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ANS and neurotransmitters Flashcards

1
Q

How big is the hypothalamus? What shape?

A

4cm squared wallnut shaped grey matter centre

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2
Q

What are the relations of the hypothalamus

A

◦ 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

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3
Q

Blood supply of the hypothalamus

A

◦ Anterior cerebral artery
◦ Perforating branches of the PCA
◦ Posteriormedial branches of PComm

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4
Q

Veinous drainage of the hypothalamus

A

into cavernous sinus via inferior hypophyseal veins and into the hypothalamo
* - hypophyseal portal system

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5
Q

What is contained in the anteiror hypothalamus

A

Supraoptic nuclei
Paracentricular nuclei

Controllin
- PSNS
- Heat loss
- Sleep
- Posterior pituitary ormones -osmoreceptors in supraoptic nuclei, oxytocin in paraventricular nuclei

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6
Q

What does the medial hypothalamus do

A

Energy balance
Sexual behaviour
Satiety

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7
Q

Lateral hypothalamic function

A

Efferent pathways ot the brainstem
Emotion and defence
Thirst
Desire to seek food

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8
Q

Posterior hypothalamus does what

A

SNS - vasomotor centres of the brain
Wakefullness

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9
Q

Main functions of the hypothalamus

A

Water balance and tonicity
Temperature
Autonomic nervous system
Pituitary endocrine function
Appetite and satirety
Behaviour and emotion
Circadian rhtyhm

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10
Q

How is the autonomic nervous system related to the hypothalamus?

A

◦ PSNS from anterior pituitary
◦ SNS from posterior pituitary - vasomotor centres of the brain

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11
Q

What are the 6 main hormones secreted from the hypothalamus triggering anterior pituitary release

A

◦ 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

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12
Q

Outline the anatomy of the sympathetic chain

A

‣ 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

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13
Q

Preganglionic SNS nerve cells arise from where? Describe their path

A

‣ 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

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14
Q

What is the path of post ganglionic sympathetic nerve fibres?

A

‣ 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

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15
Q

How is adrenal outflow different for SNS supply

A

‣ 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

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16
Q

What is the effect of the SNS

A
  • 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
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17
Q

Describe the path and type of fibre fo PSNS

A

◦ 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

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18
Q

Describe the path and characteristics of post ganglionic PSNS

A

◦ Short in length, unmyelinated C fibres
◦ In smooth muscle, heart, glands
◦ Acetylcholine via muscarinic receptors (GPCR) to modulate target organ activity

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19
Q

What are the PSNS CN

A

3 7 9 10

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20
Q

CN 3 acts as a PSNS via?

A

‣ CN 3 occulomotor nucleus —> ciliary ganglion —> ciliary muscle, iris spincter

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21
Q

CN7 acts as a PSNS

A

‣ CN 7 - Superior salivary nucleus —> submaxillary ganglion —> submaxillary and sublingual salivary glands

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22
Q

CN9 acts as a PSNS

A

‣ CN 9 - Inferior salivary nucleus —> optic ganglion —> parotid gland

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23
Q

How is CN10 implicated in PSNS function? How far down does it stretch

A

‣ 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

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24
Q

Describe the overall effects of the parasympathetic nervous system

A
  • 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
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25
Q

What is acetylcholinesterase

A
  • 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.
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26
Q

Two types of cholinesterase

A
  1. Achesterase - nerve endings & in RBCs
  2. Non-specific or pseudocholinesterases - destroy other esters - tissues & plasma
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27
Q

Acetylcholinesterase binding sites include

A

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

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28
Q

How does Acetylcholinesterase break down ACh

A

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

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29
Q

How does Acetylcholinesterase break down ACh

A

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

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30
Q

How do you classify the acetylcholinesterase drugs

A
  1. Reversible antongist via electrostatic binding - edrophonium
  2. Reversible antagnoiist via covalent binding - neostigmine
  3. Irreverrsible antagonist via covalent binding - organophosphates
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31
Q

How does edrophonium act

A

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

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32
Q

How does neostigmine act

A

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)

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33
Q

How do organophosphates act?

A

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.

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34
Q

What is a nicotinic effect

A

◦ Reversal of non-depolarising neuromuscular blockers
◦ Prolongs effect of suxamethonium (depolarising NMB)
◦ Anticholinesterase overdose → excess synaptic ACh → depolarisation block ± fasciculation

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35
Q

What is a muscurinic effect

A
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36
Q

Wh

A
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37
Q

Which occurs first a muscurinic effect or nicontinnic effect with acetylcholinesterase inhibitors

A

Muscurinic at lower doses

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38
Q

What is a muscurinic effect

A

◦ 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

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39
Q

Which occurs first a muscurinic effect or nicontinnic effect with acetylcholinesterase inhibitors

A

Muscurinic at lower doses

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40
Q

What is a central cholinergic syndromev

A

◦ 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

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41
Q

What are the clinical uses of acetylcholinesterase inhibitors

A

Reversal of non depolarising block
Diagnosis and treatment of myasthenia gravis
Treatment of cognitive impairmeent
Glaucoma
Anticholinergic syndrome

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42
Q

How is duration of effect different between acetylcholinesterase drugs?

A

◦ Edrophonium short
◦ Neostigmine medium
◦ Organophosphate long

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43
Q

Wy

A
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44
Q

Which acetylcholinesterase drugs are reversible? Which are not?

A

◦ Edorphonium and neostigmine
◦ Irreversible organophosphate

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45
Q

Edrophonium structure

A

Quaternal armine

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46
Q

O

A
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47
Q

Onset of edrophonium

A

1-2 minutes

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48
Q

Offset of edrophonium

A

10minutes

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49
Q

Does edrophonium cross BBB

A

no

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50
Q

How is edrophonium cleared

A

Liver glucoronidation

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51
Q

How is edrophonium cleared

A

Liver glucoronidation
◦ 35% as biliary metabolites and 65% renally unchanged

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52
Q

Pyridostigmine as structurally

A

An analogue of neostigmine

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53
Q

How does pyridostigmine compare to neostigmine

A

Structural analogue with 1/4 potency

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54
Q

Why is pyridostigmine useful

A

Longer mechanism of action - 6 hours
Slower onset

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55
Q

What are some pharmacokinetic factors important to organophosphates

A

◦ Lipid soluble, transcutaneous absorption
◦ Large Vd
◦ Long excretion time

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56
Q

How does G protein behaviour translate to effects in GPCR

A

◦ 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

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57
Q

Gs protein coupled receptors have what intermediaries

A

‣ Activated by epinephrine, NA, histamine, glucagon and others
‣ Stimulates adenylate cyclase –> ^cAMP (from ATP)

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58
Q

Gi protein coupled receptors act how

A

‣ Activated by NA, PG, opiates and many peptides
‣ Decreases cAMP

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59
Q

Gq protein coupled receptors act how

A

‣ Acetycholine
‣ Catalyses phosphatidylinositol conversion via phosphodiesterases to –> Increase IP3 + DAG –> increased Ca intracellularly via endoplasmic reticulum and calcium membrane channels

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60
Q

What are the neurotransmitter vesicular transport proteins

A

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

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61
Q

4 excitatory neurotransmitters

A
  • Glutamate
  • Dopamine
  • Noradrenaline
  • Acetylcholine (nicotinic receptors
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62
Q

What is the enzyme implicated in ACh creation

A
  • 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.
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63
Q

How are substrates for ACh sourced or made

A

cholinergic neurons actively suck choline up through a transporter.
◦ Acetate from acetyl CoA formed from pyruvate and CoA by pyruvate dehydrogenase

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64
Q

What is the rate limiting step in ACh creation

A

Reuptake

65
Q

How is ACh reuptaken

A

‣ One is Na/Cl dependent hihg affinity transporter
‣ The other is a lower affinity transport

66
Q

How does suxamethonium cause hyperkalaemia

A

Depolarises nicotonic receptors at NMJ which causes K flow out, Na flow in

In anyone with heaps of nicotonic receptors this is more likely to occur in large amounts e.g. burns, spinal cord injury etc

67
Q

Synaptic plasticity occurs via

A

Phosphorylation
endocytosis

To remove activity of surface membrane receptors

68
Q

Muscurinic receptors - subtypes and activity

A

M1, 3, M5 GPCR Gq

M2, M4 Gi protein coupled receptors

69
Q

How do M1 , 3 , 5 recepetors act? Where?

A

‣ Phospholipase C –> IP3, DAG system to increase IC Ca and open external calcium gated K+ channels (via phospholipase C activation of K+ channels) to hyperpolarise the cell
‣ M1 receptors in sympathetic ganglia and high affinity for antagonist pirenzepine; neural effect on memory, gastric secretio and GIT mobility

70
Q

Where do M2 receptors act? How?

A

Gi protein (decrease cAMP by inhibiting adenylyl cyclase) —> increased K+ channels
‣ M2 = heart; depressing autorhythmicity by opening inward rectifying K+ channels

71
Q

How are adrenaline and noradrenaline made?

A
72
Q

What is the amino acid from which adrenaline is produced

A

Tyrosine

73
Q

What is the intermediary molecule between tyrosine and dopamine?

A

DOPA

74
Q

How is tyrosine converted into dopamine

A
75
Q

How are catecholamines broken down?

A

MAO
COMT

76
Q

Where is MAO

A

OXIDATION MAO into inactive metabolites inside the cell (after reuptake)- this is the main way of getting rid of intracellular catecholamines. It is in high concentration in the liver and kidney but is everywhere
◦ MAO is located on the outer surface of the mitochondria, and comes in two flavours:
‣ MAO-A - peripherally located in the syncytioblast in the term placenta and the liver
* Centrally in noradrenergic neurons mainly the locus Coeruleus
‣ MAO-B - Peripehrally in platelets, lymphocytes and the liver, entrally in serotonergic neurons

77
Q

What structurally must be present for MAO to work

A

Amine group without a too large substituent, and nothing on the alpha carbon

78
Q

What is the end product of catecholamine metabolsim

A

Vanillyl Mandelic acid VMA

79
Q

COMT degrades catecholamine by?

A
  • Some of the metabolism (methylation by exchnaging hydroxyl group at the 3 position on the catechol ring for methyl group) is also performed by catechol-O-methyltransferase (COMT) and this is the main way of getting rid of extracellular catecholamines
    ◦ Concentrated in the liver and kideny but present everywhere
    ◦ In cytoplasm
    ◦ Mostly responisble for IV catecholamine metabolism
    ◦ For it to work the catechiolamine ring must be intact with 2 hydroxyl groups
80
Q

What does COMT need to wrok on catecholamines

A
  • Some of the metabolism (methylation by exchnaging hydroxyl group at the 3 position on the catechol ring for methyl group) is also performed by catechol-O-methyltransferase (COMT) and this is the main way of getting rid of extracellular catecholamines
    ◦ Concentrated in the liver and kideny but present everywhere
    ◦ In cytoplasm
    ◦ Mostly responisble for IV catecholamine metabolism
    ◦ For it to work the catechiolamine ring must be intact with 2 hydroxyl groups
81
Q

What is a catecholamine ring?

A

A benzene ring (6 carbon phenyl ring) with two hydroxyl groups in the 3 and 4 position which allow it to be effective at catecholamine receptors
◦ 3, 4 dihydroxybenzene
◦ Losing one hydroxyl group
‣ Increases lipid solubility and decreases the potency 10-fold
‣ Prevents metabolism by COMT, prolonging duration of action
◦ Losing both hydroxyl groups decreases the potency 100-fold - maximum potency occurs when separation of the hydroxy groups and ethyl amine groups is maximal.

82
Q

Draw the structure of a catecholamine including labellling the important components often altered

A
83
Q

What is the action of dobutamine at alpha and beta receptors

A
  • Dobutamine is a potent (full) beta-1 agonist
  • Dobutamine is a potent (partial) alpha agonist, which means it acts as an antagonist in situations where there is massive sympathetic overdrive (or co-administration of alpha agonist)
  • Dobutamine is a weak (partial) beta-2 agonist, which means it acts as an antagonist in presence of full beta-2 agonists like adrenaline or isoprenaline.
84
Q

How is noradrenaline created in the synapse

A
  • Noradrenaline from the cytoplasm (not in vesicles) is concentrated by VMAT 2 protein (vesicular amine transporter) into vesicles
    ◦ VMAT2 has equal affinity for dopamine, adrenaline, NA, seratonin
    ◦ Gets 90% into vesicles - the rest float about in the cytoplasm and get metabolised by mitochondrial MAO
    ◦ Once in vesicles they are trapped by low pH - existing in ionised water soluble form unable to diffuse out
    ◦ Dopamine is converted to NA by dopamine beta hydroxylase within the vesicles
85
Q

What calcium channels mediate exocytosis of neurotransmitters

A

◦ Mediated by Calcium influx through voltage gated N type calcium channels which open when the action potential reaches the synapse

86
Q

How is noradrenaline release modulated at the presynpatic membrane

A

◦ Enhanced release - presynaptic Beta 2 receptors –> increased cAMP
◦ Inhibited release - reduced cAMP
‣ Presynaptic alpha 2 AND adenosine A1 receptors presynaptically

87
Q

presynaptic alpha 2 receptors do what

A

Inhibits the release of catecholamines

88
Q

presynaptic beta 2 receptors do what

A

Enhance release of catecholamines

89
Q

Presynaptic adenosine receptors do what

A

Inhibit the release of catecholamines

Caffeine is an antagonist of this therefore enhance the release of catecholamines

90
Q

Reuptake of noradrenaline occurs via

A

DAT and NET transporters

91
Q

What is the rate limiting step of adrenaline syntheiss

A

tyrosine transformation to DOPA by tyrosine hydroxylase

92
Q

Alpha 1 action acts via which GPCR? What effect odes this have intracellularly?

A

◦ post synaptic, stimulation = vasoconstriction + contractility (different biochemical action to Beta1 receptors)
‣ MOA –> Gprotein (Gq) –> Phospholipase C –> IP3 + DAG –> Ca2+ release from sarcoplasmic reticulum and increased calcium sensitivity –> activation of calmodulin sensitive enzymes including myosin light chain kinase, calmodulin dependent protein kinase 1 and 2, phosphodiesterases
‣ Most pronounced inotropic effect an low frequencies of myocardial contraction (hypothermia) and does not affect HR
‣ Vasoconstriction in vascular smooth muscle

93
Q

What actions does alpha 1 have

A

‣ Vasoconstriction - arterioles of heart, brain, kidneys, lungs, skeletal muscle, skin
‣ Mydriasis - radial muscle of the iris (dilating pupil)
‣ Contrcats gut sphincters
‣ Inhibition of insulin release

94
Q

How does an alpha 2 receptor cause intracellular changes

A

◦ Pre and post synaptic
◦ Release of NA from presynaptic terminal activates alpha 2 receptor to inhibit the further release of noradrenaline (i.e. negative feedback), post junctional alpha 2 receptors are also located on reistsnace and capacitance vessels which mediate vasoconstriction
◦ Inhibit adenylate cyclase via Gi protein –> decreased cAMP and opening of K+ channels –> reduced phosphorylation of proteins and hyperpolarisatino of the membranes

95
Q

What are the observed effects of alpha 2 agonism

A

◦ Action
‣ relaxes the walls of the gut wall smooth muscles
‣ Central effects are sympatholytic - presynaptic inhibition takes place

96
Q

How does alpha 1 compare with alpha 2

A

Alpha 2 Difference to alpha 1
‣ Slower in onset
‣ Longer lastic
‣ More sensitive to pH and temperature change
‣ Can also be affected by AT2
‣ Central affects lower sympathetic outflow (postulated mechanism for clonidine)

97
Q

Beta 1 mechanism of action

A
  • Stimulatory Gs protein –> adenylyl cyclase –> (ATP –> cAMP) increased cAMP —> protein kinases —> phosphorylation and inhibition of K+ channels and blocks afterdepolarisation increasing ability of pyramidal cells to generate action potentials
98
Q

Beat 1 effects

A

‣ Heart - increased contractility, tachycardia (SA node rate/ectopic pacemakers), increased AV conduction velocity, reduced refractor period
‣ Increased glycogenlysis and adipose tissue lipolysis
‣ Increased renin release by the kidney
‣ Platelets –> aggregation

99
Q

Beta 2 effects

A

‣ Bronchial smooth muscle relaxation
‣ Relaxes gut wall smooth muscle and the baldder
‣ Uterine relaxation (if pregnant)
- Gluconeogenesis and glycogenlysis

100
Q

How does Beta 2 cause effects

A

(GPCR –> increased cAMP –> increased Na/K activity and hyper polarisation)

101
Q

DOpamine receptors react to what?

A

Dopamine
Catecholamines

102
Q

How many dopamine receptors

A

5 GPCRs

103
Q

Dopamine 1 receptor is what type of receptor? Intracellukar action

A

GPCR

◦ Gproteins stimulating adenylate cyclase --> increased cAMP
	‣ Inhibition of Na/K ATPase via secondary mesenger depolarising RMP
◦ D5 is essentially the same receptor
◦ post synaptic on sympathetic nerve --> stimulation leads to vasodilation of renal, mesenteric, coronary and cerebral vessels + sodium excretion
104
Q

D2 receptor is what type of receptor?

A

Reduced adenylate cyclase, reduced cAMP

Likely Gi PCR

105
Q

Effects of D1 receptors

A

Vasodilation of renal, mesenteric, coronary and cerebral vessels

106
Q

Action of D2 receptors

A

Reduced pituitary hormone release
Produces nausea and vomiting
Inhibits release of noradrenaline

107
Q

What neurotransmitters are amino acids

A

GABA
Glutamate
Glycine

108
Q

GABA stands for

A
  • Gamma aminobutyric acid - formed from the decarboxylation of glutamate (glutamate decarboxylase)
109
Q

How is GABA made

A
  • Gamma aminobutyric acid - formed from the decarboxylation of glutamate (glutamate decarboxylase)
110
Q

How is GABA metabolised

A

◦ Catabolised into succinate and plugged into the citric acid cycle by GABA transaminase

111
Q

2 GABA receptors , how do they differ

A

GABA A ligand gated chloride channel

GABA B metabotropic receptor

112
Q

GABA A receptor structure

A

pentamic structure ligand gated chloride channel hyperpolarising the membrane (5 protein subunits form a pore – 2 alpha, 2beta, gamma - multiple variants)
◦ 2x Alpha subunits - GABA binding site
‣ GABA binding causes increased opening frequency, augmenting Cl- conductance and hyperpolarising the membrane
◦ Modulatory units - Alpha/Gamma subunit - Benzodiazepines, flumazenil
‣ 2 different types Benzodiazepine binding sites - one more anxiolytic, on more sedative
◦ 2x Beta subunit - etomidate, barbiturates, propofol, volatile anaesthetics
‣ Stereospecificity evidenced by etomidate - as an enantiopure preparation the R+ isomer is the only clinically active isomer, the S- is not active
‣ Action: incease opening time –> hyperpolarisation
‣ Etomidate is GABA specific
◦ Both sites produce positive allosteric modulation – increase channel opening time so allowing for increased chloride entry resulting in hyperpolarisation

113
Q

What are the binding sites of allosteric modulators of GABA recpeotrs

A

pentamic structure ligand gated chloride channel hyperpolarising the membrane (5 protein subunits form a pore – 2 alpha, 2beta, gamma - multiple variants)
◦ 2x Alpha subunits - GABA binding site
‣ GABA binding causes increased opening frequency, augmenting Cl- conductance and hyperpolarising the membrane
◦ Modulatory units - Alpha/Gamma subunit - Benzodiazepines, flumazenil
‣ 2 different types Benzodiazepine binding sites - one more anxiolytic, on more sedative
◦ 2x Beta subunit - etomidate, barbiturates, propofol, volatile anaesthetics
‣ Stereospecificity evidenced by etomidate - as an enantiopure preparation the R+ isomer is the only clinically active isomer, the S- is not active
‣ Action: incease opening time –> hyperpolarisation
‣ Etomidate is GABA specific
◦ Both sites produce positive allosteric modulation – increase channel opening time so allowing for increased chloride entry resulting in hyperpolarisation

114
Q

What binds at the alph gamma subunit of GABA A recepeotrs

A

Benzodiazepines

115
Q

What binds to beta subunits of GABA A receptors for action

A

Propofol, barbituates, etomidate, volatile

116
Q

What binds to the alpha subunit of the GABA A recepotr

A

GABA

117
Q

Draw a GABA A channel and label the locations of bidning sites

A
118
Q

GABA B receptor type

A

Metabotropic

COupled to G protein and increases K conductance and reduced Ca influx

Generally inhibits neurotransmitter release via hyperpolarisation

119
Q

What drug acts on GABA B? Where are its receptors found

A

POst synaptically in the brain but also in the spinal cord

Involved in nociception and muscle tone

Baclofen

120
Q

Glycine is invovled in?

A

Sensitising NMDA recepeotrs
Inhibitory transmitter in the spinal cord via pentameric chloride chanel

121
Q

Glutamate produced from

A
  • Made from alpha-ketoglutarate (the krebs cycle intermediate) by reductive amination
    ◦ GABA shunt a reaction in the neuron bypassing the alpha ketogluarate dehydrogenase step of the Krebs cycle accounting for 10-40% of enuronal TCA cycle activity
122
Q

Function of glutamnate

A

75% of excitatory inputs in the CNS - fast synaptic transmission in the spinal cord, memory and learning, central sensitisation and plasticity

123
Q

Why is there glutamate build up in ischaemic areas?

A

◦ Therefore is removed from the synapse by Na mediated transport via 2 mechanisms (its own and a shared)
◦ If you can’t maintain a Na gradient however you can’t pump glutamate and the cells begin dying - this happens in ischaemic regions

124
Q

What are the receptors for glutamate?

A

NMDA
AMPA
Kainate

125
Q

Draw a NMDA receptor

A

‣ It is a heterotrtamer transmembrane protein, consisting of four subunits
* 2 x NR1 pore forming
* 1x NR2A subunit binding glutamate (orthosteric site)
* 1x NR 2B binding glycine (coactivating siter)
◦ The ligands are the neurotransmitters glycine and glutamate, both of which have to bind in order to activate the receptor
‣ Pore is blocked by Magnesium
‣ Phencyclidine binding site for Ketamine and PCP
‣ N20 and Xe antagonists at unknown site
◦ Activation
‣ Priming – activation of adjacent AMPA or NK1 receptor
‣ Partial depolarisation removes Mg or Zn plug
* Interestingly in the spinal cord with sufficient pain stimulus the magnesium ion is displaced by substance P and other cotransmitters
‣ Coactivation – binding of glycine
‣ Activation - Binding of glutamate –> opening –> ion flux
◦ Opening of the receptor channel permits the flow of:
‣ Potassium (out of the cell)
‣ sodium ( into the cell)
‣ calcium (into the cell)

126
Q

Describe the activation sequence of an NMDA receptor

A

‣ It is a heterotrtamer transmembrane protein, consisting of four subunits
* 2 x NR1 pore forming
* 1x NR2A subunit binding glutamate (orthosteric site)
* 1x NR 2B binding glycine (coactivating siter)
◦ The ligands are the neurotransmitters glycine and glutamate, both of which have to bind in order to activate the receptor
‣ Pore is blocked by Magnesium
‣ Phencyclidine binding site for Ketamine and PCP
‣ N20 and Xe antagonists at unknown site
◦ Activation
‣ Priming – activation of adjacent AMPA or NK1 receptor
‣ Partial depolarisation removes Mg or Zn plug
* Interestingly in the spinal cord with sufficient pain stimulus the magnesium ion is displaced by substance P and other cotransmitters
‣ Coactivation – binding of glycine
‣ Activation - Binding of glutamate –> opening –> ion flux
◦ Opening of the receptor channel permits the flow of:
‣ Potassium (out of the cell)
‣ sodium ( into the cell)
‣ calcium (into the cell)

127
Q

Describe the movement of electrolytes with NDMA receptor activation

A

‣ It is a heterotrtamer transmembrane protein, consisting of four subunits
* 2 x NR1 pore forming
* 1x NR2A subunit binding glutamate (orthosteric site)
* 1x NR 2B binding glycine (coactivating siter)
◦ The ligands are the neurotransmitters glycine and glutamate, both of which have to bind in order to activate the receptor
‣ Pore is blocked by Magnesium
‣ Phencyclidine binding site for Ketamine and PCP
‣ N20 and Xe antagonists at unknown site
◦ Activation
‣ Priming – activation of adjacent AMPA or NK1 receptor
‣ Partial depolarisation removes Mg or Zn plug
* Interestingly in the spinal cord with sufficient pain stimulus the magnesium ion is displaced by substance P and other cotransmitters
‣ Coactivation – binding of glycine
‣ Activation - Binding of glutamate –> opening –> ion flux
◦ Opening of the receptor channel permits the flow of:
‣ Potassium (out of the cell)
‣ sodium ( into the cell)
‣ calcium (into the cell)

128
Q

Describe AMPA receptors - agonist, action

A

◦ AMPA - 2 types, one is only for Na and the other allows Ca also
‣ Agonist: glutamate, AMPA
‣ Antagonist: CNQX
‣ Action: Na and Ca influx; K efflux

129
Q

Kainate receptors are found where? What type of receptor? Cause

A

◦ Kainate - ionotropic, presynaptic on GABA nerve endings and post synaptically elsewhere.
‣ Agonist: Kainate, glutamate
‣ Antagonist: CNQX
‣ Action: Na influx and K efflux

130
Q

Is there a GPCR for glutamate?

A

Yes

◦ G-protein coupled
◦ Increase intracellular IP3 and DAG, or decrease cAMP
◦ 11 varieties; they can be post or presynaptic
◦ Seem to be involved in synaptic plasticity and learning
131
Q

What are imidazoline receptors

A

I1 - hypotension - GPCR decreased cAMP and other signal pthways. Hyperpolarise adrenergic neurons

I2 - analgesic - found on mitochondria and potentiate opioid effects

I3 - insulin secretion effects

132
Q

How does adenosine act

A

Blocks reuptake of noradrenaline and adrenaline

  • ATP is released from synaptic vesicles with acetylcholine
  • In smooth muscle ATP produces excitation by opening Na and Ca channels
133
Q

How does substance P act

A

◦ Receptors are G-proten-coupled
◦ Activation of its receptor leads to activation of phospolipase C, as well as IP3 and DAG

134
Q

Histamine is a peptide, catecholamine, monoamine or other?

A

Monoamine
imidazole ring connected to an amine group by an etheylene group

135
Q

3 types of histamine receptors? How does each act

A

◦ H1 receptors activate phospholipase C via Gq –> increased IP3 –> increased calcium
‣ Excitatory by reducing potassium conductance and inhibiting hyperpolarisation
◦ H2 receptors Gs GPCR and increase intracellular cAMP concentration
‣ Prevent long afterdepolarisation in cortical and thalamic neurons, reducing refractory period
◦ Most of the H3 receptors are presynaptic and G-protein-coupled – inhibit the release of histamine and other neurotransmitters

136
Q

Seratonin derived from

A

Tryptophan hydroxylation and decarboxylation

137
Q

Seratonin belongs to what class of transmitters

A

Monoamines

138
Q

What is the role of seratonin

A

◦ Regulation of mood - 5HT2A
◦ Role in nausea - 5HT3 at the CTZ a dorsal medullarys tructure
◦ Intestinal motility
◦ Thermoregulation especially 5HT7 in hypothalamic nuclei
◦ Migraines

139
Q

What metabolises seratonin

A

MAO

140
Q

Describe the seratonin receptor family

A
  • Receptors - 7 receptor suptypes
    ◦ 5HT1, 5HT2, 5HT4 and 5HT7 are GPCR
    ‣ 5HT1 - is in the CNS adn vascular smooth muscles - sumatriptan acts
    * 5HT1A - cAMP activation increasing K+ ion conductance and IPSP
    ‣ 5HT2 - orbitofrontal cortex in visual processing - Mirtazepine is an antagonist (LSD an agonist)
    ‣ 5HT 4 - involved in the enteric nervous system
    ‣ 5HT7 is found in the hypothalamic nuclei and involved in thermoregulation
    ◦ 5HT3 is a ligand gated ion channel inhibited by ondansetron
    ‣ 5HT3 receptor activation increased Na and K+ conductance leading to excitatory post synaptic potential (EPSP) - non selective
    ‣ It is present in the enteric nervous system (motility) and the dorsal medullary chemoreceptor trigger zone involved in vomiting
141
Q

How does 5HT3 work

A
  • Receptors - 7 receptor suptypes
    ◦ 5HT1, 5HT2, 5HT4 and 5HT7 are GPCR
    ‣ 5HT1 - is in the CNS adn vascular smooth muscles - sumatriptan acts
    * 5HT1A - cAMP activation increasing K+ ion conductance and IPSP
    ‣ 5HT2 - orbitofrontal cortex in visual processing - Mirtazepine is an antagonist (LSD an agonist)
    ‣ 5HT 4 - involved in the enteric nervous system
    ‣ 5HT7 is found in the hypothalamic nuclei and involved in thermoregulation
    ◦ 5HT3 is a ligand gated ion channel inhibited by ondansetron
    ‣ 5HT3 receptor activation increased Na and K+ conductance leading to excitatory post synaptic potential (EPSP) - non selective
    ‣ It is present in the enteric nervous system (motility) and the dorsal medullary chemoreceptor trigger zone involved in vomiting
142
Q

What i the only ion channel of the seratonin receptors

A
  • Receptors - 7 receptor suptypes
    ◦ 5HT1, 5HT2, 5HT4 and 5HT7 are GPCR
    ‣ 5HT1 - is in the CNS adn vascular smooth muscles - sumatriptan acts
    * 5HT1A - cAMP activation increasing K+ ion conductance and IPSP
    ‣ 5HT2 - orbitofrontal cortex in visual processing - Mirtazepine is an antagonist (LSD an agonist)
    ‣ 5HT 4 - involved in the enteric nervous system
    ‣ 5HT7 is found in the hypothalamic nuclei and involved in thermoregulation
    ◦ 5HT3 is a ligand gated ion channel inhibited by ondansetron
    ‣ 5HT3 receptor activation increased Na and K+ conductance leading to excitatory post synaptic potential (EPSP) - non selective
    ‣ It is present in the enteric nervous system (motility) and the dorsal medullary chemoreceptor trigger zone involved in vomiting
143
Q

What are the GPCR seratonin receptors

A
  • Receptors - 7 receptor suptypes
    ◦ 5HT1, 5HT2, 5HT4 and 5HT7 are GPCR
    ‣ 5HT1 - is in the CNS adn vascular smooth muscles - sumatriptan acts
    * 5HT1A - cAMP activation increasing K+ ion conductance and IPSP
    ‣ 5HT2 - orbitofrontal cortex in visual processing - Mirtazepine is an antagonist (LSD an agonist)
    ‣ 5HT 4 - involved in the enteric nervous system
    ‣ 5HT7 is found in the hypothalamic nuclei and involved in thermoregulation
    ◦ 5HT3 is a ligand gated ion channel inhibited by ondansetron
    ‣ 5HT3 receptor activation increased Na and K+ conductance leading to excitatory post synaptic potential (EPSP) - non selective
    ‣ It is present in the enteric nervous system (motility) and the dorsal medullary chemoreceptor trigger zone involved in vomiting
144
Q

What agents are implicated in seratonin syndrome

A

SSRI
SNRI
MAO
TCAs
Pethidine, tramadol
MDMA
Sumatriptan, fentanyl, LSD

145
Q

What receptors are most implicated in seratonin syndrome?

A
  • Specific serotonin receptors are involved:
    ◦ 5-HT1A and 5-HT2A receptors are the most responsible
  • Stimulation of these receptors exceeds safe thresholds when:
    ◦ Serotonin synthesis is increased (eg. dietary tryptophan, soft cheese etc.)
    ◦ Serotonin release is enhanced (pethidine)
    ◦ Serotonin reuptake is inhibited (SSRIs, SNRIs, MDMA, tramadol)
    ◦ Serotonin metabolism is impaired (MAOIs, linezolid, methylene blue)
    ◦ Serotonin receptor agonists are present (eg. sumatriptan, LSD, fentanyl)
    ◦ St Johns Wart
    ◦ Or any combination of the above.
146
Q

How do agents causing seratonin syndrome act

A
  • Specific serotonin receptors are involved:
    ◦ 5-HT1A and 5-HT2A receptors are the most responsible
  • Stimulation of these receptors exceeds safe thresholds when:
    ◦ Serotonin synthesis is increased (eg. dietary tryptophan, soft cheese etc.)
    ◦ Serotonin release is enhanced (pethidine)
    ◦ Serotonin reuptake is inhibited (SSRIs, SNRIs, MDMA, tramadol)
    ◦ Serotonin metabolism is impaired (MAOIs, linezolid, methylene blue)
    ◦ Serotonin receptor agonists are present (eg. sumatriptan, LSD, fentanyl)
    ◦ St Johns Wart
    ◦ Or any combination of the above.
147
Q

How does seratonin increases result in the manifestations of seratonin syndrome?

A

◦ Altered function of other neurotransmitter systems for which serotonin is a neuromodulator (usually, an inhibitory influence)
◦ For the majority of these, serotonin excess leads to the disinhibition of presynaptic release of these mediators
◦ They include noradrenaline, acetylcholine, dopamine and glutamate

148
Q

manifestations of srratonin syndrome

A

Seratonin syndrome (RASCAL) - earlier onset (12 hours) than NMS
* Rhabdomyolysis
* Agitation
* Seizures
* Clonus (spontaneous) - hyperreflexia (differentiates from NMS where they are depressed, and NMS has rigidity without clonus)
* Autonomic - overdrive state with tachycardia, hypertension, hyperthermia, diarrhoea
* Large pupils - mydriasis (differentiated from NMS where there is no change to pupils)

149
Q

How do you manage seratonin syndrome

A

Supportively
Management - cyproheptadine, haloperidol/olanzapine/chlorpromazine

150
Q

NMS is characterised by what symptoms

A

NMS (FEVER LAD) - over days
* Fever
* Encephalopathy - stupour, coma, mutism
* Vitals unstable - hyper or hypotension, brady or tachycardia
* Elevated enzymes - CK
* Rigidity of the muscles, hypertonia
* Leucocytosis
* Acidosis and aspiration (increased secretions)
* Diaphoresis, dysphagia

Management
* Amantadine
* Bromocryptne
* Dantrolene has been used

151
Q

Describe the structural elements of a catecholamine?

A
152
Q

What is the modifications that can occur that alter function of the Beta carbon of a catecholamine (2)

A
153
Q

What alterations to the alpha carbon can be done on a catecholamien? What happens as a result? (2)

A
154
Q

What positions are the hydroxyl groups of a catecholamine on?

A

3 and 4

155
Q

What is the relevance of the hydroxyl groups on a catecholamine? How can they be modified to change function?

A
  1. Change to 3 + 5 Beta 2 selective
  2. Both at usual locations 3 + 4 necessary for COMT action
  3. Losing one OH group increased lipid soliubility but reduces potency by 10x; losing 2 decreases potency by 100x
156
Q

What relevance does the terminal amine group have on catecholamine function?

A

Smaller = alpha > beta
Bigger = Beta > alpha
Methyl groups confer beta selectivity

157
Q

What is the name of the beta and alpha carbon along with the terminal amine of a catecholamine?

A

Ethylamine tail

158
Q
A

Neuro (7 decks)

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