Introduction to the

Pharmacology of CNS Drugs

By Pharm Abdulai Jawo Bah
Lecturer, Depart of Pharmacology
COMAHS

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Introduction to the Pharmacology of
CNS Drugs
 Introduction
 Ion Channels & neurotransmitters
 Synaptic Potentials
 Sites of Drug Action
 Identification of Neurotransmitters
 Cellular Organization of the Brain
 Central Neurotransmitters
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 Introduction
 All drugs with CNS effects act on specific receptors
 General anesthetics and alcohol may be exceptions
 Drugs are among the most important tools for
studying all aspects of CNS physiology
 From the mechanism of convulsions to the laying
down of long-term memory.
 Specific agonists that mimic natural transmitters and
antagonists are extremely useful in such studies.
 Introduction
 The actions of drugs with known clinical
efficacy has led to unraveling the mechanisms
of CNS diseases:
 Antipsychotic drugs on dopamine receptors => the
pathophysiology of schizophrenia.
 Effects of ligands on γ aminobutyric acid (GABA)
receptors => the pathophysiology of anxiety and
epilepsy.
 Introduction
 Snake, scorpion, snail, bee, wasp, frog and even plant
toxins are very important in the study of CNS.
 A genus of marine snail (Conus ) includes at least 500
different species.
 Each species kills its prey with a venom that contains 50–
200 different peptides or proteins.
 There is little duplication of peptides among Conus
species!
 These toxins are excellent investigational tools for ion
channels study.
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 Ion Channels & neurotransmitters
 The membranes of nerve cells contain two types
of channels.
 They are defined on the basis of the mechanisms
controlling their gating:
 Voltage-gated
 Ligand-gated
 Voltage-sensitive Na+ channel

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 Voltage-sensitive K+ channel

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 Ion Channels & neurotransmitters
 Neurotransmitters exert their effects on neurons by
binding to two classes of receptor:
 Ligand-gated channels, or ionotropic
 Their activation is brief (milliseconds) opening
 Involved in fast transmission in hierarchical pathways
 Metabotropic receptors
 G protein-coupled
 Their effects last tens of seconds to minutes
 Involved in the diffuse neuronal systems in the CNS
 Affect two types of voltage-gated ion channels:
 Calcium channels (for presynaptic inhibition)
 Potassium channels (for postsynaptic inhibition)
 Types of ion channels and neurotransmitter receptors in the CNS. A shows a voltage-gated
channel in which a voltage sensor component of the protein controls the gating (broken
arrow ) of the channel. B shows a ligand-gated channel in which the binding of the
neurotransmitter to the ionotropic channel receptor controls the gating (broken arrow ) of the
channel. C shows a G protein-coupled (metabotropic) receptor, which, when bound,
activates a G protein that then interacts directly to modulate an ion channel. D shows a G
protein-coupled receptor, which, when bound, activates a G protein that then activates an
enzyme. The activated enzyme generates a diffusible second messenger, eg, cAMP, which
interacts to modulate an ion channel.
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 Receptor-mediated channel opening

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 Receptor-activated channels

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Amplification in signal transduction pathways

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 Synaptic Potentials
 When an excitatory pathway is stimulated, a
excitatory postsynaptic potential (EPSP) is recorded.
 When an inhibitory pathway is stimulated, an
inhibitory postsynaptic potential (IPSP) is produced.
 There is also a second type of inhibition, presynaptic
inhibition, which is axoaxonic.
 Excitatory Post Synaptic Potential (EPSP)

Single synapse Many synapses

Threshold

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Resting membrane potential = -70 mV
 Inhibitory Post Synaptic Potential (IPSP)

Excitation Inhibition Identical Excitation

Threshold

22 Resting membrane potential = -70 mV

 Inhibitory
interneurone

Ach
(nic)
Glycine
Increases Cl-
permeability
Motor neurone

Ach (nic)

Disinhibition of inhibitory fibers can cause convulsion (e.g.

Strychnine which blocks inhibitory substance Glycine)
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 Sites of Drug Action
 Virtually all CNS drugs produce their effects by
modifying some step in chemical synaptic
transmission.
 These transmitter-dependent actions can be divided
into presynaptic and postsynaptic.
 The selectivity of CNS drug action is based on the
fact that:
 Different transmitters are used by different groups of
neurons.
 These transmitters are segregated into neuronal
systems that subserve broadly different CNS functions.
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 Identification of Neurotransmitters
 Localization
 to prove that a suspected transmitter resides in the
presynaptic terminal of the pathway under study
 Release
 To determine whether the substance is released from a
particular region
 Synaptic Mimicry
 Application of the suspected substance should produce
a response that mimics the action of the transmitter
released by nerve stimulation
 Cellular Organization of the Brain
 Hierarchical systems
 Sensory perception and motor control
 Has 2 types of neurons:
 Relay or projection neurons
 Local circuit neurons
 Nonspecific or Diffuse Neuronal Systems
 Contain one of the monoamines—norepinephrine,
dopamine, or serotonin
 Central Neurotransmitters
 Inhibitory Amino Acids
Glycine, GABA
 Excitatory Amino Acids
Glutamate
 Acetylcholine
 Monoamines
Dopamine, Norepinephrine
 Peptides and 5-hydroxytryptamine

 Nitric Oxide
 Histamine
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 Schematic diagram of a glutamate synapse. Glutamine is
imported into the glutamatergic neuron (A) and converted into
glutamate by glutaminase. The glutamate is then concentrated
in vesicles by the vesicular glutamate transporter. Upon release
into the synapse, glutamate can interact with AMPA and NMDA
ionotropic receptor channels (AMPAR, NMDAR) in the
postsynaptic density (PSD) and with metabotropic receptors
(MGluR) on the postsynaptic cell (B). Synaptic transmission is
terminated by active transport of the glutamate into a
neighboring glial cell (C) by a glutamate transporter. It is
synthesized into glutamine by glutamine synthetase and
exported into the glutamatergic axon. (D) shows a model NMDA
receptor channel complex consisting of a tetrameric protein that
becomes permeable to Na+ and Ca2+ when it binds a glutamate
molecule.

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Summary

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Thank you

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 GABA

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 EndorphineEnkephaline

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 EndorphineEnkephaline

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 Dopamine

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 Acetyl choline

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 NoradrenalinSerotonin

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 Noradrenaline

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