PBL Case 3 Felipe and Garcia

PATIENT PRESENTATION
Felipe Romano (age 19) is brought into the emergency department of the Roma hospital in western
Queensland by his friend Rafael. They are young back-packers on holiday from Colombia. Felipe is
speaking mainly in Spanish, but Rafael makes it known to the staff that Felipe has severe diarrhoea and
abdominal cramps. He is wheezing and coughing and complains of feeling dizzy and nauseated.

DISCUSSION QUESTIONS
-

What is the key information?

What possible hypotheses can you suggest?
Which body systems are affected? Explain your reasoning.
What additional information do you require in order to understand the causes of Felipes
problems?

PHYSICAL EXAMINATION
With the help of Rafael, the doctor on duty takes Felipe's recent history and makes a physical
examination. The pair has been holidaying in Australia for the last month and had hired a car to drive
out to visit relatives near Charleville.
Felipe had been at a family barbecue at his aunt's earlier this afternoon. He and Rafael left the
barbecue and were making their way east, back towards the coast, when Felipe developed diarrhoea
and the other symptoms. They decided to stop at the hospital to seek help for him. Rafael had also
been at the barbecue, but had not become ill.
Rafael is adamant that neither have been taking any drugs.

On examination:
He has abdominal tenderness and he describes frequent, almost uncontrollable, bowel movements.
His pupils are somewhat constricted and he has some trouble focussing.
His coughing is accompanied by excessive salivation and some degree of airway secretion.
His coordination of movement is normal and he shows no sign of muscle weakness.
Apart from the dizziness, he is alert and has no sensory abnormality.
He is afebrile.
His heart rate and blood pressure are normal.

DISCUSSION QUESTIONS
-

Review your list of Felipes problems.

Does the new information help you refine your hypotheses about the causes of Felipes
problems? Explain your reasoning.
What additional information do you require?
o Good medical history
Is it appropriate to rely on his companion as translator?

FURTHER HISTORY
With Rafael's help, it is revealed that Felipe had eaten a couple of chops and some salad from the same
lot that everyone ate. However, Felipe is a fit soccer player and had not been interested in eating any
of the desserts or cakes that had been eaten with great enthusiasm by Rafael and the rest of the family.
Instead of cakes, Felipe had some slices of watermelon. Rafael recalls, "I don't think anyone else had
any, because I took the cover off the plate and offered it to him. It was really good watermelon that we
only bought yesterday from a truck by the side of the road somewhere".

DISCUSSION QUESTIONS
-

How has this information helped you?

What specific hypotheses can you now support?
o Pesticide poisoning
What more information do you need?

Detailed full history

PATIENT MANAGEMENT
-

The doctor gives Felipe an injection of atropine, which quickly relieves his symptoms. He
considers that Felipe may have been exposed to an organophosphate compound, probably an
insecticide. He rings the Poisons Information Centre in Brisbane and discusses the case with the
consultant on call there, and arranges for Felipe to be admitted to the hospital.
Suspecting that the watermelon is the cause of the problem, the doctor tells Felipe and Rafael
not to eat any more of the watermelon they bought at the roadside.
In hospital Felipe is given pralidoxime in addition to atropine. Treatment is continued as required
to relieve his symptoms, and he recovers completely in 48 hours.

Treatment
-

Atropine
Pralidoxime

DISCUSSION QUESTIONS
1. What is meant by the term "organophosphate compound"?
o An organophosphate (sometimes abbreviated OP) or phosphate ester is the general
name for esters of phosphoric acid. Many of the most important biochemicals are
organophosphates, including DNA and RNA, as well as many of the cofactors essential for
life. Organophosphates are the basis of many insecticides, herbicides, and nerve
agents. Their inhibitory effects on the acetylcholinesterase enzyme lead to a pathological
excess of acetylcholine in the body.
2. What is the function of atropine and pralidoxime?
a. Which body systems do these drugs affect?
i. Atropine is an antimuscarinic agent since it antagonizes the muscarine-like
actions of acetylcholine and other choline esters. Atropine inhibits the muscarinic
actions of acetylcholine on structures innervated by postganglionic cholinergic
nerves, and on smooth muscles which respond to endogenous acetylcholine but
are not so innervated. As with other antimuscarinic agents, the major action of
Atropine is a competitive or surmountable antagonism which can be overcome by
increasing the concentration of acetylcholine at receptor sites of the effector
organ (e.g., by using anticholinesterase agents which inhibit the enzymatic
destruction of acetylcholine). The receptors antagonized by Atropine are the
peripheral structures that are stimulated or inhibited by muscarine (i.e.,
exocrine glands and smooth and cardiac muscle). Responses to
postganglionic cholinergic nerve stimulation also may be inhibited by Atropine but
this occurs less readily than with responses to injected (exogenous) choline
esters.
ii. Pralidoxime (2-pyridine aldoxime methyl chloride,) or 2-PAM, usually as
the chloride or methiodide salts, belongs to a family of compounds called oximes
that bind to organophosphate-inactivated acetylcholinesterase. It is used to
combat poisoning by organophosphates or acetylcholinesterase inhibitors (nerve
agents) in conjunction with atropine and diazepam. In organophosphate
poisoning, an organophosphate binds to just one end of the acetylcholinesterase
enzyme (the esteric site), blocking its activity. Pralidoxime is able to attach to the
other half (the unblocked, anionic site) of the acetylcholinesterase enzyme. It then
binds to the organophosphate, the organophosphate changes conformation, and
loses its binding to the acetylcholinesterase enzyme. The conjoined poison /
antidote then unbinds from the site, and thus regenerates the enzyme, which is
now able to function again.
b. What are the actions of these drugs at a cellular level?
c. How have these drugs relieved Felipe's symptoms and restored his clinical
signs?
i. Atropine antagonizes ACh receptors. It inhibits the muscarinic actions of ACh on
structures innervated by postganglionic cholinergic nerves, and on smooth
muscles which respond to endogenous ACh but are not so innervated. Its a
competitive inhibitor of ACh.
3. Describe the components of a neuron and define what is meant by the term synapse.

a.
Multipolar neurons are the most common neuron in the vertebrate nervous system
and their structure most closely matches that of the model neuron: a cell body from
which emerges a single long axon as well as a crown of many shorter branching
dendrites.
Unipolar neurons, the most common invertebrate neuron, feature a single primary
projection that functions as both axon and dendrites.
Bipolar neurons usually inhabit sensory organs like the eye and nose. Their dendrites
ferry signals from those organs to the cell body and their axons send signals from the cell
body to the brain and spinal cord.
Pseudo-unipolar neurons, a variant of bipolar neurons that sense pressure, touch and
pain, have no true dendrites. Instead, a single axon emerges from the cell body and
heads in two opposite directions, one end heading for the skin, joints and muscle and the
other end traveling to the spinal cord.
b. Synapse: a junction between two nerve cells, consisting of a minute gap across which
impulses pass b diffusion of a NT.
4. How do electrical and chemical synapses differ?
i. In a chemical synapse, electrical activity in the presynaptic neuron is converted
into the release of NT that binds to receptors. The NT may initiate an electrical
response or a secondary messenger pathway that may excite or inhibit the
postsynaptic neuron.
ii. In an electrical synapse, the presynaptic and postsynaptic cell membrane are
connected by special channels called gap junctions or synaptic cleft that are
capable of passing electric current, causing voltage changes in the presynaptic
cell to induce changes in the post-synaptic cell. The main advantage of an
electrical synapse is the rapid transfer of signals from one cell to the other. One of
the main functions of electrical synapses is thought to be the synchronization of
the activity of groups of neurones (or glial, cardiac muscle, epithelial or liver cells
which can also form gap junctions).
b. Outline how cells release neurotransmitters.

ACh is synthesized from choline and acetyl-coA in the terminal axon

o Catalyzed by the enzyme choline acetlytransferase
AP arrives, large numbers of P-type calcium channels in the terminal membrane of the
nerve open, allowing calcium to enter the cell
Calcium ions then act via a membrane protein called synaptotagmin to initiate the
interaction of SNARE proteins that are embedded in the vesicular and pre-synaptic
membranes. The SNARE proteins mediate fusion of the vesicle and presynaptic membranes at an active zone such that the transmitter is released by the
process of exocytosis. The vesicular membrane then invaginates and buds off
intracellularly to be recycled for subsequent transmitter release.
Depolarization of the pre-synaptic terminal and influx of calcium triggers 100-300
vesicles to fuse with the pre-synaptic membrane at specific sites to release the ACh
into the synaptic cleft.

Post-junctional membrane receptors of motor endplate are nicotinic ACh

receptors.
o ACh bind to specific sites on the receptor opens the channel for 1msec.
o Channel allows movement of all cations movement of sodium
predominates.
o Depolarization triggers muscle action potential that results in muscle
contraction.
5. Discuss how neurotransmitters such as acetylcholine bind to cells and affect cell
function.
o

Released NT molecules bind to and activate protein receptors embedded in the post-synaptic
membrane.
If NT is excitatory (e.g. glutamate) partial depolarization of the post-synaptic membrane

If NT is inhibitory (e.g. GABA) hyperpolarization.

4 classes of receptors
1. Ligand-gated (e.g. skeletal muscles)
a. AP arrives at the synaptic terminal triggers influx of Ca
b. ACh is released via exocytosis
c. ACh binds to nicotinic receptors on the surface of the sarcolemma at the motor end place
d. Opening of cation channels leads to influx of Na (depolarization)
2. G-protein coupled receptor
a. ACh binds to G-protein coupled receptor.
b. In response to the binding of ACh, subunit of G-protein releases GDP and binds GTP
instead.
c. Binding of GTP activates the G protein and subunit dissociates.
d. subunit interacts with effector system to mediate specific responses.
3. Kinase linked
4. Nuclear receptor
7. What mechanisms are used to remove neurotransmitters from the synapse after their
release?
i. Diffusion the neurotransmitter detAChes from receptor, drifting out of the
synaptic cleft, here it becomes absorbed by glial cells.
ii. Enzyme degradation special chemicals called enzymes break it down.
iii. Reuptake re-absorption of a neurotransmitter into the neuron. Transporters, or
membrane transport proteins, pump neurotransmitters from the synaptic cleft
back into axon terminals (the presynaptic neuron) where they are stored.
6. List the effects of the parasympathetic and sympathetic divisions on the major body
systems and comment on which components of the central and peripheral nervous
systems have been affected in Felipe? (how is nervous system divided etc)
Characteristic
Origin

Location of ganglia

Parasympathetic
Craniosacral outflow: brain
stem nuclei of cranial
nerves 3, 7 , 9 and 10:
spinal cord segments S2S4
Ganglia in (intramural) or
close to visceral organ
served

Relative length of preand postganglionic

fibers
Rami communicantes

Long preganglionic; short

postganglionic

Degree of branching of
preganglionic
Functional role

Minimal

Neurotransmitters

None

Maintenance functions;
conserves and stores
energy
All fibers release ACh
(cholinergic fibers)

Sympathetic
Thoracolumbar outflow:
lateral horn of gray matter
of spinal cord segments T1L2
Ganglia within a few
centimeters of CNS:
alongside vertebral column
(symphathetic trunk, or
chain, ganglia and anterior
to vertebral column
(collateral, or prevertebral,
ganglia)
Short preganglionic; long
postganglionic
Gray and white rami
communicantes. White
rami contain myelinated
fibers; gray contain
unmyelinated
postganglionic fibers
Extensive
Prepares body for activity
All preganglionic fibers
release ACh; most
postganglionic fibers
release NE (adrenergic
fibers); postganglionic
fibers serving sweat glands

and some blood vessels of

skeletal muscles release
ACh; neurotransmitter
activity augmented by
release of adrenal
medullary hormones (NE
and epi)
target organ or system
Eye (iris)
Eye (ciliary muscle)
Glands (nasal, lacrimal,
gastric, pancreas)
Salivary glands
Sweat glands
Adrenal medulla

Parasympathetic effects
Constricts pupils
Bulging of lens for close
vision
Stimulates secretory activity

Sympathetic effects
Dilates pupils
Flattening of lens for far
vision
Inhibits secretory activity

Stimulates secretion of
watery saliva
No effect
No effect

Stimulates secretion of thick,

viscous saliva
Stimulates copious sweating
Stimulates medulla cells to
secrete epi and NE
Stimulates to contract (erects
hair and produces
goosebumps)
Increases rate and force of
heartbeat
Causes vasodilation

Arrector pili muscles

attAChed to hair follicles

No effect

Heart muscle

Decreases rate; slows heart

Heart: coronary blood

vessels
Bladder/urethra
Lungs
Digestive tract organs

Dilates coronary vessels

Liver

promotes voiding
Constricts bronchioles
Increase motility and amount
of secretion by digestive
organs; relaxes spincters to
allow movement of foodstuffs
along tract
No effect

Gallbladder
Kidney

Excites
No effect

Penis
Vagina/clitoris

Causes erection
Causes erection of clitoris

Blood coagulation
Cellular metabolism
Adipose tissue

No effect
No effect
No effect

Inhibits voiding
Dilates bronchioles
Decreases activity of glands
and muscle of digestive
system and constricts
sphincters
Stimulates release of glucose
to blood
inhibits
Causes vasoconstriction;
decreases urine output;
promotes renin release
Causes ejaculation
Causes contraction of vagina;
increases mucous secretion
Increases coagulation
Increases metabolic rate
Stimulates lipolysis

7. Outline the adrenergic and cholinergic fibers. Define them and list the different types
of receptors.

There are two main types of ACh receptors:

Nicotinic receptors (ligand gated ion channels)
Nm
Nn

Location
Skeletal muscles
(NMJ)
Autonomic ganglia

Mechanism of action
Excitatory, increases
cation

Response
Skeletal muscle
contraction
Catecholamine secretion
Post-ganglionic
excitation

Muscarinic receptors (G-protein coupled receptors)

M1

Location
Neuronal

Mechanism/action
Gq activation of PLC

Response
Neuromodulation of NT

M2

Cardiac

M3

Glandular

Eventually causing
depolarization and
excitation
Gi inhibition of AC
Causing decrease in
cAMP and hence
decrease in [Ca]
Gq

Cardiac inhibition
- Decrease HR
- Decrease contractility
Neutral inhibition
Gastric and salivary secretion
GI smooth muscle contraction
Ocular accommodation
Vasodilation

Muscarinic agonists and antagonists

Agonist
Diarrhoea
Urination
Miosis
Bronchoconstriction
Emesis
Lacrimation
Salivation
Sweating

D
U
M
B
E
L
S

Antagonist
Constipation
Urine retention
Mydriasis (pupil dilation)
Bronchodilation
Antimetic effects
Dryness

Adrenergic receptors (G-protein coupled receptor)

-

2 main types

-receptors
General location
1

Smooth muscles
(including blood
vessels)

Parasympathetic
presynaptic
receptors
Platelets

Mechanism/actio
n
Gq activation of
PLC increase
[Ca]
Gi inhibition of
AC decrease [Ca]

Effects/response
Vasoconstriction (increase in BP)
GIT smooth muscle relaxation
Salivary secretion
Glycogenolysis
Inhibition of NT release (NA, ACh) response
for feedback control of NA release
Inhibition of insulin release
Platelet aggregation

* 2 receptors are also response for the negative feedback of NE release

After NE is released, NE
1. binds to 2 receptor which then prevents further release of NE
2. binds to post-synaptic receptors

-receptors
General
location
Heart

Mechanism/actio
n
Gs stimulation of
AC increase in
[Ca] and
stimulation of PKA

Lungs
Smooth
muscles

Effects/response
+ve inotropic effect (force of contraction)
+ve chronotropic effect (HR)
+ve dromotropic effect (conduction speed of AV
node)
Bronchodilation
Vasodilation
Visceral smooth muscle relaxation
Glycogenolysis
Muscle tremors
Decrease in intraocular pressure
Lipolysis

Adipose tissue
(metabolism)
* note: stimulation of the 2 receptor reduces histamine release which is used to treat anaphylactic
reactions

Discussion Questions tutorial 2

1. Describe and outline the anatomy and innervation of striated and
smooth muscle, and the function of the innervation.
Skeletal Muscle

Muscle fibre single muscle cell, large, elongated, cylindrical. Extend whole length of the
muscle.
Myofibril contractile elements composing 80% of muscle fibre. Consists of thick filaments
(myosin) and thin filaments (actin)
Sarcomeres the functional units of muscle, the area between two Z lines
o Z line connects thin filaments of adjacent sarcomeres
o A band dark band thick filaments as well as portions of overlapping thin filament
o I band light band thin filaments which dont overlap
o M line proteins holding thick filaments together vertically
o H Zone light area in A band where thin filaments dont reach
Thick filaments several hundred myosin molecules
o Myosin two identical golf club subunits. Heads face outwards from filaments, form
crossbridges
Thin filaments actin, troponin and tropomyosin molecules
o Actin spherical, two long intertwining strands
o Troponin 3 x binding sites, one for Ca, one for myosin, one for tropomyosin
o Tropomyosin lie end-to-end along actin spiral, covering myosin binding site in relaxed
muscle
Innervated by cholinergic fibres, has nicotinic cholinoceptors

Smooth Muscle

Myocytes have a fusiform shape, 30 to 200um long, tapering to a point at each end
One nucleus, in the middle of each cell
Thin and thick filaments are not aligned no visible striations or sarcomeres
Typically arranged in sheets, and one SM cell does not extend the length of the muscle like in
skeletal
Instead of Z lines, SM has dense bodies protein rich structures which attach thin filaments to
each other and to intermediate filaments, providing anchors from which the thin filaments can
exert force
Do not contain troponin

Smooth muscle is innervated by autonomic nerves and is not subject to voluntary

control.
o E.g. blood vessels are innervated by sympathetic nerves
Smooth muscle may also contain pacemaker cells which spontaneously depolarize and
set off waves of contraction throughout entire layer of muscle i.e. peristalsis in the gut
and intestines

Smooth muscle

The cell surface forms folds or pits called calveolae, which are thought to function in a
similar way to T tubules, and which are associated with tubules of the sarcoplasmic
reticulum. The most common type of smooth muscle is visceral (single unit) muscle,
which is composed of smooth muscle cells tightly bound together with gap junctions
to form a continuous network. Gap junctions connect the cells together electrically so
that an action potential generated in one cell is transmitted to all other cells in the
network. Since any smooth muscle cell can be spontaneously active, a sheet of
visceral muscle is normally partly contracted and has tone. It is found in the walls of
small arteries and veins and lining the hollow viscera.

Smooth muscle is unique in other ways because it is activated by stretch in the

absence of external innervation and can adapt its tone to remain constant in the face
of different amounts of stretch.
Smooth muscle excitation coupling
1. AP arrives at presynaptic terminal
2. Calcium influx
3. ACh vesicles released
4. ACh binds to muscarinic receptor on post synaptic membrane
5. G-protein works to ligand gated Ca channel
6. Ca influx causes Ca to be further released from SR
7. Ca binds to calmodium
8. Ca-calmodium complexes joins with and activates Myosin light chain kinase, a
phosphorylating enzyme
9. Activated kinase enzyme catalyzes transfer of phosphate to myosin heads,
activating the myosin head ATPases
10.
Now activated , the head has the ability to bind repeatedly with the actin
filament and proceeding through the cycle
11.

Deactivated by enzyme myosin phosphatase

2. Describe the neuromuscular junction and the events that lead to the
generation and propagation of an action potential in skeletal muscle.
The neuromuscular junction is made up of a motor neurone and a motor endplate with
a synaptic cleft or junctional gap dividing them. It is critical in the production of
skeletal muscle contraction.

Each motor neurone connects to several skeletal muscle fibres to form a motor unit.
The number of muscle fibres within the motor unit varies enormously, from a few, for
fine motor control (e.g. the muscles of the eye), to several thousand for coarse actions
(e.g. the thigh muscles). There is however only one neuromuscular junction on each
skeletal muscle fibre, any others are eliminated during development.
The motor endplate is a highly specialised region of the sarcolemma of a muscle fibre.
Acetylcholine molecules bind to specific sites on the alpha subunits and when both are
occupied a conformational change occurs, opening the ion channel for just 1 msec.
The channel allows movement of all cations, however it is the movement of sodium
that predominates in terms of both quantity and effect. This causes depolarisation,
the cell becomes less negative compared with the extracellular surroundings. When a
threshold of 50mV is achieved (from a resting potential of 80mV), voltage- gated
sodium channels open, thereby increasing the rate of depolarisation and resulting in
an end plate potential (EPP) of 50-100mV. This in turn triggers the muscle action
potential that results in muscle contraction. By this method the receptor acts as a
powerful amplifier and a switch (acetylcholine receptors are not refractory).

Synapse between a nerve and a muscle cell

Synaptic knob at end of neuron connects to depression on the sarcolemma called motor end
plate
AP propagates down axon to axon terminal, triggering opening of voltage gated Ca channels,
and Ca rushes into neuron
Ca triggers the exocytosis of acetylcholine from vesicles
Ach diffuses across the synapse and binds to nicotinic receptors on the motor end plate
This opens nonspecific cation channels, leading to a large movement of Na into the cell, causing
chances in membrane potential
The result an end-plate potential opens voltage gated Na channels in adjacent membrane
Na entry causes potential to reach threshold, initiating AP which propagates throughout muscle
fibre
Ach is destroyed by acetylcholinesterase on motor end-plate membrane, terminating muscle
cells response.

3. Describe the molecular mechanisms of skeletal and smooth muscle contraction with
focus on the process of excitation contraction coupling.
A skeletal muscle is composed of thousands of elongated muscle fibres running in
parallel. Fibres are multinucleate cells, formed from the fusion of single nucleated
myoblasts.
The sarcoplasmic reticulum contains a high concentration of calcium owing to the
activity of an inwardly directed calcium pump. The release of this calcium is the link
between a muscle action potential and contraction. The sarcolemmal action potential
travels into the centre of a muscle fibre along T tubules. At each triad, the
depolarization activates voltage-sensitive dihydropyridine (DHP)-binding calcium
channels. These activate ryanodine-binding calcium channels on the sarcoplasmic
reticulum membrane. This activation, caused by either a physical link between the
two types of calcium channel or calcium entering via the activated DHP channel,
opens the ryanodine calcium channels and releases calcium from the sarcoplasmic
reticulum (Figure 3). The calcium binds to troponin C, which moves tropomyosin on
actin, exposes the actin binding sites and starts the contraction cycle. Provided the
sarcoplasmic calcium concentration is kept high, by the repeated arrival of action
potentials in the T tubules, the contraction cycle continues. However, as soon as the
action potentials cease, calcium is rapidly sequestered back into the sarcoplasmic
reticulum system, tropomyosin returns to cover the actin binding sites and the muscle
relaxes.
What happens to actin
a.

AP arrives at the synaptic terminal triggers influx of Ca via voltagegated channels

b.

ACh released via exocytosis

c.

ACh bind to the nicotinic receptors on the surface of the sarcolemma at

the motor end plate

d.

Opening of cation channel leads to influx of Na (depolarization)

e.

Ca binds to troponin, displaces tropomyosin, exposing the myosin

binding site on actin

f.

As soon as the AP cease, Ca is rapidly sequestered back into the

sarcoplasmic reticulum, tropomyosin returns to cover the actin binding
sites and the muscle relaxes

What happens to myosin

g.

As soon as myosin binding site is exposed on actin, the myosin head

binds to that

h.

ATP is hydrolysed to ADP and this causes the myosin head to bend
power stroke

i.

Another ATP binds to the myosin and it relaxes back into position

Skeletal Muscle

NMJ does its thing, AP starts in the muscle fibre

AP moves across muscle fibre membrane and then into the cell interior through T tubules. AP in
the T tubules triggers release of Ca from SR into the cytosol.
Ca binds to the troponin on the actin/thin filaments, which causes a change in the shape of
tropomyosin
The tropomyosin physically moves away and exposes the binding sites on actin for myosin
heads to form cross bridges
The binding triggers the cross bridges to bend, pulling the thin filament over the thick filament
towards the centre of the sarcomere. This is the power stroke powered by ATP
Cross bridge detaches after the power stroke if Ca is still present, it can reattach and the cycle
continues
When AP stops, Ca is actively transported back into the SR (requiring more ATP) and binds to
calsequestrin.
Lack of Ca binding to troponin allows tropomyosin to move back to original position, blocking
cross bridge formation
Muscles relax and thin filaments passively slide back to original positions.

Smooth Muscle

Similar to skeletal muscle, Ca ions enter the cytosol from SR

Ca then binds to and activates calmodulin
Ca-calmodulin complex actives MLCK this phosphorylates the myosin heads and activates their
ATPases.
Phosphorylated myosin heads can now form cross bridges with the actin filaments and
contraction occurs
Relaxation occurs when the myosin heads are dephosphorylated by MLCP and intracellular Ca
levels fall.

4. Define resting membrane potential and outline how it is maintained. Also compare
and contrast graded and action potentials and describe how action potentials are
generated and propagated along neurons.
In the normal resting state, the plasma membrane of nerve and muscle cells
generates a transmembrane electrical potential difference the intracellular surface
of the membrane being approximately 7080 millivolts (mV) negative to the
extracellular surface. This is a result of markedly different concentrations of ions
inside and outside the cell, together with different membrane permeabilities to
different ions that permits K+ to flow down their concentration gradient from inside to
outside the cell. Nerve and muscle cells are excitable because they can react to
external stimuli by generating an extremely rapid change in transmembrane electrical
potential difference known as the action potential. This comprises an initial explosive
increase in membrane Na+ permeability that allows these ions to flood down their
concentration gradient into the cell, thereby depolarizing the membrane such that the
potential difference is transiently reversed to a positive value. However, in nerve and
skeletal muscle this lasts for only a millisecond, at which time the membrane potential
is just as rapidly restored to its resting negative value (repolarization). These events
are controlled by the brief opening and closing of voltage-activated sodium and
potassium channels in the membrane. The key features of the action potential are

that it is: (1) an all-or-none event, rather than a graded response; (2) it is selfpropagating, such that the wave of depolarization travels rapidly along the plasma
membrane; and (3) it is transient, such that membrane excitability is quickly restored.
These features of the action potential allow rapid transfer of information along nerve
axons in the nervous system.
An important feature of the action potential is that it is an all-or-none event. For a
given excitable cell, all action potentials are essentially identical with regard to the
magnitude of the membrane depolarization (i.e. an action potential is not a graded
response that varies with the magnitude of the depolarizing stimulus). In contrast, the
initial membrane depolarization that takes the membrane potential towards the
threshold for action potential initiation is a localized, graded response. At the
neuromuscular junction, for example (see pages 282286 of this issue), an action
potential is triggered in the post-synaptic muscle cell by a localized membrane
depolarization caused by release of transmitter (acetylcholine) from the motor
neurone, which activates post-synaptic nicotinic acetylcholine receptors. The nicotinic
receptors are ligand-gated cation channels that open in response to acetylcholine,
allowing sodium ions to enter the post-synaptic cell and to partially depolarize it. The
magnitude of this depolarization is proportional to the amount of neurotransmitter
released (and therefore to the number and frequency of opening of the ligand-gated
channels). At the neuromuscular junction, this localized post-synaptic graded
depolarization is called the end-plate potential (EPP); at synapses between neurones,
it is called the excitatory post-synaptic potential (or EPSP; see pages 282286 of this
issue). If the EPP or EPSP reaches the critical threshold potential, an action potential is
triggered. In specialized sensory neurones, other types of stimuli can shift the
membrane potential to threshold; for example, the modified dendritic terminals of
some sensory neurones (skin touch receptors, vascular baroreceptors, etc.) respond
to mechanical stimuli such as stretching of the plasma membrane. An important
consequence of the all-or-none nature of the action potential is that information
cannot be transferred in the form of variations in action potential magnitude
(amplitude modulated) it is encoded by variations in the frequency of action
potential production, and in the patterns of repetitive neuronal firing (e.g. as bursts
rather than steady repetitive firing).

Graded Potential

Action Potential

Triggered by stimulus, either NT or shifts in

channel permeability

Triggered by depolarization to threshold,

usually from adjacent area

Produced by net movement of Na, K, Cl, Ca

across membrane by various means

Produced by sequential movement of Na in

and K out of cell

Magnitude of potential varies depending on

trigger

All or nothing magnitude of trigger is

determined by frequency not amplitude

Duration varies with trigger

Constant duration

Magnitude diminishes with distance from

initial site

Propagated thru membrane in

undiminishing fashion self-regenerating

No refractory period

Refractory period

Temporal & spatial summation

No summation

Can be depolarizing or hyperpolarizing

Always depolarizing

Occurs in specialized region of membrane

Regions of membrane abundant with

voltage gated Na channels

Depolarization first occurs slowly, until it reaches a threshold potential (-50 - -55mV)
At threshold, voltage gated Na channels open (activation gate opens) and Na ions flood into the
cell, causing a sharp depolarization to about +30mV
At peak of AP, Na channel inactivation gate closes, ending the movement of Na into the cell. At
the same time, voltage gated K channels open, allowing K to flood out of the cell.
K leaving the cell causes repolarization back to resting potential.
On the return to resting potential, the Na channels inactivation gate opens and activation gate
closes, resetting, responsible for refractory period (absolute & relative)
Further outward K movement briefly hyperpolarizes cell before the channel closes and cell
returns to resting potential.
The concentrations which have been disrupted by AP are gradually restored by Na/K ATPase

5. Describe the factors that affect nerve conduction velocity, compare continuous and
saltatory conduction and describe the formation and importance of the myelin sheath.
Myelin is a fatty white substance that surrounds the axon of some nerve cells, forming
an electrically insulating layer. It is essential for the proper functioning of the nervous
system. It is an outgrowth of a type of glial cell. Schwann cells supply the myelin for
the peripheral nervous system, whereas oligodendrocytes, specifically of the
interfascicular type, myelinate the axons of the central nervous system.
It is the speed at which an electrochemical impulse propagates down a neural
pathway. Conduction velocities are affected by a wide array of factors,
including age, sex, and various medical conditions. Ultimately, conduction
velocities are specific to each individual and depend largely on an axon's diameter
and the degree to which that axon is myelinated.
Myelinated axons only allow action potentials to occur at the unmyelinated
nodes of Ranvier that occur between the myelinated internodes. As sodium rushes
into the node it creates an electrical force which pushes on the ions already inside
the axon. This rapid conduction of electrical signal reaches the next node and
creates another action potential, thus refreshing the signal. In this manner,
saltatory conduction allows electrical nerve signals to be propagated long distances at
high rates without any degradation of the signal. Although the action potential
appears to jump along the axon, this phenomenon is actually just the rapid, almost
instantaneous, conduction of the signal inside the myelinated portion of the axon.

6. Define adrenergic and cholinergic fibres, list their different types of receptors and
the importance of drugs that mimic or inhibit their effects.

There are two main types of ACh receptors:

Nicotinic receptors (ligand gated ion channels)
Location

Mechanism of action

Response

Nm

Skeletal muscles
(NMJ)

Excitatory, increases
cation

Skeletal muscle
contraction

Nn

Autonomic ganglia

Catecholamine secretion
Post-ganglionic
excitation

Muscarinic receptors (G-protein coupled receptors)

M1

Location

Mechanism/action

Response

Neuronal

Gq activation of PLC

Neuromodulation of NT

Eventually causing
depolarization and
excitation
M2

Cardiac

Gi inhibition of AC
Causing decrease in
cAMP and hence

Cardiac inhibition
-

Decrease HR
Decrease contractility

M3

Glandular

decrease in [Ca]

Neutral inhibition

Gq

Gastric and salivary secretion

GI smooth muscle contraction
Ocular accommodation
Vasodilation

Muscarinic agonists and antagonists

Agonist

Antagonist

Diarrhoea

Constipation

Urination

Urine retention

Miosis (pupil constriction)

Mydriasis (pupil dilation)

Bronchoconstriction

Bronchodilation

Emesis

Antimetic effects

Lacrimation

Dryness

Salivation
Sweating

Adrenergic receptors (G-protein coupled receptor)

-

2 main types

-receptors
1

General location

Mechanism/actio
n

Effects/response

Smooth muscles
(including blood
vessels)

Gq activation of
PLC increase
[Ca]

Vasoconstriction (increase in BP)

GIT smooth muscle relaxation
Salivary secretion
Glycogenolysis

Parasympathetic
presynaptic
receptors
Platelets

Gi inhibition of
AC decrease [Ca]

Inhibition of NT release (NA, ACh) response

for feedback control of NA release
Inhibition of insulin release
Platelet aggregation

* 2 receptors are also response for the negative feedback of NE release

After NE is released, NE
3. binds to 2 receptor which then prevents further release of NE
4. binds to post-synaptic receptors

-receptors
1

General
location

Mechanism/actio
n

Effects/response

Heart

Gs stimulation of
AC increase in
[Ca] and
stimulation of PKA

+ve inotropic effect (force of contraction)

+ve chronotropic effect (HR)
+ve dromotropic effect (conduction speed of AV
node)

Lungs

Bronchodilation

Smooth
muscles

Vasodilation
Visceral smooth muscle relaxation
Glycogenolysis
Muscle tremors
Decrease in intraocular pressure

Adipose tissue

Lipolysis

(metabolism)
* note: stimulation of the 2 receptor reduces histamine release which is used to treat anaphylactic
reactions

A1 agonist phenylephrine nasal decongestant, constricts nasal vessels

A1 antagonist prazosin - antihypertensive, causes vasodilation
B1 antagonist metoprolol antihypertensive, decreases HR and contractility
B2 agonist salbutamol dilates bronchioles, asthma reliever
Muscarinic antagonist atropine used for bradycardia, organophosphate poisoning
Muscarinic agonist carbachol
Anti-cholinesterase (organophosphates) blocks acetylcholinesterase, leading to build up of Ach
Cholinesterase re-activators pralidoxime/2-PAM reactives acetylcholinesterase by cleaving
phosphate-ester bond

DLEPP
7. Should rural communities be provided with the same level of healthcare service as
city areas? Is the different level of health services provided in rural communities an
ethical issue? Use your understanding of some common ethical frameworks to
describe the ethical aspects of this issue.
Yes. They should be provided with the same level of health care as everywhere else. The ethics of this
issue relate to two parties.

Epistemological
may be too focused on rationality
o vulnerability is an even more basic feature of our human constitution than rationality
o our vulnerability creates a need for morality
Ontological
engaged practices and ways of living
plights not problems
contexts of time and place
sensibilities open and attentive
Principlism (Epistemological)
- vestige in Hippocratic oath
- autonomy
- non-maleficence
- beneficence
- justice
- consider
o veracity, privacy, confidentiality, fidelity
- focus on virtues of
o compassion, discernment, trustworthiness, integrity
- limitations
o shared/overlapping understanding of the cases
o assumes doctor is deciding
o too ready reduction of principles to process
Utilitarianism (Consequentialist) (Epistemological)
- aggregate harms, risks and benefits across all those affected (may include children, future
generations)
- primarily concerned with actions or outcomes rather than individuals intentions or character
- fair distribution of benefits and burdens
- value rests in good or bad consequences
- inability to express different kinds of values (assumes commensurability of value)
Deontology (Epistological)
- Duty
- An act is right or wrong in itself (de-contextualised)
- emphasis respect for personal autonomy overemphasis on this (not accommodating societal
good), cant address children or those with limited or transient capacity (attempts to link capacity to
reason with moral worth)
- maxim must be universalisable (requirement of reason)
- treat others always as ends in themselves never simply as means
Virtue Ethics (Ontological)
- focus on virtuous doctor rather than on rules or consequences
- development of dispositions and moral character
o beneficence, non-maleficence, empathy, care, courage, generosity
- use virtues to respond correctly
o do what the situation demands, for right reasons with right emotion
- role-modelling
- no clear rules about what is to be done
- no clear way how develop or evaluate character and disposition
- multiple interpretations
Phenomenology (Ontological)
- human is primarily a doer or actor
- being and becoming
- seek meaning and significance embodied in the world

Principlism: Ethical framework based on the four main principles of Autonomy,

Beneficence, Non-Maleficence, Justice

Utilitarianism: Ethical theory stating that proper action is the one that
maximizes utility i.e. greatest good for the most people. Concerned with
outcomes, not individuals

Deontology: Ethical theory that judge morality of an action based on adherence

to rules. An act is right or wrong by itself, without consideration of context.

Phenomenology: Past experiences shape individuality moral and ethical

compass and thus shape behaviour

8. If providing a lower level of healthcare service to rural communities is based on

taking a utilitarian approach to resource allocation, what criticisms could be made of
this approach?

Utilitarianism (Consequentialist) (Epistemological)

-

aggregate harms, risks and benefits across all those affected (may include
children, future generations)

primarily concerned with actions or outcomes rather than individuals intentions or

character

fair distribution of benefits and burdens

value rests in good or bad consequences

inability to express different kinds of values (assumes commensurability of value)

9. How will her treatment differ to Felipes (in view of her greater consumption of
watermelon)?
-

Theyre both exposed to organophosphate

Muscarinic receptors have higher affinity for OP than nicotinic receptors

Marcella had so much OP that it saturated the muscarinic receptors and started
affecting the nicotinic receptor

Atropine only works on muscarinic receptors but Marcella needed an antidote for
the nicotinic receptors.