR 10
- 11. 11 ER is a rough estimation of liver extraction for a drug. Many other factors may alter this estimation: the size of the dose the formulation of the drug the pathophysiologic condition of the patient
- 12. 12 Liver ER provides valuable information in determining the oral dose of a drug when the intravenous dose is known. For example, Propranolol requires a much higher oral dose compared to an IV dose to produce equivalent therapeutic blood levels, Because liver extraction is affected by blood flow to the liver, dosing of drug with extensive liver metabolism may produce erratic plasma drug levels. Formulation of this drug into an oral dosage form requires extensive, careful testing.
- 13. 13