Parkinson’s Disease

Dr Vijay Suppiah

Pharmacotherapeutics 2

Parkinson’s Disease

• Progressive neurological condition

• First described in 1817 by Dr James Parkinson

• Considered second most common progressive neurological condition after dementia

• Been estimated that around 6.3 million worldwide

• Prevalence in the 1.6 per 1 000 (UK), 1.5 per 1000 (USA) and 1 per 350 (Australia)

• Prevalence increases with age (average age of onset is 60 yrs)

• Peaks around 75- 80 year age group

• Slightly more common in males than females (ratio 5:4)

• Slight higher incidence in Caucasian races than Asian and African*

Aetiology

• Cause of Parkinson’s Disease is not fully understood

i. Age-related (Fearnley and Lees. 1991)

- 9-13% loss of dopamine-producing neurons/ decade of life

- Very old patients may lose 70-80% of these neurons

- May explain for the subtle extrapyramidal findings that are often found in the octogenarian patient.

Substantia nigra

ii. Genetics

- Familial history

a. Families with high incidence have PD carry a mutation in the alpha-synuclein gene (chr 4)

b. Young-onset PD patients carry a mutation in the Parkin gene (chr 6)

c. Four other genes have also been associated with PD (UCHL1, DJ1, PINK1, and LRRK2)

iii. Environmental trigger

- Such as environmental toxins but something substantial is yet to be identified.

Signs and Symptoms

4 cardinal symptoms

Tremor at rest

Bradykinesia

Muscle rigidity

Postural instability

Tremor

• Most commonly identified symptom (but 30% patients will not

experience tremor)

• Related to imbalance of dopamine and acetylcholine (mostly to the action of acetylcholine)

• Affects muscles at rest (disappears when purposeful movement is

initiated)

• Action tremor is initiated by active movement (daily

activities such as eating, drinking and writing affected)

• Usually starts with one upper limb

• Absent during sleep

Bradykinesia

• Means slow movement

• It takes longer and requires more effort to complete daily tasks.

• Slowness and difficulty in initiating and executing automatic repetitive movements (eg writing, walking)

• Poverty of movement results in: - Mask like face

- Monotonous speech

- Bent posture

- Slow gait

- Loss of arm swing

Rigidity

• Refers to the resistance felt in muscles when they are passively moved.

• “Lead pipe” rigidity - when the resistance is consistent and equal throughout the entire range of motion

• “Cogwheel” rigidity is the term used when the resistance to passive movements has a regular jerking characteristic.

Postural Instability

• Seen as forward flexed or bent posture.

• The ability to maintain posture and balance may be affected

• Is often the cause of falls (the ability to correct one’s balance is

compromised).

Repetitive “pill rolling” movement

Persistent tremors

Shuffling gait, taking small steps

Bent posture

Other symptoms

• Akinesia

• Anosmia

• Anxiety

• Constipation

• Depression

• Drooling (excessive)

• Fatigue

• Gait changes

• Impotence

• Loss of motivation

• Masked facial expression

• Micrographia

• Microphonia

• Postural hypertension

• Stuttering

Diagnosis

• If three of the cardinal symptoms are present a provisional diagnosis of PD may be made.

• A positive response to levodopa is often a further indicator of correct diagnosis.

• 25% of patients diagnosed by specialists as suffering from idiopathic PD did not have the disease (Hughes et al

1992)

Staging of disease progression

• Observation

• Ask the patient

• Timed walk

• Daily activities (eg dressing themselves)

• Picking up paper clips (fine movement)

• Hoehn and Yahr scale

• AIMS

• Unified PD rating scale

• On/off charts

Hoehn and Yahr scale

Stage 1: Unilateral involvement only; Minimal or no functional impairment

Stage 2: Bilateral involvement without impairment of balance

Stage 3: Evidence of postural imbalance; Some restriction in activities; Capable of leading independent life; Mild to moderate disability

Stage 4: Severely disabled, Cannot walk and stand unassisted; Significantly incapacitated

Stage 5: Restricted to bed or wheelchair unless aided

Parkinsonism vs Parkinson’s disease

Parkinsonism refers to any condition that involves a combination of the types of changes in movement seen

in Parkinson’s disease

A. Idiopathic Parkinson’s disease

• Most common variety of parkinsonism

• No obvious cause

• Main symptoms are tremor, rigidity and slowness of movement.

B. Drug or toxin induced Parkinsonism

• Any drug that blocks the action of dopamine is likely to cause parkinsonism.

• Therapeutic agents: antipsychotics (clozapine), calcium channel blockers (cinnarizine), anti-N/V (metoclopramide)

• Toxic substances: Manganese dust, Carbon disulphide after CO poisoning

• MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydro-pyridine)

C. Parkinsonism associated with other neurological diseases

• Shy-Drager syndrome

• Progressive supranuclear palsy

• Repeated episodes of head trauma (boxing)

Principles of treatment

There is no cure for Parkinson's disease, so the two principles of treatment are to:

i. Attempt to keep the patient functioning for as long as possible with the minimum amount of medication

ii. Individualise therapy.

Treatment

Pharmacological treatment

• Treatment plan

- short-term relief

- long-term management

• Side effects

• Timing of doses

• Treatment WILL have to evolve as the patient’s illness progresses

Drug classes used in treatment

• Anticholinergic drugs – Benztropine

• Levodopa preparations– Sinemet, Madopar

• Amantadine

• Dopamine agonists – Bromocriptine, Apomorphine, Cabergoline, Pramipexole

• Catechol-O-methyltransferase (COMT) inhibitors – Entacapone

• Monoamine oxidase B (MAO-B) inhibitors - Selegiline

Anticholinergics

• Used to treat PD since the mid 1800s (scopolamine)

• Block cholinergic receptors in the stratum and reduce the relative excess of cholinergic activity that accompanies dopamine deficiency

• Undesirable side effect profile and poor efficacy (relative to levodopa)

• Reserved for treatment of resting tremor early in the disease, esp in younger patients with good cognitive function.

• Drugs include: benztropine, benzhexol, biperiden

Side effect profile

• Dry mouth - Useful if patient has sialarrhoea

• Reduced bladder excitability - Useful for freq and urgency

• To be avoided in elderly men with BPH

• Other effects: constipation, blurred vision, CNS disturbances (confusion,

hallucinations, memory loss)

Levodopa

• Mainstay of treatment since the 1960

• Nearly all patients will get levodopa eventually regardless of initial therapy.

• Dopamine itself does not cross the BBB

• Levodopa, a dopamine precursor is administered

• In combination with DDIs (carbidopa or benserazide)

Metabolism of Levodopa Levodopa alone

1% eventually crosses the BBB

High peripheral conversion of levodopa to dopamine in the heart, stomach, liver and kidneys Resultant: - Nausea, vomiting and anorexia (50%) - Postural hypotension (30%) - Cardiac arrhythmias (10%)

Levodopa + DDI

Higher dose crosses the BBB, hence dose can be 80% less than levodopa alone

Peripheral conversion is reduced.

Levodopa + Carbidopa

Preparation Levodopa Carbidopa Colour of tablet

Sinemet 100/25 100 mg 25 mg Yellow-green

Sinemet 250/25 250 mg 25 mg Blue

Sinemet CR 200 mg 50 mg Peach

Levodopa + Benserazide Preparation Levodopa Benserazide Formulation type

Madopar Rapid

62.5

50 mg 12.5 mg Dispersible tab

Madopar Rapid

125

100 mg 25 mg Dispersible tab

Madopar 62.5 50 mg 12.5 mg Normal cap

Madopar 125 100 mg 25 mg Normal tab

Madopar 125 100 mg 25 mg Normal cap

Madopar 200 mg 50 mg Normal tab

Madopar 200 mg 50 mg Normal cap

Madopar HBS 100 mg 25 mg SR cap

Typical treatment regimen starting with levodopa

Source: Sellbach and Silburn 2012

Triple combination

Amantadine

• Antiviral agent

• Believed to increase the release of endogenous dopamine and possibly inhibits dopamine reuptake

• Mild effect on parkinsonian symptoms

• Modest effects on bradykinesia, tremor and rigidty

• Limited role on PD management

Amantadine

• Neuropsychiatric adverse effects limit use in elderly patients

- Confusion

- Nightmares

- Hallucinations

- Insomnia

• Other adverse effects: - Anticholingeric

- Livedo reticularis

Dopamine agonists Agonist T1/2 (H)

Bromocriptine 3 -8

Cabergoline 63 – 110

Pergolide 15- 27

Pramipexole 7 – 12

Ropinirole 6

Dopamine agonists

Agonist Ergot

derivative

Non ergot

derivative

D1 D2 D3 D3/D2 5-HT2

Bromocriptine X - +++ + 0.2 +

Cabergoline X + +++ ++ 0.5 +

Pergolide X + +++ ++ 0.4 +

Pramipexole X 0 +++ ++++ 7.8 0

Ropinirole X 0 +++ +++ 1.3 0

Rotigotine X 0 +++ ++++ 10 0

Advantages of dopamine agonists

These agents have a number of potential advantages:

1. They act directly on dopamine receptors

2. Absorption and transport into the brain.

3. Longer half life than levodopa formulations

4. Motor symptoms

5. Adequate control of symptoms

6. Good choice for initial treatment in many patients, esp young-onset

Adverse effects of dopamine agonists

• Nausea

- tend to decrease with time. Encourage patient to take drug with food.

- anti-emetics: metoclopramide, domperidone

• Compulsive behaviour

- excessive gambling, hypersexuality and compulsive shopping or eating.

- Reduction or elimination of dopamine agonist

- Antipsychotics clozapine and quetiapine can be tried but there is no documented efficacy

• Somnolence

- sleep attacks

- dose of the dopamine agonist should be reduced or the drug discontinued.

- Other drugs, MAOB inhibitor, caffeine

• Hallucinations

- up to 40%, Common visual hallucinations include people, small furry animals, insects or snakes.

- timing of hallucinations relative to dosing time

- reduced or eliminated in the following order: anticholinergics, selegiline, dopamine agonists, amantadine, COMT inhibitors and, finally, levodopa.

- Antipsychotics clozapine and quetiapine

Rotigotine

Advantages:

- Non ergot dopamine agonist

- Continuous transdermal delivery

- Absorption not influenced by food

Disadvantages:

- Skin irritation

- no evidence that rotigotine is more eff•ective than oral dopamine agonists in levodopa-treated patients

Apomorphine

• A potent D1 and D2 dopamine agonist

• Given as a SC injection

• Rapid (within 5 to 10 mins) but short acting (up to 1 hour)

• Important role in management of on-off effect in some patients

• Nausea and vomiting common

- recommended be give 1 to 3 days of domperidone 20 mg tds prior to treatment

Note:

1. Concurrent administration of ondansetron (or other serotonin antagonists) with apomorphine can cause severe hypotension

2. Concurrent administration of other anti-emetics such as prochlorperazine and metoclopramide with apomorphine can decrease the effectiveness of apomorphine (due to them being dopamine antagonists)

Monoamine oxidase B inhibitor

• Selegiline – an irreversible MAO B inhibitor

• Reduces the breakdown of dopamine thus increasing the amount available at the synaptic cleft

• May be useful in younger patients, delays the need to start levodopa therapy*

• may have a role as an adjunct to levodopa in more advanced disease**

• Partly metabolised to L-methamp and L-amphetamine (therefore given in the morning)

COMT inhibitors

• Entacapone – inhibits COMT mainly in the peripheral tissues

• Increases the amount of L-dopa available to the brain

• No role as monotherapy: used in combination with levodopa

• Reduce overall levodopa dose* and motor fluctuations in more advanced disease

Adverse effects

• Typical dopaminergic side effects:

- GI such as nausea, cramps, diarrhoea

- Hypotension

- Dizziness

- Dyskinesias

NICE Clinical Guidelines for Parkinson’s Disease 2006

• It is not possible to identify a universal first-choice drug therapy for people with early PD.

• The choice of drug first prescribed should take into account:

- clinical and lifestyle characteristics

- patient preference, after the patient has been informed of the short- and long-term benefits and drawbacks of the drug classes.

NICE Clinical Guidelines for Parkinson’s Disease 2006

Motor complications

• Wearing off

• Peak dose dyskinesias

• Early morning dystonias

• On-off phenomenon

Wearing off

• Need to smooth out the plasma conc of L-dopa

a. Increase the freq of the dose while keeping the overall dose steady eg levodopa 200 mg tds to 100 mg six times a day

b. using a combination of immediate-release and extended-release carbidopa/L-dopa or benserazide/L-dopa*

c. By adding a COMT inhibitor to the combination (increase half life of L-dopa)

d. By adding a MAO-B inhibitor to the combination (inhibit central dopamine catabolism)

Peak dose dyskinesias

• Need to smooth out the plasma conc of L-dopa

a. reduce the dose of dopaminergic agents if possible

b. Discontinuing (COMT) inhibitors or (MAO)-B inhibitors

c. Addition of amantadine, atypical antipsychotic drug clozapine

Patient may have to decide on the balance of dyskinesia and motor benefit desired

Early morning dystonia

• Clawing of toes in the morning, occurs before first waking dose of the medication

a. SR L-Dopa

b. Addition of dopamingeric agonists to the treatment regimen

On-off phenomenon

• Unpredictable change from one motor state to another

a. Same strategies as wearing off

b. Using a dispersible preparation of levodopa

c. Using apomorphine

Effective treatment of the on-off phenomenon can sometimes be difficult.

Surgery/deep brain stimulation

• Considered when:

a. Patient below the age of 60 years

b. Unilateral tremor and rigidity

c. Unresponsive to drug therapy

Further drug administration considerations

• To avoid the potential for acute akinesia, do not: – withdraw antiparkinsonian medication abruptly

– allow medication to fail suddenly due to poor absorption (for example, gastroenteritis, abdominal surgery).

• The practice of ‘drug holidays’ should not be undertaken.

• People with PD admitted to hospital or care homes should have their medication:

– given at appropriate times, which in some cases may mean allowing self-medication

– adjusted by, or adjusted only after discussion with, a specialist in managing PD.

References

• Fahn S. How do you treat motor complications in parkinson’s disease: Medicine, surgery or both? Ann Neurol 2008; 64: S56-64

• Fearnley JM and Lees AJ. Ageing and Parkinson's disease: Substantia nigra regional selectivity. Brain. 1991, 114: 2283-2301.

• Hughes et al. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992; 55: 181-184

• NICE clinical guideline 35 (Parkinson’s disease): Diagnosis and management in primary and secondary care. National Collaborating Centre for Chronic Conditions. June 2006

• Sellbach A and Silburn P. Management of Parkinson’s Disease. Australian Prescriber 2012; 35: 183-188

• Therapeutics guidelines

• www.epgonline.org/parkinsons-disease