Parkinsons 2 Flashcards
What does the loss of dopamine cause?
Alters the output of the basal ganglia circulitry resulting in changed motor control
How is dopamine degraded?
DA –(MAO)–> DOPAC –(COMT)–HVA
How is dopamine synthesised?
Tyrosine –(tyrosine hydroxylase)–> DOPA –(Dopa decarboxylase)-> Dopamine
What is ADME for L-DOPA?
- Absorbed well by duodenum and jejenum by neuronal AA transporters
- In GI/liver metabolised greatly by DDC to dopamine and degraded by MAO
- In systemic circulation DDC converts and COMT degrades
What is the blood brain barrier made up of?
What transporters are used to access BBB
- Smooth muscle cells, pericytes, endothelial cells
Large AA LAt1 transporter or SLC7A5 transporters used to enter BBB
What effects does L-DOPA have?
- Smooth, faster more controlled movements
- Tremor alleviated to lesser degree
- Improvement in initating and stopping movement
- speach
SIde effects of LDOPA
- Nausea
- Vomitting
- Postural hypotension
- Dyskinesia
- Pyshiatric disturbances
- Coloured urine
- GI bleeding
How can side effects of L-dopa be reduced?
Examples
L-DOPA + Peripheral DOPA decarboxylase inhibitors (DDCI)
Carbidopa
Benserazide
ADME for DDCI and LDOPA
- Absorbed by AA transporters in jejudenum and duodenum
- Less Ldopa converted by DDC in liver/GI
- Less Ldopa converted to DDC in systemic/ blood
- More LDopa in brain
Why should Ldopa not be taken with a large meals?
Competition between AA from food and Ldopa for AA transporter in liver
What dose should be given for DDCI and LDopa?
depends on indivdual and extend of disease progression
What first line treatments are available for people with parkinsons?
- L-Dopa and peripheral DDCI
- Oral or transdermla dopamine agonist
- MAO-B inhibitors
What second line treatments are available for people with parkinsons?
- B-adrenergic antagonist : PD with postural tremor
- amantadine
- Anticholinergics: for young people with severe tremors
What drug interactions occur with L-dopa?
- Anaesthetics: risk of arrhythmias
- Anti-depressants: hypertensive crisis
- Axiolytics/ hypnotics: antagonism with diazepam
- Antipsychotics: antagonism
- Vit B6: Antagonism except when given with DCI
What are side effects of dopamine agonists?
- Excessive day time sleepiness
- peripheral odema
- hallucinations and confusion
- Nausea and vomitting - use doperidone
- dopamine dysregulation syndrome
Who should ergot dopamine agonists not be used in?
What tests are required?
People with heart problems or people with serosal fibrosis
ECG, Blood tests, Radiological
What do antimuscularanics do in the treatment of parkinsons?
- Less effective than L-dopa
- Reduce tremor but no effect on slowness of movement
- Treatment of drug-induced parkinsons symptoms (antipyshotics)
What are side effects of antimusclarinics?
- Peripheral: dry mouth, blurred vision, constipation, urine retention
- Centeral - confusions, hallucinations, excitment, euphoria
What are the long term problems of people with PD?
- progessive decline in efficscy of drug treatment - desensitisation to dopamine
- Fluctuations in motor performance - involuntary movements. on/ off effect
What are the long term treatments of parkinsons disease?
- Manipulation of drug therpay
- More invasive drug treatments: apomorphine infusion/ intraduodenal levodopa
- neurosurgery and deep brain stimulation
What should be used in the treatment of motor complications in patients with advanced PD?
- Oral or transdermal agonists, non-ergot agonists preferred to ergot
- MAO-B inhibitors
- COMT inhibitors - reduces ‘fff’ time
What do MAO-B inhibitors do?
examples
reduces dopamine breakdown
selegiline
What are side effects of selegiline
hallucinations, insomnia, avoid sudden withdrawl
When are comt inhibitors used? what are the side effects?
In later disease progessive and used with L-dopa
dyskinesia, aneamia, urine disorder
What other drugs are used and what do they do?
- Amantadine: causes dopamine release and inhbits reuptake
- apomorphine - injection only. potent D1/2 agonist. Treats off period
