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I wish you all a very blessed Ramadan 10% 10% 80% examination ! (100%) ( 80%) Final = examination + result score select question (10%) attendance and respondence in class sign in class (10%) + experiment record sign in and experiment record Pharmacology Pharmacology 1. General Principles 2. Peripheral Nervous Drugs 3. Central Nervous Drugs 4. Cardiovascular and Blood Drugs 5. Splanchnic Drugs 6. Endocrine Drugs 7. Chemotherapeutic Drugs (7 sections ) PART 1 GENERAL PRINCIPLES OF PHARMACOLOGY 1. Introduction of Pharmacology 2. Pharmacodynamics 3. Pharmacokinetics 4. Impact factors Yuan Bing-Xiang (袁秉祥) Department of Pharmacology,Medical School, Xi’an Jiaotong University, Tel: 82657724, Email: [email protected] PHARMACOLOGIC PRINCIPLES CHAPTER 1 Introduction of Pharmacology GENERAL PRINCIPLES Pharmacology Pharmacodynamics, PD drugs Impact factors organisms Pharmacokinetics, PK Pharmacology can be defined as the science or course studying interaction between drugs and organisms (bodies) . Pharmacology GENERAL PRINCIPLES human being drugs Bodies animals pathogens pathogenic microorganisms parasites bacteria virus fungus tumor cells Peripheral Nervous drugs Central Nervous drugs Cardiovascular and Blood rugs Splanchnic drugs Endocrine drugs drugs act to systems Chemotherapeutic drugs ― drugs act to pathogens drugs bodies GENERAL PRINCIPLES Pharmacology Drugs are the substances or compounds administered beneficially altering biochemical and physiological states of the body, applied to prevent, treat or diagnose diseases. Poisons are the substances or compounds inducing the undesirable or toxic reactions on body in smaller dose. no strict limit between drugs and poisons GENERAL PRINCIPLES Pharmacology Pharmacodynamics (drug acts on body) Drug action effects Primary acting on the target Secondary Inducing effects in the organ cell signal transduction (mechanism of effect) drug-protein(receptors; ion channels; enzymes; transporter… E KD therapeutic effects adverse reaction dose-effect curves →PD parameters (KD, EMAX…) Dose Pharmacology GENERAL PRINCIPLES Pharmacokinetics (body acts on drug) Undergoing of drug in body absorption transportation distribution excretion biotransformation C-T curves PK parameters are from C-T curves (drug blood Concentration-Time curves) t1/2, Ka, Ke, F, Vd… C C-T curves T PHARMACOLOGIC PRINCIPLES CHAPTER 2 Pharmacodynamics (drug Acts on body) Basic Action Pharmacodynamics Ⅰ. Basic actions or effects of drug 1. Excitation and Inhibition The intrinsic functions of body are altered by drugs: 1) Excitation or stimulation:The functions are increased by drugs. (contraction, heart rate↑, BP↑, unstable or restlessness …) 2) Inhibition:The functions are decreased by drugs. (relaxation, heart rate↓, Bp↓, tranquilize and sedation …) Basic Action Pharmacodynamics 2. Local effects and general effects 1) Local effects are the effects of drug induced in administered locale before absorption. 2) General effects (absorptive effects, systemic effects) are the effects of circulated drugs induced in general system (injection or after absorption). Basic Action Pharmacodynamics For example: magnesium sulfate (MgSO4) Orally →80% no absorption → Local effects → intestinal osmotic pressure↑( volume ↑) → catharsis (purgation) → elimination of toxin cholagogic effect (for cholecystitis) Orally →20% absorption Injection →to circulation →general effects → vasodilation →BP↓ ------------------- central inhibition → anticonvulsion treatment of eclampsia Gravida With hypertension and convulsion Basic Action Pharmacodynamics 3. Specificity: Singularity of actions on target Selectivity: Singularity of effects in organ or sys. drug-target→specificity → selectivity Drug-subtype of receptor →higher specificity →higher selectivity┌→tight clinic indication └→less side reaction Drug-type of receptor (all subtypes of receptor) →lower specificity →lower selectivity ┌→wide clinic indication └→ more side reaction Pharmacodynamics Basic Action For example α-adrenoceptors blocker α α1 α1A α1B α1D α 2 (presynaptic) α1↓→vasodilation→BP↓ ↘(reflect) α1 α2-blocker (phentolamine) α ↓→NA release↑→β↑→heart ↑ ↑ 2 cardiopalmus, arhythmia α1-blocker (prazosin) α1D α1B ↓→ vasodilation→BP↓ α1A↓→smooth muscle of prostate↓ α1A-blocker (tamsulosin) → α1A↓→smooth muscle of prostate↓ (relieving of uroschesis of prostatic hyperplasia) Basic Action Pharmacodynamics 4. therapeutic effects are the effects that are consistent with therapeutic purposes. (in normal dose and in almost patients) Etiological treatment eliminating causes of disease. (for instance, chemotherapy…) Symptomatic treatment remission of symptoms or suffering of disease. (for instance, analgesia, sedation…) Basic Action Pharmacodynamics 5. adverse drug reactions,ADRs * ADRs can be defined as the drug effects that are not consistent with therapeutic purposes and induce harms to patients. 10-20% of patients in hospital suffer ADR. --WHO-106,000 patients in USA lost life from ADRs every year. First killer:cardiac disease, 743,000 The cause Second killer:cancer, 529,000 of death Third killer:stroke, 150,000 Fourth killer:ADRs, 106,000 Fifth killer:drug abuse, 80,000 Vietnam war (10 AIDS≈road accident, 41,000 years):56,000 Pharmacodynamics ADR 1) Side reaction The light 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. The lower selectivity, the wider clinic indication and more side reaction. therapeutic purpose therapeutic effects Atropine →M↓ side reactions A: smooth muscle ↓→spasmolysis……intestinal tympanites (stomachache) B: gland ↓→bronchus secrete↓……… dry mouth (preanesthetic medication) C: mydriasis→intraocular tension↑……eyeground check ADR Pharmacodynamics 2) Toxic effect Pharmacological effects are too strong and induce organic and functional injury in some patients when high dose and long drug administration. aminoglycosides→injury of auditory nerve→deaf dumbness Pharmacodynamics ADR 3) After effects Effects remain when drug blood concentration is reduced below threshold concentration. C TC T Transient Phenobarbital ┌ drowsiness in early morning └ nightmare in next night duration Cortine (long administration)→stop→ persistent hypofunction of adrenal cortex Pharmacodynamics ADR 4) Dependence The physical and psychic dependent states are induced following repeated drug administration, displaying compulsive, continual hunt to drugs (or narcotics). First drug administration Diamorphine(heroin) Dependence Pleasant feeling discontinue discontinue Mental desire Ice,benzedrinum (lifetime) Repeated drug administration Abstinence syndromes (5~7days) Grave social problem Vicious cycle Addict: lost of personality, responsibility and shame→crime rate↑ ADR Pharmacodynamics Physical dependence: Addiction induced following repeated administration. The vital activity depends on drugs, the serious abstinence syndromes could be induced after discontinue. Psychic dependence: Psychic desire and pleasant feeling are induced following the repeat. The mental state depends on drugs without abstinence syndromes after discontiune. Ice,benzedrinum Pharmacodynamics 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 ADR 5) allergic reaction The exceptional immunoreaction is produced by a drug as an antigen or semi-antigen in minority of allergic patients without relationship to pharmacological action and dose (in any dose). • penicillin→allergic shock (Ⅰtype) (immediate allergy) • qunine→hemolytic anemia (Ⅱtype) (cytolytic type hypersensitivity) • sulfa→drug fever or eruption (Ⅳ type) (delayed allergy) • Ⅲ type(immune complex type)is seldom seen Pharmacodynamics ADR 6) idiosyncratic reaction The exceptional reaction produced by a drug in minority of gene defect patients without relationship to pharmacological action. sulfonamides vitamin K primaquine broad beans Absence of G-6-PD Oxidizing Hemolytic Anemia & jaundice glucose-6-phosphate Dehydrogenase, G-6-PD Pharmacodynamics Dose-response relationship Ⅱ、Dose-response relationship The effects of a hypotensive drug on BP hypertensives graded response BP↓(MMHg) quantal response 10 mmHg↓=effective 1 2 3 4 5 6 7 8 9 10 statistics 15 20 8 12 6 16 25 9 22 19 15.2±6.4 + + - + - + + - + + 70% (millimeters of mercury) graded response: measured effects indicated in biologic unit (mmHg) quantal response: all-or-none effect indicated in frequency (population) or rate. x S(mean±standard deviation) Dose-response relationship Pharmacodynamics 1. Graded response (Quantitative response) Graded response is the quantitative relationship between dose and measured effects indicated in biologic unit and continuous scale. BP(mmHg), RBC(1012/L), cholesterol (mmol/L) …… Graded response Pharmacodynamics Dose-effect curve of graded response Project 纵坐标Y-axis 横坐标X-axis E Emax hyperbola Kd E Symmetry S curve Log D (C) Threshold maximal minimal dose dose Toxic dose ↓ ↓ ↙ ├─┴┴─────┴─╂─┴───┴── D (C)↑ common minimal dose lethal dose D (C) Graded response Pharmacodynamics ① Threshold dose :Minimum effective dose ② Efficacy (Emax) :Maximum effect or the limit of the drug response. ③ Potency :Dose inducing given effect, or a dose (KD) inducing 50% Emax. Dose or KD↑→ Potency↓ 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 log D (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) The qualitative relationship between dose and all-or-none effect is indicated by the frequency (population) or rate. (e.g., the death rate or population among mice in a pre-clinical study or effective rate or population among the patients in a clinical trial. Quantal response Pharmacodynamics D (mg) 1 1.1 1.2 1.3 F 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 percentage E 1.4 1.5 1.6 1.7 1.8 1.9 F cumulative distribution D supersensitivity tolerance % 50 100- cumulative 40 8030 6020 40- 10 20- 0 0 distribution lgD distribution curve→Individual variation (sensitivity). cumulative curve→qualitative parameters (LD50, ED50) 2.0 Quantal response Pharmacodynamics 1) Cumulative curve F F (%) P (probit) (%) D long tail S curves logD symmetry S curves logD straight line 2) Distribution curve F F D skew distribution logD normal distribution Quantal response E(%) 100% 95% Pharmacodynamics toxicity or death effective 50% cardiac glycoside ED95 5% ED50 ED95 LD5 LD50 Therapeutic index (TI) = LD50/ED50 Safety index (SI)=LD5/ED95 dose Quantal response Pharmacodynamics Therapeutic index (TI) and safety index (SI) are used for judging drug's safety. TI=LD50/ED50 SI=LD5 / ED95 ED50 (Median effective dose):the dose required to produce specified effect in 50% individuals (experimental animals). LD50 (Median lethal dose):The dose required to produce death in 50% of animals. Drug receptor Pharmacodynamics Ⅲ. Drug receptor 1. Drug-receptor concept Receptor The receptive substances (proteins) of cell (membrane) specifically interact with their ligands (corresponding drugs, transmitter, hormone, autacoids) and initiate the chain of signal transduction and biochemical and physiological changes. ligands: corresponding drugs, transmitters, hormones or autacoids binding to their special receptor. Drug receptor Pharmacodynamics 2. Characters of drug-receptor interaction 1) Saturation: Because of finitude of number of receptor molecules or unlimited drug molecules, the drug-receptor binding is limited. →Emax 2) Specific binding (lock-key) 3) Reversible binding 4) High potency (affinity) →low KD (dose) 5) Competitive binding 2 drugs binding to same receptor. a antagonist is competitive with an endogenous agonist Drug-receptor binding Theory Pharmacodynamics 3. Drug-receptor binding theory 1) Receptor occupancy theory: It is assumed that drug responses could be initiated from the receptor occupied by a drug. The greater response observed, the more receptor occupied. 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) E Log[D] KD [D] 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) is drug concentration occupying 50% of receptors. 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 agonist partial agonist Positive effect active receptor antagonist inactive receptor Negative effect Inverse agonist Parameter of drug-receptor Pharmacodynamics 4. Parameter of drug-receptor interaction 1) Affinity (or potency) is the ability of a drug binding to its receptor. Affinity is the concentration of drug required to occupy 50% its receptor or elicits 50% Emax. The greater concentration (KD) required, the lower 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 E Emax 50% E Emax 50% KD pD2 [D] -log [D] The more KD, the low agonist's affinity; The more pD2, the more agonist's affinity. D Parameter of drug-receptor 2) Intrinsic activity (or efficacy) Pharmacodynamics The ability of a drug inducing effect after binding to receptor. The faster dissociation rate (k2), the greater Emax, and the greater intrinsic activity. Classification of drugs Pharmacodynamics 3) 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 Drug-receptor binding Theory Pharmacodynamics 4)straight formula of hyperbola KD E [D]+[R] hyperbola [D] α [DR]┄→E D [ DR ] [ RT ] K D D Clark equation Scott method DY = [D] E E straight line [D] k2 D R KD k1 DR D E Emax K D D dose-effect formula 1b x + KaD D Emax Emax Scott straight formula b =1/Emax,a=KD/Emax, Emax=1/b,KD=a/b, 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 50% KD D KD 1 XD+ a Y = b E Emax Emax [D]/E a: intercept [D] [D] linear regression: Emax=1/b=80.5mm, KD=a/b=3.055×10-8 mol/L,pD2=-logKD =7.515. Competitive antagonism Pharmacodynamics 4. Competitive antagonism 1) agonist-antagonist: In the presence of a fixed concentration of antagonist, dose-effect curves of the agonist would be shifted to the right : a. Threshold concentrations are increased; b. Curves is shifted to the right in equal slope; (parallel) c. Emax is unchanged. Competitive antagonism Pharmacodynamics pA2 is the parameter of Blocker (antagonist) affinity, or the negative logarithm of molarity (mol) of a Blocker in double KD of Agonist. fictitious E Emax A A+BF A+B1 A+B2 A+B3 fictitious KDF / KD0 = 2 50% pA2=-log[BR] KD0 KDF KD1 KD2 KD3 [D] (agonist) [A]+[R] = [RA]─→E log(R-1) [B]+[R] = [RB] . . . [RT]=[R]+[RA]+[RB] . Y =b X + a log(R-1)=-(-log[B])+(-logK B) R= KDx / KD0 (R1, R2, R3…) linear regression: x= -log[B], y= log(R-1) according to the concept of pA2, R=2, y=0, pA2 (-logKB)= -log[B] pA2 -log[B] ACh [D] (mol/L) 3×10-9 10-8 3×10-8 10-7 3×10-7 10-6 3×10-6 Atropine [B] 0 7 20 40 62 73 10-8 (mol/L) 0 8 18 44 58 72 3×10-8 (mol/L) 0 0 5 16 47 64 74 10-7 (mol/L) 0 0 0 9 27 45 65 10-6 73 energy transducer pre-amplifier E fictitious K DF 2 KD0 KDF KD0 KD1 KD2 KD3 [D] R= KDx / KD0 (R1= KD1 / KD0, R2= KD2 / KD0, R3= KD3 / KD0 …) linear regression Y =b X + a ) log(R-1)=-(-log[B])+(-logK B R=2 or y=0, pA2= 8.05 log(R-1) pA2 -log[B] Competitive antagonism Pharmacodynamics 2) agonist-partial 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). E A A+P' A+P'' logC Competitive antagonism E Pharmacodynamics A A+P' A+P'' logC A A low concentration of agonist B high concentration of agonist Noncompetitive antagonism Pharmacodynamics 6. Noncompetitive antagonism After administration of a noncompetitive antagonist (phenoxybenzamine), high concentrations of agonist cannot completely overcome the antagonism and Emax can be reduced. Dose-effect curves of agonist are altered as that: a. Threshold concentrations are unchanged; b. Emax is decreased; c. KD is unchanged theoretically. Noncompetitive antagonism E Emax Pharmacodynamics A A+N1 1/2EmaxA+N 2 A+N3 KD fictitious pD2′= -log[N2] C (agonist) pD2′: The parameter of noncompetitive antagonist affinity. The negative mol of a noncompetitive antagonist required to decrease Emax by 50%. Pharmacodynamics The End of pharmacodynamics