1. Section 2 Pharmacodynamics:
Pharmacological effects, Basic concepts (Drug-Receptor Interaction, );dose-effect relationship; Cellular Sites of Action (mechanism), adverse drug reaction (ADR)

2. Pharmacodynamics
Pharmacodynamics is what drugs do to the body, including the study of the biochemical and physiological effects of drugs and their mechanisms of action. All of these contents are almost based on the principle of drug receptors.
Unit 1．Introduction on receptor
Unit 2. Drug Action
1．Action and Effect
2．Excitation and Inhibition
3．Selectivity of Drug Action
4. Therapeutic Effect and Adverse Reaction
Unit 3. Principles of Drug Action
1． Dose-effect relationship
2．Time-effect relationship
3．Structure-activity relationship
Unit 4. Mechanisms of Drug Action
1．Simple physical and chemical property
2．Involving or interfering physiological and biochemical process of living system

3. (1) Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects.
The receptor's affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors may limit the maximal effect a drug may produce.

4. (2) Receptors are responsible for selectivity of drug action
(2) Receptors are responsible for selectivity of drug action. The molecular size, shape, and electrical charge of a drug determine whether--and with what affinity--it will bind to a particular receptor among the vast array of chemically different binding sites available in a cell, tissue, or patient.
Accordingly, changes in the chemical structure of a drug can dramatically increase or decrease a new drug's affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects.

5. (3) Receptors mediate the actions of both pharmacologic agonists and antagonists. Some drugs and many natural ligands, such as hormones and neurotransmitters, regulate the function of receptor macromolecules as agonists; ie, they activate the receptor to signal as a direct result of binding to it.
Other drugs act as pharmacologic antagonists; ie, they bind to receptors but do not activate generation of a signal; consequently, they interfere with the ability of an agonist to activate the receptor.
Other antagonists, in addition to preventing agonist binding, suppress the basal signaling ("constitutive") activity of receptors. Some of the most useful drugs in clinical medicine are pharmacologic antagonists.

6. Macromolecular nature of drug receptor
Most receptors are proteins: e.g. regulatory proteins(neurotransmitters) ; enzymes (dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate) ; transport proteins (Na+/K* ATPase ) ; structural proteins (tubulin, the receptor for colchicine, an anti-inflammatory agent).
Traditionally, drug binding was used to identify or purify receptors from tissue extracts; However, advances in molecular biology and genome sequencing have begun to reverse this order. Now receptors are being discovered by predicted structure or sequence homology to other (known) receptors, and drugs that bind to them are developed later using chemical screening methods,.
a number of "orphan" receptors, so-called because their ligands are presently unknown, which may prove to be useful targets for the development of new drugs.

7. Three aspects of drug receptor function
(1) Receptors as determinants of the quantitative relation between the concentration of a drug and the pharmacologic response.
(2) Receptors as regulatory proteins and components of chemical signaling mechanisms that provide targets for important drugs.
(3) Receptors as key determinants of the therapeutic and toxic effects of drugs in patients.

8. RELATION BETWEEN DRUG CONCENTRATION & RESPONSE
The relation between dose of a drug and the clinically observed response may be complex. This idealized relation underlies the more complex relations between dose and effect that occur when drugs are given to patients.

9. Unit 2. Drug Action 1．Drug Action and Effect
Action（作用）means the primary action of the drug on the body；
Effect （效应）means the functional or morphological alteration of the body induced by drugs.

10. Pharmacology is defined as the study of substance that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. 1、The changes of physiological function: e.g. Acetylcholine ：a brief decrease in heart rate and cardiac output. e.g. Pilocarpine ：rapid miosis and contraction of the cillary muscle. 2、The changes of biochemical function: e.g.Epinephrine (or:Ad,Adrenaline) initiates a significant hyperglycemic effect through its increased glycogenolysis in liver and a decreased release of insulin. 3、The morphological changes of tissue or cell： e.g. The primary use of folic acid is in treating megaloblastic anemia, caused by folic acid deficiency.

11. 2．Excitation and Inhibition
The basic performances of drug action vary with different organ, such as the increase or decrease of heart rate, the contraction or dilation of skeletal muscle, and the elevation or lower of blood glucose.
But all of drug action are basically subdivided two major groups: excitation or inhibition, which strengthen or weaken the original function of the living system, respectively.
Drug that strengthens the original function of the body is defined as the stimulant, drug that weaken the original function of the body is defined as the depressant.

12. Notice：
⑴Drug is only capable of altering the rate at which any bodily function proceeds, but does not create effects.
⑵A drug is whether stimulant or depressant, depending on different organs. Because it may excite some organ and inhibit another one, even if the same tissue of different organs.
e.g.Ad(Adrenaline) contracts the cardiac muscle and relax the bronchiolar smooth muscle,effects of Ad on the blood vessels are contractile in skin vessels and relaxed in skeletal muscle vessels, respectively.
⑶ A drug is whether stimulant or depressant, depending on the dosage of drug and the condition of body.

13. 3. Selectivity of Drug Action
The selectivity of drug action means that a drug has characteristic effects on a tissue or an organ while does not on another one in the given dose or concentration.
What is responsible for selectivity of drug action(why?):
1．The existence of different receptors in the target tissues of different cell or organism.
2．The existence of different biochemical mechanisms in the target tissues of different cell or organism.
3．The existence of different micromolecular structures in the target tissues of different cell or organism.
4．The different distributions of drug in the target tissues of different cell or organism.
The selectivity of drug action is relative. No drug has a single effect.

14. The importance of understanding the selectivity:
Theoretical importance: Inferring receptor concept------
Most drugs act by associating with specific macro-molecules in ways that alter the molecules’ biochemical and biophysical activities. The existence of receptors was inferred from observations of the biochemical and physiologic specificity of drug effects.
In addition to its usefulness for explaining biology, the receptor concept has important practical consequences for the development of drugs and for arriving at therapeutic decision in clinical practice. Form the basis for understanding the actions and clinical use of drugs.

15. 2. Practical importance：
⑴The basis for classifying drugs
⑵The basis for arriving at therapeutic decision
⑶The criterion for evaluating drugs
The best approach is to learn drugs by their class

16. Clinical effects of drug action have the dualism, The aim of drug therapy is to cure or suppress disease, called therapeutic action, but also bring about some harmful effects, named untoward or adverse reaction.

17. 4.Therapeutic Effect and Adverse Action

18. Therapeutic Effect
It implied the effects that conform the goal of therapy, including etiological treatment and symptomatic treatment(e.g.fever,ache or pain).
1．etiological treatment implies primary therapy (e.g. in bacterial and parasitic infections), when the disease is eliminated and the drug is withdrawn; or auxiliary therapy, also called supplement therapy or replacement therapy. y

19. 2．symptomatic treatment means suppression of diseases or symptoms is used continuously or intermittently to maintain health without attaining cure (as in hypertension, diabetes, epilepsy, asthma) or to control symptoms (such as pain and cough) whilst awaiting recovery from the causative disease.
Generally, etiological treatment is more important than symptomatic treatment. However, symptomatic treatment is not necessarily trivial in emergency rescue, such as heart failure, shock, epilepsy, asthma, etc.

20. 5. Unusual reaction： ①Idiosyncrasy ②Allergy
Adverse Reaction (Untoward) The term adverse reaction is defined as unwanted, seriously unpleasant, or even harmful effects.
Adverse Reaction including：
1. Side effects
2. Toxic reaction
3. Residual effect
4. Withdrawal reaction
5. Unusual reaction： ①Idiosyncrasy ②Allergy

21. 1. Side effects is to be the undesired effects unrelated to therapeutic aim and occurring at doses intended (unavoidable or inevitably) for therapeutic effect.
①It is often slight, recoverable functional alteration of the body.
②Some of side effects may make a quick recovery without withdrawal of the drug, but others dose not disappear until withdrawal of the drug.
③The pharmacological basis of side effect is lower selectivity
④Side effects vary with different therapeutic goals. For example, atropine is used as an antisecretory agent to block secretions in the upper and lower respiratory tracts prior to surgery .
⑤Usually drug in combination is the best way to prevent from side effects.

22. 2. Toxic reaction is the adverse reactions that occur frequently due to overdose or longterm use(specially: sensitivity).
①Much of the serious drug toxicity in clinical practice represents a direct pharmacological extension of the therapeutic action of the drug, thus they are predictable.
②The severity of a toxicity is deteriorated with dose increase, so we cannot rise the therapeutic effect by increasing doses of drug, which is very dangerous.
③Toxicity can not automatically disappear because it often damages the function or the morphology of organs, even inducing teratogenicity, carcinogenicity and mutagenicity.
Toxicities include the acute toxicity, subacute toxicity and chronic toxicity
3. Residual effect implies the biological responses induced by residual drug below effective concentration after cessation of administration, including a short period, long term and permanent.
4. Withdrawal reaction implies a worsening of original diseases occurred after suddenly cessation of administration, also called the rebound reaction.

23. 5. Unusual reaction is the unpredictable adverse reaction which unrelated to pharmacological action of the drug.
①Idiosyncrasy is defined as a genetically determined abnormal reactivity to a drug. The observed response is qualitatively similar in all individuals, but the idiosyncratic response may take the form of extreme sensitivity to low doses or extreme insensitivity to high doses of the agent, which may be explained, not by antibodies, but by a biochemical abnormality present in an individual with a genetic defect. One example is a serious hemolytic anemia when they receive primaquine (for malaria). Such individuals have a deficiency of erythrocytic glucose-6-phosphate dehydrogenase(G-6PD).

24. ②Allergy is an adverse reaction that results from previous sensitization to a particular drug or metabolite (a nondrug element in the formulation) with subsequent re-exposure. Such reactions are mediaed by the immune system. Lack of previous exposure is not the same as lack of history of previous exposure and exposure is not necessarily medical. Drugs may elicit allergic reactions of all four types(?).
Features of allergy: A)no? correlation with known pharmacological properties of the drug, thus it is easy to predict; B)no linear relation with drug dose, very small doses may cause very severe effects; C)require an induction period on primary exposure, but not on re-exposure; D)disappear on cessation of administration and reappear on re-exposure.

25. Unit 3 Principles of Drug Action
The knowledge of pharmacodynamics is essential to the choice of drug therapy. But the well-chosen drug may fail to produce benefit or may be poisonous because too little or too much is present at the site of action for too short or too long a time.
A. dose-effect/response relationship The magnitude of the drug effect is proportional to the concentration or dose of the drug, this is, if the concentration or dose of a drug is increased or decreased, the magnitude of the drug effect is also correspondingly increased or decreased respectively. There are two basic types of dose-response relationships: the graded or the quantal?

26. Concepts of dose involved
Dose: a part of drug that is once used for therapy;
Threshold dose: a dose has exceeded a critical level；
Minimal toxic dose: a dosage regimen that is likely to produce minimal toxicity;
Maximal effective dose (极量): a dosage regimen that is the maximal dose used in patients limited by Pharmacopoeias;
Usual dose (therapeutic dose): a dosage regimen that is a safe and effective for most of patients.

27. Concentration-effect curve & receptor binding agonist
As doses increase, however, the response increment diminishes; finally, doses may be reached at which no further increase in response can be achieved.
In idealized or in vitro systems, the relation between
drug concentration and effect is described by a hyperbolic curve (Figure 2-1A p12) according to the following equation:
E=(Emax × C)/(C + EC50)
E: the effect observed at concentration C,
Emax: the maximal response
EC50: the concentration of drug that produces 50% of maximal effect.

28. drug bound to receptors (B) relates to the concentration of free (unbound) drug (C) as depicted in Figure 2-1B and as described by an analogous equation: (see above)
B=(Bmax x C)/(C+ Kd)
Bmax indicates the total concentration of
receptor sites (ie, sites bound to the drug at infinitely
high concentrations of free drug).
Kd (the equilibrium dissociation constant) represents the concentration of free drug at which half-maximal binding is observed

29. If the Kd is low, binding affinity is high, and vice versa.
Dose-response data are often presented as a plot of the drug effect (ordinate) against the logarithm of the dose or concentration (abscissa). This mathematical maneuver transforms the hyperbolic curve of Figure 2-1into a sigmoid curve with a linear midportion (eg, Figure 2-2 p13 or next figure B).

30. 1. Graded dose-response relations
Graded dose-response relation means the indicators showing drug effect, such as high or low of blood pressure, could be increased or decreased on the basis of the original amount, their determinants are the doses.
The effect of a drug is most easily analyzed by plotting the magnitude of the response versus the drug dose, this is, a graded dose-response curve, which is reflected by a rectangular hyperbolic curve (A), but it is frequently convenient to plot the magnitude of effect versus log dose, because a wide range of drug concentrations is easily displayed. In this case, the result is the symmetric sigmoidal log dose-effect curve (B). This curve is steep in the middle and even in both extremities.

31. Aim of plotting the dose-effect relation curve is to compare the relative potencies and efficacies of different drugs, obtaining two terms:
Potency (效价) also termed effective dose or concentration, is a measure of how much drug is required to elicit a given response. The lower the dose required for a given response, the more potent the drug. Potency is most often expressed as the dose of drug that gives 50% of the maximal response, ED50 (dose) or EC50 (concentration).
Efficacy (效能) is the maximal response produced by a drug. It depends on the number of drug-receptor complexes formed.

33. There is no connection between the potency and efficacy
There is no connection between the potency and efficacy. Potency is most often expressed as the dose of drug, however, efficacy focuses on the effectiveness of the drug, which is more important than potency. Drug A, B,and C have different potencies, but similar efficacies, however,drug C, D, and E have similar potencies but different efficacies.

34. In the same figure above:
Logarithmic transformation of the dose axis and experimental demonstration of spare receptors, using different concentrations of an irreversible antagonist. Curve A shows agonist response in the absence of antagonist. After treatment with a low concentration of antagonist (curve B), the curve is shifted to the right; maximal remonsiveness is preserved, however, because the remaining available receptors are still in excess of the number required. In curve C, produced after treatment with a larger concentration of antagonist, the available receptors are no longer "spare"; instead, they are just sufficient to mediate an undiminished maximal response. Still higher concentrations of antagonist (curves D and E) reduce the number of available receptors to the point that maximal response is diminished. The apparent EC50 of the agonist in curves D and E may approximate the Kd that characterizes the binding affinity of the agonist for the receptor.

35. Receptor-effect coupling & spare receptors
When a receptor is occupied by an agonist, the resulting conformational change is only the first steps. The transduction process that links drug occupancy of receptors and pharmacologic response is often termed coupling.
The effects of full agonists can be considered more efficiently coupled to receptor occupancy than can the effects of partial agonists. Coupling efficiency is also determined by the biochemical events that transduce receptor occupancy into cellular response.
Sometimes the biologic effect of the drug is linearly related to the number of receptors bound. This is often true for drug-regulated ion channels, eg, where the ion current produced by the drug is directly proportional to the number of receptors (ion channels) bound.
In other cases the biologic response is a more complex function of drug binding to receptors. This is often true for receptors linked to enzymatic signal transduction cascades, eg, where the biologic response often increases disproportionately to the number of receptors occupied by drug.

36. The concept of spare receptors is very useful clinically because it allows one to think precisely about the effects of drug dosage, without needing to consider biochemical details of the signaling response.
The Kd of the agonist-receptor interaction determines what fraction (B/Bmax) of total receptors will be occupied at a given free concentration (C) of agonist regardless of the receptor concentration:
Thus, it is possible to change the sensitivity of tissues with spare receptors by changing the receptor concentration

37. Competitive & irreversible antagonist
1,Receptor antagonists bind to receptors but do not activate them,at the same time ,to prevent agonists (other drugs or endogenous regulatory molecules) from activating receptors.
2, "inverse agonists", reduce receptor activity below basal levels observed in the absence of bound ligand.

38. Antagonists are divided into two classes:
1, reversible competitive antagonist :
2, irreversible antagonists:
In the presence of a fixed concentration of agonist, increasing concentrations of a eversible competitive antagonist progressively inhibit the agonist response; high antagonist concentrations prevent response completely. Conversely, sufficiently high concentrations of agonist can completely surmount the effect of a given concentration of the antagonist; that is, the Emax for the agonist remains the same for any fixed concentration of antagonist (Figure 2-3A). Because the antagonism is competitive, the presence of antagonist increases the agonist concentration required for a given degree of response, and so the agonist concentration-effect curve is shifted to the right.

40. The concentration (C') of an agonist required to produce a given effect in the presence of a fixed concentration ([I]) of competitive antagonist is greater than the agonist concentration (C) required to produce the same effect in the absence of the antagonist.
The relationship of ratio of these two agonist concentrations (C, C') can be explained by the Schild equation: c’/c=1+[I]/Ki

41. For the clinician, this mathematical relation has two important therapeutic implications:
1) The degree of inhibition produced by a competitive antagonist depends on the concentration of antagonist. Different patients receiving a fixed dose of propranolol, for example, exhibit a wide range of plasma concentrations, owing to differences in clearance of the drug. As a result, the effects of a fixed dose of this competitive antagonist of norepinephrine may widely in patients, and the dose must be adjusted accordingly.

42. 2) Clinical response to a competitive antagonist depends on the concentration of agonist that is competing for binding to receptors. Here also propranolol provide a useful example: When this competitive β-adrenoceptor antagonist is administered in doses sufficient to block the effect of basal levels of the neurotransmitter norepinephrine, resting heart rate is decreased. However, the increase in release of norepinephrine and epinephrine that occurs with exercise, postural changes, or emotional stress may suffice to overcome competitive antagonism by propranolol and increase heart rate, and thereby can influence therapeutic response.

43. 2, irreversible antagonists:
Some receptor antagonists bind to the receptor in an irreversible or nearly irreversible fashion, either by forming a covalent bond with the receptor or by binding so tightly that, for practical purposes, the receptor is unavailable for binding of agonist.
After occupancy of some proportion of receptors by such an antagonist, the number of remaining unoccupied receptors may be too low for the agonist (even at high concentrations) to elicit a response comparable to the previous maximal response (Figure 2-3B).

44. Therapeutically, irreversible antagonists present distinctive advantages and disadvantages. Once the irreversible antagonist has occupied the receptor, it need not be present in unbound form to inhibit agonist responses. Consequently, the duration of action of such an irreversible antagonist is relatively independent of its own rate of elimination and more dependent on the rate of turnover of receptor molecules.

45. Good case:
Phenoxybenzamine, an irreversible α-adrenoceptor antagonist, is used to control the hypertension caused by catecholamines released from pheochromocytoma, a tumor of the adrenal medulla. If administration of phenoxybenzamine lowers blood pressure, blockade will be maintained even when the tumor episodically releases very large amounts of catecholamine. In this case, the ability to prevent responses to varying and high concentrations of agonist is a therapeutic advantage. If over dose occurs, however, a real problem may arise. If the α-adrenoceptor blockade cannot be overcome, excess effects of the drug must be antagonized "physiologically," ie, by using a pressor agent that does not act viaαreceptors.

46. Partial agonist:

47. Drug A and B are said to be more potent than drug C and D because of the relative position of their dose-response curves along the dose axis. Potency refers to the concentration (EC50) or dose (ED50) of drug required to produce 50% of that drug’s maximal effect. Thus, the potency of drug A is less than that of drug B, the EC50 of A is greater than the EC50 of B. However, some dose of A can produce larger effects than any dose of B, because drug A has a larger efficacy.

48. 2. Quantal dose-response relations
A quantal response is defined as the defined effect is either present or absent(all or none). Individual effective doses usually are lognormally distributed.
A cumulative frequency distribution of individuals achieving the defined effect as a function of drug dose is the quantal dose-effect curve or concentration-percent curve. This curve resembles the sigmoid shape of the graded dose-effect curve,
but the slope of
this curve is an expression
of the pharmacodynamic
variability in the population
rather the an expression
of the dose
range from a threshold to
a maximal effect in the
individual patient.

49. e.g. An experiment was performed on 100 subjects, and the effective plasma concentration that produced a quantal response was determined for each individual. The number of subjects who required each dose is plotted, giving a lognormal frequency distribution (colored bars). The gray bars demonstrate that the normal frequency distribution, when summated, yields the cumulative frequency distribution—a sigmoidal curve.

50. The quantal dose-effect curve is often characterized by stating several values, which provide a convenient way of comparing the potencies or selectivity of drug.
ED50 (median effective dose ), the dose at which 50% of individuals exhibit the specified quantal effect, which has a different meaning from the graded one.
TD50 (median toxic dose), the dose required to produce a particular toxic effect in 50% of animals.

51. LD50 (median lethal dose), the dose required to produce the death in 50% of animals.
Quantal dose-effect curve may also be used to generate information regarding the margin of safety to be expected from a particular drug used to produce a specified effect.
TI (therapeutic index) is usually defined as the ratio of the LD50 to the ED50 for some therapeutically relevant effect. This is one measure, which relates the dose of a drug required to produce a desired effect to that which produces an undesired effect.

53. 2．Time-effect relationship
Drug effects do not develop instantaneously or continue indefinitely, they change with time, called time-effect relationship. Time-effect curve is plotted by effect as a vertical coordinate and by time as a horizontal coordinate，There are three distinct phases in all time-effect curves
1．Time for onset action （latent period）：a delay in time before the first signs of drug effect are manifested following the administration of a drug, which reflects the processes of drug absorption and distribution. )

54. 2．Duration of action (persistent period)：the duration of action of a drug extends from the moment of onset of perceptible effects to the time when an action can no longer be measured.
3．Residue period：the duration from the time when an action can no longer be measured to the time when the drugs are eliminated. Even after a primary action of drugs are terminated, it is possible for a drug to exert a residual action.
Time to peak effect: The maximum response will occur when the most resistant cell has been affected to its maximum or when the drug has reached the most inaccessible cells of the response tissue.(MEC:minimal effect concentration)