Huntington disease - mode of inferitence / chromosome and trinucleotide repeat / age
AD trinucleotide repeat disorder (anticipation)
ch 4
CAG
20-50
Huntington disease - symptoms / and movment disorders
- choreiform movements
- aggression –> athetosis, chorea
- depression
- dementia
Huntington disease - neurotransmitter alternations
- increased dopamine
- decreased GABA
- decreased Ach
Huntington disease - MRI
Atrophy of caudate and putamen with hydrocephalus ex vacuo
Huntington disease - Drugs
- Haloperidol
- Tetrabenazine
- reserpine
Huntington Drugs - Haloperidol - mechanism of action
D2 receptor antagonist
Huntington Drugs - Tetrabenazine - mechanism of action
inhibits vesicular monoamine transporter (VMAT) –> limits dopamine vesicle packagings and release
VMAT
vesicular monoamine transporter
Huntington Drugs and mechanims of action
- Haloperidol –> D2 receptor antagonist
- Tetrabenazine –> VMAT inhibitor
- reserpine –> VMAT inhibitor
Huntington Drugs - vesicular monoamine transporter (VMAT) inhibition —>
limits dopamine vesicle packagings and release
Alzheimer disease - histology exp
- loss of ach neurons
- senile plaques in gray matter
- Neurofibrillary tangles
Alzheimer disease - drugs and mechanism of action
- Memantine –> NMDA receptor antagonists
- Donepezil –> Ache inhibitors
- galantamine –> Ache inhibitors
- rivastigmine –> Ache inhibitors
- tacrine –> Ache inhibitors
Alzheimer disease - groups of drugs (no the drugs)
- NMDA receptor antagonists
2. Ache inhbitors
Alzheimer disease - NMDA receptor antagonist - drug
Memantine
Memantine - side effects
- Dizziness
- confusion
- hallucinations
Memantine - mechanims of action
NMDA receptor antagonists –>HELPS PREVENT EXCITOXICITY (mediated by Ca2+)
Alzheimer disease - Ache inhibitors - drugs
- Donepezil
- galantamine
- rivastigmine
- tacrine
Alzheimer disease - Ache inhibitors - side effects
- nausea
- dizziness
- insomnia
Parkinson disease - histology
- Lewy bodies
2. loss of dopaminergic neurons of substantia nigra pars compacta (de-pigmentation)
Parkinson disease - symproms
MNEMONIC: TRAP
- Tremor (pill-rolling tremor at rest)
- Rigidity (cogwheel)
- Akinesia (or bradykinesia)
- Postural instability
- Shuffling gait
Parkinsonism mechanism
loss of dopaminergic neurons and excess cholinergic activity
Parkinson disease drug - strategy
- dopamine agonists
- increase dopamine availability
- increase L-DOPA availability
- prevent dopamine breakdown
- curb excess cholinergic activity
Parkinson disease drug - dopamine agonists (drugs)
- bromocriptine (ergot)
- pramipexole (non-ergot)
- ropinirole (non-ergot)
Parkinson disease drug - dopamine agonists - preferred drugs
non ergot:
- pramipexole
- ropinirole
Parkinson disease drug - increase dopamine availability - drugs and mechanism?
amantadine –> increases dopamine release and decreases dopamine reuptake
amantadine - clinical use
- Parkinson disease
2. antiviral against influenza A and rubella
amantadine is also used as an antiviral against
- influenza A
2. rubella
amantadine - toxicity
- ataxia
2. livedo reticularis
Parkinson desease drugs - increase L-DOPA availability - mechanism
agents prevent peripheral (pre-BBB) L-DOPA degradation –> increase L-DOPA entering CNS –> increase central L-DOPA available for conversion to dopamine
agents that prevent peripheral (pre-BBB) L-DOPA degradation
- carbidopa
- entacapone
- tolcapone
entacapone - mechanism of action
prevent peripheral L-DOPA degradation to 3-0-methyldopa (3-OMD) by inhibiting COMT
tolcapone - mechanism of action
- prevent peripheral L-DOPA degradation to 3-0-methyldopa (3-OMD) by inhibiting peripheral COMT
- blocks conversion of dopamine to DOPAC by inhibiting central COMT
carbidopa - mechanism of action
block peripheral conversion of L-DOPA to dopamine by inhibiting peripheral DOPA decarboxylase –> reduse side effects of peipheral L-DOPA conversion into dopamine (eg. nausea, vomiting)
Parkinson disease drug - COMT inhibitors
- tolcapone (central and peripheral COMT)
2. entacapone (peripheral COMT)
Parkinson disease drug - prevenet dopamine breakdown - mechanism
agents act centrally (post-BBB) to block breakdown of dopamine –> increase available dopamine
Parkinson disease drug - prevenet dopamine breakdowν drugs
- selegiline (and rasagilini)
2. Tocpapne
tolcapone - mechanism of action
- prevent peripheral L-DOPA degradation to 3-0-methyldopa (3-OMD) by inhibiting peripheral COMT
- blocks conversion of dopamine to DOPAC by inhibiting central COMT
selegiline - mechanism of action
blocks conversion of dopamine into DOPAC by selectively inhibiting MAO-B
MAO-B preferentially metabolizes …. over …
dopamine
over
norepinephrine and seretonin
selegiline - clinical use
adjunctive agen to L-dopa in treatment of Parkinson
selegiline - toxicity
May enhance adverse effects of L-DOPA
L-dopa to dopamine - enzyme?
DOPA decarboxylase
L-dopa to 3-0-methyldopa
COMT
L-dopa - clinical use
Parkinson disease
L-dopa - toxicity
- arrhythmias from increased peripheral formation of catecholamines
- Long term use can lead to dyskenesia following administration (on-off phenomeno), akinesia between doses
L-dopa - mechanism of action
unlike dopamine, L-dopa can cross BBB and is converted by dopa decarboxylase in the CNS to dopamine
L-dopa to dopamine in the CNS- enzyme?
CNS dopa decarboxylase
Parkinson disease drug - curb excess cholinergic activity - drugs and action
Benzotropine (antimuscarinic) –> improves tremor and rigidity but has little effect on bradykinesia
memantine - side effects
- Dizziness
- confusion
- hallucinations
Parkinson disease - drug that causes livedo reticularis
amantadine
Parkinson disease - benzotropine - mechasism of action and uses
antimuscarinic –> improves tremor and rigidity but has little effect on bradykinesia
Parkinson disease - peripheral COMT inhibitors
- entacapone
2. tolcapone
Parkinson disease - central COMT inhibitors
tolcapone
all Parkinson drugs and mechanism of action (shortly)
- Bromocriptine (dopamine agonist)
- Pramipexole (dopamine agonist)
- ropinirole (dopamine agonist)
- amantadine (incr dopamine release and inh reuptake)
- Levodopa (increases dopamine levels in CNS)
- carbidopa (DOPA decarboxylase inhibitor)
- entacapone(peripheral COMT inhibitor)
- tolcapone (central and peripheral COMT inhibitor)
- selegiline (MAO-B inhibitor) (and rasagilini)
- benzotropine (antimuscarinic)