Download Drug Therapy of Parkinsonism

Parkinsonism:
Parkinsonism is a movement disorders with Signs of Rigidity of skeletal muscles, Akinesia (or
bradykinesia), Flat facies, and Tremor at rest. (RAFT)
Etiology
The cause of Parkinson disease is unknown for most patients. The disease is correlated with destruction of
dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions that are
involved in motor control.
Picture via temography.
So in parkison, the reduction in dopamine disturbs the dopamine-ACH balance leading to exacerbating the
motor effects of the later
Drug Therapy of Parkinsonism
So the Strategies of drug treatment of parkinsonism involve increasing dopamine activity in the brain or
decreasing muscarinic cholinergic activity in the brain (or both).
A. Levodopa: precursor of dopamine.
1.Mechanisms : because dopamine has low bioavailability and does not readily cross the blood-brain
barrier, its precursor, L-dopa (levodopa) is used. This amino acid is converted to dopamine by the enzyme
(DOPA decaroxylase), which is present in many body tissues, including the brain. This create problem, since,
conversion of Levodopa to dopamine at body tissues provide no benefit (the benefit must be to offer
dopamine to the brain), therefore, Levodopa is usually given with carbidopa , a drug that does not cross the
blood-brain barrier but inhibits DOPA decarboxylase in the peripheral tissues. With this combination
(Levodopa + carbidopa ) {Sinemet) higher brainʼs dopamine concerntration is obtained with lower doses of
levodopa is achieved.
2. Pharmacologic effects:
-Levodopa Ameliorates the signs of parkinsonism, particularly bradykinesia.
-But decrease of responsiveness with time occure due to progression of the disease.
3. Toxicity : Most adverse effects are dose-dependent.
a- Gastrointestinal effects: Anorexia, nausea, and emesis (primary side effects due to dopaminergic mimetic
effect). These can be reduced by taking the drug in divided doses. Tolerance to the emetic action of levodopa
usually occurs after several months.
b- Dyskinesias: On-Off phenomena .
c- Behavioral effects : may include anxiety, agitation, confusion, delusions, hallucinations, and
depression.
B- Bromocriptine and other dopamine agonists:
1- Mechanism of action:
Bromocriptine (Parlodel) is an ergot alkaloid that acts as partial agonist at certain dopamine D2 receptors in
the brain; the drug increases the functional activity of the dopamine neurotransmitters pathways.
Pergolide is anothor ergot derivative that activate dopamine receptors, it may decrease response fluctuations
and prolong the effectiveness of levodopa, but the drug loses its activity with time.
2- Clinical use:
Bromocriptine and pergolide have been used as individual drugs, in combination with levodopa (and with
anticholinergic drugs), and in patients who are refractory to or cannot tolerate levodopa.
3- Toxicity:
a-Gastrointestinal effects include anorexia, nausea, and vomiting emesis
dopaminergic mimetic effect) .
(primary side effects due to
c-Behavioral effects include confusion, hallucinations, and delusions; those occur more commonly with
bromocriptine and pergolide than with levodopa.
* Like levodopa, brompcriptine and pergolide are contraindicated in patients with history of psychosis.
* Pramipexole:
Recently introduced dopamine receptor agonists; they are not ergot derivatives.
# They are presently considered to be first-line drugs in the initial management of Parkinson’s disease.
Dyskinesias, postural Hypotension and fatigue have been reported.
C- Amantadine:
1- Mechanism of action:
Amantadine enhances dopaminergic neurotransmission by unknown mechanisms that may involve increasing
synthesis or release of dopamine. The drug also has muscarinic blocking actions.
2- Pharmacologic effect:
It may improve bradykinesia, rigidity, and tremor but is usually effective for only a few weeks.
Amanatidine also has antiviral effects.
3- Toxicity:
Behavioral effects include restlessness, insomnia, hallucination, and acute toxic psychosis.
Dermatologic reactions.
Miscellaneous effects may include gastrointestinal disturbances, urinary retention (antimuscarinic effect).
Amantidine also causes peripheral edema that responds to diuretics.
D. Selegiline:
1- Mechanism of action:
Selegiline is a selective inhibitor of MAO type B, the enzyme isoform that metabolizes dopamine. Selegiline
thus increase brain dopamine levels.
2- Pharmacologic effects:
The drug is used as an Adjunct to levodopa in parkinsonism and has also been used as the sole agent in
newly diagnosed Patients. Hepatic metabolism of selegiline results in the Formation of amphetamine.
3- Toxicity:
Adverse effects include insomnia, mood changes, dyskinesia and gastrointestinal distreess.
E-Antimuscarinic drugs:
Their use originated when hyoscine was given to parkinsonian patients in an attempt to reduce diarrhea and it
then became apparent that they had other beneficial effects in this disease. Synthetic derivatives are now used
orally. These include benzhexol (trihexyphenidyl), orphenadrine, benzatropine, procyclidine. There is little
to choose between these. Antimuscarinics produce modest improvements in tremor, rigidity, muscular
stiffness and leg cramps.
Unwanted effects include dry mouth, blurred vision, constipation, urine retention, glaucoma, toxic
confusional states and psychoses. hallucinations specially with benzhexol (trihexyphenidyl) {Arten}.