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Presentation on theme: " Pharmacology Chapter 1.Introduction About Pharmacology Chapter 2.Pharmacokinetics What the body does to a drug Chapter 3.Pharmacodynamics."— Presentation transcript:


2 Pharmacology

3 Chapter 1.Introduction About Pharmacology Chapter 2.Pharmacokinetics What the body does to a drug Chapter 3.Pharmacodynamics What a drug does to the body Chapter 4.Factor affecting drug efficacy How to use a drug rationally General Principles

4 Chapter 1 Introduction

5 What is pharmacology Pharmacology is the science of studying the effect of drugs on living organisms. Pharmacology is the science of studying the effect of drugs on living organisms. Scientific study of the interactions between drugs and the body. Scientific study of the interactions between drugs and the body.

6 Drug Action and Mechanism Absorption, Distribution, Metabolism, Excretion Pharmacodynamics, PD Pharmacokinetics, PK Drug-body interaction

7 What is drug ( A chemical substance that can modulate the current physiological status quo of a biological system. ( A chemical which is utilized for the diagnosis, prevention and cure of an unwanted health condition (definition by FDA)

8 Ancient Natural products Plants Animals Minerals Modern Active principles of natural products Artificial synthetics Full synthetic Semi synthetic Biological engineering Source of drugs

9 Poppy Raw opium Opium tincture Morphine Codeine … From natural product to active principles

10 foxglove digoxin deadly nightshade atropine From natural product to active principles

11 1.Explore the pharmacokinetic and pharmacodynamic features of drugs 2.Probe the mystery of life process 3.Find and develop new drugs Missions of pharmacology

12 The Long Road to a New Medicine Process of Drug Development synthesisScreen Phase II Clinical trial Phase III clinical trial Phase I clinical trial Animal PK/PD/Tox Dosage form Candidate chemicals Design Application Marketing

13 History of medicines Phase I: Using natural products to treat diseases China: Sheng Nongs Herbal Classic ( ), described 365 TCM; Compendium of Materia Medica ( ), described 1892 TCM Greeks; e.g. Dioscorides: De materia medica ( ), described 600 plants Islamic physicians; e.g. Avicenna: Herbal medicine Phase II: Scientific Using pure drug compounds Understanding physiopathology of diseases and pharmacology of drugs

14 1.Francois Magendie ( ), a French physiologist Experimental procedures with animals for determination of drug action. 2.Fredrick Surturner ( ) isolated the chief alkaloid of opium, Morphine – pure chemicals and repeated quantitatively 3.Claude Bernard ( ) investigated the plant extract curare and proposed a site of action for this agent. 4.Rudolph Buchheim ( ). In 1847 established the first laboratory in the basement of his home in Dorpat which is the cradle of experimental pharmacology. 5.Oswald Schmiedeberg ( ). In 1872 set up an institute of pharmacology in Strasbourg, which became a mecca for training in pharmacology Modern pharmacology originated in Europe History of pharmacology

15 Chapter 2 Pharmacokinetics

16 Why do me need to know PK? Optimize drug therapy to obtain a predictable response! 1.Drug of choice 2.How much 3.How often 4.For how long The dose makes medicine –Paracelsus 1538

17 Therapeutic Goal is to: Achieve drug concentrations… at the site of action (target tissue)… that are sufficiently high enough… to produce the intended effect… without producing adverse drug reactions.

18 Drug Administration Drug Concentration in Systemic Circulation Drug in Tissues of Distribution Drug Metabolism or Excreted Drug Concentration at Site of Action Pharmacologic Effect Clinical Response ToxicityEfficacy Pharmacokinetics Pharmacodynamics Absorption DistributionElimination

19 Drug at absorption site Metabolites Excreted drug Drug in body Time % of dose

20 Section 1 Ch. 2 Drug Transport

21 Transfer of drugs across Membranes Filtration (Aqueous diffusion) Extracellular Intracellular Simple diffusion (Lipid diffusion) Carrier-mediated transport 1.Active transport 2.Facilitated diffusion

22 1 Simple diffusion Passive process, concentration gradient dependent, requires no energy Molecules move from area of high to low concentration Rate of diffusion is proportional to: 1.lipid solubility, the greater the lipid solubility the faster the rate of diffusion 2.pKa of molecules 3.Concentration difference between both sides (Diffusion through lipid bi-layer

23 Acidic drug:HA H + + A (ionized) Basic drug: BH + H + + B (unionized) Ion trapping (Cell membranes are less permeable to ionized compounds H+H+ HA A-A- H+H+ A-A- B BH + H+H+ H+H+ B

24 Ka = [ H + ] [ A ] [HA] pKa = pH - log [ A ] [HA] [ A ] [HA] 10 pH-pKa = Acidic drug Ionization depends on pH and pKa Basic drug pKa-pH

25 A + H + HAHA H + + A [ A ] [HA] 10 pH-pKa = Plasma pH=7Stomach pH= Cromolyn Sodium ( ) pKa=2, Acidic = = 10 5 [ A ] [HA] 10 pH-pKa = = = 10 2 Total Example

26 (Small molecules diffusion through aqueous channels 2. Filtration Water solubility Small molecular Diameter of aqueous channels in Capillary wall: 4-8Å =10 10 m ) Only for water, urea filtration >100 not permeable

27 Intracellular cleft: 40Å, all solute in blood are permeable except protein Intracellular cleft Intracellular cleft: big hole

28 3. Carrier-mediated transport Active transport Against concentration gradient Requires coupling of energy (hydrolysis of ATP) Facilitated diffusion Along concentration gradient Requires no energy 1.Requiring carrier 2.Structure specific 3.Saturable (functional protein molecules are limited) 4.Competitive inhibition

29 Disposition of drug in the body Absorption, Distribution, Metabolism and Excretion Section 2 Ch. 2

30 (Transfer of a drug from its site of administration to the blood stream Oral ingestion Major site: Longer transit time = 3 hours Larger surface area of villus Abundant blood flow pH5-8 good for most of drugs intestine 1 Absorption

31 Oral cavity 0.5-l.0 m 2 Stomach m 2 Small intestine 100 m 2 Large intestine m 2 Rectum 0.02 m 2 Ficks Law of Diffusion Flux (molecules per unit time) (C1 C2)× Area×Permeability coefficient Thickness

32 First pass elimination Metabolism Site of action Intestine wall Portal vein Before drug reaches the systemic circulation, the drug can be metabolized in the liver or intestine. Stool

33 Passive diffusion Filtration Rapid and complete absorption Intramuscular & subcutaneous injection

34 Inhalation Gaseous or volatile substances and aerosol can reach the absorptive site of the lung. Highly available area of absorption (alveolus area = m 2 ; pulmonary capillary area = 80 m 2 Rapid, no first pass effect, directly reach desired site of action (asthma, COPD)

35 Transdermal Transdermal skin patches- Lipid soluble drugs can be absorpted via skin Nifedipine Glycerol trinitrate

36 ( Process by which a drug reversibly leaves he blood stream and enters the interstitial or cellular fluids of the body. 2 Distribution Free drug Bound Drug Metabolites Receptor Free bound Tissue Free bound Excretion Blood

37 Physical and chemical characteristics of the drug (lipid to water partition coefficient) Cardiac output Capillary permeability in various tissues Lipid content of the tissue Binding to plasma protein and tissue Factors that affect drug distribution

38 Plasma protein binding Reversible equilibrium Reversible equilibrium Saturable Saturable DP: Non-permeable Nonspecific & competitive Nonspecific & competitive [DP] [P T ] K D +[D] [D] D P DP KDKD Plasma proteins 1.Albumin: Weak acids 2.alpha-acid glycoprotein: Weak bases Effects of plasma protein binding 1.Free fraction: active, excreted, metabolized 2.the more binding, the less active drug 3.the more binding, the less excreted and metabolized: longer half-life

39 Drug A: 1000 molecules 99.9% bound 1 molecules free 100-fold increase in free pharmacologically active concentration at site of action. Effective TOXIC + Drug B w/ 94% bound 90.0% bound 100 molecules free Drug interaction of plasma protein binding

40 Blood-brain barrier, BBB Tight junctions Endothelial cells and associated astrocytes are stitched together by structures The row of capillary epithelial cells that regulates transfer of drug to the brain. Only drugs having a high lipid-water partition coefficient will diffuse into the brain.

41 Structure (a number of tissue layers) between fetal and maternal blood. Drugs must be able to diffuse across lipid barriers to enter the fetus. No barrier effect on drug transport Placental barrier

42 3. Metabolism, Biotransformation Sites of metabolism Most meds are biotransformed in the liver It can occur in renal tissue, lungs, blood plasma, and intestinal mucosa ( Enzymatic alteration of a drug molecule

43 Drug Oxidation (Cytochrome P450) Conjugation (Glucuronidation, etc Conjugation Stable adducts Metabolites No-polar species Billary elimination (Stool) Renal elimination (Urine) Polar species Phase I Phase II Phases of metabolism

44 X (passive diffusion) X CYP450 X-OH UGT X-OG Y (actively transported) Y CYP450 Y-OH UGT X-OG bile Blood Hepatocyte Phases of metabolism Influx transports: OATPs, OATs, OCTs, NTCP Efflux transports: MRP2, MDR1, BCRP, BSEP, MDR2 (OAT: organic anion transporter; OCT: organic cation transporter)

45 Oxidation CYP1A1/2 CYP1B1 CYP2A6 CYP2B6 CYP2E1 CYP3A4/5/7 CYP2C19 CYP2C9 CYP2C8 Non-CYP enzymes CYP 2D6 Cytochrome P50 superfamily The primary oxidative enzyme system within the liver

46 Genetic determined enzyme activity GenesEnvironment 0%10%20%30%40%50%60%70%80%90%100% Diabetes mellitus LO Breast cancer MI (males) Essential hypertension Coronary artery disease Diabetes mellitus EO Diphenylhydantoin Lithium Sodium salicylate Amobarbital Dicumarol Aspirin Antipyrine Phenylbutazone

47 Speeds up metabolism, increases drug clearance, decreases concentrations of substrates Enzyme induction No inducer phenobarbitone benzo-pyrene Clazolimine concentration µg/g tissue Time hr In rats Consequences of Induction Increased rate of metabolism Decrease in drug plasma concentration Enhanced oral first pass metabolism Reduced bioavailability If metabolite is active or reactive, increased drug effects or toxicity

48 Slows down metabolism, decreases drug clearance, increases concentration of substrates Enzyme inhibition Consequences of Inhibition Increase in the plasma concentration of parent drug Reduction in metabolite concentration Exaggerated and prolonged pharmacological effects Increased likelihood of drug-induced toxicity

49 Routes of excretion Kidney (most important) Biliary tract and the feces Others: expired air, sweat, saliva, tears and breast milk 4. Excretion Filtration Active secretion Reabsorption Acid Base99% of H Lipid soluble drugs Plasma flow 650ml/min Glomerular Filtration Rate (GFR): 125ml/min Urine 1ml/min The ways by which a drug is excreted by the kidney organic anion transporting polypeptide, OATP Organic Cation Transporters OCT ( The process by which a drug or metabolite is eliminated from the body

50 Liver Gut Feces excretion Portal vein Biliary excretion & Enterohepatic recycling Bile duct Biliary Secretion

51 Time course of drug concentration Section 3 Ch. 2

52 1. Single dose Time (min) Plasma aspirin concentration (mg/L) Cmax Tmax iv orally Area under curve (AUC) ng h/mL Absorption = elimination 1-3 h for most of drugs

53 2. Multiple dose Constant repeated administration of drugs Css-max < MTC Css-min > MEC 4-5 half-life, 90% of steady-state concentration is reached in 3.3 half-lives To produce a Css > MEC and < MTC

54 Drug accumulation and elimination 87.5% 94% 97% 90% 3.3

55 Time Plasma Drug Concentration MTC MEC

56 Time Plasma Drug Concentration MTC MEC

57 Time Log Concentration Loading dose Utilized when a therapeutic level is desired quickly and an initial larger dose is administered followed by substantially smaller maintenance doses (may increase risk of toxicity and adverse effects).

58 Elimination Kinetics Section 4 Ch. 2

59 Elimination kinetics First order elimination kinetics n = 1 dC/dt = - kC Zero order elimination kinetics n = 0 dC/dt = k dC/dt = - kC n Rate constant for elimination Plasma concentration Time Zero order First order Zero order

60 First order and zero order elimination Comparison First Order Elimination [drug] decreases exponentially w/ time Rate of elimination is proportional to [drug] Plot of log [drug] or ln[drug] vs. time are linear t 1/2 is constant regardless of [drug] Zero Order Elimination [drug] decreases linearly with time Rate of elimination is constant Rate of elimination is independent of [drug] No true t 1/2

61 Low concentration (<10mg/L): First order High concentration (>10mg/L): Zero order Saturation of metabolizing enzyme Mixd elimination kinetics

62 Important Parameters in Pharmacokinetics Section 5 Ch. 2

63 ( Time it takes for drug concentrations to decrease by one half 1. Half-life, T 1/2 Zero order elimination: t 1/2 = 0.5 C 0 /k First order elimination: t 1/2 =0.693/Ke t 1/2 Slope = -Ke/2.303 Time h Plasma Concentration `Rate of elimination proportional to plasma concentration. `t1/2 is dependent on drug amount `Constant rate of Elimination irrespective of plasma concentration `t1/2 is constant regardless of drug amount Plasma Concentration

64 ( Volume of blood in a defined region of the body that is cleared of a drug in a unit time (mL/min). CL total = D/AUC CL total =CL renal CL liver CL others 2. Clearance CL

65 3. Volume of distribution, Vd Volume in which drug appears to distribute Vd not physical volume. Vd = Dose (known)/Cp (known) Vd is proportionality constant

66 DrugVolume (L/70kg) Mepacrine Chloroquine Amphetamine 300 Propranolol 250 Theophylline 30 Tolbutamide 6 plasma 4 L Intercellular 10 L Intracellular 28 L Acidic drugs Basic drugs Amphoteric drugs Neutral drugs Basic drugs accumulate in tissue high Vd Vd of Selected drugs Total 42 L

67 1.Estimate of how well the drug is distributed. Value < L/kg indicate the drug is mainly in the circulatory system. Values > 50 L/ (70kg) indicate the drug has accumulated in specific tissues. e.g. digoxin 5mg 0.78 ng/ml Vd = 645 L, mainly in lipid tissue and muscle including cardiac muscle 2.Calculation of dosage to be given: Vd=D/C Application of Vd

68 4. Bioavailability Dose Destroyed in gut Not absorbed Destroyed by gut wall Destroyed by liver To systemic circulation

69 4. Bioavailability Relative Bioavailability Compurgation of two different drugs or different dosage forms of same drug F = (AUC test x D stand )/(AUC stand x D test ) Absolute Bioavailability ( The fraction of the dose of a drug (F) that enters the general circulatory system, F = (AUC ev x D iv )/(AUC iv x D ev ) ev: extravascular

70 Oral administration of digoxin 0.5mg Pharmaceutical Co. A Pharmaceutical Co. B Relative Bioavailability

71 Chapter 3 Pharmacodynamics

72 Drug Action and Mechanism Section 1 Ch. 3

73 1. Therapeutic effects Expected desirable and beneficial pharmacological effect 1.Etiological treatment 2.Symptomatic treatment 3.Supplementary treatment or substitution treatment

74 2. Adverse drug reactions, ADR All the reactions that can bring out the uncomfortable or painful reaction, and have no relationship with the aim of administration. ADR are a large problem: ~ 5% of hospital admissions are as a result of an ADR.

75 Reactions unrelated to the therapeutic aim and occurred at therapeutic dose. 1. Side effect Dry mouth Inhibition of salivary secretion Dilated pupils Blurred vision Inhibition of pupillary constrictor muscle Tachycardia Vagal block Spasmolysis Blocked effects on motility Atropine Muscarinic antagonist

76 Too high dosage or too long usage Harmful functional or morphous damage 1.Acute toxicity LD 50 2.Chronic toxicity 3.Teratogenesis 4.Carcinogenesis 5.Mutagenesis 2. Toxic effect, Toxicity

77 LD 50 and toxicity classification Toxicity rating Commonly used termSingle oral LD50 dosage in rat 1Extremely toxic<1 mg/kg 2Highly toxic1-50 mg/kg 3Moderately toxic mg/kg 4Slightly toxic0.5-5 g/kg 5Practically nontoxic5-15 g/kg 6Relatively harmless>15 g/kg

78 Developed by a German pharmaceutical companyGerman Before its release, inadequate tests were performed to assess the drug's safety Sold from 1957 to 1961 in almost 50 countries As an antiemetic to combat morning sickness and as an aid to help sleep in pregnant womenantiemetic morning sicknesspregnant From 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia phocomelia Thalidomide disaster


80 Phocomelia Francis Kelsey

81 Phenobarbital hypnosis dizziness, drowsiness next morning Long term administration of glucocorticoid adrenal cortex hypofunction, for several months After stop of drug administration Drug concentration below the threshold concentration Residual pharmacological effect 3. Residual effect after effect

82 4. Withdrawal reaction After stop of drug administration, the symptoms of original disease would be aggravated (rebound reaction Vasodilator nitroglycerol and troxerutin ( ) rebound vasoconstriction angina pectoris attacks

83 5. Allergy Drug-induced allergic reaction (hypersensitivity) is an exaggerated or inappropriate immune reaction and causes damage to the patient Type I: anaphylactic reaction 2.Type II: cytotoxic reaction 3.Type III: Immune complex reaction 4.Type IV: cell-mediated immunity reaction

84 Not predictable reactions Not related to pharmacological effects Generic factor 6. Idiosyncrasy Genetic G-6- PD deficiency Haemolysis Take oxidant drug e.g. aspirin

85 ALL DRUGS ARE POISONS The only thing that determines if a drug provides a benefit or kills a patient is how WE administer it. ALL DRUGS ARE POISONS The only thing that determines if a drug provides a benefit or kills a patient is how WE administer it. From Switzerland First physician using chemicals to treat disease

86 Dose-effect Relationship Section 2 Ch. 3

87 N=100 Produce a same efficacy Qualitative effect Immeasurable Positive or negative, all or none alive or die effective or ineffective spasms or no Dose response curve

88 Quantitative response Measurable Blood pressure, heart rate, blood glucose, enzyme activity

89 Efficacy Potency Quantitative dose response curve

90 Efficacy vs Potency Efficacy: Maximal response a drug can produce Potency: Measure of dose required to produce a response A is more _________ than B. A and B are more ______ than C.

91 Median toxic dose TD 50 or TC 50 ) Median lethal dose LD 50 or LC 50 ToxicityDeath TD 50 TD 50 and LD 50

92 Also known as therapeutic ratio or margin of safety. Therapeutic Index Measure of the safety of a drug

93 Therapeutic window The range of concentration over which a drug is therapeutically beneficial and safe. Drugs w/ narrow therapeutic windows require smaller & more frequent doses or a different method of administration Therapeutic window may vary from patient to patient Minimum toxic concentration Minimum effective concentration Therapeutics window

94 Mechanisms of Drug Action Section 2 Ch. 3

95 Four consequent levels of drug action 4. System alteration of system function (e.g. cardiovascular, pulmonary, digestive…) 1. Molecule (drug target): the immediate and first step of drug action 3. Tissue alteration of tissue function (e.g. heart, lung, stomach…) 2. Cell: cellular function is physically inhibited or turned on

96 Drug targets Molecular drug targets – Total: Receptors 2. Enzymes 3. Transporters Symporters Antiporters 4. Iron Channels 5. Specific Targets metal ion Surfactant Protein 6. Nucleic Acids

97 Drug – Receptor Interaction Section 4 Ch. 3

98 1. Receptor A macromolecular component of the organism that binds the drug and initiates its effect. Second messenger Physio-pharmacological effect

99 2. Drug – receptor interaction Chemical Bond: ionic, hydrogen, hydrophobic, Van der Waals, and covalent. Saturable Competitive Specific and Selective Structure-activity relationships Transduction mechanisms Characteristics of Drug-Receptor Interactions

100 k1 D + R DR k2 By Law of mass action: [D][R]K 1 = [DR]K 2 Therefore K 2 /K 1 = K d = [D][R]/[DR] If R T = total # of receptors, then R T = [R] + [DR] Replace [R] by (R T -[DR]) & rearrange: [DR] [D] RT Kd + [D] = Occupation theory of drug-receptor interactions Effect effect Max. effect = D = 0 effect = 0 D>>Kd DR/RT=100% max effect Kd=D, Kd = Conc at EC50

101 Affinity: The strength of binding between a drug and receptor K D is inversely proportional to affinity [DR] RTRT E E max = 100% 0 Intrinsic Activity : The extent to which the ligand activates the receptor 3. Affinity and Intrinsic activity

102 Full agonist = 100 Efficacy = Emax Partial agonist: 0% < < 100% Efficacy < Emax Antagonist: = 0 Effficay = 0 4. Classification of drugs % Maximum effect 100 Drug concentration Full agonist Partial agonist Antagonist 50 0

103 Competitive antagonist Fractional occupancy Agonist concentration Antagonist concentration Binds to same site for agonist-binding domain Competes with an agonist for receptors High doses of an agonist can generally overcome antagonist

104 Noncompetitive antagonist Antagonist concentration Fractional occupancy Agonist concentration Binds to a site other than the agonist-binding domain Induces a conformation change in the receptor such that the agonist no longer recognizes the agonist binding site. High doses of an agonist do not overcome the antagonist in this situation

105 Spare receptors MAX High affinity agonist produced maximal response without total receptor occupancy – increase sensitivity of the system Magnitude of response IS NOT proportional to receptor occupancy Spare receptors can bind extra ligand preventing an exaggerated response if too much ligand is present

106 5. Type of receptors 1.Channel linked receptors : Example: the ACh receptor, signal is neurotransmitter, depolarization is signal, Na+ channel is target.

107 2. G-protein coupled receptors: Signal through trimeric G proteins. The proteins can alter the function of many proteins. 5. Type of receptors

108 3. Enzyme linked receptors: Usually signal through protein kinases or protein phosphatases. Protein modification then alters intracellular enzyme activity. 5. Type of receptors

109 4. Intracellular receptors Hormone receptors Signal binds directly to an intracellular protein which then activates transcription. 5. Type of receptors

110 6. Second messengers Primitive signal binds with receptor and then trigger second messenger Small, nonprotein, water-soluble molecules or ions Readily spread throughout the cell by diffusion Two most widely used second messengers are: 1.Cycle AMP cAMP,IP3,DG,) 2.Calcium ions Ca 2+ cAMP,IP3,DG,) Intracellular effect Receptor First messengers Second messengers

111 Signal amplification Amplification No amplification No amplification ReceptorG-protein Adenylyl cyclase Cyclic cAMP Protein kinases Phosphates tranferred to target proteins Results in a tremendous increase in the potency of the initial signal permits precise control of cell behavior M Adr in blood blood glucose levels by 50%

112 7. Receptor regulation Sensitization hypersensitization, supersensitivity or Up-regulation 1.Prolonged/continuous use of receptor blocker 2.Inhibition of synthesis or release of hormone/neurotransmitter Desensitization or Down- regulation 1.Prolonged/continuous use of agonist 2.Inhibition of degradation or uptake of agonist

113 Homologous desensitization Affecting responses elicited only by the stimulated receptor Can reflect feedback from a transducer (or effector) unique to the pathway of the receptor (X1) or from an off-pathway component (K) that is sensitive to the activation state of the receptor. Heterologous desensitization Acting on several receptors or on a pathway that is common to many receptors. Initiated by transducers or effectors common to multiple receptor signaling pathways (Y or Z). Receptor regulation

114 Chapter 4 Factors affecting drug response

115 Pharmaceutical Factors Section 1 Ch. 4

116 1. Dose, formulation, route of administration 2. Drug Interactions 1 Pharmacokinetic interactions chemical or physical; GI absorption; protein binding/distribution; metabolism (stimulation/inhibition); excretion (pH/transport processes); changes in pH or electrolytes. 2 Pharmacodynamic interactions receptor (potentiation/antagonism Pharmaceutical Factors

117 Biological Factors Section 2 Ch. 4

118 Many factors affect drug response

119 1. Age Age related change: 1. liver metabolism; 2. renal elimination; 3. body composition liver metabolism- less amount of drug metabolizing enzymes in newborn infants Older people usually take more drugs, also may have more difficulty following complicated instructions for taking drugs.

120 Developmental profile of hepatic drug metabolizing enzymes BirthAdulthoodElderly Enzyme level Most drug-metabolizing enzymes CYP3A7 Age 1. Age

121 Women have more CYP3A in the liver Estrogen and progestin inhibit CYP450 leading to a lower CL of drugs in women Women tend to take more medications, including dietary supplements, than men 2. Gender

122 Vd changed CL changed 3. Body Size / Obesity

123 GFR decreased Excretion decreased 4. Disease Kidney disease: Liver disease Cell damage Reduction DME activity PK changed

124 4. Disease CYP2E1 CYP2D6 CYP1A2 CYP2C19

125 5. Placebo effects Pharmacological effect Non-specific drug effect Non-specific medical effect Natural recovery Placebo effect Often caused by psychological factors, patient- physician interaction Effective rates: 30%, pain, anxiety, angina, heart failure Adverse drug reactions: 30% dizzy, debility, nausea, abdominal pain, diarrhea, leucocyte Total response

126 5.Placebo effects

127 l Tolerance is a person's diminished response to a drug, which occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug. l Resistance refers to the ability of microorganisms or cancer cells to withstand the effects of a drug usually effective against them. 6. Variation in response

128 7. Genetic factor GTTC T CTA… CAAGAGAT… GT GCTC TA… CA CGAGAT… Single nucleotide polymorphism wt/wt wt/m m/m

129 This is only the beginning Good luck Thank you


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