Basic and Clinical Pharmacology

C21 INTRODUCTION TO THE PHARMACOLOGY OF CNS DRUGS

ANITA Q. SANGALANG, MD, MHPEd
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

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

ORGANIZATION OF THE CNS

• CNS is composed of the brain and spinal cord
• Responsible for integrating sensory information and generating motor output needed to interact
with the environment and enhance species survival

NEURONS
• Electrically excitable cells that process and transmit information via an electrochemical process

NEUROGLIA
• Large number of nonneuronal support cells
• Astrocytes
o Most abundant cell in the brain
o Provides metabolic nutrients to neurons and maintaining extracellular ion concentrations
• Oligodendrocytes
o Wrap around the axons of projection neurons in the CNS forming the myelin sheath
o Similar to the Schwann cells in peripheral neurons
o Myelin sheath insulates the axons and increases the speed of signal propagation
• Microglia
o Specialized macrophages derived from the bone marrow that settle in the CNS
o Major immune defense system in the brain

BLOOD BRAIN BARRIER (BBB)

• Protective functional separation of the circulating blood from the extracellular fluid of the CNS that
limits the penetration of substances, including drugs
• Presence of tight junctions between the capillary endothelial cells as well as a surrounding layer
of astrocyte end-feet
• To enter the CNS, drugs must either be highly hydrophobic or engage specific transport
mechanisms
o Second-generation antihistamines cause less drowsiness because they were developed
to be significantly more polar than older anti- histamines, limiting their crossing of the
BBB
o Glucose and the essential amino acids, have specific transporters that allow them to
cross the BBB

ION CHANNELS & NEUROTRANSMITTER RECEPTORS

• Most drugs that act on the CNS do so by changing ion flow through transmembrane channels of
nerve cells
• The members of the nerve cells contain two types of channels defined on the basis of the
mechanism controlling their gating (opening & closing)
• Voltage gated channels
• Ligand gated channels

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
• Include the sodium channels responsible for action potential propagation
• Cell bodies and dendrites also have voltage-sensitive ion channels for potassium and calcium

LIGAND-GATED ION CHANNELS

• Chemically gated
• Respond to chemical neurotransmitters
• Found on all cell bodies and on both the presynaptic and postsynaptic sides of the synapses
• Neurotransmitters exert their effects on neurons by binding to two distinct classes of receptor
• INOTROPIC RECEPTORS
• Multiple subunits, and binding of the neurotransmitter ligand directly opens the channel
• Results in a brief opening of the channel
• Fast synaptic transmission typical of hierarchical pathways in the CNS
• METABOTROPIC RECEPTORS
• Seven- transmembrane G protein-coupled receptors
• Binding of neurotransmitter to this type of receptor does not result in the direct gating of a channel
• It engages a G protein, which results in the production of second messengers that mediate
intracellular signaling cascades
• Membrane delimited pathways
• Potassium channels
• Calcium channels
Types of receptor channel coupling in LIGAND GATED ion channels activation and inactivation
• A receptor that acts directly on the channel protein
• A receptor that is coupled to the ion channel through a G protein
• A receptor coupled to a G protein that modulates the formation of diffusible second
messengers
• Cyclic adenosine monophosphate (cAMP)
• inositol trisphosphate (IP3)
• Diacylglycerol (DAG)

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THE SYNAPSE AND SYNAPTIC POTENTIALS

SYNAPSE
Communication between neurons in the CNS occurs through chemical synapses in the majority of cases

EXCITATORY POSTSYNAPTIC POTENTIALS (EPSPs)

• Depolarizing potential change
• Generated by
• Opening of sodium or calcium channels
• Closing of potassium channels in some synapses
• Na+, K+, Ca+2

INHIBITORY POSTSYNAPTIC POTENTIALS (IPSPs)

• Hyperpolarizing potential change
• Generated by
• Opening of potassium or chloride channels
• K+, Cl- at the postsynaptic, Ca+2 at the presynaptic

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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
• Most drugs exert their effect mainly at the synapses
• May act presynaptically to alter
• Synthesis
• Storage
• Release
• Reuptake
• Metabolism of transmitter chemicals
• Activate or block
• Pre- and postsynaptic receptors for specific transmitters
• Interfere with the action of second messengers

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 • Reserpine
• Inhibits storage of catecholamines
• Amphetamine
• Induces release of catecholamines
• Cocaine
• Blocks the uptake of catecholamines
• Anticholinesterase
• Inhibits degradation of acetylcholine

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
• Major excitatory transmitters
• Aspartate
• Glutamate
• Also include numerous small inhibitory interneurons transmitter
• Gamma amino butyric acid (GABA)
• Glycine
B. DIFFUSED/NON-SPECIFIC NEURONAL
SYSTEM
• Broadly distributed, with single cells frequently sending processes to many different parts of the
brain-tangential
• Varicosities
• Periodic enlargements that contain transmitter vesicles
• Located in the axons
• 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
• Marked effects on CNS functions

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 • Attention
• Appetite
• Emotional states

CRITERIA FOR TRANSMITTER STATUS

1. Localization
• Present in higher concentration in the synaptic area than in other areas (localized in
appropriate areas)
2. Release
• Transmitter released from a neuron in response to neuronal activity and in a calcium-
dependent manner
3. Synaptic mimicry
• Produce the same sort of postsynaptic response that is seen with physiologic activation
of the synapse

Please take note of the different neurotransmitters enumerated on Table 21.1 below and their
receptor subtypes and mechanisms.

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