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中南大学临床药理研究所
csupharmacol.com
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