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Physiology and Pharmacology 2 > CNS Disorders > Flashcards

CNS Disorders Flashcards

2
Q

Lecture 1

A

Disorders of Demyelination and Ion Channel Dysfunction

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3
Q

What causes epilepsy?

A

Temporary abnormal CNS activity.

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4
Q

What are the possible symptoms of epilepsty?

A

Tonic and clonic convulsions. Loss of consciousness. Brain damage.

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5
Q

What are tonic convulsions?

A

Convulsions with prolonged muscle contraction.

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6
Q

What are clonic convulions?

A

Muscles alternate between relaxed and contracted.

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7
Q

What are the two symptomatic classes of epilepsy?

A

Focal syndromes - Localised abnormal CNS activity. Generalised - Abnormal activity in both hemispheres.

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8
Q

What are the two causative classes of epilepsy?

A

Idiopathic - No obvious cause. Mostly genetic in origin. Symptomatic - Neurological disturbance (Stroke damage/Head trauma/Tumour)

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9
Q

How is epilepsy diagnosed?

A

Medical history + Electroencephalography recordings.

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10
Q

How does an EEG work?

A

Measures cortical (surface) neuron activity between 2 electrodes. 16 electrodes used.

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11
Q

Describe a normal EEG pattern.

A

1-30Hz (Alpha = 8-13Hz; Beta = 13-30Hz).

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12
Q

How is overactivity indicated on an EEG?

A

Spikes

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13
Q

What are the limitations of EEG and how can they be overcome?

A

Measures only surface structure activity. PET/MRI scans can be used to measure activity in deeper regions.

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14
Q

What is the common cause of idiopathic epilepsy?

A

Mutations of sodium channels.

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15
Q

Give 2 examples of idiopathic epilepsy and the gene responsible.

A

Generalised Epilepsy with Febrile Seizures plus - SCN1A; Severe Myoclonic Epilepsy of Infancy - SCN1A.

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16
Q

What effect do mutations have on sodium channels? Give an example.

A

Slower inactivation of of sodium channels causing persistent current. Caused by substitution of GAL to QQQ at 879-881.

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17
Q

Describe the symptoms observed in Q54 mice.

A

Frozen posture at 3 months. Tonic-clonic seizures (grunts/trashing of limbs) and excess salivation when older. 75% die by 6 months (brain damage).

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18
Q

Describe the development of the hippocampus in Q54 mice.

A

Normal until seizures start - Severe neural loss.

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19
Q

What is BNFC?

A

Benign Neonatal Familial Convulsions.

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20
Q

What is the cause of Benign Neonatal Familial Convulsions.

A

Inherited mutations of ACh sensitive sodium (M-current) channel genes on chromosomes 8 and 20.

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21
Q

What are the symptoms of BNFC?

A

Brief generalised convulsions between 4th day and 3rd month of life. Later development normal but increased risk of epilepsy in later life.

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22
Q

What is the M-current?

A

Heteromultimeric voltage activated Potassium current.

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23
Q

What is the function of the M-current?

A

Regulates neuronal AP firing by decreasing excitability of neurones (Adaptation).

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24
Q

How is the M-current inhibited and what are the effects?

A

Activation of muscarinic receptors, Use of xE991 channel blocker. Increased excitability of a dissociated sympathetic neuron caused by the reduction in M-current. Sustained high firing frequency after depolarisation. No repolarisation.

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25
Q

Which genes are responsible for functional expression of the M-current?

A

KCNQ2/KCNQ3.

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26
Q

Describe the structure of a M-current channel subunit.

A

6TM domains. Incomplete 7th loop between S5 and S6.

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27
Q

What Is the M-current cycle?

A

Depolarisation (P(open) = low); High frequency stimulation; P(open) slowly increases causing the potassium current to broaden the AP; Frequency of firing decreases; Repolarisation (P(open) falls).

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28
Q

What is the effect of KCNQ2/3 mutations?

A

Decrease M-current amplitude by 20-30%. Neuronal hyperexcitability.

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29
Q

Give 4 examples disorders caused by mutations of M-current channels along with the mutation responsible.

A

Long QT Syndrome, Congenital Deafness - KCNQ1+KCNE1; Childhood-Onset Deafness - KCNQ3/4; Epilepsy - KCNQ2/3.

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30
Q

Give 3 examples of mutations in other channels and the disorders they cause.

A

GLRA1 - Startle Disease (Hyperekplexia); SCN4A (sodium channel) - Hyperkalemic periodic paralysis; SCN5A - Idiopathic Ventricular Fibrillation.

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31
Q

How does multiple sclerosis arise?

A

Axon demyelination leads to autoimmune responses against the damaged myelin.

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32
Q

What are the symptoms of multiple sclerosis?

A

Blurred vision, Muscle weakness/spasms, Loss of sensation.

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33
Q

What is the effect of multiple sclerosis on the CNS?

A

Breakdown of the blood-brain barrier at asymmetrical sites in the brain.

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34
Q

Explain the effects of demyelination on electrical properties of neurons.

A

Increased Cm due to thinning of insulator - causes longer time constant hence more current is required for depolarisation. Decreased Rm - shorter length constant - less EPSPs reach soma to form APs.

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35
Q

What are the effects of demyelination on physical properties of neurons?

A

Axon develops properties of an unmyelinated axon - Ion channels distribute uniformly. Slow, unreliable AP conduction. Longer AP/refractory periods blocks high frequency firing. Prone to spontaneous AP firing. Crosstalk.

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36
Q

Lecture 2

A

Cellular Mechanisms of Drug Action.

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37
Q

What is the composition of the CNS?

A

CNS = brain + spinal cord - bulk of CNS is neurons supporting glia and endothelial cells

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38
Q

Name three types of Glia cells

A

Schwann, astrocytes, oligodendrocytes

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39
Q

Primary target of Drugs?

A

Neurons

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40
Q

Give the two therapeutic uses of drugs in the CNS and give examples of their use in treatment

A

1.) Neurological: epilepsy, Parkinson’s, Alzheimers 2.) Psychotropic: anaesthetics, anxiolytics, antidepressants etc

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41
Q

Draw a quick sketch of the blood brain barrier

A

(should include a lumen, capillary, cleft and fenestra)

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42
Q

What does drug access to the brain require?

A

Carrier mediated transport or lipid solubility

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43
Q

General targets for the cellular basis of drug action?

A

Neurotransmission/Neuronal Function

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44
Q

GPCR (Alpha)q pathway?

A

Phospholipase C - Ins(1,4,5)P3 and dicylglycerol - Ca2+ and Protein kinase C

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45
Q

GPCR (Alpha)s/I pathway?

A

adenylyl cyclase - cAMP - protein kinase A

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46
Q

Give two ways the Neurotransmitter noradrenaline is removed and or undergoes degradation from the synapse cleft

A

Uptake 1: back into the synapse and repackaged into vesicles or breakdown via MAO Uptake 2: into neighbour glial cell and broken down by COMT

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47
Q

How is Acetylcholine removed from the synaptic cleft?

A

Breakdown by acetylcholinesterase

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48
Q

Other than Ionotropic and Metabotropic receptors what are other possible receptor targets?

A

Kinase- Linked receptors, Intracellular receptors (Not particularly well-developed CNS drug targets)

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49
Q

Breakdown of current drug targets by percentage static

A

Enzymes: 47%, GPCRs: 30% Ion Channels: 7%, Transporters: 4%

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50
Q

What are Hypnotics used to treat?

A

Treats Insomnia

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51
Q

What do Anxiolytics treat?

A

Treats anxiety

52
Q

Most common Anxiolytic drug?

A

Benzodiazepines

53
Q

Simple mechanism of Benzodiazepines on GABA(A) receptor

A

The anxiolytics is an agonist of the benzodiazepine site on the alpha1 or gamma2 subunit interface. This allows Cl- influx causing hyperpolarisation and thus inhibition

54
Q

Other anxiolytics (Hint: For stress and overactivity of sympathetic nervous system)

A

Beta Blockers.

55
Q

Two examples of Beta Blockers?

A

Propranol, Oxprenolol.

56
Q

Define Epilepsy

A

Electircal disturbances in the brain leading to seizures- brief, chronically recurring, rapid onset

57
Q

Cause of epilepsy?

A

Sodium channels stay open for too long, leading to hyper excitability of the neuron. Triggers excessive calcium release which can be neurotoxic

58
Q

General treatment of Epilepsy?

A

Use-dependent block of Na+ channels: rapid firing means drug accumulation and blocked activity

59
Q

Lecture 3

A

Antidepressants and Antipsychotics.

60
Q

Use of GABA(A) receptor as Epilepsy treatment

A

Poorly-defined barbiturate site agonist, potentiate effects of GABA (inhibitory)

61
Q

How to inhibit GABA breakdown in glial cells

A

Use Vigabatrin to reduce GABA- aminotransferase (stops GABA - succinic semialdehyde - succinate)

62
Q

What is the Biological amine theory?

A

Depression caused by functional deficit of transmitters (originally noradrenaline) whilst mania due to excess. Evidence for 2-3 amines: NA, serotonin and dopamine

63
Q

Depression: 3 Ways Drug treatment aimed at increase in neurotransmission

A
  1. Inhibit reuptake 2. Inhibit metabolism 3. Enhance release
64
Q

Depression: What is used to inhibit reuptake?

A

Tricyclic antidepressants: eg. Receptor antagonists

65
Q

Depression: What is used to inhibit metabolism?

A

Monoamine oxidase inhibitors (MAOIs) increases the amount for vesicular uptake and not degradation

66
Q

Depression: What is used to enhance release?

A

Alpha 2 adrenoceptor antagonists(presynaptic receptors - regulate release (usually inhibit)

67
Q

Depression: Why does clinical efficacy take weeks?

A
  1. Neuronal adaption 2. Neurogenesis
68
Q

Characteristics of Amphetamine

A

Idirectly acting sympathomimetic - structurally related to noradrenaline. Sufficiently similar to NA to be take up by uptake 1 (although releases mainly cytosolic NA - not exocytosis

69
Q

Clinical use of amphetamine?

A

CNS Stimulant in narcolepsy. Also used in ADHD

70
Q

methylenedioxymethamphetamine

A

MDMA - ecstasy

71
Q

Cocaine use

A

Local anaesthetic = state-depedent Na+ channel block *Powerful stimulant properties similar to amphetamines

72
Q

Define Psychoses

A

Marked distortions of reality and disturbances in perception intellectual functioning, affect (mood) motivation and motor behaviour

73
Q

Schizophrenia has two symptoms types what are they?

A
  1. positive: delusions and hallucinations, disorganised speech, bizarre behaviour 2. Negative: loss or decrease of normal function
74
Q

Generally what are psychoses thought due to?

A

Overactivity of dopaminergic systems- particularly mesolimbic - associated with emotions and cognition (schizophrenia due to over activity of dopaminergic systems. Post-mortem studies show increased striatal D2 receptors)

75
Q

What is the glutamate hypothesis regarding schizophrenia?

A

Compromised NMDA receptor function. Inhibits glycine uptake - studies with inhibitors of glycine transporter underway

76
Q

Lecture 4

A

Opioids as Analgesic Drugs.

77
Q

What are opioids used for?

A

Analgesia

78
Q

What are the effects of Analgesia?

A

Nausea, hypnosis and drowsiness, mood changes mental clouding, GI motility and secretions decrease. Respitation and heart rate and pupil contriction decrease

79
Q

What are the 3 types of opioid receptor?

A

Mu. Kappa. Delta.

80
Q

Give an example of a non-selective opioid and its precursor.

A

Beta-endorphin; Preproopiomelanocortin.

81
Q

Give an example of a delta-selective opioid and its precursor.

A

Leu-enkephalin; Preproenkephalin.

82
Q

Give an example of a kappa-selective opioid and its precursor.

A

Dynorphin; Preprodynorphin.

83
Q

Give 3 examples of a mu-selective opioids.

A

Endomorphin 1; Endomorphin 2; Morphine.

84
Q

Describe the cellular mechanism of action of opioids.

A

Bind to opioid receptors (GiPCRs) which negatively control cAMP concentration. Beta/gamma subunits couple to ion channels.

85
Q

What are the 3 main neuronal effects of opioids?

A

Inhibit postsynaptic excitability. Inhibit transmitter release. Modulate presynaptic AP firing.

86
Q

What are the 3 main cellular effects of opioids?

A

Decrease in sodium channel conductance. Increase in potassium channel conductance. Decrease in calcium channel conductance.

87
Q

How do opioids decrease sodium channel conductance?

A

Decrease cAMP. PKA not activated. No phosphorylation of sodium channels.

88
Q

How do opioids increase potassium channel conductance?

A

Beta/gamma subunit positively regulates potassium channels by binding to them.

89
Q

How do opioids decrease calcium channel conductance?

A

Presynaptic membrane hyperpolarised by increased potassium conductance. Less N-type VOCCs open.

90
Q

What are the 3 mechanisms of increased drug tolerance?

A

Increased drug metabolising enzymes in liver. Altered number of receptors (insulin/BDNF). Conditioning via context of drug taking.

91
Q

How does psychological drug dependence develop?

A

Dopamine release in nucleus accumbens (Part of pleasure centre).

92
Q

What is used for morphine withdrawal? Why?

A

Biuprenorphine; Higher affinity. Less effective - eases withdrawal.

93
Q

What is used to treat opioid overdose? Why?

A

Naloxone; High affinity antagonist.

94
Q

Lecture 5

A

Parkinson’s Disease.

95
Q

What are the symptoms of Parkinson’s Disease (PD)?

A

Tremor at rest; Muscular rigidity.

96
Q

What are the two categoried of PD?

A

Parkinsonian syndromes. Symptomatic parkinsonism.

97
Q

Describe the difference in brain activity between normal and PD brains?

A

Similar to lesions of basal ganglia and locus coeruleus.

98
Q

Describe the damage of PD to basal ganglia.

A

Loss of 90% dopamine in SNpc. Degeneration of SNpc neurones. Loss of dopaminergic innervation of striatum. Abnormal increase in astrocytes (astrogliosis) (reverse causality).

99
Q

What are dopamine receptors. Name the classes.

A

GPCR receptors. D1-5.

100
Q

Describe D1 receptors.

A

G-alpha-s coupled - increase cAMP (Like D5).

101
Q

Describe D2 receptors.

A

G-alpha-i coupled - Decrease cAMP; Increase potassium conductance (Beta/gamma). Like D3/4.

102
Q

Describe D3 receptors.

A

G-alpha-i coupled - Decrease cAMP; Increase potassium conductance (Beta/gamma). Presynaptic. Inhibit DA release.

103
Q

What are lewy bodies?

A

5-25um spheres of lipids, neurofilaments, alpha-synuclein, synphilin-1 and ubiquitin.

104
Q

Where are lewy bodies found?

A

SNpc neuronal cytoplasm.

105
Q

What are lewy bodies associated with?

A

PD and cell loss.

106
Q

What is alpha-synuclein?

A

140aa protein with an amyloidogenic domain.

107
Q

What causes familial PD?

A

Mutations in alpha-synuclein gene (SNCA). Mutations of genes coding for enzymes of the ubiquitin proteosomal pathway. Mutations in PINK1 (PTEN-induced putative kinase 1). Mutations in PARK7-DJ1.

108
Q

Name 2 enzymes of the ubiquitin proteosomal pathway as well as their function, which are associated to PD.

A

PARK2 - E3 ubiquitin ligase. UchL1 - ubiquitin C-terminal hydrolase.

109
Q

What are the roles of alpha-synuclein?

A

Negative regulation of DA neurotransmission. Regulation of synaptic vesicle pools. Involved in protection of terminals from injury. Trafficking ER/Golgi cargoes.

110
Q

What can be deduced from build up of alpha-synuclein in lewy bodies?

A

Build up of toxic/damaged protein. May contribute to pathology. May be protective. Leads to cell death.

111
Q

Describe the two cell death patterns that PD may cause.

A

Acute - Loss of a part of SNpc (caused by toxin) followed by normal cell death. Accelerated rate of cell death.

112
Q

Why is PD hard to diagnose?

A

Cell death occurs 4-5 years before symptoms show - 50% cell loss.

113
Q

Describe the neurotoxic properties of PD cell death.

A

Pre-fibrillar oligomers form pores disrupting organelle function. Misfolding in ER causes neuropathology.

114
Q

What can be used as future treatment strategies for PD?

A

Modified aphla synuclein.

115
Q

What is the focus of current PD therapies? Why?

A

DA deficit. NA deficit also occurs but NA is a derivative of DA therefore focusing on DA targets both issues.

116
Q

What are the 4 therapies used in PD treatment?

A

Drugs replacing DA. Drugs mimicking DA. Drugs reducing DA metabolism. Surgery.

117
Q

Which drug is used for replacement therapies?

A

Levodopa (L-DOPA).

118
Q

How does levodopa work?

A

Substitutes DOPA in the catecholaminergic pathway. Increases DA release from alive synapses or floods them with new DA.

119
Q

What are the issues with levodopa?

A

Only 95% converted. <1% enters the brain. Side effects: Involuntary choreiform, Schizo-like syndrome.

120
Q

How has the levodopa treatment been optimised?

A

Inhibition of peripheral DA synthesis. DOPA decarboxylase inhibitors: Carbidopa/Benserazide. Inhibition of MAO-B (Selegiline) and COMT (Entacapone). Block of peripheral DA receptors.

121
Q

Which drugs are used for mimicking therapies?

A

DA receptor agonists: Bromocriptine, Pergolide, Lisuride.

122
Q

When are mimicking therapies used?

A

When DAnergic neurons are lost.

123
Q

Which drugs are used for DA metabolism reduction?

A

Selegiline/Entacapone.

124
Q

Describe surgical techniques used to treat PD.B91B89:B124B87:B124B85:B124B83:B124B81:B124B79:B124B78:B124B79B2:B124

A

Depolarisation block by deep brain stimulation or surgical ablation of Sub-thalamic nucleus/Globus Pallidus.

Physiology and Pharmacology 2 (8 decks)

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