CNS Disorders Flashcards
(123 cards)
2
Q
Lecture 1
A
Disorders of Demyelination and Ion Channel Dysfunction
3
Q
What causes epilepsy?
A
Temporary abnormal CNS activity.
4
Q
What are the possible symptoms of epilepsty?
A
Tonic and clonic convulsions. Loss of consciousness. Brain damage.
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Q
What are tonic convulsions?
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Convulsions with prolonged muscle contraction.
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Q
What are clonic convulions?
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Muscles alternate between relaxed and contracted.
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Q
What are the two symptomatic classes of epilepsy?
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Focal syndromes - Localised abnormal CNS activity. Generalised - Abnormal activity in both hemispheres.
8
Q
What are the two causative classes of epilepsy?
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Idiopathic - No obvious cause. Mostly genetic in origin. Symptomatic - Neurological disturbance (Stroke damage/Head trauma/Tumour)
9
Q
How is epilepsy diagnosed?
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Medical history + Electroencephalography recordings.
10
Q
How does an EEG work?
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Measures cortical (surface) neuron activity between 2 electrodes. 16 electrodes used.
11
Q
Describe a normal EEG pattern.
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1-30Hz (Alpha = 8-13Hz; Beta = 13-30Hz).
12
Q
How is overactivity indicated on an EEG?
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Spikes
13
Q
What are the limitations of EEG and how can they be overcome?
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Measures only surface structure activity. PET/MRI scans can be used to measure activity in deeper regions.
14
Q
What is the common cause of idiopathic epilepsy?
A
Mutations of sodium channels.
15
Q
Give 2 examples of idiopathic epilepsy and the gene responsible.
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Generalised Epilepsy with Febrile Seizures plus - SCN1A; Severe Myoclonic Epilepsy of Infancy - SCN1A.
16
Q
What effect do mutations have on sodium channels? Give an example.
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Slower inactivation of of sodium channels causing persistent current. Caused by substitution of GAL to QQQ at 879-881.
17
Q
Describe the symptoms observed in Q54 mice.
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Frozen posture at 3 months. Tonic-clonic seizures (grunts/trashing of limbs) and excess salivation when older. 75% die by 6 months (brain damage).
18
Q
Describe the development of the hippocampus in Q54 mice.
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Normal until seizures start - Severe neural loss.
19
Q
What is BNFC?
A
Benign Neonatal Familial Convulsions.
20
Q
What is the cause of Benign Neonatal Familial Convulsions.
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Inherited mutations of ACh sensitive sodium (M-current) channel genes on chromosomes 8 and 20.
21
Q
What are the symptoms of BNFC?
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Brief generalised convulsions between 4th day and 3rd month of life. Later development normal but increased risk of epilepsy in later life.
22
Q
What is the M-current?
A
Heteromultimeric voltage activated Potassium current.
23
Q
What is the function of the M-current?
A
Regulates neuronal AP firing by decreasing excitability of neurones (Adaptation).
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.
25
Q
Which genes are responsible for functional expression of the M-current?
A
KCNQ2/KCNQ3.
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Describe the structure of a M-current channel subunit.
6TM domains. Incomplete 7th loop between S5 and S6.
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What Is the M-current cycle?
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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What is the effect of KCNQ2/3 mutations?
Decrease M-current amplitude by 20-30%. Neuronal hyperexcitability.
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Give 4 examples disorders caused by mutations of M-current channels along with the mutation responsible.
Long QT Syndrome, Congenital Deafness - KCNQ1+KCNE1; Childhood-Onset Deafness - KCNQ3/4; Epilepsy - KCNQ2/3.
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Give 3 examples of mutations in other channels and the disorders they cause.
GLRA1 - Startle Disease (Hyperekplexia); SCN4A (sodium channel) - Hyperkalemic periodic paralysis; SCN5A - Idiopathic Ventricular Fibrillation.
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How does multiple sclerosis arise?
Axon demyelination leads to autoimmune responses against the damaged myelin.
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What are the symptoms of multiple sclerosis?
Blurred vision, Muscle weakness/spasms, Loss of sensation.
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What is the effect of multiple sclerosis on the CNS?
Breakdown of the blood-brain barrier at asymmetrical sites in the brain.
34
Explain the effects of demyelination on electrical properties of neurons.
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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What are the effects of demyelination on physical properties of neurons?
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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Lecture 2
Cellular Mechanisms of Drug Action.
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What is the composition of the CNS?
CNS = brain + spinal cord - bulk of CNS is neurons supporting glia and endothelial cells
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Name three types of Glia cells
Schwann, astrocytes, oligodendrocytes
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Primary target of Drugs?
Neurons
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Give the two therapeutic uses of drugs in the CNS and give examples of their use in treatment
1.) Neurological: epilepsy, Parkinson's, Alzheimers 2.) Psychotropic: anaesthetics, anxiolytics, antidepressants etc
41
Draw a quick sketch of the blood brain barrier
(should include a lumen, capillary, cleft and fenestra)
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What does drug access to the brain require?
Carrier mediated transport or lipid solubility
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General targets for the cellular basis of drug action?
Neurotransmission/Neuronal Function
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GPCR (Alpha)q pathway?
Phospholipase C - Ins(1,4,5)P3 and dicylglycerol - Ca2+ and Protein kinase C
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GPCR (Alpha)s/I pathway?
adenylyl cyclase - cAMP - protein kinase A
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Give two ways the Neurotransmitter noradrenaline is removed and or undergoes degradation from the synapse cleft
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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How is Acetylcholine removed from the synaptic cleft?
Breakdown by acetylcholinesterase
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Other than Ionotropic and Metabotropic receptors what are other possible receptor targets?
Kinase- Linked receptors, Intracellular receptors (Not particularly well-developed CNS drug targets)
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Breakdown of current drug targets by percentage static
Enzymes: 47%, GPCRs: 30% Ion Channels: 7%, Transporters: 4%
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What are Hypnotics used to treat?
Treats Insomnia
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What do Anxiolytics treat?
Treats anxiety
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Most common Anxiolytic drug?
Benzodiazepines
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Simple mechanism of Benzodiazepines on GABA(A) receptor
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
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Other anxiolytics (Hint: For stress and overactivity of sympathetic nervous system)
Beta Blockers.
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Two examples of Beta Blockers?
Propranol, Oxprenolol.
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Define Epilepsy
Electircal disturbances in the brain leading to seizures- brief, chronically recurring, rapid onset
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Cause of epilepsy?
Sodium channels stay open for too long, leading to hyper excitability of the neuron. Triggers excessive calcium release which can be neurotoxic
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General treatment of Epilepsy?
Use-dependent block of Na+ channels: rapid firing means drug accumulation and blocked activity
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Lecture 3
Antidepressants and Antipsychotics.
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Use of GABA(A) receptor as Epilepsy treatment
Poorly-defined barbiturate site agonist, potentiate effects of GABA (inhibitory)
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How to inhibit GABA breakdown in glial cells
Use Vigabatrin to reduce GABA- aminotransferase (stops GABA - succinic semialdehyde - succinate)
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What is the Biological amine theory?
Depression caused by functional deficit of transmitters (originally noradrenaline) whilst mania due to excess. Evidence for 2-3 amines: NA, serotonin and dopamine
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Depression: 3 Ways Drug treatment aimed at increase in neurotransmission
1. Inhibit reuptake 2. Inhibit metabolism 3. Enhance release
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Depression: What is used to inhibit reuptake?
Tricyclic antidepressants: eg. Receptor antagonists
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Depression: What is used to inhibit metabolism?
Monoamine oxidase inhibitors (MAOIs) increases the amount for vesicular uptake and not degradation
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Depression: What is used to enhance release?
Alpha 2 adrenoceptor antagonists(presynaptic receptors - regulate release (usually inhibit)
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Depression: Why does clinical efficacy take weeks?
1. Neuronal adaption 2. Neurogenesis
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Characteristics of Amphetamine
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
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Clinical use of amphetamine?
CNS Stimulant in narcolepsy. Also used in ADHD
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methylenedioxymethamphetamine
MDMA - ecstasy
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Cocaine use
Local anaesthetic = state-depedent Na+ channel block *Powerful stimulant properties similar to amphetamines
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Define Psychoses
Marked distortions of reality and disturbances in perception intellectual functioning, affect (mood) motivation and motor behaviour
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Schizophrenia has two symptoms types what are they?
1. positive: delusions and hallucinations, disorganised speech, bizarre behaviour 2. Negative: loss or decrease of normal function
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Generally what are psychoses thought due to?
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)
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What is the glutamate hypothesis regarding schizophrenia?
Compromised NMDA receptor function. Inhibits glycine uptake - studies with inhibitors of glycine transporter underway
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Lecture 4
Opioids as Analgesic Drugs.
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What are opioids used for?
Analgesia
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What are the effects of Analgesia?
Nausea, hypnosis and drowsiness, mood changes mental clouding, GI motility and secretions decrease. Respitation and heart rate and pupil contriction decrease
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What are the 3 types of opioid receptor?
Mu. Kappa. Delta.
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Give an example of a non-selective opioid and its precursor.
Beta-endorphin; Preproopiomelanocortin.
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Give an example of a delta-selective opioid and its precursor.
Leu-enkephalin; Preproenkephalin.
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Give an example of a kappa-selective opioid and its precursor.
Dynorphin; Preprodynorphin.
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Give 3 examples of a mu-selective opioids.
Endomorphin 1; Endomorphin 2; Morphine.
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Describe the cellular mechanism of action of opioids.
Bind to opioid receptors (GiPCRs) which negatively control cAMP concentration. Beta/gamma subunits couple to ion channels.
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What are the 3 main neuronal effects of opioids?
Inhibit postsynaptic excitability. Inhibit transmitter release. Modulate presynaptic AP firing.
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What are the 3 main cellular effects of opioids?
Decrease in sodium channel conductance. Increase in potassium channel conductance. Decrease in calcium channel conductance.
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How do opioids decrease sodium channel conductance?
Decrease cAMP. PKA not activated. No phosphorylation of sodium channels.
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How do opioids increase potassium channel conductance?
Beta/gamma subunit positively regulates potassium channels by binding to them.
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How do opioids decrease calcium channel conductance?
Presynaptic membrane hyperpolarised by increased potassium conductance. Less N-type VOCCs open.
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What are the 3 mechanisms of increased drug tolerance?
Increased drug metabolising enzymes in liver. Altered number of receptors (insulin/BDNF). Conditioning via context of drug taking.
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How does psychological drug dependence develop?
Dopamine release in nucleus accumbens (Part of pleasure centre).
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What is used for morphine withdrawal? Why?
Biuprenorphine; Higher affinity. Less effective - eases withdrawal.
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What is used to treat opioid overdose? Why?
Naloxone; High affinity antagonist.
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Lecture 5
Parkinson's Disease.
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What are the symptoms of Parkinson's Disease (PD)?
Tremor at rest; Muscular rigidity.
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What are the two categoried of PD?
Parkinsonian syndromes. Symptomatic parkinsonism.
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Describe the difference in brain activity between normal and PD brains?
Similar to lesions of basal ganglia and locus coeruleus.
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Describe the damage of PD to basal ganglia.
Loss of 90% dopamine in SNpc. Degeneration of SNpc neurones. Loss of dopaminergic innervation of striatum. Abnormal increase in astrocytes (astrogliosis) (reverse causality).
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What are dopamine receptors. Name the classes.
GPCR receptors. D1-5.
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Describe D1 receptors.
G-alpha-s coupled - increase cAMP (Like D5).
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Describe D2 receptors.
G-alpha-i coupled - Decrease cAMP; Increase potassium conductance (Beta/gamma). Like D3/4.
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Describe D3 receptors.
G-alpha-i coupled - Decrease cAMP; Increase potassium conductance (Beta/gamma). Presynaptic. Inhibit DA release.
103
What are lewy bodies?
5-25um spheres of lipids, neurofilaments, alpha-synuclein, synphilin-1 and ubiquitin.
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Where are lewy bodies found?
SNpc neuronal cytoplasm.
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What are lewy bodies associated with?
PD and cell loss.
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What is alpha-synuclein?
140aa protein with an amyloidogenic domain.
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What causes familial PD?
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.
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Name 2 enzymes of the ubiquitin proteosomal pathway as well as their function, which are associated to PD.
PARK2 - E3 ubiquitin ligase. UchL1 - ubiquitin C-terminal hydrolase.
109
What are the roles of alpha-synuclein?
Negative regulation of DA neurotransmission. Regulation of synaptic vesicle pools. Involved in protection of terminals from injury. Trafficking ER/Golgi cargoes.
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What can be deduced from build up of alpha-synuclein in lewy bodies?
Build up of toxic/damaged protein. May contribute to pathology. May be protective. Leads to cell death.
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Describe the two cell death patterns that PD may cause.
Acute - Loss of a part of SNpc (caused by toxin) followed by normal cell death. Accelerated rate of cell death.
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Why is PD hard to diagnose?
Cell death occurs 4-5 years before symptoms show - 50% cell loss.
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Describe the neurotoxic properties of PD cell death.
Pre-fibrillar oligomers form pores disrupting organelle function. Misfolding in ER causes neuropathology.
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What can be used as future treatment strategies for PD?
Modified aphla synuclein.
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What is the focus of current PD therapies? Why?
DA deficit. NA deficit also occurs but NA is a derivative of DA therefore focusing on DA targets both issues.
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What are the 4 therapies used in PD treatment?
Drugs replacing DA. Drugs mimicking DA. Drugs reducing DA metabolism. Surgery.
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Which drug is used for replacement therapies?
Levodopa (L-DOPA).
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How does levodopa work?
Substitutes DOPA in the catecholaminergic pathway. Increases DA release from alive synapses or floods them with new DA.
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What are the issues with levodopa?
Only 95% converted. <1% enters the brain. Side effects: Involuntary choreiform, Schizo-like syndrome.
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How has the levodopa treatment been optimised?
Inhibition of peripheral DA synthesis. DOPA decarboxylase inhibitors: Carbidopa/Benserazide. Inhibition of MAO-B (Selegiline) and COMT (Entacapone). Block of peripheral DA receptors.
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Which drugs are used for mimicking therapies?
DA receptor agonists: Bromocriptine, Pergolide, Lisuride.
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When are mimicking therapies used?
When DAnergic neurons are lost.
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Which drugs are used for DA metabolism reduction?
Selegiline/Entacapone.
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Describe surgical techniques used to treat PD.B91B89:B124B87:B124B85:B124B83:B124B81:B124B79:B124B78:B124B79B2:B124
Depolarisation block by deep brain stimulation or surgical ablation of Sub-thalamic nucleus/Globus Pallidus.
