1. PHT 415 BASIC PHARMACOKINETICS Course Instructor:Prf. Dr. Hnaa elsaghir Assistant lecturers, Doaa elshora and eman elfakih Text: Hand book of basic pharmacokinetics, and lab notes. Grading: Quizes (5 pts), Midterm (15 pts), Final (20 pts),), Practical (20 pts) for attendance 5 pts Lectures:, Wednesday 10-12 ( Office Hours: Sunday and Wednesday 8 -10 Email: helsagir@ksu.edu.sa

2. PK and PD PK is the study of what the body does to a drug PD is the study of what a drug does to the body

3. DRUG THERAPY Duration of Drug Therapy: Single Dose: such as to relieve a headache For the Rest of the Patient’s Life: such as in chronic diseases (epilepsy, diabetes)

4. DOSAGE REGIMEN The manner in which a drug is taken is called a Dosage Regimen Duration of Drug Therapy and Dosage regimen will depend on the therapeutic objective. Objectives of taking a drug are : Cure, Mitigation, Prevention

5. SUCCESSFUL DRUG THERAPY By optimally balancing the desirable and undesirable effects  Accurate diagnosis is made  Drug of choice  Knowledge of clinical state of patient  Understanding the pharmaco-therapeutic management of the disease  Answer the questions How much? How often? and How long?

6. Answers to Questions?????? How much? Recognizes that the magnitude of the therapeutic and toxic responses is a function of the dose given. How often? Recognizes the importance of time, in that the magnitude of the effect eventually declines with time following a single dose of drug. How long? Recognizes that a cost (in terms of side effects, toxicity, economics) is incurred with continuous drug administration.

7. In the Past Questions were answered by trial and error, i.e. the dose, interval between doses, and route of administration were selected and the patient’s progress was followed. This empirical approach established many dosage regimens but left many questions unanswered!!!!!! This empirical approach did not contribute toward establishing a safe, effective dosage regimen of another drug, i.e. did not help us understand how drugs work?

8. Event that follows drug administration Plasma conc of theophylline after an oral dose of 600-mg

9. Application of Pharmacokinetics Rarely is a drug placed at its site of action, most drugs are given orally and yet they act in the brain, heart, or elsewhere!!!! Which means a drug has to move from the site of administration to the site of action. Therefore to administer drugs optimally, knowledge is needed not only of the mechanisms of drug absorption, distribution, and elimination but also the kinetics of these processes, that is PK

10. Following Drug Administration 2 phases can be distinguished Pharmacokinetic Phase: in which the adjustable elements of dose, dosage form, frequency, and route of administration are related to drug level-time relationships in the body. Pharmacodynamic Phase: in which the conc of drug at the site of action(s) is related to the magnitude of the effect(s) produced.

11. Aimes of PK and PD Knowing the PK and PD of drugs will aid in designing a dosage regimen to achieve the therapeutic objective. OPTIMIZE PATIENT DRUG THERAPY BY MONITORING PK&PD RESPONSES

12. Advantages over the Empirical Approach 1- Distinction can be made between PK and PD causes of an unusual drug response. 2- Information gained about the PK of one drug can help in anticipating the PK of another drug. 3- Understanding the PK of a drug often explains the manner of its use. 4- Knowing the PK of a drug aids the clinician in determining the optimal dosage regimen for a patient and in predicting what may happen when a dosage regimen is changed.

13. An Approach to the Design of a Dosage Regimen

14. Where to Measure Concentration? Rarely can the concentration of the drug at the site of action be measured directly; instead the concentration is measured at an alternative and more accessible site, the plasma.

15. What is then an optimal dosage regimen? It is the one that maintains the plasma concentration of a drug within the therapeutic window and then maintaining this concentration by replacing the amount of drug lost with time.

16. Initial and Maintenance Dose Two different regimens A and B, B=2A Time Plasma conc Regimen A Regimen B Therapeutic Window

17. Therapeutic Window (TW)  The size and frequency of the maintenance dose depends on the width of the therapeutic window and the speed of drug elimination.  When the window is narrow and the drug is eliminated rapidly, small doses must be given often to achieve therapeutic success.  Both cyclosporine and digoxin have a narrow TW, but because cyclosporine is eliminated much more rapidly than digoxin, it has to be given…?…?…?…?…? ( more frequently or less frequently)

18. Oxytocin  Oxytocin is an extreme example, it also has a narrow TW, but it is eliminated within minutes. The only means to ensure a therapeutic conc is to infuse it at a precise and constant rate directly into the blood (i.v. infusion). Oxytocin can not be given orally because it is destroyed in the GIT.  Morphine can not also be given orally because it is extensively metabolized in the liver.

19. PROBLEM!!! Variability in Clinical Response  Sources of variability: patient’s age, weight, degree of obesity, type and severity of disease, the patient’s genetic makeup, others drugs concurrently administered and environmental factors.  Result: A standard dosage regimen of a drug may prove therapeutic in some patients, ineffective in others and toxic is still others.

20. Dosage Regimen Adjustment The need is greatest for drugs with narrow TW:  Digoxin used to treat cardiac disorders.  Phenytoin used to prevent epileptic convulsions  Theophylline used to diminish chronic airway resistance in athmatics.  Cyclosporine used as immunosuppressant in organ transplantation.  Warfarin used as oral anti-coagulant.

21. Drug-Drug Interaction Interactions that result in a change in PK of a drug could be due to:  Stimulation of drug metabolizing enzymes therefore increasing drug loss.  Inhibition of drug metabolizing enzymes therefore slowing drug elimination and increasing its concentration in the blood.  Interference with drug absorption.

22. SOLUTION A pragmatic approach to this problem would be to adjust the dosage until the desired objective is achieved. Control on a dosage basis alone, however, has proved difficult. Control is achieved more readily and accurately when plasma drug concentration data and the PK of the drug are known.

23. DRUG IS A VERY COMPLEX SYSTEM

24. WHAT WE WILL DO IN THIS CLASS?  Although the details of drug kinetics are complicated, it is fortunate that we can often approximate drug kinetic processes using “ SIMPLE MATHEMATICAL MODELS ”.  The use of PK equations, rather than the derivation of the equations will be taught in this class.