Parkinson Flashcards
Agonistic drug effect
1) increase precursor
2) destroy degrading enzyme
3) increase release of neurotransmitter
4) block autoreceptors (therefore block their inhibitory effect on neurotransmitter release)
5) bind to post-synaptic receptors and either activtes them or increases the effect on them of neurotransmitter molecules.
6) Block degradation or reuptake
Antagonistic drug effect
1) block synthesis
2) cause the NT to leak from the vesicles and be destroyed by degrading enzymes
3) Block the release
4) activate autoreceptors
5) receptor blocker - bind to postsynaptic receptors and blocks the effect of NT
“Involuntary tremulousmotion, with lessened muscular power, in parts not in actionand even when supported with a propensity to bend the trunk forwardsand to pass from a walking to a running pace: the senses and intellects being uninjured.”
“Involuntary tremulousmotion, with lessened muscular power, in parts not in actionand even when supported with a propensity to bend the trunk forwardsand to pass from a walking to a running pace: the senses and intellects being uninjured.”
parkinson
- Progressive neurodegenerative disease
- Extrapyramidal motor symptoms (tremors, rigidity and bradykinesia) due to striatal dopaminergic deficiency
- Various other neurotransmitters involved in non-motor symptoms (autonomic, psychiatric, sensory, ocular, gait imbalance)
- Progressive disorder
- Rate of disability progression is most marked in the early years of the disease.
- Significant disability 10-15 years after onset
- At later stages, PD patients become increasingly dependent in their activities of daily living.
epidemology
- Incidence and prevalence of PD increase with age, 1% of population aged > 60 years have PD.
- No significant difference in prevalence rates between the Chinese, Malays and Indians.
- Average age of onset early to mid-60s.
- Young-onset PD starts at age 21- 40, affects 5-10% of PD patients.
- Juvenile-onset PD starts before age 20 years. Higher frequency of genetically inherited PD amongst this group
Symptoms of parkinson
•Motor fluctuation, dyskinesias and non-motor symptoms (eg falls, postural instability, postural hypotension, confusion, dementia, suboptimal nutrition, speech and sleep disorders) are common at later stages.
Motor symptoms • Tremor at rest (“pill-rolling”) • Bradykinesia (slowness of movement) • Rigidity (“cogwheeling”) [Cardinal features of PD]
• Postural instability and gait disturbances
pathophysiology
- PD is not a single disease – sporadic, familial
- All share common end-mechanism
- Impaired clearing of abnormal/damaged intracellular proteins by ubiquitin-proteasomal system.
•Failure to clear toxic proteins
- -> accumulation of aggresomes
- -> apoptosis
•Lewybodies ≈ aggresome, containing α-synuclein and ubiquitin
Degeneration of dopaminergic neurons with Lewy body inclusions in substantia nigra –> dysfunction of nigrostriatal pathway
Substantia nigra-mediated release of inhibition permits a motor system to become active.
Normally inhibit a number of motor systems.
Loss of substantia nigra –> No release of inhibition –> Hypokinetic state
rational therapeutic strategies for the motor symptoms of PD (natural pathway of dopamine)
•Synthesis:
- L-tyrosine –> L-dopa (tyrosine hydroxylase)
- L-dopa –> dopamine (DOPA decarboxylase)
- Breakdown: -dopamine —> homovanillic acid (catechol-O-methytransferase, COMT & monoamine oxidase, MAO)
- D1 and D2 receptors (GPCRs)
Strategy to increase dopamine synthesis
- Levodopa
- Gold Standard
- First available in 1960s
- Dopamine precursor, “2-in-1” preparation with carbidopa, a DOPA-decarboxylase inhibitor to prevent side effects due to excess DA in PNS (Eg, Levodopa + carbidopa: Sinemet)
-L-dopa –> dopamine ( enzyme = DOPA decarboxylase)
therefore prevent conversation of dopa to dopamine at PNS.
Carbidopa cannot pass BBB. so only stay at PNS. and also increase half life of dopa
Side effect of levodopa
– Short term: nausea, vomiting, postural hypotension
– Long term: motor fluctuations and dyskinesia (10%/yr)
– Although levodopa is the most efficacious drug for the symptomatic management of both early and late Parkinson’s disease, the dose of levodopa should be kept to the minimum necessary to achieve good motor function.
Strategy: inhibit dopamine breakdown with COMT inhibitors
• Entacapone(Comtan®) or Tolcapone (Tasmar®)
- blocks COMT conversion of dopamine into an inactive form
- more levodopa is available to enter the brain (reduces required dose)
- only effective if used with levodopa
- increases duration of each dose of levodopa, beneficial in treating “wearing off” responses
COMT Inhibitor side effect
Entacapone(Comtan®) or Tolcapone (Tasmar®)
- Increase abnormal movements (dyskinesias)
- Liver dysfunction (Tolcapone)
- Nausea, diarrhea
- Urinary discoloration
- Visual hallucinations
- Daytime drowsiness, sleep disturbances
Strategy: inhibit dopamine breakdown with MAO-B inhibitors
- Selegiline or rasagiline(Azilect®)
- Mild antiparkinson activity
- Inhibits enzyme monoamine oxidase B, interferes with breakdown of dopamine
- Laboratory studies suggest that it may delay the nigral brain cell degeneration
Selegiline is efficacious as a symptomatic monotherapy and may be used in early stages of Parkinson’s disease.
MAO B ADR
- Heartburn, loss of appetite
- Anxiety, palpitation, insomnia
- Nightmares, visual hallucination
Strategy: activate dopamine receptors
• Dopamine agonists • Used since 1970s, adjunct or monotherapy • Available as – Bromocriptine(Parlodel®) – Pergolide(Celance®, Permax®) – Ropinirole(Requip®)
- Act directly on dopamine receptors in the brain to reduce the symptoms of PD
- Antiparkinsonianeffects not superior to levodopa (levodopa still the gold standard)
- Prevent or delay onset of motor complications
In younger Parkinson’s disease patients, therapy should commence first with dopamine agonists rather than levodopa.
