Transcript Pharmacodynamics

Chapter 2
Pharmacodynamics
Objectives
1.know the different types of adverse reactions
2.Understand the pharmacological terms in this
chapters (agonist , antagonist, side reaction,
potency et al)
3. Understand the meaning of parameters such as
Emax, ED50, TI et al.
4. Know how to analyse the D-R curve.
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Pharmacodynamics deals with the
study of the biochemical and
physiological effects of drugs and
their mechanisms of action.
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Section 1
Basic Effects of Drugs
Chapter 2
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Principles of Drug Action
 Drugs do not produce new function, only
modify existing functions.
 Actions can be considered therapeutic in
one case and adverse in another
 Drug has both therapeutic and adverse
reactions
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Ⅰ、 Drug Action & Pharmacological
Effect
Drug Action: initial actions, how the drug works
 Pharmacological Effect: consequence of drug

action on body
Example: Aspirin
action
block prostaglandin synthesis
effect
analgesia & antipyresis
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Ⅱ、Therapeutic Effects and Adverse
Reactions
Etiological treatment
Therapeutic
Symptomatic treatment
Effect
Supplement therapy
Effect
of
Drug
Side effect
Toxic reaction
Adverse
Reactions
Residual effect
Withdrawal reaction
Allergic reaction
Idiosyncrasy
Addiction
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Ⅲ、Adverse Drug Reaction (ADR)
 Effects that are not desired.
 Most ADR is the intrinsic effects of drugs. It can be
foreseen in common, but not always be avoided.
 Drug-induced disease: the unintended effect of a
drug that results in mortality or morbidity with
symptoms sufficient to prompt a patient to seek
medical attention and/or to require hospitalization.
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1. Side effect
is an effect, whether therapeutic or adverse, that
is secondary to the one intended.
1. Pharmacological effects
2. Therapeutic dose
3. Low selectivity
4. Mild and recoverable
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salivary secretion
Atropine
Macetylcholine
R blocker
Inhibition of
sphincter pupilla
Dry mouth
pupil
dilation
Relieve the cardiac
inhibition by vagus
nerve
Heart rate
gastrointestinal
relaxation
spasmolysis
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2. Toxic Reaction, Toxicity
1. Dosage or blood concentration is
above therapeutic level
2. Extention of Pharmacological effects
3. Severe pathological changes/damage
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 Acute toxicity:
– Mostly damage to the function of circulatory,
respiratory and nervous system




Digoxin
Bleomycin
Diazepam
Amphetamine /Methamphetamine/ “Ice”
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Chronic toxicity
– Mostly damage to the function of liver,
kidney, bone marrow and endocrine
secretion


Antihyperlipidemic

Furosemide

Chloramphenicol
Glucocorticoids
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 Teratogenesis
 Carcinogenesis
 Mutagenesis
phocomelia by thalidomide
Deafness by aminoglycoside(gentamycin) is related to the DNA
mutation of mitochondria in the cochlear hair cell
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3. After Effect (Residual Effect)
 The residual effect: after withdrawal of
the drug whose concentration is below
the threshold
 Barbiturates
hypnotic
hangover next morning
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4. Withdrawal Reaction
 Original disease aggravates after sudden
drug withdrawal—— Rebound Reaction
 Glucocorticoids
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5. Allergy （Hypersensitive Reaction）
D + Protein
(half-antigen)
DP
(antigen)
1. Not related to pharmacological effects
2. Degree is not related to dose
Different drugs,
Same reaction
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6. Idiosyncrasy
Unusual and unexpected sensitivity exhibited by an
individual to a particular drug or food
1. Genetic variation
2. Consistent to the pharmacological effect
3. Degree : parallel to the dose ?
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Glucose 6 phosphate
dehydrogenase(G6PD)
deficiency
acute hemolysis after
taking medicine of
Quinine/broad bean
(favism ) .
Halothane
malignant hyperthermia:
hyperthermia, hypertension, tachycardia,
muscle rigidity, and metabolic acidosis
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7. Addiction
1. A state of dependence produced by the
habitual taking of an certain drug
2. Physical dependence : narcotic drugs
opioids, cocaine, mariguana
3. Psychological dependence: barbiturates
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药物即毒物，利弊并存，
必须权衡，正确应用
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Targets of drugs
 Receptors
 Enzymes
 Ion channels: Ca2+ K+, Na+, Cl-
 Transporters
 Immune system
 Genes: gene therapy , gene engineering drug
 Others
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Chapter 2
Section 2
Interaction between Drug & Receptor
Pharmacodynamics relates to drugs binding
to receptors and their effects.
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1. Definition of Receptor
Endogenous ligand
Drug
Receptor
 A kind of functional
protein which mediates
signal transduction of cell.
Signal amplification
system
Physiological &
Pharmacological Effects
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Definitions
 Agonist: a drug is called an agonist when
binding to the receptor results in a response
 Antagonist: a drug is called an antagonist
when binding to the receptor do not produce a
response.
It ocupy the receptor and block the agonist’s action
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 Competitive antagonist
– shifts agonist curve to the right
– characteristics
• The maximum response is not depressed
• blocks active site and can be overcome by ↑ agonist
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 Noncompetitive antagonist
– shifts agonist curve downward
– characteristics
• does not block active site, therefore no ↑ antagonist can
overcome effect
• Maximum effect is reduced
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•
•
Definitions
 Affinity: ability of drug to bind to receptor, i.e. how well a
drug and a receptor recognize each other.
 Potency: amount of a drug that is needed to produce a given
effect.
EC50 is concentration or dose of drug that causes 50% of
maximum effect
– potency is determined by affinity of drug for receptor and number of
receptors available.
 Efficacy: maximum effect that a drug can produce, regardless
of dose.
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Dose-effect curve
X axis
Dose: rectangular hyperbola
LogD: “S” shape
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
Plots of dose (or log dose) versus response form D-R curve

D-R curve can reveal information about affinity, potency,
and efficacy of these agonists.
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Affinity can be compared only when two drugs
bind to the same receptor, the nearer to the Y-axis,
the greater the affinity (A:B; X:Y? )


In term of potency, A > B; X > Y;

In term of efficacy, A= B; X > Y
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100% Responses increase in
●
Drug effect
direct proportion to dose
Response increment diminishes
finally when dose reaches at Emax
maximum
effect
EC50:
50%
0
concentration of
drug that
produces 50%
of maximal
effect
●
logD
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Pre-test for USMLE
Drug affinity for a receptor is most
closely associated with its:
A. potency
B. efficacy
C. selectivity
D. toxicity
E. safety
A
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Relation between receptor binding & effect：
D+R
DR
E
[D][R]
At equilibrium , KD =
DR
(KD : the equilibrium dissociation constant)
[RT] = [R] + [DR]， So：
DR
RT
D
=
KD + D
Relative R-binding（[DR] / RT）
determines the relative effect
（E/Emax）
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E
[ DR ]
[ D]


Emax
[ RT ] K D  [ D ]
[D] = 0
E= 0
[D] ＞＞ KD
DR / RT = 100%, Maximal efficacy
DR / RT = 50%
E= 50%Emax (EC50), KD=[D]
KD is the [D] when the E reach half of Emax, means
that a drug occupy 50% of the receptors present.
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Parameters
 KD & affinity:
– KD is inversely proportional to affinity
KD = [D] EC50
pD2 = -logKD, is proportional to Affinity
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 Emax & intrinsic activity (α,the property of a drug
that determines the amount of biological effect produced per
unit of drug-receptor complex formed. )
– 100%    0
– Emax represents the efficacy of drugs
– Emax reflects the intrinsic activity of drugs
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 Full agonists : produce the maximal response,
α=1;
 Partial agonists : are incapable of eliciting a
maximal response， less effective than full
agonists；α<1
eg: Pentazocine
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Duality of Partial Agonists


The lower curve represents effects of a partial
agonist when used alone, its ceiling effect = 50%
of maximal in this example
As the partial agonist displaces the full agonist
from the receptor, the response is reduced, the
partial agonist is acting as an antagonist
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Antagonistic Index (pA2)
 The negative logarithm to the base 10 of the
molar concentration of antagonist that makes it
necessary to double the concentration of
agonist needed to elicit the original
submaximal responsein the absence of
antagonist (Schild, 1947, 1949).
pA2   log K A
pA2 indicates the potency of antagonist，the
greater of pA2，the more potent of antagonism
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Therapeutic
toxic
Therapeutic
index (TI):
LD50/ ED50
Median effective
dose
Median lethal
dose
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Safety range :
the distance between ED95 and LD5.
Therapeutic Window :
the concentration range of drug
producing therapeutic effect.
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Examples of narrow therapeutic
index drugs
•Warfarin
•Lithium
•Digoxin
•Phenytoin
•Gentamycin
•Amphotericin B
•5-fluorouracil
•AZT (zidovudine)
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Category of Receptor
 G protein-coupled receptors
 Ligand-gated ion channel receptors
 Tyrosine-kinase receptors
 Intracellular receptors
– receptors in cytoplasm: steroid hormone
– receptors in nucleus: thyroxine
 Other receptors
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Receptor Regulation
 Receptor desensitization：
– Agonist-specific desensitization:
• phosphorylation or shift inward of receptor
– Agonist-nonspecific desensitization:
 Receptor hypersensitization:
– withdrawal reaction
 down-regulation & up-regulation
– kinds of de- and hypersensitization when only
involving change of the density of receptor.
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Which statement is correct according to the above figure?
a. Drug A is most efficacious because its ED50 is lowest.
b. Drug B is the least potent drug among the three drugs shown.
c. Drug C is the most potent drug.
d. Drug B is more potent than drug C, and more efficacious the
drug A.
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