DRUGS USED IN PARKINSONISM

Functional circuitry between the cortex, basal ganglia, and thalamus:

The basal ganglia are composed of striatum (caudate nucleus and putamen), the globus pallidus,
substantia nigra and the subthalamic nuclei. They control the movements.

The direct pathway stimulates the thalamus which then stimulates the motor neurons in the cortex, while
the indirect pathway inhibits the thalamus which then inhibits the motor neurons in the cortex.
Dopaminergic neurons in the substantia nigra connected to corpus striatum secrete dopamine which
stimulates the direct pathway through D1 receptors, while inhibiting the indirect pathway through D2
receptors. Acetylcholine has opposite effects of dopamine.

Parkinsonism (Parkinson’s disease, PD):

Signs and symptoms: Akinesia (or Bradykinesia), Muscle rigidity, Resting tremor and Postural
instability.
Pathophysiology: degeneration of dopaminergic neurons in the nigrostriatal tract with imbalance
between dopamine (↓) and ACh (↑).

Dr. Hamad Alshabi

Pharmacological strategy to treat parkinsonism:
1- Restore normal dopamine (↑).
2- ↓ ACh activity at muscarinic receptor in the striatum.
Actions of dopamine: it acts on D, β1, α1.
Also it suppresses pituitary secretion of prolactin and growth hormone production. So dopamine agonists
have beneficial effect on treatment of hyperprolactinemia and acromegaly.
A- DRUGS THAT INCREASE DOPAMINE FUNCTION:
1- DOPAMINE PRECURSOR : (levodopa)
MOA: Dopamine does not cross the blood-brain barrier, but its precursor (levodopa) enters the brain (via
an L-amino acid transporter). It is converted to dopamine by dopa decarboxylase. In PD, it increases the
amount of dopamine available for release from surviving dopaminergic neurons in the basal ganglia.

Dr. Hamad Alshabi

Pharmacokinetics: Levodopa is rapidly absorbed from the small intestine. Ingestion of food delays its
absorption, moreover, certain amino acids from ingested food can compete with the drug for absorption
from the gut and for transport from the blood to the brain. Only about 1–3% of administered levodopa
actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by
decarboxylation to dopamine, which does not penetrate the blood-brain barrier. Accordingly, levodopa
must be given in large amounts when used alone. However, when given in combination with a dopa
decarboxylase inhibitor (Carbidopa) that does not penetrate the blood-brain barrier, the peripheral
metabolism of levodopa is reduced, plasma levels of levodopa are higher, plasma half-life is longer, and
more dopa is available for entry into the brain.

Clinical Use:
Levodopa is the most effective drug in the treatment of PD. It is more effective against akinesia and
rigidity than against tremor. It is given with dopa decarboxylase inhibitor (Carbidopa, benserazide).
Effectiveness diminishes over some months to a few years.
Adverse effects of levodopa:

8- Fluctuations in Response: Wearing off phenomena (time- related), On-off phenomenon.

Dr. Hamad Alshabi

2- DOPA DECARBOXYLASE INHIBITOR: (carbidopa, benserazide)
MOA: Carbidopa inhibits peripheral dopa decarboxylase (that does not penetrate the blood-brain barrier).
Addition of carbidopa to levodopa therapy results in increase entry of levodopa in brain and decrease
adverse effects due to peripherally formed dopamine.
3-CATECHOL-O-METHYLTRANSFERASE INHIBITORS: (tolcapone and entacapone)
MOA: They inhibit levodopa metabolism in periphery (both drugs) and CNS dopamine (tolcapone only)
and prolong the action of levodopa. Tolcapone has long duration of action and entacapone is short.
Uses: They are used as adjuncts to levodopa-carbidopa to prolong the action and decrease wearing off.
Adverse effects: relates to increase level of levodopa. Also Tolcapone is hepatotoxic. Entacapone has not
been associated with hepatotoxicity.

4- MONOAMINE OXIDASE (MAO) INHIBITORS (Selegiline, rasagiline):

MOA: They are selective irreversible inhibitors of monoamine oxidase B at normal doses. At higher
doses Selegiline also inhibits MAO-A.
Uses: they are used as adjunctive to levodopa. They enhance and prolong the antiparkinsonism effect of
levodopa (thereby allowing the dose of levodopa to be reduced) and may reduce mild on-off or wearing-
off phenomena. Rasagiline can be also used alone in early symptomatic parkinsonism.
Adverse effects: mainly due to increased action of levodopa taken concurrently and Selegiline may cause
insomnia when taken later during the day (amphetamine is one of the metabolites). These drugs should be
avoided by patients taking SSRIs, TCAs, and meperidine, because of the possibility of precipitating a
“serotonin syndrome.
5- DOPAMINE RECEPTOR AGONISTS:
MOA:
- Bromocriptine, Pergolide (ergot derivatives) are potent agonist at D2 receptors.

Dr. Hamad Alshabi

- Pramipexole (non-ergot derivative) is a relatively selective D3-receptor agonist. Pramipexole may be
neuroprotective because it is reported to act as a scavenger for hydrogen peroxide.
- Ropinirole (non-ergot derivative) is a relatively selective D2-receptor agonist.
Uses:
Pergolide was withdrawn from market because of cardiac valve fibrosis.
Bromocriptine is more toxic than pramipexole or ropinirole; now rarely used for antiparkinsonian effect.
It is used in hyperprolactinemia and acromegaly.
Pramipexole and Ropinirole are used as initial therapy in early Parkinson’s disease or as adjuvants to
levodopa in more advanced disease.
Dopamine agonists have theoretical advantages over L-dopa in Parkinson's disease in that they:
1. Do not require enzymatic conversion for activity, they don’t depend on functional capacities of the
nigrostriatal neurons.
2. Have a longer duration of action and may be less likely than levodopa to induce on/off effects and
dyskinesias.
3. Avoid the potential neurodegeneration associated with the conversion of L-dopa
to free radicals (radicals free accelerate loss of dopaminergic neurons).
Newer dopamine agonists have less side effects than the older drugs.
- Rotigotine is dopamine agonist, delivered daily through a skin patch, for treatment of early Parkinson's
disease.
Adverse effects: Hallucinations and sleepiness (more than with levodopa). Postural hypotension.
Dyskinesias – but less than with levodopa. They also cause impulse control disorders.
Bromocriptine (and other ergot derivatives) rarely cause fibrotic reactions.
- Apomorphine is a potent dopamine agonist and used as a "rescue therapy" for the acute intermittent
treatment of "off" episodes in patients with a fluctuating response to dopaminergic therapy. It is highly
emetogenic and requires pre- and post-treatment antiemetic therapy.
6- Amantadine:
Antiviral agent, and have antiparkinsonism properties. It potentiates dopaminergic function by
influencing the synthesis, release, or reuptake of dopamine. It also has antimuscarinic effect and Blocks
NMDA glutamate receptors. It is Antiviral agent used to treat Parkinson’s disease, Also effective against
the dyskinesia associated with levodopa therapy.
B- Acetylcholine-Blocking Dirugs (Antimuscarinic):
Benztropine, diphenhydramine, Procyclidine, Orphenadrine and Trihexyphenidyl (benzhexol)
Uses: in parkinson's disease, reduce tremor and rigidity, little effect on bradykinesia.
Side effects: atropine like.

Dr. Hamad Alshabi