Parkinson's disease 1/2 Flashcards
what occurs in the catecholamie synthesis?
tyrosin to L-dopa by ttrosine hydroxylase
L-dopa to dopamine by aromatic L-amino acid decarbosylase
DA to NA by dopamine B-hydroxylase
NA to AD by phenyl ethanolamine N-methyltransferase
how common is PD in the UK?
Parkinson’s Disease (PD) second most common neurodegenerative disorder in UK after Alzheimer’sdisease.
how does PD occur?
Degeneration of dopamine secreting nerve cells although other neurons and neurotransmitter maybe involved
how is PD most commonly presented?
Patients have severe attack of tremors that affect one hand and then spread to the leg on the same side and then to the limbs
what would be present in neurons of a PD patient?
resence of cytoplasmicinclusions called Lewy bodies in some survivingneurons
what causes the degeneration of neurons in PD?
Excess of free radicals causes the degeneration of the neurons
what are the motor symptoms of PD?
T – Tremor: Involuntary shaking, trembling caused by muscles alternately contracting and relaxing at a rapid pace R – Rigidity: raised tone, maybe asymmetrical or limited to certain muscle groups A- Akinesia: Slowness of movement P - Postural instability: Balance problems, seen in cases of classic Parkinson’s
what are the non-motar symptoms of PD?
• Neuropsychiatric – Anxiety disorders, apathy, depression, psychosis and visual hallucinations, dementia. • Sleep disturbances – Excessive daytime sleepiness • Autonomic disturbances- Constipation, urinary dysfunction, sexual dysfunction, postural hypotension, weight loss, dysphagia, excessive sweating, excessive salivation • Sensory disturbance - Pain and olfactory dysfunction
what is bradykineseia?
abnormal slowness of movement
what is akinesia?
absence or loss of the power of voluntary movement
what are the risk factors for PD?
• Non – smokers and low caffeine drinkers are at
increased risk.
• Genetic mutations particularly autosomal
dominant mutations in gene LRRK-2 (5% of UK PD
patients).
• Mutations in parkin gene (autosomal recessive
type) can also cause PD
• Neuroleptic drugs can lead to symptoms of
Parkinson’s.
• Antiemetics such as Prochloperazine &
Metoclopramide can also cause Parkinson’s
disease.
where is DA produced?
basal ganglia
what is the role of the basal ganglia?
to orchestrate the
performance of well-learnt, voluntary and semi-
automatic motor skills and movement sequences.
what effects does DA have on the basal ganglia?
Dopamine promotes the functions of basal ganglia
and also plays a major part in various cognitive tasks
such as maintaining attention, switching the focus of
attention, mood, problem solving, decision making
and visual perception.
where are DA producing neurones located?
located in the
substantial nigra within basal ganglia.
how does formation of lewy bodies occur?
Progressive degeneration in dopamine producing
neurons leads to formation of Lewy bodies – the
characteristic hallmark used for the diagnosis of
Parkinson’s disease.
what is the characteristic hallmark used for the diagnosis of PD?
lewy bodies
where do lewy bodies get deposited in?
the dopamine
producing neurons and consequently such neurones
produce little or no dopamine.
when are clinical signs of the disease evident?
when around
80% of dopamine producing neurons are lost.
what causes PD?
• Dopaminergic neurons in substantia nigra and corpus
striatum (nigrostriatal DA-ergic tract) are destroyed
• Nigrostriatal dopaminergic tract - part of the
extrapyramidal system, responsible for motor control
• 80% of dopaminergic neurons are damaged, the
symptoms of Parkinson disease appear.
• The striatum, is also rich in excitatory cholinergic
neurons that counteract the action of dopamine.
• This is the dopamine-acetylcholine balance
• The dopaminergic system inhibits the ACh system
what is step 1 in diagnosing PD?
Step 1: Diagnosis of Parkinsonian Syndrome Bradykinesia plus one of the following - Rest tremor - Rigidity - Postural instability
what is step 2 in diagnosing PD?
Step 2: Exclusion criteria including History of - Repeated strokes - Neuroleptic medications use - Head injury - Definite encephalitis Presence of atypical features such as - Early falls - Supranuclear gaze palsy - Ataxia and cerebellar features - Early autonomic features - Early cognitive decline - Poor response to L-dopa
what is step3 in diagnosing PD?
Step 3 : Supportive clinical features (at least 3 required) - Unilateral onset - Rest tremor - Evidence of progression - Persistent asymmetry - Excellent response to L-dopa - L-dopa induced dyskinesias - L-dopa response for 5+ years - Clinical course of 10+ years
what is diagnosis of PD usually based on?
TRAP- motor symptoms
what should happen if PD is suspected?
patient should be referred to a
neurologist or geriatrician with specialist PD interest
for a definite diagnosis.
how can an MRI/CT scan help with PD?
may help in the diagnosis
what drugs are used in PD to restore the dopamine levels in nigro-stratal dopaminergic tract?
Levodopa (L-dopa) and carbidopa/benserazide Dopamine agonists MAO-B inhibitors COMT inhibitors Miscellaneous (Amantadine)
what drugs restore the dopamine-acetylcholine balance?
antimuscarinic
what is the most effective medicine for PD?
levodopa
what are the standard release preparations available for levodopa?
- levodopa/carbidopa (Sinemet)
- levodopa/benserazide (Madopar)
what are the prolonged release prep for levodopa?
- levodopa/carbiopa (Sinemet CR)
- levodopa/benserazide (Madopar CR)
what is the metabolic precursor of DA?
levodopa
what do the therapeutic and adverse effects of levodopa result from?
result from
decarboxylation to DA
what is levodpa given with and why?
Given with peripheral decarboxylase inhibitor to
prevent it peripheral break down
Carbidopa , Benserazide
what is a smaller dose of levodopa needed for?
to treat symptoms
how is levodopa nausea and vom reduced?
by the presence of DOPA decarboxylase inhibitors
what are the undesireable effects of l-dopa if given alone?
n/v, cardiac arrhythmias, hypotension
when is levodopas effect best?
in the first few years of treatment
what is the major symptom relief from levodopa?
motor function
why does levodopa overtime become less effective?
- Progressive loss of dopaminergic neurons.
- Down-regulation of D1/D2 receptors on post-synaptic terminals.
- Some patients require reduced doses of levodopa to prevent side effects; but increased frequency.
what is dyskinesia and who does it occur in?
80% of patients on long term levodopa
– Excessive and abnormal involuntary movements
– Dose-related – higher doses = increased risk.
– Occur more frequently in younger Parkinson’spatients.
what is the ‘on-off’ effect caused by levodopa?
– “Off” = marked akinesia. (absence or loss of thepower of voluntary movement)
– “On” = improved mobility but marked dyskinesia.
– Thought to be related to fluctuations in levodopa plasma concentrations.
– Fluctuations can be “smoothed out” by incorporating a dopamine receptor agonist into pharmacotherapy.
what are the s/e of levodopa?
• GI disturbances: (anorexia, nausea and vomiting) • Dry mouth • Postural hypotension (early stages; monitor BP ) • Drowsiness and Sudden onset of sleep • Dystonia, dyskinesia and chorea • Neuropsychiatric symptoms : hallucination, confusion ,abnormal dreams, insomnia
how should levodopa be taken and why should it be taken like this?
- should be taken on empty stomach, 45 minutes
before a meal. - Foods inhibit the absorption from the gut of
levodopa and it`s transport into the CNS.
what risk of interaction is there with levodopa and antihypertensive drugs?
inc risk of postrual hypotension
what risk of interaction is there with levodopa and MAOIs?
- Risk of hypertensive crisis due to increased
catecholamine with MAOIs
what does pyridoxine increase the breakdown of?
l-dopa
what is bromocriptine?
selective D2 receptor agonist and partial agonist at D1 receptors
what is pergolide mesylate?
directly stimulates both D1 and D2
receptors.
• Associated with cardiac valve fibrosis• Loses efficacy over time
what are the clinical uses of da receptor agonists?
- Used as individual drugs
- In combination with levodopa (and with anticholinergic drugs)
- In patients who are refractory to and cannot toleratelevodopa
what are the DA receptor agonists s/e?
• GI disturbances: (anorexia, nausea and vomiting)
• Cardiac arrhythmias
• Postural hypotension (early stages; monitor BP )
• Drowsiness and Sudden onset of sleep
• Dyskinesia (similar to L-dopa)
• Neuropsychiatric symptoms : hallucination, confusion,
abnormal dreams, insomnia
• Pulmonary infiltrates and erythromelalgia (Ergot –
related effects)
• Impulse control disorder (eg. Pathological gambling)
where do ropinirole and pramipexole have affinity for?
preferential affinity for D2 sub class specially at D2 and D3 receptors
when are ropinirole and pramipexole considered in PD treatment?
early management
how is rotigotine administered?
• Administered as once –daily transdermal patch
Provides even pharmacokinetics for 24 hrs.
how does age 65+ affect the half life of PD drugs?
inc to 12 hours in patients older than 65
what are the DA receptor agonists s/e?
• GI disturbances: (nausea and vomiting) • Sleepiness and fatigue • Marked hypotension • Drowsiness and Sudden onset of sleep (excessive daytime sleeping) • Dyskinesia • Neuropsychiatric symptoms : hallucination, confusion ,abnormal dreams, insomnia
what is apomorphine?
a potent da agonist with high affinity for D4 receptors
what does apomorphine have low affinity for?
• Moderate affinity for D2, D3, D5 and adrenergic α1D,α2B and α2C
low affinity for D1,
how is apomorphine given?
SC injection to provide a temporartu relief of ‘off’ periods of akinesia
only lasts 2 hours
what PD drug prolongs the QT interval?
apomorphine
what are the two types of MAOIs?
MAO-A – primarily metabolizes NA and 5-HT.
MAO-B – primarily metabolizes dopamine.
what are selegiline and rasagiline?
• Selective, irreversible inhibitors of MAO-B
how do selegiline and rasagiline work?
Prevent the break down of both naturally occurring
DA and DA formed from levodopa, resulting in
dopamine levels in the brain
what is seligeline metabolised to?
methamphetamine andamphetamine
how does MAOI deal iwth on/ off flucuations?
Enables reduction in levodopa dose or may smooththe “on-off” fluctuations associated with levodopa
when/ how would you give MAOIs for PD?
effective in early Parkinson’s disease (asmonotherapy or in combination with levodopa).
what are the S/E of MAOIs?
Selectivity for brain MAO-B makes selegiline lesslikely to produce ADRs involving peripheraltyramine (i.e., wine, cheese, and chopped liver)syndrome.
– Tyramine = catecholamine releasing agent.
– Blocks MAO-A at high doses.
– Hypertensive crisis due to peripheralaccumulation of NA.
– Fatal hyperthermia – may occur when administered in conjunction with meperidine, cocaine, or fluoxetine.
how do COMT inhibitors work?
diminish peripheral
metabolism of levodopa.
may also reduce on-off flucuations
are comt inhibitors bound to plasma albumin?
extensively -98%
how are COMT inhibitors excreted?
extensively metabolized and eliminated in
feces and urine
what are the SE of COMT inhibitors?
• Related to increased plasma concentrations of
levodopa.
• Include dyskinesias, nausea, and confusion.
• Other side effects: diarrhea, abdominal pain,
orthostatic hypotension, sleep disorders, orange
urine discoloration.
• Tolcapone – potentially hepatotoxic
what is the dose of rasagiline?
1mg daily
what is the dose of selegiline?
5mg daily initially increased to 10mg daily after 2-4 weeks
what is the dose of entacapone?
200mg initially with each dose of levodopa with dopa-decarboxylase inhibitor up to a max of 2g daily
what is the dose of tolcapone?
Dose of tolcapone is 100mg three times daily (minimum
gap between doses: 6 hours). Maximum daily dose of
up to 200mg three times daily. First dose should be
taken with levodopa and dopa-decarboxylase inhibitior
when can tolcapone be continued?
only be continued if substantial
improvement is seen beyond 3 weeks.
how do anticholinergics work?
decrease the activity of ACH
what is the clinical use for anticholinergics?
Used as secondary- adjuvant medications.
• They help control tremors in the early stages of the disease.
• Used drug induced Parkinson’s disease
• Generally not used in Idiopathic PD – less effective than DA drugs and could cause cognitive impairment
what are the side effects of anticholinergics?
• Constipation
• Blurred vision
• Dry mouth
• Urinary retention
• Neuropsychiatric symptoms : memory loss, confusion,
hallucinations.
• They are not used long-term due to their side effects.
what is amantadie?
antiviral drug – used for prophylaxis and treatment of
Influenza A
what is the moa of amantadine?
- Appears to increase the DA release in striatum
- Has anticholinergic property
- Blocks NMDA glutamate receptors
what actions does amantadine produce in PD?
• less efficacious than levodopa but it has fewer side
effects
• has little effect on tremor but is more effective than the
anticholinergic against rigidity and bradykinesia
what are the side effects of amantadine?
- Difficulty in concentrating
- Confusion, Insomnia
- Nightmares, Agitation
- Hallucinations
- Leg swelling
- Dermatological reactions include Livedo reticularis
when would amantadie be used in pD?
for people in the latter stages of Parkinson’s disease, if
they have problems with dyskinesia induced by
levodopa
