Wk 29 - Parkinson's disease 2 Flashcards
Which drugs restore dopamine levels in nigrostriatal dopaminergic tract?
- Levodopa (L-dopa) + carbidopa/benserazide
- Dopamine agonists
- MAO-B inhibitors
- COMT inhibitors
- Miscellaneous (Amantadine)
Which drug restore dopamine-acetylcholine balance?
Antimuscarinic
Levodopa
- Therapeutic + adverse effects result from decarboxylation to DA
- Given w/ peripheral decarboxylase inhibitor to prevent peripheral break down (Carbidopa , Benserazide)
- Nausea + vom red by DOPA decarboxylase inhibitors
Outline the therapeutic effectiveness of Levodopa
- Best results: 1st few years
- 80%: marked initial improvement
- 20%: normal motor function
- Effectiveness dec overtime
Why does the effectiveness of levodopa dec overtime?
- Progressive loss of dopaminergic neurons
- Down-reg of D1/D2 receptors on post-synaptic terminals
- Some require red dose but inc freq
Dyskinesias occur in what percentage of patients on long-term levodopa therapy?
80%
- Excessive + abnormal involuntary movements
- Higher dose = inc risk
- Frequently in younger patients
What are the side effects of levodopa?
- Anorexia, N+V
- Dry mouth
- Postural hypotension
- Drowsiness + Sudden onset of sleep
- Dystonia + dyskinesia
How is levodopa taken?
- Empty stomach, 45 mins before meal
- Food inhibit absorption from gut
Outline the interactions of levodopa
- Inc postural hypotension w/ antihypertensives
- Risk of hypertensive crisis due to inc catecholamine w/ MAOIs
- Pyridoxine inc peripheral break down of L-dopa
What do bromocriptine + pergolide mesylate dopamine-receptor agonists do?
- Bromocriptine - selective D2 receptor agonist + partial agonist at D1 receptors
- Pergolide mesylate - directly stims D1 + 2 receptos
What is Pergolide mesylate associated w/?
- Cardiac valve fibrosis
- Loses efficacy over time
What is the clinical use of bromocriptine + pergolide mesylate dopamine-receptor agonists?
- Used as individual
- Combination w/ levodopa
- Patients who are refractory to + can’t tolerate levodopa
What are the side effects of bromocriptine + pergolide dopamine-receptor agonists?
- GI disturbances:anorexia,nausea + vomiting
- Cardiac arrhythmias
- Postural hypotension
- Drowsiness + Sudden onset of sleep
- Dyskinesia
- Pulmonary infiltrates + erythromelalgia
- Impulse control disorder
What does ropinirole + pramipexole dopamine-receptor agonists do?
- Affinity for D2 sub class especially at D2 + D3 receptors
- Early management of PD
- Pramipexole: neuroprotective - scavenge H2O2
What does rotigotine dopamine-receptor agonists do?
- Used to treat sign + symptom of early PD
- Admin as OD transdermal patch
What are the side effects of ropinirole + pramipexole + rotigotine?
- GI disturbances: N + V
- Sleepiness + fatigue
- Marked hypotension
- Drowsiness + Sudden onset of sleep
- Dyskinesia
- Neuropsychiatric: hallucination,
confusion, insomnia
What does apomorphine dopamine-receptor agonists do?
- Potent dopamine agonist
- High affinity for D4 receptors
- Low affinity for D1 receptors
- Given via SC injection to provide temp relief of ‘off periods’ of akinesia
What does MAO-A metabolize?
NA + 5-HT
What does MAO-B metabolize?
Dopamine
What does selegiline + rasagiline do (MAOIs)?
- Selective, irreversible inhibitors of MAO-B
- Prevent break down of both naturally occurring DA + DA formed from levodopa
- Doesn’t inhibit MAO-A
What is selegiline metabolised to?
- Methamphetamine
- Amphetamine
Outline the therapeutic effectiveness of MAOIs
- Early PD
- Enables red in levodopa dose or smooth on-off fluctuations
What are the side effects of MAOIs?
- Blocks MAO-A at high dose - hypertensive crisis due to peripheral accumulation of NA
- Fatal hyperthermia when admin w/ meperidine, cocaine or fluoxetine
Give examples of COMT inhibitors + what they do?
Diminish peripheral metabolism of levodopa + red on-off fluctuations
- Tolcapone
- Entacapone
- Opicapone
What are the adverse effects of COMT inhibitors?
- Inc plasma conc of levodopa
- Dyskinesias
- Nausea
- Confusion
- Diarrhea
- Sleep disorders
- Tolcapone - hepatoxic
What is the main treatment for PD before levodopa?
Anticholinergics
What is the clinical use of anticholinergics?
- Control tremor in early stage
- Used: drug induced PD
- Not used in idiopathic PD (cause cog impairment)
What are the side effects of anticholinergics?
- Constipation
- Blurred vision
- Dry mouth
- Urinary retention
What is amantadine used for?
- Prophylaxis + treatment of influenza A
- For latter stages if problem w/ dyskinesia induced by levodopa
- Inc DA release in striatum
- Anticholinergic properties
- Blocks NMDA glutamate receptors
What are the side effects of amantadine?
- Difficulty in concentrating
- Confusion
- Nightmares
- Leg swelling
- Livedo reticularis
