introduction of antiparkinson

1. SUBMITTED TO-RASHMI SHAH
SUBMITTED BY-ADARSH RAJ
ROLL NUMBER-16BPH054

2. Antiparkinsonian
drugs
J. Parkinson

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

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

6. Distribution and characteristics of DA
receptors in the central nervous system

7. 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.

8. 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.

9. 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)

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

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

12. ▼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.

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

14. ▼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.

15. ▼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-Ortho-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.

16. ▼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.

17. Treatment approaches to newly diagnosed idiopathic PD