- 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
Drug therapy in pregnancy and lactationVishnupriya K
This slide share will provide drugs which are used and which are contraindicated during pregnancy and lactation, also give information about side effects and malformations if pregnant women's used some drugs.
Drug therapy in pregnancy and lactationVishnupriya K
This slide share will provide drugs which are used and which are contraindicated during pregnancy and lactation, also give information about side effects and malformations if pregnant women's used some drugs.
A Powerpoint presentation on drugs excretion and elimination suitable for UG medical students. This ppt is already presented to my students in one of the theory classes.
1. Altered Physiology
2. Pharmaceutical factors
3. Pharmacokinetic factors
4. Pharmacodynamic factors
5. Adverse Drug Reactions in elderly
6. A few examples
7. THANK YOU
Lecture slides for Medical Undergraduate teaching in Pharmacology. Study material is based on Essentials of medical pharmacology by KD tripathi and Katzung. Figures are obtained from google image search and above mentioned textbooks.
Clinical pharmacokinetics and its application--
1)definition
2) APPLICATIONS OF CLINICAL PHARMACOKINETICS
Design of dosage regimens:
a) Nomograms and Tabulations in designing dosage regimen,
b) Conversion from intravenous to oral dosing,
c) Determination of dose and dosing intervals,
d) Drug dosing in the elderly and pediatrics and obese patients.
Pharmacokinetics of Drug Interaction:
a) Pharmacokinetic drug interactions
b) Inhibition and Induction of Drug metabolism
c) Inhibition of Biliary Excretion.
Therapeutic Drug monitoring:
a) Introduction
b) Individualization of drug dosage regimen (Variability – Genetic, Age and Weight, disease, Interacting drugs).
c) Indications for TDM. Protocol for TDM.
d) Pharmacokinetic/Pharmacodynamic Correlation in drug therapy.
e) TDM of drugs used in the following disease conditions: cardiovascular disease, Seizure disorders, Psychiatric conditions, and Organ transplantations
Dosage adjustment in Renal and Hepatic Disease.
a. Renal impairment
b. Pharmacokinetic considerations
c. General approach for dosage adjustment in renal disease.
d. Measurement of Glomerular Filtration rate and creatinine clearance.
e. Dosage adjustment for uremic patients.
f. Extracorporeal removal of drugs.
g. Effect of Hepatic disease on pharmacokinetics.
Population Pharmacokinetics.
a) Introduction to Bayesian Theory.
b) Adaptive method or Dosing with feedback.
c) Analysis of Population pharmacokinetic Data
Prokinetics are the type of drugs which enhances gastrointestinal motility/transit by
increasing the frequency or strength of contractions.
They speed up gastric emptying by enhancing coordinated propulsive motility.
Treat Gastrointestinal symptoms : Abdominal discomfort, Bloating, constipation,
Heart burn, nausea and vomiting. And few gastrointestinal disorders : irritable bowel
Syndrome, gastritis, gastroparesis and functional dyspepsia.
Increases gastric emptying
Relief of gastric stasis
Decreases reflux esophagitis/heart burn
Decreases regurgitation of gastric contents& emesis
Paediatric (pediatrics) medication-drugs therapy in pediatricsRavish Yadav
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
Introduction to the endocrine system
Growth hormone: Mechanism of Action, secretion, regulation.
Prolactin
Sex hormones
Oral contraceptives
Corticosteroids
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.
A Powerpoint presentation on drugs excretion and elimination suitable for UG medical students. This ppt is already presented to my students in one of the theory classes.
1. Altered Physiology
2. Pharmaceutical factors
3. Pharmacokinetic factors
4. Pharmacodynamic factors
5. Adverse Drug Reactions in elderly
6. A few examples
7. THANK YOU
Lecture slides for Medical Undergraduate teaching in Pharmacology. Study material is based on Essentials of medical pharmacology by KD tripathi and Katzung. Figures are obtained from google image search and above mentioned textbooks.
Clinical pharmacokinetics and its application--
1)definition
2) APPLICATIONS OF CLINICAL PHARMACOKINETICS
Design of dosage regimens:
a) Nomograms and Tabulations in designing dosage regimen,
b) Conversion from intravenous to oral dosing,
c) Determination of dose and dosing intervals,
d) Drug dosing in the elderly and pediatrics and obese patients.
Pharmacokinetics of Drug Interaction:
a) Pharmacokinetic drug interactions
b) Inhibition and Induction of Drug metabolism
c) Inhibition of Biliary Excretion.
Therapeutic Drug monitoring:
a) Introduction
b) Individualization of drug dosage regimen (Variability – Genetic, Age and Weight, disease, Interacting drugs).
c) Indications for TDM. Protocol for TDM.
d) Pharmacokinetic/Pharmacodynamic Correlation in drug therapy.
e) TDM of drugs used in the following disease conditions: cardiovascular disease, Seizure disorders, Psychiatric conditions, and Organ transplantations
Dosage adjustment in Renal and Hepatic Disease.
a. Renal impairment
b. Pharmacokinetic considerations
c. General approach for dosage adjustment in renal disease.
d. Measurement of Glomerular Filtration rate and creatinine clearance.
e. Dosage adjustment for uremic patients.
f. Extracorporeal removal of drugs.
g. Effect of Hepatic disease on pharmacokinetics.
Population Pharmacokinetics.
a) Introduction to Bayesian Theory.
b) Adaptive method or Dosing with feedback.
c) Analysis of Population pharmacokinetic Data
Prokinetics are the type of drugs which enhances gastrointestinal motility/transit by
increasing the frequency or strength of contractions.
They speed up gastric emptying by enhancing coordinated propulsive motility.
Treat Gastrointestinal symptoms : Abdominal discomfort, Bloating, constipation,
Heart burn, nausea and vomiting. And few gastrointestinal disorders : irritable bowel
Syndrome, gastritis, gastroparesis and functional dyspepsia.
Increases gastric emptying
Relief of gastric stasis
Decreases reflux esophagitis/heart burn
Decreases regurgitation of gastric contents& emesis
Paediatric (pediatrics) medication-drugs therapy in pediatricsRavish Yadav
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
Introduction to the endocrine system
Growth hormone: Mechanism of Action, secretion, regulation.
Prolactin
Sex hormones
Oral contraceptives
Corticosteroids
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.
Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Charles Locock commented in the Lancet on his use of potassium bromide in 15 cases of "hysterical" epilepsy in young women. The next development was the serendipitous discovery of the anticonvulsant properties of phenobarbital by Alfred Hauptmann in 1912. This predated by more than 20 years the screening of potential therapeutic agents against "electrical seizures" in cats by Houston Merritt and Tracy Putnam. The result was the launching of phenytoin in 1938. Next came primidone, ethosuximide, carbamazepine and valproic acid, all of which can be regarded as first generation antiepileptic drugs (AEDs). Shortly after their synthesis, the benzodiazepines were rapidly recognised as having anticonvulsant activity. The modern era focused on the systematic screening of many thousands of compounds against rodent seizure models under the Anticonvulsant Drug Development Program in the US. This resulted in the global licensing, in chronological order, of vigabatrin, zonisamide, oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam, pregabalin and lacosamide.
Drug-induced liver disease (DILD) is a potentially fatal, often debilitating outcome of drug treatment. The range of drugs associated with adverse reactions involving the liver is extensive, but in clinical practice is dominated by alcohol, antibiotics, antiseizure medications and acetaminophen. Complementary and herbal medicines also contribute disproportionately to this disease burden.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
2. Drugs pharmacology in Liver disease
– Introduction
– General guidelines
– Absorption and Liver
– Metabolism in Liver
– Drug Effect on Liver
– Liver Blood Flow
– Protein Binding
– Age Effect
– Dose Adjustment
– Specific Drugs
2
3. Introduction
• Acute liver impairment interferes with drug
metabolism and elimination.
• Chronic liver impairment affects all parameters of
pharmacokinetic.
• Because most drugs are metabolized by the liver, it is
susceptible to drug toxicity.
• Impaired liver function greatly increases the risks of
adverse drug effects.
3
4. Introduction Cont’d
• 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.
4
5. Introduction Cont’d
• 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.
5
6. General guidelines
• General guidelines when using drugs include:
– 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).
6
7. • Monitoring liver tests:
– Serum bilirubin levels above 4 to 5 mg/dl
– Prothrombin time greater than 1.5 times control
– Serum albumin below 2.0 g/dl
– Elevated alanine and aspartate aminotransferases
(ALT & AST).
General guidelines Cont’d
7
8. Absorption and Liver
• 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.
8
9. 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 .
9
11. Metabolism in Liver
• 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.
11
12. Metabolism in Liver Cont’d
• 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.
12
16. Metabolism in Liver Cont’d
• 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.
16
17. Drug Effect on Liver
• 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.
• Enzyme induction does not occur for 1-3 weeks
because new enzymes must be synthesized.
17
18. Drug Effect on Liver Cont’d
• Enzyme inducers consist of: phenytoin, rifampin,
phenobarbital, ethanol, and cigarette smoking.
• Tolerance and cross-tolerance are attributed to
activation of liver metabolizing enzymes.
• They also are attributed to decreased sensitivity
or numbers of receptor sites.
18
19. Drug Effect on Liver Cont’d
• Metabolism can be decreased in a process called
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 of
starting an inhibiting agent.
• Enzyme inhibitors consist of: Cimetidine, fluoxetine,
and ketoconazole.
19
21. Drug Effect on Liver Cont’d
• Some drugs indirectly affect liver function:
– Epinephrine decreases blood flow by constricting
hepatic artery and portal vein.
– β blockers decrease blood flow by decreasing
cardiac output.
21
22. Liver Blood Flow
• Hepatic metabolism also depends on hepatic
blood flow.
• Hepatic blood flow ↓ => delivery of drug to
hepatocytes ↓ => drug metabolism ↓ => drug
toxicity ↑
22
23. Protein Binding
• Protein binding affects distribution.
• The impaired liver is unable to synthesize
plasma proteins (albumin) adequately.
• Liver impairment causes accumulation of
substances (bilirubin) that displace drugs from
protein-binding sites.
23
24. • 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 Cont’d
24
27. Age Effect
• 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.
27
28. Age Effect Cont’d
• In elderly, physiologic changes alters all
pharmacokinetic processes in the liver.
• Many drugs are metabolized more slowly and
accumulate with chronic administration.
28
72. Acetaminophen
• 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.
72
73. Acetaminophen Cont’d
• 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.
73
76. 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.
76
77. Halothane Cont’d
• 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.
77
78. Isoniazid
• 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.
78
79. Sodium Valproate
• 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.
79
80. Phenytoin
• 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.
80
81. Amiodarone
• 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.
81
82. Erythromycin
• 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.
82
83. Oral Contraceptives
• 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.
83
84. Trimethoprim-Sulfamethoxazole
• In most cases, liver injury is self-limited.
• The hepatotoxicity is attributable to the
sulfamethoxazole component of the drug.
84
86. Drugs Pharmacology in Kidney Disease
• Drug Nephrotoxicity
• Weak Acids & Weak Bases
• Absorption
• Distribution & Protein Binding
• Metabolism & Excretion
• Age Effect
• Creatinine
• Drug selection
• Dosage
• NSAIDs & Lithium
86
87. Drug Nephrotoxicity
Drugs can lead to renal damage in a number
of different ways :
1. Alteration of renal blood flow
• NSAIDs:alteration in prostaglandin
metabolism can lead to critical reduction
in glumerular perfusion, interstitial
nephritis can also result from NSAIDs
• ACE inhibitors and ARBs: ARF or renal
impairment ????
87
88. Occurring in patients who are critically dependant
upon RAA system.
• Cyclosporine A
2. Direct tubular toxicity
• Aminoglycosides :disturbance of renal function is
seen in up to a third of patients receiving
aminoglycosides.
88
89. • Cisplatin : selectively toxic to proximal
tubules by inhibiting nuclear DNA synthesis
• Amophotercin:
3.glumerulonephritis
• Gold :
Is believed to induce an immune
complex GN
• Penicillamine :
It is dose related
89
90. 4. Other nephrotoxic effects of drugs:
• Interstitial nephritis
• Retropertoneal fibrosis
• Drug induced SLE
• Nephrogenic DI
90
91. Weak Acids & Weak Bases
• Most drugs are lipid soluble which aids their
movement across cell membranes.
• The kidneys can excrete only water-soluble
substances.
• One function of metabolism is to convert fat
soluble drugs into water-soluble metabolites.
91
92. M.H.Farjoo
Weak Acids & Weak Bases Cont,d
• Weak acids and weak bases gain or lose protons
depending on the pH.
• Their movement between aqueous & lipid
mediums varies with the pH.
• Kidney filters drugs, by changing the urine pH the
drug can be "trapped" in the urine (in overdose).
• Weak acids are excreted faster in alkaline urine
and vise versa.
92
93. Trapping of a weak base
(pyrimethamine) in the urine
when the urine is more acidic
than the blood. In the
hypothetical case illustrated,
the diffusible uncharged form
of the drug has equilibrated
across the membrane, but the
total concentration (charged
plus uncharged) in the urine is
almost eight times higher than
in the blood.
93
94. Weak Acids & Weak Bases Cont,d
• Sodium bicarbonate + phenobarbital →
increased excretion of phenobarbital.
• The sodium bicarbonate alkalinizes the urine,
raising the number of barbiturate ions in the
renal filtrate.
• The ionized particles cannot pass easily
through renal tubular membranes.
• Therefore, less drug is reabsorbed into the
blood and more is excreted by the kidneys.
94
95. Weak Acids & Weak Bases Cont,d
• A large number of drugs are weak bases. Most
of these bases are amine-containing
molecules.
• Primary, secondary, and tertiary amines
undergo protonation and vary their solubility
with pH.
• Quaternary amines are always in the poorly
lipid-soluble charged form.
95
97. Weak Acids & Weak Bases Cont,d
• The protonated form of a weak acid is the
neutral, more lipid-soluble form.
• The unprotonated form of a weak base is the
neutral form.
• The uncharged form is more lipid-soluble.
• A weak acid is more lipid-soluble at acid pH,
and a basic drug is more lipid-soluble at
alkaline pH.
97
98. Weak Acids & Weak Bases Cont,d
Body Fluid Range of pH
Total Fluid:
Blood
Concentration
Ratios for
Sulfadiazine
(acid, pKa 6.5)
Total Fluid:
Blood
Concentration
Ratios for
Pyrimethamine
(base, pKa 7.0)
Urine 5.0-8.0 0.12-4.65 72.24-0.79
Breast milk 6.4-7.6 0.2-1.77 3.56-0.89
Jejunum, ileum
contents
7.5-8.0 1.23-3.54 0.94-0.79
Stomach contents 1.92-2.59 0.11 85,993-18,386
Prostatic secretions 6.45-7.4 0.21 3.25-1.0
Vaginal secretions 3.4-4.2 0.11 2848-452
98
99. Absorption
• Absorption of oral drugs may be decreased
indirectly in renal failure by:
– Delayed gastric emptying
– Changes in gastric pH
– GI symptoms such as vomiting and diarrhea
– Edema of the GI tract (in the presence of
generalized edema).
99
100. Absorption Cont,d
• In CRF, gastric pH is altered by:
– Oral alkalinizing agents (sodium bicarbonate,
citrate).
– Use of antacids for phosphate-binding effects.
• This causes:
– Decrease in absorption of oral drugs that require
an acidic environment for absorption.
– Increases absorption of drugs that are absorbed
from a more alkaline environment.
100
101. Distribution
• Distribution of drugs is altered by changes in ECF,
plasma protein binding, and tissue binding.
• Water-soluble drugs are distributed in ECF, including
edema fluid, which is increased in renal impairment.
• Metabolic acidosis & respiratory alkalosis that occur
in renal impairment alter tissue distribution of some
drugs.
• For example, digoxin can be displaced from tissue by
metabolic products that cannot be excreted by
impaired kidneys.
101
102. Protein Binding
• Albumin is the main drug-binding plasma
protein for acidic drugs.
• Drug binding with albumin is decreased with
renal impairment.
• This is due to decreased albumin or reduced
binding capacity.
102
103. Protein Binding Cont,d
• Reasons for decreased albumin include:
– Nephrotic states in which albumin is lost in the
urine.
– Hypermetabolic states (stress, trauma, sepsis) in
which protein breakdown exceeds protein
synthesis.
– Liver disease that decreases hepatic synthesis of
albumin.
• Reasons for reduced binding capacity include:
– Uremic toxins that compete with drugs for binding
sites.
– Structural changes in the albumin molecule.
– (e.g. Carbamylation) 103
104. Protein Binding Cont,d
• When less drug is bound to albumin:
– More unbound drug distributes into sites of
metabolism and excretion.
– The higher levels of unbound drug can result in
toxicity.
– Faster elimination can decrease drug half-life and
therapeutic effects.
104
107. Protein Binding Cont,d
• For basic drugs (clindamycin, propafenone),
alpha1-acid glycoprotein (AAG) is the main
binding protein.
• The amount of AAG increases in those with renal
transplants and those receiving hemodialysis.
• In these patients larger amounts of a basic drug is
bound and a smaller amount is free to exert an
effect.
• In c/o post op., MI, RA, Infections
107
108. Metabolism
• Metabolism can increase, decrease, or does not
change by renal impairment.
• One factor is alteration of drug metabolism in the
liver:
– In uremia, reduction and hydrolysis is slower, but oxidation
by CYP enzymes and conjugation reactions proceed at
normal rates.
• Another factor is the inability of impaired kidneys to
eliminate drugs and active metabolites:
– Metabolites may have pharmacologic activity similar to or
different from that of the parent drug.
108
109. Metabolism Cont,d
• A third factor is impaired renal metabolism of
drugs.
– The kidney contains many of the same
metabolizing enzymes found in the liver.
– For example it has renal CYP enzymes, which
metabolize some chemicals and drugs.
109
110. 110
Effect of renal disease on drug metabolismMechanisms of renal elimination of drugs
111. Excretion
• Excretion of many drugs is reduced in renal
failure.
• The kidneys normally excrete both the parent
drug and metabolites produced by the liver.
• Renal excretion includes: glomerular filtration,
tubular secretion, and tubular reabsorption all
of which is affected by renal impairment.
111
115. Excretion Cont,d
• An adequate fluid intake is required to excrete
drugs by the kidneys.
• Any factor that depletes ECF increases the risk
of worsening renal impairment which include:
– Inadequate fluid intake
– Diuretic drugs
– Loss of body fluids (bleeding, vomiting, diarrhea)
115
116. Age Effect
• In the kidneys of elderly, blood flow, GFR, and
tubular secretion of drugs is decreased.
• All of these changes slow excretion and
promote accumulation of drugs in the body.
• Impaired kidney function greatly increases the
risks of adverse drug effects.
116
117. Creatinine
• Drug therapy must be individualized according to the
extent of renal impairment.
• This is determined by measuring creatinine, which is
used to calculate creatinine clearance as a measure
of the GFR.
• Creatinine is determined by muscle mass and the
GFR, so its measurement cannot be used as the sole
indicator of renal function.
• The exception is a young, relatively healthy, well-
nourished person with a sudden acute illness.
117
119. Creatinine Cont,d
• Estimations of creatinine clearance are more
accurate for:
– Clients with stable renal function (stable serum
creatinine).
– Average muscle mass (for their age, weight, and
height).
• Estimations are less accurate for:
– Emaciated and obese clients.
– For those with changing renal function (as in acute
illness).
122
120. Creatinine Cont,d
• Serum creatinine is a relatively unreliable indicator of
renal function in elderly clients.
• Because they have diminished muscle mass, they
may have a normal creatinine even if their GFR is
markedly reduced.
• Some drugs (cimetidine and trimethoprim) increase
creatinine and create a false impression of renal
failure.
• They interfere with secretion of creatinine into
kidney tubules.
123
121. Drug selection
• Drug selection is guided by renal function and
the effects of drugs on renal function.
• Many commonly used drugs may adversely
affect renal function (NSAIDs or OTC drugs).
• Some drugs are excreted exclusively by the
kidneys (aminoglycosides, lithium).
• Some drugs are contraindicated in renal
impairment (tetracyclines except doxycycline).
124
122. Drug selection Cont,d
• Drugs can be used if safety guidelines are followed
(reducing dosage, using TDM and renal function
tests, avoiding dehydration).
• Drugs known to be nephrotoxic should be avoided
when possible.
• In some instances, however, there are no effective
substitutes and nephrotoxic drugs must be given.
• Some commonly used nephrotoxic drugs include
aminoglycoside antibiotics, amphotericin B, and
cisplatin.
125
123. Principles
• Establish type of kidney disease
• Most patients with kidney failure will already be taking
a number of drugs
• Interactions are common
• Care needed to avoid drug toxicity
• Patients with renal impairment and renal
failure
• Antihypertensives
• Phosphate binders
126
124. Dosing in renal impairment
• Loading dose does not change (usually)
• Maintenance dose or dosing interval does
T ½ often prolonged
– Reduce dose OR
– Increase dosing interval
– Some drugs have active metabolites that are themselves
excreted renally
– Warfarin, diazepam
127
125. Dosing of drugs in renal patients
Antimicrobial and antiprotozoal drugs
Dosage for severe renal failureHalf-life
Normal/ESRD
(h)
Drug
Maximum 500 mgq 8h0.09-2.3/5-20Amoxycillin
Maximum 375 mg q12 hAmoxycillin
0.9-2.3/5-20
Clavulanic
acid1/3-4
Amoxycillin
Clavulanic acid PO
250-500 mg q6h0.8-1.5/7-20ampicillin
1g loading dose then 50% standard
dose
1/15Cefotaxime IV
128
126. Dosage for severe renal failureHalf-life
Normal/ESRD
(h)
Drug
0.5-1 g q24h1.2/13-25Ceftazidime IV
1-2 g q24h7-9/12-24Ceftriaxone IV
750 mg q12h1.2/17Cefuroxime IV
Standard dose1.2/17Cefuroxime PO
250-500 mg q12h0.7/16Cephalexin
Treatment:50% standard dose7-14 days/5- 50 daysChloroquiine
50% standard dose q12h3-6/6-9Ciprofloxacin IV/PO
250 mg q12h2.3-6.0/-Calrithromycin
PCP treatment:Standard dose
q48h
PCP prophylaxis
25% Standard dose q48-72h
Sulphamethoxazole
10/20-50
Trimethoprime
9-13/20-49
Cotrimoxazole
IV/PO
Sulphamethoxazole/
Trimethoprime
50-75% Standard dose
Max 1.5g in 24h
1.4/5-6Erythromycin IV/PO
129
127. Dosage for severe renal failureHalf-life
Normal/ESRD
(h)
Drug
Max PO 500 mg q6hIV 1g q 6 h0.8-1/3Flucloxacillin
Titrate to levels1.8/20-60Gentamicin IV
250 mg or 3.5 mg/kg q12 hImpenem ¼
Cilastin1/15-24
Impenem/ cilastin IV
50% standard dose q24h1.1/6-8Meropenem IV
Standard dose0.6/4.1Penoxymethyl-pencillin
4 g q12 h0.8-1.8/3.3-5.1Piperacillin IV
4.5 g q12 hPiperacillin 0.18-0.3/3.3-5.1
Dihydrochloride 1/7
Piperacillin/dihydrochloride IV
Treat,emt 5-10 mg/kg q24h9 healthy,18 malaria/ unchangedQuinine difydrochloride IV
50% standard dose9-13/20-49Trimethoprim
Titrate to levels6-8/200-250Vancomycin IV
130
128. Dosing of some drugs in renal patients
• Allopurinol-GFR 30 ml/min use
100mg,60ml/min use 200mg,90ml/min use
300mg
• Corticosteroids-no need to change the dose
• NSAIDs :-most are metabolized in the liver ,
aspirin is a good choice in renal impairment,
- In ESRD patients ,no need for dose
adjustment
131
129. • Methotrexate ,take care from hematologic
toxicity
• Sulfasalasine ,no change in dose.
• Tramadol , give dose every 12 h instead of
every 6h
• Narcotics, avoid using Darvon and
Mepiridine, for others if GFR less than
10ml/min cut 50% of the dose ,if GFR 10-
50ml/min use 75% of the dose
132
130. • Penicillamine ,avoid if GFR less than
50ml/min
• Cyclosporine, no dose adjustment in renal
insufficiency, however use of Cyclosporine
can worsen renal insufficiency
133
131. Dosage
• Dosage of many drugs needs to be decreased in renal
failure including:
– Aminoglycoside antibiotics
– Most cephalosporin antibiotics
– Fluoroquinolones
– Digoxin
• For some drugs, a smaller dose or a longer interval is
recommended in:
– Moderate renal insufficiency (creatinine clearance 10 to 50
mL/min.).
– Severe renal insufficiency (creatinine clearance < 10
mL/min.).
134
132. NSAIDs
• NSAIDs can cause renal impairment even though
they are eliminated mainly by hepatic metabolism.
• Acetaminophen is nephrotoxic in overdose because
it forms a metabolite that attacks kidney and may
cause necrosis.
• Aspirin is nephrotoxic in high doses, and protein
binding of aspirin is reduced in renal failure so that
blood levels of active drug are higher.
135
134. NSAIDs Cont,d
• NSAIDs can decrease blood flow in the kidneys by
inhibiting synthesis of prostaglandins that dilate
renal blood vessels.
• When renal blood flow is normal, these
prostaglandins have limited activity.
• When renal blood flow is decreased, their synthesis
is increased to protect the kidneys from ischemia.
• In those who depend on PGs to maintain renal blood
flow, NSAIDs result in decreased GFR, and retention
of salt and water.
137
136. NSAIDs Cont,d
• NSAIDs can also cause kidney damage by a
hypersensitivity reaction that leads to ARF.
• NSAIDs may adversely affect a fetus’s kidneys
when:
– Given during late pregnancy to prevent premature
labor.
– Given shortly after birth for patent ductus
arteriosus (PDA).
139
137. Aminoglycosides
• Highly effective antimicrobials
– Particularly useful in gram -ve sepsis
– bactericidal
• BUT
– Nephrotoxic
– Ototoxic
– Narrow therapeutic range
140
138. Prescribing Aminoglycosides
• Once daily regimen now recommended in patients
with normal kidneys
– High peak concentration enhances efficacy
– long post dose effect
– Single daily dose less nephrotoxic
• Dose depends on size and renal function
– Measure levels!
141
139. Intravenous contrast
• Used commonly
– CT scanning, IV urography, Angiography
– Unsafe in patients with pre-existing renal impairment
– Risk increased in diabetic nephropathy, heart failure &
dehydration
– Can precipitate end-stage renal failure
– Cumulative effect on repeated administration
• Risk reduced by using Acetylcysteine
( N Engl J Med 2000; 343:180-184 )
142
140. Spironolactone
• Class
• Potassium sparing diuretic
• Mode of action
• Antagonises the effect of aldosterone at levels MR
• Mineralocorticoid receptor (MR)–aldosterone complex
translocates to nucleus to affect gene transcription
• Indication
• Prevent hypokalaemia in patients taking diuretics or digoxin
• Improves survival in advanced heart failure (RALES 1999
Randomised Aldactone Evaluation Study)
• Antihypertensive (adjunctive third line therapy for hypertension or
first line for conns patients)
• Ascites in patients with cirrhosis
143
141. Spironolactone
• Side effects
– Antiandrogenic effects through the antagonism of
DHT (testosterone) at its binding site.
– Gynaecomastia, impotence, reduced libido
• Interactions
– Other potassium sparing drugs e.g. ACE
inhibitors/ARBs & potassium supplements
(remember ‘LoSalt’ used as NaCl substitute in
cooking)
144
142. Amphotericin
• Class
• Anti fungal agent for topical and systemic use
• Mode of action
• Lipid soluble drug. Binds steroid alcohols (ergosterol) in
the fungal cell membrane causing leakage of cellular
content and death. Effective against candida species
• Fungistatic or fungicidal depending on the
concentration
• Broad spectrum (candida, cryptosporidium)
145
143. Amphotericin
• Indications
– iv administration for systemic invasive fungal infections
– Oral for GI mycosis
• Side effects
– Local/systemic effects with infusion (fever)
– Chronic kidney dysfunction
» Decline in GFR with prolonged use
» Tubular dysfunction (membrane permeability)
» Hypokalaemia, renal tubular acidosis (bicarb wasting type
1/distal), diabetes insipidus, hypomagnesaemia
» Pre hydration/saline loading may avoid problems
Toxicity can be reduced substantially by liposomal packing of
Amphotericin
146
144. Lithium
• Lithium is not metabolized by the body.
• It is entirely excreted by the kidneys and has a
very narrow therapeutic range.
• Adequate renal function is a prerequisite for
lithium therapy.
• If it has to be given in renal impairment, the
dose must be reduced and TDM must be
done.
147
145. Lithium Cont,d
• 80% of a lithium dose is reabsorbed in the
proximal renal tubules.
• The amount of reabsorption depends on the
concentration of sodium in the proximal
tubules.
• A deficiency of sodium causes more lithium to
be reabsorbed => risk of lithium toxicity ↑.
• Excessive sodium intake lowers lithium levels
to non therapeutic ranges.
148