DRUG STRUCTUREACTION AND DOSERESPONSE RELATIONSHIPS

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Lecture 2 DRUG STRUCTURE-ACTION AND DOSE-RESPONSE
RELATIONSHIPS
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Objectives

• Explain the terms agonist and antagonist with
  respect to their actions on receptors
• Explain the benefits of changing a drugs
  chemical structure
• Explain the meaning and significance of the
  terms Selectivity, Potency, Side Effects,
  Solubility, Stability, Duration, Toxicity,
  Reversal
• Discuss Dose Response Relationships and their key
  parameters

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Revision

• Modes of Action
• Chemical
• Physical
• Physiochemical
• Supplements
• Inhibitors of enzymes and nucleic acids
• (Receptors)

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Modes of Actions p94-96
6. Receptor Action Receptors are specific
sites on or in cells that drugs, hormones or
neurotransmitters act on to produce an effect or
response.
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Modes of Actions

• 6. Receptor Action
• In cell membrane or inside cell
• most neurotransmitters and hormones receptor
  on cell membrane
• EXCEPT steroid hormones receptor in nucleus or
  cytoplasm

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Amino Acid Based Hormones
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Steroid Hormone
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Modes of Actions

• 6. Receptor Action
• In cell membrane or inside cell
• most neurotransmitters and hormones receptor
  on cell membrane
• EXCEPT steroid hormones receptor in nucleus or
  cytoplasm
• 2. Ion channels
• local anaesthetics block Na channels

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Agonists p97
Galbraith 12.3
An agonist binds to a specific receptor AND
produces a response
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Antagonist
A. More neurotransmitter less antagonist
B. More antagonist less
neurotransmitter
Galbraith 12.4
An antagonist binds to a specific receptor BUT
DOES NOT produces a response
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Structure Action Relationships
Lock and Key
Neurotransmitter\Hormone\Drug
Receptor
Response

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Receptor Subtypes
Neurotransmitter / Hormone
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Receptor Subtypes
Drug
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Activates a and b adrenoceptors
ADRENALINE
HO
H
HO
CH
CH2
N
CH3
OH
Activates a adrenoceptors
PHENYLEPHRINE
HO
H
CH
CH2
N

CH3
OH
Activates b receptors
ISOPRENALINE
HO
H
HO
CH
CH2
N
CH(CH3)2

OH
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Structure Action Relationships
The relationship between the chemical structure
of a drug and its resulting activity. 1.
Selectivity The drug is selective for one
receptor subtype, but not a different receptor
type. adrenaline stimulates. ?1 ?1
adrenoceptors phenylephrine stim. ?1
adrenoceptors. (peripheral vascular
effects) isoprenaline (Isuprel) ?1 (cardio
effects) salbutamol (ventolin) ?2
(respiratory effects)
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Structure Action Relationships
2. Potency The relative amount of drug that
has to be present to produce a desired
effect. procaine lignocaine (xylocaine) 3.
Side-Effects Some drugs are modified to reduce
unwanted side-effects cocaine lignocain
e
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Structure Action Relationships
4. Solubility Water / Lipid soluble. Common to
make drugs more water soluble Addition of
hydrochloride, sulphate groups 5. Stability
How chemically stable a drug is
adrenaline isoprenaline
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Structure Action Relationships
6. Duration of Action How long the drug has an
effect BARBITUATES phenobarbitone (11
hrs) pentobarbitone (3 hrs) thiopentone (15
min)
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Structure Action Relationships
7. Reduction of Toxicity Production of adverse
side effects usually related to high doses
phenacetin paracetamol 8. Drug Reversal
Drugs action can be reversed by the addition of
an agonist or antagonist Reversal of narcotics
(morphine, heroine) with naloxone
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Dose Response Relationships p98-100
Dose amount of drug administered to the
patient Response effect in the body produced
by the drug Drug Receptor ? Drug-Receptor
Complex ? Response
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100
Response (eg BP)
0
1000
0 1 10 100

Drug Dose
Dose-Response Curve
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Response
1 10 100

1000
Drug Dose
Response
10-3 10-2 10-1
Log Drug Concentration Molar
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100
3

4
Response
50
2
0
1
ED50
Log Drug Concentration Molar
KEY PARAMETERS
1. Dose required to produce any effect at all.
2. ED50 effective dose to produce 50 response
3. Dose required to produce maximum effect
4. Dose that produces a toxic response.
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Potency vs Efficacy

• Potency how much drug is required to produce a
  certain effect.

100

Response
50
2
0
1
ED50
Log Drug Concentration Molar
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Potency vs Efficacy

• Efficacy how large an effect the drug produces.

100

Response
50
2
0
1
ED50
Log Drug Concentration Molar