Pharmacodynamics Psych 223

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PharmacodynamicsPsych 223
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Lecture Outline

• Neurotransmitter receptors
• Neurons brief introduction
• Synapse brief introduction
• Receptors
• Ligand-receptor interactions
• Specificity
• Affinity
• Intrinsic activity
• Agonists antagonists
• Reversible/Irreversible
• Competitive/Noncompetitive
• Dose-response relationships
• Law of mass action
• Dose-response relationship
• ED50, TD50, LD50
• Efficacy/potency
• Competitive/noncompetitive
• Summation/potentiation

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The Neuron
Reconstruction of a neuron.
Cartoon of a neuron.
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The Neuron
Photo of a neuron.
http//www.encorbio.com/Album/pages/ChkNFH-neuron1
.htm
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The Neuron and Synapse
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The Synapse
Synapses are the connecting points between neurons
Close-up of view of various synapses
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The Synapse
Electron microscope picture of a synapse
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The Synapse and Neurotransmitters

• Release of neurotransmitter
• Exocytosis The action potential triggers
  voltage gated Ca channels. Ca signals the
  release of neurotransmitter through exocytosis.

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The Synapse and Release

• Release of neurotransmitter
• Exocytosis
• Release Neurotransmitter is spilled into the
  synapse.

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The Synapse, Release and the Receptor

• Release of neurotransmitter
• Exocytosis
• Release
• Binding neurotransmitter binds to receptors on
  the postsynaptic membrane.

http//www.blackwellpublishers.co.uk/matthews/nmj.
html
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The Receptor and Binding
PRE
Synaptic cleft
POST
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The Receptor and Binding
Chemicals (ligands) must bind to the receptor and
remain bound long enough for the receptor to be
activated.
PRE
Synaptic cleft
POST
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The Receptor - Specificity
Specificity ligands bind to specific receptors.
Not all ligands bind to all receptors.
PRE
Synaptic cleft
POST
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The Receptor - Specificity
There are a number of specific ligands and a
number of associated receptors.
PRE
Synaptic cleft
POST
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The Receptor Affinity
Affinity the extent to which the ligand is
capable of binding and remains bound to a
receptor. High Affinity the ligand binds well
and remains bound long enough to activate the
receptor. Low Affinity the ligand binds less
well and may not remain bound long enough to
activate the receptor.
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High Affinity Binding
High Affinity the ligand binds well and remains
bound long enough to activate the receptor.
PRE
Synaptic cleft
POST
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High Affinity Binding
Low Affinity the ligand binds less well and may
not remain bound long enough to activate the
receptor.
PRE
Synaptic cleft
POST
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The Receptor Intrinsic Activity
Intrinsic Activity the extent to which the
ligand activates the receptor. High Intrinsic
Activity the ligand produces a large effect on
the post synaptic cell. Low Intrinsic Activity
the ligand produces a small or inconsistent
effect on the post synaptic cell.
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High Affinity Binding
High Intrinsic Activity the ligand produces a
large effect on the post synaptic cell.
PRE
Synaptic cleft
POST
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High Affinity Binding
Low Intrinsic Activity the ligand produces a
small or inconsistent effect on the post synaptic
cell.
PRE
Synaptic cleft
POST
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Classes of Ligands

• Agonist
• High affinity
• High intrinsic activity
• Antagonist
• High affinity
• Low intrinsic activity

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Agonist

• High affinity
• High intrinsic activity

Agonist
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Antagonist

• High affinity
• Low intrinsic activity

Antagonist
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Classes of Ligands

• Antagonist
• Reversible can be unbound from the receptor.
• Irreversible cannot be unbound from the
  receptor.
• Competitive competes with other ligands for
  biding to the receptor.
• Non-competitive exerts its antagonist effects
  without competition for occupancy of the
  receptor.

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Reversible Antagonist

• High affinity
• Low intrinsic activity

Antagonist
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Irreversible Antagonist

• High affinity
• Low intrinsic activity

Irreversible Antagonist
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Competitive Antagonist
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Noncompetitive Antagonist
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Indirect Agonist
Indirect Agonist
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Law of Mass Action
D R
DR
Biological effect

• Drugs associate (bind) and dissociate (unbind)
  from the receptors
• With a fixed D and and a fixed R, DR will be
  constant and the biological effect will be
  constant.
• If D is increased or decreased (more or less
  drug), DR will increase or decrease
  proportionately.
• When all of the receptors are occupied (DR),
  adding more D does not increase DR and there is
  no further biological effect.

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Recap

• Specificity, affinity, intrinsic activity
• Agonists and Antagonists and their variants
• Affinity and intrinsic activity?
• Affect on the neuron and its biological effect
• Antagonists
• Reversible/nonreversible
• Competitive/noncompetitive
• Law of Mass Action

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Dose-Response Functions
Displays the relationship between the dose of a
ligand and some biological response to that
ligand.
Biological Effect
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Dose-Response FunctionED50
ED50 The dose at which 50 of the maximal
biological response is observed
Pain Relief
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Dose-Response FunctionTD5o
TD50 The dose at which 50 of the maximal
toxicity is observed
Toxicity
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Dose-Response FunctionLD50
LD50 The dose at which lethality is observed in
50 of subjects.
Lethality
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Dose-Response Function ED50 ,TD50 ,LD50
Percentage Responding
TD50
LD50
ED50
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Therapeutic IndexTD50/ED50
Percentage Responding
ED50
TD50
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Efficacy Potency
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Efficacy Potency
B
A
Biological Effect
Efficacy AB Potency AgtB
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Efficacy Potency
A
B
Biological Effect
Efficacy AgtB Potency AB
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Efficacy Potency
A
B
Biological Effect
Efficacy AgtB Potency AgtB
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Competitive and Noncompetitive Antagonists
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Competitive Antagonists
D R
Biological effect
DR
A R
No Biological effect
AR
Biological effect
D A R
DR
AR
D DA
DR DRAR
a
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Summation
B
A
AB
Biological Effect
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Potentiation
A
AB
Biological Effect
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Recap

• Dose-response relationships
• ED50, TD50, LD50
• Efficacy/potency
• Competitive/noncompetitive
• Summation/potentiation