INTRODUCTION TO

PHARMACOLOGY OF CNS DRUGS

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CNS PHARMACOLOGY
1. Nearly ALL drugs with CNS effects act on a
specific receptors that modulates transmission
1. CNS DRUGS are among the most important tools
for studying all aspects of CNS physiology.
2. Unraveling the actions of drugs with known clinical
efficacy led to the hypotheses regarding the
mechanism of disease.

CNS PHARMACOLOGY
ION CHANNELS & NEUROTRANSMITTER
RECEPTORS
Most drugs that act on the CNS do so by
changing ion flow through transmembrane
channels of nerve cells

CNS PHARMACOLOGY
The members of the nerve cells contain two types
of channels defined on the basis of the mechanism
controlling their gating (Opening & closing)
1. Voltage Gated Channels
2. Ligand Gated Channels

CNS PHARMACOLOGY
ION CHANNELS & NEUROTRANSMITTER
RECEPTORS
VOLTAGE-GATED ION CHANNELS
Respond to changes in membrane potential
Concentrated on the INITIAL SEGMENT of the
axons in nerve cells
Responsible for FAST action potentials

CNS PHARMACOLOGY
ION CHANNELS &
NEUROTRANSMITTER RECEPTORS
VOLTAGE-GATED ION CHANNELS
Include the sodium channels
responsible for action potential
propagation
Cell bodies and dendrites also
have voltage-sensitive ion
channels for potassium and
calcium

CNS PHARMACOLOGY
ION CHANNELS & NEUROTRANSMITTER
RECEPTORS
2 CLASSES OF NEUROTRANSMITTER RECEPTORS
1. LIGAND-GATED ION CHANNELS OR
INOTROPIC RECEPTOS
2. METABOTROPIC RECEPTORS

CNS PHARMACOLOGY
ION CHANNELS & NEUROTRANSMITTER
RECEPTORS
2 CLASSES OF NEUROTRANSMITTER RECEPTORS
1. LIGAND-GATED ION CHANNELS
Chemically-gated
Respond to chemical neurotransmitters
(NTAs) that bind to receptor subunits of
the channel

CNS PHARMACOLOGY
2 MAJOR TYPES OF ION CHANNEL
LIGAND-GATED ION CHANNELS
NTAs also bind to G protein-coupled
receptors (metabotropic receptors)
Found on all cell bodies and on both
the presynaptic and postsynaptic sides
of the synapses

CNS PHARMACOLOGY
ION CHANNELS & NEUROTRANSMITTER RECEPTORS
2 CLASSES OF NEUROTRANSMITTER RECEPTORS
2. METABOTROPIC RECEPTORS
SEVEN transmembrane G protein coupled
Binding does not result in the direct gating of a
channel
Binding engages the G-protein that results into
production of SECOND messengers that
modulates the voltage gated channels

CNS PHARMACOLOGY
ION CHANNELS & NEUROTRANSMITTER
RECEPTORS
2 CLASSES OF NEUROTRANSMITTER
RECEPTORS
2. METABOTROPIC RECEPTORS

Membrane Delimited Pathways

Potassium channels
Calcium channels

CNS PHARMACOLOGY
Types of receptor channel coupling in LIGAND
GATED ion channels activation and inactivation
1.A receptor that acts directly on the channel protein
2.A receptor that is coupled to the ion channel
through a G protein
3.A receptor coupled to a G protein that modulates
the formation of diffusible second messengers A.
cyclic adenosine monophosphate (cAMP)
B. inositol trisphosphate (IP 3)
C. diacylglycerol (DAG)

CNS PHARMACOLOGY
ROLE OF THE ION CURRENT CARRIED BY
THE CHANNEL
SYNAPSE- communication
EPSPs
IPSPs

CNS PHARMACOLOGY
EXCITATORY POSTSYNAPTIC POTENTIALS
(EPSPs)
Depolarizing potential change
Generated by
Opening of sodium or calcium channels
Closing of potassium channels in some synapses

CNS PHARMACOLOGY
EXCITATORY POSTSYNAPTIC POTENTIALS
(EPSPs)
Na+, K+, Ca+2

-70 mV

CNS PHARMACOLOGY

INHIBITORY POSTSYNAPTIC POTENTIALS

(IPSPs)
Hyperpolarizing potential change
Generated by
Opening of potassium or chloride channels

CNS PHARMACOLOGY
INHIBITORY POSTSYNAPTIC POTENTIALS
(IPSPs)
K+ , Cl- at the postsynaptic , Ca+2 at
the presynaptic

-70 mV

CNS PHARMACOLOGY
SITES AND MECHANISMS OF DRUG ACTION
Some drugs exert their effect through
direct interactions with molecular
components of ion channels on axons
Carbamazepine
Phenytoin
Local anesthetics and some drugs used for general
anesthesia

CNS PHARMACOLOGY

SITES AND MECHANISMS OF DRUG ACTION

Most drugs exert their effect mainly at the
synapses

CNS PHARMACOLOGY
SITES AND MECHANISMS OF DRUG ACTION
May act presynaptically to alter

Synthesis
Storage
Release
Reuptake
Metabolism of transmitter chemicals

CNS PHARMACOLOGY

SITES AND MECHANISMS OF DRUG ACTION

Activate or block
Pre- and postsynaptic receptors for specific transmitters
Interfere with the action of second messengers

CNS PHARMACOLOGY

SITES AND MECHANISMS OF DRUG ACTION

Parachlorophenylalanine
Inhibits synthesis of serotonin

Reserpine
Inhibits storage of cathecolamines

CNS PHARMACOLOGY

SITES AND MECHANISMS OF DRUG ACTION

Amphetamine
Inhibits release of catecholamines

Anticholinesterase
Inhibits degradation of cathecolamines

CNS PHARMACOLOGY
CNS ORGANIZATION
2 TYPES OF NEURONAL SYSTEM
A. HIERARCHICAL SYSTEM
Contain large myelinated, rapidly
conducting fibers
Control major sensory and motor functions
Excitability of the CNS

CNS PHARMACOLOGY
CNS ORGANIZATION
2 TYPES OF NEURONAL SYSTEM
A. HIERARCHICAL SYSTEM
Major excitatory transmitters

Aspartate
Glutamate

Also include numerous small inhibitory

interneurons transmitter

Gamma amino butyric acid (GABA)

Glycine

CNS PHARMACOLOGY
CNS ORGANIZATION
2 TYPES OF NEURONAL SYSTEM
B. DIFFUSED/NON-SPECIFIC NEURONAL
SYSTEM
Broadly distributed, with single cells
frequently sending processes to many
different parts of the brain-tangential

CNS PHARMACOLOGY
CNS ORGANIZATION
2 TYPES OF NEURONAL SYSTEM
B. DIFFUSED/NON-SPECIFIC NEURONAL
SYSTEM
Varicosities

Periodic enlargements that contain transmitter vesicles

Located in the axons

CNS PHARMACOLOGY
CNS ORGANIZATION
2 TYPES OF NEURONAL SYSTEM
B. DIFFUSED/NON-SPECIFIC NEURONAL
SYSTEM
Transmitters

Noradrenergic Amines (NE, dopamine and serotonin)

Peptides that act on metabotropic receptors
Found primarily in a compact cell group called locus
caeruleus in the caudal pontine central gray matter

CNS PHARMACOLOGY
CNS ORGANIZATION
2 TYPES OF NEURONAL SYSTEM
B. DIFFUSED/NON-SPECIFIC
NEURONAL SYSTEM
Marked effects on CNS functions
Attention
Appetite
Emotional states

CNS PHARMACOLOGY
CRITERIA FOR TRANSMITTER STATUS
1. Present in higher concentration in the synaptic
area than in other areas (localized in
appropriate areas)
2. Released by electrical or chemical
stimulation via a calcium-dependent
mechanism
3. Synaptic mimicry
Produce the same sort of postsynaptic
response that is seen with physiologic
activation of the synapse

CNS PHARMACOLOGY
CHEMICALS ACCEPTED AS NTAs IN THE
CNS (Table in Katzung)
ACETYLCHOLINE (Ach)
5% of neurons have receptors for Ach
G protein-coupled muscarinic M1 receptors
Slow excitation
Decrease permeability to potassium

CNS PHARMACOLOGY
CHEMICALS ACCEPTED AS NTAs IN THE
CNS
DOPAMINE
Inhibitory actions at synapses in specific
neuronal systems
G protein-coupled activation of K+ channels
D2 receptor is the main dopamine subtype
Increase cAMP

CNS PHARMACOLOGY
CHEMICALS ACCEPTED AS NTAs IN THE
CNS
NOREPINEPHRINE
Excitatory effects

Activation of 1 and 1 receptors

Decrease K+ conductance

Inhibitory effects

Activation of 2 and 2 receptors

Increase K+ conductance

CNS PHARMACOLOGY
CHEMICALS ACCEPTED AS NTAs IN THE
CNS
SEROTONIN
Multiple 5 hydroxytryptamine (5-HT)
receptor subtypes
Metabotropic
Inhibitory at many CNS sites
Excitatory depending on the receptor
subtype activated

CNS PHARMACOLOGY
CHEMICALS ACCEPTED AS NTAs IN THE
CNS
GLUTAMIC ACID
Excitatory for most neurons
N-methyl-D-aspartate (NMDA) receptor

Learning and memory

Inhibition of adenyl cyclase

CNS PHARMACOLOGY
CHEMICALS ACCEPTED AS NTAs IN THE
CNS
GABA AND GLYCINE
GABA is the primary NTA mediating IPSPs
GABAA receptor activation

Opens Cl- conductance

GABAB receptor activation

Opens K+ channels
Closes Ca+2 channels

CNS PHARMACOLOGY
CHEMICALS ACCEPTED AS NTAs IN THE
CNS
GABA AND GLYCINE
Glycine is more numerous in the cord
Glycine is inhibitory

Increases Cl- conductance

CNS PHARMACOLOGY
CHEMICALS ACCEPTED AS NTAs IN THE
CNS
OPIOID PEPTIDES
Beta-endorphins, dynorphins
Inhibitory (presynaptic)

Decrease Ca+2 conductance

Inhibitory (postsynaptic)

Increase K+ conductance