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Medicine Year 2 > Scenario 28 > Flashcards

Scenario 28 Flashcards

1
Q

What is a seizure defined as?

A

An abnormal paroxysmal synchronous discharge of a very large number of cortical neurons causing symptoms

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2
Q

What is the prevelence of epilepsy?

A

0.6%

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3
Q

What % of adults with epilepsy become seizure free with treatment

A

70%

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4
Q

What are the causes of epilepsy?

A

Brain diseases, 50% not known, tumours, brain malformation, neurological infection, cerebrovascular disease, learning disability

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5
Q

What are the signs of an epileptic fit?

A

Abrupt onset, short event, confused and drowsy after, similar each time

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6
Q

What is a generalised seizure?

A

Widepread bilatersal brain networks- all of brain affected on EEG

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7
Q

What is a focal seizure?

A

May also arise in widespread bilat brain networks but only a small part of brain affected on EEG- can be with or withour consciousness

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8
Q

What is status epilepticus?

A

Seizure that continues for hours or days

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9
Q

What is the increase in mortality in epilepsy due to?

A

Accidental. drowning, SUDEP, status epilepticus or suicide

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10
Q

What is glutamate?

A

The major excitatory transmitter in CNS, mediates most fast excitatory neurotransmission (70% of synapses) principle mediator of sensory information, motor coordination, emotions and cognition

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11
Q

What is aspartate?

A

Mediates transmission at a small number of central synapses

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12
Q

How is glutamate synthesised?

A

In the brain from the metabolism of glucose and from glutamine synthesis by astrocytes

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13
Q

How is glutamate degraded?

A

Taken up by astrocytes and converted into glutamine for uptake into neurones and converted back to glutamate

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14
Q

How is glutamate stored?

A

In synaptic vesicles that actively accumulate glutamate using an electrochemical gdt created by proton pump- vesicle conc >20mM

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15
Q

How is glutamate released?

A

AP in presynaptic neurone depolarises it opening voltage gated Ca channels, Ca flows in cause exocytosis of synaptic vesicles

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16
Q

What glutamate receptors are there?

A

Ionotropic- NMDA, AMPA, Kainate (all have 4 subunits with 3 transmembrane spanning domains and large extracellular N-terminus)
Metabotropic- GPCRs

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17
Q

What are the main features of an AMPA receptor?

A

Subunits Glu 1-4
Fast synaptic current all permeable to Na, most impermeable to K, depolarises towards reverse potential causing inward current and depolarising the neuron. Fast decay due to low affinity for glutamate

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18
Q

What are the main features of an NMDA receptor?

A

Subunits- 2GluN1 (glycine binds) and 2GluN2 (glu binds)
Permeable to Na, K and Ca, slower action (higher affinity for glutamate- doesnt dissociate as quickly)- mechanism for spatial and temporal summation.
Voltage sensitive, at membrane potentials

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19
Q

What are the main features of Kainate receptors?

A

Subunits- GluK1-3 can form functional homometric channels and GluK4/5 needs to combine with the previous
Permeable to Na and Ca, role not well understood, relatively long lasting EPSPs increasing excitability of postsynaptic neuron. Presynaptically important to modualte the amount of transmitter released.

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20
Q

What are the main features of Metabotropic receptors?

A

8 known, 7 transmembrane protein coupled receptors
Pre-synaptically they inhibit voltage gated Ca channels (reducing transmitter release) and post-synaptically inhibit some K channels increasing the excitability

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21
Q

What channel blocking drugs work on NMDA receptors?

A

Phencyclidine, ketamine, dextromethapan

Low concentrations- psychomimetic, higher concentrations- dissociative anaesthetics

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22
Q

How do Group 1 metabotropic receptors work?

A

mGluR1 and R5- activate phospholipase C, produce IP3 and DAG
IP3 causes Ca release and increase intracellular Ca conc
DAG activates PKC for protein phosphorylation

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23
Q

How do the other metabotopic receptors work? R2-4 and 6-8

A

Inhibit adenylate cycles decreasing cAMP levels

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24
Q

What is long term potentiation?

A

phosphorylation of AMPA receptor causes increased Ca and CaM kinase II activating small GTPases causing altered gene expression and actin cytoskeleton/ structural changes

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25
Q

Why does increased glutamate release (epilepsy/stroke) cause cell death?

A

Calcium excitotoxicity- calcium increases and calcium dependent proteases are activated generating damaging molecules

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26
Q

What is GABA?

A

30% of synapses in CNS, major inhibitory NT, formed from glutamate by glutamic acid decarboxylase

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27
Q

What is Vigabatrin?

A

A synthetic GABA analogue. Inhibits GABA transminase (usually breaks down GABA) increasing GABA conc in brain - effective in some epileptic patients
Major drawbacks- deptession and can cause absence seizures

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28
Q

How is GABA stored?

A

Vesicles using an ATP dependent proton pump

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29
Q

How is GABA reuptaken?

A

transporters using energy from Na gradient in pre-synaptic neurons and glia

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30
Q

What is tigabine?

A

Inhibits GABA uptake causing increased conc

31
Q

What receptors are there for GABA?

A

Ionotropic GABAa receptors (post-synaptic)
Metabotropic GABAb receptors- pre and post GPCRs
In all areas of the brain

32
Q

What is the structure of a GABAa receptor?

A

5 subunits each with 4 transmembrane spanning domains. GABA binds and the interface of alpha and beta subinits (2). They are Cl selective ion channels that mediate fast inhibition by hyperpolarising neurons so that they cant depolarise to excitatory inputs.

33
Q

What are some examples of GABAa agonists and antagonists?

A

Agonist- muscimol from magic mushrooms

Antagonists- bicculline binds to GABA binding site, picrotoxin (blocks Cl channel)

34
Q

What are benzodiazepines?

A

Selectively potentiate GABA effects on GABAa receptors by binding to an accessory site and facilitate GABA binding allosterically
Agonists- diazepam, clonasepam, tamazepam
Antagonists- flumanezil

35
Q

What are the effects of benzodiazepines?

A

Anxiolytic, sedative, reduce muscle tone, anticonvulsant, amnesia

36
Q

What are the s/e of benzodiazepines?

A

Drowsiness, confusion, amnesia, tolerance and dependence from action at alpha 1 subunit

37
Q

What are barbiturates?

A

Bind to GABAa receptor at a different site to potentiate the effect of GABA- less specific than benzodiazepines
Pentobarbital, phenobarbital (s.e/ anticonvulsant), thiopental (IV anaesthetic)
Overdose- death from resp and CV depression

38
Q

What is the role of neurosteroids on GABAa receptors?

A

Synthesised in CNS in glial cells from cholesterol precursors, facilitates and enhances GABA transmission by binding to alpha subunit enhancing GABA mediated chloride currents
Disrupted steroid regulation of GABAergic transmission in panic disorder, depression, epilepsy

39
Q

What is the role of ethanol on GABAa receptors?

A

acute GABAa potentiation or longer term voltage gated Ca channel modifications

40
Q

What is the structure of GABAb receptor?

A

Identified by sensitivity to bicuculline, 7TM spanning domains coupled to Gi (inhibit adenylate cyclase)
GABAb R1- required for funtional response
GABAb R2- not activated by GABA

41
Q

What are the pre and post synaptic actions of GABAb receptor activation?

A

Pre- inhibition of voltage gated Ca channels by beta/gamma subunits and directly inhibit synaptic vesicle release
Post- increased opening of K channels causing reduced firing, inhibition of adenylate cyclase reduces cAMP levels and PKA activity

42
Q

What are some GABAb agonists?

A

Muscle relaxant baclofen, and GABA metabolite GHB

43
Q

What is glycine?

A

Major inhibitor transmitter in vertebrate CNS for regulation of motor neurones, retina, auditory and sensory systems

44
Q

How does glycine work?

A

Small pool packaged into synaptic vesicles and released glycine is taken up by GLYT1 and 2, astrocytes and presynaptic neurons
Receptors are pentameric 2 alpha 3 beta
Strychnine (antagonist) and glycine (agonist) bind to alpha and picrotoxin

45
Q

What happens if the glycine receptor is mutated?

A

Hyperkplexia- incrased muscle tone and startle reflex

46
Q

What happens in an absence seizure?

A

Sudden loss of awareness lasting 30 secs disengagement of the synchronisation of the cortex being aroused by the thalamus- T type Ca Channels

47
Q

What is the genetic factor to developing epilepsy?

A

2-3x more likely if a close relative suffers

48
Q

What is the cause of benign febrile epilepsy?

A

Mutation in KCNQ2/3 genes that encode voltage gated- potassium channels

49
Q

How do you induce seizures in an animal model?

A

Kainic acid injection and kindling (low intensity repeated electrical stimulation)

50
Q

What are the cellular mechanisms that initiate seizure?

A

Paroxysmal depolarising shift. Depolarisation is due to activation of AMPA and NMDA and opening of voltage gated Ca channels causing a burst of APs then repolarisation depending on opening of voltage gated K channels and activation of ionotropic GABA receptors- imbalance in this in epilepsy
Weak surround inhibition by local interneurons- spreads too much

51
Q

What drugs are used for tonic clonic, partial and temporal lobe seizures to enhance the activity of GABAergic systems?

A

Benzodiazepines, barbiturates, vigabatrin and tigabin (not in absence)

52
Q

What drugs are used for tonic clonic, partial and temporal lobe seizures to act as a use dependent block of voltage gated sodium channels?

A

Carbamazepine, phenytoin, lacosamide- reduce likeihood of APs at high frequencies but little effect at low frequencies
Stabilises the refractory state limiting firing

53
Q

What drugs are usef for absence seizures only?

A

Ethosuximide- block T type voltage gated Ca channels

54
Q

What drugs are used for both tonic clonic nd absence?

A

Sodium valporate- weak inhibition of GABA transaminase and blocking of sodium channels
Lamotrigine- use dependent sodium channel blocker

55
Q

What is a channelopathy?

A

Ion channel dysfunction

56
Q

What gene mutations can cause channelopathies?

A

Carrier proteins (sickle cell anaemia), transporters (cystic fibrosis), receptor operated channels (hyperekplexia), voltage gated ion channels (erythromelalgia, GEF, BFNC)

57
Q

What is hyperekplexia?

A

Muscle spasm in response to startle and hypertonia in infants

58
Q

What are the genetics of Hyperekplexia?

A

Autosomal dominant linkage to chromosome 5q32 in the same place as the gene for the glycine receptor. Point mutation in R271G in GLRA1

59
Q

What is the mechanism of hyperekplexia?

A

Nerve usually releases ACh which inhibirs the muscle and Renshaw cell which increases glycine inhibiton of skeletal muscle. In this condition glycine receptor isnt working so no negative feedback and reduced inhibition of the muscle

60
Q

What is familial erythromelalgia?

A

Burning pain in extremities in response to warm stimuli or moderate exercise, autosomal dominant gene SCN9A Nav1.7 alpha subunit point mutation phenylalanine to valine.

61
Q

Why does the mutation in sodium channel cause burning pain?

A

Affects inactivation of the channel causing decreased threshold of firing causing fibres to become hyper excitable and cause pain

62
Q

What is generalised epilepsy with febrile seizures caused by?

A

Convulsions when experiencing fever, autosomal dominant SCN1B point mutation. After the mutation the disulphide bond between the alpha and beta subunits is not formed meaning there is still quick activation but takes a long time to inactivate- persistent inward sodium current which causes hyperexcitability

63
Q

What are benign familial neonatal seizures?

A

Recurrent seizures in early life that resolves spontaneously. KCNQ2 framshift mutation but in this critical period need two working alleles. Mutation causes loss of C terminus meaning cell no longer fires phasically but tonically (perisitant firing)

64
Q

What are some inhilational anaesthetics?

A

Sevoflurane, isoflurane and nitrous oxide

65
Q

What Iv anaesthetics?

A

Propofol

66
Q

What is the ideal outcome of anaesthetics?

A

cause analgesia, suppression of reflexes, stress response and amnesia. Rapid onset, rapid recovery, minimal afer effects, s/e and drug interactions

67
Q

What happens to the EEG amplitude as depth of anaestheia increases?

A

Increases initially in stage 2 resembling sleep then decreases through 3 and 4

68
Q

What is the effect of G.As on thalamocortical arousal?

A

Inhibition of activity in cerebral cortex directly and secondary to inhibition of thalamic nucleus reducing thalamocortical activity which slows and synchronises activity leasing to a sleep like state where the cortex is isolated from sensory input

69
Q

How do GAs work?

A

Enhancement of GABAa receptor activity by directly activating Cl channel isolating the cortex (thiopental, proposal and etomidate)
Block of glycine site at NMDA receptor activity causing a profound analgesia and a dissociative anaesthesia (ketamine)
Activation of 2 pore domain K channels stabilising the membrane potential (NO, xenon)
Some do all three- end in flurane

70
Q

How do IV GAs reach the site of action?

A

Must be lipophilic and readily absorbed by brain tissue- redistributes to tissues so most not suitable for long procedures apart from popofol

71
Q

How do inhalational GAs reach site of action?

A

Also have to go through alveolar absorption at blood fas interface- slower onset
Drugs that dissolve quickest in blood take the longest toget into the brain. Reversal by excretion and metabolism

72
Q

What is used before starting surgery?

A

Narcotic analgesic eg fentanyl as an anxiolytic, sedative, amnesic and a muscrarinic antagonist to reduce secretions

73
Q

What is used in the procedure?

A

IV inductive agent eg propofol and a mainatainence agent eg devoflurane and NO and maybe a muscle relaxnt

74
Q

What is given during recovery?

A

Analgesic eg morphine antiemetic and anticholinesterase if a muscle relaxant was used

Medicine Year 2 (19 decks)

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