Week 11: Neurology - Epilepsy, Parkinson's Disease, Dementia Flashcards
What is dementia?
Dementia is a clinical syndrome that is characterized by progressive deterioration in cognition with resulting decline in function
Cognitive Impairment symptoms of dementia
- Cognitive impairment is the hallmark of dementia
- Trouble remembering new info
- Problems with speech and language
- Spacial disorientation
- Significant problems with long term memory
Neuropsychiatric symptoms of dementia
- Mood changes
- Delusions
- Hallucinations
- Shouting and agitation
What are the causes of dementia
5 major causes
- Most common is Alzheimer’s disease
- Vascular dementia
- Primary frontal dementia
- Dementia with Lewy bodies and Parkinson’s disease dementia
- Alcohol related dementia
Pathophysiology of Alzheimer’s
- Abnormal build up of proteins (increase amyloid plaques and Tau tangles) causing neuronal death
- Brain atrophy causing loss of inter-neuronal communication
- Neurochemical changes (decreased acetylcholine signalling) causing loss of inter-neuronal communication
Dementia - Non pharmacological interventions
- Aims
- Options
Not one size fits all - address patient overall well being rather than specific symptoms
Aims:
- Reduce distress
- Improve function
- Improve cognition
- Care giver support
- Improve quality of life
Options
- Memory training
- CBT
- Environmental modification
- Alternative therapies
- Behavioral management therapy
Dementia Pharmacological Management
- Neuropsychiatric symptom options
- Pharmacological interventions best reserved for exceptional circumstances
- Atypical antipsychotics (Risperidone) can manage hallucinations, delusions and disturbed behavior
> Associated with increase risk of mortality - Benzodiazepines (Oxazepam) can manage anxiety and agitation
> Exacerbate cognitive impairment and increase fall related injuries
Dementia Pharmacological Management - Cognitive impairment aims - Options > Example > MOA > ADR > Practice point
Aims
- Offer a modest improvement in cognition and function
- Does not modify underlying progression of dementia
- Specifically benefits patients with dementia caused by Alzheimer’s
Options
- Acetylcholinesterase inhibitors
> Donepezil, Galantamine, Rivastigmine
> MOA = increase synaptic concentration of acetylcholine by reducing its enzymatic breakdown through inhibition of acetylcholinesterase
> ADR = Gastrointestinal
> Practice point = Good adherence is important due to tolerability
- NMDA antagonist
> Memantine
> MOA = Antagonise NMDA receptor reducing glutamate-induced neuronal degradation
How does the brain communicate?
Between neurons is chemical impulse
Through neurons is electrical impulse
Process
- Electrical impulse
- Vesicular fusing
- Neurotransmitter binding
Electrical impulse in brain
- Excitation neurotransmitter bind to post synpatic neuron causing influx of positive charged ions
- Nearby voltage gated sodium channels open allowing more positively charged sodium to enter neuron
Vesicular fusing in brain
- Electrical impulse reaches end of neuron, there is a resultant opening of voltage gated calcium channels
- Influx of calcium causes vesicle to fuse with pre synaptic membrane
Neurotransmitter binding in brain
- Excitatory neurotransmitters bind to post synaptic neuron and cause influx of positively charged ions
- Inhibitory neurotransmitters bind to post synaptic neuron and cause influx of negatively charges ions
What is epilepsy?
(Characterized by)
What is a seizure?
- Disease of brain characterized by either the following
> At least two unprovoked seizures occurring >24 hrs apart
> One unprovoked seizure and risk of further seizures
> Diagnosis of epilepsy syndrome
Seizures are transient occurrence of signs and/or symptoms due to abnormally excessive or synchronous neuronal activity in brain
- Seizure threshold is lowered by pharmacological substances, sleep deprivation, fasting/malnutrition, psycho physiological stress, fever, menstruation
Classification of seizure types
Focal onset
- Aware/Impaired awareness
- Motor onset/Non motor onset
- Focal to bilateral tonic-clonic
Generalized onset
- Motor/Non motor
Unknown onset
- Motor/Non motor
- Unclassified
Epilepsy is an umbrella term
- What are the classifications of epilepsy’s?
- Seizure type
- Epilepsy type
- Epilepsy syndrome
- Aeitology
- Comorbidities
Epilepsy - Pharmacological intervention
- Goal of therapy
- Common drug classes used
Goals are to
- Suppress seizures
- Avoid adverse effects
Drug classes
- Barbituates
- Benzodiazepines
- Other antiepileptics
Epilepsy - Voltage gated sodium channel blockers
- Example
- MOA
- Adverse effect
- Practice points
Example
- Carbamazepine
MOA
- Prevent excessive neuronal communication through inhibition of voltage gated sodium channels
Adverse effects
- Many and some very serious
Practice points
- Lots of monitoring
- Strong CYP inducer - many interactions
- Can also be used to manage pain and bipolar disorder
Epilepsy - Voltage gated calcium channel blockers
- Example
- MOA
- Adverse effect
- Practice points
Example
- Gabapentin
MOA
- Prevent excessive neuronal communication through inhibition of voltage gated calcium channels
Adverse effects
- Many
Practice point
- Can also be used to manage neuropathic pain
Epilepsy - GABA enhancers
- Example
- MOA
- Adverse effect
- Practice points
Example
- Benzodiazepines (Clonazepam, Midazolam)
MOA
- Prevent excessive neuronal communication by enhancing effects of inhibitory neurotransmitter GABA
Adverse effects
- Highly sedating
Practice points
- Also used in wide range of psychiatric indications
- Is dependence a concern?
Epilepsy - Broad spectrum anti-epileptic
- Example
- MOA
- Adverse effect
- Practice points
Example
- Sodium valproate
MOA
- Prevent excessive neuronal communication by inhibiting voltage gated sodium channel, inhibiting voltage gated calcium channels and enhancing effects of GABA
Adverse effects
- Many and some very serious
Practice point
- Lots of monitoring
- Can be used in migraines and bipolar disorder
Physiology of dopamine
- Dopamine degradation process
- Dopamine receptors
Dopamine is a catecholamine neurotransmitter involved in movement, mood, prolactin release and emesis
It is degraded by both MAO and COMT
- MAO-A - expressed in CNS and periphery
- MAO-B - concentrated in CNS only and responsible for degradation of most CNS dopamine
There are 5 dopamine receptors (focus on two)
- D1 is positively coupled to adenylate cyclase which activates signalling and is excitatory
- D2 is negatively coupled to adenylate cyclase which inhibits signalling
Direct dopamine pathway
Indirect dopamine pathway
Nigrostriatal Pathway
Direct pathway
- Utilizes D1 receptor
- Stimulated by dopamine release
- Enables normal movement
Indirect pathway
- Utilizes inhibitory D2 receptor
- Inhibited by dopamine
- Inhibits movement (removes pathways inhibition of movement and therefore allows normal movement)
Both use the nigrostriatial pathways (extrapyramidal system) to control movement - purposeful movement and keeping muscles stable at rest
- Balance between the two allows smooth coordinated movement
Pathophysiology of Parkinson’s disease
Slow, progressive neurodegenerative disease of extra pyramidal motor system
Selective loss of dopaminergic neurons in CNS, especially in nigrostriatal pathway which controls movement
- Loss of dopamine in substantia nigra
> Can no longer activate excitatory D1 pathway reducing ability for normal movement
> Can no longer inhibit inhibitory D2 pathway which allows this pathway to take over/stay on thus further reducing movement
PD symptoms
- Non motor
- Motor
Non motor
- Sleep disturbance (insomnia, restless leg syndrome)
- Nausea, fatigue, speech problems, pain, dysesthesias
- Autonomic symptoms (drooling, constipation, sexual dysfunction, urinary problem, sweating, orthostatic hypotension, dysphagia)
- Psychological symptoms (anxiety, psychosis, cognitive impairment, depression)
Motor’
- Tremor at rest
- Rigidity
- Akinesia
- Bradykinesia
- Difficulty standing up straight
- Gait abnormalities
Pharmacotherapy of PD
- Individualization
Initial choice is about individualization (age, occupation and activity, economic situation, presence of cognitive decline, level of functioning)
- All therapies lose effectiveness over time
- Delay treatment until symptoms distressing or impact daily functioning
Start low go slow
Benefits may take weeks to see effect
Pharmacotherapy of PD
- Options
- Levodopa
- COMT inhibitor
- Dopamine agonist
- Anticholinergic drugs
- Selective MAO-B inhibitors
Surgical options
- Deep brain stimulation
- Ablative lesioning
Pharmacotherapy of PD; Dopamine precursors - MOA - Example - Practice points - Adverse effects
MOA
- Gets converted to dopamine both in periphery and CNS (active transporters for levodopa across BBB but dopamine cannot cross)
Example
- Levodopa
Practice point
- First line in most patients
- Co administered with dopa decarboxylase inhibitor to prevent peripheral breakdown
Adverse effects
- Many
- Nausea
- Hallucinations
- Insomnia
- Dyskinesia (worsens as disease progresses and is common)
- As levodopa effect wears off (reaches max effect) it causes on/off symptoms - patient looses ability of normal movement
Pharmacotherapy of PD; COMT inhibitors - MOA - Example - Practice points
MOA
- Inhibit COMT from being able to break down dopamine in CS and levodopa in periphery
Example
- Entacapone
- Tolcapone
Practice points
- Not used as single therapy, always given with levodopa
Pharmacotherapy of PD; Dopamine agonists - MOA - Example - Practice points
MOA
- Stimulate dopamine receptors to make more responsive to dopamine signalling
Examples
- Pramiprexole
- Bromocriptine
- Cabergoline
Practice point
- Lots of psychiatric ADR
Pharmacotherapy of PD; Anticholinergics - MOA - Example - Practice points
MOA
- Help rebalance signalling of cholinergic dopaminergic neurons in PD
Example
- Benzatropine
- Benzhexol
Practice points
- Make cognitive impairment worse
- Never to be used with patients that have dementia/Alzheimer’s
- Not to be used in patients with heart disease
Pharmacotherapy of PD; MAO-B inhibitors - MOA - Example - Practice points
MOA
- Inhibit MAO-B therefore reduce breakdown of dopamine in CNS and may block DA reuptake
Example
- Selegiline
- Rasagiline
Practice points
- Selective for MAO-B they have fewer ADR than non selective MAOIs used in depression
