Drugs pharmacology in Liver disease discusses how impaired liver function affects drug metabolism and elimination in different ways depending on the extent of liver damage. For drugs highly extracted by the liver during a single pass, impaired liver function increases bioavailability but may prolong half-life only in severe cases. For drugs with low hepatic extraction, impaired liver function prolongs half-life more significantly. It also discusses changes to absorption, metabolism, protein binding, and considerations for specific drug classes. Laboratory tests of liver function are important but may not reflect hepatic drug clearance capacity.
This document discusses drugs and their interactions with the liver. It begins by describing the liver's role in metabolizing and clearing drugs from the bloodstream via processes like the cytochrome P450 system and conjugation reactions. It then explains how drug-drug interactions can occur when one drug inhibits or induces the cytochrome P450 enzymes that metabolize other drugs. The document presents a case study of a patient experiencing toxic cyclosporine levels due to an interaction with the antifungal ketoconazole. Finally, it briefly discusses how herbal supplements like St. John's Wort can also interact with prescription drugs metabolized by the cytochrome P450 system.
Pharmacokinetics variations in Disease States.Faizan Akram
The biggest issue in PK/PD and drug therapy is variability in
response. Variability factors that affect pharmacokinetics and pharmacodynamics influence clinical trials and dose regimen designs.
This document discusses dosing of drugs in patients with liver failure. It begins by introducing how the liver is involved in drug metabolism and clearance. It then classifies drugs based on their hepatic extraction: high extraction (flow limited), low extraction (enzyme limited), and intermediate extraction drugs. For each class, it discusses how liver disease impacts drug clearance and provides recommendations for dose adjustments based on the severity of liver impairment.
The pharmacokinetics of many drugs are altered in patients with hepatic disease. The extent of alteration depends on the drug's elimination pathway and the severity of the liver disease. Drugs primarily metabolized by the liver will have their clearance reduced in patients with liver dysfunction. The bioavailability of drugs undergoing first-pass metabolism may increase due to reduced first-pass effect. Child-Pugh score is commonly used to assess liver disease severity and predict changes in drug pharmacokinetics. Dosage adjustments are usually required for drugs eliminated hepatically when treating patients with hepatic impairment.
Thyroid disease and renal disease can influence drug metabolism in several ways. Thyroid dysfunction can cause changes in drug metabolism ranging from profound to moderate or negligible, depending on the drug. Renal impairment requires dosage reductions for drugs that are primarily cleared renally. Liver diseases like cirrhosis, jaundice, alcoholic liver disease, viral hepatitis, and hepatoma can also impact drug metabolism through various mechanisms such as decreasing drug clearance or inhibiting metabolic enzyme pathways. The effects are complex and unpredictable, varying with the type and severity of the disease.
Pharmacokinetic changes of drugs in hepatic diseasesDr Htet
1) The pharmacokinetics of many drugs are altered in patients with hepatic disease depending on the drug's elimination pathway and the severity of liver dysfunction.
2) For drugs that are highly extracted by the liver during first pass metabolism, hepatic impairment can increase their oral bioavailability by reducing first pass extraction.
3) Liver diseases may also decrease plasma protein binding of drugs and increase their free fractions, potentially leading to adverse effects from higher than intended drug levels.
This document discusses drug prescription considerations for patients with liver disease. It covers several topics:
1. Many drugs can cause hepatotoxicity, so drug history is important for hepatic patients. Liver function should be monitored for those on hepatotoxic medications.
2. The liver metabolizes most drugs, so liver disease can impact drug efficacy and side effects. It also increases risk of drug-drug interactions.
3. Several classes of drugs commonly used to treat liver disease or related conditions are discussed, including their potential side effects and safer or cheaper alternatives when possible.
4. Careful consideration is needed when prescribing anticoagulants, antiplatelets, diuretics, and other drugs in hepatic patients
This document discusses drugs and their interactions with the liver. It begins by describing the liver's role in metabolizing and clearing drugs from the bloodstream via processes like the cytochrome P450 system and conjugation reactions. It then explains how drug-drug interactions can occur when one drug inhibits or induces the cytochrome P450 enzymes that metabolize other drugs. The document presents a case study of a patient experiencing toxic cyclosporine levels due to an interaction with the antifungal ketoconazole. Finally, it briefly discusses how herbal supplements like St. John's Wort can also interact with prescription drugs metabolized by the cytochrome P450 system.
Pharmacokinetics variations in Disease States.Faizan Akram
The biggest issue in PK/PD and drug therapy is variability in
response. Variability factors that affect pharmacokinetics and pharmacodynamics influence clinical trials and dose regimen designs.
This document discusses dosing of drugs in patients with liver failure. It begins by introducing how the liver is involved in drug metabolism and clearance. It then classifies drugs based on their hepatic extraction: high extraction (flow limited), low extraction (enzyme limited), and intermediate extraction drugs. For each class, it discusses how liver disease impacts drug clearance and provides recommendations for dose adjustments based on the severity of liver impairment.
The pharmacokinetics of many drugs are altered in patients with hepatic disease. The extent of alteration depends on the drug's elimination pathway and the severity of the liver disease. Drugs primarily metabolized by the liver will have their clearance reduced in patients with liver dysfunction. The bioavailability of drugs undergoing first-pass metabolism may increase due to reduced first-pass effect. Child-Pugh score is commonly used to assess liver disease severity and predict changes in drug pharmacokinetics. Dosage adjustments are usually required for drugs eliminated hepatically when treating patients with hepatic impairment.
Thyroid disease and renal disease can influence drug metabolism in several ways. Thyroid dysfunction can cause changes in drug metabolism ranging from profound to moderate or negligible, depending on the drug. Renal impairment requires dosage reductions for drugs that are primarily cleared renally. Liver diseases like cirrhosis, jaundice, alcoholic liver disease, viral hepatitis, and hepatoma can also impact drug metabolism through various mechanisms such as decreasing drug clearance or inhibiting metabolic enzyme pathways. The effects are complex and unpredictable, varying with the type and severity of the disease.
Pharmacokinetic changes of drugs in hepatic diseasesDr Htet
1) The pharmacokinetics of many drugs are altered in patients with hepatic disease depending on the drug's elimination pathway and the severity of liver dysfunction.
2) For drugs that are highly extracted by the liver during first pass metabolism, hepatic impairment can increase their oral bioavailability by reducing first pass extraction.
3) Liver diseases may also decrease plasma protein binding of drugs and increase their free fractions, potentially leading to adverse effects from higher than intended drug levels.
This document discusses drug prescription considerations for patients with liver disease. It covers several topics:
1. Many drugs can cause hepatotoxicity, so drug history is important for hepatic patients. Liver function should be monitored for those on hepatotoxic medications.
2. The liver metabolizes most drugs, so liver disease can impact drug efficacy and side effects. It also increases risk of drug-drug interactions.
3. Several classes of drugs commonly used to treat liver disease or related conditions are discussed, including their potential side effects and safer or cheaper alternatives when possible.
4. Careful consideration is needed when prescribing anticoagulants, antiplatelets, diuretics, and other drugs in hepatic patients
The document discusses several key points about pharmacokinetics in geriatrics and paediatrics:
1) Physiological changes that occur with aging can impact drug absorption, metabolism, distribution and excretion in geriatric patients. This includes reduced function of the GI tract, liver and kidneys.
2) In paediatrics, drug absorption, distribution, metabolism and excretion are different compared to adults due to developmental changes. Liver and kidney function is immature at birth and develops over time.
3) When treating geriatric and paediatric patients, pharmacokinetic differences must be considered to optimize drug therapy and minimize adverse effects. Dosage adjustments may be needed for some drugs in these
Applications of pharmacokinetics parameters in disease statesUmair hanif
The document discusses how various disease states can impact pharmacokinetic parameters and drug responses. It summarizes how cardiac failure can impair drug absorption through the gastrointestinal tract and decrease distribution to tissues with low blood flow. Renal and hepatic diseases are also discussed as impacting drug clearance pathways. Specifically, cardiac and renal diseases can decrease drug clearance rates dependent on organ blood flow/function, while liver diseases impact metabolic clearance pathways. Overall, disease states can influence absorption, distribution, metabolism and excretion of drugs in complex ways that require careful titration and monitoring of drug therapy.
Drug use in hepatic and renal impairmentAkshil Mehta
- Drugs are more likely to accumulate and cause toxicity in patients with impaired liver or kidney function due to reduced drug metabolism and excretion. The pharmacokinetics of many drugs are altered in patients with hepatic or renal impairment.
- In liver disease, drug absorption, metabolism, protein binding, and elimination can all be affected. Dosage reductions are often required for drugs that are metabolized by the liver. Hepatotoxic drugs should be avoided when possible.
- In kidney disease, drug absorption and excretion may be altered. Drugs that are weak acids or bases can be "trapped" in the urine through changes in urine pH. Dosage adjustments are often needed for drugs excreted by
Hepatic disease can significantly alter the pharmacokinetics and pharmacodynamics of drugs due to changes in drug metabolism, transport, and clearance in the liver. The degree of liver impairment is assessed using tests like the Child-Pugh score, with higher scores indicating more severe impairment. Drugs eliminated primarily by the liver or highly bound to albumin are more likely to require dosage adjustments in patients with hepatic disease due to potential changes in metabolism, protein binding, and clearance. The fraction of the drug metabolized and properties of its active metabolites also influence whether dosage adjustment is necessary.
Abdominal pain has many potential causes, ranging from minor issues to serious illnesses. Doctors determine the cause of abdominal pain through characteristics of the pain, physical examination findings, laboratory and imaging tests, and sometimes surgery. The liver plays an important role in the body and can be damaged by viruses, drugs, alcohol, and other toxins, potentially causing inflammation, scarring, or cancer. Drug-induced liver injury can occur through either predictable dose-related mechanisms or unpredictable reactions in susceptible individuals, and may require stopping the causative drug or transplantation in severe cases.
1) The liver plays a key role in metabolism and detoxification, and is susceptible to damage from toxins like alcohol, chemicals, and certain drugs.
2) Drugs are a common cause of liver injury (DILI), with anti-tuberculosis drugs, anti-convulsants, NSAIDs, anti-microbials, and anesthetics carrying risks. DILI can range from asymptomatic enzyme elevations to acute liver failure.
3) Many agents have hepatoprotective properties, including N-acetylcysteine, penicillamine, antioxidants, S-adenosylmethionine (SAMe), and herbal medicines like Silybum marianum (
Hepatotoxicity, or liver toxicity, can result from anti-tuberculosis (TB) drugs and is known as drug-induced hepatitis (DIH). Patients at high risk include those with pre-existing liver conditions, alcohol use, and advanced TB. Monitoring of liver enzymes is important for high risk patients during TB treatment. Symptoms of DIH include fatigue, nausea, and jaundice. Diagnosis involves abnormal liver enzymes and symptom resolution after stopping anti-TB drugs. Management consists of gradual dose escalation while monitoring for toxicity.
The document discusses the various mechanisms through which food can influence the absorption of drugs from the gastrointestinal tract. It identifies several key mechanisms: alteration of pH, alteration of gastric emptying, stimulation of gastrointestinal secretions, food-induced changes in presystemic metabolism and blood flow, competition for absorption mechanisms, and increased viscosity. It then provides specific examples of food and drug interactions with grapefruit juice, oatmeal/bran/fiber, licorice, salt substitutes, coffee/tea, dairy products, and various vitamins. It concludes by listing important questions for patients to ask their pharmacist regarding potential drug interactions.
The document discusses drug dose adaptation in patients with hepatic diseases. It covers topics such as the epidemiology of liver diseases in India, hepatic pathophysiology, features of liver disease that alter pharmacokinetics and pharmacodynamics, general guidelines for dosing adjustments, and recommendations for specific drug classes including high extraction drugs, low extraction drugs, and intermediate extraction drugs. Special considerations are also provided for different age groups, including neonates, infants, and children.
The document discusses abnormal liver function tests (LFTs), providing information on interpreting different patterns of abnormalities. It notes that LFTs indicate hepatocellular damage rather than true liver function. Single abnormalities are difficult to diagnose but patterns of abnormalities can help determine if the issue is non-hepatic, hepatocellular, or cholestatic in origin. Common causes of abnormalities include viral hepatitis, alcohol, medications, autoimmune conditions, and fatty liver disease. A thorough history and physical exam is important to developing a differential diagnosis when LFTs are abnormal.
The document discusses hepatotoxicity, or liver injury caused by chemicals. The liver is the primary site of drug metabolism and many drugs can cause liver damage. Hepatotoxicity can be direct, through overdose, or idiosyncratic, through hypersensitivity reactions. Liver function tests are used to detect abnormalities and extent of damage. Several drugs are described that can cause hepatotoxicity through different mechanisms, such as paracetamol causing centrizonal necrosis, isoniazid causing multilobular necrosis, and halothane causing an immune response through metabolite binding. Regular monitoring of liver enzymes is recommended when taking hepatotoxic drugs.
dosage adjustment in renal and hepatic failure for medical studentDeepaJoshi41
This document discusses dosage adjustment for patients with renal and hepatic failure. It covers the basics of kidney and liver function, causes of failure, and methods for assessing renal and hepatic function. For renal failure, dosage is adjusted based on drug clearance and markers like inulin, creatinine, and blood urea nitrogen are used to assess kidney function. For hepatic failure, dosage depends on the drug's metabolism in the liver and is adjusted if metabolism is reduced. Liver function tests and markers like aminotransferases, alkaline phosphatase, bilirubin, and prothrombin time help evaluate liver function.
The document discusses the liver's role in drug metabolism and detoxification. It outlines two main pathways - phase 1 involves activation via cytochrome P450 enzymes which can make substances more toxic, while phase 2 involves conjugation via enzymes like UDP-glucuronosyl transferase to make substances more water soluble and able to be excreted. Many dermatologic drugs can cause hepatotoxicity through idiosyncratic or intrinsic mechanisms. Ketoconazole notably carries a risk of hepatotoxicity and fulminant hepatitis. The liver's role in drug interactions is also reviewed.
This document discusses the liver's functions in detoxification and drug metabolism. It outlines the liver's two main detoxification pathways, phase 1 and phase 2 reactions, which involve oxidation and conjugation reactions to make substances more water soluble and able to be excreted. Certain dermatology drugs can cause hepatotoxicity through intrinsic or idiosyncratic mechanisms. Ketoconazole and tetracycline are highlighted as drugs that have been associated with hepatotoxicity ranging from mild elevations in liver enzymes to rare cases of fulminant hepatitis.
This document discusses hepatotoxicity and liver injury. It covers clinical chemistry markers of liver injury including ALT, SDH, ALP, total bile acids, and bilirubin. It provides examples of clinical chemistry profiles that could indicate hepatocellular injury, cholestasis, or biliary obstruction. Organ weights and histopathological assessments are also important for evaluating hepatotoxicity. The liver has complex cellular architecture and various cell types can be involved in injury responses.
Drug dose adjustment for liver diseasesNeha Suresh
This document discusses drug dose adjustment for liver diseases. It explains that the liver is important for drug elimination and abnormalities can affect drug clearance and metabolism. Diseases like hepatitis, carcinoma, necrosis and cirrhosis impact drug elimination by decreasing hepatic clearance and increasing half-life. The hepatic extraction ratio determines if a drug is highly, intermediately or poorly extracted by the liver, affecting how liver disease impacts dosing. Drugs with low hepatic extraction are more dependent on liver function, so doses may need adjustment for liver disease. Antipyrine, which is only eliminated by the liver, is used to assess hepatic abnormalities.
This document discusses liver function tests and their interpretation. It begins by stating that liver function tests are a helpful screening tool but no single test can assess overall liver function, as the liver has many roles. It then discusses the uses and limitations of liver function tests, including that they lack sensitivity and specificity. The document categorizes liver function tests and discusses several specific tests - including bilirubin, aminotransferases, alkaline phosphatase, and prothrombin time - and their clinical significance in interpreting liver conditions. It emphasizes that liver function tests must be interpreted in the clinical context of each patient.
Hepatotoxicity can be caused by carbon tetrachloride, acetaminophen, ethanol, and aflatoxins. Carbon tetrachloride and aflatoxins cause liver damage through toxic free radicals produced during metabolism. Acetaminophen overwhelms the liver's glutathione reserves, producing a toxic metabolite. Ethanol induces cytochrome P450 enzymes that produce toxic radicals, depleting glutathione and causing lipid peroxidation and cell damage. Clinical signs include nausea, vomiting, mental status changes, and liver failure. Treatment focuses on supportive care, activated charcoal or N-acetylcysteine to prevent further toxicity. There are no antidotes for aflatoxins.
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.
Pharmakokinetic Variations in Kidney diseases.Maleha Sial
The kidney plays an important role in drug excretion and metabolism. Renal diseases and impairment can significantly impact the pharmacokinetics of drugs in multiple ways. Kidney function affects absorption, distribution, metabolism and elimination of drugs. Specifically, impaired renal function can decrease drug protein binding, increase volume of distribution, decrease metabolism of some drugs while increasing metabolism of others, and greatly reduce drug clearance by eliminating the kidney's excretory pathway. These alterations in pharmacokinetics require careful dosage adjustments for many drugs used in patients with renal diseases.
The document discusses several key points about pharmacokinetics in geriatrics and paediatrics:
1) Physiological changes that occur with aging can impact drug absorption, metabolism, distribution and excretion in geriatric patients. This includes reduced function of the GI tract, liver and kidneys.
2) In paediatrics, drug absorption, distribution, metabolism and excretion are different compared to adults due to developmental changes. Liver and kidney function is immature at birth and develops over time.
3) When treating geriatric and paediatric patients, pharmacokinetic differences must be considered to optimize drug therapy and minimize adverse effects. Dosage adjustments may be needed for some drugs in these
Applications of pharmacokinetics parameters in disease statesUmair hanif
The document discusses how various disease states can impact pharmacokinetic parameters and drug responses. It summarizes how cardiac failure can impair drug absorption through the gastrointestinal tract and decrease distribution to tissues with low blood flow. Renal and hepatic diseases are also discussed as impacting drug clearance pathways. Specifically, cardiac and renal diseases can decrease drug clearance rates dependent on organ blood flow/function, while liver diseases impact metabolic clearance pathways. Overall, disease states can influence absorption, distribution, metabolism and excretion of drugs in complex ways that require careful titration and monitoring of drug therapy.
Drug use in hepatic and renal impairmentAkshil Mehta
- Drugs are more likely to accumulate and cause toxicity in patients with impaired liver or kidney function due to reduced drug metabolism and excretion. The pharmacokinetics of many drugs are altered in patients with hepatic or renal impairment.
- In liver disease, drug absorption, metabolism, protein binding, and elimination can all be affected. Dosage reductions are often required for drugs that are metabolized by the liver. Hepatotoxic drugs should be avoided when possible.
- In kidney disease, drug absorption and excretion may be altered. Drugs that are weak acids or bases can be "trapped" in the urine through changes in urine pH. Dosage adjustments are often needed for drugs excreted by
Hepatic disease can significantly alter the pharmacokinetics and pharmacodynamics of drugs due to changes in drug metabolism, transport, and clearance in the liver. The degree of liver impairment is assessed using tests like the Child-Pugh score, with higher scores indicating more severe impairment. Drugs eliminated primarily by the liver or highly bound to albumin are more likely to require dosage adjustments in patients with hepatic disease due to potential changes in metabolism, protein binding, and clearance. The fraction of the drug metabolized and properties of its active metabolites also influence whether dosage adjustment is necessary.
Abdominal pain has many potential causes, ranging from minor issues to serious illnesses. Doctors determine the cause of abdominal pain through characteristics of the pain, physical examination findings, laboratory and imaging tests, and sometimes surgery. The liver plays an important role in the body and can be damaged by viruses, drugs, alcohol, and other toxins, potentially causing inflammation, scarring, or cancer. Drug-induced liver injury can occur through either predictable dose-related mechanisms or unpredictable reactions in susceptible individuals, and may require stopping the causative drug or transplantation in severe cases.
1) The liver plays a key role in metabolism and detoxification, and is susceptible to damage from toxins like alcohol, chemicals, and certain drugs.
2) Drugs are a common cause of liver injury (DILI), with anti-tuberculosis drugs, anti-convulsants, NSAIDs, anti-microbials, and anesthetics carrying risks. DILI can range from asymptomatic enzyme elevations to acute liver failure.
3) Many agents have hepatoprotective properties, including N-acetylcysteine, penicillamine, antioxidants, S-adenosylmethionine (SAMe), and herbal medicines like Silybum marianum (
Hepatotoxicity, or liver toxicity, can result from anti-tuberculosis (TB) drugs and is known as drug-induced hepatitis (DIH). Patients at high risk include those with pre-existing liver conditions, alcohol use, and advanced TB. Monitoring of liver enzymes is important for high risk patients during TB treatment. Symptoms of DIH include fatigue, nausea, and jaundice. Diagnosis involves abnormal liver enzymes and symptom resolution after stopping anti-TB drugs. Management consists of gradual dose escalation while monitoring for toxicity.
The document discusses the various mechanisms through which food can influence the absorption of drugs from the gastrointestinal tract. It identifies several key mechanisms: alteration of pH, alteration of gastric emptying, stimulation of gastrointestinal secretions, food-induced changes in presystemic metabolism and blood flow, competition for absorption mechanisms, and increased viscosity. It then provides specific examples of food and drug interactions with grapefruit juice, oatmeal/bran/fiber, licorice, salt substitutes, coffee/tea, dairy products, and various vitamins. It concludes by listing important questions for patients to ask their pharmacist regarding potential drug interactions.
The document discusses drug dose adaptation in patients with hepatic diseases. It covers topics such as the epidemiology of liver diseases in India, hepatic pathophysiology, features of liver disease that alter pharmacokinetics and pharmacodynamics, general guidelines for dosing adjustments, and recommendations for specific drug classes including high extraction drugs, low extraction drugs, and intermediate extraction drugs. Special considerations are also provided for different age groups, including neonates, infants, and children.
The document discusses abnormal liver function tests (LFTs), providing information on interpreting different patterns of abnormalities. It notes that LFTs indicate hepatocellular damage rather than true liver function. Single abnormalities are difficult to diagnose but patterns of abnormalities can help determine if the issue is non-hepatic, hepatocellular, or cholestatic in origin. Common causes of abnormalities include viral hepatitis, alcohol, medications, autoimmune conditions, and fatty liver disease. A thorough history and physical exam is important to developing a differential diagnosis when LFTs are abnormal.
The document discusses hepatotoxicity, or liver injury caused by chemicals. The liver is the primary site of drug metabolism and many drugs can cause liver damage. Hepatotoxicity can be direct, through overdose, or idiosyncratic, through hypersensitivity reactions. Liver function tests are used to detect abnormalities and extent of damage. Several drugs are described that can cause hepatotoxicity through different mechanisms, such as paracetamol causing centrizonal necrosis, isoniazid causing multilobular necrosis, and halothane causing an immune response through metabolite binding. Regular monitoring of liver enzymes is recommended when taking hepatotoxic drugs.
dosage adjustment in renal and hepatic failure for medical studentDeepaJoshi41
This document discusses dosage adjustment for patients with renal and hepatic failure. It covers the basics of kidney and liver function, causes of failure, and methods for assessing renal and hepatic function. For renal failure, dosage is adjusted based on drug clearance and markers like inulin, creatinine, and blood urea nitrogen are used to assess kidney function. For hepatic failure, dosage depends on the drug's metabolism in the liver and is adjusted if metabolism is reduced. Liver function tests and markers like aminotransferases, alkaline phosphatase, bilirubin, and prothrombin time help evaluate liver function.
The document discusses the liver's role in drug metabolism and detoxification. It outlines two main pathways - phase 1 involves activation via cytochrome P450 enzymes which can make substances more toxic, while phase 2 involves conjugation via enzymes like UDP-glucuronosyl transferase to make substances more water soluble and able to be excreted. Many dermatologic drugs can cause hepatotoxicity through idiosyncratic or intrinsic mechanisms. Ketoconazole notably carries a risk of hepatotoxicity and fulminant hepatitis. The liver's role in drug interactions is also reviewed.
This document discusses the liver's functions in detoxification and drug metabolism. It outlines the liver's two main detoxification pathways, phase 1 and phase 2 reactions, which involve oxidation and conjugation reactions to make substances more water soluble and able to be excreted. Certain dermatology drugs can cause hepatotoxicity through intrinsic or idiosyncratic mechanisms. Ketoconazole and tetracycline are highlighted as drugs that have been associated with hepatotoxicity ranging from mild elevations in liver enzymes to rare cases of fulminant hepatitis.
This document discusses hepatotoxicity and liver injury. It covers clinical chemistry markers of liver injury including ALT, SDH, ALP, total bile acids, and bilirubin. It provides examples of clinical chemistry profiles that could indicate hepatocellular injury, cholestasis, or biliary obstruction. Organ weights and histopathological assessments are also important for evaluating hepatotoxicity. The liver has complex cellular architecture and various cell types can be involved in injury responses.
Drug dose adjustment for liver diseasesNeha Suresh
This document discusses drug dose adjustment for liver diseases. It explains that the liver is important for drug elimination and abnormalities can affect drug clearance and metabolism. Diseases like hepatitis, carcinoma, necrosis and cirrhosis impact drug elimination by decreasing hepatic clearance and increasing half-life. The hepatic extraction ratio determines if a drug is highly, intermediately or poorly extracted by the liver, affecting how liver disease impacts dosing. Drugs with low hepatic extraction are more dependent on liver function, so doses may need adjustment for liver disease. Antipyrine, which is only eliminated by the liver, is used to assess hepatic abnormalities.
This document discusses liver function tests and their interpretation. It begins by stating that liver function tests are a helpful screening tool but no single test can assess overall liver function, as the liver has many roles. It then discusses the uses and limitations of liver function tests, including that they lack sensitivity and specificity. The document categorizes liver function tests and discusses several specific tests - including bilirubin, aminotransferases, alkaline phosphatase, and prothrombin time - and their clinical significance in interpreting liver conditions. It emphasizes that liver function tests must be interpreted in the clinical context of each patient.
Hepatotoxicity can be caused by carbon tetrachloride, acetaminophen, ethanol, and aflatoxins. Carbon tetrachloride and aflatoxins cause liver damage through toxic free radicals produced during metabolism. Acetaminophen overwhelms the liver's glutathione reserves, producing a toxic metabolite. Ethanol induces cytochrome P450 enzymes that produce toxic radicals, depleting glutathione and causing lipid peroxidation and cell damage. Clinical signs include nausea, vomiting, mental status changes, and liver failure. Treatment focuses on supportive care, activated charcoal or N-acetylcysteine to prevent further toxicity. There are no antidotes for aflatoxins.
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.
Pharmakokinetic Variations in Kidney diseases.Maleha Sial
The kidney plays an important role in drug excretion and metabolism. Renal diseases and impairment can significantly impact the pharmacokinetics of drugs in multiple ways. Kidney function affects absorption, distribution, metabolism and elimination of drugs. Specifically, impaired renal function can decrease drug protein binding, increase volume of distribution, decrease metabolism of some drugs while increasing metabolism of others, and greatly reduce drug clearance by eliminating the kidney's excretory pathway. These alterations in pharmacokinetics require careful dosage adjustments for many drugs used in patients with renal diseases.
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.
This document discusses drug interactions, including definitions, types, factors that influence interactions, and their clinical impact. It notes that drug interactions can occur when one drug affects another's absorption, distribution, metabolism, or excretion. Factors like polypharmacy, age, organ function, and genetics influence interaction risks. Interactions can decrease drug effectiveness, increase toxicity, and cause organ dysfunction. Clinicians must be aware of potential interactions to minimize harmful outcomes for patients.
The document discusses the effects of liver disease on anesthesia. It covers topics such as hepatic blood flow regulation, drug metabolism by the liver, and how liver dysfunction impacts the pharmacokinetics and pharmacodynamics of various anesthetic drugs. Liver disease can increase a patient's sensitivity to central nervous system depressants and decrease sensitivity to vasopressors. The duration of action of some drugs may be prolonged due to impaired hepatic clearance and metabolism in patients with liver dysfunction. Induction agents, opioids, muscle relaxants and other drugs are discussed in terms of their safety in liver disease.
This document discusses epilepsy management in patients with comorbid systemic disorders. It focuses on how liver disease, kidney disease, porphyria, infections, brain tumors, and strokes can impact epilepsy treatment. For liver disease, levetiracetam, lacosamide, topiramate, gabapentin and pregabalin are recommended first-line therapies due to their limited hepatic metabolism and excretion. For kidney disease, drug dosages may need adjustment based on creatinine clearance levels. Non-enzyme inducing antiepileptic drugs are preferred for patients with porphyria or infections. Levetiracetam has shown efficacy for brain tumor-related seizures while minimizing interactions with cancer treatments. Interactions with other medications
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own.
Variation of Pharmacokinetics in disease states-converted-converted.pdfUVAS
I am a pharmacist. These slides describe biotechnology topic. I hope students get more benefits about it. These slides very helpful for the pharmacy department students.
This document discusses various aspects of pharmacology related to drug use in kidney disease. It covers topics like how weak acids and bases are affected by pH and excreted by the kidneys, how drug metabolism and protein binding may be altered in renal impairment, how to assess renal function using creatinine and calculate drug dosing based on clearance, and how the kidneys normally excrete and metabolize drugs as well as how renal impairment can affect these processes. It also discusses direct drug-induced kidney injuries and considerations for prescribing drugs in patients with renal disease.
Variations in Pk's in disease states.pdfSARADPAWAR1
Also the degree of plasma-protein binding, in turn, influences the distribution, action, metabolism and renal excretion of drugs. Thus changes in plasma protein binding of drugs, e.g. in diseased states, may give rise to altered pharmacokinetic and possibly altered drug response.
Variations in Pk's in disease states.pdfSARADPAWAR1
Pharmacokinetic variation is when there is variability in the drug concentration at the effector site after administration of a standard dose. This can result in one dose of a drug being ineffective in one patient, but potentially toxic with unwanted side effects in another.
Hepatic disease can significantly impact drug pharmacokinetics by altering metabolism and excretion of drugs. The liver metabolizes many drugs through enzyme systems that may be impaired in diseases like cirrhosis and hepatitis. This can cause drug accumulation, changes in active metabolites, and altered protein binding. While laboratory tests can detect liver damage, no single test assesses total liver function. The Child-Pugh score is used to classify the severity of hepatic impairment. For drugs that are highly metabolized by the liver, dosage may need to be reduced based on the Child-Pugh score to avoid toxicity. The degree of dosage adjustment depends on the individual drug's pharmacokinetics and the patient's liver function status.
Variations in Pk's in disease states.pptxSARADPAWAR1
Also the degree of plasma-protein binding, in turn, influences the distribution, action, metabolism and renal excretion of drugs. Thus changes in plasma protein binding of drugs, e.g. in diseased states, may give rise to altered pharmacokinetic and possibly altered drug response.
Drug-food and drug-herb interactions can occur via several mechanisms:
1) Reduced or delayed drug absorption due to food components binding to drugs or slowing gastric emptying. Examples include calcium in milk binding tetracycline and tannins in tea impairing iron absorption.
2) Increased drug absorption when foods increase drug dissolution, secretion of gastrointestinal fluids, or delay gastric emptying. Examples include increased absorption of antibiotics with fatty foods.
3) Altered drug metabolism through effects on cytochrome P450 enzyme activity. Grapefruit juice and St. John's Wort inhibit CYP3A4, increasing drug levels of medications metabolized by this enzyme and risk of toxicity.
4) Changed
This document discusses pharmacokinetic and bioavailability variations in disease states, specifically related to hepatic disease. It defines key terms like pharmacokinetics, bioavailability, and variability. It then discusses how hepatic disease, both acute and chronic liver impairment, can interfere with drug metabolism and elimination due to changes in absorption, distribution, metabolism and excretion. Specific impacts on absorption, metabolism in the liver, enzyme induction and inhibition, as well as dosage considerations based on the fraction of drug metabolized by the liver are covered. An example calculation is provided to illustrate how a reduced hepatic clearance of 50% would impact the total body clearance and necessary dose adjustment.
This document discusses how various diseases can affect drug pharmacokinetics and metabolism. It covers effects of gastrointestinal, cardiac, renal, liver and thyroid disorders. Key points include:
- Renal and liver diseases can significantly impact drug absorption, distribution, metabolism and excretion. Dose adjustments are often needed.
- Cardiac failure can alter drug distribution and decrease elimination due to reduced hepatic and renal perfusion.
- Monitoring drug levels can help optimize therapy for individual patients, especially when inter-individual variability is high or clinical effects are difficult to assess. Close monitoring of response is important when prescribing for patients with organ dysfunction.
DILI is possible consequence of ingestion of OTC drugs like PCM.
so it require careful clinical knowledge before taking drugs without doctors prescriptions...
Similar to Drugs pharmacology in liver disease (20)
This document discusses various statistical concepts including outliers, transforming data, normalizing data, weighting data, robustness, and homoscedasticity and heteroscedasticity. Outliers are values far from other data points and should be carefully examined before removing. Data can be transformed using logarithms, square roots, or other functions to better fit a normal distribution or equalize variances between groups. Normalizing data puts variables on comparable scales. Weighting data adjusts for under- or over-representation in samples. Robust tests are resistant to violations of assumptions. Homoscedasticity refers to equal variances between groups while heteroscedasticity refers to unequal variances.
The document provides an overview of correlation, regression, and other statistical methods. It defines correlation as measuring the association between two variables, while regression finds the best fitting line to predict a dependent variable from an independent variable. Simple linear regression uses one predictor variable, while multiple linear regression uses two or more. Logistic regression is used for nominal dependent variables. Nonlinear regression fits curved lines to nonlinear data. The document provides examples and guidelines for choosing the appropriate statistical test based on the type of variables.
This document provides an overview of various statistical tests for comparing variables, including t-tests, ANOVA, MANOVA, ANCOVA, and MANCOVA. It defines each test and provides examples of their proper usage. T-tests are used to compare two groups on a continuous variable, including paired and unpaired, parametric and non-parametric versions. ANOVA and MANOVA are used to compare three or more groups and two or more dependent variables, respectively. ANCOVA and MANCOVA control for covariates/confounding variables in one-way and two-way designs with single or multiple dependent variables. Examples and best practices are given for selecting and conducting each type of test.
This document discusses key concepts in applied statistics including hypothesis testing, p-values, types of errors, sensitivity and specificity. It provides examples and explanations of these topics using scenarios about testing if feeding chickens chocolate changes the gender ratio of offspring. Hypothesis testing involves defining the null and alternative hypotheses and using a statistical test to either reject or fail to reject the null hypothesis based on the p-value. Type I and type II errors in hypothesis testing are explained. Sensitivity and specificity in diagnostic tests are introduced using an example about detecting if a car is being stolen.
This document provides an introduction to applied statistics and various statistical concepts. It discusses the normal (Gaussian) distribution, standard deviation, standard error of the mean, and confidence intervals. Examples and explanations are provided for each concept. Hands-on examples for calculating these statistics in Excel, SPSS, and Prism are also presented. The document aims to explain key statistical terms and how they are applied in data analysis.
a clinically oriented discussion of blood coagulation and related diseases and treatment. also discussing DIC, plasma fractions and anti-platelet drugs.
HMG-CoA reductase inhibitors, commonly known as statins, are the primary drugs used to treat dyslipidemia. They work by inhibiting cholesterol production in the liver, leading to increased clearance of LDL cholesterol from the bloodstream. Fibrates also effectively lower triglyceride levels by increasing fatty acid metabolism. Bile acid sequestrants function by binding bile acids in the gut, enhancing their excretion and increasing LDL receptor activity in the liver. Combination drug therapies that target multiple lipid abnormalities can provide improved treatment outcomes over single agents alone.
This document discusses various immunopharmacology drugs and their uses. It covers immunosuppressive antibodies including monoclonal antibodies used for transplantation, cancer, and autoimmune diseases. It also discusses immunosuppressive drugs classified as immunophilin ligands or cytotoxic agents that are used for transplantation and graft-versus-host disease. Common drugs discussed include cyclosporine, tacrolimus, sirolimus, mycophenolate, azathioprine, and cyclophosphamide.
The document provides guidance on rational prescription writing, including introducing the concept of "P-drugs" or personal first-choice drugs, outlining the steps in prescription writing, common abbreviations, and important instructions and information to provide to patients. It also discusses medication errors and how electronic prescribing can help reduce errors by suggesting alternative drugs. The overall goal is to teach students how to properly treat patients through skillful prescribing rather than just knowledge of drugs.
This document discusses the use of various drugs during pregnancy and lactation. It covers analgesics, antihypertensives, chemotherapeutics, central nervous system drugs, anticoagulants, endocrine drugs, antiemetics, antihistamines, and others. For each drug class or individual drug, it notes any potential risks to the fetus, such as teratogenicity, and recommendations for use during pregnancy and effects on the newborn. The overall message is that many drugs should be avoided during pregnancy if possible due to risks of harming fetal development, and careful consideration of risks and benefits is needed for drug treatment during this period.
This document discusses drug use during pregnancy and lactation. It covers principles of therapy during pregnancy and lactation, emphasizing using the lowest effective dose for shortest time. Physiologic and pharmacokinetic changes in pregnancy that affect drug distribution and metabolism are described. The fetal circulation is explained, as well as how drugs can affect the fetus. Drug categories in pregnancy from A to X are defined based on safety evidence. Common issues in pregnancy like anemia, constipation, and gestational diabetes are also covered.
This document discusses drug use during pregnancy and lactation. It covers the effects of non-therapeutic drugs like alcohol, caffeine, cigarettes, cocaine and marijuana on the fetus. It also discusses the management of selected medical conditions in pregnancy like AIDS, UTI, asthma, diabetes, hypertension and epilepsy. The final sections discuss neonatal therapeutics including vitamin K administration and treatment of ophthalmia neonatorum. It concludes with guidance on drug use during lactation, identifying drugs that are generally safe and those that require caution.
This document discusses methemoglobinemia, which is a condition caused by elevated levels of methemoglobin in the blood. Methemoglobin cannot carry oxygen, so symptoms range from cyanosis to death depending on levels. It may be congenital or acquired through medications, chemicals, and certain foods. Diagnosis involves blood tests showing abnormal hemoglobin color. Treatment focuses on reducing methemoglobin back to hemoglobin, primarily using methylene blue or ascorbic acid. The document also briefly covers cyanide poisoning, which causes tissue anoxia and can be fatal within minutes of inhalation.
This document provides guidance on proper academic writing style and conventions. It discusses things to avoid such as adjectives, negatives, long sentences, and colloquial language. It also covers proper use of punctuation like commas, semicolons, and apostrophes. Connectors are addressed to link ideas clearly. The document aims to improve clarity, precision and formality of academic writing.
This document provides an overview of the key elements of academic writing, including:
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More from Mohammad Hadi Farjoo MD, PhD, Shahid behehsti University of Medical Sciences (20)
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
- 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
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Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
8 Surprising Reasons To Meditate 40 Minutes A Day That Can Change Your Life.pptxHolistified Wellness
We’re talking about Vedic Meditation, a form of meditation that has been around for at least 5,000 years. Back then, the people who lived in the Indus Valley, now known as India and Pakistan, practised meditation as a fundamental part of daily life. This knowledge that has given us yoga and Ayurveda, was known as Veda, hence the name Vedic. And though there are some written records, the practice has been passed down verbally from generation to generation.
2. Drugs pharmacology in Liver disease
By
M. H. Farjoo M.D, Ph.D.
Shahid Beheshti University of Medical Sciences
3. Introduction
Pharmacokinetic Changes in Liver Disease
Absorption and Liver
Metabolism in Liver
Protein Binding
Age Effect
Laboratory Tests
Liver Disease and Kidney
Liver Diseases: Acute/Chronic Hepatitis & Cirrhosis
Modification of Drug Therapy in Liver Disease
Specific Drugs
Drugs pharmacology in Liver disease
4. Acute liver impairment interferes with drug
metabolism and elimination.
Chronic liver impairment affects all parameters of
pharmacokinetic.
Impaired liver function greatly increases the risks of
adverse drug effects.
On the other hand, drug-induced liver injury (DILI)
can impair liver function.
Introduction
5. Classifications of drug-induced liver injury (DILI)
Type of classification Examples
Clinical laboratory
Hepatocellular
Cholestatic
Mixed hepatocellular/cholestatic
Mechanism of hepatotoxicity
Direct hepatotoxicity
Idiosyncratic
Immune-mediated
Metabolic
Histologic findings
Cellular necrosis or apoptosis
Cholestasis
Steatosis
Fibrosis
Phospholipidosis
Granulomatous
Sinusoidal obstruction syndrome
6. Many drugs change liver function tests without
clinical signs of liver dysfunction.
Hepatotoxicity is potentially life threatening.
Liver is able to function with as little as 10% of
undamaged hepatic cells.
With severe hepatic impairment, extrahepatic
metabolism becomes more important.
Introduction
7. Clients at risk for impaired liver function include:
Primary liver disease (eg, hepatitis, cirrhosis).
Diseases that impair blood flow to the liver (heart
failure, shock, major surgery, or trauma).
Hepatotoxic drugs.
Malnourished people or those on low-protein diets.
Introduction
8. Clinical signs for hepatotixicity should be sought
(nausea, vomiting, jaundice, hepatomegaly).
Hepatotoxic drugs should be avoided if possible:
(acetaminophen, INH, statins, methotrexate,
phenytoin, aspirin and alcohol).
Introduction
9. There are two patterns of change in liver disease:
Drugs metabolized rapidly with high extraction in a
single pass through the liver.
Drugs metabolized slowly with poor extraction in a
single pass through the liver.
Pharmacokinetic Changes in Liver Disease
12. In high extraction group:
Clearance is limited by hepatic blood flow.
The predominant change for oral drugs is increased
bioavailability.
The initial and maintenance doses of such drugs
should be reduced.
With severe liver impairment the t½ of drugs in this
class may lengthen.
Pharmacokinetic Changes in Liver Disease
13. In low extraction group:
The rate-limiting factor is metabolic capacity.
The major change is prolongation of t½.
So, the interval between doses may need to be
lengthened
The time to reach steady-state (5 * t½) is
increased.
Pharmacokinetic Changes in Liver Disease
14. Some oral drugs are extensively metabolized in the
liver.
This process is called the first-pass effect or
presystemic metabolism.
With cirrhosis, oral drugs are distributed directly into
the systemic circulation.
This means that oral drugs metabolized in the liver
must be given in reduced doses.
Absorption and Liver
15. presystemic clearance
Mechanism of presystemic clearance.After drug
enters the enterocyte, it can undergo metabolism,
excretion into the intestinal lumen, or transport into the
portal vein. Similarly, the hepatocyte may accomplish
metabolism and biliary excretion prior to the entry of
drug and metabolites to the systemic circulation.
16.
17.
18. Most drugs are metabolized by enzymes in the liver
They are called the cytochrome P450 [CYP] or the
microsomal enzymes.
CYP system consists of 12 groups:
Nine of them metabolize endogenous substances.
Three of them metabolize drugs.
The three groups that metabolize drugs are: CYP1 to
CYP3.
Metabolism in Liver
19. The CYP3 metabolizes 50% of drugs, the CYP2 45%,
and the CYP1 group 5%.
They catalyze oxidation, reduction, hydrolysis, and
conjugation with glucuronic acid or sulfate.
Excretion decreases when the liver cannot metabolize
lipid-soluble drugs into water-soluble ones to be
excreted by the kidneys.
An impaired liver cannot synthesize adequate amounts
of metabolizing enzymes.
Metabolism in Liver
21. Dosage should be reduced for drugs that are
extensively metabolized in the liver including:
Cimetidine and Ranitidine
Diazepam and Lorazepam
Morphine and Meperidine (Pethidine)
Phenytoin
Propranolol
Verapamil.
Metabolism in Liver
22. With chronic administration, some drugs increase
metabolizing enzymes in the liver: enzyme induction.
Enzyme induction accelerates drug metabolism and
larger doses is required.
Rapid metabolism also increases the production of
toxic metabolites.
In one study, enzyme induction occurred within 1-3
weeks (to synthesize new enzymes?).
Metabolism in Liver: Enzyme Induction
23. Metabolism in Liver: Enzyme Induction
In another study, induction occurred within a few days
and finished over 2–3 weeks.
Both the time for onset and offset of induction, and
recovery after induction (or inhibition) depends on
enzyme turnover.
Inducing substances are usually lipid soluble, and have
a long t½.
25. Metabolism can be decreased by enzyme inhibition.
It occurs with co-administration of drugs that
compete for the same metabolizing enzymes.
In this case, smaller doses of the slowly metabolized
drug is needed to avoid toxicity.
Enzyme inhibition occurs within hours or days.
Metabolism in Liver: Enzyme Inhibition
29. If hepatic blood flow ↓ => delivery of drug to
hepatocytes ↓ => drug metabolism ↓ => drug toxicity ↑
Some drugs alter liver blood flow and indirectly affect
liver function:
Epinephrine decreases blood flow by constricting
hepatic artery and portal vein.
β blockers decrease blood flow by decreasing
cardiac output, and constricting portal vain.
Metabolism in Liver
30. The impaired liver does not synthesize albumin
adequately.
Liver impairment causes accumulation of substances
(bilirubin) that displace drugs from protein-binding
sites.
When protein binding ↓ => free drug ↑ => drug
distribution to sites of action & elimination ↑
=> onset of drug action ↑
=> duration of action ↓
When protein binding ↓ => peak blood levels and
adverse effects ↑
Protein Binding
33. Pharmacokinetics differs in neonates, especially
prematures, because their organs are not fully
developed.
Until 1 year, liver function is still immature.
Children of 1 to 12 years have increased activity of
metabolizing enzymes.
After 12 years of age, children handle drugs similarly
to adults.
In elderly many drugs are metabolized more slowly
and accumulate with chronic administration.
Age Effect
34. Many patients with DILI are asymptomatic and are
only detected by laboratory testing.
Albumin, PT (or INR), and bilirubin together, have a
better predictive value than each test alone.
AST or ALT were NOT correlated with hepatic drug
clearance.
In hepatocellular injury, there is a disproportionate
elevation of AST or ALT .
Because these enzymes reflect hepatic damage, not
hepatic function.
Laboratory Tests
35. Patients with chronic DILI may develop severe
cirrhosis.
Even hepatic encephalopathy may occur (sign of acute
liver failure).
AST or ALT levels <2 times normal, are self limiting.
For AST or ALT >3 times, withdraw the drug, even in
asymptomatic patients.
In cholestatic injury ALP is elevated.
Laboratory Tests
36. Laboratory Tests
DILI is alarming if any of the following is true:
ALT >3 times normal
ALP >2 times normal
Total bilirubin >2 times normal (whatever ALT or
ALP).
PT >1.5 times control
Albumin <2.0 g/dl
37. Renal function are depressed in liver disease.
In advanced cirrhosis, mechanisms are activated to
maintain blood pressure.
This causes intrarenal vasoconstriction that affect
sodium excretion and water retention.
Liver Disease and Kidney
38. The water retention leads to ascites, edema, and renal
failure (hepatorenal syndrome).
So reducing the doses for drugs that are eliminated by
the kidney in cirrhosis accompanied by ascites.
Cirrhotic patients are also at increased risk of acute
renal failure after being treated with ACEI and
NSAIDs
Liver Disease and Kidney
40. In general, drug elimination during acute viral
hepatitis is either normal or moderately impaired.
Drug elimination is impaired most significantly in
chronic hepatitis B, but in the late stages of disease.
Viral hepatitis or alcohol-related liver disease, have
more impact on metabolizing activity than cholestatic
conditions.
Hepatitis
41. Chronic liver disease is secondary to chronic alcohol
abuse or chronic viral hepatitis.
There is a decrease in CP450, but is compensated by
increase in liver size so metabolism is not impaired.
Cirrhosis causes collagen deposition, and reduction in
liver size, so total cytochrome P450 is reduced.
Cirrhosis affects drug metabolism more than any
other form of liver disease does.
Chronic Liver Disease and Cirrhosis
42. Deposition of collagen in hepatic sinusoids results in
functional shunting of blood past the hepatocytes.
These changes can interfere significantly with the
hepatic uptake of drugs and metabolites.
Cirrhosis causes up to 50% decrease in cytochrome
P450 content, and/or shunting of blood away from
functioning hepatocytes.
Shunts reduce drug delivery to liver, but increase
delivery to the systemic circulation.
Chronic Liver Disease and Cirrhosis
43. Vasopressin constricts splanchnic blood vessels.
Systemic, vasoconstriction are predictable
complications necessitating treatment withdrawal.
In cardiovascular disease and uncontrolled
haemorrhage, simultaneous administration of TNG
(SL or IV) allows continued use of vasopressin.
Vasopressin is cleared rapidly from the circulation so
is given by continuous infusion.
Complications of Cirrhosis
Variceal Bleeding
44. Somatostatin and octreotide reduce splanchnic blood.
Octreotide does not have the risk of cerebral or
cardiac ischemia.
Propranolol is a prophylactic drug for variceal
bleeding.
It induces splanchnic vasoconstriction via unopposed
α adrenergic vasoconstriction.
It is extracted in a single pass by the liver so its
bioavailability is less predictable in cirrhosis with
portal hypertension.
Complications of Cirrhosis
Variceal Bleeding
45. Salt restriction is effective; fluid restriction is
unnecessary unless the Na+ falls below 125 mmol/L.
Bed rest (reduces plasma renin activity) is effective,
Cirrhotic patients exhibit a reduced responsiveness to
loop diuretics.
This is related to decrease in renal function, which is
often unrecognized in these patients.
Complications of Cirrhosis
Ascites
46. Spironolactone is not dependent on GFR for efficacy,
so is the most useful diuretic, but maximum efficacy
is seen at 2 weeks.
If spironolactone does not provide adequate diuresis,
and renal function is conserved, furosemide may be
added.
Each liter of ascites removed, should be matched by
6–8 g albumin given before or with paracentesis.
Complications of Cirrhosis
Ascites
47.
48. In the pathophysiology ammonia is a key player.
Ammonia is derived from colonic urease-containing
bacteria that normally undergoes hepatic extraction.
Lactulose is an osmotic laxative to speed up clearance
of toxic substances from GI tract.
Colonic bacteria metabolize it to lactic and acetic
acids, which inhibit ammonia producing organisms
The correct dose is that which produces 2-4 soft
stools daily (usually 30–60 mL daily).
Complications of Cirrhosis
Hepatic Encephalopathy
49. Neomycin and metronidazole inhibit urease
producing bacteria, but their use is limited by
toxicity.
The non-absorbable antibiotic Rifaximin is effective
over a prolonged period without significant toxicity.
Complications of Cirrhosis
Hepatic Encephalopathy
50. The loading dose of IV drugs need not to be altered in
hepatic disease.
The maintenance dose should be lowered to reflect
the reduction in hepatic clearance.
Prescribing of most drugs is safe in compensated liver
disease.
If in doubt, check the PT, albumin and bilirubin.
Generally, for drugs with significant hepatic
metabolism, reduce the dose to 25–50% of normal.
Modification of Drug Therapy in Liver Disease
54. Take particular care with:
Impaired hepatic function (hypoalbuminaemia,
increased INR).
Current/recent hepatic encephalopathy.
Fluid retention and renal impairment.
Drugs with high hepatic extraction, high protein
binding, low therapeutic ratio, and CNS
depressants.
Modification of Drug Therapy in Liver Disease
55. Sedatives, antidepressants, and antiepileptics should
be used with extreme caution in advanced liver
disease.
Treatment of alcohol withdrawal in established liver
disease is hazardous.
Opiates can precipitate hepatic encephalopathy in
decompensated liver disease.
For pain control, doses should be reduced to 25–50%.
Modification of Drug Therapy in Liver Disease
56. Codeine can precipitate hepatic encephalopathy
through constipation alone and accumulates with
renal impairment.
NSAIDs may exacerbate impaired renal function and
fluid retention, and precipitate GI bleeding.
Antacids that contain large quantities of sodium can
precipitate fluid retention and cause ascites.
Aluminium- or calcium-based preparations and
antimotility drugs cause constipation and may
precipitate encephalopathy.
Modification of Drug Therapy in Liver Disease
58. A single dose of 10–15 g, produces liver injury and
25 g is fatal.
Maximal hepatic failure occurs 4–6 days after
ingestion, and aminotransferase levels may approach
10,000 units.
Treatment is gastric lavage, supportive measures, and
oral activated charcoal or cholestyramine.
Neither of these agents is effective if given >30 min
after acetaminophen ingestion.
Acetaminophen
59. Administration of cysteine, or N-acetylcysteine reduces
the severity of hepatic necrosis.
Therapy should begin within 8 h of ingestion but may
be effective after 24–36 h.
If hepatic failure occurs despite N-acetylcysteine
therapy, liver transplantation is the only option.
Acetaminophen
62. In ~10% of adults elevated serum aminotransferase
levels develop during the first few weeks.
In ~1% of treated patients, an illness similar to viral
hepatitis develops .
The case-fatality rate may be 10%.
Isoniazid hepatotoxicity is enhanced by alcohol,
rifampin, and pyrazinamide.
Isoniazid
63. It is associated with severe hepatic toxicity and rarely,
fatalities, predominantly in children.
Elevations of serum aminotransferase levels occurs in
45% of patients but have no clinical importance.
Its metabolite, 4-pentenoic acid, is responsible for
hepatic injury.
Hepatotoxicity is more common in persons with
mitochondrial enzyme deficiencies
It may be ameliorated by IV carnitine, which valproate
therapy depletes.
Sodium Valproate
64. Phenytoin rarely causes severe hepatitis leading to
fulminant hepatic failure.
Hepatic injury is usually manifested within the first 2
months after phenytoin therapy.
Aminotransferase and ALP levels is increased and
represent the potent enzyme–inducing properties of
phenytoin.
Phenytoin
65. Clinically important liver disease develops in <5% of
patients.
It has a half-life of up to 107 days so liver injury may
persist for months after stopping the drug.
Amiodarone
66. The important adverse effect is a cholestatic reaction.
It is more common in children than adults.
Most of these reactions have been associated with the
estolate salt.
The reaction usually begins during the first 2 or 3
weeks of therapy.
Erythromycin
67. Combination pills of estrogenic and progestational
steroids lead to intrahepatic cholestasis.
It occurs in a small number of patients weeks to
months after taking these agents.
The lesion is reversible on withdrawal of the agent.
The two steroid components act synergistically on
hepatic function but the estrogen is more responsible.
OCPs are contraindicated in patients with a history of
recurrent jaundice of pregnancy.
Oral Contraceptives
68. In most cases, liver injury is self-limited.
The hepatotoxicity is attributable to the
sulfamethoxazole component of the drug.
Trimethoprim-Sulfamethoxazole
Induction generally occurs within a few days and it passes off over 2–3 weeks following withdrawal of the inducer.
The recovery process after enzyme inhibition or induction is dependent on the enzyme turnover
The estimated duration can vary among CYP families, and other factors (genetic polymorphisms) are to be examined.
Ref: Clinical Pharmacology 2012 by Peter Bennett
Tolerance and cross-tolerance are attributed to activation of liver metabolizing enzymes. They also are attributed to decreased sensitivity or numbers of receptor sites.
Ref: ?
Nevirapine: is a benzodiazepine non-nucleoside reverse transcriptase inhibitor. In combination with other antiretroviral drugs, nevirapine reduces HIV viral loads and increases CD4 counts, thereby retarding or preventing the damage to the immune system and reducing the risk of developing AIDS.
Ref: Clinical Pharmacology 2012 by Peter Bennett
Cotrimoxazole = trimethoprim/sulfamethoxazole
Fluvoxamine
is an antidepressant which functions pharmacologically as a selective serotonin reuptake inhibitor. Though it is in the same class as other SSRI drugs, it is most often used to treat obsessive-compulsive disorder.
Fluoxetine is a type of antidepressant known as an SSRI (selective serotonin reuptake inhibitor). It is often used to treat depression, and also sometimes obsessive compulsive disorder and bulimia.
Ritonavir, sold under the trade name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Often a low dose is used with other protease inhibitors
Paroxetine is used to treat depression, panic attacks, obsessive-compulsive disorder (OCD), anxiety disorders, and post-traumatic stress disorder. It works by helping to restore the balance of a certain natural substance (serotonin) in the brain. Paroxetine is known as a selective serotonin reuptake inhibitor (SSRI).
Terbinafine
is an antifungal medication that fights infections caused by fungus. Terbinafine tablets are used to treat infections caused by fungus that affect the fingernails or toenails. Terbinafine oral granules are used to treat a fungal infection of scalp hair follicles in children who are at least 4 years old.
Ref: Clinical Pharmacology 2012 by Peter Bennett
Ref: Clinical Pharmacology 2012 by Peter Bennett
β blockers decrease blood flow by decreasing cardiac output, and constricting portal vain (unopposed alpha vasoconstriction).
binding sites. Reductions
in protein binding will tend to increase the hepatic
clearance of restrictively metabolized drugs. For drugs
that have low intrinsic clearance and tight binding to
plasma proteins, it is possible that liver disease results
in a decrease in CLint but also an increase in fu. The
resultant change in hepatic clearance will depend on
changes in both these parameters. Thus, hepatic
disease generally produces no change in warfarin
clearance, a decrease in diazepam clearance, and an
increase in tolbutamide clearance. However, as discussed
in Chapter 5, unbound drug concentrations
will not be affected by decreases in the protein binding
of restrictively metabolized drugs. Therefore, no
dosage alterations are required for these drugs when
protein binding is the only parameter that is changed.
Although reduced protein binding will not affect
Ref: PRINCIPLES OF CLINICAL PHARMACOLOGY By Arthur Atkinson 2012
DILI = Drug-induced liver injury
AST = aspartate aminotransferase
ALT = alanine aminotransferase
monitoring liver function in the early weeks of therapy is wise in detecting early reactions to drugs with hepatotoxic potential, e.g. isoniazid.
Ref: PRINCIPLES OF CLINICAL PHARMACOLOGY By Arthur Atkinson 2012 and Ref: Clinical Pharmacology by Peter Bennett 2012
Patients with acute DILI who are symptomatic may report malaise, low-grade fever, anorexia, nausea, vomiting, right upper quadrant pain, jaundice, acholic stools, or dark urine. In addition, patients with cholestasis may have pruritus.
Ref: https://www.lib.utdo.ir/contents/drug-induced-liver-injury?search=hepatotoxicity%20causes&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H213375674
ALT = alanine aminotransferase
ALP = alkaline phosphatase
PT = Prothrombin time
Ref: https://www.lib.utdo.ir/contents/drug-induced-liver-injury?search=hepatotoxicity%20causes&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H213375674
Serum bilirubin increases in both hepatocellular and cholestatic injury.
Drug therapy in patients with advanced cirrhosis is
further complicated by the fact that renal blood flow
and glomerular filtration rate are frequently depressed
in these patients in the absence of other known causes
of renal failure. Renal hemodynamics are compromised
long before cirrhosis is categorized as severe
because even moderate portal hypertension triggers
increased production of nitric oxide and other factors
that cause arterial vasodilation in the splanchnic
circulation [56]. Initially, cardiac output can increase to
compensate for the decrease in systemic vascular
resistance. However, in advanced cirrhosis, the
sympathetic nervous system, the renin–angiotensin
system, and the non-osmotic release of arginine
vasopressin must be activated to maintain arterial
pressure. Activation of these additional compensatory
mechanisms causes intrarenal vasoconstriction and
hypoperfusion that adversely affect renal sodium
excretion and solute-free water retention, leading to
the formation of ascites and edema, and ultimately
results in renal failure. This etiology of renal failure
has been termed the hepatorenal syndrome (HRS) and
has been subdivided into Type I HRS, which presents
as acute renal failure characterized by a doubling of
a previously measured serum creatinine, or a 50%
reduction in creatinine clearance, within 2 weeks; and
Type II HRS, in which refractory ascites is prominent
and progression to serum creatinine concentrations of
1.5–2.5 mg/dL occurs more gradually over a period of
weeks to months [57]. However, a number of factors,
including administration of certain drugs or spontaneous
bacterial peritonitis resulting from the bacterial
translocation from the intestine to the peritoneum, can
precipitate acute renal failure in patients with Type II
HRS.
Ref: PRINCIPLES OF CLINICAL PHARMACOLOGY By Arthur Atkinson 2012
ACEI = angiotensin-converting enzyme inhibitors
Drug therapy in patients with advanced cirrhosis is
further complicated by the fact that renal blood flow
and glomerular filtration rate are frequently depressed
in these patients in the absence of other known causes
of renal failure. Renal hemodynamics are compromised
long before cirrhosis is categorized as severe
because even moderate portal hypertension triggers
increased production of nitric oxide and other factors
that cause arterial vasodilation in the splanchnic
circulation [56]. Initially, cardiac output can increase to
compensate for the decrease in systemic vascular
resistance. However, in advanced cirrhosis, the
sympathetic nervous system, the renin–angiotensin
system, and the non-osmotic release of arginine
vasopressin must be activated to maintain arterial
pressure. Activation of these additional compensatory
mechanisms causes intrarenal vasoconstriction and
hypoperfusion that adversely affect renal sodium
excretion and solute-free water retention, leading to
the formation of ascites and edema, and ultimately
results in renal failure. This etiology of renal failure
has been termed the hepatorenal syndrome (HRS) and
has been subdivided into Type I HRS, which presents
as acute renal failure characterized by a doubling of
a previously measured serum creatinine, or a 50%
reduction in creatinine clearance, within 2 weeks; and
Type II HRS, in which refractory ascites is prominent
and progression to serum creatinine concentrations of
1.5–2.5 mg/dL occurs more gradually over a period of
weeks to months [57]. However, a number of factors,
including administration of certain drugs or spontaneous
bacterial peritonitis resulting from the bacterial
translocation from the intestine to the peritoneum, can
precipitate acute renal failure in patients with Type II
HRS.
Ref: PRINCIPLES OF CLINICAL PHARMACOLOGY By Arthur Atkinson 2012
Ref: PRINCIPLES OF CLINICAL PHARMACOLOGY By Arthur Atkinson 2012 and
Clinical Pharmacology by Peter Bennett 2012
CP450 = cytochrome P450
When diuretic therapy does result in effective fluid removal in cirrhotic patients, it is associated with a very high incidence of adverse reactions. In one study of diuretic therapy in cirrhosis, furosemide therapy precipitated HRS in 12.8%, and hepatic coma in 11.6%, of the patients [72]. Although daily doses of this drug did not differ, patients who had adverse drug reactions received total furosemide doses that averaged 1384 mg, whereas patients without adverse reactions received lower total doses that averaged 743 mg. Accordingly, when spironolactone therapy does not provide an adequate diuresis, only small frequent doses of loop diuretics should be added to the spironolactone regimen [71]. Cirrhotic patients also appear to be at an increased risk of developing acute renal failure after being treated with angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatory drugs
Ref: PRINCIPLES OF CLINICAL PHARMACOLOGY By Arthur Atkinson 2012
In fact, cirrhosis may decrease the clearance of drugs that are nonrestrictively eliminated in subjects with normal liver function to the extent that it no longer approximates hepatic blood flow but is influenced to a greater extent by hepatic intrinsic clearance. By reducing first-pass hepatic metabolism, cirrhosis also may cause a clinically significant increase in the extent to which non-restrictively eliminated drugs are absorbed.
Ref: PRINCIPLES OF CLINICAL PHARMACOLOGY By Arthur Atkinson 2012
TNG = glyceryl trinitrate
SL = sublingual
Variceal bleeding is likely once the pressure gradient between the porto-systemic systems rises above 12 mmHg.
Vasopressin, in addition to its action on renal collecting ducts (through V2 receptors), constricts smooth muscle (V1 receptors) in the cardiovascular system and particularly in splanchnic blood vessels, reducing splanchnic blood flow. Systemic, cerebral and coronary artery vasoconstriction are predictable complications necessitating treatment withdrawal in 20% of older patients. In patients with cardiovascular disease and uncontrolled haemorrhage that precludes definitive endoscopic therapy, simultaneous administration of glyceryl trinitrate (transdermally, sublingually or intravenously) allows continued use of vasopressin, reducing cardiac risk, and also reduces portal venous resistance and pressure directly. Vasopressin is cleared rapidly from the circulation so is given by continuous intravenous infusion; with concerns about distant ischaemia,
Ref: Clinical Pharmacology by Peter Bennett 2012
Octreotide has longer half life and is given as bolus injection.
Octreotide is an alternative to vasopressin
Ref: Clinical Pharmacology by Peter Bennett 2012
Management of ascites
Perform an ascitic tap to confirm the presence of a transudate
before initiating therapy. Ultrasound assesses portal
vein patency and the presence of hepatocellular carcinoma.
Treatment targets induction of natriuresis with consequent
loss of water. Salt restriction is effective; fluid restriction
is unnecessary unless the plasma sodium falls below
125 mmol/L. Measurement of urinary sodium before treatment
and changes in therapy is helpful, indicating if dietary
restriction of sodium has been achieved, helping time the
introduction of diuretics, guiding dose changes and indicating
when therapy has ceased to be effective.
Bed rest (reduces plasma renin activity) with dietary
sodium restriction is effective, but diuretics are needed
eventually. Spironolactone is most useful, although maximum
efficacy is seen at 2 weeks, following metabolism
to products with long duration of action, e.g. canrenone
(t½ 10–35 h). If renal function is conserved, loop diuretics,
e.g. furosemide, may be added, counteracting hyperkalaemia
induced by spironolactone. A ratio of spironolactone
100 mg to furosemide 40 mg works well and under careful
supervision can be increased weekly to a maximum of
spironolactone 400 mg þ furosemide 160 mg. It is rare for
patients to tolerate these doses for long.
Monitor body-weight, as patients with oedema and ascites
may exhibit rapid weight loss, which should not exceed
0.5 kg/day; extreme negative fluid balance runs the risk of
hypovolaemia, electrolyte disturbance, renal impairment
and hepatic encephalopathy.
Patients lose weight if the urinary sodium excretion
exceeds intake; those who do not respond despite a high
urinary sodium are almost certainly receiving additional
dietary sodium (sometimes iatrogenic, e.g. antacids).
Unwanted effects of diuretic use are very common; in addition
to electrolyte disturbances and renal impairment,
cramps are unpleasant and if spironolactone causes painful
gynaecomastia, amiloride is an alternative (10–40 mg/day).
Those without natriuresis should have diuretic therapy
withdrawn.
Abdominal paracentesis was once shunned because
of the risk of circulatory failure, but administration of
albumin at the time of paracentesis has led to its safe reintroduction.
Drainage leads to prompt relief of discomfort
of tense, painful ascites and improves circulatory dynamics;
it can be undertaken as other measures to control ascites are
introduced. Alternatively, paracentesis is the treatment of
choice for patients unresponsive to diuretic therapy or with
complications of diuretic treatment, especially renal impairment.
Planned procedures at intervals of 2–3 weeks restore
a degree of quality of life. It is essential to assess
subacute bacterial peritonitis at each paracentesis, limit
the duration of paracentesis (6 h) and ensure that each litre
of ascites removed is matched by 6–8 g albumin given
before or with paracentesis. Paracentesis carries a risk of
perforation of abdominal contents and abdominal wall
varices.
Patients with ascites should receive prophylaxis against
subacute bacterial peritonitis. Quinolones, for example
ciprofloxacin or norfloxacin, are effective.
Ref: Clinical Pharmacology by Peter Bennett 2012
customary doses of sedatives may precipitate the confusion, disorientation, and eventual coma that are characteristic of portal-systemic or hepatic encephalopathy that frequently occurs in the terminal phase of advanced liver disease.
Hepatic encephalopathy is primarily caused by the synergistic effects of excess ammonia production and inflammation that together result in astrocyte swelling and brain edema.
Specific measures to treat patients with hepatic encephalopathy include oral administration of lactulose and the poorly absorbed antibiotic rifaximin to reduce ammonia formation by intestinal bacteria. However, experimental hepatic encephalopathy also is associated with increased gama–aminobutyric acid-mediated inhibitory neurotransmission, and there has been some success in using the benzodiazepine antagonist flumazenil to reverse this syndrome.
This provides the rationale for using flumazenil to treat patients who fail to respond to ammonia-reduction therapy, as well as those whose hepatic encephalopathy is triggered by exogenous benzodiazepines [67], and provides a theoretical basis for the finding that brain hypersensitivity, together with impaired drug elimination, is responsible for the exaggerated sedative response to diazepam that is exhibited by some patients with chronic liver disease [68].
Changes in the cerebrospinal fluid/serum concentration ratio of cimetidine have been reported in patients with liver disease, suggesting an increase in blood–brain barrier permeability that also could make these patients more sensitive to the adverse central nervous system effects of a number of other drugs [69].
Although cirrhotic patients frequently are treated with diuretic drugs to reduce ascites, they exhibit a reduced responsiveness to loop diuretics that cannot be overcome by administering larger doses. This presumably is related to the pathophysiology of increased sodium retention that contributes to the development of ascites [70]. In addition, decreases in renal function, which is often unrecognized in these patients [59], may lead to decreased delivery of loop diuretics to their renal tubular site of action.
Because hyperaldosteronism is prevalent in these patients and spironolactone is not dependent on glomerular filtration for efficacy, it should be the mainstay of diuretic therapy in this clinical setting.
Ref: PRINCIPLES OF CLINICAL PHARMACOLOGY By Arthur Atkinson 2012
Infection, gastrointestinal bleeding, injudicious use of sedatives
and diuretics can precipitate hepatic encephalopathy
in cirrhosis. The pathophysiology is complex but ammonia
is a key player. Diagnosis is confirmed by elevated plasma
ammonia and/or typical EEG appearances. Ammonia is
derived from the action of colonic urease-containing bacteria
and normally undergoes hepatic extraction from portal
blood, but with portal/systemic shunting and impaired hepatic
metabolism, it reaches high systemic concentrations,
affecting the brain adversely.
Ref: Clinical Pharmacology by Peter Bennett 2012
Ref: Clinical Pharmacology by Peter Bennett 2012
PT = prothrombin time
Coagulation disorders are common in patients with advanced cirrhosis. beta-lactam antibiotics that contain the N-methylthiotetrazole side chain (cefotetan) that inhibits gcarboxylation of vitamin K-dependent clotting factors.
Ref: PRINCIPLES OF CLINICAL PHARMACOLOGY By Arthur Atkinson 2012 and Clinical Pharmacology by Peter Bennett 2012
drugs whose dose should be reduced
in treating patients with moderate hepatic impairment.
Most of the drugs in this table have first-pass
metabolism that is greater than 50% in normal subjects
but is substantially reduced when liver function is
Impaired.
Although initial and maintenance oral drug doses
may need to be reduced in patients with moderate to
severe liver disease, the extent of reduction cannot be
accurately predicted since neither the extent of portosystemic
shunting nor the actual hepatic blood flow
usually are known in a given patient [76]. Given this
uncertainty, maintenance doses need to be adjusted
empirically to achieve the desired pharmacologic
effect while avoiding toxicity. When medications are
administered intravenously, a normal initial or loading
dose may be administered, but the maintenance dose
should be lowered to reflect the reduction in hepatic
clearance
Ref: PRINCIPLES OF CLINICAL PHARMACOLOGY By Arthur Atkinson 2012
Ref: Clinical Pharmacology by Peter Bennett 2012
Treatment of alcohol withdrawal in established liver disease is hazardous. Reducing doses of chlordiazepoxide over 5–10 days is recommended (with high-dose thiamine).
Ref: Clinical Pharmacology by Peter Bennett 2012
PG = prostaglandin
NSAIDs may exacerbate impaired renal function and fluid retention by inhibiting PG synthesis and precipitate GI bleeding.
Ref: Clinical Pharmacology by Peter Bennett 2012
Halothane
It is an idiosyncratic hepatotoxicity.
It causes severe hepatic necrosis in a small number of individuals, many of whom had previous exposure.
Halothane is not a direct hepatotoxin but rather a sensitizing agent.
Adults, obese people and women have higher risk.
The case-fatality rate of halothane hepatitis is 20–40%.
Patients with delayed spiking fever or jaundice after halothane should not receive it again.
Cross-reactions between halothane and methoxyflurane is reported.
So the latter agent should not be used after halothane reactions.