You are on page 1of 45

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:
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

Marc Imhotep Cray, M.D. 2


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

Marc Imhotep Cray, M.D. Modified from Brody’s Human Pharmacology, 2010 4
CNS Pharmacology
Lecture 1

Methods for Study of CNS Pharmacology


 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
Marc Imhotep Cray, M.D. 5
CNS Pharmacology
Organization of the Nervous System Lecture 1

BRAIN & SPINAL CORD CENTRAL


The central nervous NERVOUS
system (CNS) consists of SYSTEM (CNS)
the brain and spinal cord.
The CNS receives and
interprets sensory AFFERENT EFFERENT
information (via peripheral PERIPHERAL
(Sensory) (Motor) NERVOUS
afferent nerves) and then
initiates appropriate NERVES NERVES SYSTEM (PNS)
motor responses (via
peripheral efferent
nerves).
EXTEROCEPTORS INTEROCEPTORS SOMATIC AUTONOMIC

SMOOTH MUSCLE,
EFFECTOR SKELETAL
CARDIAC MUSCLES
ORGANS MUSCLES
AND GLANDS

VOLUNTARY
INVOLUNTARY
Monosynaptic
Marc Imhotep Cray, M.D. Pre & Post Ganglionic Fiber
CNS Pharmacology
Lecture 1

Overview
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

Marc Imhotep Cray, M.D. 7


CNS Pharmacology
Lecture 1

Overview (2)
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)

Marc Imhotep Cray, M.D. 8


CNS Pharmacology
Lecture 1

Overview (3)
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

Marc Imhotep Cray, M.D. 9


CNS Pharmacology
Lecture 1
Overview (4)
 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
Marc Imhotep Cray, M.D. 10
CNS Pharmacology
Lecture 1

Overview (4)
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

Marc Imhotep Cray, M.D. 11


CNS Pharmacology
Lecture 1

Self-directed learning and review


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


Marc Imhotep Cray, M.D. Digital Textbooks Thumb Drive) 12
CNS Pharmacology
Lecture 1
Cell Types in the CNS: Neurons and Glia
 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
Wecker L, et al. Brody’s human pharmacology : molecular to clinical 5th ed.

Marc Imhotep Cray, M.D. 13


CNS Pharmacology
Lecture 1

Glia Cells Function, Astrocytes


 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

Marc Imhotep Cray, M.D. 14


CNS Pharmacology
Lecture 1

Glia Cells Function, Oligodendrocytes


 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

Marc Imhotep Cray, M.D. 15


CNS Pharmacology
Lecture 1

Glia Cells Function, Microglia

 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

Marc Imhotep Cray, M.D. 16


CNS Pharmacology
Lecture 1

Cell Types in the CNS: Neurons Structural components of nerve cells.

 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.
Marc Imhotep Cray, M.D. 17
CNS Pharmacology
Lecture 1
CNS Neurotransmitters, Receptors, and
Drug Targets
 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)

Marc Imhotep Cray, M.D. 18


CNS Pharmacology
Lecture 1
CNS Neurotransmitters, Receptors, and
Drug Targets (2)
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


Marc Imhotep Cray, M.D. 19
CNS Pharmacology
Lecture 1

Neurotransmitters of the Brain and Disease


 Treatable neurotransmission diseases fall into two
categories:
 those caused by too much neurotransmission and

 those caused by too little neurotransmission

Marc Imhotep Cray, M.D. 20


CNS Pharmacology
Lecture 1

“Too much” neurotransmission


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

Marc Imhotep Cray, M.D. 21


CNS Pharmacology
Lecture 1

“Too little” neurotransmission


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

Marc Imhotep Cray, M.D. 22


CNS Pharmacology
Lecture 1

CNS Drugs and Side Effects


 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

Marc Imhotep Cray, M.D. 23


CNS Pharmacology
Representative Lecture 1

Neurotransmitters
in the CNS

Marc Imhotep Cray, M.D. Wecker L, et al. Brody’s human pharmacology : molecular to clinical 5th ed. 24
CNS Pharmacology
Lecture 1
Most Well Studied Neurotransmitters
of the Brain
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

Marc Imhotep Cray, M.D. 25


CNS Pharmacology
Lecture 1
1) Norepinephrine
 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

Marc Imhotep Cray, M.D. 26


CNS Pharmacology
Lecture 1

2) Dopamine
 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

Marc Imhotep Cray, M.D. 27


CNS Pharmacology
Lecture 1

Dopamine (2)
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

Marc Imhotep Cray, M.D. 28


CNS Pharmacology
Lecture 1

Dopamine (3)
 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

Marc Imhotep Cray, M.D. 29


CNS Pharmacology
Lecture 1

Dopamine (4)
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

Marc Imhotep Cray, M.D. 30


CNS Pharmacology
Lecture 1

Dopamine (5)
 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)

Marc Imhotep Cray, M.D. 31


CNS Pharmacology
Lecture 1
3) 5-Hydroxytryptamine (5-HT, Serotonin)
 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)
Marc Imhotep Cray, M.D. 32
CNS Pharmacology
Lecture 1
Serotonin (2)
 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.
Marc Imhotep Cray, M.D. 33
CNS Pharmacology
Lecture 1

Serotonin (3)
 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

Marc Imhotep Cray, M.D. 34


CNS Pharmacology
Lecture 1

Serotonin (4)
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

Marc Imhotep Cray, M.D. 35


CNS Pharmacology
Lecture 1

4) Acetylcholine (Ach)
 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

Marc Imhotep Cray, M.D. 36


CNS Pharmacology
Lecture 1
5) Gamma-amino butyric acid (GABA)
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

Marc Imhotep Cray, M.D. 37


CNS Pharmacology
γ-aminobutyric acid (GABA) (2) Lecture 1

 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
The GABA-A receptor depicting the membrane-associated
protein composed of five subunits, the Cl– channel, and relative
 Agents which enhance actions of GABA such as BDZ location of binding sites for GABA, benzodiazepines, barbiturates,
and picrotoxin. From: Brody’s Human Pharmacology, 2010
and barbiturates are used to Tx anxiety & seizures
and as sedatives or muscle relaxants
Marc Imhotep Cray, M.D. 38
CNS Pharmacology
Lecture 1
6) Excitatory Amino Acids (EAA), Glutamate
 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
Marc Imhotep Cray, M.D. 39
CNS Pharmacology
Lecture 1

Glutamate (2)
 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

Marc Imhotep Cray, M.D. 40


CNS Pharmacology
Lecture 1

N-Methyl-D-Aspartate (NMDA)
 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

Marc Imhotep Cray, M.D. 41


CNS Pharmacology
Lecture 1
7) The Opioids
 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

Marc Imhotep Cray, M.D. 42


CNS Pharmacology
Lecture 1
8) Other Neuropeptides
 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

Marc Imhotep Cray, M.D. 43


CNS Pharmacology
Lecture 1

THE END

Marc Imhotep Cray, M.D. 44


CNS Pharmacology
Lecture 1
Further study (SDL):
Online resource center: Medical Pharmacology Cloud Folder

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

Marc Imhotep Cray, M.D. 45

You might also like