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PHARMACOLOGIC PRINCIPLES CHAPTER 3 Pharmacodynamics (drug Acts on body) Basic Action Pharmacodynamics 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 …) Basic Action Pharmacodynamics 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. 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 → General action site ↗vasodilation → BP↓ ----------↘central inhibition→sedation Treatment of eclampsia gravidarum Basic Action Pharmacodynamics 3. Specificity: Singularity of action on drug target; Selectivity: Singularity of effect on organ or tissue . 1) Interaction of drug —target high specificity→ high selectivity →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 Pharmacodynamics Basic Action α-adrenoceptors blockor Α1,α2-blockor (phentolamine) α1-blockor (prazosin) α1↓→vasodilation→BP↓ ----↘ α2↓→NA release↑→β↑→heart ↑ ↑ α1D,α1B ↓→ vasodilation→BP↓ α1A↓→smooth muscle of prostate↓ α1A-blockor → α1A↓→smooth muscle of prostate↓ (tamsulosin) (uroschesis of prostatic hyperplasia) 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…) Basic Action Pharmacodynamics 5. adverse drug reaction,ADR * ADR can be defined as the drug effects that are not consistent with therapeutic purposes and induce harm to patients in 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. 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). A type of ADR (character) • dose–dependent • forecastable • high incidence rate • less serious and low mortality. *side reaction, *toxic effect, after effect, *dependence Basic Action- adverse drug reaction Pharmacodynamics B type of ADR (bizarre) The bizarre effects of drug are independent of pharmacological action. B type of ADR (character) • not dose-dependent • difficult to forecast and find • low incidence rate • serious and high mortality allergy, idiosyncratic reaction, teratogenesis, carcinogenesis Pharmacodynamics A type of ADR A type of ADR (augmented) 1) Side reaction The reactions without relationship to therapeutic purpose of a drug administrated in normal dose are induced in almost patients, because of low selectivity of the drug. therapeutic action therapeutic purpose side reaction A type of ADR Pharmacodynamics 2) Toxic effect Pharmacological responses are too strong and induce organic and functional injury in some patients when drug administration in normal dose and period because of hypersensitivity induced by individual variation, pathological state and interaction of drugs. A type of ADR Pharmacodynamics 3) After effect Effects remain when drug blood concentration is C reduced below threshold TC concentration. T 4) Dependence New balance induced following repeated administration of some drugs. A type of ADR Pharmacodynamics Physical dependence Addiction induced following repeat administration. The vital activity of body depends on drugs, the serious abstinence syndrome is induced after discontinue. psychic dependence Psychic desire and pleasant feeling are induced following the repeat. The mental state depends on drugs without abstinence after discontiune. Pharmacodynamics A type of ADR food drug success happy amuse sports sex starvation thirsty failure go blind abstinence syndrome misery ache disappointed pain hometown family drug miss good friend lover Pharmacodynamics B type of ADR B type of ADR (augmented) 1) allergic reaction A drug as an antigen or semi- antigen produces exceptional immunoreaction in minority of allergic patients without relationship to pharmacological action and dose. (penicillin→ allergic shock) 2) idiosyncratic reaction A drug produces exceptional reaction in minority of gene defect patients without relationship to pharmacological action. Pharmacodynamics B type of ADR Glucose ATP G-6-P G-6-PD↓ glucose-6-phosphate Dehydrogenase, G-6-PD ADP NADP NADPH↓ 6-PG Acid Absence of + Oxidizing G-6-PD agent GSSG H2O2 ↑↑ GSH↓ H2O↓ Hemolytic anemia sulfonamides vitamin K primaquine anminopyrine broad beans B type of ADR Pharmacodynamics 3) teratogenesis Drug affects fetation forming teratism, especially early embryo. Thalidomide happening(1961) seal abnormity pregnancy reaction gestation reaction 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). mutagenesis carcinogenesis teratogenesis Dose-response relationship Pharmacodynamics Ⅱ、Dose-response relationship Graded BP mmHg • Continuous scale • Measured in a single biologic unit • Relates dose to intensity of effect • Mean ± standard difference (x ± s) ( t test ) Dose Quantal • All-or-none pharmacologic effect rate (%) • Population studies (χ2 test) • Relates dose to frequency of effect Dose Pharmacodynamics Dose-response relationship The antihypertensive effect of a new drug to blood pressure (mmHg) was researched in hypertensives Graded data control -21 -17 -22 -25 -18 -29 -20 -31 -25 -18 -22.6±4.8 test -25 -31 -28 -27 -18 -35 -28 -28 -35 -28 -28.3±4.9 Statistics (T test) Significant P<0.05 Quantal data control + - + + - + + + + - 7/10 70% test + + + + - + + + + + 9/10 90% Statistics (χ2 test) Not significant P>0.05 Graded response Pharmacodynamics 1. Graded response rectangular hyperbola Ordinate Effects [D]/E Abscissa arithmetic symmetry S curves (dose) Straight line E logarithm [D] E E [D] Lg[D] [D] Graded response Pharmacodynamics effect Emax E Kd logD (C) D (C) Threshold maximal minimal dose dose Toxic dose ↓ ↓ ↙ ├─┴┴─────┴─╂─┴───┴── D (C)↑ common minimal dose lethal dose Graded response Pharmacodynamics 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 potency in selecting drugs for clinical use. than Graded response Pharmacodynamics ④ Slope :Slope at 50% Emax (slope↑→range of common dose↓→less safety) ⑤ Maximal dose : The limit of dose permitted in pharmacopeia for some drugs. ⑥ Common dose:The effective dose in most of patients. maximal dose > common dose > threshold dose Graded response Pharmacodynamics E B A C logD (C) potency:A>B>C efficacy:B>C >A threshold dose:C>B>A slope:A=B>C 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) Quantal response F % Pharmacodynamics D (mg/kg) 1 distribution 0 2 4 6 10 8 6 5 4 3 2 cumulative 0 2 6 12 22 30 36 41 45 48 50 distribution 0 4 8 12 20 16 12 10 8 6 4 cumulative 0 4 12 24 44 60 72 82 90 96 100 E 1.2 1.4 1.6 1.9 2.3 2.7 3.1 3.7 4.3 cumulative distribution D 5.1 Quantal response Pharmacodynamics 1) Cumulative curve Ordinate (effects) Abscissa (dose) F long tail S curves cumulative frequency or rate probit unit(p) symmetry S curves arithmetic dose straight line logarithm dose F D p lgD lgD Quantal response Pharmacodynamics 2) Distribution curve Cumulative (effects) Abscissa (dose) distribution frequency or rate skew distribution arithmetic dose normal distribution logarithm dose F F D logD 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. E D logD Quantal response Pharmacodynamics effective toxicity or death 100% 95% 50% ED95 5% ED50 ED95 LD5 LD50 Therapeutic index (TI) = LD50/ED50 Safety index (SI)=LD5/ED95 dose Quantal response Pharmacodynamics Therapeutic index (TI): The index used for judging drug's safety. TI=LD50/ED50 ED50 (Median effective dose):The dose at which 50% of individuals (experimental animals) exhibits specified effect. LD50(Median lethal dose):The dose requied to produce death in 50% of animals. Quantal response Pharmacodynamics Safety index (SI) 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. SI=LD5/ED95 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… Mechanism of action of drugs Pharmacodynamics 2. Specific action: drug-receptors; drugion 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 * Drug receptor Pharmacodynamics Ⅳ. Drug receptor 1. Drug-receptor concept Receptor 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. Drug receptor Drug receptor Pharmacodynamics 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. 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. 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: [D]+[R] E α KD [DR]┄→E Emax (α) KD C KD: dissociation constant 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. Drug-receptor binding Theory 2) Rate theory: Pharmacodynamics [D]+[R] k1 [DR] K2 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 agonist inactive receptor partial agonist antagonist 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. 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. pD = -log K 2 c Emax 50% c Emax 50% KD pD2 C -log c The more KD, the low agonist's affinity; The more pD2, the more agonist's affinity. D 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. Classification of drugs Pharmacodynamics 4. Classification of drugs binding to receptor Classification occupancy affinity Intrinsic activity rate k1 k2 agonist antagonist + ++ + ++ + - + - partial agonist + + + + Inverse agonist + + (opposite effect) + + agonist partial agonist antagonist Inverse agonist 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. 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. A E A+B1 A+B2 KD1 / KD0 = 2 pA2=-log[B1] 1 KD0 2 KD1 3 C (agonist) KD2 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. 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). A A+P' A+P'' E A B lgC Competitive antagonism A A+P' A+P'' E A A A Pharmacodynamics B low concentration of agonist lgC B high concentration of agonist 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. Noncompetitive antagonism E Emax Pharmacodynamics A A+N1 () 1/2EmaxA+N 2 pD2′= -log[N2] A+N3 KD C (agonist) pD2′: The parameter of noncompetitive antagonist affinity. The negative mol of a noncompetitive antagonist required to decrease Emax by 50%. pD2 Pharmacodynamics ACh (mol/L) E (mm) E E 10-9 3×10-9 10-8 3×10-8 10-7 3×10-7 10-6 0 7 20 40 62 73 73 D E max K D D Emax D KD 1 XD+ a Y = b E Emax Emax [D]/E 50% a: intercept KD [D] [D] linear regression: Emax=1/b=80.5mm, KD=a/b=3.055×10-8 mol/L,pD2=-logKD =7.515. Ach [D] (mol/L) 3×10-9 10-8 3×10-8 10-7 3×10-7 10-6 3×10-6 Atropine [A] 0 7 20 40 62 73 10-8 0 8 18 44 58 72 3×10-8 0 0 5 16 47 64 74 10-7 0 0 0 9 27 45 65 10-6 73 E KD0 KD1 KD2 KD3 KDx / KD0=2 [D] log(R-1)=-(-log[A])+(-logKA) Y = b X + a log(R-1) pA2 -log[A] log(R-1)=-(-log[A])+(-logKA) R= KDx / KD0 (R1, R2, R3) linear regression: R=2 or y=0, pA2= 8.05 Pharmacodynamics The End of pharmacodynamics PHARMACOLOGIC PRINCIPLES CHAPTER 4 Impact factor to pharmacodynamics and pharmacokinetics Impact factor Drug . Structure Polar, pKa Solubility Dosage form Product No PK drug Administration Dosage Route Time, Interval Drug interaction Repeat use Withdraw PD Physical sex age weight Mentality Illness Heredity living custom Individual variation body The end of PHARMACOLOGIC PRINCIPLES