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DRUG TREATMENT OF PARKINSONISM

AND OTHER MOVEMENT DISORDERS
Basal ganglia controls movements by two balanced systems, the Cholinergic system
(excitatory) and the Dopaminergic system (inhibitory)
Parkinsons disease is associated with lesions in nigrostriatal dopaminergic system
Parkinsonism results from degeneration of doapaminergic neurons and/or dysfunction
of D2 receptors.
In Parkinsonism, the dopaminergic activity is so reduced that the cholinergic system
is dominant.
Parkinsonism is characterized by rigidity, bradykinesia, static tremors, postural
instability and mood changes. Parkinsonism is usually idiopathic, but it may
complicate viral encephalitis, carbon monoxide and manganese poisoning.
Drug-induced Parkinsonism: - Parkinsonism can be produced by:
- Drugs which block dopamine receptors e.g. Antipsychotics.
- Drugs which deplete dopamine stores e.g. Reserpine, Tetrabenazine.
- Drugs which inhibit dopamine systhesis e.g. Methyldopa.

DRUG TREATMENT OF PARKINSONISM

Treatment aims at restoring Cholinergic / Dopaminergic balance.

I- Block Cholinergic activity by anticholinergic drugs e.g. Benzhexol and
Benztropine. These drugs relieve rigidity, tremors and sialorrhea of
Parkinsonism but they have little effect on bradykinesia. They are also
effective against drug-induced Parkinsonism.
II- Enhancement of Dopaminergic activity by:
- Repleting neuronal dopamine ( e.g. Levodopa)
- Release dopamine from stores and inhibit its neuronal uptake (e.g.
Amantidine)
- Inhibit dopamine metabolism by selective MAO-B inhibitor (e.g.
Selegiline)
- Dopamine agonists (e.g. Bromocriptine).

Beta-adrenergic blockers (e.g. Propranolol and Metoprolol) can suppress tremors of

Parkinsonism.
Antipsychotic-induced Parkinsonism: - Stop the drug (if possible) and give
Anticholinergic drug but NOT L-dopa (Dopamine receptors are blocked). L-dopa can
induce psychosis which may aggravate the mental disorder for which the
antipsychotics were used.
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L-DOPA

Dopamine cannot cross the blood-brain-barrier and therefore ineffective in

Parkinsonism.
Levodopa, its immediate precursor can penetrate the brain where its
decarboxylated into dopamine. Therefore L-dopa can be used clinically.
L-dopa can ameliorate all clinical features of Parkinsonism. However its clinical
benefits begin to diminish after 3 4 years of therapy. Therefore L-dopa should
be preserved for cases with definite functional disability.
L-dopa is extensively metabolized by decarboxylase enzyme in the peripheral
tissues into dopamine and only about 5% of the oral dose reaches the brain.
Co-administration of a peripheral decarboxylase inhibitor (e.g. Carbidopa or
Benserazide) has the following advantages: -
- Reduces the daily requirement of L-dopa by 75%.
- Reduces the peripheral side effects e.g. Nausea, Vomiting, Postural
hypotension, cardiac arrythmias.
- Increases the central effects: clinical benefits also appears earlier.
Preparations and Dose of L-dopa
L-dopa is usually given with a peripheral decarboxylase inhibitor;
- Madopar: - L-dopa 100mg + Benserazide 25mg in a ratio of 4:1.
- Sinemet: - L-dopa 100mg + Carbidopa 10mg in a ratio of 10:1
Start with a small dose e.g. one capsule t.d.s, and then increase the dose gradually until
full therapeutic effect or side effects supervene.

Side Effects of L-dopa: -

1- Peripheral side effects (due to increased dopamine peripherally)
G.I.T: - Anorexia, nausea, vomiting (reduced by Domperidone and Cyclizine)
C.V.S: - Postural hypotension (Dopamine displaces Norepinephrine from Alpha-1
adrenoceptors) and cardiac arrhythmias.
2- Central Side Effects (due to increased Dopamine centrally)
- Dyskinesia, restlessness, choreoathetosis (head, lip or tongue movements)
- Psychosis, confusion, nightmares.
3- Fluctuations in response:
- Wearing-off effect (Progressive reduction in duration of benefit of each
dose).
- On-Off effect (unpredictable swings from mobility to bradykinesia due to
fluctuations in L-dopa levels).
- End of dose akinesia.

Drug Interactions with L-dopa

1) Carbidopa and Benserazide potentiate actions and reduce side effects
2) Pyridoxine enhances the peripheral decarboxylation of L-dopa.
3) Non-selective MAO inhibitors, results in hypertensive crisis.
4) Anticholinergic drugs delay gastric emptying thus hindering L-dopa absorption.
5) Amino acids in protein diet delay absorption (compete with L-dopa).
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Management of Problems with long-term Levodopa therapy (Optimization of

Levodopa therapy).

Inhibition of dopa-decarboxylase in the peripheral tissues potentiates actions of

Levodopa and reduces the peripheral side effects.
Reduce the peripheral side effects by peripheral dopamine antagonists (e.g.
Domperidone)
Reduce the interval between the doses of L-dopa to hourly or less to decrease
wearing-off and on-off effect.
Drug holidays then restart gradually to regain receptor sensitivity.
Gradual and partial substitution of L-dopa with Selegiline which delays dopamine
breakdown. It is effective for end of dose akinesia.
Substitute L-dopa by Bromocriptine which is longer acting. It is effective for end of
dose akinesia and on-off phenomenon.

Comparison between two major treatment in Parkinsonism

Antimuscarinic drugs L-dopa

- Bradykinesia Negligible relief Marked relief

- Rigidity Some relief Marked relief

- Tremors Some relief Some relief

- Preferred for Drug induced Parkinsonism Other types

- Side effects Dry mouth, Blurred vision, Nausea, Vomiting, Postural

Confusion, Urine retension, hypotension, Cardiac
Constipation, Worsen arrhythmias, Dyskinesia,
tardive dyskinesia caused Psychosis.
by antipsychotic drugs.

AMANTADINE (Antiviral drug against Influenza A2)

Increases synthesis and release of Dopamine and inhibits its neuronal uptake.
Amantadine has a weak antimuscarinic action.
It benefits rigidity, bradykinesia and tremors of Parkinsonism but less than with
L-dopa and of short duration (tolerance develops in few months).
It should be used in the early stages of Parkinsonism before most of the
dopaminergic neurons have degenerated.
Side Effects of Amantadine:
- CNS (Restlessness, Insomnia, Hallucinations, rarely fits)
- Skin rash
- Ankle oedema
- Postural hypotension
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BROMOCRIPTINE

It is a Dopamine agonist reserved for patients taking L-dopa and who have end of
dose akinesia, On-Off effect or who are refractory to treatment. This is due to its
rapid absorption, long half-life and smoother effects compared with L-dopa.

SELEGILINE
Selective MAO-B inhibitor
It delays the breakdown of Dopamine.
It is used with L-dopa for the treatment of end of dose akinesia.
No risk of hypertensive crisis due to selectivity.

PRINCIPLES OF TREATMENT OF PARKINSONISM

Give drugs only when there is definitive functional disability
Tremor is usually an early complaint that anticholinergic drugs relieve, reserving
L-dopa until there is definite functional incapacity.
Combine L-dopa with peripheral decardoxylase inhibitors (Carbidopa,
Benserazide).
Selegiline or Bromocriptine can be used in the management of problems with long
term Levodopa therapy.
Encouragement of physical exercise and physiotherapy.

OTHER MOVEMENT DISORDERS

HUNTINGTONS CHOREA: - Hypotonia and hyperkinetic movements (Clinical

and physiologic opposite of Parkinsonism)
- There is hypo-activity of striatal cholinergic neurons associated with excess dopamine
secondary to a deficiency of GABA.
Treatment of Huntingtons Chorea:
- Dopamine depleters e.g. Reserpine, Tetrabenazine
- Muscarinic activators e.g. Physostigmine
- Dopamine receptor blockers e.g. Phenothiazines and Butyrophenones

AKATHESIA: -
Features: - Motor restlessness
Mechanism: - Blockade of D2 receptors in the basal ganglia (e.g. by Antipsychotics).
Treatment: - Anticholinergic drugs (e.g. Benzhexol and Benztropine).
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DYSTONIA: -
Features: - Muscle spasm
Mechanism: - Blockade of D2 receptors in the basal ganglia
Treatment: - Anticholinergic drugs.

TARDIVE DYSKINESIA: -
Features: - Abnormal involuntary movements (e.g. Chewing, Sucking, Tongue
protrusion).
Mechanism: - Supersensitivity of Dopamine receptors following chronic blockade.
Prevension:
- Use the least possible dose of Antipsychotic
- Minimal duration
- Avoid the routine use of anticholinergic drugs
- Switch to atypical antipsychotics.

MALIGNANT NEUROLEPT SYSNDROME: -

Features: - Muscle rigidity + Fever
Mechanism: - Idiosyncrasy; Acute severe form of Parkinsonism due to rapid blockade of
D2 receptors (e.g. by Antipsychotics e.g. Phenothiazines)
Treatment:
- Dantrolene to relieve muscle spasticity.
- Anti-parkinsonian drugs (e.g. Anticholinergic drugs).

TREMORS: - are rhythmic oscillatory movements.

1) PHYSIOLOGICAL TREMOR: - due to anxiety, fatigue, thyrotoxicosis, I.V
Epinephrine, I.V Isoproterenol, Beta-2 agonists (e.g. Terbutaline).
Treatment is by Propranolol (Beta-1 blockers are ineffective).

2) ESSENTIAL TREMOR: - Probably due to Beta-1 receptor dysfunction.

Treatment is by Propranolol or Metoprolol. Primidone (anti-epileptic) is
effective in some cases.

3) INTENTION TREMOR: - Secondary to Alcohol, Phenytoin or neurological

disorders.

4) REST TREMOR: - is due to Parkinsonism.