Pharmacotherapy of Parkinson's Disease

Parkinson’s disease

RVS Chaitanya Koppala

Introduction

Parkinson's disease is the most common cause of Parkinsonism.

The second most common neurodegenerative disease, after Alzheimer's disease.

Although descriptions of the condition appeared before the nineteenth century, it was James Parkinson's eloquent account in 1817 that fully documented the clinical features of the illness now bearing his name

The identification of dopamine deficiency in the brains of people with Parkinson's disease and the subsequent

introduction of replacement therapy with levodopa represent a considerable success story in the treatment of

neurodegenerative illness in general.

EpidemiologyParkinson's disease affects 1% /65 years of age, rising to 2% /80 age. One in 20 patients is, however, diagnosed before their 40th year. It is estimated that

110,000 people have Parkinson's disease in the UK. Most epidemiological studies have indicated a small male-to-female predominance. Other causes of Parkinsonism include neurodegenerative conditions, multiple

system atrophy and progressive supranuclear palsy. The prevalence for these conditions is approximately 5.0 per 100,000. Drug-

induced Parkinsonism is a common form of so-called symptomatic Parkinsonism. 10–15% of individuals exposed to dopamine receptor blocking agents including

neuroleptics and some labyrinthine sedatives.

AetiologyBoth genetic and environmental factors have been implicated as a cause of

Parkinson's disease. Environmental factors became pre-eminent in the 1980s, when drug

addicts attempting to manufacture pethidine accidently produced a toxin called MPTP (1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine).

Ingestion or inhalation of MPTP rapidly produced a severe Parkinsonian state, indistinguishable from advanced Parkinson's disease.

Notably, not all individuals exposed to MPTP developed Parkinsonism, either acutely or on subsequent follow-up,

In a small number of patients, genetic factors are dominant. The discovery of a mutation in the gene coding for a synaptic protein called α-synuclein

The characteristic pathological features of Parkinson's disease are Neuronal loss in pigmented brainstem nucleiEosinophilic inclusion bodiesThe substantia nigra in the midbrain

Dopaminergic neurons lacks dopamineParkinson's disease, there is a loss of over 80% of nigral neurones

before symptoms appear. The ‘Braak hypothesis’ has been proposed to account for spread of

pathology within the Parkinsonian brain and suggests that α-synuclein may first accumulate in the lower brainstem and then gradually ascend to affect critical brain regions including the substantia nigra and ultimately the cerebral cortex

Dopaminergic neurones are not the only cells to die within the brainstem, and a plethora of other nuclei and neurotransmitter systems are also involved.

Cholinergic neurones within the pedunculopontine nucleus degenerate,

(postural instability, swallowing difficulty (dysphagia) and sleep disturbance (REM sleep behavioural disturbance).

Within the striatum, changes occur within γ-aminobutyric acid-containing neurones, as a consequence of nigrostriatal dopaminergic deficiency. (development of involuntary movements (dyskinesias))

The loss of noradrenergic neurons in lucus coeruleus The loss of serotonergic neurones within the raphé nucleus (may

provide a pathophysiological basis for depression)

Clinical featuresMotor featuresBradykinesiaRest tremor (rhythmic movement with a frequency of 4–6 Hz (cycles/s)extrapyramidal rigidity (so-called lead pipe and/or cog-wheel) postural instability (arms held outstretched) late feature of Parkinson's

disease and comprises an impairment of righting reflexes with a tendency to fall.

Flexed truncal posture and loss of arm swing when walkingThere is reduced blink frequency and facial expressionReduced volume (hypophonic) and monotonous speech, Writing becomes small (micrographia) and barely legible.

Non-motor featuresAutonomic dysfunction may occur in Parkinson's disease. Greasy skin (seborrhoea). Urogenital difficulties, with erectile dysfunction in males and urinary urgency in both sexes,Constipation is invariable and is multifactorial in origin. Falling blood pressure on standing (postural hypotension) Depression affects approximately 40% of people with Parkinson's disease Dementia in Parkinson's disease The cognitive impairment may be accompanied by hallucinations that are

often visual, delusional misinterpretation

Differential diagnosis

Drug-Induced ParkinsonismPerhaps the most important differential diagnosis to consider when a patient

presents with Parkinsonism is whether their symptoms and signs may be drug induced.

Potentially reversible upon cessation of the offending agent. Reports linking drug-induced Parkinsonism with the neuroleptic

chlorpromazine were first published in the 1950s. Since then, numerous other agents have been associated with drug-induced

Parkinsonism. Compound antidepressants were a problem in the past because they

contained neuroleptic drugs. For example, fluphenazine was found with nortriptyline

Repeat prescription of vestibular sedatives and anti-emetics

InvestigationsThe diagnosis of Parkinson's disease is a clinical one and should be

based, preferably, upon validated criteria.Copper studies and DNA testing to exclude Wilson's disease and

Huntington'sdisease respectively. Brain imaging by computed tomography (CT) or magnetic resonance

imaging (MRI) may be necessary to exclude hydrocephalus, cerebrovascular disease or basal ganglia abnormalities suggestive of an underlying metabolic cause.

When there is difficulty in distinguishing Parkinson's disease from essential tremor, a form of functional imaging called FP-CIT SPECT (also known as DaTSCAN) may be useful, as this technique can sensitively identify loss of nigrostriatal dopaminergic terminals in the striatum

FP-CIT SPECT cannot differentiate Parkinson's disease from these other forms of degenerative Parkinsonism.

MRI brain scanning, Anal sphincter electromyography, Tilt table testing for orthostatic hypotension and Eye movement recordings

Treatment (Drug treatment)LevodopaDopamine agonists (Ropinirole, Pramipexole)COMT inhibitors (Tolcapone, Entacapone)Amantadine (anti cholinergic, dopamine reuptake inhibition, NMDA

antagonist)Apomorphine Anti cholinergic drugs (Trihexyphenidyl, Orphenadine)Monoamine oxidase type B inhibitors (Selegiline , Rasagiline)

Surgical treatment

Therapeutic solutions