ANTIPARKINSON

Dimas P.Nugraha
Departement Farmakologi FK UR
Parkinson’s Disease
 Top: Dopaminergic neurons (red) originating in the substantia nigra normally inhibit the
GABAergic output from the striatum, whereas cholinergic neurons (orange) exert an
excitatory effect. Bottom: In parkinsonism, there is a selective loss of dopaminergic neurons
In Parkinson’s, lack inhibitory dopamine and thus an increase in
excitatory acetylcholine
Cardinal Features

Bradykinesia
Postural instability
Resting tremor
Rigidity
Motor Symptoms
Micrographia
Decreased dexterity

Dysarthria

Dysphagia

Flexed posture

Freezing at initiation of movement

Hypophonia

Slow turning
Autonomic Symptoms
• Bladder and anal sphincter
disturbances
• Constipation
• Diaphoresis
• Orthostatic blood pressure
changes
• Paroxysmal flushing
• Sexual disturbances
• Mental Status Changes
Bradyphrenia
Confusional state
Dementia
Psychosis (paranoia, hallucinosis)
Sleep disturbance
• Other
Fatiguability
Oily skin
Pedal edema
Seborrhea
Weight loss
 Anti-Parkinson drugs
• Drugs used→ in increased levels of dopamine
or to inhibit the actions of acetylcholine in the
brain
 TREATMENT OF PARKINSON’S
DISEASE

The goal in the management of IPD is to

improve motor and nonmotor symptoms so
that patients are able to maintain the best
possible quality of life.
Dopaminergic Drugs
Levodopa is mainstay of drug therapy for idiopathic
parkinsonism

Serves as the prototype

Increases dopamine concentrations in the brain

Dopamine cannot penetrate blood-brain barrier but

levodopa can. Is then converted to dopamine by
enzyme AADC.
 Levodopa dan carbidopa

Levodopa
• Levodopa is a metabolic precursor of
dopamine.
• It restores dopaminergic neurotransmission in
the corpus striatum by enhancing the
synthesis of dopamine in the surviving
neurons of the substantia nigra
Oral levodopa is absorbed rapidly from the
small bowel by the transport system for
aromatic amino acids.

Concentrations of the drug in plasma usually

peak between 0.5 and 2 hours after an oral
dose.
• The t1/2 in plasma is short (1–3 hours).
• The rate and extent of absorption of levodopa
depend on the rate of gastric emptying, the pH of
gastric juice, and the length of time the drug is
exposed to the degradative enzymes of the
gastric and intestinal mucosa.
• Competition for absorption sites in the small
bowel from dietary amino acids also may alter
absorption of levodopa; administration of
levodopa with meals delays absorption and
reduces peak plasma concentrations.
In the brain, levodopa is converted to dopamine
by decarboxylation, primarily within the
presynaptic terminals of dopaminergic neurons
in the stratium.

The dopamine thus produced is responsible for

the therapeutic effectiveness of levodopa in PD;
Carbidopa:
• The effects of levodopa on the CNS can be
greatly enhanced by coadministering
carbidopa, a dopa decarboxylase inhibitor that
does not cross the blood-brain barrier.
• Carbidopa diminishes the metabolism of
levodopa in the gastrointestinal tract and
peripheral tissues; thus, it increases the
availability of levodopa to the CNS.
Synthesis of dopamine from levodopa in the absence and presence of carbidopa,
an inhibitor of dopamine decarboxylase in the peripheral tissues.
 • Levodopa decreases the
rigidity, tremors, and
Actions: other symptoms of
parkinsonism
Adverse effects
 Interactions:

• The vitamin pyridoxine (B6) ↑ the peripheral

breakdown of levodopa and diminishes its
effectiveness.
• Concomitant administration of levodopa and
monoamine oxidase (MAO) inhibitors, such as
phenelzine→ a hypertensive crisis caused by
enhanced catecholamine production
In many psychotic patients, levodopa exacerbates symptoms, possibly
through the buildup of central catecholamines.

In patients with glaucoma, the drug can cause ↑ in intraocular

pressure

Cardiac patients should be carefully monitored because of the

possible → cardiac arrhythmias

Antipsychotic drugs are generally contraindicated in parkinsonian

patients →potently block dopamine receptors and produce a
parkinsonian syndrome
 DOPAMINE-RECEPTOR AGONISTS

• Most dopamine-receptor agonists in clinical

use have durations of action substantially
longer than that of levodopa and are useful in
the management of dose-related fluctuations
in motor state.
Bromocriptine (PARLODEL) and pergolide
(PERMAX);
• Are ergot derivatives with similar therapeutic
actions and adverse effects.
• Bromocriptine is a D2 agonist and a partial D1
antagonist; pergolide is an agonist of both
receptor types
Ropinirole (REQUIP) and pramipexole (MIRPEX)
• Ropinirole and pramipexole have selective
activity at D2 and D3 receptors and little or no
activity at receptors of the D1 class
• The duration of action of the dopamine
agonists (8–24 hours) often is longer than that
of levodopa (6–8 hours), and they are
particularly effective in the treatment of
patients who have developed on/off
phenomena
• All four also may produce hallucinosis or
confusion and may worsen orthostatic
hypotension.
Some adverse effects of dopamine agonists
 CATECHOL-O-METHYLTRANSFERASE
INHIBITORS
• Normally, the methylation of levodopa by
catechol-O-methyltransferase (COMT) to 3-O-
methyldopa is a minor pathway for levodopa
metabolism.
• Inhibition of COMT by entacapone or
tolcapone leads to decreased plasma
concentrations of 3-O-methyldopa, increased
central uptake of levodopa, and greater
concentrations of brain dopamine.
Effect of entacapone on dopa concentration in
the central nervous system (CNS).
 Adverse effects:
• Both drugs exhibit adverse effects that are
observed in patients taking levodopa-carbidopa,
including diarrhea, postural hypotension, nausea,
anorexia, dyskinesias, hallucinations, and sleep
disorders.
• Most seriously, fulminating hepatic necrosis is
associated with tolcapone use hepatic function
monitoring
• Entacapone does not exhibit this toxicity and has
largely replaced tolcapone.
 Monoamine Oxidase B Inhibitors
• Two selective MAO-B type B inhibitors
rasagiline and selegiline
• The selective inhibition of MAO-B in the brain
interferes with the degradation of dopamine
and results in prolonged dopaminergic activity
• Selegiline, also known as L-deprenyl, is
marketed for extending L-dopa effects and is
typically administered 5 mg twice daily.
• As monotherapy in early IPD, selegiline
provides modest improvements in motor
Function.
Action of selegiline (deprenyl) in dopamine
metabolism
• Rasagiline is a second-generation, irreversible,
selective MAO-B inhibitor administered at 0.5
or 1 mg once daily.
• Rasagiline is effective as monotherapy in early
IPD and also for managing motor fluctuations
in advanced IPD.
 MUSCARINIC RECEPTOR ANTAGONISTS
(Anticholinergic)
• Antagonists of muscarinic acetylcholine(ACh)
receptors were used widely for the treatment of
PD before the discovery of levodopa
• The biological basis for the therapeutic actions of
anticholinergics is not completely understood.
• These drugs probably act in the neostriatum
through the receptors that normally mediate the
response to intrinsic cholinergic innervation of
this structure, which arises primarily from
cholinergic striatal interneurons.
The agents acting as muscarinic antagonists
currently used in the treatment of PD include :
- Trihexyphenidyl (ARTANE, 2–4 mg three times
per day),
- Benztropine mesylate (COGENTIN,1–4 mg two
times per day),
- Diphenhydramine hydrochloride (BENADRYL,
25–50 mg three to four times per day;
 adverse effects
• The adverse effects of these drugs are a result
of their anticholinergic properties (principally
sedation and mental confusion, but also
constipation, urinary retention, and blurred
vision through cycloplegia);
• These drugs must be used with caution in
patients with narrowangle glaucoma.
 AMANTADINE
• Amantadine is an antiviral agent used for the
prophylaxis and treatment of influenza A . The drug
also appears to alter dopamine release in the
striatum, has anticholinergic properties, and blocks
NMDA glutamate receptors.
• Presumably through a combination of these
mechanisms, amantidine has modest
antiparkinsonian activity, and is used as initial
therapy of mild PD.
Amantidine also may be helpful as an adjunct in patients on
levodopa with dose-related fluctuations and dyskinesias.

Amantadine usually is administered in a dose of 100 mg

twice a day and is well tolerated. Dizziness, lethargy,
anticholinergic effects, and sleep disturbance, as well as
nausea and vomiting, have been observed occasionally, but
these effects are mild and reversible.
Drugs Used in Parkinson’s Disease
General approach to the management of early to advanced Parkinson’s disease
General algorithm for treating early idiopathic Parkinson's
disease.
 Algorithm for treating advanced idiopathic
Parkinson's disease

CR, controlled release; COMT, catechol-O-methyltransferase

 Monitoring Parkinson’s Disease Therapy

• Monitor medication administration times.

Educate the patient that immediaterelease
carbidopa/L-dopa is absorbed best on an
empty stomach but is commonly taken with
food to minimize nausea.
• Avoid administration of conventional
selegiline in the late afternoon or evening to
minimize insomnia.
• Monitor to ensure that the patient and/or
caregivers understand the prescribed
medication regimen. For example, catechol-O-
methyltransferase inhibitors work by
enhancing the effect of L-dopa and that the
patient should not discontinue medication
without notifying the clinician.
Monitor for nonadherence and, if present,
inquire for possible reasons (e.g., dosing
convenience, financial issues, adverse
effects) and offer suggestions
ALHAMDULILLAH….
SEKIAN TERIMA KASIH…