中南大学临床药理研究所

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Pharmacology

Chapter 1. IntroductionAbout Pharmacology

Chapter 2. PharmacokineticsWhat the body does to a drug

Chapter 3. PharmacodynamicsWhat a drug does to the body

Chapter 4. Factor affecting drug efficacyHow to use a drug rationally

General Principles

Chapter 1

Introduction

What is pharmacology

Pharmacology is the science Pharmacology is the science of studying the effect of drugs on of studying the effect of drugs on living organisms.living organisms.

Scientific study of the Scientific study of the interactions between drugs and the interactions between drugs and the body.body.

Drug Action and Mechanism

Absorption, Distribution, Metabolism, Excretion

Pharmacodynamics, PD

Pharmacokinetics, PK

Drug-body interaction

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)

Ancient Natural products

─ Plants ─ Animals─ Minerals

Modern Active principles of natural products Artificial synthetics

─ Full synthetic─ Semi synthetic─ Biological engineering

Source of drugs

Poppy

Raw opium

Opium tincture

MorphineCodeine…

From natural product to active principles

foxglove digoxin deadly nightshade atropine

From natural product to active principles

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

The Long Road to a New Medicine

Process of Drug Development

synthesis

Screen

Phase II Clinical trial

Phase III clinical trial

Phase I clinical trial

Animal PK/PD/Tox

Dosage form

Candidate chemicals

Design

ApplicationMarketin

g

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

1. Francois Magendie (1783-1855), a French physiologist ，Experimental procedures with animals for determination of drug action.

2. Fredrick Surturner (1783-1841) isolated the chief alkaloid of opium, Morphine – pure chemicals and repeated quantitatively

3. Claude Bernard (1813-1878) ， investigated the plant extract curare and proposed a site of action for this agent.

4. Rudolph Buchheim (1820-1879). In 1847 established the first laboratory in the basement of his home in Dorpat which is the cradle of experimental pharmacology.

5. Oswald Schmiedeberg (1838-1921). 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

Chapter 2

Pharmacokinetics

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

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.

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

Toxicity Efficacy

Ph

arm

acokin

etic

sP

harm

acod

yn

am

ics

Absorption

Distribution Elimination

Drug at absorption site

Metabolites

Excreted drug

Drug in body

Time

% o

f d

ose

20

40

60

80

100

Section 1

Ch. 2

Drug Transport Drug Transport

Transfer of drugs across Membranes

Filtration(Aqueous diffusion)

Extracellular

Intracellular

Simple diffusion(Lipid diffusion)

Carrier-mediated

transport 1. Active transport2. Facilitated diffusion

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

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-

HA

H+

A-

B BH+

H+

H+

B BH+

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

A + H+HAHAH+ + A

[ A ]

[HA]10pH-pKa =

Plasma ：pH=7

Stomach ：pH=4

11 102 105

Cromolyn Sodium ( 色甘酸钠 ) pKa=2, Acidic

= 107-2

= 105

[ A ]

[HA]10pH-pKa =

= 104-2

= 102

TotalTotal

Example

101 100001

Small molecules diffusion through aqueous channels

2. Filtration

Water solubility Small molecular

─Diameter of aqueous channels in Capillary wall: 4-8Å （ =1010m )

─Only for water, urea filtration─ >100 not permeable

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

Intracellular cleft

Intracellular cleft: big hole

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 specific3. Saturable (functional protein molecu

les are limited)4. Competitive inhibition

Disposition of drug in the body

Absorption, Distribution, Metabolism and Excretion

Section 2

Ch. 2

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

Oral cavity 0.5-l .0 m2

Stomach 0.1-0.2 m2 Small intestine 100 m2

Large intestine 0.04-0.07 m2

Rectum 0.02 m2

Fick’s Law of Diffusion

Flux (molecules per unit time)

＝ (C1 －C2)×

Area×Permeability coefficient

Thickness

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

Passive diffusion ＋ Filtration

Rapid and complete absorption

Intramuscular & subcutaneous injection

Inhalation

Gaseous or volatile substances and aerosol can reach the absorptive site of the lung.

Highly available area of absorption (alveolus area = 100-200m2; pulmonary capillary area = 80 m2

Rapid, no first pass effect, directly reach desired site of action (asthma, COPD)

Transdermal

Transdermal skin patches-

Lipid soluble drugs can be absorpted via skin

─ Nifedipine

─ Glycerol trinitrate

Process by which a drug reversibly leaves he blood stream and enters the interstitial or cellular fluids of the body.

2 ． Distribution

Free drug

BoundDrug

Metabolites

ReceptorFree bound

TissueFree bound

Excretion

Blood

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

Plasma protein binding

Reversible equilibriumReversible equilibrium SaturableSaturable DP: Non-permeable Nonspecific & competitiveNonspecific & competitive

Reversible equilibriumReversible equilibrium SaturableSaturable DP: Non-permeable Nonspecific & competitiveNonspecific & competitive

[DP]

[PT] KD +[D]

[D]

D ＋ P DPKD

Plasma proteins 1. Albumin: Weak acids 2. alpha-acid glycoprotein: Weak bases

Effects of plasma protein binding 1. Free fraction: active, excreted, metaboli

zed2. the more binding, the less active drug 3. the more binding, the less excreted and

metabolized: “longer half-life”

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

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.

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

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

Drug Oxidation(Cytochrome P450)

Conjugation (Glucuronidation, etc

ConjugationStable adductsMetabolites

No-polar species

Billary elimination(Stool)

Renal elimination(Urine)

Polar species

Phase I Phase II

Phases of metabolism

X (passive diffusion)

X

CYP450

X-OHUGT

X-OG

Y (actively transported)

Y

CYP450

Y-OHUGT

X-OG

bile

BloodHepatocyte 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)

Oxidation

CYP1A1/2

CYP1B1 CYP2A6

CYP2B6

CYP2E1

CYP3A4/5/7

CYP2C19

CYP2C9

CYP2C8Non-CYP enzymes

CYP 2D6

Cytochrome P50 superfamily The primary oxidative enzyme system within the liver

Genetic determined enzyme activity

Genes Environment

•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

Speeds up metabolism, increases drug clearance, decreases concentrations of substrates

Enzyme induction

No inducer

phenobarbitone

benzo-pyrene

Cla

zoli

min

e co

nce

ntr

atio

n（

µg

/g t

issu

e）

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

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

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 Base 99% of H20 +Lipid solubledrugs

Plasma flow650ml/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

Liver

Gut

Feces excretion

Portal vein

Biliary excretion&

Enterohepatic recycling

Bile duct

Biliary Secretion

Time course of drug concentration

Section 3

Ch. 2

1. Single dose

0 20 40 60 80 100 120

0

2

4

6

8

10

Time (min)

Pla

sma

aspi

rin c

once

ntra

tion

(mg/

L)

Cmax

Tmax

iv

orally

Area under curve (AUC)

ngh/mL

Absorption = elimination

1-3 h for most of drugs

2. Multiple doseConstant 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

Drug accumulation and elimination

87.5% 94% 97%

90%

3.3

Time

Pla

sm

a D

rug

Con

cen

trati

on

MTC

MEC

Time

Pla

sm

a D

rug

Con

cen

trati

on

MTC

MEC

Time Time

Lo

g C

on

cen

trat

ion

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).

Elimination Kinetics

Section 4

Ch. 2

Elimination kinetics

First order elimination kinetics

n = 1 dC/dt = - kC

Zero order elimination kinetics

n = 0 dC/dt = k

dC/dt = - kCn

Rate constant for elimination

Pla

sma

con

cen

trat

ion

Time

Zero order

First order

First order

Zero order

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

Low concentration (<10mg/L): First order

High concentration (>10mg/L): Zero order─ Saturation of metabolizing enzyme

Mixd elimination kinetics

Important Parameters in

Pharmacokinetics

Section 5

Ch. 2

Time it takes for drug concentrations to decrease by one half

1. Half-life, T1/2

Zero order elimination: t1/2 = 0.5 C0/k

First order elimination: t1/2 =0.693/Ke

t1/2 t1/2 t1/2 t1/2t1/2

Slope

= -Ke/2.303

Time （h ）

Time （h ）

Pla

sm

a

Con

cen

trati

on

`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

Pla

sm

a

Con

cen

trati

on

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

2. Clearance ， CL

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

Drug Volume (L/70kg)Mepacrine （阿的平） 40000Chloroquine （氯喹） 17000Amphetamine （苯丙胺） 300Propranolol （普萘洛尔） 250Theophylline （氨茶碱） 30Tolbutamide （甲苯磺丁脲）

6

plasma 4 L

Intercellular 10 L

Intracellular 28 L

Acidic drugs

Basic drugsAmphoteric drugs

Neutral drugs

Basic drugs accumulate in tissue high VdVd of Selected

drugs

Total ： 42 L

1. Estimate of how well the drug is distributed.

─ Value < 0.071 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 5mg0.78 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

4. Bioavailability

Dose

Destroyed in gut

Notabsorbed

Destroyed by gut wall

Destroyedby liver

To systemiccirculation

4. Bioavailability

Relative Bioavailability Compurgation of two different drugs or different dosage

forms of same drug

F = (AUCtest x Dstand)/(AUCstand x Dtest)

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

Oral administration of digoxin 0.5mg

Pharmaceutical Co. APharmaceutical Co. B

Relative Bioavailability

Chapter 3

Pharmacodynamics

Drug Action and Mechanism

Section 1

Ch. 3

1. Therapeutic effects

Expected desirable and beneficial pharmacological effect

1. Etiological treatment

2. Symptomatic treatment

3. Supplementary treatment or substitution treatment

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.

Reactions unrelated to the therapeutic aim and occurred at therapeutic dose.

1. Side effect

Dry mouthInhibition of salivary secretion

Inhibition of salivary secretion

Dilated pupils

Blurred vision Inhibition of pupillary constrictor muscle

Inhibition of pupillary constrictor muscle

Tachycardia Vagal blockVagal block

SpasmolysisBlocked effects on motility

Blocked effects on motility

Atropine Muscarinic antagonist

Too high dosage or too long usage Harmful functional or morphous damage

1. Acute toxicity ， LD50

2. Chronic toxicity

3. Teratogenesis

4. Carcinogenesis

5. Mutagenesis

2. Toxic effect, Toxicity

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 50-500 mg/kg

4 Slightly toxic 0.5-5 g/kg

5 Practically nontoxic 5-15 g/kg

6 Relatively harmless >15 g/kg

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

Thalidomide disaster

Phocomelia

Francis Kelsey

─ 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

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

5. Allergy

Drug-induced allergic reaction (hypersensitivity) is an exaggerated or inappropriate immune reaction and causes damage to the patient

1. Type I: anaphylactic reaction

2. Type II: cytotoxic reaction

3. Type III: Immune complex reaction

4. Type IV: cell-mediated immunity reaction

Not predictable reactions

Not related to pharmacological effects

Generic factor

6. Idiosyncrasy

Genetic G-6-PD deficiency Haemolysis

Take oxidant drug

e.g. aspirin

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

Dose-effect Relationship

Section 2

Ch. 3

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

Dose response curve

Quantitative response

Measurable ─ Blood pressure, heart rate, blood glucose,

enzyme activity

作用强度

Efficacy

Potency

Quantitative dose response curve

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.

Median toxic dose

（ TD50 or TC50)

Median lethal dose

（ LD50 or LC50 ）

Toxicity Death

TD

50

TD50 and LD50

Also known as therapeutic ratio or margin of safety.

Therapeutic Index

Measure of the safety of a drug

Therapeutic windowThe 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

Mechanisms of Drug Action

Section 2

Ch. 3

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”

Drug targets

Molecular drug targets – Total: 482

1. Receptors2. Enzymes3. Transporters

─ Symporters （共转运体）─ Antiporters （反向转运体）

4. Iron Channels5. Specific Targets

─ metal ion─ Surfactant Protein

6. Nucleic Acids

Drug – Receptor Interaction

Section 4

Ch. 3

1. Receptor

A macromolecular component of the organism that binds the drug and initiates its effect.

Second messenger

Physio-pharmacological effect

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

k1D + 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: [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

Affinity:

The strength of binding between a drug and receptor

KD is inversely proportional to affinity

[DR]RT

EEmax

= 100% 0

Intrinsic Activity :

The extent to which the ligand activates the receptor

3. Affinity and Intrinsic activity

Full agonist ： = 100 ％， Efficacy = Emax Partial agonist: 0% < < 100% ， Efficacy < Emax

Antagonist: = 0 ％ ， Effficay = 0

4. Classification of drugs

% M

axim

um

eff

ect 100

Drug concentration

Full agonist

Partial agonist

Antagonist

50

0

Competitive antagonist

10-2 10-1 1 10 102 103 104 105

Fra

cti

on

al

occu

pan

cy

0

0.1

1.0

Agonist concentration

0 1 10 100 1000

Antagonistconcentrat

ion

Binds to same site for agonist-binding domain Competes with an agonist for receptors High doses of an agonist can generally

overcome antagonist

Noncompetitive antagonist

Antagonist concentration

0

1

10100

1.0

0.5

0

Fra

ctio

nal o

ccup

ancy

10-2 10-1 1 10 102

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

Spare receptors

MAXMAX

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

5. Type of receptors

1. Channel linked receptors :

Example: the ACh receptor, signal is neurotransmitter, depolarization is signal, Na+ channel is target.

2. G-protein coupled receptors: Signal through trimeric G proteins. The proteins can alter the function

of many proteins.

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

5. Type of receptors

4. Intracellular receptors Hormone receptors Signal binds directly to an intracellular

protein which then activates transcription.

5. Type of receptors

6. Second messengers

Primitive signal Primitive signal binds with receptor binds with receptor and then trigger and then trigger second messengersecond messenger

Small, nonprotein, water-soluble molecules or ions Readily spread throughout the cell by diffusion Two most widely used second messengers are:

1. Cycle AMP2. Calcium ions Ca2+ （ （ cAMP,IP3,DG,)cAMP,IP3,DG,)

Intracellular effect

Receptor

First messengers Second messengers

Signal amplification

Amplification Amplification AmplificationNo amplification

No amplification

Receptor G-proteinAdenylylcyclase

CycliccAMP

Proteinkinases

Phosphatestranferred to

target proteins

Results in a tremendous increase in the potency of the initial signal permits precise control of cell behavior

10-10M Adr in blood blood glucose levels by 50%

7. Receptor regulation

Sensitization （ hypersensitization, supersensitivity ） or Up-regulation

1. Prolonged/continuous use of receptor blocker2. 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

Homologous desensitizationAffecting 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 desensitizationActing 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

Chapter 4

Factors affecting drug response

Pharmaceutical Factors

Section 1

Ch. 4

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

Biological Factors

Section 2

Ch. 4

Many factors affect drug response

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.

Developmental profile of hepatic drug metabolizing enzymes

Birth Adulthood Elderly

Enzyme level

Most drug-metabolizingenzymes

CYP3A7

Age

1. Age

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

Vd changed

CL changed

3. Body Size / Obesity

GFR decreased

Excretion decreased

4. Disease

Kidney disease:Liver disease ：

Cell damage Reduction DME activity

PK changed

4. Disease

CYP2E1

CYP2D6

CYP1A2

CYP2C19

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

To

tal r

esp

on

se

5. 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”

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.

6. Variation in response

7. Genetic factor

GTTC T CTA…

CAAGAGAT…

GT GCTC TA…

CA CGAGAT…

Single nucleotide polymorphism

wt/wt

wt/m

m/m

This is only the beginning

Good luck

Thank you

Thank you