Autonomic Pharmacology Flashcards
1
Q
Diagram detailing the organization of the nervous system.
A
2
Q
What is the function of the autonomic nervous system?
A
- ANS mediates output from CNS to the whole body – with exception of skeletal muscle (somatic nervous system)
- Regulates functions essential to human health that do not require conscious effort (e.g. during sleep) and that are mostly involuntary:
- Contraction / relaxation of vascular / visceral smooth muscle
- Heartbeat, including rate and force
- All exocrine and most endocrine secretions
- Aspects of metabolism (esp. in the liver and skeletal muscle)
- Modulation of the immune system
- Training allows conscious control over some ANS functions (e.g. micturition, defaecation, focusing of lens in the eye, etc.)
3
Q
Subdivisions of the Autonomic Nervous System
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4
Q
Describe the Basic organisation of the Autonomic Nervous System.
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5
Q
Describe the basic organisation of the parasympathetic nervous system.
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6
Q
Describe the structure and effect of sympathetic pre-ganglionic nerve fibers.
A
- Sympathetic pre-ganglionic fibres branch extensively; synapse with many post-ganglionic neurons in multiple ganglia – widespread effect.
7
Q
Describe the structure of parasympathetic pre-ganglionic nerve fibers.
A
- Parasympathetic pre-ganglionic fibers branch less extensively; effects tend to be more localized.
8
Q
In terms of myelination, what’s the difference between pre/post-ganglionic nerve fibres?
A
- Pre-ganglionic fibres (sympathetic & parasympathetic) are myelinated; fast conduction (termed B-fibres)
- Post-ganglionic fibres (sympathetic & parasympathetic) are mostly un-myelinated; slower conduction (termed C-fibres)
9
Q
Diagram of Sympathetic Outflow.
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10
Q
Diagram of Parasympathetic Outflow.
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11
Q
What are the exceptions in terms of the Autonomic Nervous System?
A
12
Q
Describe Chemical Transmission in the sympathetic nervous system.
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13
Q
What are some of the key receptors in the sympathetic nervous system?
A
- Nicotinic acetylcholine receptors: expressed on dendrites and cell body of post-ganglionic neuron (respond to release of ACh)
- Adrenoceptors: expressed on the surface of effector cells (respond to release of NA)
- Two main families of adrenoceptor (α and β): all GPCRs
- Alpha receptors: α1 (α1A, α1B, α1D), α2 (α2A, α2B, α2C)
- Beta receptors: β1, β2, β3
14
Q
Describe the chemical transmission in the parasympathetic nervous system.
A
15
Q
What are the key receptors in the parasympathetic nervous system?
A
- Nicotinic acetylcholine receptors: expressed on dendrites and cell body of post-ganglionic neuron (respond to release of ACh)
- Muscarinic acetylcholine receptors: expressed on the surface of effector cells (respond to release of ACh) – all GPCRs
- M1 receptors: neural
- M2 receptors: cardiac
- M3 receptors: glands & smooth muscle
- M4 receptors: mostly CNS
- M5 receptors: mostly CNS
16
Q
What are some of the other ANS transmitters besides ACh and NA?
A
- ACh and NA are not the only neurotransmitters released from post-ganglionic neurons in ANS
- NANC transmitters (non-adrenergic, non-cholinergic); can be released alone but more commonly as co-transmitter
- Nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) from parasympathetic neurons
- Adenosine triphosphate (ATP) and neuropeptide Y from sympathetic neurons
Note: time-dependence of effects (peep diagram)
17
Q
Graph depicting an example of co-transmission.
A
18
Q
Diagram depicting Pre-synaptic modulation.
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19
Q
What are some of the activities of the ANS?
A
20
Q
Give some drug effects on the ANS
A
- Regulation of heart rate & contractility – beta-agonists (e.g. dobutamine)
- Regulation of blood pressure – beta-blockers (e.g. atenolol)
- Bronchodilation – beta agonists (e.g. salbutamol)
- Anti-spasmodic – muscarinic antagonists (e.g. dicycloverine)
- Dilation of the pupil – muscarinic antagonists (e.g. atropine)
21
Q
What are the variations of alpha 1 receptors that you can get?
A
The alpha1 receptors come in three varieties (or subtypes) alpha 1A, alpha1B & Alpha1D. There is no Alpha1C – a long story for another day.
22
Q
How do the alpha 1 receptors within a blood vessel dictate the vascular tone of the vessel?
A
A blood vessel has smooth muscle cells within its wall, and these contract and relaxes in order to cause vasoconstriction or vasodilation respectively. The individual smooth muscle cells have alpha1-adrenoceptors and these can be acted upon by an alpha1-agonist (stimulant) drug or hormone such as adrenaline to cause contraction. However, if the cell had beta2-adrenoceptors also then adrenaline could activate that receptor to cause relaxation of the muscle cell.
Therefore. Vascular Tone is a function of the balance between vasoconstriction signals and vasodilation signals and that is determined by the receptor distribution on each and every vascular smooth muscle cell.
23
Q
How are we able to visualise receptors?
A
In order to see receptors, we can use a laser scanning (or fluorescence) microscope and fluorescent drugs. Here we see a fluoresce nt form of prazosin (an alpha1-adrenoceptor antagonist). Here is the fluorescent part of the molecule and here is the binding part that will stick to the receptor with high affinity. If we shine the light of a specific wavelength on the drug it will fluoresce and we can see the location of the receptors to which it is bound.
24
Q
Table of the affinities of adrenaline at the 9 different adrenoceptor subtypes. And what does this tell you about a cell which has alpha1D and beta-2-adrenoceptors in the presence of adrenaline?
A
They are arranged with the highest affinity receptor at the top. The table shows 10 entries but that is because the rodent (Rn) and Human (Hs) alpha1D-adrenoceptors are both shown. We can see that the Beta-2 adrenoceptors have the lowest affinity for adrenaline and alpha1D- has the highest. Therefore, in a cell that has both alpha1D and beta2-adrenoceptors a low concentration of adrenaline would activate only alpha1D receptors to cause contraction but a high concentration of adrenaline activates both contraction and relaxation simultaneously and so the degree of vascular contraction would depend on the drug concentration, receptor affinity, AND receptor distribution in each and every cell.
25
If we apply a fluorescent drug, in this case, the fluorescent prazosin, to a group of cells that express alpha1-adrenoceptors at their cell surface, what would we see?
If we apply a fluorescent drug, in this case, the fluorescent prazosin, to a group of cells that express alpha1-adrenoceptors at their cell surface then we can see where the receptor are. However, what we see is that the binding is both diffuse and clustered. Furthermore, it is very clear that small clusters of receptors inside intracellular vesicles are extremely mobile. So now we need to think of receptors as moving targets within the cells.
26
Describe what the cross-section of a blood vessel would contain.
The cross-section of a vessel would have the adventitia, media and lumen.
27
Where would we find adipose tissue in the context of the vascular wall?
Perivascular adipose tissue surrounds blood vessels. Perivascular adipose tissue and the adventitial layer of blood vessels are in direct contact with each other. Healthy perivascular adipose tissue secretes adipokines and regulates vascular function.
28
Where would we find sympathetic nerves in the context of the vascular wall?
We have the sympathetic nerves, we have smooth muscle cells in the tunica media, at the adventitial medial border.
29
What receptors are present in endothelial cells?
endothelial cells have alpha1-adrenoceptors (probably alpha1B and 1D – maybe 1A).
30
What receptors are present in the nerves within blood vessels?
We can say that on our never, the varicosities, from where the neurotransmitter is released, has beta-adrenoceptors. We also know that nerves have alpha2-receptors.
31
What can we conclude about the distribution of alpha-1 and beta-adrenoceptors?
Some cells (even those of the same tissue type) can express different receptors. Some only have beta and some only have alpha.
32
Give a summary of the receptors found in each cell type in a blood vessel.
So in summary. The endothelial cells have alpha1 receptors, beta-receptors, and alpha2-receptors. The smooth muscle cells have alpha1-receptors and beta-receptors but the distribution of those receptors is quite complex. The nerve has beta receptors and alpha2-receptors. The adventitia has alpha1-receptors (possibly beta and alpha2-) and the perivascular fat also has beta3-receptors.
33
What would happen if adrenaline was introduced into the blood vessel?
The response to adrenaline and the fact that it can stimulate both alpha- and beta-adrenoceptors. So what would happen if adrenaline was introduced to this blood vessel. You can see that it could stimulate all of the cells in the vascular wall with different efficiency depending on the affinity of the different receptors and the number of receptors expressed within each cell.
34
What do the different distributions of subtypes within a tissue allow for?
Finally, we have looked at how receptor subtypes are distributed on individual cells in a tissue and we can see how that might offer a degree of fine control. For a given concentration of adrenaline, the overall response of a tissue will be dependent on the degree of contraction and relaxation of smooth muscle cells, compounds released from the endothelium, neurotransmitters released from nerves, factors released from fat and adventitial cells. The activation of each of these cells is determined buy the receptor distribution. Thus providing fine control.
35
How can a beta-receptor illicit different responses in different cells?
Lets now think about how an individual receptor subtype can elicit different responses from different cell types. Lets consider 5 different systems and the beat adrenoceptor. All three beta-adrenoceptors have the same primary transduction mechanism. Thay all stimulate adenyl cyclase (AC) which increases cAMP formation which activates Protein Kinase A (PKA). Which in turn leads to phosphorylation of various targets. The response of that cell will depend on what other molecules/channels/proteins are available for phosphorylation.
A beta-receptor on a nerve varicosity is referred to as a pre-junctional beta-adrenoceptor. Stimulation of this beta receptor by adrenaline or noradrenaline will cause an increase in the release of the neurotransmitter (NA) output. A beta-receptor on a smooth muscle cell caises relaxation. An endothelial beta receptor stimulates Nitric oxide relasee. A beta-recptor on a cardiac myocyte will enhance contraction. A beta receptor on the juxtaglomerular cell will cause release of renin.
So a beta-receptor on different cell types will cause different responses depending on the PKA targets that are available. Or depending on the intracellular mechanisms that are regulated by intracellular levels of cAMP.
36
Image detailing Dual Innervation of the Body.
37
Image detailing the Autonomic Nervous System.
38
What's the main neurotransmitter in the autonomic ganglia?
Acetylcholine is the main neurotransmitter in the autonomic ganglia.
39
What is the acetylcholine from the pre-ganglionic nerve fibre released onto?
Released onto a nicotinic receptor on the post ganglionic nerve fibre.
40
What are the differences in the fibers in the autonomic nervous system?
_Sympathetic_
* The preganglionic fibres are relatively short.
* The postganglionic fibers release noradrenaline at the neuromuscular junction.
_Parasympathetic_
* The preganglionic fibers are relatively long.
* The postganglionic fibers release Acetylcholine at the neuromuscular junction.
41
What's different about the somatic nerves and how they bind ACh to nicotinic receptors?
The nicotinic receptor is of a different subtype. What this implicates is that there could be a drug that binds to all the nicotinic receptors in the autonomic ganglia but doesn't bind to the nicotinic receptors in, for example, skeletal muscle.
42
What drug blocks all the nicotinic receptors in the autonomic ganglia but not the nicotinic receptors in the skeletal muscle cells?
Hexamethonium is the drug that blocks all the nicotinic receptors in the autonomic nervous system, but not the nicotinic receptors in the skeletal muscles.
43
What drug blocks the nicotinic receptors in the skeletal muscles but not the nicotinic receptors in the ANS?
Curare blocks the nicotinic receptors in the skeletal muscle, however, it does not block the nicotinic receptors in the ANS.
44
What would happen to a person if they had all of the nicotinic receptors in the ANS blocked
This would blunt the autonomic nervous function and what you will obsereve is that when they lie down, the blood pressure is relatively normal. When they stand up, heart rate increases and blood pressure falls. Normally, that may happen, but the blood vessels would constrict to maintain the blood pressure. This would not happen with the reduction of autonomic nervous function in blood vessels. Therefore, the blood pressure stays low. - Orthostatic hypotension.
45
What is the core to Orthostatic Hypotension?
The cure to Orthostatic hypotension is to remove all of the patient's blood plasma and all of the associated antibodies which block the nicotinic receptors in the ANS. Following this, replace the blood plasma. However, the blood plasma will eventually build up again.
46
How many neurones can be found within the enteric nervous system?
There are 500 million neurones within the enteric nervous system.
47
What is a plexus?
A plexus is a bundle of intersecting nerves, blood vessels, or lymphatic vessels in the human body. These bundles typically originate from the same anatomical area and serve specific areas of the body. Bundles of nerves that form a plexus communicate information to your brain about pain, temperature, and pressure.
48
Diagram of Enteric Nervous System
49
What is Rauwolfia?
Rauwolfia alkaloids belong to the general class of medicines called antihypertensives. They are used to treat high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly.
They also act as an aphrodisiac. ;)
50
How do we get vasoconstriction and vasodilation?
The walls of a BV are lined with smooth muscle cells. The sympathetic nervous system would release noradrenaline onto the alpha 1 receptors to cause contraction of the smooth muscle cells causing vasoconstriction.
Noradrenaline can also activate the parasympathetic nervous system. The parasympathetic nervous system would then release ACh. The ACh can activate muscarinic receptors in the smooth muscle to also cause contraction; however, its main function is to activate the endothelial cells.
The muscarinic receptors on the endothelial cells cause them to release nitric oxide; a potent vasodilator. The NO increases levels of cyclic GMP in the smooth muscle cell and lead to vasodilation.
51
Sites of action for drugs
The nerve releases noradrenaline and acts at post a1 and post a2 adrenoceptors. Noradrenaline can also be reuptaken into the nerve via U1. Cocaine blocks this action. If cocaine is present, the conc. of noradrenaline increases.
Noradrenaline can also act on the prejunctional alpha 2 receptors to inhibit further release. A drug like Rauwolfia prevents this and also causes an increase in noradrenaline.
Teratrodoxin precents the nerve impulse from even coming down the neve
52
What is an andrenergic receptor?
This is a receptor in which adrenaline and noradrenaline act at.
53
Simplified diagram of ANS
Norepinephrine = Noradrenaline btw
54
What is a nerve varicosity?
Varicosities can be thought of as a series of small beads strung on a string, each axon has a relatively high number of these endings. Unlike common axonal endings, the varicosities have no postsynaptic terminal assigned.
55
Diagram of Nerve Varicosity and its mechanism of action in the release of Noradrenaline.
Diagram of varicosity which releases NAd.
* NAd releases onto the alpha 1 receptors on smooth muscle to activate vasoconstriction.
* NAd also acts on beta 2 receptors to cause vasodilation of the smooth muscle cells.
* NAd also acts on alpha 2 receptors to cause vasoconstriction.
* NAd can also act on the prejunctional alpha 2 receptor to inhibit further release of NAd from the variscosity.
56
How did we find out that there are post junctional and prejunctional receptors? (It's a long flashcard btw)
_In the 1930s, Z.M. Bacq demonstrated the "Yohimbine Paradox"._
In the experiment, Yohimbine blocks adrenaline but not nerve stimulation.
So, you can stimulate the nerve and get a response. You could also add adrenaline and get a response. So when we stimulate the nerve before we add yohimbine there is a nerve response, when the yohimbin is added after the stimulation, there is very little difference in the efficacy.
When adrenaline is added after yohimbine, there is a reduced efficacy as a result of yohimbine antagonising the response of adrenaline.
What this led to was the thought provoking question at the time...
"Maybe Adrenaline is not the neurotransmitter, or nerve stimulation and adrenaline must be acting at different processes."
_In 1948, Alqhuist_
He used three different drugs: noradrenaline, adrenaline and isoprenaline. Alquist found that in certain tissues noradrenaline was always the most potent agonist in most tissues, followed by adrenaline and isoprenaline respectively.
In another group of tissues the most potent agonists were Isoprenaline, Adrenaline and Noradrenaline (literallly the other way round).
This was the beginning of the idea that the same drug could ilicit a differnet response in different tissues. (Alquist called these alpha and beta responses respectively). - Not to be confused with alpha and beta receptors.
_In 1957, Brown and Gillepsie_
Phenoxybenxamine caused a huge increase in noradrenaline after sympathetic nerve stimulation in the cat spleen.
Gillepsie found that as you stimulated the nerves going into the cat spleen the concentration of transmitter released could be measured.
If you gave the cat phenoxybenzamine, the transmitter output would increase, even at the lowest frequencies. it increased the transmitter so much that even at higher frequencies, there was very little difference.
They concluded that phenoxybenzamine was blocking the ability of the receptor use the neurotransmitter - a reasonable concludion in 1957. In those days, they thought the receptor used the neurotransmitter to effect a response instead of the receptor inititating a response itself.
57
Describe the development of the prejunctional receptor hypothesis.
_There were 3 stages_
1. In 1957, scientists had realized that the input of phenoxybenzamine = PBZ increased the transmitter output of a stimulated nerve cell. The assumption here was that if the receptor was blocked, it cannot use the transmitter and the transmitter would "dribble away".
2. In the 1960s-1970s, scientists had discovered that there was in fact, an uptake mechanism that allowed noradrenaline to be uptaken back into the nerve. PBZ was believed to have blocked this uptake. There was also an uptake mechanism on the target cell itself, which PBZ also blocked, causing the transmitter to dribble away. The uptake sites were labelled Uptake 1 and Uptake 2 respectively. Cocaine and corticosterone also blocked uptake 1 and uptake 2. However, PBZ was even more potent than the combination of these two drugs in antagonising the NT.
3. In 1974, it was proposed that there was another prejunctional receptor that was blocked by PBZ. This suggestion came about as the combination of Yohimbine, cocaine and corticosterone produced NT concentrations similar to that of PBZ. It is possible that this 'new' receptor is the one that yohimbine binds to. It was likely an alpha-receptor and was labelled alpha 2 receptor. This explained the yohimbine paradox.
58
How did the development of the prejunctional receptor hypothesis explain the Yohimbine paradox?
The Yohimbine paradox came about because, yohimbine blocks responses to adrenaline. But didn't block the responses to nerve stimulation. (We now know that nerve stimulation results in the release of noradrenaline instead of adrenaline.) The reason Yohimbine didn't appear to block the response to nerve stimulation is that it was doing two things:
1. Was blocking postjunctional alpha 2 receptors on the membrane of the muscle.
2. But it was also blocking prejunctional inhibition. So more transmitter was coming out.
Also, it was noradrenaline which was the neurotransmitter, not adrenaline.
59
What was discovered about beta receptors in 1967?
It was discovered that drugs that stimulated beta receptors in different tissues had responses.
60
How were the beta receptors differentiated in the 70s?
They were differentiated by the type of response the tissue gave. Beta 1 receptors were more excitatory, while the Beta 2 receptor induced relaxation.
61
How was it established that alpha 2 adrenoceptors can be found postjunctionally?
It was found that an alpha 1 adrenoceptor agonist (phenylephrine) increased blood pressure.
When xylazine was added in the presence of prazosin (an alpha 1 adrenoceptor antagonist), there was also an increase in blood pressure.
Therefore, there are alpha 2 adrenoceptors postjunctionally.
62
Diagram of alpha and beta receptors
63
Diagram of synthesis, storage, release and inactivation of NA.
64
In reference to the synthesis, storage, release, and inactivation of NA, why is Ca2+ required?
Ca2+ is required for the mechanism of release. The rise in calcium allows for the release of the transmitter. But in the sympathetic system, the rise of calcium only increases the probability of the release of the transmitter.
65
In reference to the release of NA, how does reserpine block this mechanism?
Reserpine gets uptaken through the U1 mechanism and destroys the vesicular monoamine transporter (VMAT). This, in turn, stops dopamine from reaching the vesicle to be converted into Noradrenaline.
66
In reference to the release of NA, how does 6-oxyhydroxydopamine (6-OHDA) block this mechanism?
6-OHDA is very aggressive and effectively destroys the adrenergic nerve entirely. It also uses the U1 mechanism to enter the nerve.
67
What can the use of reserpine and 6-OHDA show you about the specifity of U1/
U1 is not specific to the uptake of noradrenaline and is actually quite non-discriminate.
68
How did 6-OHDA's effect on adrenergic nerve transmission lead to the discovery that ATP was also a neurotransmitter?
Despite the fact that 6\_OHDA would essentially destroy the adrenergic nerve, there was still seen to be a biological response. This led to the discovery that ATP was also a neurotransmitter and was released from anon-andrenergic nerves.
69
Describe the mechanism of Guanethidine.
Guanethidine enters varicosity via the U1 uptake mechanism. Once it enters, it displaces noradrenaline within the vesicle and causes guanethidine to be released through exocytosis instead of noradrenaline when the nerve is stimulated. This causes noradrenaline to exit the viscosity. Every time the Noradrenaline gets displaced, a muscle contraction occurs.
However, if the stimulation of the nerve is maintained, you get an inhibitory response from the smooth muscle. This is because the experiment that Guanethidine was used in was conducted in the presence of hexamedonium (C6) which blocks the autonomic ganglia.
Therefore these responses must be post ganglionic because the autonomic ganglia is blocked. The inhibitory response is post ganglionic.
70
Give three examples of sympathomimetics.
Tyramine, Amphetamine, Ephedrine
71
How do sympathomimetics interact with nerve varicosity?
They enter varicosity via the uptake mechanism (U1). They are then taken up into the vesicle by the VMAT. When they do this, they displace and expel Noradrenaline. This mechanism eventually depletes the varicosity of noradrenaline.
72
How are Tyramine and other sympathomimetics useful in determining whether a sample of tissue has adrenergic nerves or not?
Sympathomimetics indirectly leads to the expulsion of noradrenaline into the synapse. If the postjunctional tissue/cell alpha receptors have an alpha-blocker in it. The observed response will be blocked. Thus indicating that there is an adrenergic innervation around that tissue.
73
How are cocaine and rauwolscine useful in a pharmacological capacity?
The uptake of noradrenaline via U1 is an extremely effective mechanism. So much of the NA is reuptake. If the U1 is blocked by cocaine, for example, there would be an artificially high concentration of NA in the synapse. Leads to increased heart rate and blood pressure.
NA also binds to prejunctional alpha-2-receptors, to inhibit its own release. rauwolscine blocks this so the negative feedback loop doesn't get initiated and even more NA gets released.
74
What drugs can inhibit the synthesis pathway of noradrenaline?
75
Transmitter and receptors of the ANS.
76
Biosynthesis and release of ACh
Btw the enzyme at step 1 (the one which takes choline and Acetyle CoA and converts them into Acetylcholine and CoA is called **Cholineacetyltransferase**
77
Diagram of ANS but in more detail.
78
Muscarinic Receptor Subtypes.
79
Why are the M1, M3, and M5 muscarinic receptors classed as excitatory?
The M1, M3, and M5 muscarinic receptors are classed as excitatory G protein-coupled muscarinic receptors. Primarily because they are coupled to the Gq type G-protein. To describe the mechanism, when the ligand binds to the M1, M3, and M5 complex, in this case, ACh, this causes a conformational change in the complex and causes the phosphorylation of GDP (which is associated with the alpha subunit) into GTP. This results in the dissociation of the G protein from the M1, M3, and M5 receptors, specifically the dissociation of the alpha subunit from the beta and gamma subunits. The alpha subunit will then go on to activate its downstream pathway. This downstream pathway is positively coupled to phospholipase C. Activating PLC, will then lead to the release of AB3 which stimulates Ca2+ release.
80
Why are the M2 and M4 classed as inhibitory receptors?
The M2 and the M4 receptor proteins are bound to a Gi type G protein and they tend to be inhibitory. ACh will bind to the M2 and M4 receptor and result in the dissociation of the alpha subunit of the G protein. The G protein here is negatively coupled with adenyl cyclase. Adenyl cyclase activates cyclic AMP. Because the G protein is negatively coupled with the AC, the activation of cAMP is downregulated.
81
Diagram of agonist binding to M1 and M3 receptors.
82
Diagram of agonist binding to M2 and M4 receptors
83
Muscarinic receptor agonists
84
What are the main actions of ACh release from the heart?
85
What's the mechanism of M2 activation in the heart?
86
Actions of ACh on blood vessels.
87
Actions of parasympathetic stimulation on bronchial constriction.
88
Actions of parasympathetic stimulation of glands.
89
Parasympathetic action on GI tract.
90
Diagram detailing the mechanism of action of a secretory cell and a smooth muscle cell.
91
Parasympathetic action on the eye.
92
Where are the autonomic ganglia located?
The autonomic ganglia are located within the head, neck, and abdomen, as well as in chains along either side of the spinal cord.
93
Diagram of Nicotinic ACh receptors.
They are very different from that of the muscarinic receptor.
In diagram b) you can see that they are made up of 5 subunits which are arranged symmetrically around a central pore. Diagram a) demonstrates that each subunit is comprised of 4 transmembrane domains (M1-M4). Both the N and C terminuses are located extracellularly.
The Nicotinic acetylcholine receptors have similarities to GABAa and glycine receptors and certain types of serotonin receptors too.
94
What are the 2 subtypes of nicotinic ACh receptors?
In vertebrates, they are classed into two subtypes based on their primary sites of expression.
1. There are muscle-type nicotinic receptors.
2. There are neuronal-type nicotinic receptors.
95
What is the function of the muscle type Nicotinic ACh receptor?
96
In terms of structure, what differs an embryonic muscular nicotinic ACh receptor from an adult muscular nicotinic ACh receptor?
Depending on whether the receptor is in the embryonic form or the adult form they can be slightly different. If the receptor is in the embryonic form, they are composed of alpha 1, beta 1, gamma, and delta subunits in a 2:1:1:1 ratio. There are always at least 2 alpha subunits in a nicotinic acetylcholine receptor. In the adult receptor the composed of alpha 1, beta 1, delta, and epsilon in a 2:1:1:1 ratio.
97
Table of Nicotinic Receptor Subtypes
98
What's different about the binding of ACh to nicotinic receptors found on the NMJ and nicotinic receptors found on neurones?
In muscle-type nicotinic receptors, the ACh binding site is found on the alpha subunit and either the alpha-delta interface.
Two ACh molecules are required to bind the two different alpha subunits.
In the neuronal nicotinic receptor, the ACh would bind to the alpha-beta subunit interface
99
Ganglion Activating Drugs
100
What are the effects of peripheral ganglia stimulation (i.e. smoking)?
101
Diagram of Ganglion blocking drugs and association of carbon chain length and binding specifity.
102
What are some other Ganglion Blockers?
103
Give some Non-Receptor compounds
104
Diagram of NMJ
105
What is a motor unit?
Motor units, defined as a motoneuron and all of its associated muscle fibers, are the basic functional units of skeletal muscle. Their activity represents the final output of the central nervous system, and their role in motor control has been widely studied.
106
What is the motor endplate?
Neuromuscular junctions, also called motor endplates, are specialized chemical synapses formed at the sites where the terminal branches of the axon of a motor neuron contact a target muscle cell. ... The muscle cell plasma membrane underlying the synaptic cleft forms the postsynaptic membrane.
107
How does an action potential reach the motor unit from the NMJ?
ACh is released from the end terminal of the axon of the nerve into the endplate of the musculature. In the endplate, there are plenty of nicotinic ACh receptors. The ACh receptors open allowing an influx of sodium into the cell. If the AP is enough to depolarise the cell, the membrane they are permeated in (postsynaptic membrane) this excitement will travel along the membrane to the T-Tubule which carries the wave of depolarization down to the sarcolemma causing calcium to be expelled from the sarcolemma and then the calcium dependant contraction occurs.
108
Diagram of ACh synthesis, release and uptake at the NMJ
109
What is an endplate potential?
Endplate potentials (EPPs) are the voltages that cause the depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance.
110
What's the difference between the innervation of skeletal muscle and the innervation of smooth muscle?
In skeletal muscle, only the motor endplate has nicotinic ACh receptors. It's the only part of the skeletal muscle that responds to the ACh. This is known as the focal innervation of skeletal muscle. In smooth muscle, this is not the case. You would observe the transmitter being released from the nerve terminal and it would "ooze" onto the smooth muscle's ACh receptors and cause contraction like that.
111
What is a miniature endplate potential? And how do they aggregate to form an endplate potential?
Miniature endplate potentials (MEPPs) are the much smaller depolarizations that occur when a single packet of ACh is spontaneously released. They surmise to form an EPP.
112
Diagram of Endplate potential and Mini endplate potential in a voltage graph.
113
Endplate potential and threshold in a diagram
114
Diagram of Electrical Potentials at the Motor End Plate.
115
What are 3 ways to block neuromuscular trasnmission?
1. By inhibiting ACh synthesis
2. By inhibiting ACh release
3. By intefering with postsynaptic action of ACh.
116
What is a Non-depolarising blocker vs. a Depolarising blocker
117
Some sites of drug action in the skeletal NMJ and nerve
118
What are some drugs that can inhibit the synthesis of ACh?
The two drugs mentioned do stop the uptake, however, it takes a long time for them to deplete the nerve.
119
What drugs inhibit the release of ACh from the nerve terminal/
1. Local anaesthetics
2. Inhibitors of calcium entry including magnesium and antibiotics
3. Neurotoxins
* Botulinum Toxin
* B-Bungaratoxin
120
Diagram of Botulinum Toxin Mechanism of Action
121
List some Nicotinic Receptor Agonists and Antagonists.
**_Agonists:_**
Nicotine, Lobeline, Epibatidine, Varenicline, Suxemethonium, Decamethonium.
**_Antagonists:_**
Hexamethonium, Trimetaphan, Tubocurarune,
Pancuronium, Atracurium, Vacuronium
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What are Non-Depolarising Blockers?
Non-Depolarising Blockers are straightforward competitive antagonists at the skeletal neuromuscular junction. (e.g. tubocurarine, atracurium). They essentially block ACh from binding to these receptors. This decreases the motor end plate potential (EPP), thus decreasing depolarisations of the motor end plate region. Once this decreases significantly, there is no activation of the muscle action potential.
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Action of Non-Depolarising blockers on EPP.
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What are Depolarising Blockers? And how do they work?
These are agonists at the Nicotinic Sk.NMJ receptors (suxemethonium, succinylcholine decamethonium). They are not metabolised by Acetylcholine esterase. They produce a persistent depolarisation of the motor end plate. This gives rise to a prolonged EPP.
This prolonged, abnormally large EPP produces a prolonged depolarisation of the muscle membrane surrounding the motor end plate. This keeps the membrane potential above the threshold for the resetting of the sodium channels. Sodium channels remain refractory and so no more muscle action potentials can be generated.
There is a leak of potassium ions out of the cell due to the persistent depolarisation. This causes loss of potassium ions, which impacts the electrochemical gradient.
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What is the "leak of potassium ions out of the cell due to the persistent depolarisation" caused by a depolarising blocker known as?
This is called accommodation.
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How will the AP system work again after being in the presence of a depolarising blocker?
The system will work again once the muscle membrane is allowed to repolarise i.e. come below the threshold for sodium channels.
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What are the uses of Neuromuscular Blocking drugs?
* Used to cause paralysis during anaesthesia.
* Depolarising blockers used for short term actions such as induction of anaesthesia and intubation of the airway. They are metabolised by plasma cholinesterases.
* Non-depolarising blockers used to maintain neuromuscular block throughout an operation. They are reversible by an anticholinesterase drug which increases the quantity and duration of action of ACh.
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Describe the two different types of Cholinesterases
1. Acetylcholinesterase. (Ach.E)
* true cholinesterase
* soluble in C.S.F.
* bound to basement membrane in the synaptic cleft -
* function is to hydrolyse Ach. specific for Ach.
2. Butyrylcholinesterase (Bch.E)
* pseudocholinesterase
* soluble in plasma
* widespread distribution
• broader spectrum of substrates
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Give an example of a short acting Anticholinesterase drug.
Edrophonium
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Give examples of medium acting anticholinesterase drugs (medium as in they act between a long and short time)
Neostigmine, Physostigmine, Pyridostigmine
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Give examples of long acting anticholinesterase drugs.
Dyflos, Ecothiopate, Parathion.
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Diagram of the Enzymic Pathway of reversible anticholinesterases and irreversible anticholinesterases.
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What are some of the effects of Anticholinesterases, involving the ANS, on the body?
* Increased secretion from salivary, lacrimal, bronchial and G.I. glands.
* Increased peristalsis.
* Bronchoconstriction
* Bradycardia
* Hypotension
* Pupillary constriction
* Fixation of accommodation for near vision
* Decreased Intraocular Pressure
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What are some of the effects of Anticholinesterase on the NMJ?
Increased duration of Ach action and can reverse the effects of competitive antagonists at nicotinic receptors. (the non-depolarising blockers.)
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What are the effects of anticholinesterases on the CNS?
* Initial excitation which gives convulsions
* Followed by depression which leads to
* Unconsciousness and respiratory failure.
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