Flashcards in Autonomic Nervous System Deck (95):
What are the 2 divisions of the PNS?
Somatic nervous system
Autonomic nervous system
Where are pre-ganglionic neurons located in the ANS?
Pre-ganglionic neurons in the parasympathetic ANS leave the CNS via which cranial nerves?
III, VII, IX, X
Sacral spinal roots
In the sympathetic nervous system, pre-ganglionic fibres leave the CNS via what?
Thoracic and lumbar spinal roots.
Parasympathetic results in what symptoms?
Dec. Heart rate
Inc. GI tract activity
Glands stimulated to secrete saliva
Sympathetic results in what symptoms?
Inc. heart rate
Dec. GI tract activity
Inc. blood flow to skeletal muscle
Dec. blood flow to skin and visceral organs
Inc. glycogen and lipid breakdown
What is the general mechanism of what happens at the synapse?
Precursor -> into nerve terminal
Enzyme converts precursor -> transmitter
Transmitter -> synaptic vesicles
Nerve ending depolarised from AP
Ca voltage-gated ion channels open
Influx of Ca
Synaptic vesicles fuse with cell membrane
Transmitter -> pre and post synaptic receptors
Pre-synaptic receptors help with hyperpolarisation
No more transmitter release
Other form of transmitter termination is through enzyme degredation.
What receptor types does the parasympathetic nervous system have?
Nicotinic: Nn, Nm
Muscarinic: M1, M2, M3
What receptor types does the sympathetic nervous system have?
Other: a1, a2, b1, b2
What neurotransmitters does the parasymp. nervous system have?
ACh for both Pre and Post ganglionic neurons
What neurotransmitters does the symp. nervous system have?
Post-ganglionic: NA (except sweat glands)
What do mediators do in neuromodulation?
Increase or decrease the efficacy of synaptic transmission without participating directly as the transmitter.
Which is the faster process: neurotransmission or neuromodulation?
Neurotransmission (msec). Neuromodulation is slower (sec - days).
When can neuromodulation occur?
Pre and Post synaptically.
What are two types of pre-synaptic modulation?
Homotropic and heterotropic presynaptic inhibition.
What is homotropic presynaptic inhibition?
The transmitter acts on a presynaptic receptor to inhibit further transmitter release (autoinhibition)
What is heterotropic inhibition?
The transmitter acts on a presynaptic receptor to inhibit the release of a SECOND neurotransmitter.
Histamine inhibits which neurotransmitter to be released?
Nor adrenaline (NA).
What stimulates the release of NA?
What types of post-synaptic modulation occurs?
Chemical mediators influencing receptors to alter excitability or cell firing.
E.g. Neuropeptide Y (NPY) enhances the response of NA acting on blood vessels (vasoconstriction).
What does NANC transmission stand for?
What is NANC transmission?
A neurotransmitter that is neither adrenergic or cholinergic.
Non-peptides: ATP, NO
Peptides: NPY, VIP (vasoactive intestinal peptide)
What is co-transmission?
Where nerve terminals store and release more than one neurotransmitter (e.g. ATP and NA)
What is the significance of co-transmission?
Allows for the excitation of differences in tissue response.
E.g. ATP + ACh = Rapid response
NO + NA = intermediate response
VIP + NPY = slow response
What does ACh release stimulate with no post ganglionic neuron?
Secretion of adrenaline from adrenal medulla
What do presynaptic muscarinic receptors do in terms of a cholinergic synapse?
They inhibit further release of ACh.
What do presynaptic nicotinic receptors do in terms of a cholinergic synapse?
They facilitate ACh release.
How is ACh produced?
Glucose into terminal ->
Choline + AcCoA -- (ChAT) -->
ACh + HSCoA
ACh --> synaptic vesicles.
What converts choline + AcCoA into ACh and HSCoA?
Choline acetyl transferase
What converts ACh back into choline?
What is the rate limiting step of the degradation process of ACh?
ACh ----> choline via acetylcholine esterase
What is the concentration of ACh in:
- Axon terminal
- Synaptic space
Axon terminal: 100mM
Synaptic space: 1mM
Where does Hemicholinium act on in the cholinergic synapse and what is its effect?
It acts on choline reuptake into the pre-synaptic terminal.
Thus, it prevents the synthesis of ACh.
Where does Vesmicol act on in the cholinergic synapse and what is its effect?
It acts on the storage of ACh into synaptic vesicles by preventing this storage into vesicles.
Where does 4-aminopyridine act on in the cholinergic synapse and what is its effect?
It acts on the release of ACh by enhancing the release of it.
Where does Botox act on in the cholinergic synapse and what is its effect?
It acts on the release of ACh by preventing the release of it.
Where does Neostigamine act on in the cholinergic synapse and what is its effect?
It is an indirect agonist that inhibits acetylcholinesterase, thus preventing the breakdown of ACh.
- extends the half life of ACh
- is used for treating myasthenia (autoimmune disease)
What are two drugs that mimic or block the actions of ACh?
Where are muscarinic ACh receptors found?
At target organs
Where are nicotinic ACh receptors found?
At ganglia, motor endplate, adrenal medulla.
Mainly pre-ganglionic neurons.
ACh muscarinic receptors are what type of receptors? How many types are there?
G-protein coupled receptors
There are 5 types: M1, M2, M3, M4, M5
Which ACh muscarinic receptors are coupled with Gq to activate the inositol phosphate pathway?
M1. M3, M5.
Which ACh muscarinic receptors are coupled to Gi to inhibit adenylate cyclase, reducing cAMP levels?
Where can M2 ACh receptor be found?
In the heart.
ACh nicotinic receptors are what type of receptor?
Ligand-gated ion channel (ionotropic receptors) formed from 5 subunits that form the ion channel pore.
Where are the Nm, Nn and ganglionic ACh receptors found?
Nm - muscle (neuromuscular juncton)
Nn - neuronal (found in the brain)
Ganglionic - found in autonomic ganglia
Why are nicotinic cholinergic receptors not useful as drug targets?
There is a widespread distribution. EXCEPT nicotine can be used clinically.
Muscarinic receptors are better targets!
How do cholinergic drugs effect the heart?
Agonists: slow heart rate
Antagonists: Increase heart rate (atropine used for bradycardia)
How do cholinergic drugs effect smooth muscle?
Agonists: Stimulate contraction (M3 receptors) and peristaltic contraction
Antagonists: Promote relaxation (Ipratoprium - asthma)
How do cholinergic drugs effect exocrine glands?
Agonists: Stimulate secretion from sweat, salivary, mucous, lacrimal, gastric, intestinal and pancreatic glands.
Antagonists: Inhibit salivary, lacrimal, bronchial and sweat glands.
- Atropine: anaesthesia (reduces secretions and bronchodilator)
- Pirenzipine: (M1 receptors) inhibit gastric acid production - treats peptic ulcers.
How do cholinergic drugs effect the GI tract?
Agonists: relaxes sphincters
- Bethanechol (assists bladder emptying)
Antagonists: GI tract motility inhibited
- Atropine: treats gastric hypermotility.
How do cholinergic drugs effect the eye?
Agonists: Stimulates contraction of circular muscles of iris and other muscles (M3 receptors)
- Pilocarpine (treats glaucoma)
Antagonists: Dilates pupils
- Tropicamide (short acting dilation of pupils to allow eye exam of retina and lens)
Which is the faster receptor type? Nicotinic or muscarinic?
How do neuromuscular blockers effect nicotinic receptors?
They relax muscle.
Describe an agonist neuromuscular blocker.
It is a depolarising agent.
No new AP can be generated.
Effects cannot be reversed by increasing ACh concentration.
-> Suxamethonium is used as a muscle relaxant for anaesthesia.
Describe a competitive antagonist neuromuscular blocker.
Compete with ACh for binding to nicotinic receptor.
Prevent depolarisation of endplate.
Effects can be reversed by inc. ACh conc.
-> Pancuronium - used in lethal injection
How is NA produced?
Tyrosine (aa from diet) ---(Tyrosine hydroxylase)-->
DOPA ---(DOPA decarboxylase)--->
How is adrenaline produced?
Same as NA except:
NA ---(PNMT)----> Adrenaline
Occurs in the adrenal medulla.
What two things are in a NA vesicle?
NA and ATP.
Where does NA and ATP go once released from the vesicle?
NA -> a or b receptors
ATP -> P2 purinergic receptors
How is NA maintained in the vesicle?
Via the VMAT - vesicular monoamine transporter
What is the ratio of NA:ATP in a vesicle?
Adrenoreceptors have what type of specific system and how are they distributed?
Specific second messenger system and they are widespread.
What does the a1 adrenoreceptor activate?
Phosopholipase C ->
PIP2, IP3, DAG ->
Smooth muscle contraction
What does the a2 adrenoreceptor initiate?
The inhibition of transmitter release (prevents calcium release) and it prevents cAMP activation so smooth muscle contracts.
What do the beta adrenoreceptors initiate?
The activation of adenylate cyclase to utilise ATP to activate cAMP so that:
- B1: Heart muscle contracts
- B2: Smooth muscle relaxes
- B3: Glycogenolysis occurs
Is NA readily degraded by an enzyme in the synapse?
How is NA degraded?
Reuptake via two systems:
- NET (noradrenaline transporter) 75%, thus high affinity
- EMT (extraneuronal transporter) 25%, thus lower affinity. Non-neuronal cells (smooth/cardiac muscle, etc) take up NA.
What enzyme metabolises NA readily in the axon terminal?
MAO (monoamine oxidase).
This will occur if needed when NA is taken back into the terminal via the NET.
What is the major and minor metabolite of NA and how are they excreted?
Major: VMA (urine)
Minor: MHPEG - produced in brain (urine)
What enzymes produce the major and minor metabolites in NA metabolism?
ADH (aldehyde dehydrogenase) --> VMA
AR (aldehyde reductase) --> MHPEG
Is there direct action on adrenoreceptors by agonists and antagonists?
Which drug reduces NA release from the synaptic vesicles?
Which drugs prevents NA from being packaged into synaptic vesicles?
Reserpine. It does by blocking VMAT which would normally maintain the vesicle storage of NA.
MAO inhibitors (prevents metabolism of NA)
What is a non-selective agonist and antagonist that act on the adrenoreceptors?
What are selective agonists and antagonists that act on the adrenoreceptors?
- Phenylphrine (a1)
- clonidine (a2)
- dobutamine (b1)
- salbutamol (b2)
- prazosin (a1)
- atenolol, propranolol (b1)
- butoxamine (b2)
What does adrenaline act on adrenoreceptors and what is it good for?
It is a non-selective agonist of NA and is good for allergic reactions and cardiac arrest.
What does phentolamine act on and what is it good for?
It is a non-selective antagonist of NA and acts on the a1 and a2 receptors.
It has effects on the heart, blocking vasoconstriction -> decrease in BP. This produces a baroreceptor reflex and increase in C.O and H.R.
What is the effect of a1-adrenergic agonists on vascular smooth muscle? Name the drug associated with it.
Stimulates contraction of smooth muscle (except GI tract). Decreases vascular compliance. Reflex bradycardia due to increased BP.
What is the effect of a1-adrenergic antagonists on vascular smooth muscle? Name the drug associated with it.
Causes vasodilation thus, dec. in BP.
Postural hypotenstion, reflex tachycardia (due to dec. BP).
What is the effect of a2-adrenergic agonists on vascular smooth muscle? Name the drug associated with it.
Clonidin (treats hypertension).
Activates presynaptic receptors in CV centre in brain. --> Reduced sympathetic nerve activity and dec. in BP.
What is the effect of a2-adrenergic antagonists on vascular smooth muscle?
Blocks presynaptic a2 receptors so increase in NA.
BUT can also block postsynaptic receptors so they are complex.
What is the effect of B1-adrenergic agonists on the heart? Name the drug associated with it.
Dobutamine ->cardiogenic shock (strong inotropy but little chronotropy) with inc. C.O.
Increase contractility (positive inotropy) and increase heart rate (positive chronotropy).
Increase in C.O and oxygen consumption BUT can lead to ventric. fibrillation.
What is the effect of B1-adrenergic antagonists on the heart? Name the drug associated with it.
Propranolol - B1 and B2
Atenolol - B1 selective
Cardiac dysrhythmias, infarction, hypertenstion.
Depends on degree of sympathetic activity.
What is an unexpected effect of B-blockers?
Reduces BP in patients with hypertension. They do not cause hypotenstion in normotensive patients.
What is the effect of B2-adrenergic agonists on bronchial smooth muscle? Name the drug associated with it.
Salbutamol - bronchodilator or for premature labour
Adrenaline - anaphylactic reaction
Stimulates the relaxation of smooth muscle.
What is the effect of B2-adrenergic antagonists on bronchial smooth muscle?
Would trigger bronchial constriction. No clinical application.
What are the effects of using B-adrenergic receptors as a target for metabolism?
B-adrenergic agonists encourage the conversion of energy stores into available fuels.
B3 agonists are a possible treatment for obesity.
Where does Reserpine come from?
alkaloid from the shrub, Rauwolfia
What does Reserpine do and what are the consequences?
It blocks the transport of NA into vesicles via VMAT.
NA accumulates in cytoplasm -> broken down by MAO -> NA levels in tissue dec -> no neurotransmission.
Apart from blocking NA from going into vesicles, what else does Reserpine deplete?
5HT and dopamine.
Why is Reserpine generally not used?
Because it causes depression.
How does amphetamine effect NA release?
Amphetamine goes into vesicle and NA is shunted out to cytoplasmic space. MAO breaks down NA as well as being pushed out into synapse so release of NA is enhanced.
What are the effects of sympathomimetics?
They are similar to NA but last longer.
loss of appetite