Pharmacology of Movement Flashcards
Parkinson’s Pathology
Loss of dopaminergic cells in substantia nigra pars compacta
Lewy bodies in neurones- intracellular formations enriched in the protein alpha-synuclein
GABA inhibitory drive to thalamus becomes stronger
Dopamine Transporter (DaT) imaging
Help monitor gradual dopaminergic nigral cell loss
In striatum
Cardinal Parkinson’s signs
Resting tremor
Bradykinesia
Rigidity
Gait and postural changes
Parkinson’s other changes
Frozen facial expression Flexed posture Stop/Start movement Microphagia Depression Sleep disturbance
Non-motor features parkinsons
May precede by 12-15 years the onset of atypical Parkinsonian motor symptoms
SNCA gene
Used to make alpha-synuclein
Rare SNCA mutations, duplications or triplications cause autosomal dominant familial PD
Prevalence PD
2nd most common neurodegenerative disorder
100-180 in 100,000
M > F
Mitochondrial toxicity
MPTP= methyl-phenyl-tertrahydropyridine
Compound MPTP can be transformed into metabolite MPP+ which is neurotoxic for dopaminergic neurones
MPP+ taken up into neurone
Causes dysfunction of Complex 1 of the mitochondrial respiratory chain –> increased oxidative stress
Oxidative stress
Increased in Parkinson’s
Dopamine is highly oxidizable + its metabolism produces free radicals + oxidation products e.g. H2O2
MAO (b isoform) critically involved in oxidation processes
Dopamine biosynthesis
L-tyrosine –> L-Dopa
L-Dopa –> Dopamine
Dopaminergic pathways in CNS
Mesocortical
Mesolimbic
Nigrostriatal
Dopamine receptors
G protein coupled receptors
Dopamine binds to two types- D1-like and D2-like
D1-like receptor subtypes
D1 and D5
D2-like receptor subtypes
D2, D3, D4
L-Dopa
Biosynthetic precursor
Combined with peripherally acting DOPA decarboxylase inhibitors (carbidopa, benserazide)
Dopaminergic agonists
Ropinirole Pramipexole Rotigotine- transdermal patch Apomorphine- infusion Pergolide Bromocriptine
MAOB inhibitor
Protect residual dopamine against oxidation
Rasagiline
Selegiline
Anticholinergic (antimuscarinic) compounds
Dopamine loss leads to hyperactivity of cholinergic cells
Orphenadrine
Procyclidine
Amantidine
Inhibits dopamine reuptake
Increases dopamine release
COMT inhibitors
Used in combination with L-Dopa to enhance its effects
Entacapone
Tolcapone
L-Dopa adverse effects
Nausea/vomiting Postural hypotension Psychosis Impulse-control disorders Excessive day time sleepiness
L-Dopa motor complications
On-off effect
Wearing-off
Dyskinesia
Dystonia
Treatment stratergy
Mild- MAO-B inhibitor
Mild/moderate- Dopamine agonist
Moderate/severe- Levodopa + COMTI
Human embryonic mesencephalic graft
Graft is functional and releases dopamine
Surgical approaches to PD
Stimulation subthalamic nucleus
Thalamotomy
Pallidotomy
DBS - advance PD whose symptoms not adequately controlled by optimised pharmacological therapy
Huntington’s disease
Autosomal dominant
Changes in gene encoding protein huntingtin on chromosome 4
Gene presents with abnormal no. of repeats of glutamine in protein sequence
–> abnormal gene contains >36 repeats
–> gain of function mutation
–> mutated protein aggregates inside cells
Major degeneration of striatal neurones and cortical atrophy
Huntington’s disease pathological changes
Cortical atrophy
Prominent striatal degeneration
Loss of medium spiny neurones (striato-pallidal and striato-nigral)
Huntingtons- mechanisms underlying neurodegeneration
Excitotoxicity Loss of neurotrophic factors Accumulation of aggregates of mutant huntingtin protein Dysregulation of transcription Increased oxidative stress
Huntington’s symptoms
Choreic (jerky) movements Gait abnormalities Lack of coordination Cognitive impairment- bad attention and memories Sleep disturbance Weight loss Psychiatric disturbances
Huntington’s pharmacological management
Vesicular amine transporter inhibitor- tetrabenazine
Antidopaminergic drugs- haloperidol, olanzapine
Antidepressant drugs- imipramine, amitriptyline
