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Year 1 Semester 1 – NAS Module Notes
1
...
Voltage inside a cell is always -ve (due to excess anions)
2
...
k
...
Neurones’ Em is usually -65mV
4
...
of leak ion channels)
Ion Channels
(Remember, movement through ion channels is passive)
Classification:
1
...
Gating mechanism
 Non – Gated = determine Em of resting membrane (a
...
a
...
Chemical Gradient
[K ] high inside cell = drive to leave cell (efflux)
+

[Na+] high outside cell = drive to enter cell (influx)
2
...
k
...
ionic driving force)
VERY IMPORTANT
Voltage changes are relatively ‘large’ but are caused by the movement of very few ions
...

The Nernst Equation
The Nernst equation is used to calculate the voltage of an electrochemical cell or to find the
concentration of one of the components of the cell
...
physiologyweb
...
html
To get an electrical signal started, the membrane potential has to change
...
Because the concentration of Na+ is
higher outside the cell than inside the cell by a factor of 10, ions will rush into the cell that are driven
largely by the concentration gradient
...
The resting potential is
the state of the membrane at a voltage of -70 mV, so the sodium cation entering the cell will cause it
to become less negative
...

The concentration gradient for Na+ is so strong that it will continue to enter the cell even after the
membrane potential has become zero, so that the voltage immediately around the pore begins to
become positive
...
The membrane potential will reach +30 mV by the time sodium has entered
the cell
...
These channels are specific for the potassium ion
...
As K+ starts to leave the cell, taking a positive charge with it, the membrane potential begins
to move back toward its resting voltage
...


Repolarization returns the membrane potential to the -70 mV value that indicates the resting
potential, but it actually overshoots that value
...
Those K+ channels are slightly delayed in closing, accounting for this short overshoot
...
There are two types of refractory periods:
Absolute refractory period:
Where it is impossible for another action potential to be activated, regardless of the size of the
trigger (stimulus)
...
In the cardiovascular mechanism, this refractory period is sometimes
called effective refractory period (ERP)
Relative refractory period:
The period that occurs during the undershoot phase; where an action potential can be activated but
only if the trigger (stimulus) is large enough
...
This is because some of
the sodium channels have been reactivated and have recovered but it is a difficult process due to the
counter-acting potassium flow as some potassium ion channels are still open
...
The absolute refractory period of a human muscle fibre is
typically between 2
...
6 ms
...

The number of generated impulses or repetitive firing rate of a neuron will be limited in a given
period of time[4]
...
This is because, as the action potential is moving
forwards along axons, the resting potential will be re-established behind it
...

Glial Cells
Glia, also called glial cells or neuroglia, are non-neuronal cells in the central nervous system and the
peripheral nervous system
...

Note: A Schwann cell is a type of glial cells found in the peripheral nervous system (PNS) of higher
vertebrates
...
Properties of the Motor Unit
Objectives
• To define the meaning of the term ‘motor unit’
• To understand that the ‘motor unit’ is the functional unit of the motor system
• Name and identify cellular components of the ‘motor unit’
• Name the different types of ‘motor units’
The Motor Unit
- Motor unit = The minimal functional unit of the motor system
- Definition - a somatic efferent plus all the muscle fibres it supplies
- Made up of tissues of the body that work together to:
– Set muscle/ motor tone of the body
– Bring about voluntary movements
- Comprised of:
– 1 a-motor neurone
– all the extrafusal muscle fibres it supplies
Extrafusal = The muscle fibres surrounding a muscle spindle
e
...
1
...
quadriceps (1000 fibres)
- Each muscle cell receives motor supply from only 1 motoneurone
- Muscle cells of a motor unit are randomly distributed throughout the thickness of a muscle:
Why?
- In a sustained contraction, the individual muscle fibres alternate firing with each other so
that some are contracting while others are relaxing
...

- The whole of the muscle contracts – i
...
contraction doesn’t occur in a ‘wave’
- Uniform development of force throughout the muscle
- The nervous system can regulate the rate and speed of contraction of movements it may
choose
- Muscle contraction can be distributed throughout the muscle
Muscle Fibres of the Motor Unit
- Muscle Fibres of a Motor Unit
- They have the same:
 physiological profile
 contraction speeds
 susceptibility to fatigue
 same histochemical profile
 myosin fibre typing – enzyme expression profile, shows their metabolic profile
Structural Components of The Motor System
– Motoneurones (Neuronal)
– Skeletal Muscles (Muscular)
– The Neuromuscular Junction (Interface)

Skeletal Muscle
-striated
-voluntary
-role:
 movement
 stability of joints
 posture
 heat generation (Mechanical efficiency of skeletal muscle = ~ 20 %)
Skeletal muscles contribute to the maintenance of homeostasis in the body by generating
heat
...

This heat is very noticeable during exercise, when sustained muscle movement causes body
temperature to rise, and in cases of extreme cold, when shivering produces random
skeletal muscle contractions to generate heat
...
This fibre arrangement allows
for maximum force production)
- Parallel Muscles - fibres are parallel to the force-generating axis
...
Parallel
muscles can be further defined into three main categories: strap, fusiform, or fan-shaped
– Strap Muscles (a
...
a
...
k
...
e
...
e
...
Slow oxidative (SO) fibres (type S)
- contract relatively slowly
- use aerobic respiration (oxygen and glucose) to produce ATP
2
...
Fast glycolytic (FG) fibres (Type FF)

-

fast contractions
primarily use anaerobic glycolysis
...

The speed of contraction is dependent on how quickly myosin’s ATPase hydrolyses ATP to produce
cross-bridge action
...

The primary metabolic pathway used by a muscle fibre determines whether the fibre is classified as
oxidative or glycolytic
...

More ATP can be produced during each metabolic cycle, making the fibre more resistant to fatigue
...
As a result, glycolytic fibres fatigue at a quicker rate
...

1
...

- All of these features allow SO fibres to produce large quantities of ATP, which can sustain
muscle activity without fatiguing for long periods of time
...
FO fibres
- sometimes called intermediate fibres because they possess characteristics that are
intermediate between fast fibres and slow fibres
- produce ATP relatively quickly, more quickly than SO fibres, so can produce relatively high
amounts of tension
- They are oxidative because they produce ATP aerobically, possess high amounts of
mitochondria, and do not fatigue quickly
...


-

used primarily for movements, such as walking, that require more energy than postural
control but less energy than an explosive movement, such as sprinting
...
FG Fibres
- primarily use anaerobic glycolysis as their ATP source
- have a large diameter and possess high amounts of glycogen, which is used in glycolysis to
generate ATP quickly to produce high levels of tension
...

- are used to produce rapid, forceful contractions to make quick, powerful movements
...


Most muscles possess a mixture of each fibre type
...
This increases alpha motor neuron activity, causing the muscle fibers to
contract and thus resist the stretching
...
The reflex functions to maintain the muscle at a constant
length
...


3
...
There are 15 members in the mammalian synaptotagmin family
...
Calcium ion
binding to synaptotagmin I (SYT I) participates in triggering neurotransmitter release at the synapse
...

SYT1 senses calcium ion concentrations as low as 10 ppm and subsequently signals the SNARE
complex to open fusion pores
...
g
...

They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucerlike appearance
...
These neurotransmitters bind to receptors on the postsynaptic
membrane and lead to its depolarization
...
e
...
e
...

When the excited the t-tubule membrane depolarises = a change in the t-tubule voltage
sensor
...

Higher the frequency of motor neurone activity – the muscle stays contracted

-

Myesthenia Gravis



Muscle weakness during sustained activity
Autoimmune disease of the nicotinic acetylcholine receptors – generates antibodies that
work against the receptors
...
g
...
The action potential travels down the neuron to the presynaptic axon terminal
...
Voltage-dependent calcium channels open and Ca2+ ions flow from the extracellular fluid
into the presynaptic neuron’s cytosol
...
The influx of Ca2+ causes neurotransmitter (acetylcholine)-containing vesicles to dock and
fuse to the presynaptic neuron’s cell membrane
...
Vesicle membrane fusion with the nerve cell membrane results in the emptying of the
neurotransmitter into the synaptic cleft; this process is called exocytosis
...
Acetylcholine diffuses into the synaptic cleft and binds to the nicotinic acetylcholine
receptors in the motor end-plate
...
The nicotinic acetylcholine receptors are ligand-gated cation channels, and open when
bound to acetylcholine
...
The receptors open, allowing sodium ions to flow into the muscle’s cytosol
...
The electrochemical gradient across the muscle plasma membrane causes a local
depolarization of the motor end-plate
...
The receptors open, allowing sodium ions to flow into and potassium ions to flow out of the
muscle’s cytosol
...
The electrochemical gradient across the muscle plasma membrane (more sodium moves in
than potassium out) causes a local depolarization of the motor end-plate
...
This depolarization initiates an action potential on the muscle fiber cell membrane
(sarcolemma) that travels across the surface of the muscle fiber
...
The action potentials travel from the surface of the muscle cell along the membrane of T
tubules that penetrate into the cytosol of the cell
...
Action potentials along the T tubules cause voltage-dependent calcium release channels in
the sarcoplasmic reticulum to open, and release Ca2+ ions from their storage place in the
cisternae
...
Ca2+ ions diffuse through the cytoplasm where they bind to troponin, ultimately allowing
myosin to interact with actin in the sarcomere; this sequence of events is called excitationcontraction coupling
...
As long as ATP and some other nutrients are available, the mechanical events of contraction
occur
...
Meanwhile, back at the neuromuscular junction, acetylcholine has moved off of the
acetylcholine receptor and is degraded by the enzyme acetylcholinesterase (into choline and
acetate groups), causing termination of the signal
...
The choline is recycled back into the presynaptic terminal, where it is used to synthesize new
acetylcholine molecules
...
The Basic Anatomy of the Somatic Nervous System
Nerve cell



10% of cells is NS
Conduct impulses

Glial Cell




90% of NS
Many subtypes
Role = produce myelin etc
...
It is
capable of acting independently of the sympathetic and parasympathetic nervous systems, although
it may be influenced by them
...

CNS and PNS




Most (not all) neurones straddle the CNS & PNS at the same time
The CNS & PNS are a continuum
CNS & PNS are not necessarily independent of one another

CNS




Characterized by encasement of the cranium & vertebral column in meninges
Suspended in cerebrospinal fluid
Responsible for the sophisticated functions of the nervous system (sentience)






Is the part of the nervous system outside of the CNS
Connects the CNS to its target organs & tissues
Connects sensory organs to the CNS
Relies on integrity of the CN

PNS

Initial Segment = where action potential is generated, no myelin present
Axon Hillock = where the axon begins, it tapers to form the initial segment of the ‘axon proper’
...
No rough ER in the axon, and there are few/no free ribosomes
...
The protein composition of the axon membrane is different to the soma membrane
...
Their ultrastructure suggests they mainly synthesise proteins for intracellular use They are a
granular and concentrated section of RER and free ribosomes
...
g
...

Somatic Sensory Neurones
Have pseudo-unipolar morphology (neuron has one axon with two branches: central and
peripheral)
...

2
...

4
...


Types of dendrites
Type of connections e
...
motor/ sensory
Axon length
Type of N
...

No
...
g ganglia of the vestibulocochlear nerve, and the bipolar cells found in
the retina
3+ neurites = multipolar – found in most of the neurones in the brain

What is a motoneurone?
• It is a somatic efferent that supplies skeletal muscles to:
– Bring about displacement of limbs (i
...
movements) – & – Set Muscle Tone
• Taken together, motoneurones make up the motor system of the body
• Understanding the motor system is fundamental to the practice of neurology
Skeletal = target of somatic NS
Smooth = target of autonomic NS
Anatomy of The Neuro-muscular Junction
• It is confined to a specific area of the muscle known as the ‘nerve entry point’ or neurovascular
hilum
• The nerve entry point is the:
-

geographical centre of any given muscle
site of entry of a motoneurone into the substance of the muscle
site of entry of arterial supply to a muscle
site of exit of venous drainage of the muscle
site of aggregation of nicotinic receptors of healthy muscles

PNS Axons
Myelinated or unmyelinated
Myelination




Myelinated = faster speed of impulses
CV = 5
...
Here the high concentration of ion channels enables rapid
depolarisation and action potential generation
...
Myelinated axons are able to conduct action
potentials much faster than unmyelinated axons via saltatory conduction, where action
potentials appear to ‘jump’ between Nodes of Ranvier
Capacitance– the ability of an electrical system to store charge or the charge required to
initiate an action potential/electrical impulse; the low capacitance given to an axon by
myelination means that a lower change in ion concentration is required to initiate an axon
potential
Myelin thickness varies between neuronal types (more layers = thicker)
o Diseases caused by problems with myelin:
o MS (CNS)
o Guillain Barre (PNS)
o Diabetes (PNS)
o Polyneuropathies (PNS)

Neuroglia of PNS
-

Schwann Cell – single schwann cell forms a lose cushioning blanket around many nerve cells
Mesaxon - a pair of parallel plasma membranes of a Schwann cell, marking the point of
edge-to-edge contact by the Schwann cell encircling the axon

Neuroganglia of CNS
1
...

-

Oligodendrocyte
Produces myelin sheath
Myelinates many axons at one time
Found in white matter
Astrocytes:
Fibrous:
 Have few, long extensions
 Found in white matter
- Protoplasmic
 Have many, short extensions
 Found in grey matter
- Supportive role for neurons
- Important in embryonic and fetal development
- Control ionic environment in neurons
- Have perivascular feet that cover endothelial cells of capillary = control of blood brain
barrier and regulate vasodilation of capillary
3
...
Microglia
- Function as phagocytes – remove debris from dead/ degenerating neurons and glia

5
...
T
...

What happens:
1
...
A
...
when membrane depolarizes due to Na + ion influx through V
...
AP reaches nerve ending
4
...
G
...
Triggers exocytosis (vesicle moves towards and fuses with pre-synaptic membrane)
6
...
T
...
N
...
binds to specific receptor (exogenous substances can also do this)
8
...
On the neurone and the NT used)
1
...


Reuptake:
Transporter protein takes NT back up into presynaptic knob
Can be metabolized (hence mitochondria needed for enzyme activity)
Presence of Enzymes

Enzymes breakdown NT (outside the presynaptic knob)
The major neurotransmitters
Amino acids: glutamate (major excitatory) gamma -aminobutyric acid (GABA; major inhibitory)
glycine
Monoamines: noradrenaline, dopamine, 5-hydroxytryptamine (5-HT; serotonin)
Acetylcholine (ACh)

Neuroactive peptides: >100 different kinds e
...
opioid peptides (endorphin, enkephalin)
tachykinins (Substance P, neurokinin A)
REMEMBER ADRENALINE = HORMONE, NORADRENALINE = NEUROTRANSMITTER
Receptors
-

Transmembrane proteins
recognition site for a neurotransmitter - initiates the intracellular signal
transmitter binding causes structural change = signal
receptors are specific for a neurotransmitter
one neurotransmitter - several receptor subtypes

Receptor Signalling Mechanisms
1
...
g
...
(as before)
2
...
Receptors open = Na+ ion influx (diff
...
= depolarization of post synaptic membrane (ES????

-

Inhibitory
As before
CL- ion influx (due to moving down conc
...
p
...
Metabotropic (G -protein coupled)
- transmitter binding =conformational change =activates G-protein = activates ‘effector systems’ =
indirect effects on excitability
- slower transmission longer lasting effects
Synaptic Integration of Information
Spatial Summation
-from excitatory synapse
- (EPSC) far from threshold
-if 2 synaptic inputs (spatially separate) occur at same time can be ‘added’ together = twice as much
excitation

6
...
A
...
A
...
g
...
g
...
g
...
Becomes more alkaline less ionised than non ionised
If env
...
l
...
g
...
Acidic conditions due to metabolites produced
Increased acidity = further increassing proportion of ionised
Means fewer unionised molecules present that can enter the cell
Means infection must ‘clear up’ before anaesthetic can be used effectively

Routes of Administration of LAs:
General rule: closer the site of admin
...
Topical Anaesthesia – e
...
dentitry and work on eyes/ throat sweets – easily diffuse through
thin diff
...
g
...
Infiltration anaesthesia (by injection – one or multiple injections needed)
3
...
Epidural Anaesthesia – used for child birth, injected into epidural space and is very long
lasting
5
...
Regional Anaesthesia – Bier’s Block – guided by ultrasound – can anaesthetise an entire limb
or plexus
Potential Side Effects – quite rare
Non-specific:


Hypersensitivity reactions to other chemicals in the drug

Specific:






Acts on Na channels that you don’t want to anaesthetise
Only happens if high doses used/ injected into blood vessels
Affects other excitable tissues
Lipid soluble so can cross the blood – brain barrier = tremor, convulsions, respiratory failure
affects the Na channels on cardiovascular cells = decrease contractibility, blood vessels dilate
= low blood pressure

Other drugs administered with LA
-

Vasoconstrictors, e
...
adrenaline
Localise the LA as reduce blood flow
= less unwanted effects (as won’t enter as many areas where anaesthetic unwanted
= increased duration of action as is metabolised and excreted less quickly)

7
...






2
...
g
...

 The endoneurium, perineurium and epineurium provide guidance to the nerve sprouts on
where to attach etc
...
Neurotmesis - When the entire nerve fibre is completely severed, the axon and the connective
tissue of the nerve are all damaged
 is the most severe class of nerve damage according to Seddon’s Classification System
 Complete recovery does not occur
When Neurones Are Injured, How Does Their Local Environment Change?
The behaviour of 3 classes of glial cells is critical:
• Myelin Forming Cells
– Oligodendrocytes – myelinate many axons at one time in the CNS
– Schwann Cells – myelinate 1 segment of an axon in the PNS
• Astrocytes – Create an environment in which neurones thrive (important in blood brain barrier)
• Microglia – These are immune cells of the nervous system
Congregate around injured cells and = phagocytosis of damaged neurones???

Reactions To Injury Within A Damaged Neurone:
Minutes After Injury is Sustained
• The neurone will immediately stop conducting action potentials beyond the site of injury
• The two ends of the cut axon will be exposed and they will start leaking intracellular fluid – axonal
transport occurs in both directions
• The cut ends will soon pull apart, sealing themselves and swelling at the same time (seal = no NT
can leak)
An Hour After Injury is Sustained
• Synaptic terminal degenerates, accumulation of neurofilaments and vesicles
• Astroglia surround terminal – They react by causing terminals to be pulled away from postsynaptic
cell
Days to Weeks After Axotomy:
Fate of The Proximal Segment
-

Days after sustaining an injury, the proximal segment (cell body) undergoes a process known
as chromatolysis
The cell body soon becomes very active producing a lot of proteins for repairing the cell –
proteins = colour, hence ‘chromo’
The volume of the cell body increases and it also becomes bloated with the newly
synthesised products
The nucleus of the cell is consequently displaced from its central position to the periphery
margins of the cell body
The injured nerve soon seals the wounded stump to form a neuroma
This segment of nerve does not die
In some cases the nerve stump soon regenerates to innervate peripheral structures
Anterograde degeneration - degeneration of a neuron structure after sustaining injury, that
spreads away from the nerve cell body
...


Fate of The Distal Segment
- distal stump of axon will undergo Wallerian Degeneration
The segment of the axon distal to the site of lesion is never viable - It soon dies as a result of loss of
nutritional support from the cell body
• Thus, the axonal segment undergoes Wallerian degeneration
• The axon is digested by phagocytes
• Tissues that might be preserved are:
– Myelin sheaths
– Epineurium
– Perineurium
– Endoneurium
These form hollow tubes to guide any new regrowth of the end of the proximal end
Crush Syndrome◦ A severe, often fatal condition that follows a severe crushing injury, particularly
involving large muscle masses, characterized by fluid and blood loss, shock, hematuria, and renal
failure
...

Crushing injury = ischaemia = release of toxic metabolites

8
...
This leads
to emergence of unexpected results (or syndromes) – Crocodile tears syndrome is an interesting
example (nerve supplying salivary gland now supplies tear duct)
Disorders of A Motoneurone’s Cell Body & LMN Signs
Loss or damage to the motoneurone’s cell body (or soma) would lead to death of the motoneurone
There is a class of diseases that target cell bodies of motoneurones
Polio Myelitis
• It is a communicable infection that targets cell bodies of lower motoneurones of the body
• Also known as infantile paralysis
• Caused by infection by the polio virus
• Leads to toxic infection (death) of Cell Bodies of Neurones of the ventral horn
• Immunization programmes are effective at preventing this disease
• Any motoneurones of the spinal cord are susceptible to this virus
• Death of motoneurones leads to denervation hence paralysis of muscles they supply
-

Now mainly affects developing countries

Motoneurone Disease
There are two types:
1) When the disease simultaneously kills both upper and lower motoneurones
...
g
...
g
...
g
...
g
...
Simple Reflexes
What is a reflex? A stereotyped, involuntary reaction of the CNS to specific sensory input
...

Stereotyped = re-producible
Involuntary = don’t think about it
NOTE: DON’T SAY INVOLUNTARY AND VOLUNTARY NS
somatic = skeletal muscle, autonomic = smooth and cardiac muscle
Clinical Relevance:
Testing reflexes:
-

Pupillary reflex (autonomic)
Deep tendon reflexes (somatic)

General Functions of Reflexes:
1
...
g
...
Postural Control
e
...
walking
3
...
g
...
Sensory receptor – stimulus detected (see earlier notes)
2
...
Integration
 Happens via interneurones/intermediate neurones (NOT RELAY NEURONES)
 Found in the CNS – brain and spinal cord
 Also found in the enteric nervous system
 Allow for modulation – conscious overriding the reflex and perception of the
stimulus
Remember – reflex arc communicates w/ other areas of the NS
4
...
Effector
 Glands/muscles = appropriate response to stimulus
Simple Stretch Reflexes (Myotatic Reflex):



Posture control – adjust degree of skeletal muscle contraction
Sensory receptors = proprioceptors

1
...
g
...
Golgi Tendon Organ – group of nerve fibres in collagen fibres that make up
tendons
 Stretch = stimulus, muscles stretch and shorten = tendons stretch
 Interneuron
– 1st synapse = excitatory NT used
 2nd synapse: inhibitory NT used = less activity/no activity
 Efferent neurone = muscle relaxes and stops contracting
 This is a polysynaptic reflex arc
 Function:
 Prevents damage due to overwork
 Fine control of muscle tension
Do all reflexes use proprioceptors?
No, e
...
limb withdrawal reflex to pain, such as the cross extensor reflex?
Cross extensor Reflex:






Pain = info to brain and reflex action (many interneurones – some use inhibitory, some
excitatory NTs)
Inhibitory = muscle relaxed
Excitatory = muscle contracts, muscle moves away from damage and posture is adjusted
(via
...
The Enteric Nervous System
What is it?
-

-

3rd div
...

Intrinsically innervates viscera inc:
o GI tract (oesophagus to rectum)
o Pancreas
o Biliary system
Interchangeable w/ intramular plexus -> contained entirely within the walls of the GIT
Network of 80-100 million neurons (AKA ‘second brain’

Where is it?
-

-

2 major plexuses of ganglion cells and their fibre bundles:
o Submucosal (Meissner’s) Plexus: stomach and intestines only
o Myenteric (Auerbach’s) Plexus: full length of GIT
o The 2 are extensively connected
Longitudinal muscle contracts = shortens length of GIT
Circular muscle contracts = decrease lumen diameter

Types of Neurons:
1
...
Interneurons – coordinate input and output
o excitatory (ACh) & inhibitory (many) NTs
3
...
Effectors:
- Motor (smooth muscle):
NTs include:
o excitatory: ACh, substance P, 5-HT (investigated in disorders)
o inhibitory: nitric oxide (NO), vasoactive intestinal peptide, ATP, nitrous oxide gas
- Secretory:
NTs Include:
a
...
tonic activation
Function:
1
...
Motor reflex
 via myenteric plexus
 sensory fibres from wall of lumen carry impulse to m
...
plexus influences excitatory efferents to smooth muscle behind bolus -> constriction
behind bolus pushes it forward
m
...
Secretory reflex
via submucosal plexus
food bolus stimulates chemo- & mechanoreceptors in lumen wall -> stimulates ENS via
impulses sent by sensory afferents
s
...
Blood flow adjustment
via combination of plexuses
influence on vasoactive NTs to change vascular diameter
5
...
e
...
and function of neurones
Disease:
o Pathology:
 ENS specific
 NS more generally
 Idiopathic

-

Chaga’s Disease – Endemic in South America
o gut dysfunction
o trypanosome parasite
o toxin -> neuron death (in chronic exposure) of m
...
g
...
gut dysfunction due to antibodies vs
...
e
...
Overview of Autonomic NS Pharmacology
Overview

-

- Both sympaNS and paraNS have 2 neurones between CNs and effector
- Most drugs act in peripheral NS and target synaptic/junctional transmission
- If axons targeted by drugs no specificity to ANS (is if NTs are targeted)
- If nAChRs targeted then no specificity to either symp
...
NS
- Most don’t target CNS but hard to get drugs into it
Remember: Vagus nerve CN X – autonomic innervation to most of abdominal viscera

Acetylcholine Release and Modulation
-

Similar to NMJ (see previously)
Drug targets – few targeted clinically
 choline transporter (i
...
hemicholinium)
 choline acetyl transferase
 transport mechanism for packing ACh into vesicles
 exocytosis of ACh (presynaptic toxins i
...
botulinum)
 AChE (anticholinesterases i
...
neostigmine)

Nicotinic cholinergic receptor






ligand-gated
5 subunits
most pharmacology of receptor mediated by α-subunits
skeletal NMJ has α1-subunit
autonomic nAChRs have anywhere between α2- α7 -subunits -> benefits for pharmacology
as nAChRs in autonomic different to somatic

Hexamethonium – used historically
- Selective antagonist for the neuronal sub-type of nicotinic receptor (different sub-units =
different subtypes = drugs can effect some subtypes but not others)
- Not competitive – are poor blockers = acetylcholine still binds but channel doesn’t open
- Blocks all the effects of autonomic stimulation at a pre-ganglionic level (smp
...

transmission blocked)
- blocks the more active system more -> less active system becomes dominant, causes effects
relating to that system i
...
paraNS dominant at heart so hexamethonium causes increased
heart rate
- One of the methonium derivatives (like decamethonium)
- Historically used as an anti-hypertensive drug – as people with it had high sympathetic tone
= lowered BP (downside – must be given by injection)
Muscarinic ACh Receptors
-

Found on smooth muscle, glands and cardiac muscle
G protein coupled receptors w/ 7 transmembrane domains
Parasympathetic postganglionic transmission
5 subtypes, of which the first 3 - (M1-3) are particularly important in the periphery
different receptor subtypes located in different organs -> organs can be directly targeted
e
...
paraNS targets = cardiac & smooth muscle and glands

Muscarinic Agonists (Parasympathomimetics)
-

-

-

Called “Parasympathomimetic drugs” because exposure mimics the effects of
parasympathetic nervous system activation
E
...
effects of eating some fungi (muscarine poisoning – see later)
Effects:
o Cardiovascular - decreased heart rate and cardiac output
o Smooth muscle - contracts, although vascular smooth muscle dilates via
endothelium (Endothelial Derived Relaxing Factor = NO nitric oxide)
o Exocrine glands - secrete = sweating, lacrimation, salivation, bronchial secretion
Muscarine Poisoning
Adverse effects:
o CV: bradycardia & vasodilation (secondary to NO action) -> leads to falling BP
o smooth muscle: increased gut motility (colicky pain), bronchoconstriction, abnormal
pupillary constriction (miosis)
o exocrine: salivation, lacrimation, airway secretions
treatment = antagonist (i
...
atropine)
Muscarinic Agonist Drugs
e
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pilocarpine – used to treat glaucoma
glaucoma increases pressure in anterior compartment of eye = anterior humor drainage
important
administered topically to eye (i
...
eyedrops)
action – on M3 receptors on ciliary muscles -> muscles contract -> lens fattens -> improving
aqueous humor drainage, dropping intraocular pressure
Treatment to agonist: – muscarinic antagonist (atropine)

Muscarinic Antagonist
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5 receptor subclasses
M1-3 important in periphery
M1 – location = stomach & salivary glands e
...
pirenzepine
M2 – location = cardiac e
...
gallamine
M3 – location = smooth muscle & exocrine glands
less specific antagonists = atropine (from Belladonna), hyoscine, cyclopentolate
Most in clinical use are non-specific:

Clinical Uses of Antimuscarinic Drugs
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Asthma (ipratropium) – inhaled (narrowing airways is parasympathetic – increase symp
...
= increased HR
During operations: (to reverse parasympathetic effects of drugs given in surgery e
...

decrease secretions, decrease AChEI side-effects (atropine))
To dilate pupils (tropicamide)
Urinary incontinence (oxybutynin or tolterodine)
Motion sickness (hyoscine)
Decrease gut motility, decrease secretions (pirenzepine)

Pharmacology of Adrenergic Transmission:
1
...
  β-adrenoceptor agonist and antagonists
3
...
  Monoamine oxidase inhibitors
5
...
g
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bronchodilation, vasodilation) found in lung REMEMBER: 2 LUNGS
– β3:  Relax smooth muscle:
- bladder – prevents urination
- simulate lipolysis (white adipose tissue) and thermogenesis (brown adipose tissue)
Main uses of α-adrenoceptor receptor agonists
-

-

Vasoconstrictors (e
...
adrenaline or noradrenaline) mixed with local anaesthetics e
...

lidocaine (mainly α1 receptors affected) – adrenaline act on a1 receptors = vasoconstriction
to keep anaesthetics localised
nasal decongestants (mainly α1) – phenylephrine

-

-

hypertension (central α2) - e
...
clonidine -> central action on neurons in brain inhibits
sympNS control circuits that increase BP -> outweighs effect of vasoconstriction in periphery
to overall decrease BP
Facial erythema in rosacea – Brimonidine (α2 - direct vasoconstriction)

α1-adrenoceptor
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GPCR (Gq subtype) -> coupled to phospholipase C
-phospholipase C:
o hydrolyses PIP2 in membrane to DAG (activates signalling cascade via protein kinase
C)
o InsP3 (causes release of calcium from SR = increased smooth muscle contraction)

Main uses of a adrenoreceptor antagonists:
-

Hypertension treatment = dilation of blood vessels (α1 – e
...
doxazosin)
Benign prostatic hyperplasia – relaxes prostate = easier urination (α1 – e
...
tamsulosin)

Two main peripheral α2-adrenoceptors on blood vessels:
1
...
some smooth muscle -> contraction -> vasoconstriction & increased BP
Main uses of β-adrenoceptor agonists
-

Cardiogenic shock (β1) I heart can’t pump enough blood around body – adrenaline,
dobutamine
Anaphylactic shock (α/β) – adrenaline – increases cardiac output to counteract shock
Asthma (β2) – salbutamol – inhaled, also delays premature labour as relaxes uterine smooth
muscle

Main uses of β-adrenoceptor antagonists (reg
...
g
...
g
...
g

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