Parkinson's Disease

Shaking palsy or paralysis agitans. This is a common neurological disorder with prevalence of 1-2 per 1000 overall. Over 50 years of age this rises so that 1-2% of elderly are affected. It is a degenerative disease affecting the nervous system. The cause is idiopathic (relating to or denoting any disease or condition that arises spontaneously or for which the cause is unknown). More common among men than women. Incidence increases with age but age is not believed to be causative factor. Rarely inherited - less than 1% thought to have genetic component. Symptoms appear where there is an imbalance between dopamine and acetylcholine in brain. There is a striatal deficiency of dopamine following neuronal degeneration within the substantia nigra. This interferes with message transfer between nerve cells. If the brain cannot manufacture dopamine, Parkinson's disease results. Malnutrition is proposed as a major factor.

Symptoms: characterised by an insidious onset with slowing of emotional and voluntary movement, muscular rigidity, postural abnormality and tremor. Main one is pronounced tremor affecting extremities. Generally asymmetrical at presentation. Include muscular rigidity, drooling, loss of appetite, a stooped and shuffling gait, tremors that include a characteristic pill-rolling movement of thumb and forefinger, impaired speech and a fixed facial expression. Disease may begin with tremor of hands while at rest. Body usually becomes rigid and the limbs stiffen. Memory impairment and cognitive dysfunction rarely encountered in early PD. Depression common feature and about 30% PD victims eventually develop Alzheimer's disease or other forms of dementia.

Other features include:

· Eye movements - unaffected apart from paralysis of convergence and some limitation of up-gaze. Down gaze is spared.

· Handwriting may become small - micrograhia - due to clumsiness of hand movements and difficulty with fine motor tasks.

· Drooling saliva is common, due to failure to swallow and dysphagia may occur (swallowing difficulty).

· Constipation is almost invariable excessive

· Sweating greasy skin (seborrhea)

· Depression is very common (30%)

· Bradyphrenia. Many patients complain of slowness of thought

· Cognitive problems

· Dementia may occur later in the disease

Non-idiopathic causes - Parkinson-like symptoms can occur in head injury, carbon monoxide poisoning or drugs (ethical ones). Certain diuretics (reserpine), antipsychotics (chlorpromazine) and heart drugs (verapamil) all implicated in causing or worsening PD symptoms. Also "designer drug" MPTP (methylphenyl tetrahydropyridine). Naproxen and other NSAIDs may also exacerbate PD.

Pure idiopathic PD is only one of a very large number of possible causes. Cerebral anoxia is a shortage of oxygen. (Benign) Essential Tremor is a condition characterised by tremor of the hands, head, voice and sometimes called familial tremor. Sometimes mistaken for a symptom of Parkinson’s. However, this is an action tremor and there is no rigidity or bradykinesia (slowing of movement - major symptom of PD).

Levodopa

Levodopa is a derivative of (-)-L-amino-(3,4-dihydroxybenzene) propanoic acid as the hydrazino-methyl derivative of this aromatic amino acid. Carbidopa is an inhibitor of aromatic amino acid decarboxylation. Since Dopamine does not cross the blood-brain barrier (but its precursor Levodopa does) L-Dopa is given in an effort to replace the striatal (corpus striatum) Dopamine deficiency. Dopamine is thought to be converted to dopamine in the basal ganglia of the brain. Basal ganglia are deeper structures within the brain, concerned with normal movement and walking. The caudate (tail-like) nucleus, putamen (lateral part of the lentiform nucleus of cerebellum) and Substantia Nigra are basal ganglia affected in Parkinson's disease. However, since L-Dopa has significant peripheral metabolism, resulting in untoward side effects (nausea and vomiting) and decreased brain delivery of L-Dopa, it is combined with a peripheral decarboxylase inhibitor (Carbidopa).

Sinemet CR (Carbidopa-Levodopa) is a sustained-release combination of Carbidopa and Levodopa for the treatment of Parkinson's disease and syndrome. Polymeric based drug delivery system that controls the release of Carbidopa and Levodopa as it slowly erodes. Patients with Levodopa therapy may develop motor fluctuations characterised by end-of-dose failure, peak dose dyskinesia and akinesia (absence of body movements). The advanced form of motor fluctuations ("on-off" phenomenon) characterised by swings from mobility to immobility. Causes of these motor fluctuations are not completely understood, but they may be attenuated (in some patients) by treatment regimens that produce steady plasma levels of Levodopa. But no benefit shown of Carbidopa-Levodopa vs Levodopa. Sustained release (SR) tablets contain either 50mg Carbidopa and 200mg Levodopa or 25mg and 100mg.

Designed to release these actives over 4-6 hour period against 1.5hr normal elimination half-life. Less variation in plasma Levodopa level than conventional formulation of Carbidopa and Levodopa. This SR formulation is less systemically bioavailable than standard and may require increased daily doses to achieve the same level of symptomatic relief as provided by standard Carbidopa-Levodopa. In healthy elderly (56-67 years old) mean time to peak concentration of Levodopa after single dose of Carbidopa-Levodopa SR tablet (50/200mg) about 2 hours compared to 0.5 hr after standard formulation. The max concentration (SR) is about 35% of standard (1151 vs 3256ng/l). About double this (70-75%) compared to standard IV formulation. Fluctuations of plasma levels create a narrower range for SR against standard Carbidopa-Levodopa for similar total daily doses. Nevertheless higher overall doses of the SR must be used to sustain plasma levels within the therapeutic range.

Current evidence indicates that the symptoms of PD are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of this disease apparently because it does not cross the blood-brain barrier and presumably is converted to dopamine in the basal ganglia or brain. Thought to be mechanism whereby Levodopa relieves symptoms of PD. Oral administration it is rapidly by decarboxylation to dopamine in the extracerebral tissues (wrong place) so that only a small portion of given dose is transported unchanged to the central nervous system. For this reason large doses are required for adequate therapeutic effect and this may be attended by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues.

Carbidopa inhibits this decarboxylation of peripheral Levodopa. It does not cross the blood-brain barrier and does not affect the metabolism of Levodopa within the CNS. Levodopa is protected by Carbidopa. The absorption of Levodopa may be impaired by certain amino acids with which it competes in a high protein diet. Since the decarboxylase inhibiting action of Carbidopa is limited to extracerebral tissues, co-administration of Carbidopa with Levodopa makes Levodopa more available for transport to the brain. Vitamin B"'6"' (pyridoxine hydrochloride) may reverse effects of Levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa-Levodopa may therefore be useful in patients taking supplemental pyridoxine. Carbidopa inhibits the action of pyridoxine additionally.

In dogs, reduced formation of dopamine in extracerebral tissues (heart) provides protection against development of dopamine-induced cardiac arrhythmias. Clinical studies tend to support the hypothesis of a similar protective effect in humans but controlled data are too limited at the present time to draw firm conclusions. Carbidopa reduces the amount of Levodopa by about 75% and when co-administered with Levodopa increases both plasma and plasma half-life of Levodopa and decreases plasma and urinary dopamine and homovanillic acid. Simultaneous administration of Carbidopa and Levodopa produced greater urinary excretion of Levodopa in proportion to the excretion of dopamine than administration of the two drugs at separate times. Evidence for dopamine formed in target organ rather than in extracerebral tissues and so excreted since it cannot cross into brain as dopamine.

Carbidopa-Levodopa is indicated in the treatment of idiopathic Parkinson's disease (paralysis agitans), post-encephalitic Parkinsonism and symptomatic Parkinsonism which may follow injury to nervous system by carbon monoxide intoxication (cerebral anoxia) and manganese intoxication. Levodopa-induced nausea and vomiting is reduced with the Carbidopa-Levodopa combination than Levodopa alone - leads to a more rapid dose titration.

Although administration of Carbidopa permits control over Parkinson's disease with much lower dosage of Levodopa no conclusive evidence that it is beneficial other than reducing nausea and vomiting, allowing more rapid titration and providing somewhat smoother response to Levodopa. Carbidopa does not decrease adverse reactions due to central effects of Levodopa. By permitting more Levodopa to reach brain particularly when nausea and vomiting is not a dose-limiting factor, certain adverse CNS affects (dyskinesias) may occur at lower dosages and sooner during therapy with Carbidopa-Levodopa than with Levodopa alone. Certain patients who responded to Levodopa have improved when Carbidopa-Levodopa was substituted. Most likely due to decreased peripheral decarboxylation of Levodopa which results from administration of Carbidopa rather than to a primary effect of Carbidopa on the nervous system. Or seen another way, greater concentration of Levodopa crosses blood-brain barrier - dopamine to target organ. Carbidopa has not been shown to enhance the intrinsic efficacy of Levodopa in Parkinsonian syndromes.

Although some patients improve on Carbidopa-Levodopa management as opposed to Levodopa alone due to nausea and vomiting some do not. Trial therapy must be used to determine efficacy in specific cases. Also in controlled trials comparing Carbidopa-Levodopa with Levodopa about one-half of the patients with nausea and/or vomiting on Levodopa improved spontaneously despite being retained on the same dose of Levodopa during the controlled portion of the trial. Carbidopa has a real effect. Presumably, there is less decarboxylation to dopamine in the general circulation. As with Levodopa, Carbidopa-Levodopa may cause involuntary movements and mental disturbances. Thought to be due to increased level of dopamine in brain following administration of Levodopa.

The occurrence of dyskinesias may require dosage reduction. Levodopa should not be given to patients with a suspicious, undiagnosed skin lesion or a history of melanoma as Levodopa may activate a malignant melanoma. Carbidopa does not decrease adverse reactions due to central effects of Levodopa. By permitting more Levodopa to reach brain, particularly when nausea and vomiting is not dose-limiting factor, certain adverse CNS effects (dyskinesias) will occur at lower dosages and sooner during therapy with Carbidopa-Levodopa sustained release tablets than with Levodopa alone. More dopamine reaches brain as target organ without decomposition of precursor at same dose level. Patients receiving Carbidopa-Levodopa sustained release tablets may develop increased dyskinesia compared to Carbidopa-Levodopa. There is a more consistent concentration of dopamine with less fluctuation.

Because Carbidopa permits more Levodopa to reach brain and thus more Dopamine formed dyskinesias may occur at lower dosages and sooner with Carbidopa-Levodopa than with Levodopa. The occurrence of dyskinesias may require dosage reduction.

There is data on women of child bearing age so pregnancy and lactation does imply idiopathic Parkinson's disease can occur in less elderly people. Under 18s not established but similarly implication that it can occur in quite young people (incidence?). Paediatric use not recommended. Same implication.

Adverse Effects

The most common serious adverse reactions occurring with Carbidopa-Levodopa:

chorea (a type of dyskinesia - abnormal movement - characterised by continuing, rapid, dance-like movements and this may result from high dosages of Levodopa and/or long term Levodopa therapy)

dystonia (an involuntary spasm of muscle contraction that cause abnormal movements and postures and may appear as side effect of long term drug treatment in PD and may worsen in response to stress). Mental changes, including paranoid ideation (imagination, conception) and psychotic episodes, depression (maybe with or without suicidal tendencies) and dementia.

Common but less serious is nausea. Less frequent are cardiac irregularities and/or palpitation, orthostatic hypotensive episodes (associated with or caused by the erect posture), bradykinetic episodes (slow movement) - the "on-off" phenomenon, anorexia, vomiting, dizziness.

Rarely gastrointestinal bleeding, development of duodenal ulcer, hypertension, phlebitis (inflammation of surfaces of vein), haemolytic (destructive) and non-haemolytic anaemia (diminution in total circulating haemoglobin in blood), thrombocytopenia (abnormal decrease in number of platelets - thrombocytes - in blood), leukopenia (abnormal number of white cells in blood) and agranulocytosis (pathological state - diseased - in which there are is a marked decrease in number of granulocytes - polymorphonucleor leucocytes - in blood) have occurred.

Nervous system

· ataxia

· numbness

· increased hand tremor

· muscle twitching, muscle cramps

· blepharospasm (spasm of orbicular muscle of eyelid and is regarded as possible early symptom of excess dosage)

· trismus (lockjaw as in tetanus)

· activation of latent Horner's syndrome (combination of small pupil - miiosis, sunken eye

· erophthalmos and drooping of upper eyelid

· phosis (due to paralysis of sympathetic nerve in the region of the neck)

Psychiatric

· confusion

· sleepiness

· insomnia

· nightmares

· hallucinations

· delusions

· agitation

· anxiety

· euphoria

Gastrointestinal

· dry mouth

· bitter taste

· sialorrhea (excessive salivation)

· dysphagia (swallowing difficulties)

· bruxism (involuntary or habitual grinding of the teeth, typically during sleep)

· hiccups

· abdominal pain and distress

· constipation

· diarrhoea

· flatulence

· burning sensation of tongue

Metabolic

· weight gain or loss

· oedema (accumulation of fluid in tissues)

Integumentary

· malignant melanoma (a contraindication - if already present may activate it, must not be used if suspected or family history of melanoma)

· flushing

· increased sweating

· dark sweat

· skin rash

· hair loss

Genito-urinary

· urinary retention

· urinary incontinence

· dark urine

· priapism

Special senses

· diplopia

· blurred vision

· dilated pupils

· oculogyric crises (OGC is a drug induced movement disorder)

Miscellaneous

· weakness

· faintness

· fatigue

· headache

· hoarseness

· malaise

· hot flashes

· sense of stimulation

· bizarre

· breathing patterns

· neuroleptic malignant syndrome (drug induced movement disorder)

for drug induced movement disorder see

http://www.cmdg.org/

Side effects:

· nausea

· postural hypotension

· worsening of peptic ulcer symptoms

· sweating

· discolouration of urine/sweat

· with long-term use

· motor fluctuations

· dyskinesias

These probably represent the biggest single problem in long-term management of a patient with PD. An estimated 50% of patients develop these complications within the first 5 years of treatment and result in:

· neuropsychiatric problems

· confusion

· hallucinations

· psychosis

Surgical Treatment

Recent advances in neuro-imaging and stereotactic surgery have led to a renaissance in neurosurgery for Parkinson's Disease. By end of century PD will hopefully be both preventable and controllable.

Ropinirole (SKB) – Requip

Initial therapy and as adjunctive treatment with Levodopa (1970). Unlike older Dopamine agonists, Requip, is a second generation Dopamine agonist. Used for early PD (without Levodopa) and in patients with advanced PD (with Levodopa). Significant advancement by delaying use of Levodopa. Drug may be associated with severe motor fluctuations after long-term use. Levodopa is a standard treatment for PD - initially very effective but over time increased dosage is necessary to maintain control of symptoms. Chronic progressive disease - progressive neurodegenerative disorder. Main pathological feature is progressive death of nerve cells in critical area - substantia nigra. More cells die so more Levodopa needed. These produce dopamine (motor movement control) to transmit signals between substantia nigra and striatum. Depletion of dopaminergic neurons (estimated 70% destruction) results in characteristic PD symptoms like impaired ability to control motor movements.

Requip is highly-selective as a second-generation dopamine agonist that mimics dopamine effects. dopaminergic therapy for mild to moderate PD. Question is what causes this destruction? Consensus is that oxidative stress and metal toxicity are implicated. Free radicals catalysed by iron are responsible for neurodegenerative diseases and PD in particular. Low levels of natural oxidants (glutathione and superoxide dismutase) and high levels of iron in the substantia nigra cells of brain stem. Manganese, cadmium, copper and mercury (from dental amalgams) also implicated. High levels of aluminium in drinking water have an excessive risk of developing PD. Occupational exposure to pesticides and herbicides linked to significantly higher risk of developing PD.

· Diet is important. High levels of mono- and disaccharides (sugars) have a three times risk. Vitamin C and beta-carotene provide significant protection. High levels of animal fats carry a five-fold risk. High levels of uric acid are reported to be associated with lower risk PD. But high levels can result in gout and heart disease. The overall mortality rate was 30% higher compared to low uric acid levels. Nevertheless, provides evidence to support the antioxidant theory as protection against PD. The progressive nature of PD is slowed by antioxidant. Large doses of vitamin C (3g) and synthetic vitamin E (3200IU = over 200RDA) delayed PD for 2.5 years before L-Dopa was needed compared to group not taking these vitamins.

Later shown vitamin E not responsible - only the high levels of vitamin C. This makes sense in that fat soluble vitamin E does not cross blood-brain barrier or accumulate in cerebrospinal fluid which bathes brain. Vitamin C does not cross blood-brain barrier either but enters cerebrospinal fluid and is found there in proportion to dietary intake. As a highly effective antioxidant vitamin C is particularly adept at quenching hydroxyl radicals (main culprit of Dopamine-cell destruction) and it is becoming increasing clear that it is materially helpful in slowing down the progression of PD.

· Flavanoids - particularly proanthocyanidins (grape seed and pine bark extracts) - which are also water soluble and stronger antioxidant than vitamin C readily cross blood-brain barrier and should be excellent PD preventers and retarders. Clinical trials are necessary to support this hypothesis. Another promising candidate is coenzyme Q10 (ubiquinone) also absorbed in brain fluid and is a very powerful antioxidant. Recent research has demonstrated that coenzyme Q10 content within mitochondria declines rapidly when PD is induced in monkeys. This reduction in coenzyme Q10 leads to detrimental increase in free radical destructive reactions. The conclusion is to reduce animal fat intake and sugar avoiding excessive exposure to aluminium, iron, manganese, mercury, cadmium and copper and ensure an adequate intake of antioxidant.

The new treatment approach by these newer dopamine agonists is in early stages of disease. Stimulates dopamine receptors - dopaminergic drug effectively makes available receptor sites more sensitive. Lesser amounts of dopamine more effective. Levodopa is a precursor to dopamine. Initially effective, but long term complications include dyskinesias (involuntary movements like twitching, nodding and jerking), neuropsychiatric problems (hallucinations) and fluctuations of motor response. Ropinirole as monotherapy or adjunctive therapy with Levodopa.

Conventional medical treatment relies heavily on L-Dopa (levo-dihydroxy-phenylalanine) which can cross blood-brain barrier (dopamine precursor). L-Dopa rarely used by itself nowadays but with Carbidopa (Sinemet) or benserazide (Madopar) which prevents it breaking down before it reaches the brain tissue. L-Dopa taken between meals as it must compete with other amino acids from diet (gut, blood stream). After 4-5 years of L-Dopa medication effect becomes sporadic ("on-off syndrome"). L-Dopa therapy started as late as possible after diagnosis of PD to postpone the day when it no longer works and to limit its many serious adverse side effects.

Selegiline (Deprenyl, Eldepryl) another drug used in PD therapy. Blocks breakdown of dopamine in the brain by inhibition of monoamine oxidase type B. Can extend time to L-Dopa medication by about nine months. Selegiline and L-Dopa in early PD has shown no advantage. In fact this combination has been concluded to increase mortality rate by about 50% compared to L-Dopa management alone. The causes of death are unknown at present but it would seem to lay to rest the neuroprotective argument for Selegiline. Anticholinergic drugs (Benzhexol) work by reducing the amount of acetylcholine produced in brain and thereby redresses imbalance between dopamine and acetylcholine. Once instigated should be withdrawn only slowly to avoid rebound worsening of Parkinsonian symptoms.

No longer recommended for older patients as they have serious neuropsychiatric side effects. dopamine agonists mimic effects of dopamine by binding to and stimulating dopamine receptors in brain. Reduced level of dopamine at these receptors believed to cause motor symptoms of PD. Some examples of dopamine agonists (chemical or drug that mimics neurotransmitter activity): Bromocriptine, Pergolide, Lisuride. These three drugs vary both in duration of action and degree to which they are D1 or D2 agonists. Lisuride is short duration and mainly D2. Pergolide is the longest duration and acts on both D1 and D2 receptors. There is evidence that patients who can tolerate monotherapy with a Dopamine agonist for prolonged time that the incidence of dyskinesias and motor fluctuations in the long term is reduced. Downside of this is that the dose needs to be gradually increased very slowly and side effects are more common than L-Dopa. These act directly on the dopamine D1 and D2 receptors. Since they also act in the periphery on the dopamine receptors of the vomiting centre, they can also cause nausea and vomiting.

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