Chapter 2 Pharmacodynamics (PD)

Drug actions: refers to the primary action of a drug on the body. 1 Basic drug action Drug actions: refers to the primary action of a drug on the body. It takes place on the level of molecule /'mɔlikjul/分子. Example: interactions between drugs and receptors /ri'septə/受体 Specificity 特异性 NA -R

Pharmacological effects: refers to the response of the body to the drug 。 The expressive form includes the functional alterations such as: excitation兴奋 paralysis /pə'rælisis/麻痹 inhibition抑制 failure衰竭

NA Drug action 血管收缩 血压升高 Pharmacological effects

2 Ways of drug action Local action 局部作用 Absorptive action/General action/Systemic action 吸收作用/全身作用

Primary action 原发作用 Secondary action 继发作用

1) Therapeutic effect 治疗作用 2) Adverse reaction/effect 不良反应 3 The dual nature of drug actions 1) Therapeutic effect 治疗作用 2) Adverse reaction/effect 不良反应

3.1 Therapeutic effects of drugs 3.1.1 Etiological [i:tiə’lɔdʒikəl] treatment 对因治疗 to eradicate [ɪ‘rædɪkeɪt] 根除the pathological factors 3.1.2 Symptomatic [sɪm(p)tə'mætɪk] treatment 对症治疗 to reduce or improve the symptoms 3.1.3 Supplement treatment 补充疗法 to supply the deficiency of substances

Specificity 特异性 A particular action expressed by a drug with special construction; Selectivity 选择性 Most drugs at therapeutic dose, produce their effects only on some organs or tissues .

Specificity Selectivity Glands Eye Smooth muscle Block Heart 阿托品 M 受体 Blood vessel CNS Block 阿托品 M 受体 (Atropine)

3.2 Adverse reactions 3.2.1 Side reaction/effect 副作用 the action occurs at therapeutic dose, but unrelated to the therapeutic aim; Cause: bad selectivity of the drug; Result: not severe; restore after the withdraw of the drug

3.2.2 Toxic reaction 毒性反应 Cause: over-dose or accumulation of the drug; Result: damage to the body or death; Classification: Acute toxicity Chronic toxicity

3.2.3 Residual effect 后遗效应 It occurs under the threshold concentration after withdraw of the drug; 停药后血浓度降至阈浓度以下残留的作用。 e.g: Postantibiotic effect (PAE, 抗生素的后效应 ) 3.2.4 Allergic reaction 变态反应/过敏反应 3.2.5 Withdrawal reaction 撤药反应 It also can be called rebound reaction and results from a sudden withdraw of the drug;突然撤药后引起的症状反跳

3.2.6 Idiosyncrasy /,idiə'siŋkrəsi/特异质反应 3.2.7 Secondary reaction 继发反应 3.2.8 Teratogenesis [,terətəu'dʒenisis]致畸作用 3.2.9 Carcinogenesis [,kɑ:sinəu'dʒenisis]致癌作用 3.2.10 Mutagenesis [,mjuːtə'dʒenɪsɪs] 致突变作用 3.2.11 Drug dependence 依赖性 Congenital lack of G-6-PD  hemolysis [hɪ‘mɒlɪsɪs]溶血

不良反应小结 一）、与药理作用相关类 本类不良反应均与药物剂量及药理作用相关，包括副作用、毒性反应、后遗效应、继发反应、“三致”作用； 二）、与机体相关类 本类不良反应与个体反应的差异性相关，包括变态反应（过敏反应）、特异质反应； 三）、与连续用药相关类 包括依赖性

药物即毒物，利弊并存， 必须权衡，正确应用

4 Dose-effect relationship 量效关系 Minimum effective dose 最小有效量 Maximal effective dose 最大有效量 Therapeutic dose 治疗量 Maximum dose 极量 Minimum toxic dose 最小中毒量 Lethal dose 致死量

剂量与作用关系示意图 效应 中毒量 致死量 常用量 无效量 最小有效量（阈剂量） 最大有效量（极量） 最小中毒量 最小致死量 剂量

效能 个体差异 量效变化速度 强度

Potency 效价, 强度 relates to the concentration or dose of a drug needed to elicit a certain response. Efficacy 效能 refers to the maximal response the drug may induce.

Quantal dose-effect curves 质反应量效曲线

Safety evaluation 安全性评价 1. Therapeutic index (TI, 治疗指数) TI=LD50/ED50 2. ED95-LD5 安全范围 95%ED ~ 5%LD 效应 死亡

Mechanism of drug action Drugs may work by targeting specific macromolecules: transport system; enzymes; receptor; --- Mechanism of drug action

D + R D-R Complex Response 5.1 Act on receptors Concept of receptor: It is specific protein molecules, located usually in the cell membrane, some in plasma or nucleus, interacts with a drug (or ligand [ˈlɪɡənd] 配体) and initiates the chain of biochemical events leading to the specific effects D + R D-R Complex Response

Characters of the receptors Affinity [ə'fɪnɪtɪ] 亲和性 Selectivity 选择性 Specificity 特异性 Reversibility 可逆性 Saturability [,sætʃərə'biliti] 饱和性

Ligands Endogenous /en'dɔdʒənəs/ (内源性） Synaptic transmitters（突触递质） Hormones（激素） Endocrine factors（内分泌因子） Exogenous [ek'sɔdʒənəs]（外源性） Drugs

Types of receptor 1 Gated ion channel receptor:

2 G-protein-coupled receptor:

3 Intracellular receptor

4 Tyrosine ['taɪrəsiːn] kinase ['kaɪneɪz] receptor

Drugs and receptors Affinity Intrinsic activity/efficacy内在活性: the ability of a drug to stimulate the receptor and produce a subsequent response.

Classification of drugs acting on the receptor (1) Agonist ['ægənɪst] 激动剂 having affinity and intrinsic activity, producing efficacy;

(2) Antagonist [æn'tæg(ə)nɪst] 拮抗剂 having affinity without intrinsic activity do not produce efficacy.

Subclass: Competitive antagonists: bind to receptors reversibly;

Non-competitive antagonists: bind to receptors irreversibly Partial agonist: having affinity and low intrinsic activity, producing low efficacy.

Receptor regulation 1 Down-regulation: Continued stimulation of cells with agonists generally results in a state of down-regulation (also referred to as adaptation, refractoriness, or desensitization) such that the effect that follows continued or subsequent exposure to the same concentration of drug is diminished;

2 Up-regulation Supersensitivity to agonists also frequently follows chronic reduction of receptor stimulation; such situations can result, for example, following withdrawal from prolonged receptor blockade.

5.2 Other mechanisms (1)Physicochemical reaction: e.g. antacids, laxatives—magnesium sulfate; (2) Act on ion channels ① Modulate ion channel function by directly binding to a part of the channel protein itself (local anaesthetics). ② interact with ion channels indirectly via a G-protein and other intermediates→ change the function

(3) Interfere the transportation (4) Interfere metabolism (5) Interfere the enzyme activity (6) Interfere the immunity (7) Supplementary action

Supplementary reading In the most general sense, a drug may be defined as any substance that brings about a change in biologic function through its chemical actions. In most cases, the drug molecule interacts as an agonist (activator) or antagonist (inhibitor) with a specific molecule in the biologic system that plays a regulatory role. This molecule is called a receptor. In a very small number of cases, drugs known as chemical antagonists may interact directly with other drugs, whereas a few drugs (osmotic /ɔz'mɔtik; ɔs-/渗透性的agents) interact almost exclusively with water molecules. Drugs may be synthesized within the body (eg, hormones ) or may be chemicals not synthesized in the body (i.e., xenobiotics /,zenəubai'ɔtik; ,zi:-/外源性物质). Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus (1493–1541) famously stated that “the dose makes the poison,” meaning that any substance can be harmful if taken in the wrong dosage. Toxins are usually defined as poisons of biologic origin, i.e., synthesized by plants or animals, in contrast to inorganic /inɔ:'ɡænik/无机的poisons such as lead. To interact chemically with its receptor, a drug molecule must have the appropriate size, electrical charge, shape, and atomic composition. Furthermore, a drug is often administered at a location distant from its intended site of action, e.g., a pill given orally to relieve a headache. Therefore, a useful drug must have the necessary properties to be transported from its site of administration to its site of action. Finally, a practical drug should be inactivated or excreted from the body at a reasonable rate so that its actions will be of appropriate duration.

大纲要求 Objective and requirements Master the basic principles of drug actions and drug-receptor interactions. Teaching contents (1) Types of drug actions and the basic drug action; (2) Selectivity of drug actions, adverse reactions, dose-effect relationships (minimum effective dose, therapeutic dose, maximal effective dose, toxic dose, lethal dose, potency, efficacy), safety evaluation, therapeutic index; (3) Specific and unspecific mechanism of drug action; basic concepts in interactions between drugs and receptors: affinity, intrinsic activity, agonist, antagonist, partial agonist, receptor regulation.

Essential vocabulary Pharmacological effect Therapeutic effect/adverse reaction Specificity/selectivity Side reaction/effect Toxic reaction/acute toxicity/chronic toxicity Allergic reaction Residual effect Withdrawal reaction Dose-effect relationship Therapeutic dose/lethal dose Potency/efficacy Therapeutic index Receptor/ligand Affinity/intrinsic activity Endogenous/exogenous Agonist/antagonist Down-regulation/up-regulation