PRESENTED BY:G.V.GOWTHAMI256213886010

UNDER THE GUIDENCE:Dr.SATYABRATA BHANJAM.Pharm,Ph.D

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.

CAUSES OF NON-LINEARITY

Saturation of enzymes in process of drug

ADME

Pathologic alteration in drug ADME

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

PROCESS SATURATED

Absorption

Distribution

Metabolism

Excretion

PROCESS USUALLY SATURATED

Metabolism

Active tubular secretion

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.

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

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

Renal Excretion Cause Drug

Active secretion Mezlocillin, p-aminohippuric acid

Tubular reabsorption Riboflavin, ascorbic acid, cephapirin

Change in urine pH Salicylic acid, dextroamphetamine

Biliary Excretion Cause Drug

Biliary secretion Iodipamide, sulfobromophthalein sodium

Enterohepatic recycling Cimetidine, isotretinoin

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

• When Km = C

• -dc/dt=Vmax/2

• When Km>>C

• -dc/dt=Vmax.c/Km

• When Km<<C

• -dc/dt=Vmax

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

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.

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

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

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

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

Km and Vmax (Steady state)....contd

Graphical Method

Plot between DR and DR/Css yield straight line with slope: –Km, &

y‐intercept: Vmax

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.

SCOPE OF CHRONOPHARMACOKINETICS STUDIES:

Daily variation in pharmacokinetics.

Narrow therapeutic range.

Circadian phase dependent diseases.

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

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

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.

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

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.

• 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.

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

DRUGS THAT UNDERGO CHRONOKINETICS:

Antibiotics - Amino glycosides

Amikacin

General anaesthetics - Benzodiazepines

Halothane

NSAIDS - Indomethacin

Ketoprofen

Anticancer Drugs – 5-Flurouracil

Cisplatin

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

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

THANK YOU