Movement Disorders 2 Flashcards
When should PD treatment started?
The decision to initiate symptomatic medical therapy in patients with PD is determined by the degree to which symptoms interfere with functioning or impair quality of life
Main dopaminergic pathways
1) Mesolimbic pathway: (μεσομεταιχμιακή)
Transmits dopamine from the ventral tegmental area (VTA), which is located in the midbrain, to the ventral striatum, which includes both the nucleus accumbens (επικλινής πυρήνας) and olfactory tubercle.
Associated processes:
reward-related cognition
incentive salience (“wanting”)
pleasure (“liking”) response from certain stimuli
positive reinforcement
aversion-related cognition
Associated disorders:
ADHD
addiction
schizophrenia
2) Nigrostriatal pathway: (μελαινοραβδωτή)
Transmits dopaminergic neurons from the zona compacta of the substantia nigra to the caudate nucleus and putamen.
The substantia nigra is located in the midbrain, while both the caudate nucleus and putamen are located in the dorsal striatum.
Associated processes:
motor function
reward-related cognition
associative learning
Associated disorders:
addiction
chorea
Huntington’s disease
Schizophrenia
ADHD
Tourette’s Syndrome
Parkinson’s disease
3) Mesocortical pathway: (μεσοφλοιώδης)
Transmits dopamine from the VTA to the prefrontal cortex
Associated processes:
executive functions
Associated disorders:
ADHD
addiction
schizophrenia
4) Tuberoinfundibular pathway: (φυματοχοανική)
Transmits dopamine from the hypothalamus to the pituitary gland.
This pathway controls the secretion of certain hormones, including prolactin, from the pituitary gland.
Associated processes:
regulation of prolactin secretion
Associated disorders:
hyperprolactinaemia
5) Hypothalamospinal tract
This pathway influences locomotor networks in the brainstem and spinal cord
Associated disorders:
restless legs syndrome
6) Incertohypothalamic pathway:
This pathway from the zona incerta influences the hypothalamus and locomotor centers in the brainstem.
Associated disorders:
tremor
Metabolic pathway of dopamine biosynthesis and degradation
Dopamine synthesis is initiated with the hydroxylation of tyrosine by the enzyme TH to generate L-DOPA.
L-DOPA is converted to dopamine by AADC (aromatic L-amino acid decarboxylase).
Dopamine beta hydroxylase (DBH) hydroxylates dopamine to form norepinephrine, which is converted to epinephrine by phenylethanolamine-N-methyltransferase (PNMT).
Dopamine is primarily metabolized by two enzymatic pathways, COMT and MAO.
COMT converts dopamine to 3-methoxytyramine, which is subsequently converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.
In contrast, MAO converts dopamine to 3,4-dihydroxyphenylacetaldehyde, which is then converted by aldehyde dehydrogenase (ALDH) to DOPAC.
In the final steps of dopamine degradation, ALDH and COMT convert 3-methoxy-4-hydroxyacetaldehyde and DOPAC to HVA, respectively
Levodopa half life
90 minutes
Which PD treatment is associated with highest risk of dopaminergic motor complications (such as “wearing off” (επιδείνωση στο τέλος της δόσης) and dyskinesia)
Levodopa
Should levodopa be taken with food?
Patients should be advised to take levodopa with meals to minimize nausea and improve adherence.
In later disease, levodopa should be taken on an empty stomach because concurrent ingestion of dietary protein may block the effect of a dose of levodopa.
This risk is low in early disease, however.
Which substance is combined with levodopa and why?
Levodopa is combined with a peripheral decarboxylase inhibitor (carbidopa or benserazide) to block its conversion to dopamine in the systemic circulation and liver in order to prevent nausea, vomiting, and orthostatic hypotension.
By preventing peripheral conversion to dopamine, which does not cross the blood-brain barrier, carbidopa or benserazide allows a smaller amount of levodopa to be administered systemically to produce the desired therapeutic effect centrally.
Levodopa Initial dosing and titration
Στα αρχικά στάδια της νόσου του Πάρκινσον συνιστάται να αρχίζει η θεραπεία με 1/4 του δισκίου Madopar “250”, 3 ή 4 φορές την ημέρα
Μόλις βεβαιωθεί η ανοχή του αρχικού θεραπευτικού σχήματος (λίγες μέρες εώς μια εβδομάδα), η δοσολογία θα πρέπει να αυξηθεί με εβδομαδιαία διαλείμματα χορηγώντας μια επιπλέον απλή δόση ημερησίως (π.χ. 4 ημερήσιες δόσεις αντί 3 κλπ.).
Εάν είναι δυνατή η στενή παρακολούθηση του ασθενούς, οι προσαρμογές της δοσολογίας μπορεί να γίνουν κάθε 2 έως 3 ημέρες.
Γενικά, η βέλτιστη δράση παρέχεται με ημερήσια δόση από 300-800 mg λεβοντόπα και 75-200 mg Benserazide, που διαιρούνται σε 3 ή περισσότερες απλές δόσεις.
Can levodopa and dopamine agonists be discontinued abruptly?
Levodopa should not be stopped abruptly in patients with PD, because sudden withdrawal has been associated (rarely) with a syndrome resembling neuroleptic malignant syndrome (fever, rhabdomyolysis) or akinetic crisis
plus dopamine withdrawal syndrome: απάθεια, φοβίες, κατάθλιψη, κόπωση, εφιδρώσεις, πόνος
Carbidopa-Levodopa contraindications
- nonselective monoamine oxidase inhibitors (MAOIs) or use within the last 14 days
- Narrow angle glaucoma
- Clinical or laboratory evidence of uncompensated cardiovascular, endocrine, hepatic, hematologic or pulmonary disease (eg, including bronchial asthma), or renal disease;
- presence of a suspicious, undiagnosed skin lesion or history of melanoma
Carbidopa-Levodopa adverse effects
- GI effects (Nausea, vomiting, constipation)
- Orthostatic hypotension
- Dyskinesia
- Psychiatric behavior abnormalities (agitation, confusion, delirium, delusion, disorientation, hallucination (visual and/or auditory), paranoid ideation, and psychosis)
- Impulse control disorders (Low risk in monotherapy) (pathological gambling, compulsive shopping, binge eating disorder, punding, and compulsive sexual behavior)
- Peripheral neuropathy, low B12 levels
- Withdrawal syndrome/Parkinsonism-hyperpyrexia syndrome
Other
>10%:
Nervous system: Depression, dizziness, headache
Neuromuscular & skeletal: increased CPK
Renal: Increased blood urea nitrogen
Προσοχή πρέπει να δίδεται σε ασθενείς με ιστορικό γαστρικού έλκους ή οστεομαλάκυνσης
What does “wearing off” mean?
the duration of benefit from each levodopa dose begins to shorten, and symptoms return before the next dose is due
In which cases treatment with alternative to levodopa can be given as inital therapy in PD?
●Mild symptoms, preference for once-daily medication – In patients of any age preferring once-daily medication and only requiring modest benefit, MAO B inhibitors are a reasonable alternative to levodopa.
●Younger patients at high risk for dyskinesia – In patients under 50 years of age who are at high risk of dyskinesia, initial monotherapy with a dopamine agonist can be considered.
Risk factors for dyskinesia include younger age at disease onset, lower body weight, and female sex
●Patients with tremor-predominant disease – Occasional patients with PD have a relatively isolated and symptomatic tremor without significant bradykinesia or gait impairment.
While levodopa remains the initial agent of choice, often higher doses of levodopa are required for high-amplitude tremor.
Amantadine monotherapy can be considered in patients with milder tremor.
Anticholinergic drugs (trihexyphenidyl) are sometimes useful as monotherapy in patients with bothersome tremor but are less well tolerated in older patients because of the risk of cognitive impairment, constipation, and prostatism.
Considerations in choosing additional treatment to levodopa
●MAO B inhibitors offer a convenient once-daily option to augment overall benefit of levodopa, although the result is usually modest
●DAs provide more potent augmentation of dopaminergic benefits in appropriate patients.
When used as adjunctive therapy, DAs can be beneficial at lower doses than those used as monotherapy, thus reducing the risk of side effects.
They can also be used to keep the total levodopa dose a bit lower, reducing the risk of dyskinesia from levodopa
●The addition of amantadine may be particularly useful in patients with prominent tremor.
Risk factors for levodopa induced dyskinesia
- Young age at onset of Parkinson disease (under 50 years)
- Females
- Low bodyweight
and
- Higher levodopa doses
- Long treatment duration
- Anxious-depressed subtype
- Asymmetry of caudate binding on DaTscan
- Motor fluctuations
- Non-smoker
- Non-tremor dominant phenotype
Levodopa Vs DAs in initial treatment
- Η λεβοντόπα έχει καλύτερα αποτελέσματα ως αρχική επιλογή (π.χ. για επαγγελματικούς σκοπούς)
- Σχετίζεται ωστόσο με μεγαλύτερη πιθανότητα ανάπτυξης υπερκινησιών σε σχέση με DAs
- Μακροπρόθεσμα δεν έχει φανεί ότι υπάρχει κλινικά σημαντική διαφορά στα κινητικά συμπτώματα, κινητικές επιπλοκές ή στη θνητότητα μεταξύ των δύο επιλογών
Μια επιλογή είναι έναρξη με λεβοντόπα στη χαμηλότερη δυνατή δοσολογία με το καλύτερο κλινικό αποτέλεσμα, και στην πορεία να προστεθεί DA
What is different in levodopa usage in tremor prominent PD
Effect is dose-related (higher doses are required)
Dopamine agonists dosing and titration
●Pramipexole –
Pramipexole IR is usually started at 0.125 mg three times a day. The dose should be increased gradually by 0.125 mg per dose every five to seven days.
Pramipexole ER is usually started at 0.375 mg daily at bedtime and titrated by 0.375 mg increments every five to seven days.
Most patients can be managed on total daily doses of 1.5 to 4.5 mg.
Dose adjustments are required for renal insufficiency, and the ER formulation is not recommended in patients with a creatinine clearance <30 mL/minute.
●Ropinirole –
Ropinirole IR is usually started at 0.25 mg three times a day.
The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a total daily dose of 3 mg.
After week 4, the ropinirole dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. Ropinirole ER is usually started at 2 mg daily at bedtime and titrated by 2 mg increments every five to seven days, up to a maximum of 24 mg.
Benefit most commonly occurs in the dose range of 12 to 16 mg per day.
●Rotigotine – Transdermal rotigotine is a once-daily patch that is usually started at 2 mg/24 hours and titrated weekly by increasing the patch size in 2 mg/24 hour increments to a dose of 6 mg/24 hours.
dopamine receptors and non ergot dopamine agonists
Binding in D2 and D3 receptors
(Pramipexole mainly D3)
(D3 responsible for ICD)
Risk factors for impulse control disorders (διαταραχή ελέγχου των παρορμήσεων) in treatment with dopamine agonists
Risk factors for an ICD include:
* DA dose and duration of treatment
* younger age
* male sex
* comorbid anxiety and depression
* Family history of impulse control disorders
* Alcohol use
Dopamine agonists adverse effects
- Nausea and vomiting
- Orthostatic hypotension
- Dyskinesias: May cause or exacerbate
- Impulse control disorders (pathological gambling, increased libido (hypersexuality), compulsive or binge buying/eating, and/or other intense urges)
- Psychotic-like effects (paranoid ideation, hallucinations, delusions, confusion, mania, disorientation, aggressive behavior, agitation, delirium)
- Somnolence and sleep attacks!!!
- PERIPHERAL EDEMA
- Augmentation (worsening of symptoms in patients with restless leg syndrome)
- Heart failure (only with pramipexole)
- Withdrawal syndrome
- Postural deformity: Postural deformities, including antecollis, camptocormia (Bent Spine Syndrome) and pleurothotonus (Pisa Syndrome) have been reported following initiation, several months into treatment, or after increasing the dose.
Other
>10%:
Gastrointestinal: Constipation
Nervous system: Dizziness, drowsiness, headache, insomnia
Dopamine agonists indications
In patients under 50 years of age who are at high risk of dyskinesia (eg, younger age at disease onset, lower body weight, female sex), initial monotherapy with a DA is an alternative to early levodopa
DAs provide more potent augmentation of dopaminergic benefits in appropriate patients.
When used as adjunctive therapy, DAs can be beneficial at lower doses than those used as monotherapy, thus reducing the risk of side effects.
They can also be used to keep the total levodopa dose a bit lower, reducing the risk of dyskinesia from levodopa
They also have a role in patients with advanced PD as a treatment for motor complications of levodopa.
DAs are INEFFECTIVE in patients who have shown no therapeutic response to levodopa
Dopamine agonists contraindications
- Σοβαρή νεφρική ανεπάρκεια (κάθαρση κρεατινίνης <30ml/min) και ηπατική ανεπάρκεια για τη ροπινιρόλη
- Το υπόστρωμα του Neupro περιέχει αλουμίνιο. Προς αποφυγή δερματικών εγκαυμάτων, το Neupro πρέπει να αφαιρείται σε περίπτωση που ο ασθενής πρέπει να υποβληθεί σε μαγνητική τομογραφία (MRI) ή καρδιομετατροπή.
- κύηση/ γαλουχία: μειώνουν την έκκριση προλακτίνης
Which adverse effect can be seen in dopamine agonists but no levodopa?
Peripheral edema
MAO -B inhibitors: types, dosage and mechanism of action
Inhibitors of brain monoamine oxidase (MAO) type B, which plays a major role in the catabolism of dopamine.
Inhibition of dopamine depletion in the striatal region of the brain reduces the symptomatic motor deficits of Parkinson’s disease.
Επιβράδυνση καταβολισμού ντοπαμίνης
*Selegiline – 5 mg twice daily.
*Rasagiline – 0.5 mg once daily and then increased to 1 mg once daily as long as it is well tolerated.
*Safinamide – Safinamide is usually given as adjunctive therapy with levodopa to help with motor fluctuations;
safinamide is started at 50 mg once daily and can be increased to 100 mg daily after 14 days based upon tolerability and benefit
What time of the day should selegiline be administered? Should a specific diet be followed?
Morning and midday dosing is advised to avoid insomnia.
A tyramine-free diet is not necessary
(does not precipitate a hypertensive crisis at the doses recommended for PD)
MAO -B inhibitors contraindications and most common adverse effects
Contraindications:
- Συγχορηγούμενη θεραπεία με αναστολείς ΜΑΟ (συμπεριλαμβανομένων των φαρμακευτικών και φυτικών προϊόντων που δεν χρήζουν συνταγής π.χ. St.John’s Wort) ή πεθιδίνη.
Πρέπει να περάσουν τουλάχιστον 14 ημέρες από την διακοπή της ρασαγιλίνης μέχρι την έναρξη της θεραπείας με αναστολείς ΜΑΟ ή με πεθιδίνη.
- Aσθενείς με μέτρια ή σοβαρή ηπατική ανεπάρκεια.
Adverse effects:
Nausea and headache are the most common side effects associated with the use of MAO B inhibitors.
Other possible adverse effects of MAO B inhibitors include confusion and hallucinations.
MAO -B inhibitors special warnings
Special warnings
- Orthostatic hypotension
- Dyskinesia: Dyskinesia, exacerbation of preexisting dyskinesia, or increased dopaminergic side effects may occur when used as an adjunct to levodopa.
- Impulse control disorders
- CNS effects: May cause new or worsening mental status and behavioral changes, which may be severe, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium after starting or increasing the dose of rasagiline.
- Somnolence
- Hypertension
-
Serotonin syndrome
Η ταυτόχρονη χορήγηση της ρασαγιλίνης με φλουοξετίνη ή φλουβοξαμίνη θα πρέπει να αποφεύγεται.
Τουλάχιστον πέντε εβδομάδες θα πρέπει να παρέλθουν από την διακοπή της φλουοξετίνης μέχρι την έναρξη της θεραπείας με ρασαγιλίνη. Τουλάχιστον 14 ημέρες θα πρέπει να μεσολαβήσουν από την διακοπή της ρασαγιλίνης μέχρι την έναρξη της θεραπείας με φλουοξετίνη ή φλουβοξαμίνη. - Η ταυτόχρονη χρήση της ρασαγιλίνης με δεξτρομεθορφάνη ή συμπαθομιμητικά όπως αυτά που βρίσκονται στα ρινικά και από το στόμα χορηγούμενα αποσυμφορρητικά ή φαρμακευτικά προϊόντα κατά του κοινού κρυολογήματος που περιέχουν εφεδρίνη ή ψευδοεφεδρίνη δεν συνίστάται (Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Alpha-/Beta-Agonists)
- Η χορήγηση ρασαγιλίνης σε ασθενείς με μέτρια ηπατική ανεπάρκεια θα πρέπει να αποφεύγεται. Στην περίπτωση ασθενών των οποίων η ηπατική ανεπάρκεια εξελίσσεται από ήπια σε μέτρια, η ρασαγιλίνη θα πρέπει να διακόπτεται
Which MAO - B inhibitor may cause more confusion than the others in the elderly?
Selegiline
Indications for device-assisted therapies (παρεμβατικές θεραπείες) for PD
●Severe, troublesome motor fluctuations despite optimal oral or transdermal levodopa or adjunctive therapies
●Inconsistent response to treatment
●Dyskinesia or motor fluctuations that require frequent treatment adjustment without apparent benefit
●Levodopa dosing required four or more times daily
●Severe medication-refractory tremor (as an indication for DBS only)
Device assisted procedures in PD: exclusions
1) Patients with secondary causes of parkinsonism (eg, drug-induced, vascular) or atypical parkinsonian disorders (eg, multiple system atrophy)
2) Patients with PD who have dementia or significant cognitive impairment
Precauitons:
For patients with active psychiatric issues, such as anxiety, depression, hallucinations, and delusions, device-assisted therapies should be delayed until psychiatric symptoms are stabilized.
Clinicians should screen potential candidates for depression using standardized screening instruments and exclude those at high risk for suicide from consideration of DBS.
Psychosis in PD management
Management involves
- identifying and treating the underlying causes and contributory factors
- sequential decrease or elimination of potentially offending antiparkinson drugs as allowed by motor function
- symptomatic antipsychotic drug therapy for refractory symptoms
*Preferred drugs, when necessary
When antipsychotic drugs are deemed necessary for PD-related psychosis, pimavanserin, quetiapine, or clozapine is suggested.
Clozapine may be the most effective antipsychotic of the three but requires hematologic monitoring.
