Pharmacology 2008

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Pharmacology 2008

Chapter 1 An Introduction To Pharmacology

    Pharmacology is the science dealing with interaction between drugs and living organisms. Pharmacology (Gr. pharmakon - a drug or poison) include:

     1, pharmacodynamics: actions of drugs on the body ("What the drug does to the body ―)

     2, pharmacokinetics: the fate of drugs in the body ("What the body does to the drug").

The Duties of Pharmacology

     a. To explain the action and its mechanisms of drug,

     b. to provide the theory for clinic and enhancing the drug efficacy.

     c. To develop new drug and new indications of drug.

     d. To explore the pathway of physio-, biochemic, and pathology of the cells.

Drug definition

    A drug is a substance that can alter or influence the responsiveness of a biological system.

    A drug is a chemical which is utilized for the diagnosis, prevention, cure or amelioration of an unwanted health condition (definition by FDA).

    Most of drugs are Xenobiotics (Gr. xenos - stranger) chemicals that are not synthesized by the body, but introduced into it from outside.

Drugs can be classified into following categories:

     1. replace physiological inadequacies, Insulin

    2. cure disease, Antibiotics

    3. treat symptoms, Antihypertensives

    4. prevent disease, Bacterin

    5. alter mood or behavior (including Social drug), Alcohol, cocaine, opiate

     Modern medicine relies heavily on drugs as the main tool of therapeutics. Other therapeutic procedures such as surgery, are also important, of course, but none is so widely applied as drug-based therapeutics.

The Main Branches of Pharmacology

    Clinical pharmacology 临床药理学

    Biochemical pharmacology 生化药理学

    Molecular pharmacology分子药理学

    Immunopharmacology 免疫药理学

    Cardiovascular pharmacology 心血管药理学

    Neuropharmacology 神经药理学



Pharmacological study mainly include the following:

    The relationship between drug concentration and biological response.

    Drug action over time.

    Factors affecting absorption, distribution, binding, metabolism, and elimination of chemicals Structure-activity relationships.

    Biological changes that result from repeated drug use: tolerance, addiction, adverse reactions, altered rates of drug metabolism, and so forth

    Antagonism of the effects of one drug by another

    The process of drug interaction with cellular macromolecules (receptors) to alter physiological function (i.e., receptor theory).

The Steps for Drug Research and Development(R&D)


;Preclinical Research: 临床前研究

     1 Pharmaceutical studies药学研究

     2 Pharmacological studies药理学研究

     General pharmacology一般药理学




;Clinical Research:

     1 The Organizations for novel drug development

    Food and Drug Administration (FDA)

     Sino Food Drug Administration (SFDA)

     The Center for New Drug Evaluation. GLP, GCP, GMP

     2 Clinical Pharmacology:

     Phase ?,?, ? and ? (Postmarketing Surveillance)

Outline of the course content

    Part I- Principles of pharmacology, pharmacokinetics, pharmacodynamics.

    Part II- Neuropharmacology: Efferent, central [or drugs that act on the central and autonomic

    nervous system]

    Part III Drugs that act on cardiovascular system

    Part IV - Drugs that affect the viscera and endocrine system

    Part V The chemo-therapeutic agents.

    Chapter 2 Pharmacodynamics

Pharmacodynamics is the processes of drug action that occur when drug reaches site of action and

    produces an effect,"What the drug does to the body"

Pharmacodynamics attempts to describe the biological responses produced by drugs and define the

    underlying mechanisms by which the responses are generated.

Section 1 Basic Actions of Drug

Mechanisms of drugs (how drugs work on the body)

    1 many drugs inhibit or stimulate enzymes

     Enzymes control a number of metabolic processes. a very common mode of action of many


     in the patient (ACE inhibitors)

     in microbes (sulfas, penicillins)

     in cancer cells (5-FU, 6-MP)

    2 some drugs bind to:

     iron chanel


     the genome (cyclophosphamide)

     microtubules (vincristine)

    3 some drugs alter DNA or RNA

    4 some drugs influence carrier

    5 some drugs act on immune system

    6 gene therapy

    7 some drugs bind to receptor: the most important!

Important definitions

    ;Drug action 作用: The primary response of body induced by a drug. ---mainly biochemic ;Drug effect 效应: The physiological function and/or even shape change of body induced by a drug. ---mainly physiological

    Action vs. Effect Action = how the drug works, usually by enhancing or inhibiting cell function ---primary; Effect = consequence of drug action on body ---secondary to action

    ;Excitation or Stimulation: the intrinsic function of body is increased by drug.

    ;Inhibition: the intrinsic function of body is decreased by drug.

    ;Local action: drug acts on the local site where the drug is given (before absorption ). ;General action (absorptive or systemic action): drug acts on the general system ( after absorption) ;Selectivity a drug acts ―selectively‖ on a or some organs or tissues but not on the others, it is termed selectivity.

     we need drugs with high selectivity. Why?

Clinical result of drug treatment

    ;Therapeutic effect: the effect induced by drug is what we want or need.

    ;Adverse drug reaction (ADR) or untoward reaction: a harmful or undesirable effect of a drug.

    Any drug has the potential to cause harmful or undesirable effects

Therapeutic Effects

     Etiological treatment 对因治疗: eliminate the cause of disease.

    Symptomatic treatment对症治疗: remission of symptome

    Supplementary therapy and Replacement therapy替代疗法

ADRs include:

    1 Side reaction: Reactions without relationship to therapeutic purpose of drugs are occurred in almost patients when administration in normal dose because of the extensive actions of the drug. 2 Toxic effect: Harmful responses, usually induced by overdose or long time usage of drug.

     Acute toxication

     Chronic toxication

     Special toxications:


     Teratogenesis致畸: thalidomide


    3 Allergy: immuno-reaction, without relationship to pharmacological action and dose. 4 Tolerance, Addiction, Dependence, Habituation

    Addiction: A chronic, relapsing behavioral disorder. to use drug compulsively or uncontrollably. Tolerance: decrease in an effect following chronic use of a drug. Addicts may take increasing amounts of drug due to decreases in desired effects or decreases in side-effects

    Habituation: a constant, often unconscious, inclination to perform some act, acquired through its frequent repetition

    Dependence: state of being determined, influenced, or controlled by something else; subordination


    to someone or something needed or greatly desired; required for normal physiological or psychological function. Dependence can be classes as physiological or psychological/psychic. 5 Idiosyncratic reaction: a reaction to a drug that is peculiar to a particular individual due to interactions of the drug with unique host factors that are unrelated to the principal action of the drug

    ; May be due to unique genetic and/or environmental factors

e. Withdrawal reaction (停药反应, rebound 反跳)


    1 Drugs do not produce new function.

    2, No drug has a single action.

    3, Drugs have both therapeutic effects and ADRs.

    4, Actions can be considered therapeutic in one case and adverse in another


    ;All drugs are associated with undesirable or harmful effects at some dose or plasma concentration.

Section 2 Drug Dose and Dose-Effect Relationship

    Dose-response relationship In general, as dose increases, concentration of drug at action sites increases. It follows from receptor theory that the maximal response to a drug occurs when all receptors are being occupied by that drug.

Dose-response curve

    ;As the dose of drug increases, the response should increase.

    ;The curve generated is usually S-shape when effect is plotted against log dose. ;Effect may be measured as a graded variable or as a quantal variable. ;The slope of the curve is characteristic of the particular drug-receptor interaction. When two drugs

    act by the same receptor mechanism, we expect to see two parallel log-dose response curves.

    Log Dose-Effect Curve

    % of Maximal Effect


    Log [Drug]

What a dose-effect curve tell us?

    1 Threshold dose: minimum effective dose.

    2 Efficacy (Emax 效能): Maximum effect or the limit of the drug response.

    3 Potency?效价强度?:

    4 ED (半数有效量) 50

    5 Therapeutic Window.


6 Therapeutic Index.

    ;Potency of a drug refers to the dose required to produce a specific intensity of effect. E.X., If the ED of drug A and B are 5 and 10 mg, respectively, the Relative Potency of A is twice that of B. 50

    Relative potency specifically applies to the comparison of drugs which act by the same mechanism, and therefore have parallel dose-response curves.

    ;Efficacy, also called Maximal Efficacy or Intrinsic Activity. This is the maximum effect of which

    the drug is capable. A potent drug may have a low efficacy, and a highly efficacious drug may have a low potency. For the clinician, efficacy is much more important than potency (within limits).

     Who cares if the pill contains 5 or 10 mg of drug?

    ;ED)The median effective dose, or the dose which produces a response in 50% of subjects. If the 50

    response is death (lethality) we call it the LD.The EC refers to concentration rather than dose. 5050

    Similar abbreviations are used for other response levels: ED, LD, etc. 991

    ;Therapeutic Index (TI) This is the ratio of toxic to effective doses at the level of 50% response:

     TI=TD/ED 5050

    TI is the quantification of drug safety. In animal toxicology studies, it is usually the LD/ED. 5050

    Another measure sometimes utilized is the Certain Safety Factor, which is TD/ED. 199

    ;Therapeutic window For every drug, there exists some concentration which is just barely effective (the Effective Concentration) and some dose which is just barely toxic (the Toxic Concentration).

    Between them is the therapeutic window where most safe and effective treatment will occur.


Section 3 Drug receptors and pharmacodynamics

     The action of a drug on the body include receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action.

Drug Receptors

    ;Receptor: the component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug's observed effects. Most of receptors are proteins.Receptors have become the central focus of investigation of drug effects and their mechanisms of action.

The receptor function as

    (1) determinants of the quantitative relation between the concentration of a drug and the pharmacologic response.

    (2) regulatory proteins and components of chemical signaling mechanisms that provide targets for drugs.

    (3) key determinants of the therapeutic and toxic effects of drugs in patients.

;Endogenous substance: A substance produced by the body.

    ; Exogenous substance: A substance not produced by the body.

    ;Ligand 配基: Endogenous or exogenous substance which can specially bind to a certain receptor.

Drug receptors & biological responses

    ;Receptors are macromolecules in tissues that combine chemically with the drug. ;Receptors will interact with only a limited number of structurally related or complementary compounds.

    ;Only by interacting with receptor, a drug can induce effect.

Agonists and antagonists

    ;Chemicals that interact with a receptor and thereby initiate a cellular reaction are termed agonists.

    ;Chemicals that interact with a receptor but can not initiate a cellular reaction are termed antagonists.

    Characters of receptor

    1 Saturability 饱和性


    2 Specificity 特异性

    3 Reversibility 可逆性

    4 Sensitivity 灵敏性

    5 Multiple variation 多样性

3.1 Drug Receptor Interaction

    Drug-receptor interactions is the primary way drugs produce an action

Receptor 0ccupy theory

    ;The magnitude of the pharmacological response to a drug is proportional to the number of drug receptor interactions.

    ;Concentration of drug at receptor sites determines number of receptors occupied by drug. ;Usually, drug only has to occupy receptor for brief time period to cause its effect.

Drug - Receptor Binding:

    ;Affinity measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor.

    Covalent bonds are stable and essentially irreversible (rarely).

    Electrostatic bonds may be strong or weak, but are usually reversible. ;Efficacy-the ability of a drug to elicit a maximal response, also called intrinsic activity. Some

    drugs possess affinity but NOT efficacy.

    ;Drug potency - measure of the amount of drug required to obtain a particular response.

;K (k/k) is called the affinity constant;[DR] is the response; [D] is concentration of drug. When e1-1

    [DR] = 50 % (effect is half maximal), [D] (or EC) is equal to k, effect is a measure of efficacy. 50d

    Drugs that have parallel dose-response curves often have the same mechanism of action.

    ;Spare receptors The receptor theory assumes that all receptors should be occupied to produce a maximal response. In that case at half maximal effect EC=kd (ie., 2 receptors stimulate 2 effectors). 50

    Now imagine that the number of receptors increases to ten, but that the total number of effectors remains constant, six of the receptors are now spare in number. As a result, low concentration of agonist is able to elicit a half-maximal response, EC<kd. 50

    ;Agonist drugs (受体激动药) Drugs that interact with and activate receptors; they possess both affinity and efficacy. There are two types of agonists:


    Full agonist an agonist with maximal efficacy

    Partial agonist an agonist with less then maximal efficacy

    ;Partial agonist: An agonist which, even at full receptor occupancy, cannot elicit a response equal to that of a full agonist, also called agonist-antagonist or mixed agonist-antagonist.

     A: The percentage of receptor occupancy resulting from full agonist (FA) binding to receptors in the presence of increasing concentrations of a partial agonist (PA). Because the FA and the PA compete to bind to the same receptor sites, when occupancy by the PA increases, binding of the FA decreases.

     B: When each of the two drugs is used alone and response is measured, occupancy of all the receptors by the PA produces a lower maximal response than does similar occupancy by the FA.

     C: Simultaneous use a single high concentration of FA and increasing concentrations of PA. The fractional response caused by FA decreases as increasing PA compete to bind to the receptor; at the same time the portion of the response caused by the PA increases, while the sum of responses to the two drugs gradually decreases, eventually reaching the value produced by PA alone.

Antagonist drug

    ;Antagonists interact with the receptor but do NOT produce response. They have affinity but NO efficacy. Antagonist can block or interfere the action of agonist. Two types



    ;Competitive Antagonist competes with agonist for the same binding site of receptor, surmountable with increasing agonist concentration, displaces agonist dose response curve to the right (dextral shift), reduces the apparent affinity of the agonist i.e., increases 1/Ke

    ;Noncompetitive Antagonist drug binds to receptor and stays bound. The binding is irreversible

    does not let go of receptor. It produces slight dextral shift in the agonist DR curve in the low concentration range, but, as more and more receptors are bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect


    Drug interactions


    % of Maximal EffectAgonist + non-competitive antagonist


    The Regulation of Receptors

    a. Receptor desensitization 受体脱敏

     Down-regulation 向下调节

     Tolerance 耐受性

     b. Receptor hypersensitivity 受体超敏

     Up-regulation 向上调节

     rebound 反跳

Key Points for review

    ;drugs labeled as agonists produce actions similar to endogenous ligands ;drugs labeled as antagonists oppose actions of endogenous ligands

    ;drugs can possess both agonist and antagonist properties. ;Drugs with similar actions bind to same receptors ;competitive inhibitors: compete for same binding site ;noncompetitive inhibitors bind to alternative cellular site and alter action of ligand

    Irreversible antagonists permanently occupy (bond covalently) to their receptors

3.2 Receptor types

     By signalling Mechanisms, there are four types of receptor:

    ;Ion-channel-linked receptors

    ;G-protein coupled Receptors

    ;Kinase-linked receptors

    ;Intra-cellular receptor (nuclear receptor, cytokine receptor)

    Type 1: ligand-gated ion channels (ionotropic receptors) ;These are membrane proteins with a similar structure to other ion channels, and incorporate a

    ligand-binding (receptor) site, usually in the extracellular domain. Typically, these are the receptors on

    which fast neurotransmitters act. Examples include the nAChR; GABA-A receptor, and glutamate

    receptors of the NMDA, AMPA and kainite. ++++ Ligand binding to receptor?opening ion channel?influx of Na, or K or Ca

    ?downstream events


     nACh- receptor is a typical ligand-gated ion channel Structure of the n- receptor. There are two acetylcholine binding sites in the extracellular portion of the receptor. When acetylcholine binds, the kinked α helices either

    straighten out or swing out of the way, thus opening the channel pore.

Type 2: G-protein-coupled receptors (GPCRs)

    ;These are also known as metabotropic receptors. They are membrane receptors that are coupled to

    intracellular effector systems via a G-protein. They constitute the largest family, include receptors for many hormones and slow transmitters, for example the mAChR; adrenergic receptors and chemokine receptors. The human genome includes genes encoding about 400 GPCRs.

    ;Guanine nucleotidebinding proteins (G- proteins) The G-protein consists of three subunits (α,

    β, γ), which are anchored to the membrane. Coupling of the α subunit to an agonist-occupied

    receptor causes the bound GDP to exchange with intracellular GTP; the α-GTP complex then

    dissociates from the receptor and from the βγ complex, and interacts with a target protein. The β

    γ complex may also activate a target protein. The GTPase activity of the α subunit is increased

    when the target protein is bound, leading to hydrolysis of the bound GTP to GDP, whereupon the α

    subunit reunites with βγ.

Stimulatory and Inhibitory G-protein

    G proteins may either stimulate or inhibit an effector. In the case of adenylyl cyclase, the stimulatory

    G protein is known as G and the inhibitory G protein is known as G si

Targets for G-proteins

    ;adenylyl cyclase, responsible for cAMP formation

    ;phospholipase C, responsible for inositol phosphate and diacylglycerol (DAG) formation ;ion channels, particularly calcium and potassium channels

    ;Rho A/Rho kinase, a system that controls the activity of many signalling pathways controlling cell growth and proliferation, smooth muscle contraction, etc.

Type 3: kinase-linked and related receptors

    ;This is a large group of membrane receptors responding mainly to protein mediators. They comprise an extracellular ligand-binding domain linked to an intracellular domain. The intracellular domain is


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