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NEUROTRANSMITTERS
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NOTE ABOUT THIS LECTURE
• This is a long, tough lecture at the end of the
course, so you will be tested on it in
segments:
• Quiz 8 (slides 1-54)
• Lecture exam 4 (slides 1-85)
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Neuron Anatomy
Soma (cell body)
Axon (transmits signals)
Axon hillock
(trigger zone)
Dendrites (receive signal)
Synaptic knob
(stimulates
another cell)
•Anatomy of a neuron
–Dendrite - projections from the soma
•the sensory portion of the neuron
–Soma - main body of the neuron
–Axon hillock- trigger zone
–Axon - extends from soma to the knobs
•the effector part of the neuron
–Terminal bouton/synaptic knobs
–Synaptic vesicles
–Synaptic cleft
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Function of Dendrites in Stimulating Neurons
• Dendrites are spaced in all directions
from the neuronal soma.
– allows signal reception from a large
spatial area providing the opportunity
for summation of signals from many
presynaptic neurons
• Dendrites transmit signals after the
opening of their LGC’s
• LGC (Ligand-gated channels): these
open when a ligand (neurotransmitter)
binds to them. They do not need an
action potential to open them.
– LGC’s have receptors for
neurotransmitters
– LGC’s are located on dendrites
Axon
hillock
LGC’s
VGC’s
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Types of Ligand Gated Channels (LGC’s)
Many human diseases are associated with dysfunction
of particular types of ion channels.
Some Amino Acids have positive charges which repel
ions with a positive charge. Some AA’s have negative
charges and repel ions with a negative charge. Amino
acids that make up the LGC’s therefore control ion
selectivity (what ions may pass). Sodium (Na+) has its
own LGC. So does potassium (K+) and Cloride (Cl-).
-74 mV
Na+ LGC
K+ LGC
Cl- LGC
0
mV
What would happen to the
resting membrane potential if
these channels opened?
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• The Excitatory Postsynaptic Potential (EPSP)
– Postsynaptic refers to the dendrite of the neuron receiving the signal.
– The neurotransmitter binds to its LCG, which opens a Na+ ionophore. Na+ ions then rush
to the inside of the cell membrane. They take their positive charge with them, so the
inside of the cell membrane is now more positively charged than it was.
– This increase in voltage above the normal resting potential (to a less negative value) is
called the excitatory postsynaptic potential.
– How many mV do we need to reach threshold? Resting Membrane Potential is minus 74,
and we need to get to +30 mV to start an action potential.
dendrite
Membrane is somewhat depolarized,
more likely to reach threshold soon.
-74 plus +60 = -14 mV
+20 mV
Na+: 20 mEq/L
axon
-54mV
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• The Inhibitory Postsynaptic Potential (IPSP)
– A different NT lands on the dendrites and causes the K+ or Clchannels to open instead of Na+.
– When a K+ channel opens, K+ rushes OUT of the cell, taking its
positive charges with it. The inside of the cell membrane becomes
MORE NEGATIVE.
– When a Cl- channel opens, Cl- rushes INTO the cell, taking its
negative charges with it. The inside of the cell membrane becomes
MORE NEGATIVE. Both K+ and Cl- cause hyperpolarization of the
neuron, making the neuron LESS likely to reach threshold.
Losing +20 or gaining -8 mV will both
-74 plus 20
-94 mV of the charge
increase
the=negativity
inside the cell (hyperpolarization),
making
likely
-74 plusit 8less
= -82
mVto reach threshold.
K+ : 4.5 mEq/L
Cl- : 107 mEq/L
20 mV
8 mV
axon
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Whether a neuron “responds” or not,
depends on temporal and spatial summation
of EPSPs and IPSPs
These channels open and close rapidly providing a
means for rapid activation or rapid inhibition of
postsynaptic neurons.
There might be EPSP’s firing at the same time as
IPSP’s. Add up all the charges from the excitatory and
inhibitory potentials to see which one wins!
Temporal summation: same presynaptic neuron fires repeatedly
Spatial summation: additional presynaptic neurons fire
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Spatial summation- stimuli from two
different presynaptic neurons
(different locations)
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Stimulating an Excitable Cell
(muscles, nerves, and glands)
• Electrical stimulation (or even
mechanical stimulation) can result
in changes in voltage.
• Depolarizing currents change the
voltage on the membrane, bringing
it toward threshold:
–If stimuli are at threshold or above
threshold stimuli, the result is an
action potential.
Excitatory and inhibitory neurons
release their NT at the same time
on the same neuron. The
postsynaptic neuron has to
summarize the input of positive and
negative charges. If the overall
effect is positive enough (+30mV),
an action potential will begin.
People with Parkinson’s
disease have a problem
coordinating the excitatory
and inhibitory actions of their
skeletal muscles. They have
trouble starting and stopping any
motion, and they shake at rest.
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What happens at threshold?
•
•
•
•
•
At threshold, there is a temporary, short-lived membrane permeability change.
The cell membrane becomes 40x more permeable to Na+ and then quickly
returns to previous state.
How? By the opening and closing of voltage-gated channels (VGC).
Both VGCs and LGC’s allow Na+ into the cell. LGC’s do this when a ligand
(neurotransmitter) binds to the cell membrane (like a key in the lock of the front
door to your house). VGC’s do this when the voltage of the cell membrane goes
from negative to +30 mV (like when you push the button on your garage door
opener).
The VGC’s which are inhibitory of an action potential are those that open K+ and
Cl- channels. These ions both increase the negative voltage of the cell
membrane, making farther away from starting an action potential.
The VGC’s that are excitatory are those that open Na+ or Ca++ channels. Both of
these ions increase the positive voltage of the cell membrane. If the charge is
enough to go from negative 74 mV to +30 mV, an action potential will be
launched.
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LGC and VGC Locations
Axon
hillock
• LGC’s are on dendrites
only.
• VGC’s are on the
axon, starting at the
hillock and continuing
to the synaptic knob.
VGC’s
LGC’s
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Ion channels
Activation, Inactivation, deactivation
closed
• Depolarization causes:

Deactivation:
Closed
Na+ channels to activate
(open)
but it also causes inactivation


inactivated channels do
not pass any ions (nonconducting state)
By contrast, most K+
channels show activation
and deactivation but not
inactivation
inactivation
open
inactivated
Activation:
Open and
working
Inactivation:
Open and not
working
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Copyright © 2006 by Elsevier, Inc.
Refractory Periods
mV
0
-40
Threshold
-80
0
1
Absolute
2
3
4
5 msec
Relative
Because Na+ channels have an inactive phase, it causes a refractory period,
which prevents a new action potential from starting right away.
Refractory periods limit maximum frequency of action potentials (Aps)
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Functions of action potentials
• Information delivery to CNS
 Transfers all sensory input to CNS.
 Amplitude of the AP (how strong the AP is) does not change, but the
frequency of APs varies. The frequency pattern is a code (like Morse
Code) that transmits information about the stimulus (light, sound,
taste, smell, touch) to the brain.
• Rapid transmission over distance
 Neurons can rapidly fire thousands of times without depleting the
sodium gradient.
 Note: speed of the Action Potential depends on the size of the neuron
fiber and whether or not its axon is myelinated.
 The larger the neuron, the less resistance there is, so it is faster. The
more lanes on the freeway, the faster you get home. Myelinated
axons are also faster than unmyelinated.
 In non-nervous tissue, action potentials initiate a response.
 Muscle  contraction
 Gland  secretion
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Figure 5-17; Guyton & Hall
Saltatory Conduction
http://www.brainviews.com/abFiles/Ani
Salt.htm
The AP is a passive event: ions diffuse down their EC gradients when
gated channels open.
A “wave of depolarization” occurs along the neighboring areas.
Occurs in one direction along the axon; actually, AP regenerates
over and over, at each point by diffusion of incoming Na+ ….WHY?
Refractory period (Na+ channels become inactivated).
Saltatory Conduction
 This type of conduction is found with myelinated axons.
 AP’s only occur at the nodes (Na channels concentrated here!)
 increased velocity
Na/K ATPase Pump
 energy conservation
http://www.youtube.com/watch?v=
GTHWig1vOnY
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Conduction velocity
- non-myelinated vs myelinated -
non-myelinated
myelinated
A neuron with myelin saves on ATP.
A child under three should not be on a low fat diet because a lot of
their myelin is being made during that time.
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Multiple Sclerosis
- MS is an autoimmune
disorder where the body’s
WBC’s destroy the myelin
sheaths.
- About 1 person per 1000 in
US is thought to have the
disease - The female-to-male
ratio is 2:1 - whites of northern
European descent have the
highest incidence
http://www.emedicine.com/pmr/topic82.htm
Copyright © 2006 by Elsevier, Inc.
Patients have a difficult time describing
their symptoms. Symptoms are bizarre
and unrelated. Patients may present
with paresthesias (tingling sensation)
of a hand that resolves, followed in a
couple of months by weakness in a leg
or visual disturbances. Patients
frequently do not bring these
complaints to their doctors because
they resolve. Eventually, the resolution
of the neurologic deficits is incomplete
or their occurrence is too frequent, and
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the diagnosis of MS begins.
• Structures important to the
function of the synapse:
– presynaptic vesicles
• contain neurotransmitter substances
to excite or inhibit postsynaptic
neuron
The Synapse
– mitochondria
• provide energy to synthesize
neurotransmitter
• Membrane depolarization by an
action potential causes emptying
of a small number of vesicles into
the synaptic cleft
• Presynaptic membranes contain
voltage - gated calcium channels.
Voltage Gated
Calcium Channel
– depolarization of the presynaptic
membrane by an action potential
opens Ca2+ channels
Ca+2
2+
– influx of Ca induces the release of
the neurotransmitter substance
•Postsynaptic membrane contains receptor proteins for the
transmitter released from the presynaptic terminal.
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• Presynaptic neuron, axon:
The VGCs allow Na+ to enter the inside of the
cell membrane, then Na+ leaves again, and
the AP is propagated (carried) down the
length of the axon.
• Presynaptic neuron, terminal knob:
There are no more VGC’s for Na+. The VGC’s
are now for Ca++. They let Ca++ into the
interior of the cell. The Ca++ causes the
vesicles in the knob to move towards the
cleft and release their contents (the
neurotransmitters) into the synaptic cleft.
• Postsynaptic neuron, dendrite:
The cell membrane on the dendrite contains
proteins called LGC’s. The neurotransmitter
attaches to them. This causes nearby VGC’s
to open. If the VGC is excitatory, a new AP
begins in the postsynaptic cell. If the VGC
is inhibitory, the AP will stop.
Voltage Gated
Sodium Channels
(from hillock to end of axon)
Voltage Gated
Calcium Channels
NT
Calcium
In the meantime, an enzyme arrives at the
synaptic cleft and deactivates the
neurotransmitter. The mitochondria make
more neurotransmitters (NT) and store
them in new vesicles.
Ligand Gated Channels:
Bind to NT and open nearby VGC’s
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Synaptic Events -watch animation
http://highered.mcgraw-hill.com/sites/0072495855/student_view0/chapter14/animation__chemical_synapse__quiz_1_.html
• Neurotransmitters (NT) are
released and diffuse across
synaptic cleft
• NT bind to receptors (LGC’s)
on the post-synaptic cell
• The LGC opens, and ions
diffuse in or out, depending on
which LGC it is
• The change in voltage causes
depolarization or
hyperpolarization
• If depolarizing, called EPSP
• If hyperpolarizing, called IPSP
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NEUROTRANSMITTERS
AND
NEUROTRANSMITTER
RECEPTORS
We’re talking about signals and what
they mean to a neuron! What
happens if we block signals?
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NEUROTRANSMITTERS
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GENERAL SEQUENCE OF EVENTS AT
CHEMICAL SYNAPSES
• NT synthesis and storage in
presynaptic cell
• NT release by exocytosis
(Ca++ triggered event)
• Diffusion across cleft
• NT reversibly binds to
receptors (LGC) and opens
gates, allowing ion diffusion
• NT removal from synapse
(destruction, diffusion away)
or reuptake by presynaptic
cell for recycling
VOCC
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NTS ACTION
• NT diffuses across synaptic cleft to bind to
receptor (LGC) on postsynaptic
membrane
• Can generate an electric signal there
(EPSP’s or IPSP’s)
• These are graded potentials (the more
channels that are opened, the more the
charge changes)
• Effect depends which ions are allowed to
diffuse across membrane, how many
and for how long. Effect depends on the
selectivity of the channel.
• What if the LGC are…..
• Na+ selective
• K+ selective
• Cl- selective
• What happens to the voltage on the
postsynaptic cell? Is it an EPSP or an
IPSP?
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NEUROTRANSMITTERS (NTS)
• NTs are present within the
presynaptic neuron
• They are released in response to
presynaptic depolarization,
which requires calcium
• Specific receptors must be
present on the postsynaptic cell
• NT must be removed to allow
another cycle of NT release,
binding and signal transmission
• Removal: reuptake by
presynaptic nerve or
degradation by specific enzymes
or a combination of these
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SYMPATHETIC AND
PARASYMPATHETIC NERVOUS SYSTEM
•
•
•
•
Sympathetic Neurons
Increased heart rate and blood pressure
Decreased food digestion
“Fight or Flight”
•
•
•
•
Parasympathetic Neurons
Decreased heart rate and blood pressure
Increased food digestion
“Rest and Digest”
Notice that the heart is innervated by both sympathetic and
parasympathetic neurons….
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SYMPATHETIC AND
PARASYMPATHETIC NEURONS
• If an organ is dually innervated by sympathetic and
parasympathetic nerves, how will the organ know if
sympathetic or parasympathetic is barking louder?
The receptors that have the most transmitter bound
will cause the biggest result.
• The heart has receptors that allow both para and
sym to have effects. A lot of organs are dually
innervated so they can adjust their physiology.
• Furthermore, a sympathetic neuron can cause
excitation in one organ and inhibition in another
organ. A parasympathetic neuron can also cause
excitation in one organ and inhibition in another
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organ.
SYMPATHETIC AND
PARASYMPATHETIC NEURONS
• There are two faucets in your bathroom, turn both on halfway, and water is
lukewarm. To make it hot, either turn up hot water or turn down cold water, or
both. If we suppress the parasympathetic system (cold water), the
sympathetic system (hot water) will gain more control. If you stimulate the
parasympathetic system, it will gain control. Parasympathetic and
sympathetic neurons both fire onto the same organ at the same time. The
question is when does the sympathetic system have more control? When
does the parasympathetic system have more control?
• If a particular drug mimics the parasympathetic system, then the
parasympathetic system has more control. What effect does that have? The
heart rate will be slower. If sympathetic is stronger, how will body act? Heart
rate increases.
• We can completely shut down parasympathetic and rev up sympathetic. In
an ER show, when the patient’s heart stops, they get the epinephrine and get
the atropine. The epinephrine is stimulating the sympathetic system and the
atropine is blocking the parasympathetic system (shutting off the antagonist).
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HEART TRANSPLANT PROBLEM
• When you take out a heart, the nerves that innervate the heart are cut out too.
There is no way to suture back the nerves when you put in a new heart.
• The new heart will have a faster heart rate because cardiac cells like to beat
fast. The parasympathetic neurons cause the heart rate to slow, but they are
now cut.
• The post-op patient cannot allow themselves to become overly anxious, angry,
or sexually aroused after heart transplant.
• When they have those emotions, the sympathetic system can still release
epinephrine because it is a hormone, not a nerve. Epinephrine is made by
adrenal glands and circulates in the blood. However, the patient no longer has
parasympathetic neurons attached to the heart to counter the effects of
epinephrine.
• It will therefore take them a long time to calm down from the effects of
epinephrine due to anger, anxiety, etc, because they have to wait for the
epinephrine to be metabolized. There are no parasympathetic hormones to
calm you down.
• How can we use the parasympathetic system to make the heart cells less
active? Use a medicine to open the potassium (K+) channels, making the
inside of the cell more negative (hyperpolarized). The number one way HR is
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regulated is by potassium.
CLASSIFICATION OF NTS
• Chemical Classification
• Large Molecule
• Peptides
• Small Molecule
• Cholinergic (Ach)
• Catecholamines
• Adrenergic
• Dopaminergic
• Serotonergic
• Amino Acid NT’s
• Functional Classification
• Metabotropic
• Ionotropic
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CHEMICAL CLASSIFICATION
1) Large Molecule (Peptide) NTs
• ADH (vasopression); increases blood volume
• Angiotensin; vasoconstriction (raises BP)
• Bradykinin; vasodilation (lowers BP)
We will talk about large molecule NTs in later lectures.
This lecture will focus on small molecule NTs.
2) Small Molecule NTs
• Cholinergic (Acetylcholine; ACh)
• Catecholamines
• Amino Acid Neurotransmitters
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SMALL MOLECULE
NEUROTRANSMITTERS
• Cholinergic
• Acetylcholine (ACh)
• mACh
• nACh
• Amino Acid NTs
• Glutamate
• GABA (inhibitory)
• Glycine (inhibitory)
CATECHOLAMINES
Adrenergic catecholamines:
• Norepinephrine
• Epinephrine
Dopaminergic catecholamine:
• Dopamine
Serotonergic catecholamine:
• Serotonin
Neurons that make epinephrine or norepinephrine are called Adrenergic neurons
Neurons that make dopamine are called Dopaminergic neurons
Neurons that make serotonin are called Serotonergic neurons
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ACETYLCHOLINE (ACH)
• Neurons that use this NT
are called cholinergic
neurons.
• All skeletal muscle is
innervated by cholinergic
neurons.
• Also used by sympathetic
and parasympathetic
neurons
• Ach is removed from the
synaptic cleft by the
enzyme Acetylcholine
esterase (AChE)
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GLUTAMATE
• Very important in CNS
• Nearly all excitatory
neurons use it
• Too much glutamate
causes excitotoxicity
due to unregulated
calcium influx
• Antagonists to
Glutamate receptor
help stop neuronal
death after stroke
• Too little glutamate
leads to psychosis
(delusional, paranoid,
lack of contact with
reality)
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GLUTAMATE
• Dangerous: someone with stroke or trauma releases a lot of
NTs, causes damage to undamaged neurons, The healthy
neurons are being over stimulated, too much calcium, causes
cytotoxicity. Too much NT can kill the cell.
• Only 10% of people with Parkinson’s and Alzheimer’s are
caused by bad genes; the rest are caused by calcium
dyshomeostasis (The calcium is not being monitored properly
in the body).
• Those who have stroke are given a glutamate antagonist to
protect them.
• If you don’t have enough glutamate, inhibitory NTs will gain
momentum.
• Too little glutamate leads to psychosis, perceives reality
differently than normal.
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GABA
AND
• Major inhibitory
neurotransmitter in CNS
 Decreased GABA causes
seizures
 Anticonvulsants target
GABA receptors or act as
GABA agonists
 Benzodiazepines (valium)
and ethanol (drinking
alcohol) both trigger GABA
receptors……use
benzodiazepines during
alcohol detox.
GLYCINE
• Glycine- also inhibitory
• Mostly in spinal cord and
brainstem motor neurons
http://pharma1.med.osaka-u.ac.jp/textbook/Anticonvulsants/GABA-syp.jpg
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GABA
• Alcohol stimulates GABA receptors, so you are
causing IPSPs, reflexes slow down, reach
threshold less quickly. They have to work at
overcome their lazy tongue to get words out.
• When they try to stop drinking all at once, the
excitatory NTs gain control, and they get
tremors and visual overstimulation. Need
benzodiazepam (valium) while weaning off the
alcohol.
• GABA agonists (drugs that act like GABA, such
as anti-convulsants) can also be given.
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GABA
• Benzodiazepines (such as valium) enhance the
effect of gamma-aminobutyric acid (GABA), which
results in sedative, hypnotic (sleep-inducing),
anxiolytic (anti-anxiety), anticonvulsant, muscle
relaxant and amnesic action.
• These properties make benzodiazepines useful in
treating anxiety, insomnia, agitation, seizures,
muscle spasms, alcohol withdrawal and as a
premedication for medical or dental procedures.
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SMALL MOLECULE
NEUROTRANSMITTERS
• Cholinergic
• Acetylcholine (ACh)
• mACh
• nACh
• Amino Acid NTs
• Glutamate
• GABA (inhibitory)
• Glycine (inhibitory)
CATECHOLAMINES
Adrenergic catecholamines:
• Norepinephrine
• Epinephrine
Dopaminergic catecholamine:
• Dopamine
Serotonergic catecholamine:
• Serotonin
Neurons that make epinephrine or norepinephrine are called Adrenergic neurons
Neurons that make dopamine are called Dopaminergic neurons
Neurons that make serotonin are called Serotonergic neurons
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CATECHOLAMINES
• These are released by adrenal glands in response to stress; they are
part of the sympathetic nervous system (fight or flight). They circulate
in the bloodstream.
• Removed by reuptake into terminals via sodium dependent transporter
• Mono-amine oxidase (MAO) is an enzyme that degrades
catecholamines. Therefore, an MAO inhibitor will allow catecholamines
to excite the nervous system.
• Anti-anxiety and anti-depression medicines are MAO-inhibitors
• DO NOT MIX SYMPATHOMIMETIC (those that imitate catecholamines)
WITH MAO INHIBITORS. It doubles the excitatory effect in the nervous
system and can be deadly.
• Examples of Sympathomimetic are medicines for cardiac arrest, low
blood pressure, and some meds that delay premature labor.
• MAO inhibitors plus sympathomimetics allow the excitatory effect of
fight-or-flight to continue to excess, and the person’s blood pressure
goes up to a crisis level.
• In other words, don’t mix anti-depressant meds with meds for cardiac
arrest, low blood pressure, and some meds that delay premature labor.
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CATECHOLAMINES
• Epinephrine (“above the kidney”)
• Epinephrine is secreted by the adrenal gland, which sits above
the kidney.
• It’s action is excitatory (fight or flight)
• Norepinephrine
• Norepinephrine is secreted by neurons from CNS and by
neurons in sympathetic ganglia
• Its action is mainly excitatory, can be inhibitory.
• Dopamine
• Secreted by neurons in CNS
• Its action is inhibitory
• Epi and norepi are made from dopamine
• Serotonin
• Secreted by neurons in the CNS
• Its action is mainly excitatory. It can excite one cell but inhibit
another.
43
DOPAMINE
• Parkinson’s Disease
(Parkinsonism)
• Loss of dopamine from
neurons in substantia
nigra of midbrain
• Resting tremor, “pill
rolling”, bradykinesia
(slow walking) gait
• Treat with L-dopa.
(Crosses BBB) or MAO
inhibitors
• Side effects
(hallucinations, motor
problems)
The Case of the Frozen Addicts,
by Langston, J. W
44
BRAIN REGIONS
• The motor cortex is the region of the brain that contains the
neurons that move the muscles of the skeleton.
• The basal nuclei region of the brain (between the corpus
callosum and thalamus) inhibits some motor neurons so that
unwanted body movements do not occur. The basal nuclei
regulate stopping, starting, and coordination of movements.
The basal nuclei are inhibitors of movement. They are like strict
parents that tie their kids up to keep them from doing wild
things.
• The substantia nigra region of the brain secretes dopamine,
which inhibits the basal nuclei (it inhibits the inhibitor). Thus, the
excitatory neurons can make the body move. The substantia
nigra and Dopamine are like social workers who tell the
parents (basal nuclei) not to be so restrictive with the kids. With
the inhibitor out of control, the kids throw a house party.
45
BRAIN REGIONS
• If the substantia nigra (the social worker) is damaged (no more
dopamine), the basal nuclei (the parents) are no longer
inhibited. So the parents stay home and tie the kids up to keep
them from moving throwing a party. This is the problem in
Parkinson’s disease.
• If the basal nuclei (the parents) are damaged (social worker is
controlling them too much) the patient will have excessive
movement. This is Huntington’s disease.
• Thus, there are two ways the basal nuclei (the parents) can be a
problem: either the basal nuclei themselves are dysfunctional
(not enough inhibition of movement; the parents leave town
and the kids throw a party; Huntington’s disease), or the
dopamine levels (the social worker) are too low the parents are
too strict and tie the kids up; Parkinson’s disease).
46
PARKINSON’S DISEASE
• Parkinson’s Disease is a problem in the substantia nigra region
of the midbrain; that area secretes dopamine.
• People with Parkinson’s disease lack dopamine (the social
worker), so the basal nuclei (the parents) inhibit body
movements.
• Therefore, the patient has trouble initiating body movements.
They also develop a “pill rolling” tremor at rest.
• Parkinson’s Disease symptoms are the opposite of Huntington’s
disease.
• Parkinson’s Disease patients cannot initiate movements.
• Huntington Disease patients have sudden, jerky movements.
47
HUNTINGTON’S DISEASE
• Huntington’s disease: rapid, jerky motions.
• Since the basal nuclei are damaged, the inhibition
of the motor cortex is removed, so excitatory
neurons go unchecked, and the person has sudden
jerky movements. Their body writhes around like
they are dancing (chorea).
• Other symptoms include cognitive decline and
psychiatric problems.
• Huntington’s disease is hereditary (50% chance of
each child getting it if one parent has it).
• Age of onset is usually 35-45 years of age, so
symptoms do not manifest until after they have
48
children and pass on the bad gene.
DOPAMINE
• Using too much of the drug “Meth” will kill Dopaminergic neurons,
causing Parkinson’s symptoms.
• Dopamine is used in the substantia nigra portion of the midbrain
where excitatory and inhibitory neurons need to integrate.
• If you lose excitatory neurons, you will gain inhibitory stimulus.
• Parkinson’s patients have problems starting movements, and
coordinating the excitatory/inhibitory stimulus to muscles while
walking. Stopping motions is also hard. They need a trained dog
to pull them up from a seated position and help them to take the
first step, and to stop them when they want to stop.
• Treatment is an MAO inhibitor or L-dopa, which can cross BBB,
unlike dopamine. Cells can convert L-dopa to the required
dopamine earlier on in the disease, but as cells die later, they
cannot perform this conversion.
• Stem cells can be injected to cause the remaining neurons to
replicate and help them get more control.
49
SEROTONIN
• Synthesized from
tryptophan
• Serotonin reuptake
inhibitors are antidepressant drugs
• Ecstasy causes more
release!
• Mood elevator, “feelgood” neurotransmitter
50
SEROTONIN
• At certain times of the day you get your
serotonin surge. Some are morning people,
some are night people.
• If you take an SSR inhibitor, it helps serotonin to
stay in cleft longer, feel good longer.
• These types of drug are prescribed for
depression.
• The street drug, Ecstasy, mimics serotonin. If you
meet someone while taking Ecstasy, you will fall
in love. Better wait six months for it to clear out
your system before you marry them!
51
DISORDER OF PHENYLALANINE METABOLISM
PHENYLKETONURIA (PKU)
• Catecholamines (such as epinephrine) are
derived from the amino acid tyrosine.
• PKU is a genetic, autosomal recessive
disorder (1:20,000 births)
• Lack of enzyme phenylalanine hydroxylase
• Inability to convert phenylalanine (aa) from
the diet to tyrosine (aa)
• Without this enzyme, waste products
(ketones) build up in the blood and are
toxic to neurons. The ketones are spilled in
the urine as well. Symptoms are seizures,
poor motor development and mental
retardation in a developing child.
phenylalanine
Phenylalanine
hydroxylase
Tyrosine
Phenylalanine  TYROSINE  L-DOPA  dopamine  norepinephrine  epinephrine
52
DISORDER OF PHENYLALANINE METABOLISM
PHENYLKETONURIA (PKU)
• Routine testing at birth by heel stick blood sample
• Prevented by dietary restriction of phenylalanine.
• No whole protein during childhood, while nervous system is
developing (until age 20).
• After that, the person can go off the diet, but the ketones will
begin to accumulate. When they start to feel sluggish, and
can’t finish a task on time, they need to go back on the diet for
a while.
• A woman must stay on the diet during pregnancy or the
ketones will cross the placental and kill the neurons of her baby.
• Artificial sweeteners such as Sweet N Low, and diet sodas are
high in phenylalanine, and must be avoided in PKU patients.
• This genetic condition is more likely to occur if you have a child
with your first cousin (or closer relative)
53
EFFECTS OF CNS NEUROTRANSMITTERS
54
End of material for Quiz 8
RECEPTORS
FOR NEUROTRANSMITTERS
55
WAYS TO CLASSIFY NT RECEPTORS
• Functional Classification
• Ionotropic
• Metabotropic
• Structural Classification
• ACh Receptors
• Muscarinic ACh receptors
• Nicotinic ACh receptors
• Adrenergic Receptors
• Alpha 1 and Alpha 2 receptors
• Beta 1 and Beta 2 receptors
• Dopaminergic Receptors
• Serotonergic Receptors
• Glutamate, GABA, and Glycine Receptors
56
FUNCTIONAL CLASSIFICATION
OF NT RECEPTORS
• Ionotropic receptors bind to a NT and have a
channel that extends into cell. They are the
receptor and the transporter
• Metabotropic receptors need a series of enzymatic
actions to change a gated channel somewhere
else. The binding of the NT outside of the cell
activates a G-protein on the inside of the cell which
breaks apart into two pieces. One of those pieces
goes somewhere else in the membrane to open up
another channel.
• G protein receptors are involved in many diseases,
and are also the target of approximately 30% of all
57
modern medicinal drugs.
Ionotropic
Metabotropic
58
G-PROTEINS
• When the G-Protein is activated, it breaks into two
pieces. One of the pieces is called the second
messenger, which is the part that opens the nearby
ion channel.
• It also activates other enzymes inside the cell which
may cause various changes.
• These changes include activation of gene
transcription (to form new proteins, changing the
metabolism; used especially in making new
memories)
59
Receptor Types
• Some of the cell membranes in the
body have receptors which are
activated by voltage, like when the
owner of a house comes home and
enters by clicking the garage door
opener.
• Some receptors are activated by a
ligand, which is like a key that fits
exactly into a specific lock. It is like the
owner of a house coming home and
enters by using a key on the front door.
• Thyroid Stimulating Hormone (TSH) acts
as a ligand on the thyroid gland cell. It
causes activity in the thyroid gland,
and the gland produces thyroid
hormone.
60
LIGAND RECEPTORS USE G-PROTEINS
• When TSH acts as a ligand to bind to the cell
membrane, it activates the “Butler” protein,
called a G-protein on the inside of the cell.
• The G-protein breaks apart into two pieces.
One of those pieces goes somewhere else in
the membrane to change the activity in the
cell.
• It is like the owner of a mansion who comes
home, puts his key in the lock of the front
door, and twin butlers greet him at the door.
One of the butlers holds the door open for
the owner while the other (called the
second messenger) runs off and tells the
other servants in the house that the master
has arrived, so get busy!
61
62
G PROTEINS
• Step 1: Ligand binds to receptor
• Step 2: The G proteins activate
• Step 3: Second messenger activates another protein called
the late effector protein
• Step 4: A protein kinase in the thyroid gland cell becomes
activated.
• We ultimately want kinase
activity, which
phosphorylates (puts a
phosphate molecule on)
other proteins in a cell.
• This increases the activity
level of the cell.
• The servants of the
mansion get busy!
63
SEQUENCE OF EVENTS OF A
METABOTROPIC RECEPTOR
• Step 1: NT binds to receptor
• Ach binds to muscarinic receptors
• Norepi and epi bind to adrenergic receptors
• Step 2: The G proteins activate
• The G-protein (used by both muscarinic and adrenergic receptors) is found
inside every cell of the body. There are different types of G proteins; either GS
(stimulating G protein) or GI (inhibiting G protein). GS means the G protein will
lead to events that lead to an increase in activity in the cell. We will only focus
on these. You will hear about the GI proteins in pharmacology.
• Step 3: Second messenger activates another protein called the late effector
protein
• G-Proteins of sympathetic s neurons activate protein kinase A
• G-Proteins of parasympathetic s neurons activate protein kinase B
64
STRUCTURAL CLASSIFICATION
OF NT RECEPTORS
•
•
•
•
•
Two Types of ACh Receptors (Acetylcholine)
Muscarinic ACh receptors
Nicotinic ACh receptors
Two Types of Adrenergic Receptors (epi and norepi)
Alpha adrenergic receptors
• Alpha 1 receptors
• Alpha 2 receptors
• Beta adrenergic receptors
• Beta 1 receptors
• Beta 2 receptors
• There are also receptors for Dopamine, Serotonin,
Glutamate, GABA, and Glycine, but we will not cover them.
65
ACH RECEPTORS
• Muscarinic ACh receptors (mAChR)
• more sensitive to muscarine than to nicotine
• Muscarinic substances activate the parasympathetic
nervous system (rest and digest). Increased saliva, tears,
diarrhea.
• Antidote for overdose is atropine.
• They use G-proteins to activate a nearby ion channel
• Nicotinic ACh receptors (nAChR)
• more sensitive to nicotine than to muscarine
• They do not use G-proteins; they open ion channels directly
• Both Muscarinic and nicotinic receptors are found on
skeletal muscle, which contract when ACh binds there.
These receptors are also found in the CNS.
66
MUSCARINIC ACETYLCHOLINE
RECEPTORS
• All mACH receptors use the G-proteins, so their
functional classification is “metabotropic”.
Drugs that block the mACh receptor include:
Medicines that treat Parkinson's disease
Atropine (to dilate the pupil for eye exam)
Scopolamine (to prevent motion sickness)
Ipratropium (treatment of COPD)
Amanita muscaria, the
mushroom from which
muscarine was first isolated.
67
The G-protein can be
excitatory or inhibitory,
depending on which ion
channel it opens.
68
NICOTINIC ACETYLCHOLINE
RECEPTORS
• All nACH receptors use a ligand-gated ion channel
mechanism.
• The opening of an ion channel, permits either K+, Na+, Cl- or
Ca++ to diffuse into or out of the cell.
• If a K+ channel opens, K+ will leak out of the cell. If the Clchannel opens, Cl-, it will leak into the cell. Both of these
outcomes will inhibit an action potential (inhibitory). GABA
and Glycine are the two NT’s that will do this.
• If a Na+ or Ca++channel opens, those will leak into the cell,
causing an action potential (excitatory). Glutamate,
serotonin, and ACH using a nACH receptor will do this.
• The functional classification of all nACH receptors is
“ionotropic”.
69
IONOTROPIC RECEPTORS
Nicotinic ACH
Serotonin
Glutamate
GABA
These use an
ionizer to
Glycine
freshen the air!
70
WHAT NEURONS SECRETE ACH?
• Somatic motor neurons to skeletal muscle use ACH
• All ANS preganglionic neurons (sympathetic and
parasympathetic) and postganglionic
parasympathetic neurons secrete Ach, using
nicotinic receptors there.
• About 98% of postganglionic sympathetic neurons
secrete norepi and use an adrenergic receptor,
but 2% of postganglionic sympathetic neurons
secrete Ach (those that supply the sweat glands),
and use muscarinic receptors.
71
Somatic Nervous
System
Nicotinic (Ionotropic)
Nicotinic (Ionotropic)
Nicotinic (Ionotropic)
Muscarinic (Metabotropic)
Nicotinic (Ionotropic)
ACh
Adrenergic (Metabotropic)
Muscarinic (Metabotropic)
2%
Sweat
Glands
98%
Cardiac muscle
Smooth muscle
Glands
Cardiac muscle
Smooth muscle
Skeletal
muscle
72
EFFECTS OF NICOTINE
• Acts as a stimulant: increases dopamine (in the
reward center of the brain), which causes euphoria
and relaxation, and it is addictive.
• Nicotine has a higher affinity for acetylcholine
receptors in the brain than those in skeletal muscle.
• Tobacco smoke contains MAO inhibitors. MAO
enzymes break down dopamine, norepinephrine,
and serotonin. Smoking prevents the breakdown of
these neurotransmitters.
• This contributes to the addictive properties of
tobacco.
73
NICOTINIC RECEPTORS
• Nicotinic acetylcholine receptors can be blocked
by curare, hexamethonium and toxins present in the
venoms of snakes and shellfishes, such as αbungarotoxin. Drugs such as the neuromuscular
blocking agents bind reversibly to the nicotinic
receptors in the neuromuscular junction and are
used routinely in anesthesia.
• Nicotinic receptors are the primary mediator of the
effects of nicotine. In myasthenia gravis, the
receptor at NMJ is targeted by antibodies, leading
to muscle weakness. Muscarinic acetylcholine
receptors can be blocked by the drugs atropine
and scopolamine.
74
ADRENERGIC RECEPTORS
• Alpha adrenergic receptors
• Alpha 1 receptors
• Causes vasoconstriction
• increases blood pressure
• Decreases GI motility
• Alpha 2 receptors
• Causes vasodilatation
• decreases blood pressure
• Decreases GI motility
• Beta adrenergic receptors
• Beta 1 receptors
• Increases heart rate
• Increases cardiac output
• Beta 2 receptors
• Causes vasodilatation
• Decreases blood pressure
• Opens bronchioles
• Decreases GI motility
All of these receptors use G-Protein (the
functional classification is metabotropic)
75
METABOTROPIC RECEPTORS
RECEPTORS WHICH ARE METABOTROPIC
Muscarinic Acetylcholine receptors
 Mostly used by post-ganglionic parasympathetic neurons
Alpha and Beta-Adrenergic receptors
 Mostly used by sympathetic neurons
Dopaminergic receptors
 Mostly used by sympathetic neurons
Who lives in the mansion with the butler (metabotropic) and
who uses the ionizer to freshen the air (ionotropic)?
76
Somatic Nervous
System
Nicotinic (Ionotropic)
Nicotinic (Ionotropic)
Nicotinic (Ionotropic)
Muscarinic (Metabotropic)
Nicotinic (Ionotropic)
ACh
Adrenergic (Metabotropic)
Muscarinic (Metabotropic)
2%
Sweat
Glands
98%
Cardiac muscle
Smooth muscle
Glands
Cardiac muscle
Smooth muscle
Skeletal
muscle
77
Small Molecule Neurotransmitters
• Acetylcholine (ACh)
– mACh (“cholinergic”)
– nACh (“cholinergic”)
• Amino Acid NTs
– Glutamate
– GABA (inhibitory)
– Glycine (inhibitory)
Catecholamines
Adrenergic catecholamines:
• Norepinephrine
• Epinephrine
Dopaminergic catecholamine:
• Dopamine
Serotonergic catecholamine:
• Serotonin
IONOTROPIC RECEPTORS ARE IN RED
METABOTROPIC RECEPTORS ARE IN BLACK
78
Somatic Nervous
System
Nicotinic (Ionotropic)
Nicotinic (Ionotropic)
Nicotinic (Ionotropic)
Muscarinic (Metabotropic)
Nicotinic (Ionotropic)
ACh
Adrenergic (Metabotropic)
Muscarinic (Metabotropic)
2%
Sweat
Glands
98%
Cardiac muscle
Smooth muscle
Glands
Cardiac muscle
Smooth muscle
Skeletal
muscle
79
Effects of ACH receptors
80
WANT MORE DIAGRAMS?
• The following slides have addition
pictures illustrating the same concept.
• Pick the one you like best!
81
Notice that the parasympathetic neurons exit from
the brain (Vagus nerve) and sacral area
82
Somatic
83
84
85
86
87
88
DRUGS AND TOXINS
Spastic paralysis vs. flaccid paralysis
89
SPASTIC VS. FLACCID PARALYSIS
• Flaccid paralysis is when the muscle cannot
contract at all. The muscle stays weak and floppy.
• Spastic paralysis is when the muscle stays in
contraction. You still cannot move the muscle
properly, but in this case, the muscle is too rigid.
90
VESICLE BLOCKERS
• Clostridium botulinum:
• Bacterium that has a protease (enzyme
that breaks down proteins) called
botulism. Botulinum breaks down the
docking proteins that anchor vesicles to
the cell membrane)
• Inhibits ACh neurotransmitter release;
muscles can’t contract.
• Botulism is found in undercooked turkey
and dented cans of food. If ingested
orally, will paralyze the diaphragm; die
of suffocation.
• It causes flaccid paralysis
• It is the muscle killer in “BOTOX”
injections. The muscles die so the
wrinkle lines relax. These small facial
muscles can grow back in three
months; need another shot. It is also
used for migraines.
91
SODIUM VGC BLOCKERS
• Lidocaine- used as
local anesthesia
• Tetrodotoxin-puffer
fish and newts (TTX)
• Saxitoxin- caused
by red tide; a type
of red algae called
dinoflagellates
accumulates in
shellfish (SXT)
• Curare: poison
arrows
All these cause
flaccid paralysis
92
SODIUM VGC BLOCKERS
• Na+ VGC blockers will block the sodium channel,
so you can’t have AP at all. Get flaccid paralysis.
• When preparing a puffer fish for food, if the chef
makes one nick in its liver, it will contaminate the
whole meat with TTX toxin, which paralyzes the
diaphragm.
• Salamanders and newts have this toxin as well.
Sometimes the toxins can get through the skin just
by handling them; get tingling. Don’t lick a
salamander!
93
SODIUM VGC BLOCKER
• Curare
• nACH-R blocker/
competitor
• From tree sap
• Causes flaccid
paralysis
• Large dose:
asphyxiation
94
CURARE
• South American Indians use curare as a poison on
the tips of arrows. Injecting it into the bloodstream
causes death of the animal. However, the digestive
system can deactivate it, so it is safe to eat an
animal that was killed with curare. How does it kill?
• Nicotinic Ach receptors (nACH-R) are mainly found
in skeletal muscle. If you block them with curare,
you block the ability for ionotropic receptors to
open, so Na+ cannot move in. That blocks
excitation, so muscle will not contract, and you get
flaccid paralysis. This is considered a Na+ VGC
blocker.
95
MACH-R BLOCKER/ COMPETITOR
• Atropine
• Flaccid paralysis
• Smooth muscle,
heart, and glands
mACH receptors are
metabotropic (use the G
protein), so atropine blocks
the Na+ VGC indirectly.
96
MACH-R BLOCKER/ COMPETITOR
• Atropine and other mACH blockers are not
classified as a Na+ VGC blocker because they use
mACH receptors, which are metabotropic (use the
G protein), so atropine blocks the Na+ VGC
indirectly.
• Only substances that use ionotropic receptors (such
as nACH) can block the Na+ VGC directly.
Examples are lidocaine, tetrodotoxin, saxitoxin, and
curare. Atropine is not in this category, even though
all of them result in flaccid paralysis.
97
MACH-R BLOCKER/ COMPETITOR
• mACH receptor blockers will block the
parasympathetic system, so the sympathetic gets
more control.
• Blocking the parasympathetic neurons will cause
flaccid paralysis in the intestines.
• If heart has stopped, inject atropine to block mACH
receptors on cardiac muscles, and heart rate will
increase.
98
MACH-R BLOCKER/ COMPETITOR
• Your iris has smooth muscle. If we block Ach, the
muscles will pull, opening pupil.
• Opium derivatives block muscarinic Ach receptors,
causes dilated pupils.
• Chemical warfare drugs that stimulate the
muscarinic Ach receptors causes the
parasympathetic system to gain more control;
increase gut motility, sweat, diarrhea, salivation. A
type of mushroom does this, too, and it can kill you.
99
ATROPINE
• Atropine is a competitive muscarinic acetylcholine
receptor antagonist. It is a naturally occurring
alkaloid extracted from the deadly nightshade
plant (Atropa belladonna).
•
• The species name "belladonna" ("beautiful woman"
in Italian) comes from the original use of deadly
nightshade to dilate the pupils of the eyes for
cosmetic effect. Both atropine and the genus name
for deadly nightshade derive from Atropos, one of
the three Fates who, according to Greek
mythology, chose how a person was to die.
100
ATROPINE
• In general, atropine counters the "rest and digest"
activity of glands regulated by the
parasympathetic nervous system. This occurs
because atropine is a competitive antagonist of the
muscarinic acetylcholine receptors. Atropine dilates
the pupils, increases heart rate, and reduces
salivation and other secretions.
101
ATROPINE
• Secretions and bronchodilatation
• Atropine's actions on the parasympathetic nervous
system inhibit salivary and mucus glands. The drug
may also inhibit sweating via the sympathetic
nervous system. This can be useful in treating
hyperhidrosis, and can prevent the death rattle of
dying patients. Even though atropine has not been
officially indicated for either of these purposes by
the FDA, it has been used by physicians for these
purposes.
102
ATROPINE
• Atropine is not an actual antidote for
organophosphate poisoning such as insecticides
and sarin gas. However, by blocking the action of
acetylcholine at muscarinic receptors, it serves as a
treatment for poisoning by these toxins.
• Troops who are likely to be attacked with chemical
weapons often carry autoinjectors with atropine for
rapid injection into the thigh muscles.
• However, if they are exposed to sarin gas for too
long before being given atropine, they must be put
on an artificial ventilator and pressure chamber.
• Insecticide poisoning is just treated with atropine.
103
ATROPINE
• Atropine is given as a treatment for SLUDGE
syndrome (salivation, lacrimation, urination,
diaphoresis, gastrointestinalmotility, emesis)
symptoms caused by organophosphate poisoning.
Another mnemonic is DUMBBELSS, which stands for
diarrhea, urination, miosis, bradycardia,
bronchoconstriction, excitation (as of muscle in the
form of fasciculations and CNS), lacrimation,
salivation, and sweating (only sympathetic
innervation using Musc receptors).
104
ATROPINE
• A common mnemonic used to describe the
physiologic manifestations of atropine overdose is:
"hot as a hare, blind as a bat, dry as a bone, red as
a beet, and mad as a hatter". These associations
reflect the specific changes of warm, dry skin from
decreased sweating, blurry vision, decreased
sweating/lacrimation, vasodilation, and central
nervous system effects on muscarinic receptors,
type 4 and 5. This set of symptoms is known as
anticholinergic toxidrome, and may also be caused
by other drugs with anticholinergic effects, such as
scopolamine, diphenhydramine, phenothiazine
antipsychotics, and benztropine.
105
ACHE (ACETYLCHOLINE ESTERASE)
BLOCKERS
• Neostigmine
• Physostigmine
• Spastic paralysis
• These drugs are
used to treat
Myasthenia Gravis,
an autoimmune
disease that causes
ptosis (droopy
eyelid)
106
MYASTHENIA GRAVIS
• Myasthenia Gravis (autoimmune disorder). The
body’s antibodies attacks the nicotinic Ach
receptors, so there are fewer of them, less Na+
coming in, fewer action potentials.
• Symptoms usually begin in the eyelid and facial
muscles, and manifests as drooping muscles on half
or both sides of the face, drooping eyelids, and
slurred speech.
• Their eyelid muscles are often the first muscles to
become fatigued.
• To test for this, force open the eyelids, have them
look up, and will quickly cause fatigue, and their lids
107
will droop (ptosis).
MYASTHENIA GRAVIS
• Treatment is to give a medicine to inhibit ACh-ase.
• That way, the ACh will not be deactivated and it can stay
around longer to keep muscles contracting. Too much will
cause spastic paralysis.
• Neostigmine is an anti-cholinesterase drug which reduces the
symptoms by inhibiting Ach-ase activity, preventing the
breakdown of Ach. Consequently, Ach levels in the synapse
remain elevated, so Ach is available to bind to those few
functional Ach receptors that are left.
• Neostigmine is reversible, so you need to keep taking it daily. It is
therefore useful as a medicine.
108
ACH-ASE INHIBITOR:
NEOSTIGMINE
• Neostigmine is a parasympathomimetic that acts as
a reversible acetylcholinesterase inhibitor.
• Neostigmine stimulates both nicotinic and
muscarinic receptors. Unlike physostigmine,
neostigmine does not enter the CNS.
• Its effect on skeletal muscle is greater than that of
physostigmine.
• Neostigmine’s duration of action is 2-4 hours.
• In myasthenia gravis there are too few
acetylcholine receptors so with the
acetylcholinesterase blocked, acetylcholine can
bind to the few receptors and trigger a muscular
109
contraction.
ACH-ASE INHIBITOR:
NEOSTIGMINE
• It is used to improve muscle tone in people with
myasthenia gravis and routinely in anesthesia to
reverse the effects of muscle relaxants at the end of
an operation.
• It can also be used for urinary retention resulting
from general anesthesia and to treat curariform
drug toxicity.
• Another indication for use is the Ogilvie syndrome
which is a pseudoobstruction of the colon in
critically ill patients.
• Sometimes, hospitals use an intravenous version of
neostigmine to delay the effects of snakebite
110
venom.
ACH-ASE INHIBITOR:
NEOSTIGMINE
• Though it is one of only two treatments available for
myasthenia gravis, this drug is no longer available in
the United States to anyone using the Medicare
Part D program. The other drug is Pyridostigmine,
which has to be used with caution in people with
asthma.
•
• Neostigmine will cause slowing of the heart rate
(bradycardia); for this reason it is usually given along
with a parasympatholytic drug such as atropine.
111
NEOSTIGMINE SIDE EFFECTS
•
•
•
•
•
•
•
•
•
•
•
headache, drowsiness;
mild nausea, vomiting, gas;
urinating more than usual;
cold sweat, warmth or tingly feeling;
mild rash or itching
extreme muscle weakness;
slurred speech, vision problems;
severe stomach cramps or diarrhea;
trouble breathing, cough with mucus;
fast or slow heart rate;
seizure (convulsions)
112
MESTINON
• The most commonly used anticholinesterase is
"Mestinon". This comes in 60 milligram (mg) or 10 mg
tablets and is released immediately.
• “Mestinon TimeSpan" is a 180 mg tablet in which 60
milligrams is released immediately and the
remaining 120 milligrams are released over several
hours.
• TimeSpan is usually prescribed for patients who
require medication throughout the night (this allows
for comfortable, uninterrupted sleep and
reasonable strength in the morning).
113
MESTINON
• Timespan's uneven release provides less predictable
results than with ordinary Mestinon and is usually not
recommended for day time use, but some
myasthenics prefer taking it.
• Liquid "Mestinon" syrup is for children and for adults
who have trouble swallowing pills.
114
DIAGNOSIS OF MYASTHENIA GRAVIS
• Tensilon Test
• Baseline assessment of the cranial muscle strength should
be done first
• Edrophonium chloride (Tensilon) is administered, which is a
medication that inhibits the breakdown of Ach, making it
available for use. If muscle strength improves = positive for
MG. (muscle strength will only last for approx. 5mins). FYI:
Atropine should be available as antidote for Tensilon
115
MEDICINES FOR MYASTHENIA GRAVIS
• Medications
• Anticholinesterase Agents, which inhibit breakdown
of Ach and prolong its effect
• Pyridostigmine (Mestinon) is the Drug of Choice
• use cautiously on patients with bronchial asthma, bradycardia,
arrhythmias, epilepsy, recent coronary occlusion, renal
impairment, hyperthyroidism or peptic ulcer
• Adverse reaction: bradycardia, cardiac arrest, bonchospasms,
bronchoconstriction
• Neostigmine (Prostigmin)
• Note: do not give medication on patients with bladder or bowel
obstruction
116
NURSING CONSIDERATIONS FOR
MYASTHENIA GRAVIS
Monitor respiratory status
Check gag reflex before feeding
Use energy conservation measures
Provide small, high calorie meal give meals when
meds are peaking
• Sit upright when eating and use thickener as
necessary
• Lubricating eye drops and eye patch at night if
clients were unable to completely close their eyes
•
•
•
•
117
COMPLICATIONS
MYASTHENIC CRISIS
(undermedication)
CHOLINERGIC CRISIS
(overmedication)
Respiratory muscle weakness
(mechanical ventilation)
Muscle twitching to the point of
respiratory muscle weakness
Hypertension
Hypotension
Weakness, incontinence, fatigue
Hypersecretions (nausea, diarrhea)
hypermotility
Tensilon test =temporary
improvement if symptoms
Tensilon test= no effect or worsens the
symptoms
Symptoms improve after atropine
(anticholinergic) is given
(mechanical ventilation)
ACH-ASE INHIBITOR:
PHYSOSTIGMINE
• Physostigmine is also a parasympathomimetic that
acts as a reversible acetylcholinesterase inhibitor.
• However, it is not used to treat myasthenia gravis.
• It is used to treat glaucoma, Alzheimer's disease,
and orthostatic hypotension.
• It can cross the blood–brain barrier, so it is also used
to treat the central nervous system effects of
atropine, scopolamine and other anticholinergic
drug overdoses.
Physostigmine is the antidote of
choice for Belladona poisoning.
119
ACETYLCHOLINE ANTAGONISTS
• Some INSECTICIDES inhibit acetylcholinesterase, so
Ach accumulates in the synaptic cleft and acts as a
constant stimulus to the muscle fiber. The insects die
because their respiratory muscles contract and
cannot relax: spastic paralysis
• Other poisons, such as CURARE, the poison used by
South American Indians in poison arrows, bind to the
Ach receptors on the muscle cell membrane and
prevent Ach from working. That prevents muscle
contraction, resulting in flaccid paralysis.
120
IRREVERSIBLE ACHE INHIBITOR
• Sarin gas
• Spastic paralysis
• Ventilator until AchE turnover
• This is a permanent AchE inhibitor.
The people who survive Sarin gas
attack are hospitalized. They have
to work to breathe (diaphragm
stops working, so they use their
abdominal muscles), so they need
a ventilator and pressure chambers
until there is a turnover in Ach after
enough gene expression (takes a
few weeks).
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SARIN GAS ATTACK BY SYRIA, 2013
• https://www.youtube.c
om/watch?v=doytZVNl
tc4
• Video
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INHIBITORY NEURON BLOCKERS
• Tetanus toxin
• Blocks release of
inhibitory
neurotransmitters
• Muscles can’t relax
• Spastic paralysis
• Opposing flexor
and extensor
muscles contract
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INHIBITORY NEURON BLOCKERS
• When you walk, it takes coordination with activating and inhibiting muscles.
Extension of leg activates quadriceps and inhibits hamstrings. Where does this
coordination originate?
• The somatic motor neurons innervate these muscles. When it reaches
threshold, will release ACh onto inhibitory neurons and excitatory neurons. This
causes flexor muscles to contract and extensor muscles to relax, then viceversa, so you can walk.
• If you have a toxin that prohibits release of inhibitory NT, then excitatory will
override, and cause more muscle contraction.
• That is what happens with tetanus toxin. When all of the NT is excitatory and
none are inhibitory, all muscle groups contract, causing back arching, and
diaphragm contracts too, and stays that way. Person dies from suffocation.
• Treatment is Ach blockers like Curare. But you have to be careful with that
medicine…. Not just nicotinic, but muscarinic receptors also bind to ACh in
skeletal muscle. Atropine will also help.
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SPIDER VENOM
• Black widow: causes ACh
release
• Lack of inhibitory
neurotransmitters
• Spastic paralysis
• Brazilian Wandering Spider
(banana spider)
• Spider venom increases nitric
oxide release
• Most venomous of all spiders/
more human deaths
•
Video: start at 1:45
•
http://www.youtube.com/watch?v=zOMgx7GQreY
•
Brazilian Wandering Spider Warning Dance
•
http://www.youtube.com/watch?v=N5yJS9mcEc8
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SPIDER VENOM
• Spider venom works like tetanus toxin.
• The Banana spider makes a lot of nitric oxide, which
stimulates receptors of the penis, causing it to flood
with blood, causing erection.
• Pharmaceutical companies decided to modify this
toxin and add it to Viagra, making the Viagra
longer lasting. Spider venom and Viagra both work
by blocking the enzyme that degrades nitric oxide.
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Flaccid Paralysis
Na+ VGC Blockers
•
•
•
•
Lidocaine
Tetrodotoxin
Saxitoxin
Curare
Ach Blockers
• Atropine (mACH)
Vesicle Blocker
• Botulism toxin
Spastic Paralysis
• Ach-ase inhibitors
•
•
•
•
Neostigmine
Physostigmine
Sarin gas
Insecticides
• Ach competitors
• Chemical warfare drugs (other than sarin gas)
• Increases nitric oxide release
• Banana Spider venom
• Blockers of NT which inhibit Ach
• Tetanus toxin
• Black widow spider toxin
WHAT TO FOCUS ON
• Know the classifications, including metabotropic vs ionotropic.
• Which NT is for skeletal muscle? Smooth? Cardiac? Glands?
• Which NT is used for the illnesses mentioned (stroke, myasthenia
gravis)?
• How does alcohol affect a NT or its receptors?
• Know the effects of Alpha, Beta (1 and 2), muscarinic, and nicotinic
receptors.
• Know the drugs and toxin section VERY WELL.
• Where are the nACH and mACH receptors found in the body? What
part of the ANS do they effect: Sympathetic or Parasympathetic?
• Know the diseases, and which receptors are affected.
• Know which diseases cause flaccid vs. spastic paralysis.
• Know which branch of the ANS (sym vs parasymp) uses metabotropic
and which uses ionotropic receptors.
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