Chapter 2 Pharmacodynamics What the drug does to the body

1. Chapter 2PharmacodynamicsWhat the drug does to the body

2. Action and Effect of drug Effect: Response resulting from interactions between drugs and molecules in body. It is a result of the drug action. Such as ：Noradrenaline ↓ Blood pressure raise ↓ Vascular smooth muscle contract ↓ Vasoconstriction

3. Action: Initial response of leading to the drug’s observed effects. It is fashion processes which drug brings about the molecules response in organism(body).

4. Such as: interaction between adrenaline and receptor Noradrenaline ↓ α-receptor ↓ vasoconstriction ↓ blood pressure raise ↓ heart rate decrease (Reflex response to blood pressure changes)

5. Analysis of drug effect Basic expression of drug effect • Excitation: increasing or raising of function Adrenaline: blood pressure ↑ • Inhibition: decreasing of function Insulin: blood glucose ↓ Benzodiazepines: Sedative-Hypnotic action • Same drug may produce different effects on various tissues and organs

6. Selectivity Selectivity is relative • High selectivity: high pharmacological activity • Low selectivity: wide pharmacological activity, may be more side reaction Such as Morphine: distribution in kidney, but target organ is CNS Atropine: low selectivity , wide action, more side reaction

7. Specificity Drugs Selectivity Sensitive Range Question: If a drug has high specificity, can we say the drug has good selectivity?

8. Therapeutic effect • 对因治疗（etiological treatment） • 对症治疗（symptomatic treatment） 急则治其标，缓则治其本； 标本兼治，是其道也。

9. 不良反应（Adverse reaction） • Concept：all the reactions that can bring out the uncomfortable or painful reaction, and have no relationship with the aim of administration, are called adverse reaction. • 副作用（side reaction）: is the inherent property of drugs, it appears at the clinical dosage because of the selectivity of the drugs. • 毒性反应（toxic reaction）：When dosage was excessive or drugs are concentrated in certain tissue, there will be harmful responses which are serious and can be avoid.

11. 后遗效应（residual effect，after effect）：when the administration ceased, the concentration of drug in the plasma would decrease below the threshold concentration, but there still would resist some residual pharmacological effect • 停药反应（withdrawal reaction）： when the administration ceased ，the symptoms of original disease would be aggravated ,又称回跃反应（rebound reaction）。 • 变态反应（allergic reaction）：又称过敏反应（hypersensitive reaction）。 characters： • immunoreaction ，半抗原(hapton) • Having no relationship with dosage • Having no relationship with inherent effect • Pharmacological antagonist having no efficacy on it when poisoning

12. 特异质反应(idiocyncrasy)： 特点： 非免疫反应 高敏体质 • 与剂量有关 • 症状与药物固有作用基本一致 • 药理性拮抗药有效

13. Dose-effect relationship(Dose-response relationship)

14. Dose effect relationship • effect of the drug increases or decreases followed by the change of the drug dose or concentration

15. Dose-response (dose-effect) curve

16. According to the properties of effect： • 量反应（graded response） • The effect was changed continuously, could be expressed by concrete number or maximal ratio, eg. Bp，HR • Dose-effect relationship：effect intensity for y-axis, • Dose/concentration for x-axis：rectangle hyperbola • Log Dose/concentration for x-axis ：symmetrical ”s” curve

17. 质反应（quantal response/all-or-none response）：pharmacological effect was not followed by continuous dosage changes, but expressed by quantitative change. • Positive or negative，all or none • Dose-effect relationship： • Frequency for y-axis，dose for x-axis：normal distribution curve • Cumulative positive ratio for y-axis， dose for x-axis ：long tai “s” curve • Cumulative positive ratio for y-axis， logD for x-axis ：symmetrical “s” curve

19. Dose-response (dose-effect) curve Pharmacological effects

20. 最小有效量（minimal effective dose）：the dosage could elicit the minimal effect, also could be called threshold dose • 最大效应（maximal effect，Emax）：也称效能（efficacy） • EC50：the concentration could elicit 50 percentage of maximal effect • 效价强度（potency）：the relative concentration or dose could elicit equivalent effect (50% Emax), smaller the value is, more intensive the potency is。 • 斜率（slope）：variation of drug。

21. Drug efficacy, Emax • The ability of a drug to elicit a maximal response • Also called intrinsic activity of a drug (receptor theory)

22. Graded Dose-Response Slope A Slope B

23. Drug potency • A measure of the amount of drug required to obtain a particular response % of animal population tested 50 10 mg 20 mg

24. Dose-response curves % of population tested

28. ED50: Median effective dose • ED50 (median effective dose): • The dose of a drug that produces a specified, desired effect in 50% of the animal population tested

29. LD50: Median lethal dose • LD50 (median lethal dose): • The dose of a drug that produces death in 50% of the animal population tested

30. NO DRUG IS RISK-FREE • All drugs are associated with undesirable or harmful effects at some dose or plasma concentration

31. Toxic levels Drug plasma concen-tration Therapeutic levels Subtherapeutic levels

32. Therapeutic index (TI) TI = LD 50 ED50 • The ratio of the dose producing a lethal effect in 50% of the test population (LD50)to the dose producing a specified desired effect in 50% of the test population (ED50)

33. Narrow therapeutic index 10 mg ED50 25 mg LD50

35. Certain safety factor LD1 ED99 • The ratio of the dose producing a lethal effect in 1% of the test population (LD1) to the dose produced a specified desired effect in 99% of the test population (ED99)

36. Overlap between effective and toxic drug plasma levels ED99 LD1

37. safety margin LD5~ED95 • The distance of the dose producing a lethal effect in 5% of the test population (LD5) to the dose produced a specified desired effect in 95% of the test population (ED95)

38. TI compared with Safety Margin % of animal population tested ED95 LD5 Dose (units) LD50 ED50 20 60

39. Drug v.s. Receptor

40. Receptor • 受体（receptor）： is a macromolecular substance that may be a protein or an enzyme which is located on cell membrane or in cell plasma. It could recognize the minim chemical substances and bound with them.

41. Ligand • 配体（Ligand）：is the substance that can specially bind to receptor 。 a) Endogenous : transmitter, hormone, b) Exogenous

42. Properties of receptor： • sensitivity： • specificity： • saturability： • reversibility： • Multiple-variation：

43. Classical theory——occupation theory • Only if drugs bound with receptor, the drugs could be activated which intensity was proportional with the number of occupative receptors. When all receptors were occupied, the effects were the maximal effect.

44. Interaction between receptor with drug • 亲和力（affinity）：is the capabilities that drug could bind with receptors, and can be expressed by the concentration at which reach 50% Emax • 1954，modified • the effect that drugs could bind with receptors and be activated not only need affinity, but also need intrinsic activity. • 内在活性（intrinsic activity，α）：is the information encoded in a drug’s chemical structure causes the receptor to change accordingly when the drug is bound.

45. D+R DR E [RT]=[R]+[DR] 代入 KD：平衡解离常数，表示药物与受体亲和力，KD越大,药物与受体亲和力越小(反比)

46. [D] = 0 E = 0 [D]>>> KD E=Emax KD = [D] KD：单位mol/L，引起最大效应一半(50%受体被占领)时所需的药物浓度

47. KD • KD represents the concentration of free drug at which half-maximal binding is observed. • The KD is the drug concentration for 50% saturation of the receptors. • The KD is the dose of 50% for the maximal effect. • The KD is inversely proportionate to the affinity of the drug . pD2 affinity index pD2 = -㏒KD KD ↓， pD2 ↑，affinity ↑； KD ↑, pD2 ↓，affinity↓

48. Intrinsic activity 0 ≤ ≤ 1

49. If affinity is equal, Emax depends on intrinsic activity If intrinsic activity is equal, affinity depends on potency of drug

50. Classification of drugs Endogenous ligand (e.g. endorphin on opoid receptor) Agonist (e.g. morphine on opoid receptor) Antagonist (e.g. naloxone on opoid receptor)