Chapter 2 Pharmacokinetics

1. Chapter 2 Pharmacokinetics Department of pharmacology M. Y. Liu

2. Pharmacokinetics • Transmembrane transport • Processes of drug in the body • Basic concepts of pharmacokinetics

3. Part 1Transmembrane transport of drugs

4. LOCUS OF ACTION “RECEPTORS” TISSUE RESERVOIRS Bound Free Free Bound ABSORPTION EXCRETION Free Drug SYSTEMIC CIRCULATION Bound Drug BIOTRANSFORMATION

5. The structure of cell membrane？ How to transport it？

6. Transmembrane transport • Procedure of permeating through the various barriers Such as: various cell membrane the walls of the capillary the walls of the intestine blood-brain barrier placental barrier • Ability that the drug permeates through various membranes • Two types of transmembrane transport

7. Passive transport (down hill movement) • According to the concentration gradient of the permeating drug, the direction of diffusion was from higher concentration to lower concentration. Small molecules: membrane pores Large molecules: lipid diffusion • Not requiring energy • Having no saturation • Having no carriers • Not resisting competitive inhibition

8. Affecting factors : the size of molecule lipid solubility polarity degree of ionization the PH of the environment such as: fluid of body fluid in cell blood, urine

9. Generally speaking The drugs which are Unionized, low polarity and higher lipid solubility are easy to permeate membrane. The drugs which are ionized, high polarity and lower lipid solubility are difficult to permeate membrane.

10. Effect of the environment PH on drug transportation • Most of drugs are weak acids or weak bases. • The ionization of drugs may markedly reduce their ability to permeate membranes. • The degree of ionization of drugs is determined by the surrounding pH and their pKa.

11. For acids： Handerson-Hasselbalch Equation The pKa is the pH at which the drug is 50% ionized.

12. For bases： pH和pKa算术差的变化，就会导致解离与非解离药物浓度差的指数变化，因此pH的微小变化将显著的影响药物的解离和转运。

13. When the pH is different from the intracellular and extracellular membrane and the passive transport of weak acid/base drugs are in the balance, the drug concentration of intracellular and extracellular membrane are compared as below： eg. For weak acid drug whose pKa is equal to 5.4 unionized ionized total plasma pH=7.4 [HA] 1 [A-] 100 101 Gastric juice pH=1.4 [A-] 0.0001 1.0001 [HA] 1 When drug concentration of the intracellular and extracellular membrane are balanced, the total concentration isn’t equal; while the concentration of unionized drug are same .

14. pKa= 3.4

15. When the pH of the intracellular and extracellular are not equal, the total concentration of the drug in the two sides of membrane are given by the equation as below: For acid: For base: Q：What kind of drugs can be excreted to the latex which pH is tend to acidity?

16. The other forms of passive transport • Filtration: • water solubility • small molecular • Facilitated transport： • （in fact it is a kind of passive transport） • Transport from high concentration to low concentration • Not requiring energy • Requiring carriers • eg the absorption of Vitamin B12 from GI tract • The transportation of Glucose to the intra cellular membrane of red blood cells.

17. Active transport • permeating membrane from lower concentration to higher concentration. • Requiring energy • Requiring carriers • Be Saturable • H aving competitive inhibition Such as : peptide, amino acid

18. The conditions which need active transport • Na+-K+-ATPase • The transmitters were concentrated in the vesicle. • The excretion and secretion of renal tract Active transport can concentrate drugs in certain organ or tissue (the iodine pump )

19. Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport

20. Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport

21. Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport

22. Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport

23. Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport

24. Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport Sugars, amino acids, vitamins

25. Diffusion Bulk Flow Most drugs are absorbed and distributed by diffusion. Endocytosis Ion Pair Facilitated Transport Active Transport

26. 药物代谢动力学 The processes of drugs（ADME）

27. Pharmacokinetics • movement of drugs in the body • what the body does to the drug “ADME” Absorption Distribution Metabolism Excretion

28. The disposition to drugs by living systems can be divided into four related duration: • 吸收（Absorption） • 分布（Distribution） • 代谢（Metabolism） • 排泄（Excretion） ADME 系统 Metabolism + Excretion = Elimination Absorption + Distribution + Excretion = Transportation Metabolism= Transformation

29. Absorption is the transfer of a drug from its site of administration to the blood stream. • Characters： • Most of drugs are absorbed by the way of passive transport. • Intravenous administration has no absorption. • The absorptive speed affects the time of appearing effect. • The absorptive extent affects the intensity of action.

30. Factors affecting absorption: • drug properties: lipid solubility、Molecular Weight,polarity,etc. • Routes of Administration(important): • Enteral; parenteral • Other: • Blood flow to the absorption site; • Total surface area available for absorption • Contact time at the absorption surface • Affinity with special tissue

31. Enteral administration • Oral • Sublingual • Rectal

32. Oral administration First Pass Elimination (首关消除,首关代谢，首关效应） Before the drug reaches the systemic circulation, the drug can be metabolized in the liver or intestine. As a Result, the concentration of drug in the systemic circulation will be reduced.

33. FIRST PASS ELIMINATION Metabolism in the liver Buccal cavity Stomach Vena cava Intestine Portal vein Rectum

34. Sublingual Administration (硝酸甘油) • Rectal Administration(水合氯醛)

35. Buccal or rectal administration are ways to by-pass the liver and avoid “first pass” Buccal Buccal cavity Stomach Vena cava Intestine Rectum Rectal

36. Parenteral • Inhalation • 注射给药 静脉内 intravenous (IV) 肌内 intramuscular (IM) 皮下 subcutaneous (SC) • other：intranasal(经鼻给药), intraventricular(心室内给药), Transdermal（经皮给药）

37. Intravenous administration has no absorption phase. According to the rate of absorption： Inhalation→Sublingual→Rectal→intramuscular→subcutaneous→oral→transdermal

38. Route IV SL Transdermal Onset immediate 1-3 min 40-60 min Example: 硝酸甘油（Nitroglycerin）

39. Distribution • Drug distribution is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of the tissues.

40. 药物的体内过程 分布 • Factors affecting drug distribution： • Blood flow • Capillary permeability • Capillary structure • Drug structue • Binding of drugs to proteins • Most drugs found in the vascular compartment are bound reversibly with one or more of the macromolecules in plasma. • Many acidic drugs bind principally to albumin，while basic drugs frequently bind to other plasma proteins such as lipoproteins and α1-acid glycoprotein (α1-AGP)。

41. 药物与血浆蛋白结合（Protein binding） • Characters： • Drugs ordinarily bind to protein in a reversible fashion and in dynamic equilibrium. Those bound to protein are called bound drug, and those unbound to protein are called free drug. • Only the unbound drugs can diffuse through the capillary wall, produce its systemic effects, be metabolized and be excreted. • Bound drugs lose pharmacological activity momentarily，and act as a drug reservoir. • Having saturation and competitive inhibition. • Patient with low plasma protein (uraemia, hepatic disease) or old people with low albumin in plasma ,their percentage of protein binding may be changed, amount of unbound drug increases, effect precipitate.

42. interaction When the two kind of drugs that possess the higher protein binding rate are associated for clinical using, the drug interaction may occur. If the amount of unbound drug displaced from plasma protein increases, the unbound drug concentration and effect also increases, and perhaps, produce toxicity. Such as: phenylbutazone (保泰松) Dicoumarin （双香豆素）

43. How to salvage the toxic effect of barbital drugs? • With NaHCO3 • Alkalizing plasma to force the weak acidic drug (barbital drug) from brain to plasma. • Alkalizing urine to increase the excretion of the drugs

44. Biological barriersbound/ ionized drug can not pass through the BBB! • 血脑屏障 Blood Brain Barrier • 毛细血管内皮细胞联结紧密，管壁外被星型 • 胶质细胞包围。 • 炎症可改变通透性

45. 14C-Promazine 14C-PromazineQuaternary Analog +

46. 生物膜屏障（membrane barriers) • 胎盘屏障 Placental barriers having no barrier effect on drug transport, but the pregnant women should especially pay attention. • Blood-eye barriers

47. Metabolism： most often eliminated by biotransformation Drugs are and /or excretion into the urine or bile. • The liver is the major site for drug metabolism. • Two phase of metabolism: Phase I：oxidation(氧化) 、hydrolysis(水解反应) 、reduction(还原) Phase Ⅱ：conjugation(结合反应)： glucuronic acid（葡萄糖醛酸） sulfuric acid glycin （甘氨酸） • Changes after metabolism: • The pharmacological activity of the drugs is decreased or lost, while certain drugs must metabolize to exert the reaction.

48. Variety of drug activity after biotransformation: A active drug inactive metabolites B inactive drug active/enhanced activity Such as : P-450 Cyclophosphamide(环磷酰胺) blood tumor aldophosphamide（醛磷酰胺） Phosphamide mustard（磷酸胺氮芥）

49. C active drug active product Phenacetin非那西丁 Acetaminophen (paracetamol) 对乙酰氨基酚（扑热息痛） (prototype drug or parent drug)

50. D no toxic or less toxic drug toxic metabolites Isoniazid(Rimifon) Acetylisoniazid INH 异烟肼 Acetyl INH mutagenicity致突变 teratogenicity致畸变 carcinogenicity致癌 hepatotoxicity肝毒性