Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, through, and out of the body—the time course of its absorption, bioavailability, distribution, metabolism, and excretion.
Presentation made by Dr. Resu Neha Reddy, M.D. Pharmacology, Osmania Medical College. The presentation is about excretion of the drugs by kidneys, liver and other routes and kinetics of elimination, which includes zero, first and mixed (Michaelis - Menton equation) order kinetics. It also includes information regarding clearance, half-life, loading dose, maintenance dose and fixed dose drug combinations.
Pharmacokinetics is the study of the movement of drug molecules in the body. It includes absorption, distribution, metabolism, and excretion of drugs. Pharmacokinetics is the study of what happens to drugs once they enter the body (the movement of the drugs into, within, and out of the body). For a drug to produce its specific response, it should be present in adequate concentrations at the site of action. This depends on various factors apart from the dose.
Four pharmacokinetic properties determine the onset, intensity, and the duration of drug action (Figure 1.6.1):
• Absorption: First, absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma.
• Distribution: Second, the drug may then reversibly leave the bloodstream and distribute it into the interstitial and intracellular fluids.
• Metabolism: Third, the drug may be biotransformed by metabolism by the liver or other tissues.
• Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces.
In short, pharmacokinetics means what the body does to the drug.
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watch video:https://www.youtube.com/watch?v=v3rI1lf2TZ8&t=403s
This slide describes the Important Synthesis of Antiviral Drugs
Presentation made by Dr. Resu Neha Reddy, M.D. Pharmacology, Osmania Medical College. The presentation is about excretion of the drugs by kidneys, liver and other routes and kinetics of elimination, which includes zero, first and mixed (Michaelis - Menton equation) order kinetics. It also includes information regarding clearance, half-life, loading dose, maintenance dose and fixed dose drug combinations.
Pharmacokinetics is the study of the movement of drug molecules in the body. It includes absorption, distribution, metabolism, and excretion of drugs. Pharmacokinetics is the study of what happens to drugs once they enter the body (the movement of the drugs into, within, and out of the body). For a drug to produce its specific response, it should be present in adequate concentrations at the site of action. This depends on various factors apart from the dose.
Four pharmacokinetic properties determine the onset, intensity, and the duration of drug action (Figure 1.6.1):
• Absorption: First, absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma.
• Distribution: Second, the drug may then reversibly leave the bloodstream and distribute it into the interstitial and intracellular fluids.
• Metabolism: Third, the drug may be biotransformed by metabolism by the liver or other tissues.
• Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces.
In short, pharmacokinetics means what the body does to the drug.
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watch video:https://www.youtube.com/watch?v=v3rI1lf2TZ8&t=403s
This slide describes the Important Synthesis of Antiviral Drugs
Therapeutic Drug Monitoring (TDM)
Discuss the logic for therapeutic drug monitoring, which refer to as (TDM)
List various classes of drugs that require TDM
General description of this therapeutic drag TD
Discuss the proper sample timing and method for TDM
And Discuss analytical methods available for TDM
List various drugs that not require TDM
Steady state
Therapeutic Drug Groups
Digoxin, quinidine, procainamide, disopyramide.
- Aminoglycosides (amikacin, gentamicin, kanamycin, tobramycin) - vancomycin
leucovorin rescue ?
First-pass metabolism
HPLC methods
clinical pharmacokinetics half-life first-order elimination zero order elimination steady-state conc applied aspect of steady-state applied aspect of half-life advantage and disadvantage
Pharmacokinetic concepts and principles in humans in order to design individualized dosage regimens which optimize the therapeutic response of a medication while minimizing the chance of an adverse drug reaction.
Therapeutic drug monitoring (TDM) of drugs used in seizure disordersAbel C. Mathew
Therapeutic drug monitoring (TDM) of drugs used in seizure disorders- Phenytoin, Valproic acid, Carbamazepine are major drugs used in epilepsy disorders. These drug need TDM to ensure their proper usage.
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
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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
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.
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!
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
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
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
3. Pharmacokinetic parameters
1. Peak plasma concentration:- Cmax is the maximum
concentration of a drug that can be obtained
Cmax expressed as mcg/ml
Depends upon-
• Dose administered
• Rate of absorption
• Rate of elimination
4. EXAMPLE-
The aminoglycoside antibiotics are rapidly bactericidal. Bacterial
killing is concentration dependent.
• Cmax/MIC--key predictor of aminoglycoside efficacy.
• Have significant post antibiotic effect. .
• Advantages of extended interval aminoglycoside over
traditional intermittent administration:
Possibility of decreased nephrotoxicity
Ease of administration and serum concentration
monitoring
Reductions in administration and monitoring related costs
• All these properties account for the efficacy of high-dose,
extended- interval dosing regimens
5. 2. Time of peak concentration( Tmax ):- tells about the time to reach
maximum concentration, i.e. rate of absorption
o Expressed in hours
o Has importance in assessing the efficacy of drugs used to treat acute
conditions like pain and insomnia.
6. 3. Area under the curve (AUC) :- AUC tells about the extent of absorption
of the drug
o AUC = EXPOSURE
o Expressed in mcg/ml * hours
o Imp parameter in evaluating bioavailability of a drug
o AUC proportional to the dose and the extent of bioavailability for a
drug if its elimination is first-order.
o Bioavailability is defined as the fraction of unchanged drug reaching
the systemic circulation following administration by any route .
8. For a drug administered orally, F<1 due to
Incomplete extent of absorption across the gut wall
first-pass elimination by the liver
Rate of absorption
Extraction ratio and first pass effect.
9. A. Extent of Absorption
Only 70% of a dose of digoxin reaches the systemic circulation--
Due to lack of absorption from the gut.
If too hydrophilic(ATENOLOL), the drug cannot cross the lipid
cell membrane;
if too lipophilic(ACYCLOVIR), the drug is not soluble enough to
cross the water layer adjacent to the cell.
Drugs may not be absorbed because of a reverse transporter
associated with P-glycoprotein.
10. B. FIRST PASS METABOLISM-
Liver – responsible for metabolism or may excrete the drug into the
bile----lead to reduction in bioavailability, and the overall process known
as first-pass elimination.
Extraction ratio (ER):
Q is hepatic blood flow, normally about 90 L/h in a person weighing 70
kg.
F of the drug can be predicted by
for e.g. A drug such as morphine f (extent of absorption) = 1, thus loss
in the gut negligible.
However, the hepatic extraction ratio for morphine is 0.67.
So its oral bioavailability (1 – ER) is therefore expected to be about 33%.
11. C. Rate of Absorption
The rate of absorption is determined by the site of administration and
the drug formulation.
Differences in rate of absorption may become important for drugs given
as a single dose, such as a hypnotic used to induce sleep.
13. D. Extraction Ratio & the First-Pass Effect
Lidocaine and verapamil both used to treat cardiac arrhythmias
and have F< 0.4, but lidocaine never given orally because its
metabolites contribute to CNS toxicity.
Other drugs highly extracted by the liver include morphine,
isoniazid, propranolol, and several tricyclic antidepressants
Drugs poorly extracted by the liver include warfarin, diazepam,
phenytoin, theophylline, tolbutamide, and chlorpropamide
14. Vancomycin
Staphylococcus aureus and coagulase-negative staphylococci
may express reduced or “intermediate” susceptibility to
vancomycin (MIC 4–8 μg/mL) or, very rarely, high-level
resistance (MIC ≥ 16 μg/mL).
Animal studies and limited human data demonstrate that
AUC/MIC is a predictive pharmacokinetic parameter for
vancomycin
Investigators suggested an average AUC/MIC of 345 for a
successful clinical outcome and a ratio of 850 for a successful
microbiological outcome.
15. DRUGS WITH HIGH ORAL BIOAVAILABILITY:-
Levofloxacin- 99% (oral and iv )
Clonidine
Chloramphenicol
Linezolid
Furosemide
16. HALF LIFE
The t1/2 is the time it takes for the plasma concentration
to be reduced by 50%
If metabolism is more, half life is less and vice-versa.
It is a secondary pharmacokinetic parameter derived from
two primary parameter; Vd and CL.
t1/2 = 0.693 * Vss/CL
It determines the dosing interval and time required to
reach the steady state and time required for elimation.
Drugs having short half lives are administered more
frequently than those having longer half life.
It takes 4-5 half lives for a drug to reach its steady state.
.
17. Terminal Half-Life
With prolonged dosing -- drug may penetrate into secondary
body compartments that equilibrate only slowly with the
plasma.
When the infusion or dosing stops, the drug initially cleared
from plasma then net diffusion from the secondary
compartments begins, and this slow equilibration produce a
prolongation of the half-life of the drug, referred to as the
terminal half-life
18. Examples of drugs with marked differences in terminal t1/2 versus
steady-state t1/2 are gentamicin and indomethacin.
Gentamicin has a t1/2 of 2–3 h following a single administration,
but a terminal t1/2 of 53 h because drug accumulates in spaces
such as kidney parenchyma (where this accumulation can result
in toxicity).
Biliary cycling probably is responsible for the 120-h terminal
value for indomethacin (compared to the steady-state value of
2.4 h).
19. THE TIME COURSE OF DRUG ACCUMULATION AND
ELIMINATION.
The “rule of thumb” that four half-lives must elapse after starting a
drug-dosing regimen before full effects will be seen is based on the
approach of the accumulation curve to over 90% of the final
steady-state concentration
21. The duration of action of single intravenous doses of
anesthetic/hypnotic drugs is short for all.
after prolonged infusions, drug half-lives and durations of
action depend on a complex interaction between the
rate of redistribution of the drug, the amount of drug
accumulated in fat, and the drug’s metabolic rate.
This phenomenon has been termed the context sensitive
half-time; that is, the t1/2 of a drug can be estimated
only if one knows the context—the total dose and over
what time period it has been given.
half-times of some drugs such as etomidate, propofol,
and ketamine increase only modestly with prolonged
infusions; others (e.g., diazepam and thiopental) increase
dramatically.
22. ACCUMULATION
Whenever drug doses are repeated, the drug will accumulate in
the body until dosing stops. This is because it takes an infinite
time (in theory) to eliminate all of a given dose. In practical
terms, this means that if the dosing interval is shorter than four
half-lives, accumulation will be detectable
23. TIME COURSE OF DRUG EFFECT
a) IMMEDIATE EFFECT-
ACE inhibitor, such as enalapril . After an oral dose of 20 mg, the
peak plasma concentration at 2.5 hours is about 64 ng/mL. The
half-life that explains ACE inhibition is about 4 hours. Enalapril is
usually given once a day.
24. B) DELAYED EFFECTS-
warfarin works as an anticoagulant by inhibiting vitamin K epoxide
reductase (VKOR) in the liver THUS decrease in the concentration of the
prothrombin complex of clotting factors.
But the already formed complex has a long half-life (about 14 hours),
and it is this half-life that determines how long it takes for the
concentration of clotting factors to reach a new steady state and for a
drug effect to reflect the average warfarin plasma concentration.
C) CUMULATIVE EFFECTS-
Aminoglycosides
25. C) CUMULATIVE EFFECTS-
The renal toxicity of aminoglycoside antibiotics (eg, gentamicin) is
greater when administered as a constant infusion than with
intermittent dosing.
It is the accumulation of aminoglycoside in the renal cortex that is
thought to cause renal damage. Even though both dosing schemes
produce the same average steady-state concentration, the intermittent
dosing scheme produces much higher peak concentrations, which
saturate an uptake mechanism into the cortex; thus, total
aminoglycoside accumulation is less.
26. VOLUME OF DISTRIBUTION
• V = Amount of drug in body/C
• The volume here refers to the fluid volume that would be required
to contain all of the drug in the body.
• It is an imaginary volume.
• V exceeds known volume of any and all body compartments.
• E.g.. - value of V for the highly lipophilic antimalarial chloroquine is
15,000 L
27.
28. Drugs highly bound to plasma proteins that have a relatively small
volume of distribution like oral anticoagulants, sulfonylureas, certain
NSAIDs and antiepileptic drugs are particularly liable to displacement
interactions
29. CLEARANCE
• CLEARANCE of a drug is its rate of elimination
by all routes normalized to the concentration
of drug C in some biological fluid
• With first-order kinetics, clearance CL will vary
with the concentration of drug (C),
30. Clearance of drug by several organs is additive-
EXAMPLES :
Antibiotic cephalexin-90% elimination is by renal
clearance
Beta antagonist propranolol – by liver
Tacrolimus- extra hepatic metabolism
31. HEPATIC CLEARANCE
Metabolism or excretion of drug into bile
Drugs cleared by liver- diltiazem , imipramine, Lidocaine,
morphine, and propranolol.
Drugs that are poorly extracted by the liver include warfarin,
diazepam, phenytoin, theophylline, tolbutamide, and
chlorpropamide
RENAL CLEARANCE
32. Probenecid & Penicillin interaction-- Inhibition of tubular secretion →
prolongation of antibiotic Ampicillin action; Desirable interaction
utilized for single dose therapy.
33. LOADING DOSE
Vss= volume of distribution
Consider -treatment of arrhythmias with lidocaine. t1/2 =1–2 h.
Arrhythmias encountered after myocardial infarction may be life
threatening, and one can not wait for 4 half lives to achieve the
therapeutic concentrations of lidocaine. Hence loading dose of
lidocaine in the coronary care unit is standard.
34. DISADVANTAGES
First, sensitive individual exposed abruptly to a toxic
concentration.
Loading doses large & often given parentally and rapidly.
ALTERNATIVES AVAILABLE-
o divide the loading dose into a number of smaller fractional doses
that will be administered over a period of time.
o can be administered as a continuous intravenous infusion over a
period of time using computerized infusion pumps.
35. MAINTENANCE DOSE
• To maintain the chosen steady-state or target concentration, the
rate of drug administration is adjusted such that the rate of input
equals the rate of loss.
• It is mainly dependent on CL.
36. EXAMPLE-
Oral digoxin to be used as maintenance dose to gradually
“digitalize” a 63-year-old, 84-kg patient with CHF.
TC (Css) = 0.7–0.9 ng/mL ,
therapeutic range- 0.5- to 1.0ng/mL range.
CLcr =56 mL/min/84 kg
digoxin’s clearance =0.92 mL/min/kg
For 84 kg patient, digoxin’s clearance =4.6 L/min
F = 0.7
target Cp =0.75 ng/mL
Dosing rate(MD) = Target Cp · CL/F = 119 μg/d (Oral dose
available=0.125mg)
Css=0.79 ng/ml
T1/2 = 3.1 days
Loading dose= 639 µg
37. • So, we would use a loading dose of 0.625 mg in divided doses
to avoid toxicity,
• initial 0.25-mg oral dose followed by a 0.25-mg dose 6–8 h
later, with careful monitoring of the patient, and the final
0.125-mg dose given another 6–8 h later
38. STEADY STATE --
When rate of administration becomes equal to rate of
elimination, plasma concentration stabilizes. This is called steady
state.
1. Time to reach steady state depends on t½. It takes
approximately 5 half lives.
2. Steady stateplasma concentration achieved depends on dose
rate.
40. NON – LINEAR PHARMACOKINETICS
• Usually caused by saturation of protein binding, hepatic metabolism
, or active renal transport of the drug.
Saturable Elimination
In the case of saturable elimination, the Michaelis-Menten equation
usually describes the nonlinearity.
Km= Michelis constant--- reflect the capacity of enzyme system
(mass/vol)
Vm= max elimination rate (mass/time)
41. • Consider an extreme case of a 70kg adult to whom the
phenytoin is administered
Css = 15 mg/L, Km = 1 mg/L, νm = 5.9 mg/kg/day, or 413
mg/day/70kg. dosing rate = 387 mg/day t1/2= 6-24hrs
(In this case, the dosing rate is just below the elimination capacity.)
• If Dosing rate vary upward by 10% (to 387 + 38.7 or ~426
mg/day), the dosing rate would exceed the elimination
capacity and the Cp of phenytoin would begin a slow climb to
toxic levels.
• Conversely, if the dosing rate vary downward by 10% (to
387-38.7 or ~348 mg/day), the Css achieved would be 5.4
mg/L, a drastic reduction to a level below the therapeutic
range
42. • Now, Consider Km= 8 mg/L, Css =15mg/L , νm = 413 mg/day,
dosing rate = 269 mg/day.
• An increase in dosing rate by 10% (to 296 mg/day) would not
saturate the elimination capacity ( Css = 20.2 mg/L) .
• A 10% downward variance to 242 mg/day produce a Css =
11.3 mg/L, a much less drastic decrease than above and still in
the therapeutic range.
• Therefore, for patients in whom the target concentration for
phenytoin is ≥10 times the Km, alternating between
inefficacious therapy and toxicity is common, careful
monitoring is essential.
• Other agents exhibiting saturated metabolism include aspirin,
fluoxetine, verapamil, and ethanol.
43. ENTEROHEPATIC CIRCULATION
• Leflunomide is a (DMARD) .
Leflunomide…first pass metabolism…..trileflunomide…prevent
activation of T LYMPHOCYTES….undergo enterohepatic
circulation…leading to prolonged half life of 15-18 days
TRADITIONAL approach-aminoglycoside dosing inadults involves the administration OF weight based dose divided 2-3 times daily in patients with normal renal function.
Dose reduced or dosing interval extended in patients with decreased renal function
Extended interval aminoglycoside therapy also known as once daily aminoglycoside dosing utilizes a higher weight based dose administered at an extended interval (every 24 hr for normal renal function and longer for those with renal dysfunction)
Protective effect is thought to be associated with extended interval aminoglycoside administration---becoz of dimished aminoglycoside accumulation in the renal cortex
Concept of saturable transport of gentamicin in rat models explain how at higher doses more of the drug is excreated without undergoing tubular reaborption and therefore without accumulating in and injuring the tubular cells.
Higher peaks for shorter period and prolonged period of very low exposure may allow for more efficient handling and exceation.
After oral administration, a drug may be incompletely absorbed
This process actively pumps drug out of gut wall cells back into the gut lumen. Inhibition of P-glycoprotein and gut wall metabolism, eg, by grapefruit juice, may be associated with substantially increased drug absorption.
Following absorption across the gut wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation.
The effect of first-pass hepatic elimination on bioavailability is expressed as the extraction ratio (ER):
BIOAVAILBILITY LESS THAN 40%
the higher the concentration, the greater the rate of bacterial killing.
Linezolid- 100% (iv)
Solid line: Plasma concentrations reflecting drug accumulation during a constant-rate infusion of a drug. Fifty percent of the steady-state concentration is reached after one half-life, 75% after two half-lives, and over 90% after four half-lives. Dashed line: Plasma concentrations reflecting drug elimination after a constant-rate infusion of a drug had reached steady state. Fifty percent of the drug is lost after one half-life, 75% after two half-lives, etc.
This graph shows Time course (hours) of ACE inhibitor concentrations and effects. This explains why a drug with a short half-life can be given once a day and
still maintain its effect throughout the day
The blue line shows the plasma enalapril concentrations in nanograms per milliliter after a single oral dose. The red line indicates the percentage inhibition of its target, ACE
Inhibition of VKOR decreases the synthesis of these clotting factors,
This volume does not necessarily refer to an identifiable physiological volume but rather to
, whereas the volume of total-body water is about 42 L in a 70-kg male.
AMT OF DRUG/ CONC OF DRUG IN BLOOD OR PLASMA
These drugs bypassing hepatic sites of elimination (eg, in hepatic cirrhosis with portosystemic shunting) result in substantial increases in drug bioavailbility
As noted, repeated administration of a drug more frequently than its complete elimination will result in accumulation of the drug to or around a steady-state level (see Figure 2–7). When a constant dosage is given, reaching a steady-state drug level (the desired therapeutic concentration) will take four to five elimination half-times. This period can be too long when treatment demands a more immediate therapeutic response
Now steady state would reach in after 4-5 half lives .
3. Variation between peak and trough concentration at steady state depends on dosing interval. However, average steady state plasma concentration remains same irrespective of dosing interval provided dose rate remains same
where the dosing rate is the dose per time interval and is dose/T, F is the fractional bioavailability, and CL is clearance. Note that substitution of infusion rate for [F ⋅ dose/T] provides the concentration maintained at steady state during continuous intravenous infusion (F = 1 with intravenous administration
All active processes are undoubtedly saturable, but they will appear to be linear if values of drug concentrations encountered in practice are much less than Km for that process . When drug concentrations exceeds Km, nonlinear kinetics are observed
In a 70 kg subject
Factoring in all the variables, predicting and controlling dosage so precisely (<10% error) can be difficult.
in the lining of the gut and hepatocytes to the active compound teriflunomide.
Teriflunomide inhibits dihydrooroatase dehydrogenase, thereby preventing the activation of T lymphocytes. Teriflunomide undergoes significant entero hepatic circulation, leading to a prolonged half-life of approximately 15 to 18 days. When serious hepatic or pulmonary complications are suspected, interruption of this cycling with administration of either oral cholestyramine or activated charcoal will rapidly reduce the serum concentrations of teriflunomide.