chapter 2 pharmacodynamics. 2 objectives 1.know the different types of adverse reactions...
TRANSCRIPT
Chapter 2
Pharmacodynamics
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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
actionaction
effect
block prostaglandin synthesis
analgesia & antipyresis
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Ⅱ、 Therapeutic Effects and Adverse Reactions
Effect of
Drug
Effect of
Drug
Therapeutic Effect
Adverse Reactions
Etiological treatment
Symptomatic treatment
Supplement therapySide effect Toxic reactionResidual effectWithdrawal reactionAllergic reactionIdiosyncrasyAddiction
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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
1. Pharmacological effects
2. Therapeutic dose
4. Mild and recoverable
is an effect, whether therapeutic or adverse, that is an effect, whether therapeutic or adverse, that is secondary to the one intended.is secondary to the one intended.is an effect, whether therapeutic or adverse, that is an effect, whether therapeutic or adverse, that is secondary to the one intended.is secondary to the one intended.
3. Low selectivity
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Dry mouthsalivary secretionsalivary secretion
pupil pupil dilationdilation
Inhibition of sphincter pupilla
Inhibition of sphincter pupilla
Heart rateHeart rateRelieve the cardiac inhibition by vagus
nerve
Relieve the cardiac inhibition by vagus
nerve
spasmolysisspasmolysisgastrointestinal relaxation
Atropine
M-acetylcholine
R blocker
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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 thalidomidethalidomide
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 hangover next morninghypnotic
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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 ）
1. Not related to pharmacological effects
2. Degree is not related to dose
D + Protein DP (half-antigen) (antigen)
Different drugs, Same reaction
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6. Idiosyncrasy
1. Genetic variation
3. Degree : parallel to the dose ?
Unusual and unexpected sensitivity exhibited by an individual to a particular drug or food
Unusual and unexpected sensitivity exhibited by an individual to a particular drug or food
2. Consistent to the pharmacological effect
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Halothane malignant hyperthermia: hyperthermia, hypertension, tachycardia,
muscle rigidity, and metabolic acidosis
Glucose 6 phosphate dehydrogenase(G6PD)deficiency
acute hemolysis after taking medicine of Quinine/broad bean (favism ) .
acute hemolysis after taking medicine of Quinine/broad bean (favism ) .
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7. Addiction
1. A state of dependence produced by the habitual taking of an certain drug
3. Psychological dependence: barbiturates
2. Physical dependence : narcotic drugs opioids, cocaine, mariguana
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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 2Interaction between Drug & Receptor
Pharmacodynamics relates to drugs binding to receptors and their effects.
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Signal amplification system
Physiological & Pharmacological Effects
A kind of functional protein which mediates signal transduction of cell.
Receptor
Endogenous ligand
Drug
1. Definition of Receptor
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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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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.
Definitions• • • • • • • •
• • •
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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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Dru
g ef
fect
logD
100%
50%
0
EC50:
concentration of drug that produces 50% of maximal effect
●
Responses increase in direct proportion to dose maximum
effect
●
Response increment diminishes finally when dose reaches at Emax
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Drug affinity for a receptor is most closely associated with its:
A. potency
B. efficacy
C. selectivity
D. toxicity
E. safety
Pre-test for USMLE
A
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Relation between receptor binding & effect：
D+R DR E
=
[RT] = [R] + [DR] ， So ：
DR D RT KD + D
[D][R] DRKD =At equilibrium ,
Relative R-binding （ [DR] / R
T ） determines the relative effect （ E/Emax ）
(KD : the equilibrium dissociation constant)
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][
][
][
][
Tmax DK
D
R
DR
E
E
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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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
Duality of Partial Agonists
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Antagonistic Index (pA2)
AKpA log2
pA2 indicates the potency of antagonist ， the greater of pA2 ， the more potent of antagonism
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).
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Therapeutic index (TI): LD50/ ED50
Therapeutic toxic
Median lethal dose
Median effective 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)
•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.
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.