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Parkinson's Disease |
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Parkinson's DiseaseDefinition
Epidemiology
History
Examination
Pathophysiology
Causes of Parkinsonian Syndrome
Differential Diagnosis
Principles of treatment
Patients with Parkinson’s disease are more likely to be levodopa
responsive. Other causes are less
likely to respond. Physiotherapy, occupational therapy and social support are important
adjuncts to treatment. Drugs affecting the dopaminergic
system. Dopaminergic activity can be enhanced by the following methods: 1)
Administration of Levodopa with a peripheral dopa decarboxylase
inhibitor. 2)
Increased release of endogenous dopamine. 3)
Stimulation of dopamine receptors. 4)
Inhibition of catechol-O-methyl transferase (COMT). 5)
Inhibition of monoamine oxidase type B (MAO-B). Levodopa
As the immediate precursor of dopamine in the catecholamine synthesis,
levodopa is decarboxylated in the brain to replenish striatal dopamine.
Dopamine itself cannot be given as it is not absorbed orally and does not
cross the blood-brain barrier. The
nigrostriatal dopamine deficiency is therefore partially corrected and an
improvement in symptoms of rigidity and bradykinesia are noted. Levodopa is used in combination with a peripheral dopa-decarboxylase
inhibitor, which reduces the adverse peripheral effects of dopamine.
The peripheral inhibitors are drugs which block peripheral levadopa
decarboxylation. These polar drugs
cannot cross the blood-brain barrier and thus do not influence decarboxylation
of levodopa in the brain. This combined therapy allows a four to five fold decrease in
the levodopa dose and the incidence of vomiting and arrhythmias is also reduced.
Central side effects such as hallucinations are not reduced by the
combination therapy. Combined preparations (co-careldopa or co-beneldopa) are used in
idiopathic Parkinson’s Disease. However,
levodopa is contraindicated in schizophrenia and must not be used for
parkinsonism caused by antipsychotic drugs, as it can exacerbate the psychotic
symptoms. Pharmacokinetics
Levodopa is absorbed from the jejunum and may compete with dietary
aromatic amino acids. Oral
absorption is variable and following administration of 15mg/kg levodopa, peak
plasma concentrations occur at 1 to 2 hours.
An increased half life is achieved by combining the levodopa with a COMT
inhibitor, such as tolcapone. Further,
in the presence of dopa decarboxylase inhibitors, the plasma levodopa
concentrations rise, excretion of dopamine and its metabolites falls and the
availability of levodopa within the brain for conversion to dopamine increases. Clinical Use The combined preparations of levodopa and carbidopa (Sinemet) or
levodopa and benserazide (Moldopar) are given three times daily starting at a
low dose, which is increased after 2-3 weeks and then reviewed at intervals of
6-8 weeks. The dose starts at
200-300mg and can increase up to 1g daily of levodopa.
After 2-5 years, the efficacy of levodopa becomes limited by the
complications of motor fluctuations and dyskinesias. Motor fluctuations are ‘wearing-off’ where individual
doses produce only short lived effects, or ‘on-off’ where the patient may
switch from symptomatic benefit from medication (on) to an akinetic-rigid state
(off). These states are often without any predictable relationship to the time
of the drug doses. Dyskinesias are involuntary movements occurring in association with drug
treatment. Twisting and turning
movements are seen when the dopamine levels are high (peak-dose dyskinesias) and
painful sustained muscle contractions, typically of the feet are seen when
dopamine levels are low (wearing-off dystonias). These fluctuations and
dyskinesias can be partially alleviated in some patients by 1)
Frequent small doses of levodopa drugs 2)
Controlled release preparations 3)
Combined use of levodopa preparations with selegiline (MAO-B inhibitor)
or a direct dopamine agonist (pergolide). Adverse effects These include nausea and vomiting, postural hypotension, involuntary
movements (dystonia) including akathisia, chorea and myoclonus, psychological
disturbances, cardiac arrhythmias and endocrine effects of levodopa including
stimulation of growth hormone and suppression of prolactin.
Dopamine antagonists such as Domperidone can be used to reduce nausea and
Clozapine is used to treat the hallucinations. Drug interactions MAO I’s can produce hypertensive reactions if given concurrently with
levodopa. The hypotensive actions
of other drugs are potentiated by levodopa. As the efficacy of levodopa falls off with long term treatment, this
indicates that the underlying neurological disease progresses and is not
reversed by levodopa treatment. Many
neurologists are now advising that dopamine agonists alone should be used
initially to treat Parkinson’s Disease, paticularly in younger patients who
are more at risk of developing the dopa-induced dyskinesias. Increased release of endogenous
dopamine Since Parkinson’s disease results from the loss of inhibitory
dopaminergic neurones in the nigrostriatal system, increasing endogenous release
of dopamine from the remaining neurones can help to restore the normal neural
circuits. Amantidine Mechanism: Inhibits
reuptake of dopamine into nerve terminals. Clinical use: Improves mild
bradykinesia, tremor and rigidity in approximately 60% of
patients. Less
effective than levodopa and action declines with time.
Oral dose is
initially 100mg daily, increased after one week to 100mg twice daily. Adverse effects: Relatively
free from side effects compared with levodopa although those experienced are qualitatively similar.
GI upsets, anorexia, nausea, livedo
reticularis, peripheral oedema, peripheral oedema, manifestations of CNS
toxicity
(nervousness, inability to concentrate, insomnia, dizziness,
convulsions,
hallucinations, blurred vision etc), rarely leucopenia. Pharmacokinetics: Half-life
varies between 10 and 30 h thus it takes 4-7 days to reach
steady-state concentrations. 95%
is eliminated by the kidney, thus contraindicated in severe renal impairment. Dopamine receptor agonists These attempt to bypass the need for endogenous dopamine in the
nigrostriatal system by directly stimulating dopamine receptors.
They are currently used as an adjunctive therapy in patients for whom use
of levodopa alone is no longer adequately controlling their symptoms; however,
it is currently being studied as to whether early use of these drugs in order to
delay commencement of levodopa therapy could slow disease progression.
These drugs share many of the side effects experienced with levodopa, and
when used in combination with levodopa, abnormal involuntary movements and
confusion are common. Peripheral
side-effects such as nausea (due to stimulation of dopamine receptors in the
chemoreceptor trigger zone) can be reduced by use of a peripheral dopamine
receptor antagonist such as domperidone. This
is unable to cross the blood-brain barrier, hence its selective peripheral
action. This group of drugs comprises the ergot derivatives (bromocryptine,
lysuride and pergolide) and the non-ergot derivatives (ropinirole, apomorphine
and pramipexole). Bromocryptine Mechanism: Potent agonist
at D2 receptors (which underlies its efficacy in treating PD) and a weak
partial agonist at D1 receptors. Clinical use: Useful in
reducing ‘off’ periods in levodopa therapy and stabilising
fluctuations in late-stage disease.
Dose is 1-2.5 mg at night, increased to a
maximum total of 10-40 mg per day, given in 3 divided doses.
Taken with food. Adverse effects: Nausea and
vomiting, headache, dizziness, postural hypotension, vasospasm
of fingers and toes, constipation; with high doses, confusion, dyskinesia,
hallucination, leg cramps, pleural effusions. Pharmacokinetics: Half-life
is 6-8 h, longer than levodopa hence usefulness in reducing
fluctuations. Lysuride Mechanism: Agonist at D2
receptors and 5-HT1 and 5-HT2 receptors. Clinical use: Similar to bromocryptine. Dose is initially 200 mg
with food at bedtime,
increasing to max. 5mg daily in 4 divided doses.
Taken with food. Adverse effects: CNS (headache, lethargy, confusion, dizziness,
hallucinations), GI
(N+V, constipation, diarrhoea), rashes, cardiac arrhythmias, rarely
severe
hypotension. Pharmacokinetics: Complete
absorption but extensive first-pass metabolism. Half-life of 8h. Pergolide Mechanism: Agonist at D1,
D2, 5-HT1 and 5-HT2 receptors. Clinical use: Used in
combination with levodopa. Oral
dose is initially 50mg
at bedtime, increasing
to a maximum of 2-5 mg daily, in 3 divided doses.
May allow cautious
reduction of dose of levodopa. Adverse effects: Similar
CNS and GI symptoms to lysuride; also, abdominal pain dyspepsia,
pleural effusion, rhinitis, dyspnoea, pericarditis, hypotension, rash. Pharmacokinetics: Hepatic
metabolism. Half-life 15-42h. Ropinirole Mechanism: Agonist at D2,
D3 and D4 receptors. Clinical use: Either alone
or as an adjunct to levodopa (may allow a reduction in dose of
levodopa of up to 20%). Dose
is usually 3-9 mg per day. Oral. Adverse effects: CNS
(hallucinations, drowsiness, confusion), GI (nausea, abdominal
pain, vomiting), somnolence, occasionally severe hypotension. Pharmacokinetics: Metabolised
in the liver. Half-life 6h. Drug interactions: Ciprofloxacin
reduces clearance of ropinirole due to inhibition of
cytochrome P4501A2. Apomorphine Mechanism: Agonist at D1
and D2 receptors. Clinical use: Used to
stabilise refractory fluctuations in on-off activity with levodopa
therapy. Use requires specialist supervision. Patient must be established on
domperidone for 3 days before apomorphine is commenced.
Dose is initially 0.5
mg given s.c., increasing to 3-30mg daily in divided doses.
Dose regime may progress to s.c. infusion. Adverse effects: severe N+V,
dyskinesias, postural instability, cognitive impairment,
confusion, hallucinations, sedation, postural hypotension. Pharmacokinetics: Half-life
is only 30 mins. Inhibition of Catechol-O-Methyl
Transferase (COMT) COMT is an enzyme which metabolises L-dopa. Thus inhibition of COMT reduces metabolism of L-dopa,
increasing the amount of dopamine in the nigrostriatal neurones. Tolcapone Mechanism: Tolcapone is a
reversible competitive inhibitor of COMT. It is relatively
specific for central COMT, thus increasing the concentration of L-dopa in
the brain,
without significantly increasing the concentration in the plasma. Clinical use: Recently use
has been suspended following reports of serious hepatotoxicity.
Previously used as an adjunct to levodopa, reducing end-of-dose deterioration and allowing a reduced dose of
levodopa. Adverse effects: Hepatitis,
nausea, hallucinations, dyskinesia, occasional severe hypotension. Pharmacokinetics: Hepatic
metabolism. Inhibition of monoamine oxidase type B
(MAO B) Inhibition of MAO B prevents intraneuronal degradation of dopamine,
increasing the availability of dopamine in the nigrostriatal neurones.
MAO B predominates in the dopaminergic regions of the CNS whereas MAO A
acts more peripherally. Selective
inhibition of MAO B thus protects from unwanted peripheral effects of
non-selective MAO inhibitors (‘cheese reaction’, drug interactions etc). Selegiline
Mechanism: Selective MAO B
inhibitor so metabolism of dopamine in the striatum is decreased without
affecting the other major transmitter amines. Increased levels of dopamine enhances
the dopaminergic function in the nigrostratal tract. Selegiline does not
produce the hypertensive reactions with ‘cheese and wine’ when
using non-selective
MAO inhibitors e.g. phenelzine, because MAO-A remains active and metabolises
noradrenaline and tyramine (which triggers the hypertensive reaction).
It may slow the
neurodegenerative process of Parkinson’s Disease by preventing the breakdown of
substances but this is unconfirmed. E.g.
MPTP is taken up by and kills dopaminergic neurones, is
metabolised by MAO-B to the toxic product MPP+. Clinical use: Used in
severe parkinsonism as an adjunct to levodopa to reduce end-of-
dose deterioration.
As with dopamine receptor agonists, it has been suggested that early treatment with selegiline,
delaying onset of levodopa treatment, may delay disease progression, but there is
no convincing evidence to support this claim. Unconfirmed studies have suggested
that L-dopa and selegiline together may be associated with increased mortality in
long term. Can be given to patients with Parkinson’s Disease or symptomatic parkinsonism
but not for drug-induced extrapyramidal disorders. Dose: 10 mg daily as 2 divided doses of 5mg at breakfast and 5 mg at
midday.
Sudden withdrawal may exacerbate symptoms. Adverse effects: CNS
(depression, confusion, psychosis, agitation, headache, tremor,
dizziness, vertigo), GI (constipation, diarrhoea, N+V), hypotension, back
and joint pain, muscle cramps. Pharmacokinetics:
Oral selegiline is 100% absorbed but is extensively metabolised by the
liver to active metabolite desmethylselegiline, which is also a MAO-B inhibitor.
It is then metabolised to amphetamine and methamphetamine.
Plasma T1/2 is long with a mean value of 39 hours.
Drug
interactions:
Tyramine: Hypertension
occurs at very high doses as MAO-B selectivity is lost and the pressor
response to tyramine is potentiated. Cheese & wine reactions are rare.
Amantadine and centrally acting anti-muscarinic agents e.g. orphenadrine,
potentiate the anti-parkinsonian
effects of selegiline. Hyperpyrexia and CNS toxicity with pethidine Antidepressants – hypertension and CNS excitation with fluoxetine,
paroxetine. CNS toxicity
with TCA’s. Drugs affecting the cholinergic system
Muscarinic receptor antagonists
E.g. benzhexol, orphenadrine, procyclidine
Use
·
Their main use is
parkinsonian effects caused by anti-psychotic agents (drug-induced parkinsonism) that can’t be withdrawn from
psychiatric patients ·
For patients with mild parkinsonian symptoms especially tremor can use
anti-muscarinic drugs alone initially or with selegiline.
L-dopa may be added to the treatment or substituted for as the symptoms
progress. ·
Also used in post-encephalitic parkinsonism. ·
Benhexol, orphenadrine (antihistamine) and procyclidine are effective at
decreasing parkinsonian tremor and to
some extent rigidity and sialorrhoea. Bradykinesia
is least reduced. ·
In an acute parkinsonian crisis i.v. procyclidine (5mg) or benztropine
(2mg) are effective. ·
If patient is on a long term dopamine receptor antagonist,
anticholinergics should be reserved for those with severe Parkinson’s disease. Dose
·
Given in divided doses, increased every 2-5 days until their optimum
benefit is reached or their toxic effects appear. ·
All are given orally either before eating if dry mouth or after meal if
GI symptoms predominate. (Benzatropine and orphenadrine can be given
intravenously or intramuscularly when treating phenothiazine-induced dystonia.) ·
Benzhexol 1-4 mg tds (up to maximum15mg /day) ·
Orphenadrine 150-400mg bd ·
Benztropine 0.5-4g daily in single or divided doses (maximum 6mg daily) ·
Procycilidine 2.5. mg tds (maximum of 60 mg /day) Mechanism of action
·
Non-selective muscarinic receptor antagonists restore balance to the
dopaminergic/ cholinergic pathways in the striatum by correcting the central
cholinergic excess in parkinsonism thought to be due to the dopamine deficiency.
·
By acting on the postsynaptic muscarinic receptor in the striatal nuclei
of the basal ganglia they antagonise the excitatory action of acetylcholine and
thus reduce the extrapyramidal effects seen in Parkinson’s Disease. Adverse effects (antimuscarinic
effects)
1)
CNS – confusion, disorientation, excitation, sedation, psychosis 2)
CVS – tachycardia, arrhythmia 3)
GI – dry mouth, constipation 4)
GUS – Urinary urgency and frequency (contraindicated in prostatic
hypertrophy) 5)
Paralysis of visual accommodation and glaucoma (contraindicated in
glaucoma) Pharmacokinetics
·
Benzhexol, Orphenadrine and Procyclidine can all be administered orally
and are metabolised and excreted by the liver.
Orphenadrine has the longest half-life of 13.7-16.1 hours and is
metabolised to an active metabolite. ·
Benzatropine is excreted very slowly so changes in dose should be
carried out gradually. ·
Procyclidine has a t1/2 of 13.7-16.1 hours and benzhexol t1/2 is 3-7
hours. Drug interactions
·
Antimuscarinic effects e.g. dry mouth, urinary retention and
constipation are enhanced with concominant use of nefopam, disopyramide, TCA’s,
MAOI’s, antihistamines, phenothiazines and amantadine.
·
Antagonise the GI effect of cisapride, metoclopramide and domperidone. ·
Parasympathomimetics: effects are antagonised. Drugs used in other
extrapyramidal diseases
DRUG-INDUCED EXTRAPYRAMIDAL SYNDROMES ·
Mostly seen after phenothiazine treatment for schizophrenia and other psychoses and after anti-emetics
with dopamine receptor blocking properties e.g. metaclopramide. ·
Symptoms include: ·
Parkinsonian symptoms in elderly patients ·
Acute dystonic reactions of rigidity, muscle spasm and opisthotonus
progressing to tardive dyskinesia in younger patients. ·
Tardive dyskinesia ·
Treatment is decrease in dosage of drugs or long term anticholinergic
drug therapy. CHOREA
·
Commonly Huntingdon’s Chorea or secondary to cerebrovascular damage in
basal ganglia. ·
There is repetitive semi-purposeful movement resembling L-dopa induced
dyskinesia. ·
It is due to a deficiency of inhibitory GABA, which results in the
overactivity of the dopamine systems in basal ganglia. ·
Treatment: Tetrabenazine
which depletes dopamine from the nerve
endings
Haloperidol or phenothiazine which are dopamine receptor antagonists
Sodium Valproate which increases GABA availability in brain DYSTONIA
·
Slowly sustained abnormal movement is dystonia. ·
Depending on where affected can get blephrospasm, torticollis, segmental
dystonia and others. I.m. Botulinum
toxin may be helpful. SUMMARY
·
The aims of the pharmacological treatments for Parkinson’s Disease are
to replace or mimic the action of DOPAMINE (e.g. L-dopa) and to use muscarinic
antagonists to inhibit the excitatory effect of ACETYLCHOLINE. ·
Combination of L-dopa and a dopa-decarboxylase inhibitor are first line
therapy for Parkinson’s Disease. The
benefit of treating with MAO-B inhibitor, selgeline, to retard disease
progression is unconfirmed. Dopamine
agonists and COMT inhibitors are helpful as adjuvent drugs for patients with end
of dose deterioration and reducing on-off motor fluctuations. ·
Polypharmacy is inevitable and as the doses are increased with the
progression of the disease there is increased incidence of unwanted effects from
the drugs used. ·
Anticholinergic drugs are the first-line treatment for drug-induced
parkinsonism due to anti-psychotic drugs. ·
Besides medication, Parkinson’s Disease may be treated surgically e.g.
thalamotomy or pallidotomy, physical and speech therapy are used to keep the
patients as active as possible. There
may be benefit from transplantation of foetal dopaminergic neurones although
this is still under investigation. |
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