1. Clinical Pharmacokinetics Department of Pharmacology

2. Two important aspects of Pharmacology:  Pharmacodynamics – study the effects of drug upon the body ( what drug does to the body ).  Pharmacokinetics – study the effects of body systems and organs upon absorption, distribution, metabolism and elimination of the administered drug ( what the body does to the drug ).

3. In other words, Pharmaco = Medicine Kinetics = Movement or Motion Pharmacokinetics is the study of movement of drug throughout the body after it is administered. How does the drug molecule moves from the entrance to the exit and what are the sequence of events since it has been administered?

4. Dose of drug administered absorption Drug concentration in systemic circulation Elimination ( drug is metabolized and/or excreted) distributionDrug in tissue

5. Pharmacokinetic principles 1.Transfer of drug molecule across the cell membrane Non-polar substances  readily cross the lipid layer of cell membrane  can cross by passive diffusion i.e., free passage of a drug molecule down its concentration gradient.  Unionized, non-polar molecules are soluble in non- polar solvents, such as lipid in cell membrane.  The rate of transfer is related to the nature of membrane, e.g., blood brain barrier

6. Polar compounds contain chemical bonds in which the shared electrons are unevenly shared between adjacent electrons,i.e., The electrons are polarized (e.g.,water molecule)

8. Types of movement of drug molecule across the cell membrane : 1)Passive diffusion 2)Facilitated diffusion 3)Active transport

9. Passive diffusion Is the free passage of a drug down its concentration gradient.  Only unionized molecules  drugs with small molecular weight  Not bound to the plasma protein can transfer in this way.

10. The net transfer is governed by Fick equation: δQ/δt = K. A. C /D δQ/δt = rate of diffusion K = diffusion constant A = surface area of the membrane D = thickness of the membrane C = concentration gradient across the membrane

11. Facilitated diffusion is carrier mediated but not energy dependent movement of the drug molecules across the cell membrane. Carrier molecule is usually transmembrane protein which binds the drug molecules and releases them on the other side of the membrane. e.g., glucose transport

12. Active transport is a carrier-mediated process that require energy to move drug molecules against an electro-chemical or concentration gradient. It is more important in elimination or secretory processes than for absorption of the drug.

13. Routes of administration (1) Topical drugs Example :  Skin lotions and ointment  Eye, ear, nasal drops  Lozenges  Aerosol inhalers in asthma Advantage : do not need to cross many barriers like oral drugs

14. (2) Enteral or oral Means the drug reaches its target via the gut 1.The least predictable route but commonly used. 2.Drug must cross many barriers before it reaches its target. 3. Physicochemical properties of the drug 4. Local factors like pH of gastric/ intestinal juice 5. Ion trapping 6. 1 st pass metabolic effect of the liver 7. Protein binding

15. Ion trapping Strong acids and bases in solution dissociate almost completely into their conjugate base and hydrogen ions. HCL H+ + CL- Most drugs are weak acids or weak bases which do not completely dissociate like that of the strong acids or bases. Generally there are both ionized and unionized form of the drug at the same time but the amount depending upon the pH of the body compartment.

16. (Ion trapping contd.) So the acidic drug will be concentrated in the high pH compartment e.g.,(1) aspirin in the small intestine (2) urinary acidification accelerates the excretion of weak base like pethidine Ion trapping usually occurs in 1.The stomach 2.The kidney 3.Across the placenta

17. Buccal or sublingual Can avoid portal circulation so that no 1 st pass metabolism by the liver Onset of action of the drug is also faster e.g., nitroglycerine in angina Per rectal as suppositories Drug can reach the systemic circulation directly without passing the liver (because of the anatomy )

18. Parentral Administration means the drug reaches the systemic circulation without passing through the gut. e.g., insulin – is the protein that will be destroyed by the gastric acid and proteolytic enzymes secreted from the small intestine So it is usually given subcutaneously. Advantages of parentral route : 1.Faster onset of action 2.More reliable than oral route

19. Other parentral routes are: 1.intravenous The most direct route to reach systemic circulation bypassing all the absorption barriers The fastest onset of action Useful to administer the drugs that are strongly irritating 2. Subcutaneous, intramuscular 3. Epidural 4. Intrathecal 5. transdermal

20. Bioavailability of a drug Not all the administered drugs are not absorbed and enter the systemic circulation if it is administered other than intravenously. (which is 100% available) It is measured by administering the same dose of drug on separate occasions like orally and IV and measuring plasma concentration.

21. Distribution of drugs Involves studying how the drug is transported throughout the various body compartments after being absorbed from the site of entry.

22. Factors determining the distribution: 1. Blood flow at the site of administration of drug 2. Blood volume 3. Physical properties of the drug like a)Lipid solubility b)Plasma protein binding c)Tissue affinity e,g,. Thiopentone – fat Tetracycline – bones and teeth

23. Blood flow to the respective tissue e.g., 1.Intramuscular morphine – during the hypovolemic state and normovolemic state 2.Intravenous drugs like thiopentone Onset of action during one arm - brain circulation time and short duration of action because of redistribution.

24. Lipid solubility of the drugs – Are more completely distributed to body tissues than water soluble compounds. e.g., diazepam Vs quartenary ammonium compounds Intravascular / interstitial /intracellular fluid

25. Tissue affinity e.g., Diazepam and thiopentone – fat Lead -- bone Mepacrine – in the liver, concentration in the liver may be as high as 200 times that of plasma as it binds to nucleic acid inside the liver cell

26. Plasma protein binding  Most drugs are bound to plasma protein after absorption into the circulation.  Acidic drugs have a high affinity for albumin.  Basic drugs have a high affinity for lipoproteins and α1- acid glycoprotein.  The degree of protein binding is expressed as the % of the drug that is bound to plasma protein.

27. Competition of the binding site among drugs – Important cause of drug interaction e.g., aspirin and diazepam Half-life of a drug Is the time taken for the plasma concentration of that drug to fall to half of its original value.

28. Drug metabolism Sites of metabolism – liver, kidney, lungs, GI tract Some drugs taken orally are extensively metabolized in the small intestine or the liver and it is known as first- pass metabolism. Phase 1 and phase 2 metabolic reactions occur in liver cells (hepatocytes).

29. Phase 1 metabolic reactions : Are oxidation, reduction, hydrolysis. They introduce a functional group to drug molecule such as –OH or – NH2 thereby :  increasing the polarity of the drug molecule and  providing sites for phase 2 reaction.

30. Oxidation Most common type of reaction Located on the smooth ER Microsomal P450 enzyme Mostly, oxidative reaction causes inactivation of a drug Prodrugs Codeine  demethylated  morphine

31. Reduction Involves microsomal enzymes Less common than oxidation Hydrolysis Can also occur in other tissues than in liver,e.g., Plasma pseudocholinesterase Phase 2 reaction  Conjugation Attachment of a large chemical group to the functional group of the drug.

32. Drug molecule is more hydrophyllic after conjugation. Conjugate is almost invariably inactive except – Morphine-6-glucuronide

33. Excretion of the drugs  Rate of excretion depends on concentration of drug in blood and tissue.  Primary site – kidney  Filtration through the glomerulus and secretion in the renal tubules e.g.,10% of penicillin G is filtered and 90% is secreted in the tubules.  Secretion mechanisms are less active in infants And old age group

34. Ion trapping in the renal tubules  Weak acids like aspirin is excreted faster in the alkaline medium  So also diazepam,weakly basic drug in slightly acidic medium Can be applied in enhancing excretion of drugs in critical condition.

35. Pharmacokinetics – 1.Absorption of drugs from the site of entry 2.Transport of the drug molecules across various membrane and compartments of the body (Distribution). 4. Metabolism of the drug molecules inside the body 5.Elimination (Excretion) of the administered drug from the body 6.Physicochemical properties of the drug Clinical pharmacokinetics – linkage of the above knowledge with the management (Therapeutics) of the organ and system disorders of the patients. http://www.pharmpk.com http://www.icp.org.nz/ interactivehttp://www.icp.org.nz/ interactive clinical pharmacology http://pharmacology2000.com

36. Dr.Khin Saw Yu Room 25, Level 1, Medical Faculty Building ksyu.dr@gmail.com Ph : 017 647 2505 ext: 1331