Download Anti-Parkinsonism drugs

DRUGS FOR PARKINSONISM
Parkinsonism is a movement disorder due to
defective function of basal ganglia : Caudate
nucleus, Putamen, Globus pallidus, Substantia
nigra, and Subthalamic nucleus . The combination
of caudate nucleus + putamen is known as
striatum .
The basal ganglia controls movements and
posture by 2 main balanced mechanisms :
A. Cholinergic muscarinic : stimulatory; due to
small cholinergic neurons are present in striatum
B. Dopaminergic : inhibitory ; this comes from
nigrostrial tract that originate from substantia
In parkinsonism, the inhibitory
dopaminergic transmission is reduced in the
striatum so that the stimulatory cholinergic
transmission predominates , leading to the
main symptoms of :
tremor ,
rigidity of muscles , and
hypokinesia ,
with
loss of protective postural reflexes .
These clinical features occur when dopamine
(DA) content is < 20% of normal in striatum
Parkinsonism is usually caused by idiopathic
degeneration of the dopaminergic fibers of
nigrostriatal tract (Parkinson”s disease) .
Organic (secondary) causes of parkinsonism are :
1. Toxins : e.g. environmental toxins e.g. MPTP
(1-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine )
which is catabolized by MAO-B in glial cells in
striatum into MPP+ and damaging free radicals ;
its metabolism and toxicity is prevented by MAO-B
inhibitor Selegiline. Others toxins are Mn,& CO
2. Post-encephalitis
3. Ischemia : due to atherosclerosis
4. Tumours ; granulomas 5. Trauma e.g. boxers
6. Drugs e.g. DA2 receptors blockers , rarely by
alpha-methyldopa, or large doses of reserpine
Treatment of Parkinsonism :
1. Find cause ,if present; and treat it or avoid it ,if
possible
2. Reduce symptoms of the disease : by the
drugs that restore the balance of chemical
neurotransmission in striatum , namely :
A. Central antimuscarinic drugs
B. Drugs that increase dopaminergic
activity in striatum
A. Central anti-muscarinic drugs :
Include benzhexole (trihexyphenidyl) (trade name :
Artane) , benztropine , as well as :
Anti-H1 drugs with anti-muscarinic action e.g.
procyclidine, diphenhydramine , orphenadrine .
These drugs are useful in mild parkinsonism in
young patients ; they decrease tremor and
rigidity but have little effect on hypokinesia .
They are first choice drugs for treatment of
drug-induced parkinsonism
S.Es: some peripheral antimuscarinic side effects
: dry mouth, difficult urination, blurred vision
In overdose , they can cause acute confusional
B. Dopaminergic drugs :
1. L-DOPA : amino acid precursor of DA.
DA is not used as it poorly enters CNS.
L-DOPA is the drug of first choice in moderate
to severe parkinsonism; it relieves all
symptoms. Given orally , it is 30% absorbed in
small intestine by active transport ; peak plasma
levels occur in 1-2 h; food reduces its absorption
About 95% of absorbed fraction is decarboxylated by
peripheral tissues to DA, then oxidized to NA .
Only about 5% enter CNS to be converted by
remaining nigrostriatal fibers into dopamine that
is released into striatum . Its plasma t½ is 1-3 h.
Large doses are needed which cause side effects
S.Es :
A. Peripheral :
Nausea and Vomiting due to stimulation of DA2
receptors in CRTZ . Vomiting is decreased by
cyclizine or domperidone
Postural hypotension
Cardiac arrhythmias
Increased intra-ocular pressure
B. Central : - psychiatric (depression or hallucination)
- involuntary movement or dyskinesias
These side effects are dose-related
C. Long term central adverse effects :
a. Reduction in therapeutic efficacy ,
b. Clinical fluctuations : causing end-of-dose
deterioration , and later the “on-off “ effect .
The peripheral side effects esp. vomiting can be
reduced or prevented by peripheral decarboxylase
inhibitors that do not cross the blood-brain
barrier (i.e. do not enter CNS)
e.g. :
A. Carbidopa : the combination of L-DOPA +
carbidopa (in ratio of 4 or 10 :1 in tablet ) is
called Co- careldopa (Sinemet)
B. Bensarazide :The combination of L-DOPA +
benserazide is called Co-beneldopa (Madopar)
These combinations inhibit peripheral tissue
decarboxylation of L-DOPA, thus causing increase
in its plasma level and t½, and allow more L-DOPA
to enter CNS from plasma; thus they reduce the
But central side effects of L-DOPA still occur with
these combinations and may increase in incidence
Drug interactions of L-DOPA preparations :
1. Hypertensive crisis may occur with :
1. Amphetamine (not with tyramine )
2. MAO inhibitors esp. tranylcypromine
2. Pyridoxine (which is coenzyme for decarboxylase)
reduces therapeutic benefit from L-DOPA by
enhancing its peripheral decarboxylation;
this interaction does not occur with the combined
L-DOPA / carbidopa preparation Sinemet
2. Inhibitors of DA catabolism :
A. Selegiline : selective MAO-B inhibitor
This drug increases DA content in synapses of
striatum. It may be used in early parkinsonism .
It may also be given with L-DOPA or Sinemet to
treat end-of-dose deterioration due to L-DOPA
Its side effects include insomnia .
B. COMT inhibitor: Entacapone prolongs action of
dopamine formed from L-DOPA in striatum;
In plasma it also inhibits conversion of L-DOPA
to 3-O-methyldopa which competes with L-DOPA
for entry into brain.
it is used for end-of-dose deterioration of L-DOPA
3. Amantadine : it stimulates DA synthesis and
release by remaining nigrostriatal fibers and may
inhibit DA reuptake .It is used in early parkinsonism
, and may be given with antimuscarinic drugs or
L-DOPA to enhance their effect .
If used alone, tolerance occurs to its beneficial
effect in few months
S.E. vomiting , ankle oedema , livedo reticularis,
CNS stimulation with insomnia, hallucination,
seizures
NOTE : Amantadine has independent ANTIVIRAL
action and is used in preventing influenza A2
4. Direct dopamine receptor (DA2) agonists :
A. Ergot derivative
1. Bromocryptine : has DA2- receptor agonist action;
eliminated by liver; t½ is about 5 h. It may be used :
a. With L-DOPA to enhance motor response
b. For end-of-dose deterioration of L-DOPA , or
for on-off attacks to replace L-DOPA
S.Es include: nausea & vomiting; postural hypotension
In high doses: delusions & hallucination (so avoided
in psychotic patients); dyskinesia may also occur;
ergot effects with chronic use include lung infiltrates
and erythromelalgia
2. Cabergoline : long t½ 80 h, used once/d or twice/W
B. Non-ergot derivatives :
1. Ropinirole (relatively pure DA2 agonists) &
Pramipexole (has higher affinity for DA3 receptors
than DA2) : Either of these drugs can be used as
monotherapy in early mild disease; Pramipexole
may also have a neuro-protective action by acting
as scavenger for hydrogen peroxide radical.
Both may also be used later for clinical fluctuations
of L-DOPA
2. Apomorphine stimulates DA2 receptors; it may be
used SC to terminate the freezing on-off attacks
of chronic L-DOPA therapy in young patients;
Vomiting is common side effect; it is prevented
by domperidone