CNS Disorders (Lecture 18) Flashcards
What (2) things do we need to know to treat CNS disorders?
- The pathophysiological mechanism
- The symptomatic pathway - the transmitter pathway for impaired function
What are the 2 treatment strategies for schizophrenia?
- Affecting dopaminergic transmission
Antagonism of D2 (metabotrophic, postsynaptic) receptors
Which decreases the effects of excess dopamine signalling
E.g. Chlorpromazine - Affecting serotonergic transmission
‘Atypical antipsychotics’ - antagonise D2 & 5-HT2A receptors
This also works on negative symptoms
E.g. Clozapine
What are 2 drugs used in the treatment of schizophrenia and what pathways do they affect?
Chlorpromazine - dopaminergic transmission
Clozapine - serotonergic transmission
What is the treatment strategy for Alzheimer’s disease?
No cure
Increasing ACh signalling in the brain can provide some minor symptomatic improvements
Done through AChE inhibitors
What is the precursor for dopamine synthesis?
L-DOPA
What is the pathophysiology of schizophrenia ?
A GAIN & LOSS of function disorder - causes positive & negative symptoms
Characterised by excess dopamine
Altered serotonin & glutamate signalling likely upstream of excess dopamine
Is Parkinson’s disease a loss or gain of function disorder?
Loss of function (neurodegenerative) disorder
What is Parkinson’s disease caused by?
- Reduced dopamine signalling due to progressive dopamine neuronal death in substansia nigra (80% loss before symptomatic)
- Drug treatment for schizophrenia
Is Alzheimer’s disease a loss or gain of function disorder?
Loss of function (neurodegenerative) disorder
What are the 2 pathological hallmarks of AD?
Extracellular beta-amyloid plaques
Intracellular neurofibrillary tangles (tau protein)
What is the pathophysiology of AD?
2 pathological hallmarks: extracellular beta-amyloid plaques & intracellular neurofibrillary tangles (tau protein)
Accumulation of these protein deposits is followed by synapse loss and neuronal death - causing gross atrophy of brain tisse starting in the temporal lobe
Mechanism of neuronal death is unclear
AD patients have lower brain ACh levels & loss of cholinergic neurones
What is the relationship between AD and dementia?
AD is the most common form of dementia - progressive impairment of cognition & memory (60-70% of cases)
Is epilepsy a loss or gain of function disorder and what is it caused by?
A GAIN of function disorder caused by increased glutamatergic and / or decreased GABAergic signalling
The imbalance in excitation / inhibition in the brain causes seizures
What type of disorder is epilepsy?
A motor disorder
Causes abnormal activity in movement control circuitry
What is the pathophysiological mechanism of strokes?
Neuronal death (ischemia / haemorrhage)
What is the symptomatic pathway of strokes?
No specific pathway (localised legion)
What is the treatment strategy for strokes?
None - neurones cannot be restored
What is the pathophysiological mechanism of AD?
Amyloid plaques & tau tangles (still under research)
What is the symptomatic pathway for AD?
(Reduced) cholinergic signalling in the CNS (cortex)
What is the treatment strategy for AD?
Symptomatic treatment - through increasing ACh signalling in the brain, using AChE inhibitors
(Very limited due to side effects)
What happens if you reduce dopamine signalling (below the normal level) in the treatment of schizophrenia?
Causes Parkinson’s disease
What happens if you over-stimulate D2 receptors (in the treatment of Parkinson’s disease) ?
Causes schizophrenia
What conditions are caused by a LOSS of function / decreased activity?
Depression
Parkinson’s
AD
Negative symptoms of schizophrenia
What conditions are caused by a GAIN of function / increased activity?
Epilepsy
Anxiety
Pain
Positive symptoms of schizophrenia
What causes Parkinson’s disease?
A loss of neurones in the substansia nigra, causing a reduction of dopamine in the brain
What are the symptoms of Parkinson’s disease?
Primarily a MOTOR disorder - symptoms of tremor & rigidity (can’t initiate movement)
In late stages - disruption to emotion, motivation & cognitive function
What are the recent findings surrounding the treatment of AD?
Lecanemab (antibody therapy)
Targets amyloid accumulation directly - decreases amyloid plaques
Thus slows the onset / progression of symptoms of cognitive decline
What are the positive symptoms of schizophrenia?
Positive symptoms (caused by increased activity):
Hallucinations (mostly auditory)
Paranoia
Delusions
What are the negative symptoms of schizophrenia?
Negative symptoms (caused by decreased activity):
Flat affect - lack of emotional expressiveness / response to stimuli
Anhedonia - loss of pleasure / interest in activities
Reduced speech
Catalonia - state of abnormal motor behaviour characterised by immobility, extreme rigidity, or repetitive, purposeless movements
Describe the motor & non-motor seizures in epilepsy
Motor:
Clonic - repeated rhythmical jerking of the body
Tonic-clonic - person becomes unconscious, body goes stiff, body jerks and shakes
Non-motor (absence):
Individual becomes unconscious for a short time
What are the 3 types of focal onset seizures?
- Focal to bilateral tonic-clonic - seizures that spread to both sides of the brain
- Focal aware - awareness during seizure, knowledge of self & environment, consciousness intact
- Focal impaired awareness - affect a bigger part of one hemisphere of the brain than focal aware, consciousness is affected
What are the 4 targets of drugs for modulating synaptic transmission?
- Synthesis
- Release
- Effects (on target neurone)
- Removal
How can drugs increase / decrease synthesis of NT in the modulation of synaptic transmission?
Increase - add more precursor
Decrease - inhibit enzymes
How can drugs increase / decrease release of NT in the modulation of synaptic transmission?
Increase - agonists
Decrease - antagonists of presynaptic receptors
How can drugs increase / decrease effects of NT in the modulation of synaptic transmission?
Increase - with agonists
Decrease - with antagonists of postsynaptic receptors
How can drugs decrease removal of NT in the modulation of synaptic transmission?
Decrease by inhibition of re-uptake / metabolism of transmitter
What are the 4 main types of epilepsy?
- Focal
- Generalised
- Combination focal & general
- Unknown
*a person’s seizure determines which type of epilepsy they have
What are the 3 major treatment strategies to increase dopamine signalling in the treatment of Parkinson’s disease?
- Add L-DOPA precursor - increase dopamine synthesis
- increasing L-DOPA alone is ineffective as most is converted to dopamine in the periphery which cannot cross the blood-brain barrier
- AADC inhibitors (e.g. Carbidopa) used in addition to prevent the conversion of L-DOPA to dopamine so that it can cross the blood-brain barrier - Use D2 receptor agonists - mimic effects of dopamine in the brain by binding to dopamine receptors
- e.g. pramipexole, ropinirole, bromocriptine - Decrease metabolism (i.e. removal) of dopamine
- (central) COMT inhibitors (e.g. tolcapone)
What are the 2 treatment strategies for epilepsy and what do they target?
- Increase inhibition - target GABA
- Decrease excitation - target glutamate
How is inhibition increased in the treatment of epilepsy (target GABA)? (3 ways)
- Barbiturates (e.g. Phenobarbital) to open Cl- channels to cause hyperpolarisation
- Benzodiazepines (e.g. Diazepram) for positive modulation of GABA-A receptor (more subtle affect)
- Block GABA re-uptake (e.g. Tiagabine)
How is excitation decreased in the treatment of epilepsy (target glutamate) ?
- Block presynaptic Ca2+ channels = less release of glutamate (e.g. Gabapentin)
- Block postsynaptic Na+ channels = preventing AP generation (e.g. Carbamazepine)
Outline CNS disorders
They can be simplistically considered to be caused by a GAIN or LOSS of function
If this gain / loss can be mitigated or reversed then it may be possible to treat the disorder
What is the pathophysiological mechanism of Parkinson’s disease?
Neuronal death (dopaminergic neurones)
What is the symptomatic pathway of Parkinson’s disease?
Reduced signalling in the nigrostriatal dopamine pathway
What is the treatment strategy for Parkinson’s disease?
Delay / symptomatic
Increasing dopamine signalling
Why is the efficacy of AChE inhibitors limited?
- Short duration of action (short half-life)
- Limited selectivity - can result in unwanted side effects - dose needs to be low enough not to affect autonomic & motor function in the periphery
- Central vs. Peripheral affects - some can cross blood-brain barrier, others can’t
- Tolerance - can build from prolonged use
- Adverse effects - inc. nausea, diarrhoea, muscle weakness
