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Microsoft word - parkinson's disease.doc

Parkinson’s disease

Pathophysiology

Degeneration of dopaminergic neurones in the substantia nigra, pars compacta1
Balance of dopaminergic and cholinergic activity in the extra-pyramidal system determines activating outflow to
motor cortex
In Parkinson’s disease, a relative dopaminergic deficit causes the clinical features of ‘TRAP’ Tremor (‘pill-rolling’, absent in 20-30%)
Rigidity (‘lead pipe’, esp. arms)2
Akinesia/bradykinesia (esp. arms)
Postural reflex loss, gait disturbance
Usually asymmetrical (cf. drug-induced: symmetrical)
Overview of dopamine metabolism

Synt hesi s of f ur t her cat echol ami nes
Release pathway

1 Note that Parkinsonism refers to the classical clinical features regardless of aetiology; Parkinson’s disease is idiopathic Parkinsonism. 2 Cogwheeling = rigidity with superimposed tremor
Dopamine receptors
At least 5 dopamine receptors have been cloned to date (D1-5), but only D1 and D2 are of significance in
Parkinsonism.
D2 receptor is principal target for anti-Parkinsonian drugs. Chronic D1 stimulation also appears to be beneficial –
paradoxically so, since
Both subtypes have opposite effects on the cAMP second messenger system (D1 is Gs-coupled and stimulates adenylate cyclase, D2 is Gi/o-coupled and inhibits it). Both subtypes have different spatial localization. D1 is mostly found in the vasculature, whereas D2 is concentrated in the areas shown later.
Consequent rationale for pharmacological management

Pharmacological treatment cannot cure Parkinson’s disease – this would require replacing lost neurones. It can,
however, improve motor function through restoring DA/ACh balance by

Disease modification refers to delaying the progression of neuronal degeneration. Such an effect has been proposed
for selegiline but has never been proven.
Drug classes

L-dopa (=levodopa) and dopa-decarboxylase inhibitors (DDC-Is)
Why not give dopamine itself?
Rapid GI/liver/blood metabolism by MAO and COMT Dopamine is poorly lipid soluble and cannot traverse the blood-brain barrier; L-dopa enters through the neural amino-acid transporter
Why give a DDC-I as well?
99% of L-dopa is converted to dopamine prematurely by peripheral DDC, causing side-effects of nausea, postural hypotension and cardiac arrhythmias Merely 1% enters the brain to be converted to dopamine Would have to give huge doses with consequently prominent side-effects DDC-Is (carbidopa, benserazide) do not cross the blood-brain barrier and selectively inhibit the extracerebral metabolism of L-dopa. Advantages: Smoother clinical response with a more rapid onset
Indications
Most potent treatment available, and treatment of choice for idiopathic Parkinson’s disease. Over 75% of patients regain normal or near-normal physical activity. Usually slow response over 6-18 months and then maintained for up to 2 years followed by gradual decline. After 8 years, 50% have choreo-athetoid dyskinesia and end-dose akinesia. The ELLDOPA (Early vs. Late L-dopa) trial has shown that disease progression is not influenced by L-dopa therapy. Consequently, instigation of therapy should depend on symptomatology and quality of life. Elderly patients or those with longstanding disease, who may not tolerate a dose large enough to overcome the deficit. Parkinsonism due to degenerative brain disease (e.g. multiple system atrophy) Neuroleptic-induced Parkinsonism. Instead, withdraw the offending drug and give antimuscarinics. A duodenal gel formulation provides a more constant L-dopa plasma level because it circumvents irregular gastric emptying and unpredictable small bowel absorption. It is an alternative to IV L-dopa, which is impractical as L-dopa is hydrophobic and requires large liquid volumes to dissolve. The duodenal formulation requires a percutaneous tube and portable pump, and is an advanced treatment for patients with severe motor fluctuations or dyskinesia.
Preparations
Oral
Co-careldopa

Adverse effects
Central
Enhanced dopaminergic action is not confined to the nigro-striatal tract.

Note that the chemoreceptor trigger zone is sensitive to substances outside the blood-brain barrier; vomiting is
therefore not a purely central side-effect.
Peripheral
Postural hypotension through D1 activity.
Thus up-titrate the dose until the best trade-off between decreasing symptoms and increasing side-effects is reached.
Interactions
Remember the interaction between L-dopa and non-selective MAO-Is:
2. Diversion of dopamine into
further catecholamine synthesis
3. Excessive adrenaline
causes hypertensive crisis
Synt hesi s of f ur t her cat echol ami nes 1. Catabolic pathway blocked

Pharmacokinetics
t1/2 = 90min
Dopamine agonists
Classification
Use of any dopaminergic medication, esp. dopamine agonists Behavioural disturbance including hypersexuality, pathological gambling and stereotypic motor acts
Bromocriptine
Most commonly used ergot-derived agonist
Indications
Has no advantage over L-dopa and is used When L-dopa alone is no longer adequate to control symptoms When L-dopa is associated with intolerable side-effects Useful for akinetic periods and on-off phenomena (has a longer t1/2 of 5h and hence a smoother action than levodopa) Also a weak α-blocker, hence more marked postural hypotension All ergot derivatives carry a risk of retroperitoneal/pulmonary/pericardial/heart valve fibrosis (5-HT2B overstimulation; regurgitant valve lesions)3 Obtain ESR/crea/CXR ± lung function tests before starting Monitor for abdo pain/tenderness, SOB/cough/CP or features of heart failure Progression of fibrosis can be prevented by early diagnosis and cessation of drug treatment
Pergolide
Very similar, but also stimulates D1.
Cabergoline

3 ZANETTI, R. ET AL. (2007): Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. NEJM
356:39-46.
SCHADE, R. ET AL. (2007): Dopamine agonists and the risk of cardiac-valve regurgitation. NEJM 356:29-38.
Extra-long half-life of 80h, thus suitable for once daily or even twice weekly dosing, but clinical experience is still
limited.
Ropinirole
Newer drug with similar side-effect profile. D1-3 agonist.
Indications
As monotherapy in young patients at risk of developing disabling dyskinesias with long-term therapy
Apomorphine
Morphine derivative that is a full D1 and D2 agonist; lacks activity at opioid receptors.
Indications
Useful for stabilizing patients with unpredictable ‘off’ periods with L-dopa Potent emetic4; thus need to give domperidone (DA antagonist that does not cross the blood-brain barrier) for 3 days before initiating therapy, then tailed off over weeks Rare but well-described: haemolytic anaemia Needs to be given by SC injection5/infusion under Consultant supervision. This route allows for fast onset and abortion of an ‘off’ period
Rotigotine
Neupro® is a transdermal patch, avoids fluctuating dopaminergic stimulation
Monoamine oxidase inhibitors (MAO-Is)
The MAO enzyme exists in two isoforms:
Central location
Peripheral location
Substrate
Principally phenylethylamine, also NorAdr/Adr/DA
In Parkinson’s disease, the nigrostriatal neurons and their MAO-A activity are lost. Therefore DA is predominantly
catabolised by MAO-B in the glia. MAO-B blockade can thus boost prevailing DA concentration.
Selegiline
Selective irreversible inhibitor of MAO-B
Indications
Adjunct to L-dopa in severe Parkinsonism to reduce end-of-dose deterioration Delayed need for L-dopa treatment/disease progression through early selegiline? – untrue Increased mortality with combination of selegiline and L-dopa? – UKPRG (1995) trial suggests so, but used a flawed method of data collection and analysis
Rasagiline
Selective irreversible inhibitor of MAO-B
Indications
4 Famously used by a murderer in an Agatha Christie novel who drank poisoned tea with her victim and then injected herself with apomorphine to vomit up the poison. 5 ‘Penjet’ devices available, i.e. like insulin Catechyl-O-methyl transferase inhibitors (COMT-Is)
Inhibit an alternative enzyme involved in the breakdown of dopamine. Theoretically more attractive than MAO-Is
since COMT also catabolises L-dopa.
The original compound, tolcapone, is only used with extreme caution due to potential hepatotoxicity and NMS.
Entacapone (Comtess®) was subsequently introduced
Indications
Adjunct to L-dopa therapy in patients with end-of-dose deterioration Available as a combined formulation: Stalevo® = L-dopa + carbidopa + entacapone Ensures entacapone maximally effective as taken at same time as L-dopa
Amantadine
Developed as an antiviral agent to treat influenza, amantadine was noticed to improve Parkinsonian
symptomatology by chance.
Mechanism: increases synthesis and release of dopamine by acting as an NMDA antagonist; reduces re-uptake of
dopamine
Less effective than L-dopa but more than anticholinergics
Mild improvement in all 3 major symptoms
Adverse effects
Relatively free from side-effects (ankle oedema, mild D2 effects), but Only a small proportion of patients derive benefit
Antimuscarinic agents
E.g. benzhexol, procyclidine, orphenadrine
Generally less useful than levodopa
Greater effect on tremor and rigidity than on bradykinesia
Possible indications
Post-encephalitic or drug-induced Parkinsonism6
Adverse effects
Typically anticholinergic: dry mouth, blurred vision, mydriasis, tachycardia, constipation, urinary retention, erectile
impotence
Pharmacological management in context

Commence drug therapy once symptoms impact significantly on quality of life Mainstay of treatment remains L-dopa + DDC inhibitor Especially bradykinesia and rigidity; tremor less well controlled Use lowest effective dose and titrate up gradually After several years of L-dopa therapy, side-effects usually supervene 6 L-dopa is largely ineffective here: it would have to act at receptors which are already blocked. But don’t give antimuscarinics in tardive dyskinesia (see antipsychotics) – they make it worse! End of dose akinesia with drug-resistant off periods Random ‘on-off’ phenomena whose timing is unrelated to the dose schedule7 Add in selegiline (helps with end of dose deterioration) Not drug holidays – risk of NMS
Options in early disease: L-dopa, dopamine agonists, MAO-B inhibitors Options in later disease: dopamine agonists, MAO-B inhibitors, COMT inhibitors Considered in patients who (NICE guidelines) Have motor complications that are refractory to best medical treatment Are biologically fit with no clinically significant active co-morbidity Have no clinically significant active mental health problems, for example, depression or dementia In PD, neuronal activity is abnormally increased in the subthalamic nucleus and the globus pallidus pars interna Deep brain stimulation (DBS) involves the implantation of electrodes into one or other of these areas bilaterally, connected to an implantable pulse generator. High frequency stimulation of the above areas induces a functional lesion. This is preferable to ablative surgery since It can be performed bilaterally with relative safety Stimulation parameters can be adjusted and optimised after implantation On average 60% of dopaminergic drug doses can be replaced with DBS 10% of subjects no longer require any L-dopa Off-periods and dyskinesias are reduced by 60-70% Intraputaminal implantation of retinal pigment epithelium (RPE) cells, which produce L-dopa and can be isolated from human eyes post mortem Intrastriatal infusion of a viral vector containing the gene for human L-amino acid decarboxylase 7 One possible mechanism is receptor downregulation

Source: http://www.jaiser.com/notes/Parkinson's%20disease.pdf

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