non linear pharmacokinetics
TRANSCRIPT
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PRESENTED BY:G.V.GOWTHAMI256213886010
UNDER THE GUIDENCE:Dr.SATYABRATA BHANJAM.Pharm,Ph.D
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NON-LINEAR PHARMACOKINETICS
It is a Dose Dependent Pharmacokinetics.
Nonlinear pharmacokinetic models imply that some
aspect of the pharmacokinetic behaviour of the drug is
saturable.
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CAUSES OF NON-LINEARITY
Saturation of enzymes in process of drug
ADME
Pathologic alteration in drug ADME
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EXAMPLES
Amino glycoside may cause renal nephrotoxicity,
thereby altering renal drug excretion
Obstruction of the bile duct to the formation of
gallstone will alter biliary drug excretion
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PROCESS SATURATED
Absorption
Distribution
Metabolism
Excretion
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PROCESS USUALLY SATURATED
Metabolism
Active tubular secretion
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GI absorption
CAUSE DRUG
Saturable gastric or GI Decomposition
Penicillin G, Saquinavir
Saturable transport in gut wall Riboflavin, Gebapentin, L-dopa,baclofen
Intestinal Metabolism Salicilamide, Propranolol
Low Solubility but high dose Chlorotiazide, griseofulvin, danazol.
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DistributionCAUSE DRUG
Saturable transport into/ out of tissues
MTX
Saturable plasma protein binding Phenylbutazone, lidocaine, salicylic acid
Cellular uptake Methicillin
Tissue binding IMI
CSF transport Benzylpenicillins
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Metabolism Cause Drug
Saturable metabolism Phenytoin, salicylic acid, theophyllin, valproic acid
Enzymes induction Carbamazepine
Enzymes limitations PCT, alcohol
Altered hepatic blood flow Propranolol, verapamil
Metabolite inhibition Diazepam
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Renal Excretion Cause Drug
Active secretion Mezlocillin, p-aminohippuric acid
Tubular reabsorption Riboflavin, ascorbic acid, cephapirin
Change in urine pH Salicylic acid, dextroamphetamine
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Biliary Excretion Cause Drug
Biliary secretion Iodipamide, sulfobromophthalein sodium
Enterohepatic recycling Cimetidine, isotretinoin
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MICHAELIS MENTEN EQUATION
Nonlinear pharmacokinetics can be best described by Michaelis
Menten Equation.
-dc/dt=Vmax.c/Km+c
Where:
dC/dt : rate of decline in drug conc. with time
Vmax : theoretical maximum rate of process
Km: Michaelis constant
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• When Km = C
• -dc/dt=Vmax/2
• When Km>>C
• -dc/dt=Vmax.c/Km
• When Km<<C
• -dc/dt=Vmax
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Estimation of Km and VmaxIntegration of Michaelis Menten Equation
log C = log Co + (Co –C)–Vmax2.303Km 2.303KmSemilog plot of C vs t yields a curve with terminal linear portion, which on back extrapolation to time zero give y intercept log Co.
log C = log Co –Vmax2.303Km
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Km and Vmax....……....contd.
At low plasma concentration:
(Co –C)/2.303 Km = log Co/Co
So Km can be obtained from this equation while Vmax can be obtained from slope by putting value of Km.
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Estimation of Km and Vmax (steady state)
In case of I.V. infusion a steady state concentration is maintained by a suitable dosing rate (DR).
This DR at steady state equals rate of elimination.
So Michaelis Menten equation can be written: DR = Vmax . Css
Km + Css
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LINEWEAVER-BURKE PLOT/KLOTZ PLOT: Taking reciprocal of equation:
DR=Vmax .Css/Km+Css
1/DR = Km/Vmax.Css + 1/Vmax
A plot of 1/DR Vs 1/Vmax yields a straight line with slope Km/Vmax and y-intercept 1/Vmax
1/DR slope=Km/Vmax
1/Vmax
1/Css
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DIRECT LINEAR PLOT A pair of Css,1 and Css,2
obtained with 2 different dosing rates DR1 and DR2 is plotted.
The points Css,1 and DR1 are joined to form a line and a second line is obtained similarly by joining Css,2 and DR2.
DR
Vmax
DR1
DR2
Css,1 Css,2 Km
Css 0 Km
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THIRD GRAPHICAL METHOD Estimating Km and Vmax involves rearranging the
following eq.
DR=Vmax .Css/Km+Css
Gives DR=Vmax-Km.DR/Css
Km and Vmax can also be calculated numerically by using following equations
DR1=Vmax.Css,1/Km+Css,1 & DR2=Vmax.Css,2/Km+Css,2
By combining above equations
Km=DR2-DR1DR1/Css,1-DR2/Css,2
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Km and Vmax (Steady state)....contd
Graphical Method
Plot between DR and DR/Css yield straight line with slope: –Km, &
y‐intercept: Vmax
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CHRONOPHARMACOKINETICS• CHRONOPHARMACOKINETICS:
It involves the study of temporal changes in drug absorption, distribution, metabolism & excretion with respect to time of administration.
CHRONOBIOLOGY:
Science that studies the biological rhythms.
CHRONOTHERAPEUTICS:
Application of chrono biological principles to the treatment of diseases.
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SCOPE OF CHRONOPHARMACOKINETICS STUDIES:
Daily variation in pharmacokinetics.
Narrow therapeutic range.
Circadian phase dependent diseases.
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BODY RHYTHMS
These are the biological process that show cyclic variation over
time.
TYPES OF BODY RHYTHMS:
1. Carcadian rhythms:
Which lasts for about one day like:
Sleep walking rhythm
The body temperature
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2.Ultradian rhythms:
shorter than a day
Seconds(like heart beat)
Infradial rhythms:
Longer than a day
Monthly rhythm-menstrual cycle
Yearly rhythm-bird migration
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CIRCADIAN DEPENDENCE OF DRUG PHARMACOKINETICS
ABSORPTION:
Is altered by circadian changes in
Gastric emptying time
Gastrointestinal blood flow
Gastric acid secretion & pH
Most liphophilic drugs seems to be absorbed faster when the drug is taken in
the morning compared with the evening.
Eg: absorption of valproic acid larger in the morning than in the evening.
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DISTRIBUTION : Is altered by circadian changes in
Body size & composition
Blood flows in various organs
Drug protein binding
Peak plasma concentration of plasma proteins like albumin occurs early in the afternoon, while troughs are found during the night.
Eg: maximum binding of antineoplastic like cisplatin to plasma proteins is in afternoon & minimum in the morning
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METABOLISM:
Is altered by circadian changes in
Liver enzyme activity
Hepatic blood flow
For drugs with low extraction ratio depends on liver
enzyme activity.
For drugs with high extraction ratio depends on
hepatic blood flow.
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• EXCRETION:
• Is altered by circadian changes in
• Glomerular filtration
Renal blood flow
Urinary pH
Tubular reabsorption
• All lower during the resting period than in activity period.
Eg: Acidic drugs like sodium salicylate excreted quickly after evening
than morning administration.
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FACTORS EFFECTING CIRCADIAN RHYTHMS
• Food
Meal timing
Gastro-intestinal motility
Digestive Secretions
Intestinal blood flow
Light
The timing of exposure to light
The length of exposure
Intensity & wavelength of light
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DRUGS THAT UNDERGO CHRONOKINETICS:
Antibiotics - Amino glycosides
Amikacin
General anaesthetics - Benzodiazepines
Halothane
NSAIDS - Indomethacin
Ketoprofen
Anticancer Drugs – 5-Flurouracil
Cisplatin
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Diseases Circadian Rhythms
Osteoarthritis Symptoms worse in middle (or) later of the day
Rheumatoid Arthritis Most intense on awakening
Peptic Ulcers Symptoms worse in the early (sleep)
Bronchial Asthma Exacerbations more common during sleep
Allergic rhinitis Worse in early a.m/upon arising
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Pharmacokinetics and pharmacodynamics in the elderly
Age related Physiological Alterations
Pharmacodynamics
Cardiovascular Effects
Effects on central nervous system
Electrolytes
Drug-Drug interactions
Drug-disease interactions
Drug-food interactions
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THANK YOU