Pharmacology Ch 8 93-108
Principles of Nervous System Physiology and Pharmacology
Neuroanatomy – nervous system divided into peripheral nervous system (all nerves between
CNS and somatic/visceral sites), which is itself divided into autonomic (involuntary) and sensory
and somatic (voluntary nervous system).
-the central nervous system (CNS) includes cerebrum, diencephalon, cerebellum,
brainstem, and spinal cord; processes signals from peripheral nervous system, and then
sends signals back to periphery
Anatomy of the Peripheral nervous System – autonomic nervous system regulates smooth
muscle and glandular tissue, such as vascular tone, heart rate, pupillary constriction, sweating,
salivation, piloerection, uterine contraction, GI motility, and bladder function
-Autonomic nervous system is divided into sympathetic system (fight or flight responses) and
parasympathetic system (rest and digest)
-Sensory and somatic peripheral nervous systems carry sensory signals from periphery to CNS
and motor signals from CNS to striated muscle for voluntary movement
Autonomic Nervous System – autonomic nerve fibers connect w/ organs by 2-neuron pathway
-the 1st neuron originates in brainstem or spinal cord, and is called preganglionic neuron
-preganglionic neuron synapses outside the spinal cord with a postganglionic neuron that
innervates the target organ
1. Anatomy of Sympathetic Nervous System – also called thoracolumbar system because
preganglionic fibers arise from first thoracic segment to second/third lumbar segment of
cord
a. Preganglionic nerve cell bodies arise in the intermediolateral columns of spinal
cord, and exit at ventral roots of each vertebral level to synapse with postganglionic
neurons in sympathetic ganglia (25 pairs of interconnected ganglia on either side of
the vertebral column)
i. First three ganglia: superior cervical ganglion, middle cervical ganglion, and
inferior cervical ganglion, send their fibers via cranial and cervical nerves
1. superior cervical ganglion innervates pupil, salivary glands, lacrimal
glands, blood vessels/sweat glands in head and face
2. post-ganglionic neurons in middle/inferior cervical ganglia as well as
thoracic ganglia innervate heart and lungs
3. fibers from remaining paravertebral ganglia innervate sweat glands,
pilomotor muscles, and blood vessels of skeletal muscle and skin
ii. Neurons innervating GI tract down to colon, with liver/pancreas arise from
ganglia located anterior to aorta, at the origins of celiac, superior
mesenteric, and inferior mesenteric arteries
1. Ganglia are called prevertebral ganglia and are compsed of the
celiac ganglion, superior mesenteri ganglion, and inferior
mesenteric ganglion
a. In contrast to paravertebral ganglia, prevertebral ganglia
have LONG preganglionic fibers and SHORT postganglionic
b. Adrenal Medulla contained in adrenal glands on superior surface of kidneys and
contain postsynaptic neuroendocrine cells that synthesize epinephrine and release
it into bloodstream as opposed to synapse on specific organ
c. Sympathetic agonists such as albuterol can dilate bronchioles selectively, while
antagonists such as metropolol can decrease heart rate and contractility
2. Anatomy of the Parasympathetic Nervous System – nearly all parasympathetic ganglia lie in
or near the organs they innervate; preganglionic fibers arise in brainstem or sacral spinal
cord, and is thus called the craniosacral system
a. Preganglionic fibers of cranial nerve III (oculomotor) arise from midbrain region
known as Edinger-Westphal nucleus and innervate the pupil for constriction
b. Medulla of brain contains nuclei for parasympathetic fibers in CN VII, IX, X
i. CN VII stimulates salivary gland secretion by submaxillary/sublingual glands
as well as tear production by lacrimal gland
ii. CN IX (glossopharyngeal) parasympathetic fibers stimulate parotid gland
iii. CN X (Vagus) - parasympathetic innervation to organs in chest and
abdomen: heart, tracheobronchial tree, kidneys, GI, proximal colon
iv. Sacral parasympathetics innervate remainder of colon, bladder, genitalia
c. Bethanechol – parasympathomimetic that promotes GI and urinary motility
d. Antagonists include atropine (dilate pupils or increase heart rate), and ipratriopium
(dilate bronchioles)
3. Peripheral Motor and Sensory Systems – fibers of somatic nervous system innervate target
striated muscles directly
a. First-order neurons from motor cortex send projections that cross in lower medulla
and descend through spinal cord in lateral corticospinal tract before synapsing on
second-order neurons in ventral horns of spinal cord
i. Projections from second-order neurons exit through ventral roots and join
dorsal roots (sensory nerve fibers) to form spinal nerves, which exit
vertebral column through intervertebral foramina, after which they
separate into peripheral nerves
ii. Somatic components of peripheral nerves innervate muscles directly and in
a myotomal distribution (neurons from a particular root level innervate
specific muscles)
b. Sensory neruons have cell bodies in dorsal root ganglia and have indings in skin and
joints and enter the spinal cord through dorsal roots
i. Neurons for vibration and proprioception ascend through ipsilateral dorsal
columns in spinal cord and synapse with secondary neurons in contralateral
lower medulla
ii. Sensory neurons carrying pain and temperature synapse with secondary
neurons in posterior horn of spinal cord and cross within spinal cord to
ascend in contralateral spinothalamic tract
iii. Both spinothalamic tract and dorsal column tracts connect with third-order
neurons in the thalamus, part of the diencephalon
iv. Sensory information is encoded in a dermatomal distribution
v. Antagonists of neuromuscular junction activity = pancuronium used to
induce paralysis during
vi. Agonists of neuromuscular junction activity are edrophonium and
neostigmine used in diagnosis and treatment of myasthenia gravis
Anatomy of the Central Nervous System – CNS divided into 7 divisions: cerebral hemispheres,
diencephalon, cerebellum, midbrain, pons, medulla, and spinal cord
-midbrain, pons, and medulla together are known as the brainstem and connect spinal cord
with cerebrum, diencephalon, and cerebellum
Cerebrum – largest division of human brain containing cerebral cortex, its underlying white
matter, and basal ganglia; left and right hemispheres connected by corpus callosum, and the
cortex is responsible for high-level functions, including sensory perception, planning ,and
ordering motor functions, cognitive functions, and language
-functionally, cortex Is divided into frontal, temporal, parietal, and occipital lobes
-precentral gyrus is involved in peripheral motor function (movement)
-Barbiturates and benzodiazepines are hypnotics and sedatives that potentiate action of
inhibitory neurotransmitters in cortex
-General anesthetics are thought to have effects on cortex
-Cerebral white matter, including corpus callosum, transmit signals between cortex and other
areas of CNS and from one cortex to another
-consists of myelinated axons with associated network of vasculature, where
inflammatory cells collect in diseases such as multiple sclerosis and these blood vessels
can cause hypertension
-Basal ganglia consist of 3 deep nuclei of gray matter including caudate and putamen, together
known as the striatum and the globus pallidus
-these nuclei help initiate and control cortical actions, including movement, behavior,
and cognition
-Parkinson’s disease caused by degeneration of dopaminergic pathway that arises in substantia
nigra in midbrain and terminates in striatum (called nigrostriatal tract)
-Levodopa acts on striatum to ameliorate clinical manifestations of parkinsons
-Limbic system – consists of cingulate gyrus, hippocampus, and amygdala – all responsible for
emotion, social behavior, autonomic control, pain perception, and memory
-alzheimers memory loss is associated with hippocampal degeneration
-many abusive drugs stimulate brain reward pathway, including nucleus accumbens
Diencephalon – divided into thalamus and hypothalamus
1. Thalamus – located medially in brain and inferior to cerebral cortex; some thalamic
nuclei link sensory pathways from periphery to cerebral cortex; others act as nuclei
connecting basal ganglia and cortex
2. Hypothalamus – lies ventral to thalamus and controls autonomic nervous system,
pituitary gland, and behaviors such as hunger and thermoregulation
a. Descending pathways from medial hypothalamus regulate autonomic
preganglionic neurons in medulla and spinal cord
i. Clonidine is believed to be antihypertensive because of its action at
receptors on brainstem neurons controlled by hypothalamus
b. Other neurons act directly on systemic circulation (vasopressin, ADH)
Cerebellum – inferior and posterior to cerebrum and dorsal to brainstem, contains cerebellar
vermis, the lateral cerebellar hemispheres, and the small flocculonodular lobe
-sends output primarily to the motor areas of cerebral cortex via thalamus
-coordinates voluntary movement in space and time, maintains balance, controls eye
movement, and has roles in motor learning (hand-eye coordination)
-alcohol and antiepileptic drugs are toxic to the cerebellum, specifically affecting
the vermis, which controls balance
Brainstem – midbrain, pons, and medulla are known as brainstem, which connects spinal cord
to the thalamus and cerebral cortex; midbrain superior, medulla inferior, and pons bridging the
two
-brainstem gives rise to most of the cranial nerves; cranial nerves control motor output to
skeletal muscles of face swallowing, eye movement; sensation from head, hearing, balance,
taste; brainstem also regulates parasympathetic output to salivary glands and iris
-Medulla – contains control centers that direct output of autonomic nuclei, pacemakers
regulating heart rate and breathing, and centers that control reflex actions such as coughing and
vomiting
-Pons – plays a role in vital functions such as respiration; base of pons has white matter tracts
connecting cerebral cortex and cerebellum
-neurons in the periaqueductal gray (especially in midbrain), send descending projections to
spinal cord that modulate pain perception
-Reticular Activating System – comprises of nuclei inside locus ceruleus, raphe nucleus and
others; responsible for consciousness and sleep regulation, each using different
neurotransmitter, and so many different medications will work
Spinal Cord – runs from base of brainstem (medulla) down to L1 vertebra; white matter in
periphery and gray matter forms nuclear columns laying in an H shape in center
-Neurons are defined by location relative to the gray matter H
-sensory neurons are in the DORSAL HORN of H, and relay their information from
periphery through dorsal columns or spinothalamic tracts
-motor neurons are in the VENTRAL HORNS of H and receive commands from central
motor areas that descend in corticospinal tract to peripheral muscles
-interneurons connect sensory and motor neurons and mediate reflexes by coordinating action
of opposing muscle groups
Cellular Organization of Nervous System – somatic/sensory information is carried directly
between spinal cord and periphery
-autonomic nerves must synapse between pre- and post- ganglionic neurons
-neurons can synapse with hundreds of other neurons; three motifs have been proposed:
1. Long Tract Neuronal Systems – involve neural pathways connecting distant areas of nervous
system, used by PNS and within CNS
-in the PNS, sensory neurons respond to stimuli and transmit action potential directly to spinal
cord to synapse with somatic motor neurons to form reflex arcs, and they also synapse with
ascending spinal neurons to transmit the information higher
-motor neurons carry info directly from spinal cord through ventral root to motor end
plate
-preganglionic neurons of autonomic nervous system form synaptic connections with
postganglionic neurons at ganglia that are located prevertebrally, paravertebrally, or at organs
-one preganglionic neuron can make connections with thousands of postganglionic neurons,
called divergent signaling, resulting in some modification of information
-in the CNS, neurons relay AND integrate/modify signals and CNS long tract neurons display
divergent signaling, but also receive connections from upstream neurons (convergent signaling).
-CNS uses both excitatory and inhibitory neurotransmitters to localize a signal, known as
center-surround signaling
-sensory perception in CNS can precisely localize signal by activating cortical
neurons mapping to one area and inhibiting others
2. Local Circuit Neuronal Organization – these neurons maintain connectivity primarily within
the immediate area and are responsible for MODULATING SIGNAL TRANSMISSION
-in cerebral cortex, neurons are organized in layers of 6, allowing information to be
changed as it flows through different tracts
-local synpases can be both excitatory and inhibitory to ensure that only certain patterns of
inputs are passed along
-info from lateral geniculate neurons  primary visual cortex through a long tract
connection called the optic tract
-patterns of neurons will help distinguish lines, tic-tac-toe boards, etc…
3. Single-Source Divergent Neuronal Organization – nucleo in the brainstem, hypothalamus,
and basal forebrain follow single-source divergent circuit organization where neurons in one
nucleus innervate many target cells
-because it acts on a number of neurons, it is also called diffuse system of organization
-DO NOT STIMULATE directly, but instead, use neurotransmitters (amines) that act on G protein
coupled receptors to alter resting potential for altered EASY OF DEPOLARIZATION
-these neurons generally DON’T have myelin sheaths and axons are highly branches
-sources include dopaminergic neurons in the substantia nigra which innervate the striatum
which affect downstream pathways that initiate movement and inhibit pathways to suppress
movement as well
-another example of single-source divergence involves the noradrenergic nucleus in the
pons called the locus ceruleus, which innervates cerebral cortex and cerebellum and
maintains vigilance and responsiveness to unexpected stimuli
-cocaine – inhibits reuptake of catecholamines like norepinephrine and
activates system of hypervigilance
-neurons in the raphe nuclei in caudal brainstem use serotonin for modulating pain
signals in spinal cord and locus ceruleus; other neurons from raph nuclei innervate
forebrain, modulating responsiveness of neurons in cortex
-serotonergic neurons regulate wakefulness and sleep, disruption of which
thought to cause depression
(antidepressents block reuptake of
serotonin SSRIs)
-Other nuclei innervating cortex sare basal nucleus of
Meynert and Pedunculopontine nucleus which both
use acetylcholine; basal nucleus of Meynert regulates
sleep-wake cycles and arousal
-Pedunculopontine neurons send signals to
basal forebrain implicated in alzheimer’s
-last nucleus is the Tuberomamillary nucleus, which
uses histamine as neurotransmitter to help maintain
arousal, and antihistamines may cause somnolence
Neurophysiology – Neurotransmitters – PNS only
uses two neurotransmitters: acetylcholine and
norepinephrine, whereas CNS uses wide variety of
small molecule neurotransmitters as well as
neuroactive peptides
-Small molecule neurotransmitters can be organized
into categories based on structure and function:
1. Amino Acid Neurotransmitters – glutamate, aspartate, GABA, and glycine
2. Biogenic Amine Neurotransmitters – dopamine, norepinephrine, epinephrine serotonin,
histamine
3. Acetylcholine, neither an amino acid nor an amine, is used in both CNS and PNS
4. Adenosone and ATP used in central neurotransmission
5. Nitric Oxide (NO) is lipid soluble and has many effects on CNS and periphery
Amino Acid Neurotransmitters – primary excitatory and inhibitory neurotransmitters in CNS;
two types of AA neurotransmitters are used: acidic amino acids glutamate and aspartate, which
are EXCITATORY, and the neutral amino acids GABA and glycine which are INHIBITORY
-glutamate is primary excitatory neurotransmitter acting on ligand-gated ion channels and
metabotropic (G protein coupled) receptors
-excessive excitation of glutamate receptors can cause ischemic injury and death
-Felbamate used in refractory epilepsy inhibits NMDA glutamate receptor to reduce
excessive neuronal activity associated with seizures; use limited by liver failure and bone
marrow suppression
-GABA is primary inhibitory neurotransmitter in CNS, and the barbiturates and benzodiazepines
bind to GABA receptors to potentiate endogenous inhibitory effect
Biogenic Amines – used by diffuse neuronal systems to modulate complex CNS functions like
alertness and consciousness. In PNS, norepinephrine is released by sympathetic postganglionics
to affect the sympathetic response
-adrenal medulla releases epinephrine into circulation in response to stress
-these are all synthesized from amino acid precursors divided into three categories:
1. Catecholamines (dopamine, norepinephrine, epinephrine) – synthesized from tyrosine
-tyrosin is oxidized to L-DOPA, which is then decarboxylated to dopamine
-dopamine is transported to synaptic vesicles and released as neurotransmitter
-in adrenergic and noradrenergic neurons, dopamine is converted to norepinephrine
WITHIN the vesicles by enzyme dopamine-β-hydroxylase
-in small number of neurons and in adrenal medulla, norepinephrine is
transported back into cytoplasm and methylated to epinephrine
-central dopaminergic receptors are a target of therapeutics, such as when dopamine
receptor agonists and dopamine precursors are used to treat parkinsons
-Clonidine is a partial agonist that acts on presynaptic alpha2 receptors
-some antidepressants INCREASE synaptic concentration of norepinephrine by blocking its
reuptake (tricyclic antidepressants or TCAs) while others increase intracellular pool of
norepinephrine available for synaptic release (monoamine oxidase inhibitors (MAOIs)
2. Indolamine (serotonin) is synthesized from tryptophan by oxidation at 5 position and
decarboxylation
-(5-hydroxytryptamine or 5-HT is also known as serotonin)
-tricyclic antidepressants to block reuptake are called selective serotonin reuptake
inhibitors (SSRIs) which act selectively on serotonin to treat depression
3. Histamine is synthesized from histidine by decarboxylation and functions as a diffuse
neurotransmitter in CNS
-also has a role in maintenance of arousal by tuberomammillary nucleus of
hypothalamus and in sensation of nausea by area postrema in 4th ventricle
-drugs act on peripheral histamine H1 receptors to mediate inflammatory response or on H2
receptors to treat peptic ulcer disease
Acetylcholine plays a role in peripheral neurotransmission by acting on neuromuscular junction
to depolarize striated muscle
-in autonomic nervous system, Ach is used by preganglionic neurons and by parasympathetic
postganglionic neurons
-acetylcholinesterase inhibitors increase local Ach concentrations by interfering with
breakdown, and muscle paralytic which interfere with neurotransmission
-in CNS, Ach acts as a diffuse system neurotransmitter thought to regulate SLEEP and
WAKEFULNESS
-donezepil – reversible Ach inhibitor acts at central cholinergic synapses helps brighten
patients with dementia
-scopolamine – antimuscarinic drug (peripheral Ach receptor antagonist) but can cause
drowsiness, amnesia, fatigue, and dreamless sleep
-pilocarpine – cholinergic agonist can induce adverse effects of cortical arousal
Purinergic neurotransmitters are adenosine and ATP, and become evident with caffeine, which
is a competitive antagonist at adenosine receptors and causes mild stimulant effect
-adenosine receptors are on PRESYNAPTIC noradrenergic neurons act to inhibit release of
norepinephrine
-caffeine antagonizes this receptor and causes norepinephrine release which causes
stimulatory effects
Nitric Oxide (NO) – is a peripheral vasodilator but acts in brain as neurotransmitter by diffusing
through neuronal membrane and binding INSIDE the cell
-receptors are on PRESYNAPTIC neuron allowing NO to act as a retrograde messenger
Neuropeptides – examples are opioids, tachykinins, secretins, insulins, gastrins
-also include pituitary releasing/inhibiting factors CRH, GnRH, TRH, GRH, and somatostatin
-opioid family includes kephalins, dynorphins, and endorphins
-opioid receptors distributed in spinal cord and brain and are involved in pain sensation
are principle agents of opioid analgesics such as morphine and abuse such as heroin
Blood-Brain Barrier – regulates transport of molecules from blood into brain and protects brain
tissue from both toxic substances that circulate in blood and from neurotransmitters such as
epinephrine, norepinephrine, glutamate, and dopamine which would have systemic body effects
-structural bases for BBB is in cerebral microcirculation; in most tissues, there are small gaps
called fenestrae between endothelial cells that line microvasculature to allow H2O and
molecules to diffuse without resistance, but filter out large proteins
-in the CNS, endothelial cells form tight junctions that prevent diffusion of small
molecules across vessel wall
-CNS endothelial cells do not have pinocytotic vesicles that transport fluid from blood
lumen to extacellular space
-CNS blood vessels are covered by astroglia which transport many nutrients
-without selective transport mechanism, BBB excludes H2O-soluble substances, but lipophilic
substances like O2 and CO2 can diffuse across endothelial membranes
-glucose, a hydrophilic nutrient, needs a hexose transporter to allow it to move down its
concentration gradient across the BBB, called facilitated diffusion
-Amino acids are transported by 3 different transporters:
1. One for neutral AA like valine/phenylalanine
2. One for smaller neutral and polar AA (glycine/glutamate)
3. One for Alanine, serine, cysteine
4. L-DOPA is transported by large neutral amino acid transporter, but dopamine is
EXCLUDED by BBB, this is why L-DOPA is administered pharmacologically to parkinsons
patients
-many toxic lipophilic compounds can be excluded from brain by multiple drug resistance
transporters (MDRs) which pump hydrophobic compounds out of the brain and back into blood
vessels
-metabolic blood-brain barrier adds a layer of protection against toxic compounds and
is maintained by enzymes that metabolize compounds transported into CNS endothelial
cells
-aromatic L-amino acid decarboxylase (DOPA decarboxylase) metabolizes
peripheral L-DOPA to dopamine, which is unable to cross BBB
-Carbidopa is an inhibitor of DOPA carboxylase and needs to be taken
with L-DOPA to ensure proper uptake into CNS