Non linear pharmacokinetics
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The document discusses nonlinear pharmacokinetics and chronopharmacokinetics. Nonlinear pharmacokinetics occurs when the body's absorption, distribution, metabolism, or excretion of a drug becomes saturated at higher doses. This can cause the rate of drug elimination to decrease. Examples of processes that can become saturated include drug metabolism and renal excretion. Circadian rhythms can also impact drug pharmacokinetics by influencing absorption, distribution, metabolism, and excretion over 24-hour periods. Accounting for these temporal changes can improve drug therapy for circadian phase-dependent diseases.
Non linear pharmacokinetics
- 1. PRESENTED BY: G.V.GOWTHAMI 256213886010 UNDER THE GUIDENCE: Dr.SATYABRATA BHANJA M.Pharm,Ph.D
- 2. 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.
- 3. CAUSES OF NON-LINEARITY Saturation of enzymes in process of drug ADME Pathologic alteration in drug ADME
- 4. 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
- 5. PROCESS SATURATED Absorption Distribution Metabolism Excretion
- 6. PROCESS USUALLY SATURATED Metabolism Active tubular secretion
- 7. 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.
- 8. Distribution CAUSE 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
- 9. 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
- 10. Renal Excretion Cause Drug Active secretion Mezlocillin, p-aminohippuric acid Tubular reabsorption Riboflavin, ascorbic acid, cephapirin Change in urine pH Salicylic acid, dextroamphetamine
- 11. Biliary Excretion Cause Drug Biliary secretion Iodipamide, sulfobromophthalein sodium Enterohepatic recycling Cimetidine, isotretinoin
- 12. 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
- 13. • When Km = C • -dc/dt=Vmax/2 • When Km>>C • -dc/dt=Vmax.c/Km • When Km<<C • -dc/dt=Vmax
- 15. Estimation of Km and Vmax Integration of Michaelis Menten Equation log C = log Co + (Co –C)–Vmax 2.303Km 2.303Km Semilog 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 –Vmax 2.303Km
- 17. 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.
- 18. 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
- 19. 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
- 20. 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
- 21. 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-DR1 DR1/Css,1-DR2/Css,2
- 25. Km and Vmax (Steady state)....contd Graphical Method Plot between DR and DR/Css yield straight line with slope: –Km, & y‐intercept: Vmax
- 26. 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.
- 27. SCOPE OF CHRONOPHARMACOKINETICS STUDIES: Daily variation in pharmacokinetics. Narrow therapeutic range. Circadian phase dependent diseases.
- 28. 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
- 29. 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
- 31. 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.
- 32. 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
- 33. 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.
- 34. • 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.
- 35. 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
- 36. DRUGS THAT UNDERGO CHRONOKINETICS: Antibiotics - Amino glycosides Amikacin General anaesthetics - Benzodiazepines Halothane NSAIDS - Indomethacin Ketoprofen Anticancer Drugs – 5-Flurouracil Cisplatin
- 37. 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
- 38. 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
- 39. THANK YOU