PHARMACOLOGIC PRINCIPLES CHAPTER 3 Pharmacodynamics （ drug Acts on body ）

1. PHARMACOLOGIC PRINCIPLES CHAPTER 3 Pharmacodynamics （drug Acts on body）

2. Pharmacodynamics Basic Action Ⅰ. Basic Action of Drug 1. Excitation and Inhibition The intrinsic functions of the body are altered by drugs: 1) Excitation or stimulation：the functions are increased by drugs. ( heart rate↑, BP↑, contraction, unstable …) 2) Inhibition：the functions are decreased by drugs. (heart rate↓, Bp↓, relaxation, stable or sedation …)

3. Pharmacodynamics Basic Action 2. Local action and general action 1) Local action：action on the locale before absorption of administered drugs. 2) General action (absorptive action, systemic action)：action of drugs on general system after absorption.

4. Pharmacodynamics Basic Action Local action and general action For example, magnesium sulfate (orally) →80% no absorption →intestinal osmotic pressure↑→ volume ↑→catharsis (purgation) ↘cholagogic action For example, magnesium sulfate (injection) →circulation → Generalaction site ↗vasodilation → BP↓ ----------- ↘central inhibition→sedation Treatment of eclampsia gravidarum

5. Pharmacodynamics Basic Action 3. Specificity: Singularity of action on drug target; Selectivity: Singularity of effect on organ or tissue. 1) Interaction of drug —target • high specificity→highselectivity →high clinic pertinency →less side reaction • low specificity→low selectivity→ low pertinency → more side reaction and wide clinical use 2) high concentration of drug in the organ or tissue →high selectivity iodine→intaked by thyroid gland →high concentration→action on thyroid

6. Pharmacodynamics Basic Action α-adrenoceptors blockor α1↓→vasodilation→BP↓ ----↘ α2↓→NA release↑→β↑→heart ↑ ↑ Α1,α2-blockor (phentolamine) α1D,α1B↓→vasodilation→BP↓ α1A↓→smooth muscle of prostate↓ α1-blockor (prazosin) α1A↓→smooth muscle of prostate↓ (uroschesis of prostatic hyperplasia) α1A-blockor (tamsulosin) →

7. Pharmacodynamics Basic Action 4.therapeutic effect Therapeutic effect can be difined as the drug effects that are consistent with therapeutic purposes. etiological treatment Eliminate cause of a disease. (Chemotherapy…) symptomatic treatment Remission of symptoms or suffering of a disease. (analgesia, sedation…)

8. Pharmacodynamics Basic Action 5. adverse drug reaction，ADR* ADR can be defined as the drug effects that are not consistent with therapeutic purposes and induce harm to patientsin normal use and dose for a qualified drug. -- WHO-- • 5-10% of patients in hospital are because of ADR. 10-20% of patients in hospital suffer ADR. --WHO-- 106,000 patients in USA lost life from ADR in 2002. The cause of death was fourth mortality in USA.

9. Basic Action-adverse drug reaction Pharmacodynamics A type of ADR (augmented) The augmented effects of drug are too strong to induce harm following increasing dose (normal dosage). • dose–dependent • forecastable • high incidence rate • less seriousand • low mortality. A type of ADR (character) *side reaction, *toxic effect, after effect, *dependence

10. Basic Action-adverse drug reaction Pharmacodynamics B type of ADR (bizarre) The bizarre effects of drug are independent of pharmacological action. • not dose-dependent • difficult to forecast and find • low incidence rate • serious and high mortality B type of ADR (character) allergy, idiosyncratic reaction, teratogenesis, carcinogenesis

11. Pharmacodynamics A type of ADR A type of ADR (augmented) 1) Side reaction The reactions withoutrelationship to therapeutic purpose of a drug administrated in normal dose are induced in almost patients, because of low selectivityof the drug. therapeutic purpose therapeutic action side reaction

12. Pharmacodynamics A type of ADR 2) Toxic effect Pharmacological responsesare too strong and induce organic and functional injury in some patientswhen drug administration in normal dose and period because of hypersensitivity induced by individual variation, pathological stateand interaction of drugs.

13. Effects remain whendrug blood concentration is reduced below threshold concentration. Pharmacodynamics A type of ADR 3) After effect C TC T 4) Dependence New balance induced following repeated administration of some drugs.

14. Pharmacodynamics A type of ADR Physical dependence Addiction inducedfollowing repeat administration. The vital activity of body depends on drugs, the serious abstinence syndrome is induced after discontinue. psychic dependence Psychic desire andpleasant feeling are induced following the repeat. The mental state depends on drugs without abstinence after discontiune.

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

16. Pharmacodynamics B type of ADR B type of ADR (augmented) A drug as an antigen or semi- antigenproduces exceptional immunoreaction in minority of allergicpatients without relationship to pharmacological action and dose. (penicillin→ allergic shock) 1) allergic reaction 2) idiosyncraticreaction A drug produces exceptional reaction in minority of gene defect patients without relationship to pharmacological action.

17. Pharmacodynamics B type of ADR glucose-6-phosphate Dehydrogenase, G-6-PD Glucose ATP ADP G-6-P GSSG H2O2 ↑↑ NADP G-6-PD↓ GSH↓ NADPH↓ H2O↓ 6-PG Acid Hemolytic anemia sulfonamides vitamin K primaquine anminopyrine broad beans Absence of G-6-PD Oxidizing agent +

18. Thalidomide happening（1961） seal abnormity Pharmacodynamics B type of ADR Drug affects fetation forming teratism, especially early embryo. 3) teratogenesis pregnancy reaction gestation reaction

19. Pharmacodynamics B type of ADR 4) carcinogenesis Long osculation of chemical substances including drugs could induce malignancy or cancer, about 80%～85% of human cancers would be induced by chemical substances.. 5) mutagenesis Drug induce damnification of germ plasm (DNA). carcinogenesis mutagenesis teratogenesis

20. Pharmacodynamics Dose-response relationship Ⅱ、Dose-response relationship Graded • Continuous scale • • Measured in a single biologic unit • • Relates dose to intensity of effect • Mean ± standard difference (x ± s) • ( t test ) BP mmHg Dose Quantal • All-or-none pharmacologic effect • Population studies (χ2 test) • Relates dose to frequency of effect rate (%) Dose

21. Pharmacodynamics Dose-response relationship The antihypertensive effect of a new drug to blood pressure (mmHg) was researched in hypertensives Graded data Quantaldata

22. Ordinate Effects [D]/E Abscissa arithmetic logarithm Graded response Pharmacodynamics 1. Graded response rectangular hyperbola symmetry S curves (dose) Straight line E E [D] E [D] [D] Lg[D]

23. Threshold dose maximal dose minimal Toxic dose ↓↓↙ ├─┴┴─────┴─╂─┴───┴── D (C) ↑ common dose minimal lethal dose Graded response Pharmacodynamics effect Emax E logD (C) Kd D (C)

24. ① Threshold dose：Minimum effective dose ② Efficacy (Emax)：Maximum effect of a drug or the limit of the drug response. ③Potency：Dose inducing given effect, or a dose (KD) inducing 50% Emax. Dose or KD↑→ Potency↓ Efficacy is usually more important than potency in selecting drugs for clinical use. Graded response Pharmacodynamics

25. Graded response Pharmacodynamics ④ Slope ：Slope at 50% Emax (slope↑→range of common dose↓→less safety） : The limit of dose permitted in pharmacopeia for some drugs. ：The effective dose in most of patients. maximal dose＞common dose＞threshold dose ⑤ Maximal dose ⑥ Common dose

26. E B A C logD (C) Graded response Pharmacodynamics potency： efficacy： threshold dose： slope： Ａ＞Ｂ＞Ｃ Ｂ＞C ＞Ａ Ｃ＞Ｂ＞Ａ Ａ＝Ｂ＞Ｃ

27. Quantal response Pharmacodynamics 2. Quantal response (Qualitative Response) An all-or-none response to a drug and relates to the frequency with which a specific dose of a drug produces a specific response in a population. (e.g., death among the mice in a pre-clinical study or effective among the patients in a clinical trial. （response frequency or rate (%), χ2 test）

28. E D Quantal response Pharmacodynamics F % cumulative distribution

29. F F p D lgD lgD Quantal response Pharmacodynamics 1) Cumulative curve long tail S curves cumulative frequency or rate Ordinate (effects) probit unit（p） symmetry S curves arithmetic dose Abscissa (dose) straight line logarithm dose

30. Cumulative (effects) distributionfrequency or rate skew distribution arithmetic dose Abscissa (dose) normal distribution logarithm dose F F D logD Quantal response Pharmacodynamics 2) Distribution curve

31. E D Quantal response Pharmacodynamics • Individual variation: There is variation of sensitivity to a drug among population (patients or animals). • Supersensitivity or tolerance to a drug are produced in a few population, most of them are middle sensitivity. logD

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

33. (Median effective dose)：The dose at which 50% of individuals (experimental animals) exhibits specified effect.（Median lethal dose）：The dose requied to produce death in 50% of animals. Quantal response Pharmacodynamics Therapeutic index (TI): The index used forjudging drug's safety. TI＝LD50／ED50 ED50 LD50

34. The TI may be misleading if the dose-responses curves for effectiveness and toxicity have different slopes (i.e., not parallel). Therefore, the Safety index(SI) may be more useful. Quantal response Pharmacodynamics Safety index (SI) SI＝LD5/ED95

35. Mechanism of action of drugs Pharmacodynamics Ⅲ.Mechanism of action of drugs 1. Unspecific action 1) Alteration of chemical or physical condition of locale administered to: osmotic diuretics; antacid; osmotic laxatives.2) Participate in nutrition and metabolism of cells：Vitamin, ferrous sulfate、glucose.Calcium…

36. Mechanism of action of drugs Pharmacodynamics 2. Specific action:drug-receptors; drug-ion channels; drug-enzymes; 1) Influence on activity of enzymes： Insulin→oxygenase of glucose↑→blood sugar↓; Neostigmine→cholinesterase↓→ACh↑ 2) Action on ion-channel of：Antiarrhythmics 3)Action on release of transmiters or hormones： Ephedrine→release of noradrenaline↑ Iodide→release of thyroxine↓ 4) Drug-receptor*

37. Drug receptor Pharmacodynamics Ⅳ. Drug receptor 1. Drug-receptor concept The receptive substances of a cell or an organism that specifically interacts with their ligands (corresponding drugs, transmitter or hormone) and initiates the chain of biochemical and physiological changes. ligand：A corresponding drug, transmitter or hormone binding to a receptor. Receptor

38. Pharmacodynamics Drug receptor Drug receptor 2. Characters of drug-receptor interaction 1) Saturation: Because of finitude of number of receptor molecule for unlimited drug molicular →Emax 2) Specific binding 3) Reversible binding: ionic bond, hydrogen bond, molecular attraction covalend bond. Therefore, there is competitive binding between 2 drugs binding to same receptor.

39. Drug-receptor binding Theory Pharmacodynamics 3. Drug-receptor binding Theory 1) Receptor occupancy theory: It is assumed that response emanates from the receptor occupied by a drug. The greater response observed, the more receptor occupation.

40. E Emax (α) KD C 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

41. 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 Active receptor inactive receptor agonist partial agonist antagonist

42. Parameter of drug-receptor Pharmacodynamics 4. Parameter of receptor-specific interaction 1) Affinity (or potency) The ability of a drug's binding to receptor. A drug's affinity for binding its receptor determines the concentration of drug required to occupy 50% its receptor or elicits 50% Emax. The greater concentration required, the weaker affinity of a drug.

43. Emax Emax c c 50% 50% KD pD2 -log c C Parameter of drug-receptor Pharmacodynamics pD2 is 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.

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

45. Classification of drugs Pharmacodynamics 4. Classification of drugs binding to receptor agonist partial agonist antagonist Inverse agonist

46. Competitive antagonism Pharmacodynamics 5. Competitive antagonism 1) antagonist-agonist: In the presence of a fixed concentration of antagonist, dose-effect curves of the agonist would be shifted following increasing concentration of agonist: a. Threshold concentrations are increased; b. Curves is shifted to the right in equal slope; c. Emax is unchanged.

47. E AA+B1 A+B2 1 2 3 C (agonist) KD0 KD1 KD2 Competitive antagonism Pharmacodynamics pA2: The parameter of Blocker’s affinity. The negative logarithm of molarity(mol) of a blocker required to inducing same effect (or 50% Emax) in double concentrations of agonist. KD1 / KD0 = 2 pA2=-log[B1]

48. a. Threshold concentrations↓ b. Emax is unchanged; c. Curves is shifted to the left at low concentration of agonist (partial agonist would like agonist). d. Curves is shifted to the right at high concentration of agonist (like antagonist).  Competitive antagonism Pharmacodynamics 2)partial agonist–agonist: In the presence of a fixed concentration of partial agonist, dose-effect curves of the agonist would be altered following increasing concentration of agonist. A A+P' A+P'' E lgC B A

49. A A+P' A+P'' E lgC B A Competitive antagonism Pharmacodynamics  A low concentration of agonist B high concentration of agonist A

50. Noncompetitive antagonism Pharmacodynamics 6. Noncompetitive antagonism After administration of a noncompetitive antagonist, high concentrations of agonist cannot completely overcome the antagonism and Emax can be reduced. Dose-effect curves of agonist are altered: a. Threshold concentrations are unchanged; b. Shifted to the right ; c. Emax is decreased.