Autonomic Nervous System Flashcards
Autonomic nervous system function
control of involuntary activities, i.e. CV responses, respiration, endocrine secretion (smooth muscle around endocrine glands), GI motility and secretions, reproductive and urogenital control
Parasympathetic nervous system (PNS)
long pre-ganglionic fibres: ACh–> nicotinic receptors
short post-ganglionic fibres: ACh–>muscarinic receptors
Sympathetic nervous system (SNS)
Short pre-ganglionic fibres: ACh–>nicotinic receptors
Long post-ganglionic fibers:
- Noradrenaline (NA)–>alpha and beta adrenergic receptors
- ACh–> muscarinic receptors
Autonomic ganglia of adrenal gland; adrenaline–>alpha and beta adrenoceptors
SNS ganglia/cell bodies/ NTS
short pre- and long post-synaptic fibres
Cell bodies for pre-synaptic fibres are found at the inter-mediolateral columns of the spinal cord from the 1st thoracic to the 3rd lumbar segment (T1-L3)
Axons synapse at 1) paired paravertebral ganglia 2)pre-vertebral ganglion (near aortic bifurcation) 3) terminal (within end organ itself).
ACh is pre-synaptic NT
NA is post-synaptic NT
Adrenal medulla chromaffin cells (modified neurons) release adrenaline into the peripheral nervous system
Innervations are much more diffuse, with many more ramifications than the PNS.
Functions of SNS
If you treat with an SNS agonist (i.e. synthetic analog of NA)
- mydriasis (pupil dilation)
- positive chronotropic effect (increase HR)
- positive inotropic effect (increase force of contraction)
- positive dromotropic effect (increased speed of conduction within the heart)
- vasoconstriction or vasodilation depending on the receptor
- bronchodilation
- decreased gastric motility
- increased sphincter tone
- glycogenolysis
- gluconeogenesis
- bladder wall distension (Beta receptors)/bladder neck constriction (alpha receptors)
PNS ganglia/cell bodies/ NTs
Cranial outflow: oculomotor, facial, glossopharyngeal and vagus
Sacral outflow: nervi erigentes
Axons of the long pre-synaptic fibres synapse in or near the organ innervated
PNS has a more localized effect than SNS
ACh is pre and post synaptic NT
ANS has tone, can up/down regulate function within a system
Functions of PNS
CV system: decrease rate, conduction velocity, force of contraction
vasodilation: INDIRECT physiological effects, as no innervation. ACh induces NO release from vascular endothelial cells, but can’t be stimulated pharmacologically.
Gi system: increased motility, increased secretion
Urinary tract: contraction of detrusor, urethral peristalsis, relaxation of sphincter
Miosis: constriction of pupil
Respiratory: bronchoconstriction (only INNERVATED by PNS) and increased secretion.
Response of lungs to ANS is only driven by PNS- remember SNS affects adrenaline release and adrenaline can have an effect on the lungs. Lungs aren’t bronchodilating in response to SNS nerves, but rather circulating adrenaline release.
Noradrenaline
synthesized in the nerve terminal from tyrosine
stored in vesicles until an AP induces its release
Undergoes reuptake and enzymatic degradation
Has an effect on alpha and beta adrenoceptors
Noradrenaline action with the SNS
Production of NA: tyrosine–>L-DOPA by tyrosine hydroxylase
L-DOPA–> dopamine–>Noradrenaline
NA is exocytosed out of the pre-synaptic neuron and binds to the receptors.
Extracellular uptake of NA is done either presynaptically or by neuronal cells in the vicinity. There’s also a vesicular uptake mechanism from the cytosol into synaptic vesicles.
Uptake 1: presynpatic uptake by NA transporter- cocaine inhibits this uptake
Uptake 2: by non-neuronal cells- phenoxybenzamine inhibits this uptake
Uptake 3: vesicular uptake mechanism into synaptic vesicles- reserpine inhibits this uptake
Metabolites of NA produced by these enzymes: COMT, MAO, PMNT
SNS receptors
NA acts through G-protein coupled receptors (semitransmembrane domains)
Alpha receptors: Alpha 1 and Alpha 2. Alpha 1 receptors broken up into Alpha1a, 1b, 1d
Alpha 3 receptors broken up into Alpha2a, 2b, 2c
Beta receptors broken up into Beta 1, 2, 3, and 4.
No commercially available veterinary drugs that can target B3, B4 or any alpha 1 and 2 subtypes.
Alpha 1 adrenoceptors
Alpha 1a, 1b, 1d subtypes
Couple mainly to Gq
2nd messenger: activation of phospholipase C leading to formation of IP3 and diacylglycerol (DAG)
IP3 induces release of intracellular calcium from SR and DAG activates protein kinase C.
IP3 results in stimulation of tissues carrying alpha 1 receptors
Alpha 1 receptors are widely distributed:
- VSM: vasoconstriction
- Myocardium: positive inotropic effect (increased force of contraction)
- prostatic smooth muscle: contraction
Alpha 2 adrenoceptors
Alpha 2a, 2b, 2c subtypes
Alpha 2 receptors couple to Gi and Go
Inhibit adenylate cyclase and thus decrease cAMP.
Inhibit voltage gated calcium channels, and activate Ca2+ dependent K+ channels–> inhibit activity of any system which predominantly expresses alpha 2 receptors
Functions: located prejunctionally (on synaptic fibres) and inhibit NT release
-CNS: mediate sedation and analgesia- inhibit prejunctionally, decreased activity of CNS (i.e. sedation).
Postjunctionally, in VSM–> vasoconstriction- principle side effects of alpha 2
also present in uterus, gut and platelets
nb: alpha 2a presynaptic subtype: sedative effects without effects on VSM
Beta 1 adrenoceptors
Couple mainly to Gs
Stimulation of adenylate cyclase which increases cAMP.
Increased cAMP increases protein kinase A
Beta 1 found mainly in the heart.
Activation leads to: increased force of contraction, conduction and rate of impulse formation
Beta 2 adrenoceptors
Mediative activity through Gs and Gi
Can stimulate or inhibit cAMP production
Main effects:
- VSM relaxation- inhibitory effect
- bronchodilation- inhibitory effect
- stabilize respiratory mast cells.
Recap of SNS receptors
Alpha 1 (stimulatory)–>increase IP3 and DAG–>increase Ca2+–>vasconstriction of SM except in GIT
Alpha 2 (inhibitory)–>decrease AC–>decrease cAMP–>presynaptic inhibition (lots of alpha 2 in CNS), contratction of VSM
Beta 1 (stimulatory)–>increase AC–>increase cAMP–> increase protein kinase A–> increase Ca2+–> increase force of contraction, conduction and increase HR
Beta 2–> increase or decrease cAMP–> inhibitory: relaxation of smooth muscle (e.g. bronchodilation and vasodilation in skeletal muscle).
Cholinergic receptors- Nicotinic
Ligand-gated ion channel–> Nmusc, Ngang, Nneur
these don’t particularly affect ANS atthe level of the end organ
They increase permeability to Na+ and K+ (stimulatory)
3 types: found in skeletal muscle, ganglia and brain
Cholinergic receptors- Muscarinic
G-protein coupled receptor–> M1, M2, M3, M4, M5
Used to manipulate ANS
M1 (neural): ganglia, CNS, gastric parietal cells: activate protein lipase c (PLC)–> formation of IP3 and DAG–>decreased K+ conductance. M1 agonist is STIMULATORY
M2 (cardiac): All areas of heart and also in brain-stem. Pre-synaptic inputs to peripheral autonomic neurons. Inhibit AC and open K+ channels, inhibiting Ca2+ channels. M2 agonist would DECREASE activity.
M3 (glandular/smooth muscle): smooth muscle and glandular tissue and in cerebral cortex: activate PLC. Relaxation of vascular smooth muscle d/t Nitric Oxide (NO). Bind drug to M3, get activation, but decrease of VSM activity (i.e. decreased contraction) d/t NO.
M4 (CNS): inhibit AC- inhibitor system unclear
M5 (CNS): activate PLC- stimulatory receptor
Drug classes
Direct acting: bind specifically to receptors which get activated by ANS
Agonists= sympathomimetics, parasympathomimetics
Antagonists= sympatholytics, parasympatholytics
Indirect acting: change amount of NT release–> indrect effects on end-organ via manipulation of ANS
Sympathomimetics- displace NA from terminal itself (not the AP stimulated)
Parasympathomimetics: anticholinesterases, displace ACh
Pharmacological maniupation of ANS relative to the eye
Mydriatics: dilate pupil
Glaucoma: increased build-up of fluid. Control of fluid production is very important.
Horner’s syndrome: condition that affects SNS–can use drug intervention to prove where the lesion is
ANS receptors in the eye
M3 in constrictor pupillae (constriction)
Alpha 1 in dilator pupillae (dilation)
Alpha 1 in ciliary body blood supply (constrict VSM)
B1, B2, Alpha 2, M3 in ciliary body- nb: aqueous humor produced in ciliary body.
Beta receptors in ciliary muscle–> slight relaxation
M3 in ciliary muscle–> contraction
Humor flows from ciliary body through pupil, across pupillary muscles to the trabecular meshwork and into the canal of schlemm.
Mydriatics (dilate eye)
diagnostic: short-acting
Treatment of uveitis (prevent synechia- lens sticking to cornea): long-acting
M3 receptors on constrictor pupillae–>antagonism of M3 receptors will lead to mydriasis (dilation)
Parasympatholytic/cholinergic antagonist- bring about dilation of pupil. No M3 specificc drugs available
Atropine, tropicamide, cyclopentone–> all non-specific muscarinic drugs
Give topically to reduce systemic effects.
Side effects can be predicted: accomodation paralysis (cyclopegia), hypersalivation, GI ileus— contraindicated with glaucoma (because it’s opposite of what we want to achieve).
Alternative: alpha 1 adrenoceptors located on dilator pupillae. Can give sympathomimetic, ideally alpha 1 adrenergic agonist i.e. phenylephrine–> give topically to avoid systemic effects.
Glaucoma
problem= increase intraocular pressure
Open angle glaucoma: occurs slowly over time due to an obstruction of trabecular meshwork by neoplasm/inflammation. No passage of fluid leaving trabecular mesthwork.
Closed angle glaucoma: acute–> iris is displaced against cornea and fluid can’t get out
Primary glaucoma: no hx of trauma or ocular disease
Secondary glaucoma: ocular inflammation, lens dislocation, introcular tumours or trauma
Different ways of treating due to different nature of underlying problem
Open angle: can move via dilation
Closed angle: need to stop fluid production
IOP: blindness due to compression of nerve
Glaucoma treatment 1: closed- angle glaucoma
Aim: decrease aqueous humour production (no effect on pupil)
Sympatholytics:
- Timolol (non-specific beta adrenoceptor antagonist)–> decreased aqueous production, possibly via B2 receptors
- Betaxolol (B1 adrenoceptor antagonist)
Sympathomimetics:
- epinephrine: non-specific adrenoceptor agonist–> decreases aqueous production via alpha 1 vasoconstriction of ciliary blood vessels (change VSM, decrease Q, decrease aqueous humor production)
- apraclonidine: alpha 2 adrenoceptor agonist (also weak alpha 1 agonist–>capitalizing on this action)
Glaucoma treatment 2: open angle glaucoma
Miosis (pupillary constriction) will open the drainage angle
Direct parasympathomimetic: non-specific muscarinic agonists (local application to bring about effect) e.g. pilocarpine, carbachol
Indirect parasympathomimetic: acetylcholinesterase inhibitors–>increase [ACh]–targets NT rather than receptor e.g. demecarium bromide
Glaucoma treatment 3: decrease aqueous production
Carbonic anhydrase inhibitors: decreased aqueous production- not affecting ANS
Horner’s syndrome symptoms
Ptosis (lowering/drooping of eye), protrusion of 3rd eyelid, elevation of lower lid, miosis (not pronounced in farm animals), enophthalmia (not pronounced in farm animals), unilateral heat increase/sweating
Cause: damage to SNS- local inflammation, nerve damage, neoplasia–> can occur in any of the neuron orders
1st order: central lesion
2nd order: pre-ganglionic
3rd order: post-ganglionic
ANS pharmacological intervention is principally diagnostic
Horner’s syndrome lesion diagnosis
Mydriasis should occur after noradrenaline binds to alpha adrenoceptors on dilator pupillae. Can use an alpha 1 agonist e.g. phenylephrine.
if there’s a lesion in the CNS (1st order): dilation occurs in about 60-90 minutes
if there’s a lesion in the 2nd order (preganglion), dilation occurs in 45 minutes
If there’s a lesion in the 3rd order (postganglion), dilation occurs in 20 minutes
The time taken to dilate relates to denervation hypersensitivity–when you lose normal neuronal control, body becomes hypersensitive to NT. Reuptake is disrupted, so drug remains in cleft longer, leading to an exaggerated response.
Horner’s diagnosis: cocaine drop test and hydroxyamphetamine test
Cocaine eyedrops block the reuptake of NA, resulting in dilation of the normal pupil. In Horner’s syndrome, the lack of NA in the synaptic cleft causes failure to dilate.
Hydroxyamphetamine: this test helps to localize cause of miosis. If the third order neuron (post-ganglionic) is intact, then the amphetamine causes NT vesicle release, thus releasing NA into the cleft and resulting in a robust dilation of the pupil. If the lesion itself is in the third order neuron, then the amphetamine will have no effect and the pupil will remain constricted.
Pharmocological manipulation of the ANS relative to micturition
Disorders of storage: urinary incontinence
- hypercontractile detrusor (wall of bladder too active)
- hypocontractile sphincter/urethea (sphincter isn’t closing)
Disorders of storage: urinary retention
- hypocontractile detrusor (not voiding)
- hypercontractile sphincter/urethra (can’t urinate)
Receptor distribution in urinary system
M3 (stimulatory): large amounts in detrusor
Some M2 on detrusor/sphincter; large M2 on where SNS inputs (M2 is inhibitory)
B2 on detrusor and sphincter (inhibitory)
Alpha 1 only on sphincter (stimulatory)
Storage: sympathetic dominance + alpha 1 (constriction of sphincter) + B2 (relaxation of detrusor)
Voiding: parasympathetic stimulation + M3 (increase in M3 actively contracts detrusor) + M2 (relaxes sphincter, inhibits SNS input); sympathetic relaxation (alpha 1- relax sphincter)
Detrusor hypercontractility/spasticity (urinary incontinence)
Cause: bladder infections, neurogenic disorders, over-activity of detrusor wall itself
Aim: decrease destrusor activity (M3 receptor)- Antimuscarinic
Oxybutalin, propantheline, flavoxate, atropine- non-specific muscarinic antagonists given systemically
side effects: low saliva, GI stasis, tachycardia, excitement, sedation, increased IOP, mydriasis, anti-spasmodic effects on GI
Detrusor atony- urinary retention
decrease in activity of detrusor wall itself, can be caued by neurogenic disorders, over-distension
Aim: increase detrusor activity–> cholinergic agonists
Bethanechol- non-specific muscarinic agonist, but higher affinity for M3.
nb: if dose is too high, will bind to other M reeptors
Oral admin side effects: GI stimulation, hypersalivation, defecation
Antidote: Atropine
Urethral sphincter incompetence
Common in spayed bitches- etiology not fully characterized
Steroids: estradiol is common tx (not directly ANS), eventually fails to work
Aim: increase sphincter tone–> alpha 1 agonists
Oral phenylpropanolamine (non specific alpha adrenergic agonists) and ephedrine (stimulates NA release, less predictable- binds to alpha and beta receptors)
note: systemic distribution
side effects: hypertension, restlessness, increased IOP
Urethral spasticity
too much activity in urethra
cause: infections, inflammatory neurological disorders, urethral obstructions, bethanacol treatment
Phenoxybenzamine- non-selective alpha antagonist but preferential binding to alpha 1–IRREVERSIBLE
Side effects: hypotension, reflex tachycardia, increased IOP, GI upset
Prazosin, terazosin- selective alpha 1 antagonist
Side effects: hypotension, GI upset
Co-transmission
transmitters released from nerve terminals other than ACh and NA
non-peptides: ATP, GABA, 5HT3 (serotonin), dopamine, NO
peptides: NPY, VIP, substance P, GnRH and CGRP
example: ATP is released from post-ganglionic sympathetic nerve terminals in conjunction with NA
Advantages: duration/distribution and variation in response.
