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  1. experiment record attendance in class 10% 10% 80% examination I wish you all a very blessed Ramadan Enjoy summer holiday! Enjoy summer holiday! (100%) ( 80%) (10%) (10%) examination result attendance and respondence in class experiment record Final score + + = sign in and experiment record select question sign in class

  2. Pharmacology Pharmacology 1. General Principles 2. Peripheral Nervous Drugs 3. Central Nervous Drugs 4. Cardiovascular and Blood Drugs 5. Splanchnic Drugs 6. Endocrine Drugs 7. Chemotherapeutic Drugs (7 sections )

  3. PART 1 GENERAL PRINCIPLES OF PHARMACOLOGY 1. Introduction of Pharmacology 2. Pharmacodynamics 3. Pharmacokinetics 4. Impact factors Yuan Bing-Xiang (袁秉祥) Department of Pharmacology,Medical School, Xi’an Jiaotong University, Tel: 82657724, Email: ybx@mail.xjtu.edu.cn

  4. PHARMACOLOGIC PRINCIPLES CHAPTER 1 Introduction of Pharmacology

  5. Pharmacology GENERAL PRINCIPLES Pharmacodynamics, PD organisms drugs Impact factors Pharmacology can be defined asthe science or course studying interaction between drugs and organisms (bodies) . Pharmacokinetics, PK

  6. drugs drugs Bodies bodies Pharmacology GENERAL PRINCIPLES human being animals bacteria virus fungus pathogenic microorganisms pathogens parasites tumor cells Peripheral Nervous drugs Central Nervous drugs Cardiovascular and Blood rugs Splanchnic drugs Endocrine drugs drugs act to systems drugs act to pathogens Chemotherapeutic drugs ―

  7. Pharmacology GENERAL PRINCIPLES Drugsarethe substances or compounds administered beneficially altering biochemical and physiological states of the body, applied to prevent, treat or diagnose diseases. Poisons are the substances or compounds inducing the undesirable or toxic reactions on body in smaller dose. no strict limit between drugs and poisons

  8. E KD Dose Pharmacology GENERAL PRINCIPLES Pharmacodynamics(drug acts on body) Drug action effects Secondary Inducing effects in the organ Primary acting on the target cell signal transduction (mechanism of effect) drug-protein(receptors; ion channels; enzymes; transporter… therapeutic effects adverse reaction dose-effect curves →PD parameters (KD, EMAX…)

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

  10. PHARMACOLOGIC PRINCIPLES CHAPTER 2Pharmacodynamics(drug Acts on body)

  11. Pharmacodynamics Basic Action Ⅰ. Basic actions or effects of drug 1. Excitation and Inhibition Theintrinsic functions of body are altered by drugs: 1) Excitation or stimulation:The functions are increased by drugs. (contraction, heart rate↑, BP↑, unstable or restlessness …) 2) Inhibition:The functions are decreased by drugs. (relaxation, heart rate↓, Bp↓, tranquilize and sedation …)

  12. Pharmacodynamics Basic Action 2. Local effects and general effects 1) Local effects are the effects of drug induced in administered locale before absorption. 2) General effects(absorptive effects, systemic effects) are the effects of circulated drugs induced in general system (injection or after absorption).

  13. Pharmacodynamics Basic Action For example: magnesium sulfate (MgSO4) Orally →80% no absorption → Local effects →intestinal osmotic pressure↑( volume ↑) → catharsis (purgation) → elimination of toxin cholagogic effect (for cholecystitis) Orally →20% absorption Injection →to circulation →generaleffects→ vasodilation →BP↓ ------------------- central inhibition → anticonvulsion treatment of eclampsia Gravida With hypertension and convulsion

  14. Pharmacodynamics Basic Action 3. Specificity: Singularity of actions on target Selectivity: Singularity of effects in organ or sys. drug-target→specificity → selectivity • Drug-subtype of receptor →higher specificity →higherselectivity┌→tight clinic indication └→less side reaction • Drug-type of receptor (all subtypes of receptor) →lower specificity →lower selectivity ┌→wide clinic indication └→ more side reaction

  15. α1A α1B α1D α1 α α2 (presynaptic) Pharmacodynamics Basic Action For example α-adrenoceptors blocker α1↓→vasodilation→BP↓↘(reflect) α2↓→NA release↑→β↑→heart ↑ ↑ α1 α2-blocker (phentolamine) cardiopalmus, arhythmia α1D α1B↓→vasodilation→BP↓ α1A↓→smooth muscle of prostate↓ α1-blocker (prazosin) α1A-blocker (tamsulosin) → α1A↓→smooth muscle of prostate↓ (relieving of uroschesis of prostatic hyperplasia)

  16. Pharmacodynamics Basic Action 4.therapeutic effectsare the effects that are consistent with therapeutic purposes. (in normal dose and in almost patients) Etiological treatment eliminating causes of disease. (for instance, chemotherapy…) Symptomatic treatment remission of symptoms or suffering of disease. (for instance, analgesia, sedation…)

  17. Pharmacodynamics Basic Action 5.adverse drug reactions,ADRs* ADRs can be defined as the drug effects that are not consistent with therapeutic purposes and induce harms to patients. 10-20% of patients in hospital suffer ADR. --WHO-- 106,000 patients in USA lost life from ADRs every year. First killer:cardiac disease, 743,000 Second killer:cancer, 529,000 Third killer:stroke, 150,000 Fourth killer:ADRs, 106,000 Fifth killer:drug abuse, 80,000 The cause of death Vietnam war (10 years):56,000 AIDS≈road accident, 41,000

  18. Pharmacodynamics ADR 1) Side reaction The light reactions withoutrelationship to therapeutic purpose of a drug administrated in normal dose are induced in almost patients, because of low selectivityof the drug. The lowerselectivity, the wider clinic indication and more side reaction. therapeutic purpose side reactions therapeutic effects A: smooth muscle ↓→spasmolysis……intestinal tympanites (stomachache) B: gland ↓→bronchus secrete↓………dry mouth (preanesthetic medication) C: mydriasis→intraocular tension↑……eyeground check Atropine →M↓

  19. Pharmacodynamics ADR Pharmacological effects are too strong and induce organic and functional injury in some patientswhen high dose and long drug administration. 2) Toxic effect aminoglycosides→injury of auditory nerve→deaf -dumbness

  20. Effects remain whendrug blood concentration is reduced below threshold concentration. Pharmacodynamics ADR 3) After effects C TC T Transient duration Phenobarbital ┌drowsiness in early morning └ nightmare in next night Cortine (long administration)→stop→ persistent hypofunction of adrenal cortex

  21. Pharmacodynamics ADR 4) Dependence The physical and psychic dependent states are induced following repeated drug administration, displaying compulsive, continual hunt to drugs (or narcotics). First drug administration Pleasant feeling Repeated drug administration Diamorphine(heroin) discontinue Abstinence syndromes (5~7days) Dependence discontinue Mentaldesire (lifetime) Grave social problem Ice,benzedrinum Vicious cycle Addict: lost of personality, responsibility and shame→crime rate↑

  22. Pharmacodynamics ADR Physical dependence: Addiction induced following repeated administration. The vital activity depends on drugs, the serious abstinence syndromes could be induced after discontinue. Psychic dependence: Psychic desire andpleasant feeling are induced following the repeat. The mental state depends on drugs without abstinence syndromesafter discontiune. Ice,benzedrinum

  23. success drug food happy amuse sports sex failure go blind misery ache pain disappointed hometown family drug miss lover good friend Pharmacodynamics ADR abstinence syndrome starvation thirsty

  24. Pharmacodynamics ADR 5) allergic reaction • The exceptional immunoreaction is produced by a drug as an antigen or semi-antigenin minority of allergicpatients without relationship to pharmacological action and dose (in any dose). • penicillin→allergic shock (Ⅰtype) (immediate allergy) • qunine→hemolytic anemia (Ⅱtype) • (cytolytic type hypersensitivity) • sulfa→drug fever or eruption (Ⅳ type) (delayed allergy) • Ⅲ type(immune complex type)is seldom seen

  25. Pharmacodynamics ADR 6) idiosyncraticreaction The exceptional reaction produced by a drug in minority of gene defect patients without relationship to pharmacological action. sulfonamides vitamin K primaquine broad beans Absence of G-6-PD Hemolytic Anemia & jaundice Oxidizing glucose-6-phosphate Dehydrogenase, G-6-PD

  26. Pharmacodynamics Dose-response relationship Ⅱ、Dose-response relationship The effects of a hypotensive drug on BP (millimeters of mercury) graded response: measured effects indicated in biologic unit (mmHg) quantal response: all-or-none effectindicated infrequency (population) or rate. (mean±standard deviation)

  27. Pharmacodynamics Dose-response relationship 1. Graded response (Quantitative response) Graded response is the quantitative relationship between dose and measured effects indicated in biologic unit and continuous scale. BP(mmHg), RBC(1012/L), cholesterol (mmol/L) ……

  28. Emax E Log D (C) Kd D (C) Threshold dose maximal dose minimal Toxic dose ↓↓↙ ├─┴┴─────┴─╂─┴───┴── D (C) ↑ common dose minimal lethal dose Graded response Pharmacodynamics Dose-effect curve of graded response Project 纵坐标Y-axis 横坐标X-axis E hyperbola Symmetry S curve

  29. ① Threshold dose:Minimum effective dose ② Efficacy (Emax):Maximum effect or the limit of the drug response. ③ Potency:Dose inducing given effect, or a dose (KD) inducing 50% Emax. Dose or KD↑→ Potency↓ ④ Slope: Slope at 50% Emax (slope↑→range of common dose↓→less safety) ⑤Maximal dose: The limit of dose permitted in pharmacopeia for some drugs. ⑥ Common dose:The effective dose in most of patients. maximal dose>common dose>threshold dose Graded response Pharmacodynamics

  30. E B A C log D (C) Graded response Pharmacodynamics potency: efficacy: threshold dose: slope: A>B>C B>C >A C>B>A A=B>C

  31. Quantal response Pharmacodynamics 2. Quantal response (Qualitative Response) The qualitative relationship between dose and all-or-none effectis indicated by the frequency (population) or rate. (e.g., the death rate or populationamong mice in a pre-clinical study or effective rateor populationamong the patients in a clinical trial.

  32. E cumulative distribution D Quantal response Pharmacodynamics F % • distribution curve→Individual variation (sensitivity). • cumulative curve→qualitative parameters (LD50, ED50) percentage F 50 40 30 20 10 0 % 100- 80- 60- 40- 20- 0 cumulative distribution supersensitivity tolerance lgD

  33. F (%) F (%) P D logD logD straight line symmetry S curves long tail S curves F F D logD Quantal response Pharmacodynamics 1) Cumulative curve (probit) 2) Distribution curve normal distribution skew distribution

  34. Quantal response Pharmacodynamics toxicity ordeath E(%) effective 100% 95% 50% cardiac glycoside ED95 5% dose ED50 ED95 LD5 LD50 Therapeutic index(TI) = LD50/ED50 Safety index (SI)=LD5/ED95

  35. ED50(Median effective dose):the dose required to produce specified effect in 50% individuals (experimental animals).LD50 (Median lethal dose):The dose required to produce death in 50% of animals. Quantal response Pharmacodynamics Therapeutic index (TI) and safety index (SI)are used for judging drug's safety. TI=LD50/ED50 SI=LD5 /ED95

  36. Drug receptor Pharmacodynamics Ⅲ.Drug receptor 1. Drug-receptor concept Receptor The receptive substances (proteins) of cell (membrane) specifically interact with their ligands (corresponding drugs, transmitter, hormone, autacoids) and initiate the chain of signal transduction and biochemical and physiological changes. ligands: corresponding drugs, transmitters, hormones or autacoidsbinding to their special receptor.

  37. Pharmacodynamics Drug receptor 2. Characters of drug-receptor interaction 1) Saturation: Because of finitude of number of receptor molecules or unlimited drug molecules, the drug-receptor binding is limited. →Emax 2) Specific binding (lock-key) 3) Reversiblebinding 4) High potency (affinity) →low KD (dose) 5) Competitive binding 2 drugs binding to same receptor. a antagonist is competitive with an endogenous agonist

  38. Drug-receptor binding Theory Pharmacodynamics 3. Drug-receptor binding theory 1) Receptor occupancy theory: It is assumed that drug responses could be initiated from the receptor occupied by a drug. The greater response observed, the more receptor occupied.

  39. E Emax (α) KD [D] Drug-receptor binding Theory Pharmacodynamics In general, the effect (E) is a equation of the quantity of the drug-receptor complex [DR], and can be expressed as: KD α [D]+[R] [DR]┄→E E = α[DR] Once all receptors are saturated, the maximum effect (Emax) is achieved. If the 50% of receptors were occupied, 50% Emax is produced. KD (dissociation constant) is drug concentration occupying 50% of receptors. E Log[D]

  40. k1 [D]+[R] [DR] K2 Drug-receptor binding Theory Pharmacodynamics 2) Rate theory: The effect associates not only with binding rate (k1), but also with dissociation rate (k2). k2↑→the effect↑→Emax↑ 3) two state theory agonist partial agonist Negative effect active receptor inactive receptor Positive effect antagonist Inverse agonist

  41. Parameter of drug-receptor Pharmacodynamics 4. Parameter of drug-receptor interaction 1) Affinity (or potency) is the ability of a drug binding to its receptor. Affinity is the concentration of drug required to occupy 50% its receptor or elicits 50% Emax. The greater concentration (KD) required, the lower affinity of a drug.

  42. Emax Emax E E 50% 50% KD pD2 -log [D] [D] Parameter of drug-receptor Pharmacodynamics pD2is the parameter of agonist's affinity and the negative logarithm of molarity (mol) concentration (KD) of a drug binding 50% receptor or inducing 50% Emax. pD2 = -log KD The more KD, the low agonist's affinity; The more pD2, the more agonist's affinity.

  43. Parameter of drug-receptor Pharmacodynamics 2) Intrinsic activity (or efficacy) The ability of a drug inducing effect after binding to receptor. The faster dissociation rate (k2), the greater Emax, andthe greater intrinsic activity.

  44. Classification of drugs Pharmacodynamics 3) Classification of drugs binding to receptor agonist partial agonist antagonist Inverse agonist

  45. E α [D]+[R] [DR]┄→E hyperbola [D] [D] E straight line [D] Drug-receptor binding Theory Pharmacodynamics 4)straight formula of hyperbola KD Clark equation dose-effect formula Scott method Y = b x + a Scott straight formula b =1/Emax,a=KD/Emax, Emax=1/b,KD=a/b,

  46. pD2 Pharmacodynamics Y = b X + a Emax [D]/E E b: slope 50% a: intercept KD [D] [D] linear regression:Emax=1/b=80.5mm, KD=a/b=3.055×10-8 mol/L,pD2=-logKD =7.515.

  47. Competitive antagonism Pharmacodynamics 4. Competitive antagonism 1) agonist-antagonist: In the presence of a fixed concentration of antagonist, dose-effect curves of the agonist would be shifted to the right : a. Threshold concentrations are increased; b. Curves is shifted to the right in equal slope; c. Emax is unchanged. (parallel)

  48. Competitive antagonism Pharmacodynamics pA2 is the parameter of Blocker (antagonist) affinity, or the negative logarithm of molarity (mol) of a Blocker in double KDof Agonist. fictitious E AA+BFA+B1 A+B2 A+B3 fictitious Emax KDF / KD0 = 2 pA2=-log[BR] 50% [D] (agonist) KD0 KDF KD1 KD2 KD3

  49. log(R-1) b= -1 pA2 -log[B] . . . . [A]+[R] = [RA]─→E [B]+[R] = [RB] [RT]=[R]+[RA]+[RB] Y =b X + a log(R-1)=-(-log[B])+(-logKB) R= KDx / KD0(R1, R2, R3…) linear regression: x= -log[B], y= log(R-1) according to the concept of pA2, R=2, y=0, pA2 (-logKB)= -log[B]

  50. energy transducer pre-amplifier