ANTI-PARKINSONISM

INTERN LECTURER:QUEEN DADA

What is parkinsons disease

Parkinsons

disease is a progressive neurological

disorder characterised by tremor, rigidity, bradykinesia
and postural disturbances.

Substantia

nigra and striatum are areas in the brain

which are important in controlling motor activity.

The

substantia nigra is connected to the striatum by

neurones that secrete the inhibitory transmitter GABA
in the substantia nigra (see Fig 1)

Parkinons disease
In

turn the cells of the substantia nigra send neurons

back to the striatum secreting dopamine.

The striatum also contains many cholinergic neurons.

Their function is to counterbalance the doperminergic
activity in the nigra-striatal system. Therefore there is
an endogenous balance between doperminergic and
cholinergic activities.

Fig 1.

Pathogenesis
Pathology:

in Parkinson's disease there is loss of

dopamine neurons in the substantia nigra a
deficiency of dopamine in the basal ganglia.

This

results in a deficiency of dopamine in the basal

ganglia and an imbalance in neurotransmitter activitytoo little dopamine and too much acetylcholine is
thought to bring about most of the symptoms.

Symptoms
Parkinsonism

affect functional activities such as balance

,walking, speech ,fastening buttons as they are usually
controlled by the mechanisms of dopamine and the basal
ganglia.
The main motor symptoms of parkinsonism are:
Bradykinesia-slowness of movement
Rigidity-due to continually contracted muscles
Tremor-involuntary shaking
Postural instability-balance problems
Non motor symptoms; depression, dementia, sleep
disturbances, postural hypotension, constipation.

Treatment
Pharmacotheray

is based on correcting the imbalance

between dopaminergic and cholinergic systems at the
basal ganglia.

Two

major groups of drugs are used: drugs that

facilitate stimulation of dopamine receptors and drugs
that antagonise acetylcholine at muscarinic receptors

Drugs that facilitate stimulation of dopamine

receptors
Dopamine

precursors

Levodopa

is an example of dopamine precursor

MOA :It can penetrate the blood brain barrier to
replenish dopamine in the striatum.

Levodopa is well absorbed from the intestines.

Much of it is inactivated by MAO in the small intestines

Drugs that facilitate stimulation of dopamine

receptors

95% of the drug is decarboxylated to dopamine in the

periphery by dopa decarboxylase; <1 % enters the brain
Therapy loses effectiveness after approximatly 2 years5 years.
This manifests itself as end of dose deterioration and
the on-off effect ( rapid fluctuation in the clinical state

Drugs that facilitate stimulation of dopamine

receptors
AE: The extensive peripheral metabolism of levodopa
means that large doses have to be given to produce
therapeutic effects in the brain.
Large doses are more likely to produce the following
adverse effects;
Nausea and vomiting
Psychiatric side effects
Cardiovascular effects(hypotension)
dyskinesias

Drugs that facilitate stimulation of dopamine

receptors
Three

strategies have been developed to optimise levodopa

treatment, the maximise the central effects of levodopa
within the brain and minimise its unwanted peripheral
effects. These strategies involve combining levodopa with;

Carbidopa, an inhibitor of dopa decarboxylase in the

periphery, it cannot penetrate the BBB.

Domperidone, a dopamine antagonist, that does not

penetrate the BBB and can therefore block the stimulation of
dopamine receptors in the periphery.

Drugs that facilitate the stimulation of

dopamine receptors

Selegiline and entacapone, MAO type B and

COMT inhibitor respectively, which inhibit
dopamine degradation in the CNS.

Drugs that facilitate the stimulation of

dopamine receptors
Dopamine

agonists
Examples of dopamine agonists are bromocriptine,
apomorphine,lisuride
Bromocriptine
MOA :Dopamine receptor agonist
I:used in combination with levodopa to reduce the late
adverse effects of levodopa therapy (end of dose
deterioration and on off effect) or when levodopa alone
does not adequately control the symptoms.

Drugs that facilitate the stimulation of

dopamine receptors
Bromocriptine has many side effects and it is also very
expensive;used nly for cases that cannot be effectively
treated with levodopa.
AE: Nausea, dizziness ,drowsiness postural
hypotension, dyskinesia, hallucinations,
dementia, depression.
Drugs stimulating dopamine release.
Amantadine is an example of a drug that stimulates
the release of dopamine.
It is an antiviral with moderate anti-parkinson activity.

Drugs that facilitate stimulation of dopamine

receptors
AE; Discolouration of the skin, especially the legs ad
oedema of the ankles, hallucinations, anorexia.
Monoamine oxidase B inhibitors
Selegiline is an example,
MOA: It inhibits the MAO type B enzyme in the brain
that is responsible for the degradation of dopamine.
I: used in mild cases of parkinsonism or in
conjunction with levodopa to reduce end of dose
deterioration in severe parkinsonism.

Drugs that facilitate stimulation of dopamine

receptors
AE: Abdominal pain, dyskinesia, dry mouth.
Catechol-o-methyl

transferase inhibitors
Entacapone is an example.
MOA:COMT is responsible for the degradation of
dopamine, COMT inhibitors inhibit the enzyme
I used as an adjunct to levodopa
AE Abdominal pain, diarrhoea, nausea

Drugs that antagonise acetylcholine at muscarinic receptors

Orphenadrine,

benzatropine, trihexyphenidyl
MOA: They are antagonists at the muscarinic receptors that
mediate striatal cholinergic excitation.

The

major action in the treatment of parkinsonism is to reduce the

excessive striatal cholinergic activity that characterises the disease.

AE: dry mouth, blurred vision, constipation.