Drug treatment of Parkinson's Disease

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					Drug treatment of Parkinson’s Disease
Drug          Generic name      Mechanism of          Indication                        Side effects Common/Serious or potentially life
Class                           action                                                 threatening
DOPAMINERGIC
Levodopa      Levodopa/         Converted in the      To reverse motor                 Nausea/vomiting, postural hypotension, insomnia,
              carbidopa or      brain to dopamine     symptoms in early or late        hallucinations, dyskinesias (ie. dopaminergic side
              levodopa/         Carbidopa and         disease                          effects)
              benzeraside       benserazide are
                                peripheral dopa
                                decarboxylase
                                inhibitors
DOPAMINE AGONISTS (Pramipexole, sumarinole and ropinirole are dopamine agonists that show significant benefits both in early PD
and as later therapy and are believed not to have the fibrosing effects of the older agonists. However, somnolence has been recorded
more often with these agonists than with other dopaminergic drugs, and caution is advised with driving. Not readily available in Aust.)
Ergoline-     Bromocriptine,    Stimulate             Early IPD, may delay or         Dopaminergic side effects (more likely to provoke
derived       cabergoline,      dopamine              likelihood of developing         hallucinations, confusion and psychosis than
dopamine      pergolide         receptors             motor fluctuations (esp.         levodopa); peripheral oedema.
agonists                                              dyskinesias).                    Contraindicated in active IHD or PVD (digital
                                                      Improve motor fluctuations       vasospasm and erythromelalgia), as well as
                                                      in later disease                 pulmonary fibrosis or evidence of pulmonary
                                                                                       asbestosis because of vasospastic and fibrotic
                                                                                       properties. Up to 3% will develop pulmonary or
                                                                                       retroperitoneal (rarer) fibrosis. Baseline CXR,
                                                                                       ESR and renal Fx, regular symptomatic review,
                                                                                       pulmonary auscultation in all pts.
Non-          Apomorphine       Stimulates            Improves sudden motor            Patients must be pre-treated for 3/7 with
ergoline-                       dopamine              fluctuations in later            domperidone and continue in short-medium term to
derived                         receptors             disease. Must be given           prevent severe vomiting and hypotension.
dopamine                                              subcutaneously, acts with        Injection site pain, erythema, nodule formation.
agonist                                               5-10 minutes, effect lasts
                                                      ~ 60 minutes.
COMT (Catechol-O-methyltransferase) INHIBITORS
              Entacapone        Inhibits enzymatic    Improves motor                   Dopaminergic side effects (can be managed by 
                                breakdown of          fluctuations. Must be            levodopa intake); urine discolouration (harmless);
                                levodopa to           taken at same time as            abdominal pain, diarrhoea
                                inactive              levodopa. Has short t1/2 so
                                metabolites in gut    effect lasts only for that
                                and blood             dose
              Tolcapone         Inhibits enzymatic    Improves motor                   As for entacapone; very rare reports of severe or
              (Special          breakdowns of         fluctuations. Has longer         fatal hepatic failure (pts must have frequent
              Access            levodopa to           t1/2 than entacapone, so it      LFTs)
              Scheme only       inactive              is taken twice to three
              due to            metabolites in gut    times daily.
              hepatotoxicity)   and blood
N-methyl-D-aspartate (NMDA) ANTAGONIST
              Amantadine        Multiple, not well    To suppress dyskinesias,         Livedo reticularis (common, harmless); nightmares,
                                understood            also has minor beneficial        hallucinations and confusion, anticholinergic side
                                                      effect on reversing motor        effects
                                                      symptoms
MONOAMINE OXIDASE (MAO) B INHIBITOR
              Selegiline        Inhibits enzymatic    Improves motor                   Nightmares, hallucinations and confusion,
                                breakdown of          fluctuations (modest             worsening of dyskinesias. Potential for cheese
                                levodopa and          effect); also has minor          effect or serotonin syndrome when used in
                                dopamine to           beneficial effect on             combination with other MAO (including MAO-A)
                                inactive              reversing motor symptoms         inhibitors or serotonergic drugs (MAO also
                                metabolites                                            metabolises serotonin)
ANTICHOLINERGIC
              Benzhexol,        Inhibits              Drug-resistant rest tremor       Dry mouth, memory impairment, confusion,
              Benztropine       acetylcholine         in younger patients              constipation, blurred vision, exacerbation of
                                                                                       glaucoma, urinary retention (together these are
                                                                                       referred to as anticholinergic side effects). May be
                                                                                       difficult to wean after long term use. Avoid
                                                                                       sudden withdrawal to prevent cholinergic crisis.

                                                                                   Drugs affecting metabolism of levodopa
 Levodopa
 - absorbed from small intestine                        Dopamine agonists
 - transported to brain  converted to dopamine          - oral dopamine agonists directly stimulate
 - short plasma t1/2 (~ one hour)                          striatal neurons
 - early in PD has long duration of action (days)        - longer plasma t1/2 than levodopa  more
   which is independent of plasma [ ] but with             continuous dopaminergic stimulation
   disease progression, duration s (short               - at doses tolerated by most patients usually
   duration effect strongly linked to plasma [ ] and       don’t provide =  of motor improvement as
   lasts hours (at most))                                  levodopa (don’t work if levodopa has not
 - slow release preparations – absorbed gradually          worked)
    more sustained plasma [ ] but have                 - newer agonists probably better tolerated than
   bioavailability (ie. need higher dose to match          bromocriptine
   benefit of equiv. strength of standard prep.)         - usually cause nausea and postural hypotension
 - rapid release preparations – liquid form             - introduce slowly over a few weeks
   enhance passage through stomach and                   - some patients require domperidone when
   absorption from small intestine                         starting treatment
 - nausea due to stimulation of dopamine                 - avoid dopamine agonists in all pts with
   receptors in area postrema (vomiting centre) in         hallucinations or cognitive impairment (risk
   brainstem (lies outside BBB) – minimise                 confusion and prolonged delirium)
   nausea by starting with low dose, introducing         - see table for other side
   slowly, taking with food, giving in combination         effects/contraindications/caveats
   with peripheral dopa decarboxylase inhibitor          - apomorphine – short acting, given as ‘rescue’
   (avoid metoclopramide and prochlorperazine              medication for severe fluctuations in younger
   as they are dopamine antagonists)                       pts (rapid and reliable onset of action within 5-
 - use domperidone if antiemetic required                  10 min) but must receive domperidone for at
   (dopamine antagonist that does not cross BBB)           least 48 hrs to counteract potent emetic effect
Anticholinergics
 - limited usefulness because of relative lack of        MAO-B inhibitors
    efficacy and frequent occurrence of side effects     - selegiline selectively inhibits MAO-B 
    (memory impairment, confusion, psychosis, dry          prolongs duration of effect of levodopa
    mouth, difficulty with micturition, constipation)
                                                         - also mild symptomatic benefit as monotherapy
 - occasionally beneficial where tremor is
                                                         - confusion or delirium most common sig.
    prominent and has shown poor response to
                                                           adverse effect
    dopaminergic therapy
                                                         - warn patients about possibility of tyramine-
COMT inhibitors                                            induced HTN if selective MAO-A (eg. MAOI
 - prolong t1/2 of levodopa   motor fluctuations         antidepressant) also prescribed (warn against
 - dopaminergic adverse effects incl.  peak-dose          consumption of high [tyramine] foods (aged
   dyskinesia, confusion                                   cheeses etc)
 - Entacapone has short t1/2 (90 minutes) – must
   be taken concurrently with each dose of
   levodopa

				
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