ANS and neurotransmitters Flashcards
How big is the hypothalamus? What shape?
4cm squared wallnut shaped grey matter centre
What are the relations of the hypothalamus
◦ Mammilary bodies, periaqueductal grey matter and tegmentum posteriorly
◦ Lamina terminalis anteriorly / optic chiasm
◦ Inferior to the 3rd ventricle
◦ Surrounded by basal ganglia
◦ Extends from mammillary bodies posteriorly to the lamina terminalis anteriorly
◦ Connected to the pituitary by the infundibulum inferiorly
◦ Separated from the thalamus by the sulcus of Monro
Blood supply of the hypothalamus
◦ Anterior cerebral artery
◦ Perforating branches of the PCA
◦ Posteriormedial branches of PComm
Veinous drainage of the hypothalamus
into cavernous sinus via inferior hypophyseal veins and into the hypothalamo
* - hypophyseal portal system
What is contained in the anteiror hypothalamus
Supraoptic nuclei
Paracentricular nuclei
Controllin
- PSNS
- Heat loss
- Sleep
- Posterior pituitary ormones -osmoreceptors in supraoptic nuclei, oxytocin in paraventricular nuclei
What does the medial hypothalamus do
Energy balance
Sexual behaviour
Satiety
Lateral hypothalamic function
Efferent pathways ot the brainstem
Emotion and defence
Thirst
Desire to seek food
Posterior hypothalamus does what
SNS - vasomotor centres of the brain
Wakefullness
Main functions of the hypothalamus
Water balance and tonicity
Temperature
Autonomic nervous system
Pituitary endocrine function
Appetite and satirety
Behaviour and emotion
Circadian rhtyhm
How is the autonomic nervous system related to the hypothalamus?
◦ PSNS from anterior pituitary
◦ SNS from posterior pituitary - vasomotor centres of the brain
What are the 6 main hormones secreted from the hypothalamus triggering anterior pituitary release
◦ Thyrotropin-releasing hormone (TRH) - release cycle time 2-4 hours, T4 negative feedback
◦ Gonadotropin-releasing hormone (GnRH) - Pulsatile cycle time 90 mins, emotion, circadian, sexual stimuli cause release
◦ Growth hormone-releasing hormone (GHRH) - 3 isoforms, circadian release in sleep, physiological stress increases release
◦ Corticotropin-releasing hormone (CRH) - GC main regulatory feature over release
◦ Somatostatin
◦ Dopamine - suppressing prolactin
Outline the anatomy of the sympathetic chain
‣ Cervical part - extending superiorly from thoracic origin to head, neck and thorax
‣ Thoracic part T1-5 extends to aortic plexus, pulmonary plexus, cardiac plexus and thoracic splanchnic nerves
‣ Lumbar ganglia - coeliac plexus
‣ Pelvic plexus
thoracolumbar (T1 - L2) paraspinal columns from which arise post-ganglionic nerves which travel to peripheral locations for effect
Preganglionic SNS nerve cells arise from where? Describe their path
‣ Cell bodies arise from grey matter of lateral horns T1-L2–> leave through ventral route of spinal nerve/ primary anterior rami –> rami communicates (myelinated B fibres) –> sympathetic chain (ganglia of sympathetic trunk) synapse with post ganglionic neurones in ganglion
* Preganglionic fibre length short
* release ACh to stimulate post ganglionic cells (nicotinic receptor) - in the sympathetic chain at the same level,
* a different level of leaving through splanchnic nerves to a prevertebral ganglion
What is the path of post ganglionic sympathetic nerve fibres?
‣ unmyelinated pass into adjacent spinal nerve via grey rami communicates and travel with spinal nerves to target organs
‣ Post ganglionic nerve cell body in the sympathetic chain pre/para vertebral
‣ Long fibre length
‣ Adrenergic –> release norepinephrine stimulating alpha or beta G protein coupled receptors.
* Special circumstance –> adrenal medulla which has preganglionic nerves directly synapsing with chromaffin cells which secrete adrenaline (80%) into the blood stream in response to ACh stimulation
‣ Cholinergic –> sweat glands, vasodilator blood vessels in skeletal muscle
How is adrenal outflow different for SNS supply
‣ unmyelinated pass into adjacent spinal nerve via grey rami communicates and travel with spinal nerves to target organs
‣ Post ganglionic nerve cell body in the sympathetic chain pre/para vertebral
‣ Long fibre length
‣ Adrenergic –> release norepinephrine stimulating alpha or beta G protein coupled receptors.
* Special circumstance –> adrenal medulla which has preganglionic nerves directly synapsing with chromaffin cells which secrete adrenaline (80%) into the blood stream in response to ACh stimulation
‣ Cholinergic –> sweat glands, vasodilator blood vessels in skeletal muscle
What is the effect of the SNS
- Fight or flight response as a diffuse physiological accelerator
- Cardiovascular
◦ Increased chronograph, inotropy, lusitrophy and dromotrophy
◦ Increased afterload due to increased vascular constriction with increased venous return from increased venous tone - Pulmonary - bronchial dilation
- MSK - sweating, constriction, lipolysios
- Pupillary dilation
- GI/GUT - decreased secretions, increased sphincter tone, gluconeogenesis
◦ Saliva production decreases
Describe the path and type of fibre fo PSNS
◦ Myelinated B fibres
◦ Site of ganglia for synapse with post ganglionic cells near or in effector organ
◦ Therefore long pre-ganglionic fibres
‣ Cell body within the brain stem for cranial nerves or sacral grey matter (hypo gastric plexus)
◦ Acetylcholine released from preganglionic cell activates post ganglionic neuron via nicotinic receptors
Describe the path and characteristics of post ganglionic PSNS
◦ Short in length, unmyelinated C fibres
◦ In smooth muscle, heart, glands
◦ Acetylcholine via muscarinic receptors (GPCR) to modulate target organ activity
What are the PSNS CN
3 7 9 10
CN 3 acts as a PSNS via?
‣ CN 3 occulomotor nucleus —> ciliary ganglion —> ciliary muscle, iris spincter
CN7 acts as a PSNS
‣ CN 7 - Superior salivary nucleus —> submaxillary ganglion —> submaxillary and sublingual salivary glands
CN9 acts as a PSNS
‣ CN 9 - Inferior salivary nucleus —> optic ganglion —> parotid gland
How is CN10 implicated in PSNS function? How far down does it stretch
‣ CN10 Vagal nuclei in medulla from —> dorsal nucleus of vagus (visceral), nucleus ambiguus (PSNS to heart, motor to larynx), NTS (visceral afferents and taste) and spinal tract of trigeminal nucleus
* vagus is the major parasympathetic nerve innervating
◦ Cardiac plexus - SA node by R vagus, AV node by L vagus, and ventricles sparsely by L vagus
◦ Lungs via pulmonary plexus
◦ Stomach, liver, spleen, pancreas and gut proximal to the splenic flexure by the gastric plexus
Describe the overall effects of the parasympathetic nervous system
- Rest and digest - a physiological brake on cellular function
- CN3 - pupillary constriction (M3)
- CN 7 - lacrimation
- CN 9 - salivation
- CN10
◦ Cardiac (M2) - reduced chronotropy, reduced dromotropy, minor reduction in inotropy and lusitropy (affects atria more than ventricles)
◦ Respiratory (M3) - bronchoconstriction, increased mucous production
◦ GIT (M3 motility, Beta 2 and alpha glycogen)- increased secretions, increased motility, decreased sphincter tone - Sacral plexus - GU - (M3) detrusor contraction and erection,anus relaxation with rectal contraction, uterine contraction
What is acetylcholinesterase
- Acetylcholinesterase (AChE) is an enzyme that hydrolyse acetylcholine (ACh) into choline & acetate AChE is found in synaptic clefts and is responsible for the termination of synaptic transmission
- Common action of anti-cholinesterases = allow build up of Ach and prevent it from being destroyed.
Two types of cholinesterase
- Achesterase - nerve endings & in RBCs
- Non-specific or pseudocholinesterases - destroy other esters - tissues & plasma
Acetylcholinesterase binding sites include
anionic and esteratic
◦ ANionic site binds quaternary amine group of ACh
◦ Esteratic site binds ester group of ACh
◦ Binding –> hydrolysis and breakdown into choline and Acetyl CoA
How does Acetylcholinesterase break down ACh
anionic and esteratic
◦ ANionic site binds quaternary amine group of ACh
◦ Esteratic site binds ester group of ACh
◦ Binding –> hydrolysis and breakdown into choline and Acetyl CoA
How does Acetylcholinesterase break down ACh
anionic and esteratic
◦ ANionic site binds quaternary amine group of ACh
◦ Esteratic site binds ester group of ACh
◦ Binding –> hydrolysis and breakdown into choline and Acetyl CoA
How do you classify the acetylcholinesterase drugs
- Reversible antongist via electrostatic binding - edrophonium
- Reversible antagnoiist via covalent binding - neostigmine
- Irreverrsible antagonist via covalent binding - organophosphates
How does edrophonium act
Reversible antagonist via electrostatic binding – e.g. edrophonium
‣ causes electrostatic attachment to the anionic site of the enzyme -> stabilising the H+ bond at the esteratic site -> edrophonium-AchE complex prevents Ach from binding
How does neostigmine act
Reversible antagonist via covalent bonding – e.g. neostigmine
‣ [Formation of carbamyl esters (carbamates)] - ie. neostigmine, physostigmine & pyridostigmine
‣ antagonise AchE enzyme by being competitive substrate for Ach -> forms a carbamyl-ester complex at the esteratic site of enzyme. - longer lasting bond (15-30min)
How do organophosphates act?
Irreversible antagonist via covalent bonding – e.g. organophosphates
‣ combine with Ach at the esteraic site to form a stable covalent bond -> does not undergo hydrolysis. - synthesis of a new AchE is required.
What is a nicotinic effect
◦ Reversal of non-depolarising neuromuscular blockers
◦ Prolongs effect of suxamethonium (depolarising NMB)
◦ Anticholinesterase overdose → excess synaptic ACh → depolarisation block ± fasciculation
What is a muscurinic effect
Wh
Which occurs first a muscurinic effect or nicontinnic effect with acetylcholinesterase inhibitors
Muscurinic at lower doses
What is a muscurinic effect
◦ CVS – bradycardia ± hypotension
◦ RESP – bronchoconstriction ± bronchospasm
◦ CNS – miosis, cholinergic syndrome – confusion, agitation, nausea/vomiting
◦ GIT – hypersalivation, ↑GIT motility, nausea/vomiting, diarrhoea
◦ GUT – urination, incontinence
◦ OTHER – lacrimation, diaphoresis
‣ Mnemonic SLUDGE-BM: Salivation/Sweating, Lacrimation, Urination, Diaphoresis/Diarrhoea, GI upset, Emesis, Bradycardia/bronchospasm, Miosis
Which occurs first a muscurinic effect or nicontinnic effect with acetylcholinesterase inhibitors
Muscurinic at lower doses
What is a central cholinergic syndromev
◦ CVS – bradycardia ± hypotension
◦ RESP – bronchoconstriction ± bronchospasm
◦ CNS – miosis, cholinergic syndrome – confusion, agitation, nausea/vomiting
◦ GIT – hypersalivation, ↑GIT motility, nausea/vomiting, diarrhoea
◦ GUT – urination, incontinence
◦ OTHER – lacrimation, diaphoresis
‣ Mnemonic SLUDGE-BM: Salivation/Sweating, Lacrimation, Urination, Diaphoresis/Diarrhoea, GI upset, Emesis, Bradycardia/bronchospasm, Miosis
What are the clinical uses of acetylcholinesterase inhibitors
Reversal of non depolarising block
Diagnosis and treatment of myasthenia gravis
Treatment of cognitive impairmeent
Glaucoma
Anticholinergic syndrome
How is duration of effect different between acetylcholinesterase drugs?
◦ Edrophonium short
◦ Neostigmine medium
◦ Organophosphate long
Wy
Which acetylcholinesterase drugs are reversible? Which are not?
◦ Edorphonium and neostigmine
◦ Irreversible organophosphate
Edrophonium structure
Quaternal armine
O
Onset of edrophonium
1-2 minutes
Offset of edrophonium
10minutes
Does edrophonium cross BBB
no
How is edrophonium cleared
Liver glucoronidation
How is edrophonium cleared
Liver glucoronidation
◦ 35% as biliary metabolites and 65% renally unchanged
Pyridostigmine as structurally
An analogue of neostigmine
How does pyridostigmine compare to neostigmine
Structural analogue with 1/4 potency
Why is pyridostigmine useful
Longer mechanism of action - 6 hours
Slower onset
What are some pharmacokinetic factors important to organophosphates
◦ Lipid soluble, transcutaneous absorption
◦ Large Vd
◦ Long excretion time
How does G protein behaviour translate to effects in GPCR
◦ Alpha - subunit can bind GDP and GTP; inactive GDP is bound to the alpha subunit ; when activated by extracellular ligand GDP exchanged for GTP and alpha unit dissociates from Beta/Gamma chains enabling it to affect ion channels or intracelluilar messengers
‣ Signal amplification occurs via multuple secondary mesengers and ion channels being affected by one GPCR
‣ Inactivated when alpa unit hydrolyses GTP to GDP and rejoins complex
‣ Intrinisc GTPase of the unit mens self limiting step
Gs protein coupled receptors have what intermediaries
‣ Activated by epinephrine, NA, histamine, glucagon and others
‣ Stimulates adenylate cyclase –> ^cAMP (from ATP)
Gi protein coupled receptors act how
‣ Activated by NA, PG, opiates and many peptides
‣ Decreases cAMP
Gq protein coupled receptors act how
‣ Acetycholine
‣ Catalyses phosphatidylinositol conversion via phosphodiesterases to –> Increase IP3 + DAG –> increased Ca intracellularly via endoplasmic reticulum and calcium membrane channels
What are the neurotransmitter vesicular transport proteins
nside the cell, there are two vesicular monoamine transporters: VMAT1 and VMAT2
‣ They transfer the reabsorbed neurotransmitter back into the vesicles
‣ They have little specificity- they will just take anything and drag it back into the vesicles
4 excitatory neurotransmitters
- Glutamate
- Dopamine
- Noradrenaline
- Acetylcholine (nicotinic receptors
What is the enzyme implicated in ACh creation
- Ester of choline (acetylated)
- Synthesized from choline (quaternary saturated amine water soluble nutrient complexed with B vitamins) and acetyl-CoA by choline acetyltransferase; cholinergic neurons actively suck choline up through a transporter.
How are substrates for ACh sourced or made
cholinergic neurons actively suck choline up through a transporter.
◦ Acetate from acetyl CoA formed from pyruvate and CoA by pyruvate dehydrogenase