Parkinson's disease is caused by degeneration of dopamine-containing neurons in the substantia nigra. The symptoms are connected to dopamine depletion and include bradykinesia, rigidity, and tremor. Treatment aims to restore the dopamine/acetylcholine balance through levodopa supplementation, dopamine agonists like bromocriptine, MAO-B inhibitors like selegiline, and antimuscarinic drugs. Levodopa is effective initially but often causes dyskinesias long-term, so dopamine agonists may be preferred, though they are less effective at treating symptoms.

1. AntiparkinsonianAntiparkinsonian
drugsdrugs
(Abstract)(Abstract)
J. Parkinson

2. Parkinson’s disease (PD) is a progressive neurodegenerative
disorder. It is caused by degeneration of substantia nigra in the
midbrain, and consequent loss of DA-containing neurons in the
nigrostrial pathway. Two balanced systems are important in the
extrapyramidal control of motor activity at the level of the corpus
striatum and substantia nigra; in the first the neurotransmitter is
ACh, in the second – DA.
The symptoms of PD are connected with loss of nigrostrial
neurons and DA depletion. The symptomatic triad includes
bradykinesia, rigidity and tremor with secondary manifestations
like defective posture and gait, mask-like face and sialorrhoea;
dementia may accompany.

4. ParkinsonismParkinsonism

5. Sponsored
Medical Lecture Notes – All Subjects
USMLE Exam (America) – Practice

6. Clinical Pharmacology – 9th
Ed. (2003)Clinical Pharmacology – 9th
Ed. (2003)

7. Rang et al. Pharmacology – 5st
Ed. (2003)Rang et al. Pharmacology – 5st
Ed. (2003)

8. Distribution and characteristics of DA
receptors in the central nervous system
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

9. The normally high concentration of DA in the basal ganglia of the
brain is reduced in PD, and pharmacologic attempts to restore
DA-ergic activity with levodopa and DA agonists have been
successful in alleviating many of the clinical features of the disorder.
An alternative but complementary approach has been to restore the
normal balance of cholinergic and dopaminergic influences on the
basal ganglia with antimuscarinic drugs. The pathophysiologic basis
for this therapy is that in idiopathic parkinsonism, dopaminergic
neurons in the substantia nigra that normally inhibit the output of
GABA-ergic cells in the corpus striatum are lost.
In contrast, Huntington's chorea involves the loss of some cholin-
ergic neurons and an even greater loss of the GABA-ergic cells that
exit the corpus striatum. Drugs that induce parkinsonian syndromes
are DA receptor antagonists (e.g., antipsychotic agents) which
lead to the destruction of the DA-ergic nigrostriatal neurons.

10. The cause of selective degeneration of nigrostrial neurones in PD
is not precisely known. It appears to be multifactorial. Oxidation of
DA by MAO-B and aldehyde dehydrogenase generate hydroxyl
free radicals (˙OH) in the presence of ferrous iron (basal ganglia
are rich in iron). Normally these radicals are quenched by gluta-
thione and other endogenous antioxidants. Age-related (e.g. in
atherosclerosis) and/or otherwise acquired defect in protective
antioxidant mechanisms allows the free radicals to damage lipid
membranes and DNA resulting in neuronal degenerations. Gene-
tic predisposition may contribute to high vulnerability of substantia
nigra neurons. Environmental toxins or some infections (grippe)
may accentuate these defects. A synthetic toxin N-methyl-4-phenyl
tetrahydropyridine (MPTP), which occurs as a contaminant of
some illicit drugs, produces nigrostrial degenerations similar to PD.
Neuroleptics and other DA blockers may cause temporary PD too.

11. Production of free radical by the metabolism of dopamine (DA).
DA is converted by MAO and aldehyde dehydrogenase (AD) in
3,4-dihydroxyphenylacetic acid (DOPAC), producing hydrogen
peroxide (H2O2). In the presence of ferrous ion hydrogen per-
oxide undergoes spontaneous conversion, forming a hydroxyl
free radical (The Fenton reaction).
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

12. Factors contributing to degeneration ofFactors contributing to degeneration of
nigrostrial DA-ergic neurones causing PDnigrostrial DA-ergic neurones causing PD
Grippe
Essential of Medical
Pharmacology –
5st
Ed. (2003)
Essential of Medical
Pharmacology –
5st
Ed. (2003)

13. The key steps in the synthesis and degradation of dopamine
and the sites of action of various psychoactive substances at the
dopaminergic synapse

14. Objectives of antiparkinsonian pharmacotherapy
The dopaminergic/cholinergic balance may be
estored by two mechanisms.
1. Enhancement of DA-ergic activity by drugs which may:
a) replenish neuronal DA by supplying levodopa, which
is its natural precursor; administration of DA itself is
neffective as it does not cross the BBB;
b) act as DA agonists (bromocriptine, pergolide, cabergoline, etc.);
c) prolong the action of DA through selective inhibition of its
metabolism (selegiline);
d) release DA from stores and inhibit reuptake (amantadine).
2. Reduction of cholinergic activity by antimuscarinic
drugs; this approach is most effective against tremor and rigidity,
and less effective in the treatment of bradykinesia.

15. Levodopa Levodopa
Dopamine
MAO-B
Selegiline
Amantadine Reuptake Amantadine
Bromocriptine
Pergolide
D2-receptors
(-)
(-)
(+)
(+)
Central DA-ergic DrugsCentral DA-ergic Drugs
The Principles of Medical
Pharmacology (1994)
The Principles of Medical
Pharmacology (1994)

16. ▼LEVODOPA
(DOPA – DihydroOxy-
PhenylAlanine;
(t1/2 1,5 h)
is a natural amino acid
precursor of DA.
The major disadvantage
is the extensive
decarboxylation
of levodopa to DA in
periferal tissues. So that
only 1–3% of an oral dose
reaches the brain.

17. Basic & Clinical Pharmacology – 10th
Ed. (2007)Basic & Clinical Pharmacology – 10th
Ed. (2007)

18. Thus large quantities of levodopa would have to be given.
Levodopa and its metabolites cause significant adverse reactions
(ARs) by peripheral actions, notably nausea, arrhythmia, postural
hypotension. This problem has been largely circumvented by
decarboxylase inhibitors (benserazide, carbidopa), which do
not enter the CNS; they prevent only the extracerebral metabolism
of levodopa. The inhibitors are given in combination with
levodopa; but in this case only 25% of the dose of levodopa is
required and ARs diminish significantly. Levodopa alone and in
combination is introduced gradually and titrated according to
clinical response; the dose being altered every two weeks.
• Co-careldopa (carbidopa and levodopa in proportions
12.5/50 mg, 25/100 mg, 25/250 mg) – Sinemet®
.
• Co-beneldopa (benserazide and levodopa in proportions
12.5/50 mg, 25/100 mg, 50/200 mg) – Madopar®
.

19. Basic & Clinical Pharmacology – 10th
Ed. (2007)Basic & Clinical Pharmacology – 10th
Ed. (2007)

20. ▼BROMOCRIPTINE (t1/2 5 h) –
a derivative of ergot
(Ergot de savle,
Secale cornutum).
It is a D2-receptor agonist, but also
a weak alpha-adrenoceptor anatagonist. Bromocriptine is com-
monly used with levodopa. It should be started at very low
doses (1–1,25 mg p.o. at night), increasing at weekly interval
and according to clinical response. It is also used for treatment
of prolactin-secreting adenomas, amenorrhea/galactorrhea to
hyperprolactinemia, to stop lactation, acromegaly.
ADRs: Nausea and vomiting, which may be prevented with
domperidone; postural hypotension (may cause dizziness or
syncope); after prolonged use – pleural effusion and
retroperitoneal fibrosis.

21. ▼CABERGOLINE, also an ergot derivative, has a t1/2 >80 h.
This allows it to be used in a single daily (or even twice weekly)
dose. Cabergoline alleviates night-time problems in parkinso-
nian patients due to lack of levodopa.
▼PRAMIPEXOLE is a non-ergot D2-receptor agonist; it is
more effective against tremor than the others.
▼ROPINIROLE (Requip®
) is a new non-ergot direct
D2-receptor agonist. There are insufficient data to allow
an informed choice between pramipexole and ropinirole.
▼ENTACAPONE inhibits COMT (catechol-O-methyltrans-
pherase), one of the main enzymes responsible for the
metabolism of DA; the action of levodopa is thus prolonged.
Entacapone is most effective for patients with early
end-of-dose deterioration.

22. ▼SELEGILINE. The problem with nonselective MAO inhibitors is
that they prevent degradation of dietary adrenomimetic amines,
especially tyramine, by MAO-A inhibition which causes
hypertensive “cheese reaction”.
Selegiline does not cause the cheese reaction, because
MAO-A is still presented in the liver to metabolize tyramine.
MAO-A also metabolizes tyramine in the sympathetic nerve
endings in periphery. Selegiline inhibits selectively and
irreversibly only MAO-B in the CNS and protects DA
from intraneuronal degradation.
It is used as an adjunct drug in PD if levodopa/carbidopa or
levodopa/benserazide therapy is deteriorating.
In a transdermal patch selegiline is used as a treatment
for major depression.

23. ▼AMANTADINE is an antivirus drug which, given for influenza
to a parkinsonian patient, was noted to be beneficial. Antiviral
and antiparkinsonian effects of amantadine are probably
unrelated. Antiparkinsonian effect is due to increase
synthesis and release of DA, and diminish neuronal
reuptake too. Amantadine also has slight
antimuscarinic effect.
It is used for oral adjunct treatment of PD and influenza A
virus infection. Amantadine is relatively free from
ARs, which, however, includes ankle edema
(probably a local effect on blood vessels),
orthostatic hypotension, insomnia,
hallucinations, rarely – fits.

24. Atropa
belladonna L.
(Deadly night shade)
Radix
Belladonnae:
(cura bulgara)
– atropine
Belladonna roots have been empirically used for
treatment of PD in 1920s in Bulgaria by healer
Ivan Raev (Sopot: 1876–1938).
Belladonna roots have been empirically used for
treatment of PD in 1920s in Bulgaria by healer
Ivan Raev (Sopot: 1876–1938).
Central antimuscarinic drugsCentral antimuscarinic drugs

25. ▼BIPERIDEN, TRIHEXYPHENIDYL, TRIPERIDEN
are synthetic compounds (central M-cholinolytics). They benefit
parkinsonism by blocking ACh receptors in the CNS, thereby
partially redressing the imbalance created by decreased DA-ergic
activity. They also produce modest improvement in tremor,
rigidity, sialorrhoea (hypersalivation), muscular stiffness and leg
cramp, but little in bradykinesia, which is the most disabling
symptom of Parkinson’s disease. ARs of antimuscarinic drugs
include dry mouth (xerostomia), blurred vision, constipation,
urine retention, glaucoma, hallucinations,
memory defects, toxic confusional states
and psychoses (which should be
distinguish from presenile dementia).
Trihexyphenidyl

26. Pharmacotherapy of PD
(Clinical Pharmacology – 9th
Ed., 2003)
The main features that require alleviation are tremor, rigidity
and bradykinesia. Drug therapy has the most important role in
symptom relief, but it does not alter the progressive course of PD.
Treatment should begin only when it is judged necessary in
each individual case. Two conflicting objectives have to
be balanced: the desire for satisfactory relief of current symptoms
and the avoidance of ARs as a result of long-continued treatment.
There is a debate as to whether the treatment should commence
with levodopa or a synthetic DA agonist. Levodopa provides
the biggest improvement in motor activity but its use is associated
with the development of dyskinesia (involuntary movement
of the face and limbs) after 5–10 years, and sometimes sooner.

27. DA agonists have a much less powerful motor effect but are less
likely to produce dyskinesias. The treatment usually begins with
levodopa in low doses to get a good motor response and adds
a DA agonist when the initial benefit begins to wane.
A typical course is that for about 2–4 years on treatment with
levodopa or DA agonist, the patient’s disability and motor
performance remains near normal despite progression of the
underlying disease. After some 5 years about 50% of patients
exhibit problems of long-term treatment, namely, dyskinesia
and end-of-dose deterioration with the “on-off” phenomenon.
After 10 years virtually 100% of patients are affected.

28. End-of-dose deterioration is managed by increasing the
frequency of dosing with levodopa (e.g. to 2 or 3-hourly), but
this tends to worsen the dyskinesia. The motor response then
becomes more brittle with abrupt swings between hyper- and
hypomobility (the on-off phenomenon). In this case a more
effective approach is to use a COMT inhibitor, e.g. entacapone,
which can sometimes allay early end-of-dose deterioration
without causing dyskinesia.
Some 20% of the patients with Parkinson’s disease, notably the
Elderly ones, develop impairment of memory and speech with a
fluctuating confusional state and hallucinations. As these
symptoms are often aggravated by medication, it is preferable
gradually to reduce the antiparkinsonian treatment.

29. Antimuscarinic drugs are suitable only for younger patients predo-
minantly troubled with tremor and rigidity. They do not benefit bra-
dyskinesia, the main disability symptom. The ARs of acute angle
glaucoma, retention of urine, constipation and psychiatric distur-
bance are general contraindications to their use in the elderly.
Drug-induced Parkinsonism is alleviated by antimuscarinics, but
not by levodopa or DA agonist, because antipsychotics block
D2-receptors by which these drugs act. The piperazine
phenothiazines (e.g. trifluoperazine) and butyrophenones
(e.g. haloperidol) often cause Parkinsonism because they block
D2-receptors.

30. Treatment approaches to newly diagnosed idiopathic PD

31. Comparison of levodopa + benserazide,
levodopa + benserazide + selegiline
and bromocriptine on progression of PD symptoms