Lect.1 Introduction to CNS and Drug Action

DRUGS USED IN DISORDERS OF THE
CENTRAL NERVOUS SYSTEM AND
TREATMENT OF PAIN
Lecture 1:
Introduction to the CNS and Drug Action
Marc Imhotep Cray, M.D.

CNS Pharmacology
Lecture 1
Goal of Presentation:
2
The goal of this presentation is to provides an introduction to
the functional organization of the CNS and its synaptic
transmitters as a basis for understanding the actions of the
neurologic and psychiatric drugs described in subsequent
lectures.
o MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders
o Companion eNotes: CNS- Central Nervous System Pharmacology
o Textbook Reading: Nicoll RA. Ch. 21 Introduction to the Pharmacology of CNS Drugs.
In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 359-71

CNS Pharmacology
Lecture 1
Classification Schema: CNS AGENTS
Antiepileptics
(Anticonvulsants)
Phenytoin
Carbamazepine
Topiramate
Valproic acid
Ethosuxmide
Gabapentin
Tiagabine
GABAergic
Phenobarbital
Thiopental
Diazepam
Zolpidem
Baclofen
General Anesthetic*
Halothane
Local Anesthetic
Procaine
Glutamate Antagonists
Memantine
Riluzole
Serotonin Agonists &
Antagonists
Sumatriptan
Ergotamine
Buspirone
Ondansetron
Alosetron
Antidepressants
Amitriptyline
Fluoxetine
Nefazodone
Phenelzine
Dopamine Agonists &
Antagonists
Levodopa/carbidopa
Pramipexole
Prochlorperazine
Antipsychotics
Chlorpromazine
Haloperidol
Olanzapine
Lithium
Opioids & Opioid Antagonists
Morphine
Codeine
Pentazocine
Diphenoxylate
Methadone
Naloxone
3See: Most Common Drugs (Classes) with Phonetic Pronunciations
*General anesthetics are included
in CNS, although their MOA is not
mediated by neurotransmitters
Note: A drug may be
classified by the
chemical type of the
active ingredient, its
molecular target or by
the way it is used to
treat a particular
condition (therapeutic
indication). Each drug
can be classified into
one or more drug
classes.

CNS Pharmacology
Lecture 1Major Neuropsychiatric
Disorders and Classes of
Drugs Used for Treatment
4Modified from Brody’s Human Pharmacology, 2010
(N-methyl-D-aspartate)

CNS Pharmacology
Lecture 1
Methods for Study of CNS Pharmacology
5
 Glass microelectrodes permit intracellular neuronal recording
 The brain slice technique permitted an analysis of physiology and pharmacology of
synapses
 Patch clamp technique permits recording of current through single channels
 Channels can be expressed in cultured cells and currents evoked by their activation
recorded
 Histochemical, immunologic, and radioisotopic methods enable mapping of the
distribution of specific transmitters, their associated enzyme systems, and their receptors
 Molecular cloning has made it possible to determine the precise molecular structure of
receptors and their associated channels
 Finally, mice with mutated genes for specific receptors or enzymes (knockout mice) can
provide important information regarding the physiologic and pharmacologic roles of
these components

CNS Pharmacology
Lecture 1Organization of the Nervous System
BRAIN & SPINAL CORD CENTRAL
NERVOUS
SYSTEM (CNS)
PERIPHERAL
NERVOUS
SYSTEM (PNS)
AFFERENT
(Sensory)
NERVES
EFFERENT
(Motor)
NERVES
EXTEROCEPTORS INTEROCEPTORS SOMATIC AUTONOMIC
EFFECTOR
ORGANS
SKELETAL
MUSCLES
SMOOTH MUSCLE,
CARDIAC MUSCLES
AND GLANDS
VOLUNTARY
Monosynaptic
INVOLUNTARY
Pre & Post Ganglionic Fiber
The central nervous
system (CNS) consists of
the brain and spinal cord.
The CNS receives and
interprets sensory
information (via peripheral
afferent nerves) and then
initiates appropriate
motor responses (via
peripheral efferent
nerves).

CNS Pharmacology
Lecture 1
Overview
7
The properties of the CNS, like the properties of peripheral organs
(ANS), are mediated by neurochemical transmitters acting at
receptor sites
Thus, at the molecular level, the fundamental mechanism of
action (MOA) of drugs affecting the CNS differ little from MOA of
drugs that act on PNS
However, although neurotransmission in CNS parallels that in ANS,
the CNS utilizes several chemicals (amino acid) and peptides as
transmitters in addition to acetylcholine and norepinephrine

CNS Pharmacology
Lecture 1
Overview (2)
8
As in the ANS, the CNS consists of opposing neurotransmitter
systems
 The major excitatory neurotransmitters are the amino acids
glutamate (Glu) and aspartate (Asp)
 The major inhibitory neurotransmitters are GABA and
glycine (Gly)

CNS Pharmacology
Lecture 1
Overview (3)
9
The etiology of CNS functional disorders is often difficult to
determine
Psychosocial and cultural influences are important in
many disorders
Thus, CNS functional disorders are best treated with a
combination of pharmacotherapy and psychosocial
/cultural interventions

CNS Pharmacology
Lecture 1
Overview (4)
10
 Many CNS disorders are not completely understood and thus, they are
imperfectly treated with current medications
 basic research findings continuously provide promising leads for
new drugs
 More is also being learned about the disorders themselves
For example:
 It is now recognized that clinical depression and clinical anxiety
are biochemically distinct from normally experienced feelings of
sadness or apprehension (respectively)
 Schizophrenia is now known to consist of what are known as
positive and negative symptoms
 Pain is now known to be multifaceted
 Neuronal atrophy is implicated in conditions in which it was not
previously suspected

CNS Pharmacology
Lecture 1
Overview (4)
11
Drugs targeted to CNS disorders, like drugs used for
conditions affecting the PNS but to a much larger extent,
are subject to abuse--sometimes by patients but more
often by non-patients
Such abuse can adversely affect the availability of
these drugs (such as opioids for relief of severe
pain) to patients in need

CNS Pharmacology
Lecture 1
Self-directed learning and review
12
Along with the data provided in UNIT 3 of your MedPharm Digital
Guidebook (DRUGS USED IN DISORDERS OF THE CNS AND Tx OF PAIN) the
following illustration plates in Netter's Illustrated Pharmacology, Updated
Edition (2014) * should serve useful to review for this introduction to CNS
Pharm presentation:
 Development of the Nervous System (NIP 3-1)
 Anatomy of the Nervous System (NIP 3-2)
 Functional Correlations and Visualization of Brain Structures (NIP 3-3)
 Resting Membrane and Action Potentials (NIP 3-4)
 Excitatory and Inhibitory Postsynaptic Potentials (NIP 3-5)
* Hyperlink offline. Student access (MS1 & MS2 Core
Digital Textbooks Thumb Drive)

CNS Pharmacology
Lecture 1
Cell Types in the CNS: Neurons and Glia
13
Wecker L, et al. Brody’s human pharmacology : molecular to clinical 5th ed.
 The CNS is composed of two predominant
cell types, neurons and glia, each of which
has many morphologically and functionally
diverse subclasses
 Glial cells outnumber neurons and contain
many neurotransmitter receptors and
transporters
 There are three types of glial cells:
1. Astrocytes
2. Oligodendrocytes
3. Microglia

CNS Pharmacology
Lecture 1
Glia Cells Function, Astrocytes
14
 Astrocytes physically separate neurons and multineuronal
pathways, assist in repairing nerve injury, and modulate the
metabolic and ionic microenvironment
 Astrocytes express ion channels and neurotransmitter
transport proteins and play an active role in modulating
synapse function

CNS Pharmacology
Lecture 1
Glia Cells Function, Oligodendrocytes
15
 Oligodendrocytes form the myelin sheath around axons
and play a critical role in maintaining transmission down
axons
 Polymorphisms (SNP) in the genes encoding several myelin
proteins have been identified in tissues from patients with
both schizophrenia and bipolar disorder and may
contribute to the underlying etiology of these disorders

CNS Pharmacology
Lecture 1
Glia Cells Function, Microglia
16
 Microglia proliferate after injury or degeneration, move
to sites of injury, and transform into large macrophages
(phagocytes) to remove cellular debris
 These antigen presenting cells (APC) with innate immune
function also appear to play a role in endocrine
development

CNS Pharmacology
Lecture 1
Cell Types in the CNS: Neurons
17
 Neurons are the major cells involved in
intercellular communication because of
their ability to conduct impulses and
transmit information
 They are structurally different from other
cells, with four distinct features:
 Dendrites
 A perikaryon (cell body or soma)
 An axon
 A nerve (or axon) terminal
Wecker L, et al. Brody’s human pharmacology : molecular to clinical 5th ed.
Structural components of nerve cells.

CNS Pharmacology
Lecture 1
CNS Neurotransmitters, Receptors, and
Drug Targets
18
 Many substances within the CNS modulate neurotransmitter (NT) actions
 ACh and norepinephrine (NE), predominant in the PNS, also function
in CNS
 Dopamine and 5-HT (serotonin)-more prominent in the CNS-and
peptides such as endorphins are important in CNS function
 Transduction mechanisms for NT action are similar to those in the PNS:
 Ionotropic types include: voltage-gated ion channels (respond to membrane
potential changes) and ligand-gated ion channels (alter membrane ion permeability
in response to ligands such as neurotransmitters or drugs)
 Metabotropic types include: GPCRs and involve second-messenger pathways
(affect ion channels or biochemical reactions)

CNS Pharmacology
Lecture 1
CNS Neurotransmitters, Receptors, and
Drug Targets (2)
19
Drugs affect various sites along neuronal pathways, including:
 neurotransmitter synthesis, storage, and release;
 receptor activation and inhibition;
 modulation of intrasynaptic neurotransmitter metabolism or
reuptake; and
 direct second-messenger pathway effects

CNS Pharmacology
Lecture 1
Neurotransmitters of the Brain and Disease
20
 Treatable neurotransmission diseases fall into two
categories:
 those caused by too much neurotransmission and
 those caused by too little neurotransmission

CNS Pharmacology
Lecture 1
“Too much” neurotransmission
21
May be due to:
A focus of hyperexcitable neurons that fire in the absence of
appropriate stimuli (e.g., seizure disorders)
 Therapy is directed toward reducing automaticity of these
cells
Too many neurotransmitter molecules binding to postsynaptic
receptors (possible explanation for psychoses)
 Therapy includes administration of antagonists which block
postsynaptic receptors

CNS Pharmacology
Lecture 1
“Too little” neurotransmission
22
May be due to:
 Too few neurotransmitter molecules binding to postsynaptic
receptors (e.g., depression, Parkinson's disease)
 Several treatment strategies increase neurotransmission,
including:
1) drugs that cause release of NT stores from presynaptic terminal,
2) neurotransmitter precursors that are taken-up into presynaptic
neurons and metabolized into active neurotransmitter,
3) drugs which inhibit enzymes that degrade neurotransmitters
4) agonists that act at postsynaptic receptors

CNS Pharmacology
Lecture 1
CNS Drugs and Side Effects
23
 Because numerous pathways in brain use the
same neurotransmitter, manipulating transmission in a
diseased pathway simultaneously affects synapses of
normal neurons
 For this reason, CNS drugs are notorious for causing a
variety of side effects

CNS Pharmacology
Lecture 1Representative
Neurotransmitters
in the CNS
24Wecker L, et al. Brody’s human pharmacology : molecular to clinical 5th ed.

CNS Pharmacology
Lecture 1
Most Well Studied Neurotransmitters
of the Brain
25
1) Norepinephrine
2) Dopamine
3) 5-Hydroxytryptamine (5-HT, Serotonin)
4) Acetylcholine
5) Gamma-amino butyric acid (GABA)
6) Excitatory Amino Acids (EAA), Glutamate
7) The Endogenous Opioids
8) Other Neuropeptides

CNS Pharmacology
Lecture 1
1) Norepinephrine
26
 As you learned during the study of the PNS, there are four classes of
adrenergic receptors: α1, α2, β1, β2
 Pathways in the brain that utilize NE have not been as clearly
identified as in the PNS
 A leading hypothesis suggests depression is caused by impaired
monoamine (e.g., norepinephrine, dopamine, serotonin)
neurotransmission
 Drugs which induce monoamine release are indicated for attention
Deficit Hyperactivity disorder (ADHD) and narcolepsy
 However, the biochemical disturbance responsible for these two
diseases is still not well understood and under ongoing
investigation

CNS Pharmacology
Lecture 1
2) Dopamine
27
 Dopamine is synthesized from Dopa, the
hydroxylated congener of the amino acid
tyrosine
 It is degraded by monoamine oxidase A in
the brain and monoamine oxidase B and
catechol-o-methyl transferase (COMT)
outside the CNS

CNS Pharmacology
Lecture 1
Dopamine (2)
28
Dopamine (DA) receptors are classified as D1 & D2
 Both subtypes reside in numerous regions of the brain
No specific D1 agonists have been identified
Activation of either subtype inhibits the rate of neuronal
firing

CNS Pharmacology
Lecture 1
Dopamine (3)
29
 In the CNS, dopamine serves as a neuromodulator
 Two groupings can be distinguished:
 the family of D1-like receptors (comprising subtypes D1 and D5) and
 the family of D2-like receptors (comprising subtypes D2, D3, and D4)
 Subtypes differ in their signal transduction pathways
 For example, synthesis of cAMP is stimulated by D1-like
receptors but inhibited by D2-like receptors
 Released DA can be reutilized by neuronal reuptake and re-
storage in vesicles or can be catabolized like other
endogenous catecholamines by the enzymes MAO and COMT

CNS Pharmacology
Lecture 1
Dopamine (4)
30
Particularly important dopaminergic pathways include:
1) the nigrostriatal pathway (from substantia nigra to
striatum)
2) neurons of the chemoreceptor trigger zone (CTZ) of the
medulla, which controls vomiting, and
 E.g., Apomorphine is a D2 agonist=emesis-inducing
3) projections from the hypothalamus to the intermediate
lobe of the anterior pituitary, which regulate prolactin
release
 In other words PIF is mediated via DAergic neurons

CNS Pharmacology
Lecture 1
Dopamine (5)
31
 Antipsychotic drugs inhibit dopamine-stimulated adenylate cyclase
(usually associated with D1 receptor activation) and block D2
dopamine receptors
 suggest psychoses may result from overstimulation of dopamine
receptors
 Parkinson's Disease, is caused by too little dopaminergic input from
the substantia nigra into the striatum
 Loss of the nigrostriatal dopamine neurons results in a relative
decrease in dopamine input (inhibitory) compared to
acetylcholine input (excitatory)

CNS Pharmacology
Lecture 1
3) 5-Hydroxytryptamine (5-HT, Serotonin)
32
 The amino acid tryptophan is hydroxylated and
then decarboxylated to form 5-HT
 In neurons, 5-HT is stored (in vesicles), released,
taken up into presynaptic neurons and either
recycled or metabolized
 5-HT is released from inhibitory neurons
originating in the raphe nuclei of the pons and
midbrain
 5-HT stimulates either 5-HT1 or 5-HT2 receptors
which are distinguished by specific antagonists
 methysergide (5-HT1-specific) and
 ketanserin (5-HT2-specific)

CNS Pharmacology
Lecture 1
Serotonin (2)
33
 The hallucinogenic drug, lysergic acid diethylamide (LSD) is a
potent agonist at both receptor subtype
 In addition to its role as a neurotransmitter, 5-HT increases
small intestine motility and modulates vasodilation
 Ninety percent of the body's 5-HT is stored in
enterochromaffin cells of the small intestine
Clinical correlation:
Carcinoid Syndrome: An unusual manifestation of
carcinoid tumor, a neoplasm of enterochromaffin cells. In
patients whose tumor is not surgically resectable, a
serotonin antagonist may constitute a useful treatment.

CNS Pharmacology
Lecture 1
Serotonin (3)
34
 Depression, attention deficit disorder and headaches
have been attributed to serotonergic imbalances
 Many serotonergic agents have been developed in
the last few years for the treatment of these diseases
N.B. Serotonin is an important neurotransmitter, a local hormone in the gut,
a component of the platelet clotting process, thought to play a role in
migraine headache and several other clinical conditions, including carcinoid
syndrome (previous slide).
More on 5-HT in the ”Histamine, Serotonin, & the Ergot Alkaloids” UNIT

CNS Pharmacology
Lecture 1
Serotonin (4)
35
Excess 5-HT can result from accidental or intentional overdose
of drugs that directly activate serotonin receptors or, more
commonly,
drugs that indirectly enhance serotonin levels
 by inhibiting presynaptic neuronal reuptake of serotonin
 by inhibiting serotonin breakdown by monoamine oxidase
 E.g., selective serotonin reuptake inhibitors,
 nonselective serotonin reuptake inhibitors, and
 MAOIs

CNS Pharmacology
Lecture 1
4) Acetylcholine (Ach)
36
 The synthesis, release and degradation of acetylcholine was learned in
PNS study
 Acetylcholine binds to both muscarinic (AChm ) and nicotinic (AChn )
receptors throughout the brain
(Drugs which mimic or modify acetylcholine neurotransmission were also covered in PNS)
 Cholinergic antagonists are used in the treatment of Parkinson's
disease to correct the imbalance of ACh and DA neurotransmission
created by the degradation of dopaminergic nerves
 Cholinergic or anti-cholinergic drugs are not otherwise used to
treat CNS disorders

CNS Pharmacology
Lecture 1
5) Gamma-amino butyric acid (GABA)
37
GABA is an inhibitory amino acid neurotransmitter of
brain interneurons and other cerebral neurons
The enzyme glutamic acid decarboxylase catalyzes the
synthesis of GABA from glutamate
GABA is stored in presynaptic vesicles and binds to
either GABA-A or GABA-B receptors upon release

CNS Pharmacology
Lecture 1
γ-aminobutyric acid (GABA) (2)
38
 GABA receptors reside on two subunits of a four
subunit receptor complex that surrounds and
regulates a chloride ion channel
 GABA activation of the receptor induces chloride
influx into the neuron>>> this hyperpolarizes the
neuron, making it more difficult to fire when
stimulated by excitatory neurotransmitters
 Benzodiazepines (BDZ) enhance the actions of GABA
at GABA-A receptors, but not GABA-B receptors
 Agents which enhance actions of GABA such as BDZ
and barbiturates are used to Tx anxiety & seizures
and as sedatives or muscle relaxants
The GABA-A receptor depicting the membrane-associated
protein composed of five subunits, the Cl– channel, and relative
location of binding sites for GABA, benzodiazepines, barbiturates,
and picrotoxin. From: Brody’s Human Pharmacology, 2010

CNS Pharmacology
Lecture 1
6) Excitatory Amino Acids (EAA), Glutamate
39
 Glutamate or a structurally-similar chemical is an excitatory
neurotransmitter in many areas of the brain
 Stimulation of EAA receptors increases cation conductance,
leading to depolarization, or stimulates phosphatidyl inositol
turnover
 Glutamate transmission occurs via N-methyl-D-aspartate
(NMDA) receptors
 Memantine, used in the Tx of Alzheimer’s disease,
binds to NMDA receptor channels in a use-dependent
manner and produces a noncompetitive blockade

CNS Pharmacology
Lecture 1
Glutamate (2)
40
 Excitatory amino acids such as glutamate are thought to
be important in learning, memory and other brain
functions
 Glutamate induced excitotoxicity is implicated in the
pathogenesis of Alzheimer's Disease, Huntington's
Disease, stroke, epilepsy and amyotrophic lateral sclerosis
(ALS)
 Riluzole protects neurons from glutamate toxicity in
animals and minimally slows progression of ALS

CNS Pharmacology
Lecture 1
N-Methyl-D-Aspartate (NMDA)
41
 Glutamate is an excitatory neurotransmitter, and NMDA
receptors (NMDAR) are one type of glutamate receptor
 Binding of glutamate to NMDA receptors results in
opening of Ca2+ channels, leading to cellular
depolarization and increased neuronal activity
 Blockade of glutamate at NMDA receptors therefore
results in reduced excitation of neurons in the brain

CNS Pharmacology
Lecture 1
7) The Opioids
42
 Endorphins, enkephalins and dynorphins are endogenous
opiate receptor agonists that are cleaved from a protein
called pro-opiomelanocortin
 Opiate receptors are located along the periaqueductal gray
matter
 Morphine and related drugs act at opiate receptors to
relieve pain
 In times of stress or pain, endogenous peptides act at opiate
receptors

CNS Pharmacology
Lecture 1
8) Other Neuropeptides
43
 In addition to the endogenous opiate peptides, other
peptides function as neurotransmitters e.g.,
 Substance P
 vasoactive intestinal peptide (VIP)
 These agents are generally cleaved from larger peptide
precursors
 They can assume a variety of three dimensional shapes,
making it difficult to assess the chemistry of peptide-receptor
interactions
 For this reason, no chemical agonists (other than morphine) or
antagonists have been identified for peptide receptors

CNS Pharmacology
Lecture 1
THE END
44

CNS Pharmacology
Lecture 1
45
Lectures/discussions to follow:
2. Sedative-Hypnotic and Anxiolytic Drugs
3. Antiepileptic Agents
4. Antidepressants
5. Drugs Affecting Bipolar Disorder
6. Antipsychotic Agents
7. Drugs Affecting Movement Disorders and Other Neurodegenerative Disorders
8. CNS Skeletal Muscle Relaxants
9. Analgesics and Anesthetics
Further study (SDL):
Online resource center: Medical Pharmacology Cloud Folder

Lect.1 Introduction to CNS and Drug Action

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Lect.1 Introduction to CNS and Drug Action