Unit 3: Drugs Affecting the Central Nervous System
16
Lecture 1 - Neurodegenerative
Diseases
Parkinsonism
It is a progressive neurological disorder of muscular
movement characterize by:
Tremor, muscular rigidity, hypokinesia and postural
reflexes.
The disease is correlated with a reduction in the activity
of inhibitory dopaminergic neurons in the substantia nigra
(Substantia nigra is the source of dopaminergic neurons)
and corpus striatum-parts of the brain basal ganglia
system that are responsible for motor control
The basal ganglia control movement by two balance
systems Ach and dopamine.
In Parkinsonism the dopaminergic system is effective
(basal ganglia dopamine concentration is low) so:
Parkinsonism can be regarded as a dopamine deficiency
disease.
Parkinsonism like syndrome may arise from several
causes as cerebral atherosclerosis, viral encephalitis and
effects of certain drugs like
Antipsychotic agent such as
phenothiazine
&
haloperidol
Reserpine
(blocks the uptake of neurotransmitter into the
adrenergic nerve).
Anticholinesterase (as
physostigmine
and
neostigmine
)
Drugs used in Parkinson’s disease
Currently available drugs offer temporary relief from the
symptoms of the disorder, but do not arrest or reverse the
neuronal degeneration caused by the disease.
There are two possibilities for restoring the balance
between excitatory and inhibitory transmission.
1. To reduce cholinergic activity that by
anticholinergic drugs.
2. To enhance dopaminergic activity by the
dopaminergic drugs.
Anticholinergic drugs (Antimuscarinic):
These drugs enter CNS and decrease the Ach activity.
Natural
(atropine and scopolamine)
Synthetic
(Benzohexol, Benztropine, procyclidine)
Antihistamine with marked anticholinergic
(Diphenhydramine).
Dopaminergic drugs
1) Levodopa (L-dopa)
About two-thirds of the dose appears in the urine as
metabolites within 8 hours of an oral dose, the main
metabolic products being 3-methoxy-4-hydroxy phenyl
acetic acid (homovanillic acid HVA) and dihydroxy
phenyl acetic acid (DOPAC). Only about 1-3% of
administered Levodopa actually enters the brain
unaltered, the reminder being metabolized extra-
cerebrally by decarboxylation to dopamine, which does
not penetrate the blood brain barrier this means that
Levodopa must be given in large amount when it is used
alone. So
Levodopa is given with
Carbidopa
, the Carbidopa
inhibits the decarboxylation of peripheral Levodopa under
the trade name (Sinemat) or Levodopa is given with
benserazide (Madopar)
for the same purpose.
Drug interaction:
1- With non-selective MAOI causes hypertension crisis.
2- With pyridoxine (vit B
6
). Pyridoxine can enhance
peripheral conversion of Levodopa to Dopamine also
can lead to hypertension crisis.
Adverse effects
GIT disturbances
* Nausea: may be a limiting factor if the dose is increased
too rapidly; it may be helped by cyclizine.
* Vomiting: is central effect.
Postural hypotension.
Involuntary movements of head lip or tongue.
Mental changes may be seen: these include depression,
dreams and hallucination.
Agitation and confusion occur but it may be difficult to
decide whether these are due to drug or to disease.
2) Selegiline
Is a selective irreversible inhibitor of MAO type B. It acts
by inhibition the metabolism of Dopamine. It therefore
lacks the unwanted peripheral effects of non-selective
MAO inhibitors. Long-term trials showed that the
combination of Selegiline and Levodopa was more
effective than Levodopa alone in relieving symptoms and
prolonging life.
Adverse effects
Are those of increased dopamine activity, insomnia (give
in morning). Interaction with pethidine (causes respiratory
depression).
Unit 3: Drugs Affecting the Central Nervous System
16
3) Bromocriptine
Is a derivative of ergot that has dopamine agonist activity
(D2 receptor agonist) with vasoconstrictor action and a
weak partial agonist at D1-receptors. Activity at D2
receptors is thought to underlie its efficacy in
Parkinsonism. It inhibits the anterior pituitary gland, and
was first introduced for the treatment of galactorrhoea and
gynaecomastia. Its duration of action is longer than that of
Levodopa. The drug produces little response in patients
who do not react to Levodopa, but it is commonly used
with Levodopa in patients responding to drug therapy.
The dose is increased gradually during a period of 2 to 3
months.
Uses:
Parkinsonism
In case of hyperprolactinemia (it decreases prolactine
release)
Infertility
Amenorrhea and galactorrhoea
In acromegaly by decreasing the level of growth
hormone, but in normal person it increases growth
hormone release.
Adverse effects:
Nausea and vomiting, which may be ameliorated by
taking the drug with meals. Dizziness, constipation and
postural hypotension may also occur.
4) Apomorphine
Is a derivative of morphine having structural similarities
to dopamine. It is a full agonist at D1 and D2 receptors
and it is commonly used as an emetic drug in the
management of oral drug overdose. So it may need to be
accompanied by an antiemetic e.g. domperidone to
prevent its characteristic emetic action. Overdose causes
respiratory depression; it is antagonized by naloxone.
5) Amantadine
It was introduced as an antiviral drug. Many possible
mechanisms for its action in the treatment of Parkinson
disease based on neurochemical evidence of increased
dopamine release, inhibition of amine uptake or a direct
action on dopamine receptor.
Amantadine is less effective than L-dopa or
Bromocriptine and its action decline with time. Its side
effects are considerably less sever, though qualitatively
similar to those of Levodopa.