M&R Session 10: autonomic nervous system Flashcards
ANS functions?
Controls all involuntary functions
Separate from voluntary (somatic) system
Entirely efferent, but regulated by afferent inputs
Sympathetic division?
Fight or flight
Increase HR, force of contraction and blood pressure, pupils dilate, adrenaline release, sweating
Parasympathetic division?
Regulates basal activities-“rest and digest”
Largely has effects opposing the sympathetic system
Parasympathetic nerve characteristics
Originate in lateral horn of medulla and sacral region of spinal cord
Long myelinated pre-ganglionic neurones, short unmyelinated post-ganglionic neurones
Ganglia in tissues innervated by postsynaptic fibres
Sympathetic nerve characteristics
Originate in lateral horn of the lumbar and thoracic spinal cord
Short myelinated pre-ganglionic neurones, long unmyelinated post-ganglionic neurones
Ganglia in the paravertebral chain close to the spinal cord
Neurotransmitter and receptors for all pre-ganglionic neurones?
All are cholinergic (use ACh)
So cause activation of post-ganglionic nicotinic ACh receptors (ligand-gated ion channels)
Neurotransmitter and receptors for parasympathetic post-ganglionic neurones?
Cholinergic: use ACh
Acts on muscarinic ACh receptors in the target tissue (GPCRs. 5 types)
Neurotransmitter and receptors for sympathetic post-ganglionic neurones?
Most:
Noradrenergic: use noradrenaline which acts on alpha or beta adrenoceptors (9 types, further subdivided, GPCRs)
Some:
Cholinergic: use ACh to act on mAChR
e.g. sweat glands, hair follicles (piloerection)
Adrenal glands different-release adrenaline into blood rather than target tissue. The sympathetic postganglionic neurones here differentiate to form neurosecretory chromaffin cells
Non-adrenergic, non-cholinergic transmitters?
May be co-released with either NA or ACh
Examples: ATP nitric oxide 5-hydroxytryptamine (serotonin) neuropeptides such as VIP
Parasympathetic release of ACh effect on heart + receptors
M2 muscarinic ACh receptors activated, causing:
- bradycardia (act on SA node to decrease beats)
- reduced conduction velocity (act on AV node to decrease conduction from atria to ventricles)
Parasympathetic release of ACh effect on smooth muscle + receptors
M3 muscarinic ACh receptors
Lungs: bronchial and bronchiolar contraction
GI tract: increased intestinal mobility and secretion
GU tract: bladder contraction (detrusor) and relaxation (sphincter). Also penile erection but via NO: ACh causes NO release which causes the erection
Eye: ciliary muscle and iris sphincter contraction
Parasympathetic release of ACh effect on glands and receptor
M1 and M3 muscarinic ACh receptors
Increased sweat/salivary/lacrimal secretions
Sympathetic release of NA effect and receptor-heart
Positive chronotropy-tachycardia-from SA node
Positive inotropy-increase FoC-from ventricles
B1 receptors (B2)
Sympathetic release of NA effect and receptor-smooth muscle
Arteriolar contraction/venous contraction-a1 adrenoceptors
Some arteriolar relaxation in exercising muscle to run fast-so b2 adrenoceptors here to relax
Bronchiolar/intestinal/uterine relaxation: b2 (b3) adrenoceptors
Bladder sphincter contraction-b3 adrenoceptors
Radial muscle contraction-a1 adrenoreceptors
Sympathetic release of NA effect and receptor-kidney
Renin release
b1 and b2 adrenoreceptors
Sympathetic release of NA effect and receptor-glandular
Increased viscous secretions
Describe the afferent (sensory) inputs to the ANS
- Sensory neurones monitor levels of CO2, O2, nutrients in blood, arterial pressure, and GI tract content
- blood composition also sensed by the carotid body (chemoreceptors of carotid artery): send info to CNS via glossopharyngeal nerve
- nucleus tractus solitarius: integrates all visceral afferent info
- this also receives input from the area postrema (detects blood and CSF toxins)
What is dysautonomia?
Distinct malfunctions of the ANS
Catecholamine disorders?
Pheohromocytoma
Baroreflex failure
Central autonomic disorders?
Mutiple system atrophy:
Peripheral autonomic disorders?
Guillain-Barre syndrome
Familial dysautonomia
Orthostatic intolerance syndromes?
Postural orthostatic tachycardia syndrome (POTS)
Paroxysmal autonomic syncopes?
Neurocardiogenic syncope
List the basic steps in neurotransmission, indicating which are the most common sites of drug action (*)
- Uptake of precursors
- Synthesis of transmitter
- Vesicular storage of transmitter
- Degradation of transmitter *
- Depolarisation by propagated action potential
- Depolarisation-dependent influx of Ca2+
- Exocytotic release of transmitter
- Diffusion to post-synaptic membrane
- Interaction with post-synaptic receptors*
- Inactivation of transmitter*
- Re-uptake of transmitter*
- Interaction with pre-synaptic receptors*
Manipulating cholinergic function?
Interfere at nicotinic ganglia-there will not be discrimination between sympathetic and parasympathetic
Interfere at muscarinic receptors: more selective, mainly parasympathetic effects
How is ACh synthesised?
acetyl CoA + choline –> acetylcholine + coenzyme A
Via choline acetyltransferase
How is ACh degraded?
acetylcholine –> acetate + choline
Via acetylcholinesterase
How can nAChRs be targeted?
Differ in structure at autonomic ganglia and the neuromuscular junction
So some drugs select for autonomic ganglia action: e.g. tripemethaphan (blocks ganglia) used in hypertensive emergencies. But undesirable side effects
How can mAChRs be targeted?
5 subtypes (M1-M5), but only a few subtype-selective agonists/antagonists currently available
Agonists: pilocarpine (glaucoma), bethanechol (stimulate bladder emptying)
Antagonists: ipratropium and tiotropium (COPD), tolterodine, darifenacin and oxybutynin (overactive bladder)
How can AChE inhibitors be used therapeutically?
Enhance the actions of endogenous ACh by preventing breakdown
E.g. pyridostigmine (myasthenia gravis) and donepezil (Alzheimer’s disease)
Side effects of non-selective muscarinic ACh receptor agonists?
Heat: decrease HR and output
Smooth muscle: increase bronchoconstriction and peristalsis
Exocrine glands: increase sweating and salivation
“Sludge syndrome”
Describe the synthesis of noradrenaline
- Tyrosine to DOPA by tyrosine hydroxylase DOPA a drug itself for Parkinson’s treatment
- DOPA to dopamine by DOPA decarboxylase. Dopamine moved from cytosol into vesicles
- Dopamine to noradrenaline by dopamine beta-hydroxylase
What happens after Ca2+-dependent exocytotic release of NA?
- NA diffuses across synaptic cleft to interact with adrenoceptors in post-synaptic membrane to initiate signalling in effector
- NA interacts with pre-synaptic adrenoceptors to regulate processes within the nerve terminal
Only limited time for effects as rapidly removed by noradrenaline transporter proteins
Termination of noradrenergic transmission?
Uptake 1: re-uptake into pre-synaptic terminal by this Na+-dependent, high affinity transporter (most)
Uptake 2: residual NA taken up by a combination of lower-affinity, non-neuronal mechanisms
Metabolism of NA?
Within the pre-synaptic terminal, NA not taken up into vesicles is metabolised by:
- monoamine oxidase (MAO)
- catechol-O-methyltransferase (COMT)
How can presynaptic GPCRs e.g. a2 adrenoceptor regulate neurotransmitter release?
Inhibit Ca2+-dependent exocytosis:
G protein betagamma subunits inhibit specific types of VOCCs thus reducing Ca2+ influx and neurotransmitter release
Indirectly-acting sympathomimetric agents?
E.g. tyramine, amphetamine, ephedrine
Taken up into NA synaptic vesicles, NA leaks from vesicle, then leaks into synaptic cleft
Uptake 1 inhibitors?
E.g. tricylclic antidepressents, selective NA reuptake inhibitors
Exert ajor effects in CNS. Unwanted peripheral side effects can be minimised by choice of drug and dose
Salbutamol in asthma effect?
It is a beta 2 adrenoceptor-selective agonist
Relieves bronchoconstriction
The selectivity minimises possible CVS side effects (positive inotropic and chronotropic)
Hypertension treatment?
Alpha 1 adrenoceptor-selective agonists e.g. doxazosin
Beta 1 adrenoceptor-selective antagonists, e.g. atenolol
Chronic heart failure treatment?
Beta blocker, ACE inhibitor and diuretic
Beta 1 adrenoceptor selective antagonists e.g. bisoprolol, metoprolol
Mixed alpha1/beta1/beta2 adrenoceptor antagonist-carvedilol. Very useful for chronic heart failure
