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# Pharmacokinetics: Lecture One

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The first lecture for Pharmacy students pharmacokinetics class

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### Pharmacokinetics: Lecture One

1. 1. Introduction To PharmacokineticsPharmacokinetics A Mathematical Tool Anas Bahnassi PhD RPh
2. 2. Lecture ObjectivesAfter completing this lecture, the student will be ableto:1. Given patient data of the following types, the student will be able toproperly construct a graph and compute the slope using linearregression: response (R) vs. concentration (C), response (R) vs. time(T), concentration (C) vs. time (T)2. Given any two of the above data sets, the student will be able tocompute the slope of the third by linear regression.3. Give response vs. time and response versus concentration data, thestudent will be able to compute the terminal (elimination) rateconstant and half life of the drug.
3. 3. What is Pharmacokinetics? The mathematical descriptionof drug behavior inside the human body It is the study of factors affecting the absorption, distribution, metabolism and excretion of drug As well as the quantitative description of how these processes affect the time course and intensity of response.
4. 4. What is Pharmacokinetics?This powerful mathematical tool is usedto study the drug’s• Fate in normal and pathophysiological conditions• Distribution / location /penetration• Clearance / organs• Conc vs. response• Bioavailability• It compares dosage forms and different drug brands• It quantitatively evaluate the magnitude of drug interactions• It provides the basics to make clinical predictions
5. 5. What is Biopharmaceutics? How the pharmaceutical formulationvariables affect drug availability and performance (absorption) in vivo The use of these information helps optimizing therapeutic outcomes of drug products
6. 6. Distribution Elimination Metabolites• IV Medication• PO in Circulation• IM• MDI Dosage Regimen Concentration Response Route ofAdministration • Pharmacological • Adverse Effect The Pharmacokinetic Process
7. 7. The Pharmacological Response Drug must get intoThe occupation theory bloodThe intensity of a pharmacological and blood is inresponse (E) is proportional to the contactconcentration of a reversible drug- with receptor. receptor complex where E is the intensity of the pharmacological response, Emax is the = maximum attainable value of , [D] is the molar concentration of free drug at the active complex and KR is the dissociation constant of the drug-receptor complex.
8. 8. m:slope Response vs. Drug E=m.lnX+b Concentration X:dose = C.V V:volume ofEmax distribution
9. 9. The Relationship Between The Administered Dose and The Amount of the Drug in The Body • The Fraction of the drug reaches the systemic circulation is the amount available to elicit pharmacologic effect. • For iv administration, the amount of drug reaches the general circulation is equal to the dose administered. ∞ = 0 = ()0 (AUC)∞0 is the area under curve of plasma drug concentration versus time (AUC) from time zero to time infinity K is the first-order elimination rate constant V (or Vd) is the drug’s volume of distribution. 9
10. 10. Volume of Distribution“The apparent volume into which a given massof drug would need to be diluted in order to givethe observed concentration.” = Basic Pharmacokinetics: S. Jambhekar , Phillip Breen 2009 Anas Bahnassi PhD 2011 10
11. 11. The Relationship Between TheAdministered Dose and The Amount of theDrug in The BodyFor the extravascular route, the amount ofdrug that reaches general circulation is theproduct of the bioavailable fraction (F) andthe dose administered. ∞ . = 0 = ()0 Anas Bahnassi PhD 2011 11
12. 12. Min. Toxic Conc. Min. Effective Conc.Previous equations suggest that we must know or determineall the parameters (i.e. AUC, 0 , K, V, F) for a given drug;therefore, it is important to know the concentration of a drugin blood (plasma or serum) and/or the amount (mass) of drugremoved in urine (excretion data). Anas Bahnassi PhD 2011 12
13. 13. Onset of Action:The time at which the administered drug reaches the therapeutic range and begins to produce effect. Therapeutic Range: The plasma or serum concentration range within which the drug is likely to produce the therapeutic activity or effect Duration of Action: The time span from the beginning of the onset of action up to termination of action Termination of Action: The time at which the drug concentration in plasma falls below the minimum effective concentration Anas Bahnassi PhD 2011 13
14. 14. Amount of Drug in the Urine Anas Bahnassi PhD 2011 14
15. 15. Sites of Drug Administration 1. There is no absorption phase. Intra- 2. There is immediateIntravascular venous onset of action. 3. The entire administered Routes dose is available to Intra- produce pharmacological arterial effects. 4. This route is used more often in life-threatening situations. 5. Adverse reactions are difficult to reverse or control; accuracy in calculations and administration of drug Anas Bahnassi PhD 2011 dose, therefore, are very 15 critical.
16. 16. Sites of Drug Administration Oral Inhalation Intra- mascular Extra- vascular Sub-Rectal cutaneous Trans- Sub- dermal lingual Anas Bahnassi PhD 2011 16
17. 17. Important Features of Extravascular Routes 1. An absorption phase is present.2. The onset of action is determined by factors such as formulation and type of dosage form, route of administration, physicochemical properties of drugs and other physiological variables. 3. The entire administered dose of a drug may not always reach the general circulation (i.e. incomplete absorption). Anas Bahnassi PhD 2011 17
18. 18. Review of the ADME Process • The process by which a drug proceeds fromAbsorption the site of administration to the site of measurement • the process of reversible transfer of drug toDistribution and from the site of measurement • the process of a conversion of one chemicalMetabolism species to another chemical species • The irreversible loss of drug from the site ofElimination measurement. It may occur by metabolism or excretion. Anas Bahnassi PhD 2011 18
19. 19. Excretion DispositionThe irreversible loss of Once a drug is in the systemic,a drug in a chemically it is distributed simultaneouslyunchanged or unaltered to all tissues including the organform. responsible for its elimination. Anas Bahnassi PhD 2011 19
20. 20. Pharmacokinetic ModelsThe change in drug’s concentration after administration can be describedusing certain equations mostly exponential. This suggests that ADMEprocesses follow a first order process and therefore drug transport ismediated through passive diffusion mechanism. This means that there is adirect relationship between the plasma concentration of the drug and theamount eliminated in the urine and the original administered dose. Thisidentifies the term Linear Pharmacokinetics. Anas Bahnassi PhD 2011 20
21. 21. Compartment Concept in PK• It is necessary to describe the pharmacokinetic parameters adequately and accurately.• The selection of the compartment model depends solely on the distribution characteristics of the drug administered.• The corresponding equation depends on the compartment model and the route of administration. Anas Bahnassi PhD 2011 21
22. 22. The model selection process is highly dependent upon the following factors.1. The frequency at which plasma samples are collected. It is highly recommended that plasma samples are collected as early as possible, particularly for first couple of hours, following the administration of the dose of a drug.2. The sensitivity of the procedure employed to analyze drug concentration in plasma samples. (Since inflections of the plasma concentration versus time curve in the low concentration regions may not be detected when using assays with poor sensitivity, the use of a more sensitive analytical procedure will increase the probability of choosing the correct compartment model.)3. The physicochemical properties (e.g. the lipophilicity)of a drug. Basic Pharmacokinetics: S. Jambhekar , Phillip Breen 2009 Anas Bahnassi PhD 2011 22
23. 23. Pharmacokinetic ModelsAnas Bahnassi PhD 2011 23
24. 24. IV Bolus Dose - One CompartmentConsidering the body tobehave as a singlecompartment. In order tosimplify the mathematics itis often possible to assumethat a drug given by rapidintravenous injection, abolus, is rapidly mixed. Thisfigure represents theuniformly mixed drug veryshortly after administration. Niazi, S. 1979 Textbook of Biopharmaceutics and Clinical Pharmacokinetics, Appleton-Century-Crofts, New York, p142 Anas Bahnassi PhD 2011 24
25. 25. IV Bolus Dose - One Compartment = 0 − = − 1 = − (2) E=m.lnX+b − 0 − = (3) E=E0-RtBasic Pharmacokinetics REV. 99.4.25 3-4 1996-1999 Michael C. Makoid Niazi, S. 1979 Textbook of Biopharmaceutics and Clinical Pharmacokinetics, Appleton-Century-Crofts, New York, p142 Anas Bahnassi PhD 2011 25
26. 26. IV Bolus Two Compartment ModelOften a one compartment model is not sufficient to represent thepharmacokinetics of a drug. A two compartment model often haswider application. Here we consider the body is a centralcompartment with rapid mixing and a peripheral compartmentwith slower distribution.The central compartmentis uniformly mixed veryshortly after drugadministration, whereasit takes some time for theperipheral compartmentto reach a pseudoequilibrium.Niazi, S. 1979 Textbook of Biopharmaceutics and Clinical Pharmacokinetics, Appleton-Century- Crofts, New York, p175l.;l Anas Bahnassi PhD 2011 26
27. 27. Semi-log GraphRapid Distribution Slow Distribution Anas Bahnassi PhD 2011 27
28. 28. Absorption and EliminationOne Compartment with Two Compartment with absorption phase Semi-log Graph absorption phase 28 Anas Bahnassi PhD 2011
29. 29. Anas Bahnassi PhD 2011 29
30. 30. A basic model for absorption and Disposition The model is based on mass balance considerations: At any time t, for the 1. The amount (e.g. mg) of extravascular route: unchanged drug and/or F(Dose) = absorbable amount at metabolite(s) can be measured in the absorption site + amount in the urine. body + cumulative amount2. Drug and metabolite(s) in the metabolized + cumulative amount body (blood, plasma or serum) excreted unchanged are measured in concentration units (e.g. μgmL-1). For the intravascular route:3. Direct measurement of drug at Dose = amount in the body + the site of administration is amount metabolized + cumulative impractical; however, it can be amount excreted unchanged: assessed indirectly. Anas Bahnassi PhD 2011 30
31. 31. Characteristics of One Compartment Model 1. Equilibrium between drug concentrations in different tissues or organs is obtained rapidly (virtually instantaneously), following drug input. Therefore, a distinction between distribution and elimination phases is not possible.2. The amount (mass) of drug distributed in different tissues may be different.3. Following equilibrium, changes in drug concentra- tion in blood (which can be sampled) reflect changes in concentration of drug in other tissues (which cannot be sampled). Anas Bahnassi PhD 2011 31
32. 32. Drug Concentration versus TimeFrom a graph such as this we can see the relationship between drug concentration and drug effect. If a drug has to reach an effective concentration at a receptor site this will be reflected as a required blood concentration. Barr, W.H. 1968 Principles of Anas Bahnassi PhD 2011 32biopharmaceutics, Amer. J. Pharm. Ed., 32, 958
33. 33. Drug Product Performance Parameters The figure shows some of the bio- pharmaceutic parameters which can be used to measure drug product performance. Later in the semester we will use the trap- ezoidal methodDittert, L.W. and DiSanto, A.R. 1973 The bioavailability of drug of calculating products, J. Amer. Pharm. Assoc., NS13, 421-432 AUC. Anas Bahnassi PhD 2011 33
34. 34. Rate Processes After administration, the drug is subject to a number ofprocesses (ADME) whose rates control the concentration of drug in the elusive region known as ‘‘site of action.’’These processes affect the onsetof action, as well as the duration and intensity of pharmacological response. Anas Bahnassi PhD 2011 34
35. 35. Zero-order Process Applications of zero- order processes include administration of a drug as an intravenous infusion, formulation and administration of a drug through controlled release dosage forms and administration of drugs through trans-dermal drug delivery systems. Anas Bahnassi PhD 2011 35Rectilinear Paper
36. 36. First-order Process Rectilinear PaperAnas Bahnassi PhD 2011 36
37. 37. First-order Process -dX/dt xX-1 =K, where units are mgh-1 x mg-1  K has unit is: h-1. Rectilinear PaperAnas Bahnassi PhD 2011 37
38. 38. First-order Process Rectilinear PaperAnas Bahnassi PhD 2011 38
39. 39. First-order ProcessRectilinear Paper Semilogarithmic Paper Anas Bahnassi PhD 2011 39
40. 40. Comparison of Zero First order processesTerm Zero order First order-dx/dt = K0 Rate remains KX Rate changes over time constantRate =K0 =Kconstant unit = mgh-1 unit=h-1X X=X0-Kt lnX=lnX0-Kt or logX=logX0-kt/2.303 Anas Bahnassi PhD 2011 40
41. 41. PharmacokineticsAnas Bahnassi PhD RPh abahnassi@gmail.com http://www.linkedin.com/pub/anas-bahnassi/8/707/693 http://bahnassi.coursesites.com attribution – non-commercial – share alike
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