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1 Pharmacology 中南大学 临床药理研究所 csupharmacol.com

2 General Principles 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

3 Chapter 1 Introduction

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

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

6 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)

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

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

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

10 Missions of pharmacology
Explore the pharmacokinetic and pharmacodynamic features of drugs Probe the mystery of life process Find and develop new drugs

11 Process of Drug Development
The Long Road to a New Medicine synthesis Screen Phase II Clinical trial Phase III clinical trial Phase I clinical trial Animal PK/PD/Tox Dosage form Candidate chemicals Design Application Marketing 25) Idea-to-new medicine road - Full Development phase In this Full Development stage, known as Phase lll, several thousand patients with the particular disease receive the drug in carefully controlled studies to test its safety, tolerability, and efficacy. Finally, if the compound has proved its worth in all these tests, it enters the Registration phase in which the data of its entire history are compiled and analyzed in a regulatory submission. This New Drug Application, or NDA, is submitted to the FDA for review. In parallel, a Marketing Authorization Application (MAA) is filed in Europe, followed by a Japanese NDA. Only after a successful regulatory review does the candidate become a new medicine.

12 History of medicines Phase I: Using natural products to treat diseases
China: Sheng Nong’s Herbal Classic (神农本草经), described 365 TCM; Compendium of Materia Medica (本草纲目), described 1892 TCM Greeks; e.g. Dioscorides: De materia medica (药物 学), 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

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

14 Chapter 2 Pharmacokinetics

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

16 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.

17 Toxicity Efficacy Pharmacokinetics Pharmacodynamics
Drug Administration Absorption Drug Concentration in Systemic Circulation Drug in Tissues of Distribution Drug Metabolism or Excreted Pharmacokinetics Distribution Elimination Drug Concentration at Site of Action Pharmacologic Effect Pharmacodynamics Clinical Response Toxicity Efficacy

18 % of dose Metabolites Excreted drug Time Drug at absorption site
20 40 60 80 100 Drug at absorption site Metabolites Drug in body Excreted drug

19 Section 1 Drug Transport Ch. 2

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

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

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

23 Ionization depends on pH and pKa
Acidic drug: Ka = [ A ] [HA] pKa = pH - log [ A ] [HA] pKa-pH 10 pH-pKa = Basic drug:

24 Cromolyn Sodium (色甘酸钠) pKa=2, Acidic
Example Cromolyn Sodium (色甘酸钠) pKa=2, Acidic Stomach:pH=4 Plasma:pH=7 Total HAH+ + A A + H+HA Total 101 1 102 105 1 100001 [ A ] [HA] [ A ] [HA] 10pH-pKa = 10pH-pKa = = 104-2 = 102 = 107-2 = 105

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

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

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

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

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

30 Fick’s Law of Diffusion Area×Permeability coefficient
Flux (molecules per unit time) Area×Permeability coefficient Thickness =(C1-C2)× Oral cavity l .0 m2 Stomach m2 Small intestine 100 m2 Large intestine m2 Rectum m2

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

32 Intramuscular & subcutaneous injection
Passive diffusion + Filtration Rapid and complete absorption

33 Inhalation Gaseous or volatile substances and aerosol can reach the absorptive site of the lung. Highly available area of absorption (alveolus area = m2; pulmonary capillary area = 80 m2 Rapid, no first pass effect, directly reach desired site of action (asthma, COPD)

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

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

36 Factors that affect drug distribution
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

37 Plasma protein binding
[DP] [PT] KD +[D] [D] D+P DP KD Reversible equilibrium Saturable DP: Non-permeable Nonspecific & competitive Plasma proteins Albumin: Weak acids alpha-acid glycoprotein: Weak bases Effects of plasma protein binding Free fraction: active, excreted, metabolized the more binding, the less active drug the more binding, the less excreted and metabolized: “longer half-life”

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

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

40 Placental barrier 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

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

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

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

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

45 Genetic determined enzyme activity
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 Genes Environment

46 Clazolimine concentration
Enzyme induction Speeds up metabolism, increases drug clearance, decreases concentrations of substrates 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

47 Enzyme inhibition Consequences of Inhibition
Slows down metabolism, decreases drug clearance, increases concentration of substrates 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

48 The ways by which a drug is excreted by the kidney
4. Excretion The process by which a drug or metabolite is eliminated from the body The ways by which a drug is excreted by the kidney Routes of excretion Kidney (most important) Biliary tract and the feces Others: expired air, sweat, saliva, tears and breast milk Glomerular Filtration Rate (GFR): 125ml/min Urine 1ml/min Plasma flow 650ml/min Acid Base 99% of H20 + Lipid soluble drugs organic anion transporting polypeptide, OATP Organic Cation Transporters OCT Filtration Active secretion Reabsorption

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

50 Time course of drug concentration
Section 3 Ch. 2 Time course of drug concentration

51 1. Single dose iv orally Area under curve (AUC) ngh/mL
Absorption = elimination iv 20 40 60 80 100 120 2 4 6 8 10 Cmax orally Plasma aspirin concentration (mg/L) Tmax Area under curve (AUC) ngh/mL 1-3 h for most of drugs Time (min)

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

53 Drug accumulation and elimination
90% 3.3 87.5% % 97%

54 Plasma Drug Concentration
MTC Plasma Drug Concentration MEC Time

55 Plasma Drug Concentration
MTC Plasma Drug Concentration MEC Time

56 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). Log Concentration Time Time

57 Section 4 Elimination Kinetics Ch. 2

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

59 Comparison First order and zero order elimination
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

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

61 Important Parameters in Pharmacokinetics
Section 5 Ch. 2 Important Parameters in Pharmacokinetics

62 First order elimination: Zero order elimination:
1. Half-life, T1/2 Time it takes for drug concentrations to decrease by one half First order elimination: t1/2 =0.693/Ke Zero order elimination: t1/2 = 0.5  C0/k  `Constant rate of Elimination irrespective of plasma concentration  `t1/2 is constant regardless of drug amount  `Rate of elimination proportional to plasma concentration.  `t1/2 is dependent on drug amount Slope = -Ke/2.303 Plasma Concentration Plasma Concentration t1/2 t1/2 t1/2 t1/2 t1/2 Time(h) Time(h)

63 CLtotal=CLrenal+CLliver+CLothers
2. Clearance,CL Volume of blood in a defined region of the body that is cleared of a drug in a unit time (mL/min). CLtotal = D/AUC CLtotal=CLrenal+CLliver+CLothers

64 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

65 Basic drugs accumulate in tissue  high Vd
Vd of Selected drugs Acidic drugs Basic drugs Amphoteric drugs Neutral drugs plasma 4 L Basic drugs accumulate in tissue  high Vd Intercellular 10 L Drug Volume (L/70kg) Mepacrine(阿的平) 40000 Chloroquine(氯喹) 17000 Amphetamine(苯丙胺) 300 Propranolol(普萘洛尔) 250 Theophylline(氨茶碱) 30 Tolbutamide(甲苯磺丁脲) 6 Intracellular 28 L Total:42 L

66 Application of Vd 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 Calculation of dosage to be given: Vd=D/C

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

68 4. Bioavailability Absolute Bioavailability
The fraction of the dose of a drug (F) that enters the general circulatory system, F = (AUCev x Div)/(AUCiv x Dev) ev: extravascular Relative Bioavailability Compurgation of two different drugs or different dosage forms of same drug F = (AUCtest x Dstand)/(AUCstand x Dtest)

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

70 Chapter 3 Pharmacodynamics

71 Drug Action and Mechanism
Section 1 Ch. 3 Drug Action and Mechanism

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

73 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.

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

75 2. Toxic effect, Toxicity Too high dosage or too long usage
Harmful functional or morphous damage Acute toxicity,LD50 Chronic toxicity Teratogenesis Carcinogenesis Mutagenesis

76 Single oral LD50 dosage in rat
LD50 and toxicity classification Toxicity rating Commonly used term Single oral LD50 dosage in rat 1 Extremely toxic <1 mg/kg 2 Highly toxic 1-50 mg/kg 3 Moderately toxic mg/kg 4 Slightly toxic 0.5-5 g/kg 5 Practically nontoxic 5-15 g/kg 6 Relatively harmless >15 g/kg

77 Thalidomide disaster Developed by a German pharmaceutical company
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 women From 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia

78

79 Phocomelia Francis Kelsey

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

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

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

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

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

85 Dose-effect Relationship
Section 2 Ch. 3 Dose-effect Relationship

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

87 Quantitative response
Dose response curve Quantitative response Measurable Blood pressure, heart rate, blood glucose, enzyme activity

88 Quantitative dose response curve
Efficacy 作用强度 Potency

89 Efficacy vs Potency A is more _________ than B.
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.

90 TD50 and LD50 Median toxic dose (TD50 or TC50) Median lethal dose
Toxicity Death Median lethal dose (LD50 or LC50) TD50

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

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

93 Mechanisms of Drug Action
Section 2 Ch. 3 Mechanisms of Drug Action

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

95 Molecular drug targets – Total: 482
Receptors Enzymes Transporters Symporters (共转运体) Antiporters (反向转运体) Iron Channels Specific Targets metal ion Surfactant Protein Nucleic Acids

96 Drug – Receptor Interaction
Section 4 Ch. 3 Drug – Receptor Interaction

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

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

99 Occupation theory of drug-receptor interactions
k1 D + R <=> DR k2 By Law of mass action: [D]•[R]•K1= [DR]•K2 Therefore K2 /K1= Kd = [D]•[R]/[DR] If RT = total # of receptors, then RT = [R] + [DR] Replace [R] by (RT-[DR]) & rearrange: Effect D = 0:effect = 0 D>>Kd:DR/RT=100%, max effect Kd=D, Kd = Conc at EC50 [DR] [D] RT Kd + [D] effect = = Max. effect

100 3. Affinity and Intrinsic activity
The strength of binding between a drug and receptor KD is inversely proportional to affinity Intrinsic Activity  : The extent to which the ligand activates the receptor E Emax [DR] = 100%    0 RT

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

102 Competitive antagonist
Binds to same site for agonist-binding domain Competes with an agonist for receptors High doses of an agonist can generally overcome antagonist 10-2 10-1 1 10 102 103 104 105 Fractional occupancy 0.1 1.0 Agonist concentration Antagonist concentration

103 Noncompetitive antagonist
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. Antagonist concentration 1 10 100 1.0 0.5 Fractional occupancy 10-2 10-1 102 Agonist concentration High doses of an agonist do not overcome the antagonist in this situation

104 Spare receptors 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 MAX MAX

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

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

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

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

109 6. Second messengers Primitive signal binds with receptor and then trigger second messenger Intracellular effect Receptor First messengers Second messengers Small, nonprotein, water-soluble molecules or ions Readily spread throughout the cell by diffusion Two most widely used second messengers are: 1. Cycle AMP 2. Calcium ions Ca2+ ( cAMP,IP3,DG,)

110 Signal amplification Amplification No amplification Receptor G-protein Adenylyl cyclase Cyclic cAMP Protein kinases Phosphates tranferred to target proteins 10-10M Adr in blood   blood glucose levels by 50% Results in a tremendous increase in the potency of the initial signal permits precise control of cell behavior

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

112 Receptor regulation 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).

113 Chapter 4 Factors affecting drug response

114 Pharmaceutical Factors
Section 1 Ch. 4 Pharmaceutical Factors

115 Pharmaceutical Factors
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

116 Section 2 Ch. 4 Biological Factors

117 Many factors affect drug response

118 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.

119 Developmental profile of hepatic drug metabolizing enzymes
1. Age Developmental profile of hepatic drug metabolizing enzymes CYP3A7 Most drug-metabolizing enzymes Enzyme level Birth Adulthood Elderly Age

120 2. Gender 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

121 3. Body Size / Obesity Vd changed CL changed

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

123 4. Disease CYP2E1 CYP2D6 CYP1A2 CYP2C19

124 5. Placebo effects Total response Pharmacological effect
Non-specific drug effect Total response Placebo effect Non-specific medical effect Natural recovery 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

125 Placebo effects: 医生良好的语言不是药物胜似药物
医生应学会讲话 四句话说死病人(一个真实故事) 一久病农村病人进城专家门诊 “你来晚了” “没治了” “回家吧”,病人求 “你早干什么去了”

126 6. Variation in response 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. Resistance refers to the ability of microorganisms or cancer cells to withstand the effects of a drug usually effective against them.

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

128 This is only the beginning Good luck
Thank you

129 Thank you


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