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1. examination result attendance and respond in class experiment record Final score + + = (100%) ( 80%) (10%) (10%) sign in and experiment record sign in and respond in class select question

2. Pharmacology Pharmacology 1. General Principles of Pharmacology (Yuan) 2. Peripheral Nervous Pharmacology (Cao) 3. Central Nervous Pharmacology (Liu) 4. Cardiovascular Pharmacology (Zang) 5. Splanchnic and Blood Pharmacology (Ma) 6. Endocrine Pharmacology (Zhao) 7. Chemotherapeutic Pharmacology (Lin) (7 sections )

3. PART 1 GENERAL PRINCIPLES OF PHARMACOLOGY Dr. Yuan Bing-Xiang Department of Pharmacology, Medical School, Xi’an Jiaotong University, Tel: 82657724, Email: ybx@mail.xjtu.edu.cn

4. Pharmacology GENERAL PRINCIPLES CHAPTER 1 Introduction of Pharmacology 1.Pharmacology can be defined as the science or course studying the interaction between drugs and bodies (living systems) including human being, animals and pathogens including pathogenic microorganisms (bacteria, virus, fungus…) , parasites and tumor cells… ⅠCONCEPTION

5. Pharmacology GENERAL PRINCIPLES Drugs are the chemicals beneficially altering biochemical and physiological states of body, applied to prevent, treat or diagnose diseases. Peripheral Nervous Pharmacology Central Nervous Pharmacology Cardiovascular Pharmacology Splanchnic Pharmacology Blood Pharmacology Endocrine Pharmacology Systems of bodies Drugs Act on Bodies Pathogens- Chemotherapeutic Pharmacology Antibacterial drugs; Antifungal drugs; Antivirus drugs; Antiparasitics Anticancer drugs

6. Pharmacology GENERAL PRINCIPLES 2. Three aspects of pharmacology Pharmacodynamics, PD drug body Pharmacokinetics, PK Impact factors

7. E D Pharmacology GENERAL PRINCIPLES 1) Pharmacodynamics(drug acts on body) Drugs actions effects Secondary Inducing effects in the organ or system Primary acting on the target effects * therapeutic effects * adverse reaction * dose-effect curves └→PD parameters (KD, EMAX…) action（mechanism of effect） * Specific actions:drug-receptors; drug-ion channels; drug-enzymes; * Unspecific actions:drugs influence physical and chemical condition around cells (pH, osmosis …)

8. Pharmacology GENERAL PRINCIPLES 2) Pharmacokinetics(body acts on drug) • absorption • distribution • excretion • biotransformation Undergoing of drug in body drug blood Concentration-Time curves └→PD parametersfrom C-T curves: t1/2, Ka, Ke, F, Vd… transportation C-T curves C T

9. Pharmacology GENERAL PRINCIPLES Drug Body 3) Impact factors Drug physico-chemical property dosage form batch number physiolo- patho- psycho- geno- living habit …… PK drug body Medication dose and route time and interval course of treat association PD

10. PHARMACOLOGIC PRINCIPLES CHAPTER 2 pharmacokinetics （ bodyActs on drug ）

11. Undergoing of drugs pharmacokinetics (sites of action) binding free (accumulation) free binding distribution (plasma) Free drugs binding drugs metabolites (renal)excretion absorption distribution drugs po sc im out of body distribution Metabolism (liver) transport transformation

12. O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O O＜ ＞O lipids Lipid diffusion a pore b Filtration carrier Facilitated transport c carrier d Active transport ATP ion channels Ion transport e permeation across membranes pharmacokinetics Ⅰ.Drug permeation across membranes 1. Membrane The membranes with pore are composed of lipids and proteins in a ratio of 70:1. The liquid-form double-deck of membranes is formed from lipid molecules; The special proteins inserted into the double-deck are receptors, enzymes, ion channels, carriers…… p a s s i v e

13. permeation across membranes pharmacokinetics 2. Passive transport across membranes (down hill) low high A drug molecule moves from a side of membrane relatively high concentration to another side of low concentration without requiring energy, until an equilibrium has been achieved on both sides of the membrane. ….. ….. ….. ….. ….. .. ….. ….. ….. ….. ….. ….. ….. ….. ….. ….. ….. ….. … ….. ….. … equilibrium Lipid diffusion; Filtration; Facilitated transport

14. k1 k2 permeation across membranes pharmacokinetics 1) Lipid diffusion ( Simple diffusion) The most important mechanism of drug transport Drug movement across membranes is driven by a concentration gradient after solution in the lipids of membranes. Nonionized form Ionized form pKa is pH when Ionized rate is 50% pH (pKa) ┐ more lipid soluble less lipid soluble easy permeation hard permeation ←less polar molecules polar molecules→ ion trapping

15. Lipid diffusion pharmacokinetics HA (weak acids)B (weak bases) k1 k1 HAH+＋A-B＋H+ BH+ k2k2 k1 [H+][A-]k1[H+][B] Ka＝──＝─────Ka＝──＝ ──── k2 [HA]k2 [BH+] [A][B] pKa＝pH－log ───pKa＝pH－log ─── [HA][BH+] [A-][B] pH－pKa＝log ───pH－pKa＝log ─── [HA][BH+]  [A-][B] ───＝10pH－pKa───＝10pH－pKa [HA][BH+]

16. Lipid diffusion pharmacokinetics [A-][B] ───＝10pH-pKa───＝10pH-pKa [HA][BH+] weak acidsweak bases ★ pH↑↓→[A-]↑↓→★ pH↑↓→[BH+]↓↑→ Degree of ionization↑↓degree of ionization↓↑ →lipid solution↓↑→lipid solution↑↓ →permeation↓↑→permeation↑↓ Neither weak acids or weak bases are dissolved in same acid-base solution, the lipid solution↑, permeation↑; They are dissolved in opposite solution, the lipid solution↓, permeation↓.

17. Lipid diffusion pharmacokinetics For example, Bicarbonate (NaHCO3) is very effective for treatment of acute toxication from weak acid drugs (like barbiturates). why？

18. Lipid diffusion pharmacokinetics ① Alkalization of gastric juice →ionization↑ → permeation↓ →absorption ↓ ②Alkalization of blood plasma → permeation↓→across blood-brain barrier↓ pH ↑ > pH [A-]↑> [A-] blood gastric juice drug drug Gastrolavage of NaHCO3 pH↑> pH [A-]↑> [A-] Cerebrospinal fluid blood drug drug Intravenous drop of NaHCO3

19. Lipid diffusion pharmacokinetics ③ Alkalization of humor (extra-cellular fluid) →ionization↑ →permeation↓ ④Alkalization of urine→ionization↑ →permeation↓→ drugtubular reabsorption↓→ excretion↑ cell pH < pH↑ [A-] < [A-] ↑ drug drug blood urinepH ↑ drug[A-]↑

20. filtration pharmacokinetics 2) Filtration (Aqueous diffusion): Small molecules (<100-200 dalton) pass through aqueous pores without requiring energy driven by concentration gradient. *Water-soluble drugs with low molecular weight (Inc. some polar molecules) can diffuse through the aqueouspores of membrane. * A almost free drugs can be filtrated across large pores of capillaries from or to plasma. (like drug distribution, glomerular filtration and absorption following im or sc injection)

21. facilitated transport pharmacokinetics The movement of a drug across the membrane could be facilitated by its special carrier and concentration gradient. In the carrier-mediated transport, the drug is released to another side of the membrane, and the carrier then returns to original side and state. 3) Facilitated transport (Carrier-mediated transport)

22. facilitated transport pharmacokinetics The properties of facilitated transport are as follows: a. saturable process; b. special binding to the carrier c. cannot move against a concentration gradient without energy.

23. Active transport pharmacokinetics 2. Active transport (up hill) A drug molecule moves from a side of membrane relatively low to one of high concentration with requiring energy and special carrier. a. saturable process b. special binding to the carrier c.transport against concentration gradient with consuming energy.

24. Active transport pharmacokinetics For example: penicillin and probenecid Blood→tubule Blood→tubule After glomerular filtration, penicillin undergoes tubular secretion (an active transport), having a very short half-life (t1/2=20~30 min); probenecid having the same active mechanism can competitively inhibit the tubular secretion of penicillin. The t1/2 & effects of penicillin are prolonged. Glomerular filtration (passive) tubular Secretion (active) H2O absorption penicillin Tubule high osmosis probenecid Excretion of penicillin competitively inhibit

25. The transport of drugs from administration locale to bloodstream. Absorption pharmacokinetics Ⅱ.Absorption

26. Absorption pharmacokinetics 1. The routes of absorption 1) im or sc Absorption of drugs in solution through filtration from subcutaneous or intramuscular injection sites to blood is limited mainly by blood perfusion rate. im > sc (adrenalin), why? a. blood perfusion rate (im > sc) b. adrenalin ┌α↑→vesseel↑(subcutaniea) → perfusion↓ └β↑→vesseel↓(skeleton muscle) →perfusion ↑

27. Absorption pharmacokinetics 2) po (per oral) What about weak acids? Drugs are absorbed in gastrointestinal tract through lipid diffusion. The absorption takes place mainly in the upper small intestine. With oral administration of drugs, extensive gastrointestinal and hepatic metabolism may occur before the drugs are absorbed into systemic circulation and reach its site of action. This process is defined as the first-pass elimination. gastric mucosa small intestinemucosa

28. Nitroglycerin given sublingually bypasses liver and enters the superior vena cava and, in turn, perfuses the coronary circulation, therefore is immediately effective to relive patients with angina pectoris. Absorption pharmacokinetics 3) Sublingual or rectal administration Absorption properties of the administration a. incomplete and irregular absorption; b. without or less First-pass elimination. For example

29. Absorption pharmacokinetics 2. Bioavailability (F) F would be the extent and rate of drug absorption following extravascular administration (like orally). F could be the absolute rate of a drug, used for indicating the absorptionamount (AUC)compared with that of intravenous administration, or relative rate of a pharmaceutical product, used for indicating the absorptionamount (AUC)compared with that of standard preparation in the same administration (same route and dose).

30. Absorption pharmacokinetics F (absolute) A (drug amounts in body) ＝───────────── ×100% D (administered dose) AUC (area under extravascular curve) ＝────────────────── ×100% AUC (area under intravenous curve)  AUC (test pharmaceutics) ＝──────────────×100% AUC (standard preparation) F (absolute) F (relative) C C iv standard im test po T T

31. Distribution pharmacokinetics pharmacokinetics Ⅲ.Distribution The transport of drugs from bloodstream to various organs and tissues, or to different physical compartments of body.

32. Distribution pharmacokinetics 1. Compartments According to perfusion rate of drugs to various organs and tissues, body can abstractly be divided into one, two or more parts (one compartment model, two compartments model, three…).

33. Ka drug Ke Distribution 1) One compartment model Drugs within the model are assumed to be distributed just to the organs or tissues with high blood flow and rapid uniform (brain, heart, liver, kidneys, lungs, active muscle, …). The C-T curve have one phase: elimination. The distribution is too rapid to be found in the C-T curve.. T 。 。

34. C Co 1/2 1/4 T t1/2t1/2 Ke 。 。 Distribution drug Ke logC logC0 T

35. Distribution pharmacokinetics 2) Two compartments model Drugs are not only distributed to the organs or tissues with rich blood perfusion (central compartment), but also to that with low blood flow (peripheral compartment: fat, skin, bone, resting muscle). The C-T curve have two phases: a. The distribution rate is known as the alpha half-life, t1/2α. b. The elimination rate is known as the beta half-life, t1/2β.

36. Distribution pharmacokinetics central peripheral K1 K2 Ka Ke C distribution α α β β T 。 。 elimination Ct＝CAe-kαt＋CBe-kβt

37. Distribution pharmacokinetics 2. Apparent volume of distribution (Vd) Vd is that drug in a plasma concentration should be solved in apparent volume of body fluid including the general circulation and the tissues. Vd is used for measuring distribution range, relating the amount in the body (A) to the concentration of drug (C ) in blood. total amount of drug in body, A(mg) F.D Vd(L)＝──────────────────── ＝── concentration of drug in plasma, C(mg/L) C

38. Distribution pharmacokinetics 1) Barrier: blood-brain barrier, placental barrier)a. less ionized drug & small particle→permeableb. inflammation→permeable 3. Factors influencing distribution 2) active transport→tissues concentration↑ active transport iodium thyroid 3) regional blood flow subcutaneous < intramuscular

39. free drug＋plasma binding drug (active form) (inactive storage form) small particle of druglarge particle of drug→rapid filtration → no filtration →rapid distribution → → no distribution →┌ action ┌no action└elimination└noelimination (metabolism & excretion) Distribution pharmacokinetics 4) Binding rate to plasma：binding ratio to plasma protein at the therapeutic dosage. moving balance

40. Characters of binding to plasma a. saturability Dose↑→binding rate ↓→free drug ↑ Malnutrition liver function↓ Renal function↓ free drug↑ Plasma- albumin↓ binding rate↓ b. Unspecific competition binding rate↓ free drug↑ competive binding combination warfarin A 98% (2%) ┅ ┅ ┅ ┅ ┅→96% (4%) →effect (toxicity)↑↑→bleeding 2%↓ B 92% (8%) ┅ ┅ ┅ ┅ ┅→90% (10%) →effect (toxicity) ↑ phenylbutazone

41. Biotransformation pharmacokinetics Ⅳ.Biotransformation mainly in the liver hepatic microsomal mixed function oxidase system 1. two phases Phase 1 Prodrugs activation oxidation reduction hydrolysis drug activity↓ Inactivation toxicity↓ binding rate↓ more polar Phase 2 conjugation excretion↑ with glycuronic acid

42. Biotransformation pharmacokinetics 2. Factors affecting drug metabolism 1) drugs activity of enzyme↑ enzyme inducer →tolerance (dosage↑) Chlorpromazine phenobarbital enzyme inhibiter activity of enzyme↓ →hypersensitivity (dosage↓) phenylbutazone chloromycetin

43. Biotransformation pharmacokinetics 2) Pharmacogenetics hereditary variation in handling of drugs For example: * Deficiency in the activity of acetylase results peripheral neuritis from isoniazid; * Absence of glucose 6-phosphate dehydrogenase (G6PD) results hemolytic anemia from: sulfonamides vitamin K (antihemorrhagic) primaquine (antimalarial agent) phenacetin (antipyretic analgesic) broad beans.

44. Glucose Oxidizing agent ATP ADP G-6-P GSSG H2O2 ↑↑ NADP G6PD↓ GSH↓ NADPH↓ H2O↓ 6-PG Acid Hemolytic anemia Biotransformation pharmacokinetics sulfonamides vitamin K primaquine anminopyrine broad beans Absence of G6PD +

45. Biotransformation pharmacokinetics 3) Physiological and pathological condition Age 完善flaw elder toxicity of drugs deficiency of drug elimination liver function renal function newborn Less dosage For example: newborn gray syndrome chloromycetin Circulatory failure elder toxicity↑ numerous drugs

46. Biotransformation pharmacokinetics Illness enzyme production↓ drug metabolism↓ hepatic disease Plasma production↓ Plasma binding↓ →free drug↑ Renal dysfunction Plasma loss↑ hypersensitivity Should dosage↓

47. pharmacokinetics Ⅴ.Excretion of drugs Drugs and their metabolites in circulation are excreted by kidneys, bile, milk, sweat and lungs.

48. excretion pharmacokinetics • Renal excretion tubular secretion • tubular reabsorption Plasma (Drug & metabolites) Penicillin? glomerular filtration Bicarbonate? Probenecid? tubular water reabsorption hyperosmotic in renal tubules active diffusion lipid-solubility tubular reabsorption tubular secretion Drug excretion ↓ Drug excretion ↑

49. excretion pharmacokinetics 2. Excretion in bile bile active transport Plasma (drug) liver Hepato-enteric circulation intestine portal vein PO • prolongation of half-life • high concentration in bile Excretion Beneficial for antiinflammatory of cholecystitis Exclusion

50. excretion pharmacokinetics If the mather is the addict, whai would be resulted? 3. Excretion in milk lactiferous Ducts milk (low pH) weak alkaline drugs (morphine, atropine) nursing mother concentrations in breast milk↑ effects↑ reabsorption  reactions in infant dissolved in the milk↑ fat-solubledrugs (sodium pentothal)