ANS and neurotransmitters Flashcards

Question

What is acetylcholinesterase

Answer 1

* 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.

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

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

Answer 6

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

Answer 7

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

Answer 8

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)

Answer 9

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.

Answer 10

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

Answer 11

Muscurinic at lower doses

Answer 12

◦ 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

Answer 13

Muscurinic at lower doses

Answer 14

◦ 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

Answer 15

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

Answer 16

◦ Edrophonium short ◦ Neostigmine medium ◦ Organophosphate long

Answer 17

◦ Edorphonium and neostigmine ◦ Irreversible organophosphate

Answer 18

Quaternal armine

Answer 19

1-2 minutes

Answer 20

Liver glucoronidation

Answer 21

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

Answer 22

An analogue of neostigmine

Answer 23

Structural analogue with 1/4 potency

Answer 24

Longer mechanism of action - 6 hours Slower onset

Answer 25

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

Answer 26

◦ 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

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

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

Answer 31

* Glutamate * Dopamine * Noradrenaline * Acetylcholine (nicotinic receptors

Answer 32

* 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.

Answer 33

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

Answer 34

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

Answer 35

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

Answer 36

Phosphorylation endocytosis To remove activity of surface membrane receptors

Answer 37

M1, 3, M5 GPCR Gq M2, M4 Gi protein coupled receptors

Answer 38

‣ 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

Answer 39

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

Answer 40

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

Answer 41

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

Answer 42

Vanillyl Mandelic acid VMA

Answer 43

* 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

Answer 44

* 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

Answer 45

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.

Answer 46

* 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.

Answer 47

* 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

Answer 48

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

Answer 49

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

Answer 50

Inhibits the release of catecholamines

Answer 51

Enhance release of catecholamines

Answer 52

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

Answer 53

DAT and NET transporters

Answer 54

tyrosine transformation to DOPA by tyrosine hydroxylase

Answer 55

◦ 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

Answer 56

‣ 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

Answer 57

◦ 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

Answer 58

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

Answer 59

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)

Answer 60

* 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

Answer 61

‣ 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

Answer 62

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

Answer 63

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

Answer 64

Dopamine Catecholamines

Answer 65

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

Answer 66

Reduced adenylate cyclase, reduced cAMP Likely Gi PCR

Answer 67

Vasodilation of renal, mesenteric, coronary and cerebral vessels

Answer 68

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

Answer 69

GABA Glutamate Glycine

Answer 70

* Gamma aminobutyric acid - formed from the decarboxylation of glutamate (glutamate decarboxylase)

Answer 71

* Gamma aminobutyric acid - formed from the decarboxylation of glutamate (glutamate decarboxylase)

Answer 72

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

Answer 73

GABA A ligand gated chloride channel GABA B metabotropic receptor

Answer 74

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

Answer 75

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

Answer 76

Benzodiazepines

Answer 77

Propofol, barbituates, etomidate, volatile

Answer 78

Metabotropic COupled to G protein and increases K conductance and reduced Ca influx Generally inhibits neurotransmitter release via hyperpolarisation

Answer 79

POst synaptically in the brain but also in the spinal cord Involved in nociception and muscle tone Baclofen

Answer 80

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

Answer 81

* 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

Answer 82

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

Answer 83

◦ 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

Answer 84

NMDA AMPA Kainate

Answer 85

‣ 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)

Answer 86

‣ 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)

Answer 87

‣ 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)

Answer 88

◦ 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

Answer 89

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

Answer 90

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

Answer 91

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

Answer 92

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

Answer 93

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

Answer 94

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

Answer 95

◦ 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

Answer 96

Tryptophan hydroxylation and decarboxylation

Answer 97

Monoamines

Answer 98

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

Answer 99

* 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

Answer 100

* 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

Answer 101

* 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

Answer 102

* 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

Answer 103

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

Answer 104

* 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.

Answer 105

* 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.

Answer 106

◦ 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

Answer 107

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)

Answer 108

Supportively Management - cyproheptadine, haloperidol/olanzapine/chlorpromazine

Answer 109

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

Answer 110

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

Answer 111

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

Answer 112

Ethylamine tail

ANS and neurotransmitters Flashcards

(158 cards)