THE NERVOUS SYSTEM

1) INTRODUCTION TOO THE NERVOUS SYSTEM

Describe the different cell types found within the nervous system
Identify the coverings and parts of the central nervous system
Explain the structure and functions of the different components of
the peripheral nervous system
2.MEMBRANE POTENTIALS

1. Describe the physico-chemical properties of nerve cell membranes

2. Differentiate between active and passive transport mechanisms
3. Describe, both qualitatively and quantitatively, the transmembrane
gradients for major ion

4. Describe the Na-K pump as driving force for membrane potential,

transporters, and exchangers
Membrane-spanning enzyme
Transports Na+ out, K+ in
3 Na+ out for 2 K+ in uses energy (ATP) 200 million ions/sec
Establishes concentration gradients for Na+ and K+ 3 Na+ 2 K+ ECF ICF
Note: The Na-K ATPase pump is an electrogenic pump that continually transports Na to the
outside of the cell and K into the cell. It is called electrogenic because it maintains an electrical
potential across the membrane
 5. Calculate membrane potentials according to Nernst

E = + 61 x log Co Ci
Co = conc. ion outside
Ci = conc. ion inside
E = Equilibrium potential for ion in mV
61 = constant:
incorporating Gas constant R; absolute temperature (T),
ions valence when the valence is +1: as we have Na+ /K+ (z), the Faraday constant and logarithmic
conversion (natural to base 10) 61 = (RT/zF) EK+ = 61 x log 150mM 5mM EK+ = - 90 mV Note:

Nernst equation is used to calculate the equilibrium potential of a permeable ion at a given
concentration difference across a cell membrane OR
It calculates the potential at which the ion would be in electrochemical equilibrium

Why is the K+ equilibrium potential important?

The resting membrane potential is always close to the potassium equilibrium potential
(membrane potential at rest is 25-30 times more permeable to K than to Na)
If the membrane becomes permeable to another ion, it will move toward its equilibrium
potential
The membrane potential will change as a result
So, if you open a channel for Na+ it will drive the membrane potential toward the ENa+ (i.e.
membrane potential will go from negative to positive) the entry of Na may neutralise or cancel
some of the potentials that would have been produced by K alon

6. Quantitatively describe a cells resting membrane potential

 7. Describe the structure and role of ion channels (Na, K, Cl, Ca)

8. Identify and describe the differences between voltage and ligand

gated ion channels
Feature of ion channel
Integral Membrane Proteins (compare lecture Biological Membrane Structure) membrane
passage
Structurally diverse: Tetra (e.g. K+ channel) or pentamers (ligand-gated cation and anion
channels) with one common pore, or intracellular pore in each subunit (e.g. certain Cl- channels
or aquaporins)
Selectivity filter (pore diameter, shape, electric charges along pore): Permits certain ion(s) to
pass, but not others ion selectivity
Gates (gate-like extensions closing over channel by conformational changes)controls
permeability over time Voltage gating, ligand/chemical gating, mechanical gating,
phosphorylation gating
Rectification: Direction of current flow Na+

Examples of drugs modifying voltagesensitive ion channels

Local anaesthetics i.e. Xylocaine/Lidocaine - inhibit voltagegated sodium channels
Ca2+- channel blockers i.e. Nifedipine (antihypertensive drugs)

2) NEUROTRANSMISSION

1. Differentiate between autonomic and sensory-somatic nervous

system
2. Differentiate between sensory and motor neuro

3. Define what a neurotransmitter is

Typically small, rapid-acting molecules

e.g. Acetylcholine, Dopamin, glutamate, noradrenaline, GABA
Generally, neurones release one type of major NT
4. Describe the differentiation between depolarisation (excitation) and
hyperpolarisation (inhibition)
5. Describe the mechanism of action potential generation and
propagation and the mechanism of action of local anaesthetics
PHARMACOLOGIC OR PATHOLOGIC INTERFERENCE WITH NERVE CONDUCTION

- Local anaesthetics inhibit voltage-gated Na+ channels.

-This leads to an inhibition of the formation and propagation of action potentials along nerve
fibres.
Examples: benzocaine , lidocaine.
- Cold, ischaemia (reduction in blood flow)
- Demyelinating diseases (Multiple sclerosis)

6. Identify and describe the defects in nerve conduction in multiple

sclerosis
- MULTIPLE SCLEROSIS
Chronic disorder
Multiple plaques of demyelination in brain and spinal cord
Prevalence higher in cold climate
Inflammatory genesis through autoimmune mechanism
Attack of white matter by CD4+ cells demyelination
Also autoantibodies against myelin oligodendrocyte glycoprotein (MOG)

3) NEUROMUSCULAR JUNCTION
1. Differentiate between skeletal, smooth muscle and cardiac muscle

2. Describe the sequence of events occurring during

neurotransmission at the neuromuscular junction
3.. Describe the role of acetylcholinesterase in neurotransmission at the
neuromuscular junction
ACETYLCHOLINESTERASE (AChE)
concentrated on the external surface of the postsynaptic membrane and in the synaptic cleft.
enzyme breaks down the neurotransmitter ACh in the neuromuscular junction ( 25,000
molecules per second).
the sodium channels close, and
the field is cleared for the arrival of another nerve impulse.
5. Characterise the nicotinic receptors at the neuromuscular junction
Receptor for ACh at postsynaptic membrane of skeletal NMJ is the muscle-type nicotinic receptor
(NM)
The drug nicotine also activates this receptor
Nicotinic receptors are ionotropic ion channel is intrinsic part of the receptor
Nicotinic ACh receptors mediate very rapid responses NICOTINIC RECEPTORS
- found at the neuromuscular junction of skeletal muscles
- also found in the autonomic nervous system (ganglion) and the central nervous system

6.NEUROMUSCULAR BLOCKING AGENTS

Nicotinic cholinergic receptors at the NMJ can be blocked by several drugs
Curare contains substances that inhibit binding of ACh to nAChR
Curare paralyses skeletal muscles
D-Tubocurarine and related agents used as neuromuscular blocking agents during surgical
anaesthesia to relax skeletal muscle Amazon: South American Indians using poison dart. (extract
from plants- not the frogs!) Neuromuscular Blocking Agents NEUROMUSCULAR BLOCKING
AGENTS
Botulinum toxin (Botox) blocks release of ACh - prevents muscles responding to nerve
impulses works by cleaving synaptic proteins required for vesicle release
Ingesting 0.0001 mg can kill an adult
Caused by improperly canned food
Treats dystonias disorders including spasms, involuntary twitches
Cosmetic use: reduce wrinkles/frown lines permanently contracted muscles

6.MYASTHESIA GRAVIS
Myasthenia gravis, disease in which immune system attacks motor end-plate ACh receptor.
Commonest primary disorder of neuromuscular transmission.
Mainly in adulthood: 20 / 100,000
Too little ACh effect extreme muscle contraction weakness
Treated with AChE inhibitor (neostigmine) prolongs effect of ACh, or immuno-suppressants
5.AUTONOMIC NERVOUS SYSTEM 1

1. Describe the divisions of the nervous system

2. Define the role, function and regulation of the ANS

Role of the autonomic nervous system (I)
ANS is the (involuntary) branch of the efferent division of the PNS
ANS controls the body's internal environment (visceral activities) in a coordinated manner
Heart rate & circulation, digestion, respiration
Prepares us for "fight or flight

ANS has two divisions*: parasympathetic & sympathetic

Most visceral organs innervated by both divisions
Two divisions exert (mostly) opposing effects
Partial activation under most circumstances Tonic activity *Technically, the enteric nervous
system is a 3rd division: vast network of nerve fibers that innervate the digestive tract.

Role of the autonomic nervous system (III)

Parasympathetic function Restorative/maintenance "rest & digest
Sympathetic function Activated in emergency situation "Fight or Flight"

Role of the autonomic nervous system (IV)

Advantage of "dual system" Rapid and precise control over organ/tissues activity Like
having an accelerator and a brake on a car
e.g. like letting up on accelerator vs applying brake Very rapid transitions from rest state to
fight or flight
Role of the autonomic nervous system (V)
The parasympathetic system promotes normal maintenance of the body
Promotes secretions and mobility of different parts of the digestive tract
Also involved in urination, defecation

Role of the autonomic nervous system (VI)

Sympathetic NS: Emergency situations, body needs sudden burst of energy
Increases cardiac output and pulmonary ventilation, routes blood to muscles, raises blood
glucose and slows down digestion, kidney filtration and other functions not needed during
emergencies
Whole sympathetic system tends to "go off" together Parasympathetic does not tend to go
off together

3. Describe in detail as well as differentiate parasympathetic

(cholinergic) control of tissues and sympathetic (adrenergic)
control of tissues

4. Describe the neuroeffector junction in ANS

5.

5.Describe the neurotransmitters and receptors located in the ANS

Neurotransmitters of the ANS
ANS uses two main neurotransmitters
Acetylcholine (ACh)
Noradrenaline (NA, norepinephrine (NE))
All preganglionic ANS nerves releaseACh
Postganglionic parasympathetic nerves releaseACh
Postganglionic sympathetic nerves release NA
5.AUTONOMIC NERVOUS SYSTEM 2

1. Understand and describe the neurotransmitters and receptors

located in the ANS
ANS uses just two neurotransmitters
Acetylcholine (ACh) & Noradrenaline (NA) All preganglionic ANS nerves releaseACh
Postganglionic parasympathetic nerves release Ach
Postganglionic sympathetic nerves release NA

2.Describe the properties and mechanisms of action of neurotransmitter

receptors within the ANS
3. Describe how parasympathetic (cholinergic) control of tissues relates to
pathophysiology of disease
Third-order neuron disorder:
Postganglionic lesions at the level of the internal carotid artery (e.g. a tumor in the cavernous sinus
or a carotid artery dissection).
Partial Horner's syndrome In case of a third-neuron disorder, anhidrosis is limited to the middle part
of the forehead or can be absent, resulting in a partial Horner's syndrome.
Impaired sweating above the waist affecting only one side of the body, yet they do not have a
clinically apparent Horner's syndrome, then the lesion is just below the stellate ganglion in the
sympathetic chain.
Extra notes Horners syndrome for Medical students means Pancoasts tumour Horners syndrome
Emergency Department could mean some kind of dissection originating or extending to the carotids
(spontaneous or trauma related) cavernous sinus thrombosis
We also hope the patient presents with pain, otherwise well not bother looking for it. So what is
Horners syndrome?
Consists of: miosis, ptosis, anhydrosis can we simplify this?
small pupil on the side of the lesion droopy lid on the side of the lesion no one cares that your face
doesnt sweat so forget about it
Bottom line: The sympathetic supply to the eye was disrupted.
Turn off the lights tell your patient first.
When the lights are off the pupils should dilate up. If theres a Horners syndrome the normal pupil
will get bigger and the affected one will remain fairly unchanged.
A patient I saw told me that he noticed the pupil big when he looked in the mirror when he got up to
go to the loo in the middle of the night but it was normal when he looked in the morning light reflex
should be intact
the efferent part of this is mediated by the parasympathetics so should be unaffected in Horners

4. Describe how sympathetic (adrenergic) control of tissues relates to

pathophysiologydisease

Dysautonomia
Many forms: Orthostatic hypertension, neurogenic syncope, chronic stress disorders (chronic
activation of HPA-axis)
Trauma, Inflammation, Drugs, Neurodegenerative disease
E.g. deficiency of sympathetic activity to lesion /compression (trauma, tumor) in Horners
syndrome: drooping eyelid (ptosis) + constriction of pupil (miosis) together with anhydrosis
(decreased sweating)
Pathophysiology: a deficiency of sympathetic activity.
The site of lesion to the sympathetic outflow is on the ipsilateral side of the symptoms.
Causes:
First-order neuron disorder:
Central lesions that involve the hypothalamospinal tract (e.g. transection of the cervical spinal
cord).
Second-order neuron disorder:
Preganglionic lesions (e.g. compression of the sympathetic chain by a lung tumor).

4) PHARMACOLOGY OF THE SYMPATHETIC NERVOUS SYSTEM

1. Describe where and how the autonomic nervous system can be

pharmacologically manipulated for clinical advantage
TARGETS FOR PHARMACOLOGICAL INTERVENTION WITH ADRENERGIC TRANSMISSION
1.Receptor ligands
2. Neurotransmitter synthesis
3. Re-uptake into neuron
4. Re-uptake into post-synaptic tissue
5. Feedback pathway

BIOSYNTHESIS OF NEUROTRANSMITTER
Transmitter synthesis involves:
L-tyrosine is converted to dopa
Dopa is converted to dopamine
Dopamine is converted to noradrenaline (NA) in synaptic vesicles.
In the adrenal medulla, NA is converted to adrenaline. Dopamine, noradrenaline and
adrenaline are referred to as catecholamines or monoamines

2. Describe the mechanisms of action, uses and predictable side effects of

commonly used classes of drugs which impact on the adrenergic ANS
3. Outline adrenergic receptor agonists/antagonists as well as explain
indirect adrenergic receptor mimetics/lytics

5) PHARMACOLOGY OF THE CHOLINERGIC SYSTEM

1. Classify cholinergic receptors and describe their principal functions

2. Explain in detail the mechanisms of action and uses of commonly

used classes of drugs which impact the
1. Display knowledge of indirect cholinergic receptor mimetics/lytics
2. Describe the process of events in neuromuscular junction blockade

CLINICAL APPLICATION OF NEUROMUSCULAR BLOCKING AGENTS

Depolarizing blockers: Depolarizes the post synaptic membrane with the inflow of sodium ions

Nondepolarizing blockers: Blocks the sodium ions conductance

Neuromuscular blocking agents are used primarily as an adjunct to general anesthesia.
Produces skeletal muscle relaxation which facilitates operative procedures
TUBOCURARINE: first non-depolarizing NM blocking agent
It was demonstrated that curare extracts prevented skeletal muscle contractions by an effect at
the neuromuscular junction
Side effects: a fall in arterial blood pressure due to ganglion block
3. Describe the management of myasthenia gravis
A neuromuscular disease leading to fluctuating weakness and fatigability.
It is one of the best known autoimmune disorders
Weakness is caused by circulating antibodies that block acetylcholine receptors at the post-
synaptic neuromuscular junction, inhibiting ACh.
Muscles become fatigued; but can recover after period of rest
Severe myasthenia (Myasthenic crisis) may cause respiratory failure due to exhaustion of the
respiratory muscles.
Myasthenia is treated with cholinesterase inhibitors and immunosuppression.

Edrophonium test
The Edrophonium test" is infrequently performed to diagnose Myesthenia Gravis (MG)
Normally diagnosed by physical examination, blood tests and electrodiagnostic techniques
. This test requires the intravenous administration of Edrophonium chloride or neostigmine;
AChE-inhibitor drugs that temporarily increases the levels of Acetylcholine at the neuromuscular
junction.
In people with myasthenia gravis involving the eye muscles, Edrophonium chloride will briefly
relieve weakness.
4. Describe and list cholinergic receptor agonists/antagonists