The Autonomic Nervous System and Pharmacology Flashcards
why is the ANS important?
- ensures we survive despite lack of consciousness and cortical input
- self-governing when we sleep
maintains homeostasis
what are the 4 major components of the nervous system?
- sensory/afferent PNS:
- somatic nervous system - receptive to stimuli on skin/muscles
- visceral nerves - receptive to things entering organs - CNS - brain and spinal cord
- Motor/efferent PNS:
- somatic nervous system - voluntary
- ANS - involuntary - effectors
- somatic = skeletal muscle
- autonomic = smooth muscle, cardiac muscle, glands
what are the 2 major pathways of the ANS?
- sympathetic (fight or flight)
- activated during exercise, excitement, emergency, embarrassment
- can be whole body or organ specific response - parasympathetic (rest and digest)
- activated during digestion, defecation and diuresis
- functions in discrete, organ specific manner
what does the sympathetic nervous system stimulate?
- dilation of pupils
- increase in heart rate and contractility
- vasodilation of blood vessels to muscles by contraction of smooth muscle
- vasoconstriction of blood vessels to gut
- contraction of smooth muscle in bronchioles to widen airways
- breakdown of glucose in liver
- ejaculation and orgasm
what does the parasympathetic nervous system stimulate?
- constriction of pupils
- slowing of heart rate (doesn’t change contractility)
- vasodilation to GI tract
- release of enzymes and bile in GI tract
- bladder wall contraction and sphincter relaxation to allow urination
- arousal
how do sympathetic and parasympathetic innervations work in relation to one another?
- they innervate the same tissues but have opposing effects
- antagonistic actions but work synergistically - one increases, the other decreases
- rapid, precise control of tissue function
which tissues are stimulated by sympathetic innervation only?
- sweat glands, hair follicles, blood vessel smooth muscle and adrenal medulla
What is the general organisation of the ANS? (both sympathetic and parasympathetic)
- preganglionic neuron located in the CNS
- preganglionic neuron innervates a postganglionic neuron in the PNS (peripheral ganglion)
- postganglionic neuron innervates a target cell
except adrenal medulla in sympathetic pathway (preganglionic to target cell)
what are preganglionic neurons?
- always cholinergic neurons (ACh is neurotransmitter)
- ACh activates ionotropic nAChRs on postsynaptic membrane
- this allows ions to move into the postganglionic neuron and excite it
what is the organisation of the sympathetic pathway?
- short, cholinergic preganglionic neurons originate from T1 to L3
- long adrenergic postganglionic neurons release noradrenalin to target cells
- target cells express metabotropic alpha and beta adrenergic receptors
how does the sympathetic nervous system innervate the adrenal medulla?
- chromaffin cells (preganglionic neurons) function similarly to postganglionic neurons but release adrenaline which moves into blood stream
- this leads to a broad sympathetic response throughout the body
- adrenaline acts as a neurohormone as it is released neuronally but dispersed hormonally
- target tissues express alpha and beta adrenergic receptors
what is the organisation of the parasympathetic pathway?
- long, cholinergic preganglionic neurons from brain stem and sacral spinal cord
- short, cholinergic postganglionic neurons release ACh to target cells
- target cells express metabotropic mAChRs (muscarinic)
why is the vagus nerve important?
- also called Cranial Nerve X
- carries around 80& of parasympathetic outflow
- carries tonnes of visceral afferents
what are the 2 essential components of the ANS?
- spinal cord
- cell bodies of preganglionic neurons are located in the lateral horn
- mediates autonomic reflexes
- receives sensory afferent and brainstem input - brainstem nuclei
- mediate autonomic reflexes
how is the hypothalamus used in the ANS?
- feeding
- thermoregulation
- circadian rhythms
- water balance
- sexual drive
- reproduction, birth and lactation
what else regulates ANS output?
forebrain:
- minimal conscious cortical control regulates output
- e.g. anxiety/stress leads to GI disturbance
- e.g. fear leads to fight or flight response (limbic system)
visceral afferents:
- sensory input from visceral afferents takes priority over cortical functions
- e.g. bladder distension
what are the 2 principle neurotransmitters in the ANS?
- acetylcholine (ACh)
- noradrenalin (NA)
what receptors does ACh act upon?
- nicotinic ACh receptors (nAChRs) - ionotropic
- found in preganglionic -> postganglionic communication - muscarinic ACh receptors (mAChRs) - metabotropic
- found on organs via the parasympathetic system (and sweat glands in sympathetic)
what receptors does NA act upon?
- alpha adrenoreceptors
- beta adrenoreceptors
- both are metabotropic and are found upon chromaffin cells
what is the principle neurotransmitter of the sympathetic nervous system?
- most organs are innervated by NA
- (except sweat glands and adrenal medulla which use ACh)
what is the principle neurotransmitter of the parasympathetic nervous system?
- ACh to innervate mAChRs on target tissues
what discoveries did Dale make about the activity of ACh?
- muscarinic actions resemble effects of parasympathetic innervation
- atropine blocks muscarinic effects
- curare blocks effect of nicotine and ACh on nAChRs
what effects do large doses of ACh produce, once muscarinic effects have been blocked by atropine?
- stimulation of all autonomic ganglia
- stimulation of voluntary muscle
- secretion of adrenaline from adrenal medulla
what are the different subtypes of mAChRs?
M1, M2, M3, M4, M5
what are M1 receptors?
M1 (neural): coupled to Gq-protein
- activate PLC, IP3 and intracellular Ca2+ influx
- common to all postsynaptic mAChRs, autonomic ganglia, glands and cerebral cortex
what are M2 receptors?
M2 (cardiac): coupled to Gi- protein
- inhibit adenylyl cyclase, decrease cAMP, open GIRK channels, inhibit Ca2+ channels due to less PKA activity
- found in atria of heart
what are M3 receptors?
smooth muscle: coupled to Gq-protein
- found on endothelial cells
- regulates production of nitric oxide which causes vasodilation and drop in blood pressure
- innervate exocrine glands, smooth muscle, eye, airways, bladder
what are M4 receptors?
- coupled to Gi-proteins
- found in CNS
what are M5 receptors?
- coupled to Gq-proteins
- located in substantia nigra, salivary glands and CNS
how do M2 ACh receptors work on cardiac muscle?
- M2 receptors are negatively coupled to adenylyl cyclase through Gi protein and reduce cAMP formation
- this inhibits opening of L-type calcium channels, slowing Ca2+ influx
- M2 receptors open GIRK channels via beta-gamma subunits
- causes an increase in K+ permeability, causing hyperpolarisation of atria
- causes heart rate to slow
how do M2 receptors mediate effects of pilocarpine agonist?
- pilocarpine opens GIRK channels via beta-gamma subunit binding
- causes hyperpolarisation of pacemaker and slows AP firing
- causes slowing of heart
what are the actions of M1 and M3 ACh receptors?
they are Gq coupled receptors
they:
1. increase bronchoconstriction
2. increase GI motility
3. increase secretion from exocrine glands so increase mucus in lungs
what are the affects of agonist muscarine on mAChRs?
- eating over a gram causes nausea
- decrease in blood pressure is due to decrease in cardiac output (M2) and increased nitric oxide production by endothelial cells (M3)
- increase in saliva, tear-flow, sweating and abdominal pain (M3)
what is cevimeline?
an M3 selective agonist which is used to improve salivary and lacrimal secretions in Sjogrens syndrome
what is glaucoma? how can glaucoma be treated?
- an eye condition that can cause blindness due to drainage tubes in the eye becoming blocked
- build up on intraocular pressure can damage the optic nerve
- pilocarpine (muscarinic agonist) eye drops are used to reduce pressure inside the eye by increasing drainage from eye into bloodstream
give an example of a muscarinic antagonist and its effects:
atropine:
- inhibition of secretion of saliva and mucus
- smooth muscle relaxant of blood vessels and bronchioles
- pupillary dilation
- increase in heart rate
- decrease in GI motility and acid secretion
- CNS agitation and disorientation
- increase in body temperature
what is Pirenzipine?
- M1 selective antagonist used to treat peptic ulcers
- controls acid secretion in the gut
what is darifenacin?
- M3 selective antagonist used to treat overactive bladder
- relaxes smooth muscle of the bladder
what are cholinomimetic drugs?
they mimic the effects of activating the cholinergic pathway
- they inhibit AChE to indirectly increase ACh levels to increase activation of cholinergic receptors
- they can increase activity of both mAChRs and nAChRs
which cholinomimetic drugs inhibit AChE?
physostigm-ine is an AChE drug used to treat glaucoma
- sarin (nerve gas), organophosphate pesticides are used as poisons to inhibit AChE, leading to build up of ACh and activate cholinergic receptors
where are receptors for NA found?
- tissues that respond to postganglionic sympathetic neurons
- smooth muscle, cardiac muscle, glands
what are alpha and beta adrenoreceptors involved in?
alpha 1 = vasoconstriction of blood vessels
alpha 2 = clot formation
beta 1 = increased contractility of heart
beta 2 = dilation and relaxation of smooth muscle in airways
which adrenoreceptor is targeted to treat asthma?
beta 2
how are receptors classified?
- by their signalling mechanism, pharmacology and which G-protein they are coupled to
alpha 1 = due to NA being found to be more potent than adrenaline, coupled to Gq, increase in Ca2+ and so more contraction
alpha 2 - increased sensitivity to adrenaline over NA, coupled to Gi
beta = more potent for isoprenaline, coupled to Gs, increase in cAMP production
how do beta-1 adrenoreceptors cause increase in heart rate?
- coupled to Gs protein
- increase in cAMP to activate PKA to open L-type calcium channels, causing influx of Ca2+ into cardiac muscle, thus depolarisation and increased contraction
what are the clinical uses of adrenaline?
adrenaline is an endogenous agonist
- released by chromaffin cells of adrenal gland
- affects all adrenoreceptors
found in EpiPens to treat anyphalactic shock - drop in blood pressure
- causes increase in heart rate and stronger contractions
- treats cardiac arrest
how does salbutamol affect beta-2 adrenoreceptors?
- it is an agonist that causes bronchodilation of airways
- used in inhalers to treat asthma
what does ephedrine do?
- nasal decongestant
- causes constriction of smooth muscle lining the arteries to reduce leakage
- indirectly acting sympathetic drug (sympathomimetic) which causes NA release
what are amphetamines?
- indirect sympathomimetic drug (mimics effects of increased sympathetic signalling via NA)
- they are taken up by trnasporters in plasma membrane of NA neurons
- structurally related to NA, dopamine and 5-HT
how does amphetamine increase NA action
- inhibits enzymes which hydrolyse NA
- binds to NA recycling transporters to prevent NA being taken back up into cell, allowing it to accumulate in cleft and innervate target tissues
what are prazosin, carvedilol and propranolol? what are their actions?
antagonists of adrenoreceptors (they are beta blockers)
- prazosin: alpha-1 selective
- combats vasoconstriction and hypertension - carvedilol: alpha and beta selective
- decreases workload of heart to combat heart failure - propranolol: beta-1 and beta-2 selective
- relieves fast breathing and increased heart rate to treat anxiety
what are the unwanted effects of beta blockers?
- bronchoconstriction
- can be fatal for asthma patients
- cardiac depression and exacerbations
- brachycardia - reduced cardiac output
- fatigure
- cold extremities due to loss of beta-receptor mediated vasodilation
