Parkinsons' disease Flashcards
Pathophysiology of Parkinsons’ Disease
- degeneration of dopaminergic neurons in SNc
-> more cholinergic than dopaminergic input
- dopaminergic neurons: inhibit GABAnergic output in D2 pathway
- cholinergic neurons : excitatory effect on D2 pathway
Motor and non motor symptoms of Parkinsons
Motor:
- rigidity
- akinesia/ bradykinesia
- flat facies
- tremor at rest
Non motor:
- delusions/ hallucinations
- depression and anxiety
- speech and swallowing problems
- postural hypotension
Why dopamine not used as drug for Parkinsons
- readily metabolized peripherally
- cannot pass thru BBB
Name Levodopa MOA
- precursor of dopamine
-> increase dopaminergic transmission in nigrostriatal pathway
Name Levodopa CNS effects
CNS:
- marked symptomatic improvement in patients (hypokinesia, tremor, rigidity)
- some may have excitement frank psychosis
Name Levodopa peripheral effects
- tachycardia
- postural hypotension
- inhibit prolactin release + increase GH release
- enhance GFR
- nausea and vomitting (by excitation at chemoreceptor trigger zone)
gastric emptying and levodopa
- slow emptying
-> less available to penetrate BBB (longer exposure to degrading enzymes)
What competes with levodopa for same carrier
- amino acid
- compete for carrier for absorption
-> lower levodopa blood levels when taken with meal
What competes with levodopa for same carrier
- amino acid
- compete for carrier for absorption
-> lower levodopa blood levels when taken with meal
Levodopa adverse effects
- nausea, vomitting
- postural hypotension
- excessive: psychological disturbance
Cautious use of levodopa needed in
- elderly
- ischemic heart disease
- cerebrovascular
- psychiatric
- hepatic and renal (high first pass in liver)
- peptic ulcer (increase risk of bleeding)
- glaucoma
- gout
Long term effect of Levodopa
- wearing off - decline in efficacy for same dose
- On-off effect: oscillation between state of decreased mobility (off) and when med working and symptoms controlled (on)
- peak dose dyskinesia/ dystonic muscle spasm
- end of dose akinesia
State two peripheral decarboxylase inhibitor
- carbidopa
- benserazide
Benefits of combination with levodopa
- prolong levodopa plasma half live -> 1/4 dose reduction
- minimize on-off effect
- more sustained cerebral DA levels and reduced systemic conc.
-> reduce cardiac complications - minimize nausea and vomitting
Problems not resolved/ accentuated with peripheral decarboxylase inhibitor use
- involuntary movements more pronounced/ earlier
- postural hypotension
- excessive daytime sleepiness
-> not used along levodopa if patient develop MARKED involuntary mvmt with its use
SINEMET
MADOPAR
SINEMAT: levo + carbidopa
MADOPAR: levo+ berserazide
Name four dopaminergic agonis
- pramipexole
- ropinirole
- bromocriptine
- rotigotine
side effects of high dose bromocriptine
- vomitting
- hallucination
- hypotension
side effects of ropinirole and pramipexole
- behavioural side effects (gambling, impulsive shopping) , sexual overactivity
- nausea, dizziness
- hallucintaion
- postural hypotension
- daytime sleep -> shd not drive
advantage of pramipexole and ropinirole
- fewer GI symptoms
- slower rate of neuronal degeneration
- reducing frequency of on off effect
Use of ropinirole and pramipexole
- frequently used for monotherapy
- supplementary drugs to levodopa-carbidopa (in advanced case)
Name MAO-B inhibitor
Selegiline
State MAO-B inhibitor MOA
- selective and irreversible inhibitor
-> retard intracerebral degradation of DA
-> increase dopaminergic transmission in nigrostriatal pathway
State use of MAO-B inhibitor
- administered with Levodopa
-> prolongs and enhance levodopa action
-> decrease wearing off and motor fluctuation
Name COMT inhibitors
- Entacapone
-Tolcapone
COMT inhibitors MOA
- selective and reversible inhibitor
- block peripheral metabolism of levodopa & central metabolism of dopamine
- prolongs half live of levodopa/ dopamine
- entacapone acts only in periphery
- tolcapone prevents peripheral and central metabolism of levodopa
Name glutamate/ NMDA receptor antagonist
Amantadine
State amantadine MOA
- promotes presynaptic synthesis and release of DA in brain
- directly activates dopamine receptors
- blocks dopamine reuptake at high doses
State side effects of amantadine
- insomnia, nightmare
- restlessness
- confusion
- anticholinergic effects
*5. local release of catecholamine
-> postcapillary vasoconstriction -> bluish discolouration (livedo reticularis) + edema of ankle
- side effects attenuated when combined with anticholinergics
State use of antimuscarinic agents (benztropine and trihexyphenidyl)
- improve resting tremor and rigidity
- good for antipsychotics induced Parkinsonism
- NOT good for bradykinesia/ patients showing signs of dementia (who may have degeneration of cortical chorlinergics)
State undesirable effets of antimuscarinic agents
- dry mouth
- constipation
- urinary retention
- confusion, dementia
Name antimuscarinic agents
- benztropine
(- trihexyphenidyl)
